Photooxygenation catalyst for transthyretin amyloid, and pharmaceutical composition containing same

Abstract

[Problem] To provide a novel, safe and effective photooxygenation catalyst which can inhibit the aggregation of transthyretin (TTR), which is a pathogenic amyloid mainly accumulated in a peripheral nervous system, through photooxygenation. [Solution] In the present invention, it has been found that a compound having a curcumin-like skeleton selectively binds to an amyloid such as transthyretin and can achieve the introduction of hydrophilic oxygen atoms into (photooxygenation of) the amyloid through a chemical reaction when irradiated with light, thereby acting as a novel catalyst capable of suppressing the aggregation of amyloids, weakening amyloids and promoting the metabolism of amyloids.

Description

Photooxygenation catalyst for transthyretin amyloid and pharmaceutical composition containing the same

[0001] The present invention relates to novel photooxygenation catalytic compounds that inhibit the aggregation of pathogenic amyloids such as transthyretin amyloid, and pharmaceutical compositions for preventing or treating diseases involving such pathogenic amyloids.

[0002] Generally, proteins fold to form specific native structures and perform vital functions. However, they can also misfold and aggregate into fibrils rich in β-sheet structures (amyloidization). The aggregates (oligomers, protofibrils, and fibrils) produced during this amyloidization process are known to cause various functional disorders (such diseases are collectively referred to as "amyloid diseases"). More than 35 proteins have been identified as causative agents of amyloid diseases. Examples of such amyloids include amyloid β (Aβ) peptide, tau protein, α-synuclein in Parkinson's disease, amylin in diabetes, transthyretin (TTR) in systemic amyloidosis, and huntingtin in Huntington's disease.

[0003] The number of diagnosed cases of amyloid diseases caused by the aggregation and accumulation of amyloid has been increasing in recent years due to the aging society, and the development of therapeutic drugs for these diseases is an urgent issue. In response to this, the present inventors have been developing compounds that can reduce the aggregation and toxicity of Aβ, which are causative substances of Alzheimer's disease, by photooxygenation reaction, which adds oxygen atoms to Aβ and tau proteins (Non-Patent Documents 1 and 2, etc.).

[0004] However, there is currently no cure for transthyretin amyloidosis, a typical example of a late-onset amyloid disease, and many patients still lack a cure for the toxic amyloid that continues to accumulate in the body. Therefore, there is a need to develop new compounds that can lead to safe and effective treatments for transthyretin amyloidosis.

[0005] Taniguchi, A. et al., Nat. Chem. 2016, 8, 974-982Sohma, Y.; Sawazaki, T.; Kanai, M. Org. Biomol. Chem. 2021, 19, 10017

[0006] In view of the problems of the conventional techniques, an object of the present invention is to provide a safe and effective novel photooxygenation catalyst that can inhibit the aggregation of transthyretin (TTR), a pathogenic amyloid that accumulates mainly in the peripheral nervous system, through photooxygenation, and to provide a drug for preventing and treating amyloid-related diseases using the same.

[0007] As a result of intensive research aimed at solving the above-mentioned problems, the present inventors have found that compounds having a curcumin-like skeleton selectively bind to amyloids such as transthyretin and, upon light irradiation, introduce hydrophilic oxygen atoms through a chemical reaction (photooxygenation), thereby functioning as novel catalysts capable of inhibiting amyloid aggregation, attenuating toxicity, and enhancing metabolism. In particular, they have found that such novel photocatalytic compounds have a relatively small molecular weight and an excellent balance between water solubility and membrane permeability. These findings have led to the completion of the present invention. Here, the term "oxygenation" is used broadly to refer to the chemical reaction of oxidation, particularly the addition or bonding of oxygen atoms.

[0008] That is, in one aspect, the present invention relates to a photooxygenation catalyst for pathogenic amyloid, comprising: <1> a photooxygenation catalyst for pathogenic amyloid, comprising a compound represented by the following formula (I) or a salt thereof: (wherein ring X is an optionally substituted aromatic ring or an optionally substituted heteroaromatic ring; R 1 is a halogen atom; R ２ is a halogen atom or a linear or branched C １ ~C ５ is a halogenated alkyl group; R ３ is a hydrogen atom or a halogen atom; R ａ and R ｂare each independently selected from the group consisting of a hydrogen atom and an optionally substituted linear or branched alkyl group; R ｃ and R ｄ are each independently selected from the group consisting of an optionally substituted linear or branched alkyl group and an optionally substituted linear or branched ether group; R ｃ and / or R ｄ may form a ring structure including the nitrogen atom to which they are attached and optionally the atoms that make up ring X; R ｃ and R ｄ The N atom to which L is attached may be located at any position on the ring X; 1 is a direct bond, a carbon atom, or a conjugated linker having 2 to 10 carbon atoms; L ２ is a direct bond, a conjugated linker having 2 to 10 carbon atoms; <2> R 1 is a fluorine atom; R ２ But C １ ~C ５ The photooxygenation catalyst according to the above item <1>, which is a fluorinated alkyl group; <3> R ２ But CF ３ or CF ２ CF ３ <4> The photooxygenation catalyst according to the above <1>, which is ３ <5> the photooxygenation catalyst according to the above <1>, wherein R is a fluorine atom or a bromine atom; ｃ and R ｄ are each independently an optionally substituted alkyl group having 1 to 10 carbon atoms or an optionally substituted ether group having 1 to 10 carbon atoms; ｃ and / or R ｄ has a terminal hydroxyl group, a carboxyl group, or an ester group; <7> the photooxygenation catalyst according to the above <1>, wherein ring X is a 4- to 6-membered monocyclic aromatic ring or heteroaromatic ring; <8> L 1 <9> the photooxygenation catalyst according to the above <1>, wherein L is an alkenylene group having a conjugated double bond, an arylene group, or a combination thereof; ２ is an alkenylene group having a conjugated double bond;ａ and R ｂ are each a methyl group; <11> X—N(R ｃ ) (R ｄ ) is a partial structure selected from the following group: (Wherein, the wavy line represents L ２ (12) The photooxygenation catalyst according to the above item (1), wherein the compound represented by formula (I) has a CLogP in the range of 2.0 to 6.0. (13) The photooxygenation catalyst according to the above item (1), wherein the pathogenic amyloid is transthyretin (TTR) amyloid.

[0009] In another aspect, the present invention also relates to a pharmaceutical composition comprising the photooxygenation catalyst and a method for using the photooxygenation catalyst, and more specifically provides: <11> a pharmaceutical composition comprising the photooxygenation catalyst described in any one of the above <1> to <13> and a pharmaceutically acceptable carrier; <15> the pharmaceutical composition described in the above <14>, which is a drug for preventing or treating a disease associated with pathogenic amyloid; <16> the pharmaceutical composition described in the above <15>, wherein the disease associated with pathogenic amyloid is transthyretin amyloidosis; <17> use of the photooxygenation catalyst described in any one of the above <1> to <13> for the manufacture of a drug for preventing or treating a disease associated with pathogenic amyloid; <18> a method for preventing or treating a disease associated with pathogenic amyloid, which comprises the step of administering the photooxygenation catalyst described in any one of the above <1> to <13> to a patient and, after the administration, irradiating the affected area of ​​the patient with light from outside the body.

[0010] According to the present invention, it is possible to selectively and highly efficiently oxygenate pathogenic aggregated amyloids by irradiation with light, and furthermore, it is possible to provide a photooxygenation catalyst that has a good balance of water solubility and excellent membrane permeability because it has a smaller molecular weight than existing catalysts.

[0011] This makes it possible to inhibit or reduce the aggregation and toxicity of transthyretin (TTR), a pathogenic amyloid that accumulates mainly in the peripheral nervous system, by a non-invasive method of administering the compound intravenously or otherwise followed by external light irradiation, thereby enabling the prevention and treatment of diseases associated with such pathogenic amyloid.

[0012] FIG. 1 shows the chemical structures, molecular weights, and CLogP values ​​of catalyst compounds C to E of the present invention. FIG. 2 shows the chemical structures, molecular weights, and CLogP values ​​of other examples of catalyst compounds of the present invention. FIG. 3 is a graph showing the absorption spectra of catalyst compounds B to E. FIG. 4 shows the WT- and V30M-TTR cells used in the examples. FIG. 5 is a graph showing the results of a cell rescue experiment using catalyst compound D. FIG. 6 is a graph showing the changes in the absorption and fluorescence spectra of catalyst compound D in the presence and absence of TTR. FIG. 7 is an electron microscope image of TTR fibrillary amyloid (scale bar: 500 nm). FIG. 8 is a graph showing the amyloid oxygenation selectivity relative to aggregated TTR. FIG. 9 is a graph showing the results of a comparison of the TTR disaggregation ability of catalyst compound B with that of existing compounds (AB, MB, BD, and catalyst compound A (cat. A)). Figure 10 is a graph showing a comparison of the TTR disaggregation ability of catalyst compounds B to D of the present invention. Figure 11 is a graph showing the results of testing the TTR disaggregation ability by changing the concentration of catalyst compound D added. Figure 12 is a graph showing the results of photooxygenation in an in vivo disease model animal system using nematodes. Figure 13 is a graph showing the results of improvement of pathological conditions by photooxygenation.

[0013] The following describes embodiments of the present invention. The scope of the present invention is not limited to these descriptions, and other than the following examples, the present invention can be implemented with appropriate modifications within the scope that does not depart from the spirit of the present invention.

[0014] 1. Definitions As used herein, the term "halogen atom" refers to a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.

[0015] In this specification, "alkyl (or alkyl group)" may be any of a linear, branched, or cyclic aliphatic hydrocarbon groups, or a combination thereof. The number of carbon atoms in the alkyl group is not particularly limited, but for example, alkyl groups having 1 to 20 carbon atoms (C １～２０ ), carbon number 1 to 15 (C １～１５ ), carbon number 1 to 10 (C １～１０ In this specification, the alkyl group may have one or more optional substituents. For example, C １～８ Alkyl includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neo-pentyl, n-hexyl, isohexyl, n-heptyl, n-octyl, and the like. Examples of the substituent include, but are not limited to, an alkoxy group, a halogen atom (which may be a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom), an amino group, a mono- or di-substituted amino group, a substituted silyl group, or an acyl. When an alkyl group has two or more substituents, these may be the same or different. The same applies to the alkyl moiety of other substituents containing an alkyl moiety (e.g., an alkoxy group, an arylalkyl group, and the like).

[0016] In the present specification, "alkylene" refers to a divalent group consisting of a linear or branched saturated hydrocarbon, and examples thereof include methylene, 1-methylmethylene, 1,1-dimethylmethylene, ethylene, 1-methylethylene, 1-ethylethylene, 1,1-dimethylethylene, 1,2-dimethylethylene, 1,1-diethylethylene, 1,2-diethylethylene, 1-ethyl-2-methylethylene, trimethylene, 1-methyltrimethylene, 2-methyltrimethylene, 1,1-dimethyltrimethylene, 1,2 2-dimethyltrimethylene, 2,2-dimethyltrimethylene, 1-ethyltrimethylene, 2-ethyltrimethylene, 1,1-diethyltrimethylene, 1,2-diethyltrimethylene, 2,2-diethyltrimethylene, 2-ethyl-2-methyltrimethylene, tetramethylene, 1-methyltetramethylene, 2-methyltetramethylene, 1,1-dimethyltetramethylene, 1,2-dimethyltetramethylene, 2,2-dimethyltetramethylene, 2,2-di-n-propyltrimethylene, and the like.

[0017] In this specification, the term "aromatic ring" refers to a monocyclic or fused polycyclic conjugated unsaturated hydrocarbon ring structure, and the term "heteroaromatic ring" refers to an aromatic ring containing one or more heteroatoms (e.g., oxygen atom, nitrogen atom, sulfur atom, etc.) as ring-constituting atoms.

[0018] In this specification, the term "aryl (or aryl group)" may be either a monocyclic or fused polycyclic aromatic hydrocarbon group, or may be an aromatic heterocycle containing one or more heteroatoms (e.g., oxygen, nitrogen, or sulfur atoms) as ring-constituting atoms. In this case, it is referred to as a "heteroaryl group" or a "heteroaromatic group." Whether the aryl is a monocyclic or fused ring, it may be bonded at any available position. Non-limiting examples of monocyclic aryls include a phenyl group (Phe), a thienyl group (2- or 3-thienyl group), a pyridyl group, a furyl group, a thiazolyl group, an oxazolyl group, a pyrazolyl group, a 2-pyrazinyl group, a pyrimidinyl group, a pyrrolyl group, an imidazolyl group, a pyridazinyl group, a 3-isothiazolyl group, a 3-isoxazolyl group, a 1,2,4-oxadiazol-5-yl group, or a 1,2,4-oxadiazol-3-yl group. Non-limiting examples of fused polycyclic aryls include 1-naphthyl, 2-naphthyl, 1-indenyl, 2-indenyl, 2,3-dihydroinden-1-yl, 2,3-dihydroinden-2-yl, 2-anthryl, indazolyl, quinolyl, isoquinolyl, 1,2-dihydroisoquinolyl, 1,2,3,4-tetrahydroisoquinolyl, indolyl, isoindolyl, phthalazinyl, quinoxalinyl, benzofuranyl, 2,3-dihydrobenzofuran- Examples of the aryl group include a 1-yl group, a 2,3-dihydrobenzofuran-2-yl group, a naphthyridinyl group, a dihydronaphthyridinyl group, a tetrahydronaphthyridinyl group, an imidazopyridinyl group, a pteridinyl group, a purinyl group, a quinolidinyl group, an indolizinyl group, a tetrahydroquinolidinyl group, and a tetrahydroindolizinyl group, a 2,3-dihydrobenzothiophen-1-yl group, a 2,3-dihydrobenzothiophen-2-yl group, a benzothiazolyl group, a benzimidazolyl group, a fluorenyl group, and a thioxanthenyl group. In the present specification, the aryl group may have one or more optional substituents on the ring. Examples of the substituent include, but are not limited to, an alkoxy group, a halogen atom, an amino group, a mono- or di-substituted amino group, a substituted silyl group, and an acyl group. When the aryl group has two or more substituents, the substituents may be the same or different.The same applies to the aryl moiety of other substituents containing an aryl moiety (for example, an aryloxy group or an arylalkyl group).

[0019] As used herein, an "ether group" refers to a functional group having at least one ether bond (-O-) in the alkyl chain. Similarly, a "thioether group" refers to a functional group having at least one thioether bond (-S-) in the alkyl chain.

[0020] In this specification, when a functional group is defined as "optionally substituted," the type, substitution position, and number of substituents are not particularly limited, and when two or more substituents are present, they may be the same or different. Examples of the substituent include, but are not limited to, alkyl groups, alkoxy groups, hydroxyl groups, carboxyl groups, halogen atoms, sulfo groups, amino groups, alkoxycarbonyl groups, and oxo groups. These substituents may further have a substituent. Examples of such substituents include, but are not limited to, halogenated alkyl groups.

[0021] As used herein, the term "ring structure" means a heterocyclic or carbocyclic ring when formed by the combination of two substituents, and such rings can be saturated, unsaturated, or aromatic, and thus includes cycloalkyl, cycloalkenyl, aryl, and heteroaryl, as defined above.

[0022] As used herein, certain substituents can form ring structures with other substituents, and when such substituents are bonded together, those skilled in the art will understand that certain substitutions, such as bonds to hydrogen, are formed. Thus, when certain substituents are described as forming a ring structure, those skilled in the art will understand that such ring structures can be formed and are readily produced by conventional chemical reactions. Both such ring structures and the processes for their formation are within the knowledge of those skilled in the art. Furthermore, such ring structures may have optional substituents on the ring.

[0023] 2. Photooxygenation Catalyst of the Present Invention The photooxygenation catalyst of the present invention comprises a compound having a curcumin-like skeleton, and is characterized by being capable of oxygenating pathogenic amyloid upon irradiation with light.

[0024] More specifically, the photooxygenation catalyst of the present invention comprises a compound represented by the following formula (I):

[0025] The compound of formula (I) has a conjugated resonance structure between a six-membered ring structure containing a central boron atom and an oxygen atom and a side chain structure having an amino group. In a dilute solution, after photoexcitation, the single bond connecting to the side chain structure rotates, consuming energy through a twisted intramolecular charge transfer (TICT) state. In contrast, in an aggregated state, bond rotation is hindered, resulting in the development of luminescence properties. By utilizing this property, oxygenation activity can be exhibited only in the presence of aggregated amyloid. Furthermore, since the compound of formula (I) has a highly planar skeleton, it also has a high affinity for the cross-β-sheet structure in aggregated amyloid.

[0026] The compound of formula (I) is characterized by having a smaller molecular weight than conventional photooxygenation catalysts, a relatively high hydrophilicity, and a CLogP index, which is an index of hydrophilicity, preferably in the range of 2.0 to 6.0, and by having a good balance of water solubility and excellent membrane permeability. Preferably, the CLogP can be in the range of 3.5 to 6.0.

[0027] In formula (I), ring X is an optionally substituted aromatic ring or an optionally substituted heteroaromatic ring. As the heteroaromatic ring, typically, an aromatic ring containing one or more nitrogen atoms or oxygen atoms can be used. Ring X can be monocyclic, bicyclic, or tricyclic, but is preferably a 4- to 6-membered monocyclic aromatic or heteroaromatic ring, and more preferably a 6-membered monocyclic aromatic or heteroaromatic ring. Specific examples include a benzene ring, a pyridine ring, a pyrazine ring, a pyrimidine ring, a pyridazine ring, a pyrrole ring, a furan ring, a pyran ring, a quinoline ring, an isoquinoline ring, a quinoxaline ring, a benzopyran ring, a naphthalene ring, an anthracene ring, and the like. More preferably, ring X is a benzene ring. Ring X may be substituted with a substituent such as a halogen atom.

[0028] R 1 is a halogen atom, preferably a fluorine atom.

[0029] R ２ is a halogen atom or a linear or branched C １ ~C ５ A halogenated alkyl group, preferably C １ ~C ５ Fluorinated alkyl groups, more preferably CF ３ or CF ２ CF ３ In a preferred embodiment, R 1 is a fluorine atom, and R ２ But C １ ~C ５ It can be a fluorinated alkyl group.

[0030] R 1 and R ２ can be said to be an electron-withdrawing group that can produce a heavy atom effect.

[0031] R ３ is a hydrogen atom or a halogen atom, preferably a fluorine atom or a bromine atom.

[0032] R ａ and R ｂare each independently selected from the group consisting of a hydrogen atom and an optionally substituted linear or branched alkyl group. ａ and R ｂ are each independently a linear or branched alkyl group having 1 to 5 carbon atoms which may be substituted. For example, R １ and R ２ can be methyl, ethyl, n-propyl, i-propyl, n-butyl. Preferably, R ａ and R ｂ are both methyl groups, and in this case, the compound of formula (I) has an absorption band in the orange region (approximately 590 to 640 nm), and can undergo photo-oxygenation by irradiation with light of this wavelength.

[0033] R ｃ and R ｄ are each independently selected from the group consisting of an optionally substituted linear or branched alkyl group and an optionally substituted linear or branched ether group. ｃ and R ｄ are each independently an optionally substituted alkyl group having 1 to 10 carbon atoms or an optionally substituted ether group having 1 to 10 carbon atoms. ｃ and R ｄ are each independently an optionally substituted alkyl group having 2 to 6 carbon atoms or an optionally substituted ether group having 2 to 6 carbon atoms. ｃ and / or R ｄ may form a ring structure including the nitrogen atom to which they are attached, or may form a ring structure including the atoms that make up ring X. ｃ and / or R ｄ may form a ring structure including both the nitrogen atom to which they are attached and the atoms that make up the ring X.

[0034] For example, R ｃ and R ｄ can form a first ring structure including the nitrogen atom to which it is attached and optionally the atoms that make up ring X. Alternatively, R ｃ forms a first ring structure containing the nitrogen atom to which it is attached and optionally atoms constituting ring X, and Rｄ However, the first ring may form a second ring structure containing the nitrogen atom to which it is bonded and, optionally, atoms constituting ring X. In this case, the first and second ring structures may be linked to each other. Such a ring structure may be, for example, a 4- to 10-membered ring, preferably a 4- to 6-membered ring.

[0035] In a preferred embodiment, R ｃ and / or R ｄ may have a hydroxyl group, a carboxyl group, or an ester group at the end of the alkyl group or ether group. More preferably, it may have one or two hydroxyl groups at the end. In this case, R ｃ and / or R ｄ can be a hydroxyalkyl group and a hydroxyether group.

[0036] For example, R ｃ and R ｃ Typical examples of the hydroxyalkyl group and hydroxyether group that can be used include, but are not limited to, substituents having the following structures:

[0037] R ｃ and R ｄ The N atom to which L is bonded to ring X may be located at any position on ring X. Preferably, the N atom is located at any position on ring X. ２ It can be bonded in the meta position to

[0038] In formula (I), L 1can be a direct bond, a carbon atom, or a conjugated linker having 2 to 10 carbon atoms. The conjugated linker refers to a divalent group that can link the ring X and the amino group on the left chain while maintaining a conjugated system. Such conjugated spacers may have a structure having a conjugated double bond, and examples thereof include alkenylene groups, arylene groups, and combinations thereof. As long as the conjugated system can be maintained, the spacer may contain any heteroatom, such as thiophene, and may further have a substituent at a substitutable position, such as an alkyl group, an alkoxy group, an aryl group, a halogen atom, an alkenyl group, an alkynyl group, a carbonyl group, a cyano group, a nitro group, a phosphoryl group, or a sulfonyl group. Preferably, L is an alkenylene group or an arylene group, and more preferably, any alkenylene group having 2 to 10 carbon atoms, a phenylene group, or a combination thereof.

[0039] In formula (I), L ２ is a direct bond, a conjugated linker having 2 to 10 carbon atoms. For the types of covalent linkers, see the above L 1 Preferably, L ２ is an alkenylene group having a conjugated double bond, and more preferably any alkenylene group having 2 to 10 carbon atoms.

[0040] In a preferred embodiment, "X-N(R ｃ ) (R ｄ The moiety of (I) can be a partial structure selected from the following group: ２ This is the connection position with (Wherein, the wavy line represents L ２ This is the connection position with .

[0041] The compound of formula (I) preferably has a molecular weight in the range of 300 to 650. Such a relatively small molecular weight allows for excellent membrane permeability.

[0042] The compound represented by formula (I) in the present invention may exist as a salt. Examples of such salts include base addition salts, acid addition salts, and amino acid salts. Examples of base addition salts include metal salts such as sodium salts, potassium salts, calcium salts, and magnesium salts, ammonium salts, and organic amine salts such as triethylamine salts, piperidine salts, and morpholine salts. Examples of acid addition salts include mineral acid salts such as hydrochlorides, sulfates, and nitrates, and organic acid salts such as carboxylates, methanesulfonates, paratoluenesulfonates, citrates, and oxalates. Examples of amino acid salts include glycine salts. However, the salts are not limited to these salts.

[0043] The compound of the present invention represented by formula (I) may have one or more asymmetric carbon atoms depending on the type of substituent, and may exist as stereoisomers such as optical isomers or diastereoisomers. Pure stereoisomers, any mixtures of stereoisomers, racemates, etc. are all included in the scope of the present invention.

[0044] Furthermore, the compound represented by formula (I) or a salt thereof may exist as a hydrate or solvate, and all of these substances are included in the scope of the present invention. The type of solvent that forms the solvate is not particularly limited, and examples thereof include water, ethanol, acetone, isopropanol, and the like.

[0045] The examples in this specification specifically show production methods for representative compounds included in the catalyst compounds of the present invention, and therefore, by referring to the disclosures of this specification and by appropriately selecting starting materials, reagents, reaction conditions, etc. as necessary based on common technical knowledge in the technical field, a person skilled in the art can easily produce any compound included in each formula.

[0046] 2. Pharmaceutical compositions, etc., containing the photooxygenation catalyst of the present invention As described above, the photooxygenation catalyst of the present invention can catalyze the oxygenation reaction of pathogenic amyloid aggregates. The oxygenation reaction proceeds by exciting the catalytic compound with light, generating singlet oxygen, which then adds oxygen atoms to amino acid residues in the amyloid, resulting in oxidation. This can inhibit or reduce the aggregation of pathogenic amyloid.

[0047] Therefore, in another aspect, the present invention also relates to a pharmaceutical composition containing a photooxygenation catalyst and a pharmaceutically acceptable carrier. The pharmaceutical composition can be a drug for preventing or treating a disease associated with pathogenic amyloid. It can also be said that the present invention provides an agent for inhibiting the aggregation of pathogenic amyloid.

[0048] "Pathogenic amyloid" includes amyloids such as tau protein, amyloid β (Aβ) peptide, amylin, transthyretin, α-synuclein, and huntingtin, which are known to be involved in Alzheimer's disease, Parkinson's disease, diabetes, Huntington's disease, and systemic amyloidosis in animals, including humans. Preferably, the pathogenic amyloid is transthyretin (TTR) amyloid.

[0049] The compound represented by formula (I) of the present invention preferably has a maximum absorption wavelength (λmax) in the range of 450 to 900 nm, and is preferably capable of being excited at this wavelength. From the viewpoint of avoiding cytotoxicity due to light irradiation, the compound represented by formula (I) of the present invention desirably has an absorption band in the region of 595 nm or more. By having an absorption band in this wavelength region, the compound can be excited by long-wavelength light that has high biological permeability.

[0050] The pharmaceutical composition of the present invention can be prepared by various methods using a pharmaceutically acceptable carrier and an appropriate formulation selected according to the administration method. Examples of the dosage form of the pharmaceutical composition containing the catalyst compound of the present invention as a main ingredient include tablets, powders, granules, capsules, liquids, syrups, elixirs, oily or aqueous suspensions, etc., as oral preparations.

[0051] Injectable preparations may contain stabilizers, preservatives, and solubilizing agents, and a solution that may contain these agents may be placed in a container and then freeze-dried or otherwise processed into a solid preparation that can be prepared just before use. A single dose may be placed in one container, or multiple doses may be placed in one container.

[0052] Examples of topical preparations include liquids, suspensions, emulsions, ointments, gels, creams, lotions, sprays, and patches.

[0053] Solid preparations can be formulated by mixing the catalyst compound of the present invention with pharmaceutically acceptable additives, such as fillers, extenders, binders, disintegrants, dissolution promoters, wetting agents, lubricants, etc. as needed. Liquid preparations can include solutions, suspensions, emulsions, etc., and may contain suspending agents, emulsifiers, etc. as additives.

[0054] When the catalyst compound of the present invention is used as a medicine for human use, the daily dose for an adult is preferably in the range of 1 mg to 1 g, and more preferably 1 mg to 300 mg.

[0055] In a further aspect, the present invention also relates to a method for preventing or treating a pathogenic amyloid-associated disease, comprising administering an effective amount of the photooxygenation catalyst to a patient. The method includes irradiating the affected area of ​​the patient with light from outside the body after administration of the photooxygenation catalyst. As described above, the photooxygenation catalyst of the present invention can be excited by long-wavelength light, which is highly biotransparent, and therefore, the aggregation and toxicity of pathogenic amyloid in the body can be suppressed or reduced by a non-invasive technique of administering the catalyst intravenously or otherwise and then irradiating the patient with light from outside the body.

[0056] Specifically, the photooxygenation catalyst of the present invention may be introduced into a living body or a cell, and then irradiated with light when the compound has reached the target site. The means of administration into the living body include intramuscular injection, intravenous injection, topical administration, oral administration, etc.

[0057] Diseases associated with pathogenic amyloid include Alzheimer's disease, Parkinson's disease, diabetes, Huntington's disease, systemic amyloidosis, etc. in animals, including humans. A typical disease associated with pathogenic amyloid is transthyretin amyloidosis.

[0058] The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these examples.

[0059] 1. Synthesis of Catalyst Compounds of the Present Invention Catalyst compounds C to E shown in FIG. 1 were synthesized according to the following synthesis scheme.

[0060] S11 in the scheme was synthesized based on the literature (H. Umeda et al., CS Chem. Neurosci. 14, 2710-2716 (2023)).

[0061] Synthesis of Catalyst Compound C. To a stirred solution of SI1 (275.0 mg, 0.829 mmol, 1.0 equiv.) and 4-dimethylaminobenzaldehyde (275 mg, 1.85 mmol, 2.2 equiv.) in toluene (8.3 mL, 0.1 M), n-BuNH (33 μL, under argon protection, 0.332 mmol, 0.40 equiv.) and tributyl borate (1.1 mL, 4.15 mmol, 5.0 equiv.) were added, and the reaction mixture was heated at 80 °C overnight. After cooling to room temperature, the mixture was concentrated in vacuo. The resulting residue was purified by column chromatography on silica (hexane / DCM = 2 / 1 to DCM only) to give catalyst compound C as a dark reddish-brown solid (138 mg, 0.298 mmol, 36% yield). For in vivo experiments, further purification was performed using preparative HPLC to remove trace amounts of NMR-undetectable impurities.

[0062] Chemical shifts as TFA salt: 1H NMR (500 MHz, ACETONITRILE-D3) δ 8.16 (d, J = 11.6 Hz, 1H), 7.58 (d, J = 15.2 Hz, 1H), 7.55 (d, J = 8.3 Hz, 2H), 7.12 (d, J = 15.2 Hz, 1H), 6.75 (d, J = 8.3 Hz, 2H), 5.74 (d, J = 11.6 Hz, 1H), 3.34 (s, 3H), 3.12 (s, 3H), 3.03 (s, 6H); 13 C NMR (126 MHz, ACETONITRILE-D3) δ 172.8, 165.4, 159.8, 153.4, 144.2, 131.5, 123.5, 115.3, 112.9, 93.1, 92.8, 47.5, 40.3, 39.3; 11 B NMR (126 MHz, ACETONITRILE-D3) δ -1.22; 19 F NMR (369 MHz, ACETONITRILE-D3) δ -77.1 (3F), -77.7 (3F), -159.2 (1F); HRMS (ESI): m / z calcd for C 18 H 21 BBrF4N2O2 + [M+H] + 463.0811, 465.0790, Found 463.0803, 465.0790.

[0063] <Synthesis of Catalyst Compound D> The following compound SI2 was synthesized from the literature (US Patent No. US 2009 / 0124624).

[0064] To a stirred solution of SI1 (162.2 mg, 0.489 mmol, 1.0 equiv) and SI2 (108.0 mg, 0.765 mmol, 1.6 equiv) in toluene (9.8 mL, 0.05 M), n-BuNH (20 μL, 0.196 mmol, 0.40 equiv) and tributyl borate (0.65 mL, 2.45 mmol, 5.0 equiv) were added under argon protection, and the reaction mixture was heated at 80 °C for 6 h. After cooling to room temperature, the mixture was filtered through a pad of Celite covered with a thin layer of silica (DCM / MeOH = 4 / 1, 3 column volumes). The crude product was partially purified by silica column chromatography (DCM / MeOH = 1 / 50 to 1 / 10) to give a viscous purple oil. After filtration through a Sartorius RC15 0.45 μM syringe filter using acetonitrile as the eluent, the mixture was further purified in batches by preparative HPLC to give catalyst compound D as a dark purple solid (58.4 mg, 0.0943 mmol as the TFA salt, 19% yield).

[0065] Chemical shifts as TFA salt: 1 H NMR (500 MHz, ACETONITRILE-D3) δ 8.14 (d, J = 11.7 Hz, 1H), 7.59 (d, J = 15.1 Hz, 1H), 7.54 (d, J = 8.6 Hz, 2H), 7.09 (d, J = 15.1 Hz, 1H), 6.59 (d, J = 8.6 Hz, 2H), 5.73 (d, J = 11.7 Hz, 1H), 4.51-4.48 (m, 1H), 3.53-3.36 (m, 3H), 3.33 (s, 3H), 3.24 (m, 1H), 3.11 (s, 3H), 2.14-1.96 (m, 2H); 13 C NMR (126 MHz, ACETONITRILE-D3) δ 172.8, 165.6, 159.6, 151.0, 144.5, 131.8, 123.1, 114.7, 112.9, 93.0, 92.7, 71.0, 56.8, 47.5, 46.5, 39.2, 34.5; 11B NMR (126 MHz, ACETONITRILE-D3) δ -1.5; 19 F NMR (369 MHz, ACETONITRILE-D3) δ -77.1 (3F), -77.6 (3F), -159.1 (1F); HRMS (ESI): m / z calcd for C 20 H 22 BBrF4N2NaO3 + [M+Na] + 527.0736, 529.0715, Found 527.0737, 529.0717.

[0066] <Synthesis of catalyst compound E> First, the following compound SI3 was synthesized according to the literature (TL Bouder, et al., Tetrahedron Lett. 39, 6869-6872 (1998)).

[0067] To a stirred solution of SI1 (175.3 mg, 0.528 mmol, 1.0 equiv.) and SI3 (165.8 mg, 0.792 mmol, 1.5 equiv.) in toluene (11 mL, 0.05 M), n-BuNH2 (21 μL, 0.211 mmol, 0.40 equiv.) and tributyl borate (0.99 mL, 3.70 mmol, 7.0 equiv.) were added under argon protection, and the reaction mixture was heated at 80 °C for 6 h. After cooling to room temperature, the mixture was filtered through a pad of Celite covered with a thin layer of silica (DCM / MeOH = 1 / 1, 3 column volumes). The crude product was roughly purified by silica column chromatography (DCM / MeOH = 1 / 10 to 1 / 5) to give a viscous red-purple oil. After filtration through a Sartorius RC15 0.45 μM syringe filter using acetonitrile as eluent, the mixture was further purified by preparative HPLC in multiple batches to give cat. E (95.3 mg, 0.150 mmol, 28% yield) as a dark reddish-brown solid.

[0068] Similarly, the catalyst compounds shown in FIG. 2 were synthesized.

[0069] The absorption spectra of the obtained catalyst compounds B to E are shown in Figure 3. Figure 3A shows the absorption spectra of catalyst compounds C to E (20 μM) in chloroform. Figure 3B shows the absorption spectra of catalyst compounds B to E (20 μM) in a phosphate buffer solution at pH 7.4 (compound B is shown in Figure 2).

[0070] 2. Preparation of Aggregated Recombinant TTR Samples Aggregated TTR was prepared according to the protocol described in the literature (M. Mizuguchi, et al., Proteins 72, 261-269 (2008)) (Figure 4).

[0071] <Full-length WT- and V30M-TTR> To a solution of 146 μM recombinant 6His-WT- or 6His-V30M-TTR (200 μL), 100 mM AcOH buffer (pH 4.0) (160 μL) and 1 M aqueous KCl solution (40 μL) were added and vigorously stirred at 37°C for 1 week. After checking the aggregation level by ThT fluorescence assay, the mixture was diluted with NH ３ The solution was neutralized to pH 7.0 by addition of aqueous solution to prepare acid-induced TTR aggregates at a final concentration of 37 μM.

[0072] <TTR81-127> PBS (540 μL) was added to a solution of 1 mM recombinant TTR81-127 (60 μL) and vigorously stirred at 37°C for 24 hours. Subsequently, the aggregation level was assessed by ThT fluorescence assay, and neutral pH aggregated TTR was prepared at a final concentration of 50 μM.

[0073] <TTR81-127::EGFP> A solution of recombinant TTR81-127::EGFP (7.8 < concentration < 16 μM) in PBS (100 μL) was vigorously stirred at 37 °C for 24 hours. The intrinsic fluorescence of EGFP, particularly near the ThT emission spectrum, precluded the use of the ThT assay to assess aggregation levels. Consequently, evaluation of aggregation by fluorescence microscopy (Zeiss AxioImager.M2) revealed the formation of aggregate-like clusters similar to those observed with C. elegans-expressed TTR81-127::EGFP, but only after the specified stirring and incubation period.

[0074] 3. In Vitro Photooxygenation <Catalyst Screening> Catalysts (final concentrations of 1 mM: 15 μM in DMSO; 100 μM: 1.5 μM in DMSO) were added to a 37 μM solution of aggregated TTR (25 μL). Unless otherwise specified, the reaction mixture was irradiated with a light-emitting diode (LED) (λ = 595 or 660 nm) at 37°C for 1 hour. The reaction vessel was positioned 10 cm from the light source. The reaction mixture was digested overnight with trypsin-gold (0.2 or 0.4 μL) in the dark at 37°C, followed by matrix-assisted laser desorption / ionization time-of-flight mass spectrometry (MALDI-TOF MS).

[0075] <Reaction monitoring: MALDI-TOF MS> Using α-cyano-4-hydroxycinnamic acid as the matrix, the reaction solution was desalted using ZipTip U-C18 (Millipore) and subjected to MALDI-TOF MS analysis. The MS peak intensities of the resulting Fragments I and II were quantified using Fiji (J. Schindelin, et al., Nat Methods 9, 676-682 (2012)).

[0076] Peaks with intensities less than 5% of the maximum peak intensity were ignored (not included in the yield calculation). The oxygenation degree was expressed as the oxygenation intensity ratio (%) = (sum of MS intensities of n[O] adducts) / (sum of MS peak intensities of the remaining raw material and n[O] adducts) × 100.

[0077] Reaction monitoring: Coomassie Brilliant Blue (CBB) staining. The reaction solution was analyzed under reducing (dithiothreitol) conditions using a 15% acrylamide / bis-mixture (37.5:1) (Fujifilm Wako Pure Chemical Industries, Ltd.) and 0.1% SDS running buffer. Peptide bands were visualized by CBB staining. The molecular weights of the detected bands were estimated using Precision Plus Protein Standards Dual Color (Bio-Rad, USA).

[0078] <Verification of Cytotoxicity> To investigate the effect of photooxygenation on the toxicity of TTR amyloid, a cell rescue experiment was performed. Rat pheochromocytoma PC12 cells suspended in DMEM containing 5% horse serum and 10% fetal bovine serum were seeded at 10,000 cells / 100 μL / well onto poly-D-lysine-coated 96-well plates (Greiner CELLCOAT, PDL, μClear) and incubated at 5% CO2 and 37°C for 4 days. After removing the medium, the cells were washed with 150 μL of serum-free DMEM. Subsequently, 75 μL of DMEM containing 0.1% horse serum and 25 μL of photooxygenated or non-photooxygenated TTR solution in PBS (50 μM) were added to each well. The cells were then incubated for an additional 48 hours at 5% CO2 and 37°C, after which cell viability was assessed using Cell Count Reagent SF (Nacalai Tesque) and WST-8 according to the manufacturer's protocol.

[0079] The results are shown in Figure 5. In PC12 cells treated with untreated TTR and with TTR treated without light irradiation in the presence of catalyst compound D, cell viability decreased by approximately 70% at both catalyst concentrations of 1.5 and 0.15 μM, with no significant difference observed. In contrast, cell viability was significantly restored in the group treated with photo-oxygenated TTR in the presence of catalyst compound D at both concentrations, indicating that photo-oxygenation not only alters the shape of TTR amyloid fibrils but also reduces their toxicity.

[0080] <Verification of the deaggregation effect of oxygenation> To confirm the effect of photooxygenation on TTR aggregation, we observed the change in aggregation property of the highly amyloidogenic C-terminal fragment of TTR consisting of residues 81-127 by catalytic compound D. TTR 81-127 has been reported to have high aggregation ability and toxicity, and corresponds to the fragment expressed in the ATTR model nematode.

[0081] First, to confirm the interaction between aggregated TTR and the catalytic compound, we investigated the changes in the absorption and fluorescence spectra of catalytic compound D in the presence and absence of TTR. To a PBS solution of TTR81-127 (10 μM, 200 μL), 1.0 equivalent of catalytic compound D (DMSO solution, final concentration: 10 μM) was added, and the reaction mixture was incubated at 37°C for 1 hour under 595 nm LED light irradiation.

[0082] As a result, both the absorbance (Fig. 6A) and fluorescence (Fig. 6B) of catalytic compound D increased in the presence (+) of TTR compared with its absence (-), suggesting that catalytic compound D bound to aggregated TTR and changed its conformation (interacted with it).

[0083] Catalyst compound D (DMSO solution, final concentration: 1.5 μM) was added to a PBS solution of TTR81-127 (50 μM, 100 μL), and the reaction mixture was incubated at 37°C for 24 hours under 595 nm LED light irradiation. 5 μL of the oxygenated reaction solution was placed on a collodion membrane-attached mesh (Nissin EM Co., Ltd., Tokyo) and allowed to stand for 2 minutes. The moisture on the mesh was then absorbed, and 20 μL of 2% sodium phosphotungstate was applied in several portions while absorbing the moisture. After wiping off the moisture thoroughly, the mixture was stored in a dark place.

[0084] The stained TTR fibrils were photographed using a transmission electron microscope (JEOL Ltd., JEM-1200EX electron microscope). The results are shown in Figure 7 (scale bar: 500 nm). In the image of the untreated sample on the far left, thick, dense fibrous clusters were observed. In contrast, in the image of the oxygenated sample on the far right, thin needle-like clusters were observed, confirming the inhibition of amyloid formation by photooxygenation. The sample containing only the catalyst (center row) also showed a change in the morphology of TTR fibrils. While thicker than the oxygenated group, the fibrils were slightly thinner than the untreated group. These results suggest the aggregation-inhibiting effect of catalyst compound D itself.

[0085] <Verification of Selectivity for Aggregated TTR> Functional, unmodified, and aggregated wild-type TTR was oxygenated using catalyst compound D (Figure 8). The left panel of Figure 8A shows the results of adding catalyst (DMSO solution, final concentration: 0.15 or 1.5 μM) to a PBS solution of unmodified, aggregated, and functional wild-type TTR (37 μM, 25 μL) and irradiating it with LED light at 595 nm or 660 nm at 37°C for 1 hour. The right panel of Figure 8A shows the results of adding catalyst (DMSO solution, final concentration: 0.15 μM) to a PBS solution of unmodified, aggregated wild-type TTR (37 μM, 25 μL) and irradiating it with LED light at 595 nm or 660 nm at 37°C for 1 hour. Figure 8B shows the results of monitoring the reaction by CBB staining of the reaction solution after oxygenation (n=3). The reaction solution after oxygenation was subjected to peptide fragmentation with trypsin, and the reaction was monitored by MALDI-TOF-MS analysis (n=3, mean±standard deviation).

[0086] As a result, a slight amount of oxygenated forms was detected at a catalyst concentration of 1.5 μM, but no oxygenated forms were detected at a concentration of 0.15 μM. On the other hand, as a comparative example, a MB without an amyloid-selective ON / OFF switch was used. Oxygenation proceeded to approximately 70%, confirming that catalyst compound D exhibits high amyloid oxygenation selectivity.

[0087] <Comparison with other compounds> The TTR deaggregation ability of catalyst compound B synthesized above was compared with a group of existing compounds (AB, MB, BD, catalyst compound A (cat. A)), and the results are shown in Figure 9. As a result, it was found that catalyst compound B has superior deaggregation ability compared to the comparative compounds.

[0088] A comparison of the TTR disaggregation ability of the catalyst compounds B to D of the present invention synthesized above is shown in Figure 10. Among these, catalyst compound D was found to have the most excellent disaggregation ability.

[0089] <Investigation of catalyst compound concentration> Next, the TTR deaggregation ability was examined by changing the concentration of the catalyst compound added. As a result, it was found that the reaction proceeded without a significant loss of oxygenation yield even when the concentration of catalyst compound D was reduced to 1.5 μM (corresponding to 4.1 mol%) ( FIG. 11 ).

[0090] <Oxygenation of cardiac amyloid fibrils from human ATTR patient samples> Catalyst compound D (DMSO solution, 20 or 40 mol%) was added to an aqueous solution (2.9 μM, 10 μL) of cardiac amyloid fibrils extracted from ATTR patients and irradiated with 595 nm LED light at 37°C for 1 hour. The oxygenated reaction solution was subjected to peptide fragmentation with trypsin, followed by MALDI-TOF-MS analysis. As a result, we successfully detected the oxygenated peaks of fragment 2 or 2 prime derived from wild-type and V30M mutant, as well as the oxygenated peak of fragment 1, which is common to both. This demonstrated that photooxygenation is possible even on patient-derived amyloid fibrils.

[0091] 4. In vivo photooxygenation Based on the results of the in vitro experiment described in 3. above, we applied this to an in vivo disease model animal system using C. elegans.

[0092] C. elegans were cultured according to a previously published protocol (S. Brenner, et al., Genetics 77, 71-94 (1974)). Live E. coli OP50 was seeded onto Nematode Growth Medium (NGM) agar plates, and worms were transferred to fresh plates every three days. The C. elegans transgenic strain KXK1073zyeEx1073[Punc-54-TTR81-127::EGFP] expresses TTR81-127::EGFP under the control of the unc-54 enhancer / promoter (Y. Tsuda, et al., Sci. Rep. 8, 17884 (2018)). The extrachromosomal DNA was integrated into the nematode chromosome by UV irradiation according to a previously published protocol (S. Mitani, et al., Dev. Growth Differ. 37, 551-557 (1995)). To avoid unwanted mutations due to UV irradiation, the resulting nematodes were crossed four times with the wild-type N2 (Bristol) strain to obtain the ATTR model nematode KXK1225zyeIs1225[Punc-54-TTR81-127::EGFP], which expresses TTR81-127::EGFP intrachromosomally. N2 was used as the wild-type strain for control experiments.

[0093] Reaction Monitoring: Western Blotting (WB) 250 μg of catalyst (suspended in DMSO) was added to an agar plate containing nematodes. The nematodes were allowed to feed on the catalyst overnight to allow it to internalize. The plate was then exposed to light for two 2-minute periods, with 5-minute intervals between each. The nematodes were then immediately collected and pelleted in M9 buffer and stored frozen at -80°C until use. Samples for reaction monitoring were prepared as follows: 500 μL of cOmplete Mini (Roche, 1 tablet / 10 mL) in PBS was added to the pellet, which had been thawed on ice, and homogenized by sonication. The pellet was diluted with SDS sample buffer and heated to 95°C. The reaction was monitored by Western blotting (WB). Primary antibodies used were anti-GFP rabbit polyclonal antibody (TAKARA, 632592, 1:1000 dilution) or anti-α-tubulin mouse monoclonal antibody (Sigma-Aldrich, T5168, 1:10,000 dilution). The secondary antibodies used were anti-rabbit HRP (Cell Signaling Technology, 7074S, 1:5000 dilution) or anti-mouse HRP (GE Healthcare Life Sciences, NA931V, 1:10000 dilution). Signals were detected using an Amersham ImageQuant 800 (Cytiva). Band intensities were quantified using tubulin as an internal standard (ImageJ version 1.54g: n = 9, mean ± standard deviation, Tukey's test: **** < 0.0001).

[0094] Nematode Bending Assay: 25 μg of catalyst (suspended in DMSO) was added to agar plates where nematodes were cultured. The nematodes were allowed to feed on the catalyst overnight to allow it to be internalized. Under Condition 1, the plates were exposed to 10-minute light exposures four times at 10-hour intervals, followed by two days of darkness. The number of bending movements of n = 20 nematodes was recorded. Under Condition 2, a continuous treatment was performed with 5-minute light exposures repeated daily. The number of bending movements of n = 10 nematodes was recorded on the first and third days of treatment. Three 30-second bending movements per nematode were recorded, and the average was calculated (mean ± standard deviation, Tukey's test: ** < 0.01).

[0095] <Results> The products of the reaction of proteins with singlet oxygen are known to include not only simple oxidation products of amino acid side chains, but also crosslinks formed by the nucleophilic addition of highly nucleophilic amino acids to oxidized histidine intermediates. Therefore, we extracted and purified TTR from nematode lysates before and after oxygenation, and then attempted to detect oxygenated crosslinks of TTR by Western blotting.

[0096] As a result, in the photo-oxygenated group, a decrease in the unreacted TTR band and an increase in the high-molecular-weight band corresponding to the cross-linked form were confirmed (Fig. 12). Quantitation of band intensity using tubulin as an internal standard confirmed a significant increase in the cross-linked form band under the conditions of entry 4 in which both the catalyst and light were present, suggesting that oxygenation also occurs within the nematode individual.

[0097] Next, we investigated the improvement of pathology by photooxygenation. The results are shown in Figure 13. In Condition 1 shown on the left side of Figure 13, 10-minute light exposure was repeated four times, followed by leaving the nematodes in the dark for two days, and then the number of bending movements of the nematodes was recorded. The motility of the oxygenated nematode group (entry 4) was significantly improved compared to the untreated group (entry 1), and we successfully observed an improvement in pathology comparable to that of wild-type nematodes that do not express TTR.

[0098] In condition 2, shown in the center and right panels of Figure 13, we investigated the application of milder light exposure to continuous light therapy, with one set consisting of 5-minute sessions every day. While no significant differences were observed between the groups on day 1, on day 3, the oxygenated group (entry 4), similar to condition 1, showed significantly higher motility than the untreated group (entry 1) and the light-only group (entry 2). Furthermore, no significant difference was observed when compared with the group treated with only the catalyst but without light exposure (entry 3). This is likely due to background reactions occurring during the microscopic manipulation required for the nematode culture process, which involves exposure to light for a certain period of time.

Claims

1. A photooxygenation catalyst for pathogenic amyloid, comprising a compound represented by the following formula (I) or a salt thereof: (wherein ring X is an optionally substituted aromatic ring or an optionally substituted heteroaromatic ring; R 1 is a halogen atom; R ２ is a halogen atom or a linear or branched C １ ~C ５ is a halogenated alkyl group; R ３ is a hydrogen atom or a halogen atom; R ａ and R ｂ are each independently selected from the group consisting of a hydrogen atom and an optionally substituted linear or branched alkyl group; R ｃ and R ｄ are each independently selected from the group consisting of an optionally substituted linear or branched alkyl group and an optionally substituted linear or branched ether group; R ｃ and / or R ｄ may form a ring structure including the nitrogen atom to which they are attached and optionally the atoms that make up ring X; R ｃ and R ｄ The N atom to which L is attached may be located at any position on the ring X; 1 is a direct bond, a carbon atom, or a conjugated linker having 2 to 10 carbon atoms; L ２ is a direct bond, a conjugated linker having 2 to 10 carbon atoms.

2. R 1 is a fluorine atom; R ２ But C １ ~C ５ The photooxygenation catalyst according to claim 1 , which is a fluorinated alkyl group.

3. R ２ But CF ３ or CF ２ CF ３ 2. The photooxygenation catalyst according to claim 1, wherein 4. R ３ The photooxygenation catalyst according to claim 1, wherein is a fluorine atom or a bromine atom.

5. R ｃ and R ｄ are each independently an optionally substituted alkyl group having 1 to 10 carbon atoms or an optionally substituted ether group having 1 to 10 carbon atoms.

6. R ｃ and / or R ｄ The photooxygenation catalyst according to claim 1 , wherein the group has a terminal hydroxyl group, a carboxyl group, or an ester group.

7. The photooxygenation catalyst according to claim 1, wherein ring X is a 4- to 6-membered monocyclic aromatic or heteroaromatic ring.

8. L 1 The photooxygenation catalyst according to claim 1 , wherein is an alkenylene group having a conjugated double bond, an arylene group, or a combination thereof.

9. L ２ The photooxygenation catalyst according to claim 1 , wherein is an alkenylene group having a conjugated double bond.

10. R ａ and R ｂ The photooxygenation catalyst according to claim 1 , wherein each of the groups is a methyl group.

11. X-N (R ｃ ) (R ｄ 2. The photooxygenation catalyst according to claim 1, wherein: (Wherein, the wavy line represents L ２ This is the connection position with .

12. The photooxygenation catalyst of claim 1, wherein the compound represented by formula (I) has a CLogP in the range of 2.0 to 6.

0.

13. The photooxygenation catalyst according to claim 1, wherein the pathogenic amyloid is transthyretin (TTR) amyloid.

14. A pharmaceutical composition comprising the photooxygenation catalyst according to any one of claims 1 to 13 and a pharmaceutically acceptable carrier.

15. The pharmaceutical composition according to claim 14, which is a drug for preventing or treating a disease associated with pathogenic amyloid.

16. The pharmaceutical composition of claim 15, wherein the pathogenic amyloid-associated disease is transthyretin amyloidosis.

17. Use of the photooxygenation catalyst according to any one of claims 1 to 13 for the manufacture of a drug for the prevention or treatment of a disease involving pathogenic amyloid.

18. A method for preventing or treating a disease associated with pathogenic amyloid, comprising administering to a patient the photooxygenation catalyst described in any one of claims 1 to 13, and after said administration, irradiating the affected area of ​​the patient with light from outside the body.

Images