WO2016010092A1 - ベンゾチアゾール化合物及びこれを含有する医薬 - Google Patents
ベンゾチアゾール化合物及びこれを含有する医薬 Download PDFInfo
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- C07D455/03—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
- C07D455/04—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing a quinolizine ring system condensed with only one six-membered carbocyclic ring, e.g. julolidine
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/472—Non-condensed isoquinolines, e.g. papaverine
- A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
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- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
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- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
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- C07—ORGANIC CHEMISTRY
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- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
Definitions
- the present invention relates to a medicament for preventing or treating various amyloid-related diseases.
- proteins fold to form a specific native structure and take on vital functions.
- misfolding may cause aggregation (amyloidation) into fibers rich in ⁇ -sheet structures.
- Aggregates oligomers, protofibrils, fibers
- amyloid diseases Has been identified as a causative agent of amyloid disease.
- amyloid for example, amyloid ⁇ of Alzheimer's disease, tau protein, ⁇ -synuclein of Parkinson's disease, amylin of diabetes, transthyretin of systemic amyloid-cis, huntingtin of Huntington's disease and the like are known.
- amyloid ⁇ (abbreviated as A ⁇ ) which is the causative amyloid of Alzheimer's disease, an enzyme inhibitor that produces A ⁇ from a precursor protein, A ⁇ Known as a degrading enzyme promoter, immunotherapy, A ⁇ aggregation inhibitor and the like.
- a ⁇ an enzyme inhibitor that produces A ⁇ from a precursor protein
- a ⁇ Known as a degrading enzyme promoter, immunotherapy, A ⁇ aggregation inhibitor and the like.
- a ⁇ a small amount of Met oxidized form of A ⁇ peptide (oxidized form in which the sulfur atom of the Met residue of A ⁇ peptide is oxidized (O)) remains in the living body, and the Met oxidized form is converted to A ⁇ peptide. It has been reported that the cohesiveness is lower than that (Non-patent documents 1 to 3).
- an object of the present invention is to provide a compound useful as an amyloid oxidation catalyst that can be applied in vivo and applicable not only to A ⁇ peptide but also to other amyloid, and an agent for preventing and treating amyloid-related diseases using the same. It is in.
- the present inventor has conducted various studies to develop a catalyst having oxidative activity against amyloid and applicable in vivo.
- the benzothiazole compound represented by the following general formula (1) is A ⁇ peptide and other amyloid
- the present invention was completed by discovering that it is useful as an in vivo catalyst that produces an amyloid oxidant that has a strong oxidative activity and has no aggregation properties.
- the present invention provides the following [1] to [13].
- R 1 represents a hydrocarbon group which may have a substituent
- R 2 represents a hydrogen atom or an optionally substituted hydrocarbon group
- R 3 and R 4 are the same or different and each represents a hydrogen atom, an optionally substituted hydrocarbon group, an alkoxy group, a halogen atom, an amino group, a nitro group, or a cyano group
- R 2 and R 4 together may form an alkylene group
- R 5 represents an anion
- the hydrocarbon groups in R 1 , R 2 , R 3 and R 4 are the same or different, and are halogen atoms, amino groups, nitro groups, cyano groups, alkoxy groups, acyl groups, carboxyl groups.
- R 2 together with R 4 forms a C 2 -C 4 alkylene group, or an alkyl or alkenyl group having 1 to 12 carbon atoms (this alkyl or alkenyl group includes a carboxyl group, an alkoxy group)
- a carbonyl group, amino-CO group or dipeptide to hexapeptide-CO- group is substituted, and this amino acid, dipeptide to hexapeptide is further substituted with 1 to 2 groups selected from a C 6-14 aryl group and an alkoxycarbonyl group.
- the benzothiazole compound according to any one of [1] to [6].
- a medicament comprising the benzothiazole compound according to any one of [1] to [7] as an active ingredient.
- a pharmaceutical composition comprising the benzothiazole compound according to any one of [1] to [7] and a pharmaceutically acceptable carrier.
- a method for preventing or treating a disease associated with pathogenic amyloid which comprises administering the compound according to any one of [1] to [7].
- the benzothiazole compound (1) of the present invention has a high catalytic activity for oxidizing pathogenic amyloid such as A ⁇ peptide, suppresses amyloid aggregation by oxidizing amyloid in vivo, and is a disease associated with pathogenic amyloid. It is useful as a prophylactic treatment.
- the analysis of the oxygenation reaction of A ⁇ 1-42 by compound (1a) using MALDI-TOF MS analysis is shown.
- Analysis of the oxygenation site of A ⁇ 1-42 using amino acid analysis (dark: equivalent to native A ⁇ , light: equivalent to oxygenated A ⁇ ) is shown.
- FIG. 6 shows the analysis of the oxygenation site of A ⁇ 1-42 using enzymatic digestion with endopeptidase Lys-C.
- A potential energy of compound (1a) in ground state (S 0 ) and excited state (S 1 ) (horizontal axis: dihedral angle between benzothiazole site and julolidine site, vertical axis: minimum energy of ground state is 0 )
- B Fluorescence spectrum of compound (1a) in BD, glycerol / water mixed solvent, reaction to furfuryl alcohol (C), reaction to benzoylmethionine (D)
- the aggregation property and cytotoxicity of native A ⁇ 1-42 and oxygenated A ⁇ 1-42 are shown.
- (A) Nile red fluorescence assay (b) Atomic force microscope analysis (incubation time: 6 hours) (c) Circular dichroism spectroscopy (incubation time: 6 hours) (d) Cell viability using PC12 cells Evaluation. 2 shows the analysis of oxygenation reaction of A ⁇ 1-42 by compound (1e) in cell culture medium (including 0.1% horse serum) (indicated by MALDI-TOF MS spectrum). The amino acid sequence of amylin (the oxygenation identification site is indicated by a red underline) is shown. The oxygenation reaction with respect to amylin (pre-incubation time 0h: monomer state, 1h: moderate aggregation, 2h: highly aggregation) by riboflavin and compound (1a) is shown.
- the aggregability (nile red fluorescence assay) of native amylin and oxygenated amylin is shown. It shows the aggregation properties of native amylin and oxygenated amylin (circular dichroism spectroscopy (incubation time: 1 hour) (dark: equivalent to native amylin, light: equivalent to oxygenated amylin). 1 shows a conceptual diagram of selective oxygenation of aggregated amylin. The analysis of oxygenation reaction of amylin by compound (1a) using MALDI-TOF MS analysis is shown. Analysis of the oxygenated site of amylin by amino acid analysis is shown (dark: equivalent to native amylin, light: equivalent to oxygenated amylin).
- A A size distribution analysis of A ⁇ 1-42 oligomer using atomic force microscope analysis is shown.
- B Binding analysis of compound (1a) to A ⁇ 1-42 oligomer using a fluorescence assay is shown.
- (D) shows the aggregability of oxygenated A ⁇ 1-42 oligomer by compound (1a) using a fluorescence assay and atomic force microscope (compared with non-oxygenated A ⁇ 1-42 (Native)).
- A Shows analysis of oxygenation reaction of insulin by compound (1a) using MALDI-TOF MS analysis.
- B Analysis of oxygenation reaction of ⁇ 2-microglobulin by compound (1a) using MALDI-TOF MS analysis. The analysis of oxygenation reaction of transthyretin by compound (1a) using MALDI-TOF MS analysis is shown. The analysis of oxygenation reaction of transthyretin by compound (1a) using MALDI-TOF MS analysis is shown.
- the analysis of oxygenation reaction of transthyretin by compound (1a) using MALDI-TOF MS analysis is shown.
- the analysis of oxygenation reaction of ⁇ -synuclein by compound (1a) using MALDI-TOF MS analysis is shown.
- the analysis of oxygenation reaction of ⁇ -synuclein by compound (1a) using MALDI-TOF MS analysis is shown.
- the analysis of oxygenation reaction of L-ascorbic acid with compound (1a) and riboflavin using MALDI-TOF MS analysis is shown.
- X represents a halogen atom.
- a halogen atom a chlorine atom, a bromine atom, a fluorine atom, or an iodine atom is mentioned, Among these, a chlorine atom or a bromine atom is more preferable, and a bromine atom is further more preferable.
- R 1 , R 2 , R 3 and R 4 may represent a hydrocarbon group which may have a substituent.
- the hydrocarbon group include linear or branched alkyl groups or alkenyl groups, cycloalkyl groups, cycloalkenyl groups, and aromatic hydrocarbon groups.
- the linear or branched alkyl group or alkenyl group is preferably a linear or branched alkyl group having 1 to 12 carbon atoms, or a linear or branched alkenyl group having 2 to 12 carbon atoms.
- a straight chain or branched chain alkyl group having 6 or a straight chain or branched chain alkenyl group having 2 to 6 carbon atoms is more preferable.
- alkyl groups or alkenyl groups include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, n-pentyl group, n-hexyl group, vinyl group, allyl group and the like. It is done.
- Examples of the cycloalkyl group and the cycloalkenyl group include a cycloalkyl group having 3 to 8 carbon atoms and a cycloalkenyl group having 3 to 8 carbon atoms.
- the cycloalkyl group having 3 to 6 carbon atoms and the cycloalkenyl group having 3 to 6 carbon atoms are used.
- Alkenyl groups are preferred. Specific examples of these cycloalkyl groups and cycloalkenyl groups include cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group and the like.
- the aromatic hydrocarbon group is preferably an aromatic hydrocarbon group having 6 to 14 carbon atoms, and specific examples include a phenyl group, an indenyl group, a naphthyl group, and a biphenyl group.
- hydrocarbon groups represented by R 1 to R 4 a linear or branched alkyl group or alkenyl group is preferable, a linear or branched alkyl group is more preferable, and a linear or branched alkyl group having 1 to 12 carbon atoms.
- a branched alkyl group is more preferable, and a linear or branched alkyl group having 1 to 6 carbon atoms is more preferable.
- the group that can be substituted for the hydrocarbon group is selected from a halogen atom, an amino group, a nitro group, a cyano group, an alkoxy group, a carboxyl group, an alkoxycarbonyl group, an acyl group, an aromatic hydrocarbon group, and a heterocyclic group. 1 to 3 may be mentioned.
- the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
- alkoxy group examples include an alkoxy group having 1 to 12 carbon atoms, preferably an alkoxy group having 1 to 6 carbon atoms, such as a methoxy group, an ethoxy group, an n-propyloxy group, an isopropyloxy group, and an n-butyloxy group. More preferred.
- alkoxycarbonyl group examples include a C 1-6 alkoxycarbonyl group.
- acyl group include an alkanoyl group, an aroyl group, a carboxyalkylcarbonyl group, an alkoxycarbonylalkylcarbonyl group, an amino acid-CO-group, a peptide-CO-group, and the like.
- An alkanoyl group having 1 to 12 carbon atoms C 6- Examples thereof include a 14 -aroyl group, a carboxy C 1-12 alkylcarbonyl group, a C 1-12 alkoxycarbonyl C 1-12 alkylcarbonyl group, an amino acid —CO— group, and a dipeptide to hexapeptide-CO— group.
- the aromatic hydrocarbon group is preferably an aromatic hydrocarbon group having 6 to 14 carbon atoms, and examples thereof include a phenyl group and a naphthyl group.
- Examples of the heterocyclic group include 5- to 10-membered heterocyclic groups having 1 to 3 heteroatoms selected from N, O, and S.
- pyrrolyl group, thienyl group, furanyl group examples include imidazolyl group, oxazolyl group, thiazolyl group, pyridyl group, pyrimidinyl group and the like.
- Substituents on these hydrocarbon groups include halogen atoms, amino groups, nitro groups, cyano groups, C 1-12 alkoxy groups, C 1-12 alkanoyl groups, C 6-14 aroyl groups, carboxy C 1-12 Alkylcarbonyl group, C 1-12 alkoxycarbonyl C 1-12 alkylcarbonyl group, carboxyl group, alkoxycarbonyl group, amino acid-CO- group, dipeptide-hexapeptide-CO- group, C 6-14 aryl group, and N;
- One to three members selected from 5- to 10-membered heterocyclic groups having 1 to 3 heteroatoms selected from O or S are preferred.
- the alkoxy group represented by R 3 and R 4 is preferably an alkoxy group having 1 to 12 carbon atoms, more preferably an alkoxy group having 1 to 6 carbon atoms. Specific examples include a methoxy group, an ethoxy group, and n-propyloxy group. Group, isopropyloxy group and n-butyloxy group.
- R 1 is preferably an alkyl or alkenyl group having 1 to 12 carbon atoms, a cycloalkyl or cycloalkenyl group having 3 to 8 carbon atoms, or an aromatic hydrocarbon group having 6 to 14 carbon atoms. Further, an alkyl or alkenyl group having 1 to 12 carbon atoms is more preferred, an alkyl group having 1 to 12 carbon atoms is more preferred, an alkyl group having 1 to 6 carbon atoms is further preferred, and an alkyl group having 1 to 4 carbon atoms is further preferred. preferable.
- R 3 is preferably a hydrogen atom, an alkyl or alkenyl group having 1 to 12 carbon atoms, a cycloalkyl or cycloalkenyl group having 3 to 8 carbon atoms, or an aromatic hydrocarbon group having 6 to 14 carbon atoms, An alkyl or alkenyl group having 1 to 12 carbon atoms is more preferable, and a hydrogen atom is more preferable.
- R 2 is preferably an alkyl or alkenyl group having 1 to 12 carbon atoms, a cycloalkyl or cycloalkenyl group having 3 to 8 carbon atoms, or an aromatic hydrocarbon group having 6 to 14 carbon atoms, and has 1 to 12 carbon atoms.
- An alkyl or alkenyl group is more preferable, and an alkyl or alkenyl group having 1 to 12 carbon atoms is further preferable (these may have a substituent).
- a halogen atom amino group, nitro group, cyano group, C 1-12 alkoxy group, C 1-12 alkanoyl group, C 6-14 aroyl group, carboxy C 1-12 alkylcarbonyl group, C 1-12 alkoxycarbonyl C 1-12 selected from alkylcarbonyl group, carboxyl group, alkoxycarbonyl group, amino acid-CO- group, dipeptide to hexapeptide-CO- group, C 6-14 aryl group, and N, O or S It is preferably 1 to 3 selected from 5- to 10-membered heterocyclic groups having 1 to 3 heteroatoms.
- the substituent is preferably a carboxyl group, an alkoxycarbonyl group, an amino acid-CO-group, or a dipeptide-hexapeptide-CO group.
- These amino acids, dipeptide-hexapeptide have a C 6-14 aryl group and an alkoxy group.
- One or two selected from a carbonyl group may be substituted.
- the alkylene group formed by combining R 2 and R 4 is preferably an alkylene group having 2 to 4 carbon atoms, and examples thereof include an ethylene group, a trimethylene group, and a tetramethylene group.
- R 4 is preferably substituted at the 8-position on the tetrahydroquinoline ring.
- the anion represented by R 5 is preferably a halogen anion, a sulfonate anion, or a triflate anion.
- R 1 is an alkyl or alkenyl group having 1 to 12 carbon atoms, a cycloalkyl or cycloalkenyl group having 3 to 8 carbon atoms, or an aromatic hydrocarbon group having 6 to 14 carbon atoms, These groups may have a substituent;
- R 2 is a hydrogen atom, an alkyl or alkenyl group having 1 to 12 carbon atoms, a cycloalkyl or cycloalkenyl group having 3 to 8 carbon atoms, or an aromatic hydrocarbon group having 6 to 14 carbon atoms, and these groups are substituted
- R 3 and R 4 are the same or different and each represents a hydrogen atom, an alkyl or alkenyl group having 1 to 12 carbon atoms, a cycloalkyl or cycloalkenyl group having 3 to 8 carbon atoms, or an aromatic hydrocarbon group having 6 to 14 carbon atoms ( These groups may have a substituent), an alkoxy group, a halogen
- R 1 is an alkyl or alkenyl group having 1 to 6 carbon atoms, a cycloalkyl or cycloalkenyl group having 3 to 6 carbon atoms, or an aromatic hydrocarbon group having 6 to 14 carbon atoms.
- R 2 is a hydrogen atom, an alkyl or alkenyl group having 1 to 6 carbon atoms, a cycloalkyl or cycloalkenyl group having 3 to 6 carbon atoms, or an aromatic hydrocarbon group having 6 to 14 carbon atoms, and these groups are substituted May have R 3 and R 4 are the same or different and each represents a hydrogen atom, an alkyl or alkenyl group having 1 to 6 carbon atoms, a cycloalkyl or cycloalkenyl group having 3 to 6 carbon atoms, an aromatic hydrocarbon group having 6 to 14 carbon atoms ( These groups may have a substituent), a C 1-6 alkoxy group, a halogen atom, an amino group, a nitro group or a cyano group; R 2 and R 4 together may form a C 2 -C 4 alkylene group; R 5 is an anion; The substituent is a halogen atom, amino group, nitro
- R 1 is an alkyl or alkenyl group having 1 to 12 carbon atoms, more preferably an alkyl group having 1 to 12 carbon atoms;
- R 3 is a hydrogen atom or an alkyl or alkenyl group having 1 to 12 carbon atoms, more preferably a hydrogen atom;
- R 2 together with R 4 forms a C 2 -C 4 alkylene group, or an alkyl or alkenyl group having 1 to 12 carbon atoms (this alkyl or alkenyl group includes a carboxyl group, an alkoxycarbonyl group, An amino-CO group or a dipeptide to hexapeptide-CO- group is substituted, and this amino acid, dipeptide to hexapeptide may be further substituted with 1 to 2 groups selected from a C 6-14 aryl group and an alkoxycarbonyl group. Good). More preferably, R 5 is an anion.
- the present invention includes optical isomers, and includes both optical isomers and racemates.
- the compound (1) of the present invention can be produced, for example, according to the following reaction formula.
- the 2-aminobenzothiazole (2) is reacted with iodide R 1 -X 2 (3) to obtain a quaternary ammonium salt (4), and the quaternary ammonium salt is reacted with an alkali to give a compound (5 Then, the compound (5) is reacted with the compound (6) to produce the compound (1) of the present invention.
- reaction of 2-aminobenzothiazole (2) and iodide (3) may be carried out in an amide solvent such as dimethylformamide at room temperature to reflux temperature for 5 minutes to 5 hours.
- Examples of the alkali to be reacted with the quaternary ammonium salt (4) include potassium hydroxide and sodium hydroxide.
- the reaction between the quaternary ammonium salt (4) and the alkali may be carried out in a solvent such as ethylene glycol at room temperature to reflux temperature for 5 to 48 hours.
- the compound (5) is first reacted with a reducing agent such as tris (2-carboxyethyl) phosphine hydrochloride, and then the compound (6) is reacted.
- a reducing agent such as tris (2-carboxyethyl) phosphine hydrochloride
- the reaction between the compound (5) and the reducing agent may be carried out in a solvent such as water or alcohol at room temperature for 10 minutes to 2 hours. Further, the reaction of the compound (4) and the compound (6) may be carried out at room temperature to 100 ° C. for 30 minutes to 12 hours.
- the compound (6) can be produced, for example, by formylating the 6-position of the tetrahydroquinolines by performing a Vilsmeier-Hack reaction in which dimethylformamide and phosphoric acid trichloride are reacted with tetrahydroquinolines.
- the resulting compound (1) of the present invention can be isolated and purified from the reaction mixture by usual means such as washing, crystallization, recrystallization, chromatography and the like.
- the maximum absorption wavelength of the compound (1) of the present invention is shifted to a wavelength longer by about 50 nm than that of thioflavin T, and the compound (1) of the present invention is more in the presence of A ⁇ than in the absence of A ⁇ .
- a slight increase in the absorption wavelength was observed, and a significantly higher fluorescence was observed. From this result, it can be seen that, like thioflavin T, the compound of the present invention emits fluorescence as a result of binding to A ⁇ and inhibiting twisting in the molecule.
- native A ⁇ decreased with time and oxygenated A ⁇ with 1 to 4 oxygen atoms added increased.
- the oxidation efficiency was significantly higher than that of Thioflavin T.
- the compound (1) of the present invention has remarkably strong oxidizing power against A ⁇ oligomers and A ⁇ aggregates having a cross ⁇ -sheet structure as compared with the oxidizing power against A ⁇ 1-42 (non-aggregated), and the A ⁇ oligomer and A ⁇ aggregated It is considered that the neurotoxicity of A ⁇ is suppressed by specifically oxidizing the aggregated ⁇ -sheet structure.
- the oxygenation reaction by the compound (1) of the present invention is extremely weak against non-amyloid proteins such as angiotensin IV, methionine enkephalin, desacyl ghrelin, somatostatin, and is selective for amyloid protein.
- this invention compound (1) acts as a catalyst which selectively oxidizes pathogenic amyloid, such as A (beta) peptide, amylin, transthyretin, (alpha) cyanuclein, tau protein, and Huntington.
- pathogenic amyloid such as A (beta) peptide, amylin, transthyretin, (alpha) cyanuclein, tau protein, and Huntington.
- pathogenic amyloids are oxidized, they do not form a ⁇ -sheet structure laminate, and therefore do not cause pathogenicity. Therefore, the compound (1) of the present invention is useful as a prophylactic / therapeutic agent for diseases involving pathogenic amyloid such as Alzheimer's disease, Parkinson's disease, diabetes, Huntington's disease, and systemic amyloidosis in animals including humans.
- the present compound (1) catalyzes the oxidation reaction of pathogenic amyloid. This oxidation reaction proceeds when the compound (1) of the present invention is excited by light and oxidizes amyloid. Accordingly, when the compound (1) of the present invention is used as a medicine, it is preferable to irradiate the patient with light after administering the compound (1) of the present invention. In addition, since the wavelength of light for bringing the compound (1) of the present invention into an excited state is 600 to 1200 nm, it has a feature that it easily passes through a living body.
- the pharmaceutical composition containing the compound (1) of the present invention can be prepared by selecting an appropriate preparation according to the administration method and preparing various preparations using a pharmaceutically acceptable carrier.
- a pharmaceutically acceptable carrier for example, tablets, powders, granules, capsules, liquids, syrups, elixirs, oily or aqueous suspensions and the like are used as oral preparations. It can be illustrated as
- stabilizers As injections, stabilizers, preservatives, and solubilizing aids may be used in the preparation. After storing a solution that may contain these adjuvants in a container, it may be prepared as a solid preparation by lyophilization or the like. It is good also as a formulation. Further, a single dose may be stored in one container, and multiple doses may be stored in one container.
- liquid preparations suspensions, emulsions, ointments, gels, creams, lotions, sprays, patches and the like can be exemplified as external preparations.
- the solid preparation contains a pharmaceutically acceptable additive together with the compound (1) of the present invention.
- a pharmaceutically acceptable additive for example, fillers, extenders, binders, disintegrants, dissolution promoters, wetting agents, lubricantskinds and the like can be selected and mixed as necessary to prepare a formulation.
- liquid preparations include solutions, suspensions, emulsions and the like, but additives may include suspending agents, emulsifiers and the like.
- the dosage is preferably 1 mg to 1 g, preferably 1 mg to 300 mg per day for an adult.
- Example 3 (Characteristics of Compound of the Present Invention, Pharmacological Test 1) A. Method (1) Oxidation Reaction Phosphate buffer (10 mM, pH 7.4) containing A ⁇ 1-42 (20 ⁇ M), amylin (5 ⁇ M), angiotensin IV (30 ⁇ M) or methionine enkephalin (30 ⁇ M), thioflavin T (20 ⁇ M), Riboflavin (4 ⁇ M), compound a (20 ⁇ M) or compound (1a) (20 ⁇ M) was added and incubated at 37 ° C. under LED irradiation (wavelength 500 nm), followed by mass spectrometry (MALDI-TOF MS) or LC / MS ( The reaction was followed by ESI-Q).
- a ⁇ affinity A ⁇ 1-42 (aggregation condition: 20 ⁇ M, phosphate buffer (10 mM, pH 7.4), 37 ° C., 3 hours) previously aggregated with thioflavin T or phosphate containing compound (1a)
- buffer (10 mM, pH 7.4) final concentration of A ⁇ : 0.5 ⁇ M, final concentration of thioflavin T or compound (1a): 0 to 20 ⁇ M
- fluorescence intensity was measured after incubation at room temperature for 1 hour.
- Thioflavin T had an excitation wavelength of 420 nm and a fluorescence wavelength of 485 nm
- compound (1a) had an excitation wavelength of 460 nm and a fluorescence wavelength of 515 nm.
- a Kd binding curve was obtained from the fluorescence intensity using KaleidaGraph 4.5 (Synergy Software, Reading, PA).
- riboflavin (4 ⁇ M) or compound a (20 ⁇ M) was added to the glycerol / water solution in which furfuryl alcohol (200 ⁇ M) or benzoylmethionine (200 ⁇ M) was dissolved, and after LED irradiation (wavelength 500 nm) at room temperature, LC The reaction was followed by / MS (ESI-Q).
- Nile Red Fluorescence Assay Experiment Compound (1a) (20 ⁇ M) was added to phosphate buffer (10 mM, pH 7.4) in which A ⁇ 1-42 (20 ⁇ M) or amylin (5 ⁇ M) was dissolved. 500 nm) at 37 ° C. A part of the solution was added to phosphate buffer (10 mM, pH 7.4) containing Nile Red (A ⁇ 1-42 or amylin final concentration: 0.5 ⁇ M, Nile Red final concentration: 5 ⁇ M), and 1 at room temperature. After incubation for a period of time, the fluorescence intensity of Nile Red (excitation wavelength: 530 nm, fluorescence wavelength: 610 nm) was measured.
- S 1 state (dihedral angle: about 30 degrees) immediately after excitation spontaneously becomes S 1 'state (dihedral angle: about 90 degrees). It was suggested to cause intramolecular twist. Moreover, since the energy gap between S 1 'state and S 0 ' state at 90 degrees is small, it was suggested that S 1 'state easily relaxed to the ground state S 0 ' state. On the other hand, in the presence of A ⁇ , it is considered that TICT does not occur because intramolecular rotation is inhibited by binding to A ⁇ (FIG. 1b).
- Compound (1e) (50 mmol%) had an activity of oxygenating A ⁇ by about 40% in a cell culture medium when irradiated with light for 30 minutes (wavelength: 500 nm) (FIG. 5).
- Compound a could hardly oxygenate A ⁇ under the same conditions including medium (A. Taniguchi, D. Sasaki, A. Shiohara, T. Iwatsubo, T. Tomita, Y. Sohma, M. Kanai). , Angew.Chem.Int.Ed., 2014,53,1382-1385.),
- Compound (1e) produces singlet oxygen at a position closer to A ⁇ , and thus is not interfered with by components in the medium. It is considered that A ⁇ could be oxygenated efficiently.
- Example 4 (Selectivity of oxygenation reaction by the compound of the present invention) Phosphate buffer (10 mM, pH 7.) containing A ⁇ 1-42 (20 ⁇ M), angiotensin IV (20 ⁇ M), methionine enkephalin (20 ⁇ M), desacyl ghrelin (20 ⁇ M) or somatostatin (20 ⁇ M) previously incubated at 37 ° C. for 6 hours. 4) is added with riboflavin (4 ⁇ M), compound (a) (20 ⁇ M) or compound (1a) (4 ⁇ M), incubated at 37 ° C. for 60 minutes under LED irradiation (wavelength 500 nm), and then subjected to mass spectrometry (MALDI- The reaction was followed by TOF MS) or LC / MS (ESI-Q).
- FIG. 8 shows the results of studies on the A ⁇ selectivity of the oxygenation reaction.
- Riboflavin (20 mmol%), compound (a) (100 mmol%), and compound (1a) (20 mmol%) have similar A ⁇ levels (50 to 70 under light irradiation conditions in neutral buffer (37 ° C.) for 1 hour). %) Oxygenated.
- riboflavin and compound (a) were angiotensin IV (VYIHPF (SEQ ID NO: 2)), methionine enkephalin (YGGFM (SEQ ID NO: 3)), desacyl ghrelin (GSSFLSPEHQRVQQRKESKKPPAKLQPR (SEQ ID NO: 4)), somatostatin (ATCNKFW) (SEQ ID NO: 5) was oxygenated by 20 to 35%, 40 to 70%, 15 to 30%, and 60 to 80%, respectively, whereas in the reaction using compound (1a), oxygenated products were formed. Was suppressed to 2% or less.
- Example 5 (the compound of the present invention selectively binds to the cross ⁇ sheet structure and is oxygenated)
- Thioflavin T was added to each of four types of aggregated A ⁇ 1-42 prepared by incubating A ⁇ 1-42 (20 ⁇ M) in phosphate buffer (10 mM, pH 7.4) at 37 ° C. for 0, 1, 3, 6 hours. The fluorescence intensity was measured. The shape was analyzed using an atomic force microscope. As a result, as shown in FIG. 9a, it did not show fluorescence for those that were not incubated (0 hour), but it showed fluorescence for those that were incubated for 1, 3, 6 hours, Longer incubation time showed stronger fluorescence.
- the increase in oxygenation intensity rate (%) is (Oxygenation intensity rate of aggregated A ⁇ 1-42 (incubation for 37 hours at 37 ° C.)) ⁇ (Oxygenation intensity rate of aggregated A ⁇ 1-42 (incubation at 37 ° C. for 0 hours)) Calculated with The oxygenated strength rate (%) was calculated by (total oxygen adduct strength) / ((non-oxygen adduct strength) + (total oxygen adduct strength)).
- Example 6 Selective oxygenation to A ⁇ oligomers and A ⁇ aggregates (1) Each of two types of A ⁇ 1-42 prepared by incubating A ⁇ 1-42 (20 ⁇ M) in phosphate buffer (10 mM, pH 7.4) at 0 ° C. (sample E) and room temperature (sample F) for 24 hours. The size distribution was analyzed using an atomic force microscope. As a result, as shown in FIG. 10a, uniform oligomers were observed for any of A ⁇ 1-42 prepared by incubation at 0 ° C. and room temperature. A larger oligomer was observed in the A ⁇ 1-42 oligomer prepared by incubation at room temperature.
- a solution containing two types of A ⁇ 1-42 oligomers prepared by incubating A ⁇ 1-42 (20 ⁇ M) in phosphate buffer (10 mM, pH 7.4) at 0 ° C. and room temperature for 24 hours.
- Compound (1a) (10 ⁇ M) was added to each, and the fluorescence intensity of compound (1a) was measured.
- FIG. 10b shows that all of the A ⁇ 1-42 oligomers prepared by incubation at 0 ° C. and room temperature showed fluorescence, and it was clear that the compound (1a) was bound to the A ⁇ 1-42 oligomers. became.
- the A ⁇ 1-42 oligomer prepared by incubation at room temperature showed stronger fluorescence.
- a solution containing two types of A ⁇ 1-42 oligomers prepared by incubating A ⁇ 1-42 (20 ⁇ M) in phosphate buffer (10 mM, pH 7.4) at 0 ° C. and room temperature for 24 hours.
- Compound (1a) (4 ⁇ M) was added to each, and the mixture was incubated at room temperature for 10 minutes under LED irradiation (wavelength 500 nm), and then the reaction was followed with a mass spectrometer (MALDI-TOF MS).
- the oxygenated strength rate (%) was calculated by (total oxygen adduct strength) / ((non-oxygen adduct strength) + (total oxygen adduct strength)).
- compound (1a) can be oxygenated in any of the A ⁇ 1-42 oligomers prepared by incubation at 0 ° C. and room temperature.
- the A ⁇ 1-42 oligomer prepared by incubation at room temperature showed higher oxygenation strength.
- a solution containing two kinds of A ⁇ 1-42 oligomers prepared by incubating A ⁇ 1-42 (20 ⁇ M) in phosphate buffer (10 mM, pH 7.4) at 0 ° C. and room temperature for 24 hours.
- Compound (1a) (4 ⁇ M) was added to each and incubated at room temperature for 1 hour under LED irradiation (wavelength 500 nm). Thereafter, each solution was incubated at 37 ° C., Nile red was added, and the fluorescence intensity was measured. About what was incubated for 6 hours, the shape by atomic force microscope analysis was also analyzed.
- Non-oxygenated A ⁇ 1-42 oligomer (Native) was prepared without light irradiation.
- Example 7 (Oxygenation effect on amyloid aggregation other than compound A ⁇ amyloid of the present invention)
- Neutral buffer containing non-aggregated (0-hour incubation) and aggregated (12-hour incubation) insulin (160 ⁇ M) prepared by incubating insulin (400 ⁇ M) in 25 mM hydrochloric acid solution at 60 ° C. with stirring (1000 rpm)
- Compound (1a) (20 ⁇ M) was added to the solution, and the mixture was incubated at 37 ° C. for 30 minutes under LED irradiation (wavelength: 500 nm), and then the reaction was followed with a mass spectrometer (MALDI-TOF MS).
- MALDI-TOF MS mass spectrometer
- Non-aggregated (0 hour incubation) and aggregated (3 hour incubation) transthyretin (36 ⁇ M) prepared by incubating transthyretin (80 ⁇ M, 100 mM NaCl) in 10 mM hydrochloric acid solution at room temperature
- Compound (1a) (20 ⁇ M) was added to the buffer, incubated at 37 ° C. for 30 minutes under LED irradiation (wavelength 500 nm), digested with endoproteinase (Lys-C), and mass spectrometer (MALDI-TOF MS). )
- LED irradiation wavelength 500 nm
- Lys-C digested with endoproteinase
- MALDI-TOF MS mass spectrometer
- Non-aggregation (0 hour incubation) prepared by incubating ⁇ -synuclein (69 ⁇ M) in 20 mM Tris buffer (containing pH 7.5, 100 mM NaCl and 1 mM MgCl 2 ) at 37 ° C. with stirring (1000 rpm) and Aggregation (incubation for 24 hours) Compound (1a) (20 ⁇ M) was added to this buffer containing ⁇ -synuclein (69 ⁇ M), incubated at 37 ° C. for 30 minutes under LED irradiation (wavelength 500 nm), and then endoproteinase (Lys ⁇ C) and digested with a mass spectrometer (MALDI-TOF MS).
- Example 8 the compound of the present invention is specific for amyloid aggregation accompanied by the formation of a cross- ⁇ sheet structure
- a phosphate buffer solution (10 mM, pH 7.4) containing nucleoside phosphorylase (0.1 mg / mL) is incubated at 60 ° C., and a fluorescence assay kit (Protein Stability and Aggregation Assay Kit (ProFoldin, Hudson, MO, USA)) ) was used to track the degree of thermal aggregation.
- a fluorescence assay kit Protein Stability and Aggregation Assay Kit (ProFoldin, Hudson, MO, USA)
- FIG. 12a when a phosphate buffer containing nucleoside phosphorylase was incubated, an increase in the fluorescence intensity (thermal aggregation degree) of the kit was observed over time.
- Those prepared by incubation for 0 hour and 1 hour were used for oxygenation reaction analysis as non-aggregated and aggregated phosphorylase, respectively.
- Non-aggregation (0 hour incubation) and aggregation (6 hours) prepared by incubating a phosphate buffer (10 mM, pH 7.4) containing A ⁇ 1-42 (20 ⁇ M) previously incubated at 37 ° C. at 37 ° C. Incubation) Riboflavin (4 ⁇ M) or compound (1a) (4 ⁇ M) is added to A ⁇ 1-42, incubated for 10 minutes at room temperature under LED irradiation (wavelength 500 nm), and then reacted with a mass spectrometer (MALDI-TOF MS). Tracked.
- a phosphate buffer (10 mM, pH 7.4) containing A ⁇ 1-42 (20 ⁇ M) previously incubated at 37 ° C. at 37 ° C. Incubation
- Riboflavin (4 ⁇ M) or compound (1a) (4 ⁇ M) is added to A ⁇ 1-42, incubated for 10 minutes at room temperature under LED irradiation (wavelength 500 nm), and then reacted with a mass
- Non-aggregated (0 hour incubation) and aggregated (1 hour incubation) nucleoside phosphorylase prepared by incubating phosphate buffer (10 mM, pH 7.4) containing nucleoside phosphorylase (0.1 mg / mL) at 60 ° C.
- Example 9 Compound (1a) (20 ⁇ M) or riboflavin (4 ⁇ M) was added to a culture medium containing L-ascorbic acid (500 ⁇ M), and incubated at 37 ° C. for 30 minutes under LED irradiation (wavelength 500 nm). -MSMS) followed the reaction. As a result, as shown in FIG. 13, when compound (1a) (4.0 mmol%) or riboflavin (0.8 mmol%) was added to L-ascorbic acid and irradiated with light, compound (1a) was used. L-ascorbic acid remained at 100%. On the other hand, when riboflavin was used, L-ascorbic acid was completely lost. From this result, it has been clarified that the compound of the present invention does not show an oxidizing action only by being irradiated with light, but shows an oxidizing action only after binding to a cross ⁇ sheet structure such as amyloid aggregation.
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Abstract
Description
一方、Aβに関しては、AβペプチドのMet酸化体(AβペプチドのMet残基の硫黄原子が酸化(O)された酸化体)が生体内に少量残存すること、及び当該Met酸化体はAβペプチドに比べて凝集性が低いことが報告されている(非特許文献1~3)。かかる観点から、本発明者は、式(a)で表されるAβ結合部位を有するフラビン光触媒を用いてAβペプチドを酸化するとAβペプチド酸化体が得られ、当該Aβペプチド酸化体はAβの凝集を抑制することを報告した(非特許文献4)。
従って、本発明の課題は、生体内に適用可能で、Aβペプチドだけでなく他のアミロイドにも適用可能なアミロイド酸化触媒として有用な化合物及びこれを用いたアミロイド関連疾患予防治療薬を提供することにある。
R1は、置換基を有していてもよい炭化水素基を示し;
R2は水素原子、又は置換基を有していてもよい炭化水素基を示し;
R3及びR4は、同一又は異なって、水素原子、置換基を有していてもよい炭化水素基、アルコキシ基、ハロゲン原子、アミノ基、ニトロ基、又はシアノ基を示し;
R2とR4は一緒になってアルキレン基を形成してもよく、
R5はアニオンを示す)
で表されるベンゾチアゾール化合物。
〔2〕R1、R2、R3及びR4における炭化水素基に置換し得る基が、同一又は異なって、ハロゲン原子、アミノ基、ニトロ基、シアノ基、アルコキシ基、アシル基、カルボキシル基、アルコキシカルボニル基、芳香族炭化水素基及び複素環式基から選ばれる1~3個である〔1〕記載のベンゾチアゾール化合物。
〔3〕R1が、炭素数1~12のアルキル又はアルケニル基である〔1〕又は〔2〕記載のベンゾチアゾール化合物。
〔4〕R1が、炭素数1~12のアルキル基である〔1〕~〔3〕のいずれかに記載のベンゾチアゾール化合物。
〔5〕R3が、水素原子又は炭素数1~12のアルキル又はアルケニル基である〔1〕~〔4〕のいずれかに記載のベンゾチアゾール化合物。
〔6〕R3が、水素原子である〔1〕~〔5〕のいずれかに記載のベンゾチアゾール化合物。
〔7〕R2が、R4と一緒になってC2-C4アルキレン基を形成するか、あるいは炭素数1~12のアルキル又はアルケニル基(このアルキル又はアルケニル基には、カルボキシル基、アルコキシカルボニル基、アミノ-CO基又はジペプチド~ヘキサペプチド-CO-基が置換し、このアミノ酸、ジペプチド~ヘキサペプチドにはさらにC6-14アリール基及びアルコキシカルボニル基から選ばれる1~2個が置換していてもよい。)である〔1〕~〔6〕のいずれかに記載のベンゾチアゾール化合物。
〔8〕〔1〕~〔7〕のいずれかに記載のベンゾチアゾール化合物を有効成分とする医薬。
〔9〕病原性アミロイドが関与する疾患の予防又は治療薬である〔8〕記載の医薬。
〔10〕〔1〕~〔7〕のいずれかに記載のベンゾチアゾール化合物及び薬学的に許容される担体を含有する医薬組成物。
〔11〕病原性アミロイドが関与する疾患の予防又は治療に使用するための〔1〕~〔7〕のいずれかに記載の化合物。
〔12〕病原性アミロイドが関与する疾患の予防又は治療薬製造のための〔1〕~〔7〕のいずれかに記載の化合物の使用。
〔13〕〔1〕~〔7〕のいずれかに記載の化合物を投与することを特徴とする病原性アミロイドが関与する疾患の予防又は治療方法。
直鎖又は分岐鎖のアルキル基又はアルケニル基としては、炭素数1~12の直鎖又は分岐鎖のアルキル基、炭素数2~12の直鎖又は分岐鎖のアルケニル基が好ましく、炭素数1~6の直鎖又は分岐鎖のアルキル基、炭素数2~6の直鎖又は分岐鎖のアルケニル基がより好ましい。これらのアルキル基又はアルケニル基の具体例としては、メチル基、エチル基、n-プロピル基、イソプロピル基、n-ブチル基、n-ペンチル基、n-ヘキシル基、ビニル基、アリル基等が挙げられる。
ここで、ハロゲン原子としては、フッ素原子、塩素原子、臭素原子、ヨウ素原子が挙げられる。アルコキシ基としては、炭素数1~12のアルコキシ基が挙げられ、炭素数1~6のアルコキシ基が好ましく、メトキシ基、エトキシ基、n-プロピルオキシ基、イソプロピルオキシ基、n-ブチルオキシ基等がより好ましい。アルコキシカルボニル基としては、C1-6アルコキシカルボニル基が挙げられる。アシル基としては、アルカノイル基、アロイル基、カルボキシアルキルカルボニル基、アルコキシカルボニルアルキルカルボニル基、アミノ酸-CO-基、ペプチド-CO-基等が挙げられ、炭素数1~12のアルカノイル基、C6-14-アロイル基、カルボキシC1-12アルキルカルボニル基、C1-12アルコキシカルボニルC1-12アルキルカルボニル基、アミノ酸-CO-基、ジペプチド~ヘキサペプチド-CO-基が挙げられる。芳香族炭化水素基としては、炭素数6~14の芳香族炭化水素基が好ましく、フェニル基、ナフチル基等が挙げられる。複素環式基としては、N、O又はSから選ばれるヘテロ原子を1~3個有する5員~10員の複素環式基が挙げられ、具体的にはピロリル基、チエニル基、フラニル基、イミダゾリル基、オキサゾリル基、チアゾリル基、ピリジル基、ピリミジニル基等が挙げられる。
R2が水素原子、炭素数1~12のアルキル又はアルケニル基、炭素数3~8のシクロアルキル又はシクロアルケニル基、又は炭素数6~14の芳香族炭化水素基であり、これらの基は置換を有していてもよく;
R3及びR4が同一又は異なって、水素原子、炭素数1~12のアルキル又はアルケニル基、炭素数3~8のシクロアルキル又はシクロアルケニル基、炭素数6~14の芳香族炭化水素基(これらの基は置換基を有していてもよい)、アルコキシ基、ハロゲン原子、アミノ基、ニトロ基又はシアノ基であり;
R2及びR4が一緒になってC2-C4アルキレン基を形成してもよく;
R5がアニオンであり;
前記の置換基が、ハロゲン原子、アミノ基、ニトロ基、シアノ基、カルボキシル基、アルコキシカルボニル基、アルコキシ基、アシル基、芳香族炭化水素基及び複素環式基から選ばれる1~3個であるのが好ましい。
R2が水素原子、炭素数1~6のアルキル又はアルケニル基、炭素数3~6のシクロアルキル又はシクロアルケニル基、又は炭素数6~14の芳香族炭化水素基であり、これらの基は置換を有していてもよく;
R3及びR4が同一又は異なって、水素原子、炭素数1~6のアルキル又はアルケニル基、炭素数3~6のシクロアルキル又はシクロアルケニル基、炭素数6~14の芳香族炭化水素基(これらの基は置換基を有していてもよい)、C1-6アルコキシ基、ハロゲン原子、アミノ基、ニトロ基又はシアノ基であり;
R2及びR4が一緒になってC2-C4アルキレン基を形成してもよく;
R5がアニオンであり;
前記の置換基が、ハロゲン原子、アミノ基、ニトロ基、シアノ基、C1-12アルコキシ基、C1-12アルカノイル基、C6-14アロイル基、カルボキシC1-12アルキルカルボニル基、C1-12アルコキシカルボニルC1-12アルキルカルボニル基、カルボキシル基、アルコキシカルボニル基、アミノ酸-CO-基、ジペプチド~ヘキサペプチド-CO-基、C6-14アリール基、及びN、O又はSから選ばれるヘテロ原子を1~3個有する5員~10員の複素環式基から選ばれる1~3個であるのがより好ましい。
R1が炭素数1~12のアルキル又はアルケニル基であり、より好ましくは炭素数1~12のアルキル基であり;
R3が水素原子又は炭素数1~12のアルキル又はアルケニル基であり、より好ましくは水素原子であり;
R2が、R4と一緒になってC2-C4アルキレン基を形成するか、あるいは炭素数1~12のアルキル又はアルケニル基(このアルキル又はアルケニル基には、カルボキシル基、アルコキシカルボニル基、アミノ-CO基又はジペプチド~ヘキサペプチド-CO-基が置換し、このアミノ酸、ジペプチド~ヘキサペプチドにはさらにC6-14アリール基及びアルコキシカルボニル基から選ばれる1~2個が置換していてもよい。)であり;
R5がアニオンであるのがさらに好ましい。
化合物(5)と還元剤との反応は、水、アルコール等の溶媒中、室温で10分~2時間行えばよい。また、化合物(4)と化合物(6)の反応は、室温から100℃で30分~12時間行えばよい。
また、Aβに本発明化合物(1)を添加し、生理的条件下で光照射すると、経時的にネイティブAβが減少するとともに、酸素原子が1~4個付加した酸素化Aβが増加した。その酸化効率は、チオフラビンTに比べて顕著に高かった。また、本発明化合物(1)は、Aβ1-42(非凝集体)に対する酸化力に比べてクロスβ-シート構造を有するAβオリゴマー及びAβ凝集体に対する酸化力が顕著に強く、Aβオリゴマー及びAβ凝集体のクロスβシート構造特異的に酸化することにより、Aβの神経毒性を抑制するものと考えられる。また、本発明化合物(1)による酸素化反応は、アンギオテンシンIV、メチオニンエンケファリン、デスアシルグレリン、ソマトスタチン等の非アミロイド性タンパクに対しては極めて弱く、アミロイドタンパクに選択的である。さらに、本発明化合物(1)のアミロイド酸素化反応は、細胞存在下でも確認された。従って、本発明化合物(1)は、Aβペプチド、アミリン、トランスサイレチン、αシアヌクレイン、タウ蛋白質、ハンチントン等の病原性アミロイドを選択的に酸化する触媒として作用する。これらの病原性アミロイドは、酸化されるとβ-シート構造の積層体を形成しなくなるため、病原性を生じなくなる。従って、本発明化合物(1)は、ヒトを含む動物のアルツハイマー病、パーキンソン病、糖尿病、ハンチントン病、全身性アミロイド-シス等の病原性アミロイドが関与する疾患の予防治療薬として有用である。
液体製剤としては溶液、懸濁液、乳液剤等を挙げることができるが添加剤として懸濁化剤、乳化剤等を含むこともある。
(4)化合物(1b)(288.9mg)を溶解したメタノール(50mL)に、1M NaOH水溶液(8.28mL)を氷浴中でゆっくりと加え、室温で10時間撹拌した。その反応液を2M塩酸で中和、減圧下濃縮、NaClで飽和させ、酢酸エチルで抽出した。その有機相をNa2SO4で乾燥、減圧下乾燥した。その残渣を分取用HPLC(0.1% aqueous TFA/MeCN=80/20 to 30/70,50分間)により精製して化合物(1c)(48.6mg,エステル体から7%)を得た。黄色固体;1H NMR(500MHz,CDCL3)δ:8.06(d,J=1.8Hz,1H),7.86(dd,J=8.6,1.7Hz,1H),7.80(d,J=9.2Hz,1H),7.60(dd,J=9.2,2.3Hz,1H),7.35(d,J=2.3Hz,1H),6.75(d,J=8.6Hz,1H),4.31(s,3H),3.46(t,J=6.3Hz,2H),3.41(t,J=7.5Hz,2H),2.81(t,J=6.3Hz,2H),2.37(t,J=6.9Hz,2H),1.97-1.99(m,2H),1.65-1.71(m,4H),1.39-1.45(m,2H);HRMS(ESI):m/z calcd for C23H26BrN2O2S+
[M]+ 473.0893,found 473.0904.
A.方法
(1)酸化反応
Aβ1-42(20μM)、アミリン(5μM)、アンジオテンシンIV(30μM)又はメチオニンエンケファリン(30μM)を含むリン酸緩衝液(10mM,pH7.4)に、チオフラビンT(20μM)、リボフラビン(4μM)、化合物a(20μM)又は化合物(1a)(20μM)を加え、LED照射下(波長500nm)、37℃でインキュベートした後、質量分析装置(MALDI-TOF MS)又はLC/MS(ESI-Q)にて反応を追跡した。
酸化Aβ1-42及び酸化アミリンのアミノ酸分析(ペプチド研究所によって実施)を行った。また、酸化Aβ1-42及び酸化アミリンをそれぞれエンドペプチダーゼLys-C及びキモトリプシンで酵素消化し、得られた消化物を質量分析装置(MALD-TOF MS)及びLC/MS/MS(ESI-Q-TOF)にて分析した。
リン酸緩衝液(10mM,pH7.4)中、Aβ1-42(20μM)共存下又は非共存下でチオフラビンT(20μM)又は化合物(1a)(20μM)を溶解し、37℃にて3時間インキュベートした後、吸光及び蛍光スペクトルを測定した。チオフラビンT及び化合物(1a)の励起波長はそれぞれ420及び460nmとした。
予め凝集させたAβ1-42(凝集条件:20μM、リン酸緩衝液(10mM,pH7.4)、37℃、3時間)を、チオフラビンT又は化合物(1a)を含むリン酸緩衝液(10mM,pH7.4)に加え(Aβの最終濃度:0.5μM、チオフラビンT又は化合物(1a)の最終濃度:0~20μM)、室温で1時間インキュベート後に蛍光強度を測定した。チオフラビンTについては励起波長420nm、蛍光波長485nmとし、化合物(1a)については励起波長460nm、蛍光波長515nmとした。蛍光強度からKaleidaGraph 4.5(Synergy Software, Reading, PA)を用いてKd結合曲線を得た。
チオフラビンT及び化合物(1a)について、基底状態の各二面角における構造最適化及びエネルギー計算はB3LYP/LAV3P*(Maestro 9.3/Jaguar 7.9;Schrodinger,LLC,New York,NY,2012)を用いたDFT計算によって行った。励起状態の各二面角におけるエネルギー計算は、B3LYP/LAV3P*を用いたTDDFT計算によって行った。励起状態(S1)のエネルギーは、基底状態(S0)のエネルギーと遷移エネルギーの和として算出した。
グリセロール/水(0:100、12.5:87.5、50:50、62.5:37.5又は75:25)にチオフラビンT(20μM)又は化合物(1a)(20μM)を加え、蛍光スペクトルを測定した。チオフラビンT及び化合物(1a)の励起波長はそれぞれ420及び460nmとした。
また、フルフリルアルコール(200μM)またはベンゾイルメチオニン(200μM)を溶解した上記グリセロール/水の溶液に、リボフラビン(4μM)又は化合物a(20μM)を加え、室温でLED照射(波長500nm)した後、LC/MS(ESI-Q)にて反応を追跡した。
Aβ1-42(20μM)又はアミリン(5μM)が溶解したリン酸緩衝液(10mM,pH7.4)に化合物(1a)(20μM)を加え、LED照射下(波長500nm)、37℃でインキュベートした。その溶液の一部を、ナイルレッドを含むリン酸緩衝液(10mM,pH7.4)に加え(Aβ1-42又はアミリンの最終濃度:0.5μM、ナイルレッドの最終濃度:5μM)、室温で1時間インキュベート後、ナイルレッドの蛍光強度(励起波長:530nm、蛍光波長:610nm)を測定した。
Aβ1-42(20μM)が溶解したリン酸緩衝液(10mM,pH7.4)に化合物(1a)(20μM)を加え、LED照射下(波長500nm)、37℃でインキュベートした。その溶液の一部をマイカ上にのせ、室温で3分間インキュベートした後、水(20μL)で洗浄し、風乾した。測定は、Nano Wizard II(JPK instruments AG,Berlin,Germany)を使用し、空気中室温でタッピングモードにより行った。
Aβ1-42(20μM)又はアミリン(5μM)が溶解したリン酸緩衝液(10mM,pH7.4)に化合物(1a)(20μM)を加え、LED照射下(波長500nm)、37℃でインキュベートした。その溶液の一部を、Model 202SF(AVIV Biomedical,Inc.,Lakewood,NJ)を使用して分析した。
Aβ1-42(20μM)が溶解した0.1%ウマ血清を含むダルベッコ変法イーグル培地に化合物(1e)(10μM)を加え、LED照射下(波長500nm)、37℃で30分間インキュベートした後、質量分析装置(MALD-TOF MS)にて反応を追跡した。
ポリDリジンコート96穴プレートに播種したラット副腎髄質由来褐色細胞腫PC12細胞(理化学研究所から購入)に、50μLの上記溶液を加えて同様に反応させた。50μLの0.1%ウマ血清を含むダルベッコ変法イーグル培地で希釈した後(Aβ最終濃度:10μM)、5%CO2雰囲気下、37℃で48時間インキュベートした。WST-8を含む生細胞数測定試薬SF(10μL:ナカライから購入)を加え、5%CO2雰囲気下、37℃で3時間インキュベートした後、450nm(参照波長:655nm)における吸光度から細胞生存率を測定した。
(1)合成した化合物(1a)の最大吸光波長(456nm)は、ジュロリジンのより強い電子供与性に起因して、チオフラビンTと比べて50nm程度長波長シフトしていた(図1a左)。Aβ存在下では、Aβ非存在下の場合と比べて、吸光波長のわずかな長波長化が観察されるとともに、顕著に高い蛍光が観測された(図1a)。本結果より、化合物(1a)はチオフラビンTと同様、Aβと結合して分子内のねじれが阻害される結果、蛍光を放出することが示唆された。蛍光強度に基づく結合曲線より、化合物(1a)がAβに対してチオフラビンTと同程度のKd値(1:2.9μM,4:1.1μM)を有することも明らかとなった(図1b)。
以上の結果より、Aβ非存在下においては、TICTが進行して酸素化が起こらない一方、Aβ結合時においては、S1 stateからT1 stateへの項間交差が進み、T1 stateによる一重項酸素の産生と、続く一重項酸素によるAβの酸素化が進行した結果、高いAβ選択的酸素化が実現できたものと考えられる(図3d)。
予め37℃で6時間インキュベートさせたAβ1-42(20μM)、アンジオテンシンIV(20μM)、メチオニンエンケファリン(20μM)、デスアシルグレリン(20μM)又はソマトスタチン(20μM)を含むリン酸緩衝液(10mM,pH7.4)に、リボフラビン(4μM)、化合物(a)(20μM)又は化合物(1a)(4μM)を加え、LED照射下(波長500nm)、37℃で60分インキュベートした後、質量分析装置(MALDI-TOF MS)又はLC/MS(ESI-Q)にて反応を追跡した。
(1)リン酸緩衝液(10mM,pH7.4)中のAβ1-42(20μM)を37℃で0、1、3、6時間インキュベートして調製した4種類の凝集Aβ1-42それぞれにチオフラビンTを加え、この蛍光強度を測定した。また、原子間力顕微鏡を用いて形状を解析した。
その結果、図9aに示すように、インキュベートしなかったもの(0時間)に対しては蛍光を示さなかったが、1、3、6時間インキュベートしたものに対してはいずれについても蛍光を示し、インキュベート時間が長いほうがより強い蛍光を示した。また、インキュベートしなかったもの(0時間)は凝集が観測されなかったが、1、3、6時間インキュベートしたものについてはそれぞれオリゴマー(1時間)、前原線維(3時間)及び強硬な線維(6時間)が観測された。
酸素化強度率(%)の増加は、(凝集Aβ1-42の酸素化強度率(37℃、所定時間インキュベート))-(凝集Aβ1-42の酸素化強度率(37℃、0時間インキュベート))で算出した。
酸素化強度率(%)は、(酸素付加体の強度の合計)/((非酸素付加体(Native)の強度)+(酸素付加体の強度の合計))で算出した。
(1)リン酸緩衝液(10mM,pH7.4)中のAβ1-42(20μM)を0℃(サンプルE)及び室温(サンプルF)で24時間インキュベートして調製した2種類のAβ1-42それぞれについて、原子間力顕微鏡を用いてサイズ分布を解析した。
その結果、図10aに示すように、0℃及び室温でインキュベートして調製したAβ1-42のいずれについても均一なオリゴマーが観測された。尚、室温でインキュベートして調製したAβ1-42オリゴマーのほうがより大きなサイズのオリゴマーが観測された。
その結果、図10bに示すように、0℃及び室温でインキュベートして調製したAβ1-42オリゴマーのいずれについても蛍光を示し、化合物(1a)がAβ1-42オリゴマーに結合していることが明らかとなった。また、室温でインキュベートして調製したAβ1-42オリゴマーのほうがより強い蛍光を示した。
酸素化強度率(%)は、(酸素付加体の強度の合計)/((非酸素付加体(Native)の強度)+(酸素付加体の強度の合計))で算出した。
その結果、図10cに示すように、0℃及び室温でインキュベートして調製したAβ1-42オリゴマーのいずれについても、化合物(1a)が酸素化できることが明らかとなった。また、室温でインキュベートして調製したAβ1-42オリゴマーのほうがより大きな酸素化強度を示した。
その結果、図10dに示すように、0℃及び室温でインキュベートして調製したAβ1-42オリゴマーのいずれについてもNativeと比較して弱い蛍光強度を示し、化合物(1a)がAβ1-42オリゴマーのクロスβ構造の増加を抑えていることが明らかとなった。また、線維化も同様に抑えられていた。
(1)25mM塩酸溶液中のインスリン(400μM)を60℃で撹拌(1000rpm)しながらインキュベートして調製した非凝集(0時間インキュベート)及び凝集(12時間インキュベート)インスリン(160μM)を含む中性緩衝液に、化合物(1a)(20μM)を加え、LED照射下(波長500nm)、37℃で30分インキュベートした後、質量分析装置(MALDI-TOF MS)にて反応を追跡した。
その結果、図11aに示すように、非凝集インスリンでは酸素化の進行は認められず、凝集インスリンにおいては酸素化の進行が観察された。尚、光照射を行わなかった場合、凝集インスリンの酸素化は観測されなかった。
その結果、図11bに示すように、非凝集β2ーミクログロブリンでは酸素化の進行は認められず、凝集β2ーミクログロブリンの酸素化が観察された。尚、光照射を行わなかった場合は、凝集β2ーミクログロブリンの酸素化は観測されなかった。
その結果、図11c~図11eに示すように、非凝集ランスサイレチンでは酸素化の進行は認められず、凝集トランスサイレチンの酸素化が観察された。尚、光照射を行わなかった場合は、凝集トランスサイレチンの酸素化は観測されなかった。
その結果、図11f及び図11gに示すように、非凝集αーシヌクレインでは酸素化の進行は認められず、凝集αーシヌクレインの酸素化が観察された。尚、光照射を行わなかった場合は、凝集αーシヌクレインの酸素化は観測されなかった。
(1)ヌクレオシドホスホリラーゼ(0.1mg/mL)を含むリン酸緩衝液(10mM,pH7.4)を60℃でインキュベートし蛍光アッセイキット(Protein Stability and Aggregation Assay Kit(ProFoldin、Hudson、MO、USA))を用いて熱凝集度を追跡した。
その結果、図12aに示すように、ヌクレオシドホスホリラーゼを含むリン酸緩衝液をインキュベートしたところ、時間経過に伴いキットの蛍光強度(熱凝集度)の増加が観測された。0時間及び1時間インキュベートして調製したものをそれぞれ非凝集及び凝集ホスホリラーゼとして酸素化反応解析に用いた。
ヌクレオシドホスホリラーゼ(0.1mg/mL)を含むリン酸緩衝液(10mM,pH7.4)を60℃でインキュベートして調製した非凝集(0時間インキュベート)及び凝集(1時間インキュベート)ヌクレオシドホスホリラーゼに、リボフラビン(4μM)又は化合物(1a)(4μM)を加え、LED照射下(波長500nm)、室温で10分インキュベートした後、エンドプロテイナーゼ(Lys-C)で消化し、質量分析装置(MALDI-TOF MS)にて反応を追跡した。
それぞれの酸素化率の比は、(凝集Aβ1-42の酸素化強度率)/(非凝集Aβ1-42の酸素化強度率)及び(凝集ヌクレオシドホスホリラーゼの酸素化強度率)/(非凝集ヌクレオシドホスホリラーゼの酸素化強度率)として算出した。
非凝集及び凝集ヌクレオシドホスホリラーゼにリボフラビン及び化合物(1a)を添加し、生理的条件下(pH7.4、室温)光照射を行ったところ、リボフラビンを用いた場合の酸素化率比は1.4程度であり、化合物(1a)を用いた場合の酸素化率比は1.2程度であった。
L-アスコルビン酸(500μM)を含む培養培地に、化合物(1a)(20μM)又はリボフラビン(4μM)を加え、LED照射下(波長500nm)、37℃で30分インキュベートした後、質量分析装置(LC-MSMS)にて反応を追跡した。
その結果、図13に示すように、L-アスコルビン酸に化合物(1a)(4.0mmol%)又はリボフラビン(0.8mmol%)を添加し、光照射を行ったところ、化合物(1a)を用いた場合にL-アスコルビン酸は100%残存していた。一方で、リボフラビンを用いた場合はL-アスコルビン酸は完全に消失していた。
この結果から、本発明化合物は、単に光照射を受けただけでは酸化作用を示さず、アミロイド凝集のようなクロスβシート構造に結合して初めて酸化作用を示すことが明らかになった。
Claims (13)
- R1、R2、R3及びR4における炭化水素基に置換し得る基が、同一又は異なって、ハロゲン原子、アミノ基、ニトロ基、シアノ基、アルコキシ基、アシル基、カルボキシル基、アルコキシカルボニル基、芳香族炭化水素基及び複素環式基から選ばれる1~3個である請求項1記載のベンゾチアゾール化合物。
- R1が、炭素数1~12のアルキル又はアルケニル基である請求項1又は2記載のベンゾチアゾール化合物。
- R1が、炭素数1~12のアルキル基である請求項1~3のいずれか1項に記載のベンゾチアゾール化合物。
- R3が、水素原子又は炭素数1~12のアルキル又はアルケニル基である請求項1~4のいずれか1項に記載のベンゾチアゾール化合物。
- R3が、水素原子である請求項1~5のいずれかに記載のベンゾチアゾール化合物。
- R2が、R4と一緒になってC2-C4アルキレン基を形成するか、あるいは炭素数1~12のアルキル又はアルケニル基(このアルキル又はアルケニル基には、カルボキシル基、アルコキシカルボニル基、アミノ-CO基又はジペプチド-ヘキサペプチド-CO-基が置換し、このアミノ酸、ジペプチド~ヘキサペプチドにはさらにC6-14アリール基及びアルコキシカルボニル基から選ばれる1~2個が置換していてもよい。)である請求項1~6のいずれか1項に記載のベンゾチアゾール化合物。
- 請求項1~7のいずれにか1項に記載のベンゾチアゾール化合物を有効成分とする医薬。
- 病原性アミロイドが関与する疾患の予防又は治療薬である請求項8記載の医薬。
- 請求項1~7のいずれか1項に記載のベンゾチアゾール化合物及び薬学的に許容される担体を含有する医薬組成物。
- 病原性アミロイドが関与する疾患の予防又は治療に使用するための請求項1~7のいずれか1項に記載の化合物。
- 病原性アミロイドが関与する疾患の予防又は治療薬製造のための請求項1~7のいずれか1項に記載の化合物の使用。
- 請求項1~7のいずれか1項に記載の化合物を投与することを特徴とする病原性アミロイドが関与する疾患の予防又は治療方法。
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JP2016534476A JP6562361B2 (ja) | 2014-07-16 | 2015-07-15 | ベンゾチアゾール化合物及びこれを含有する医薬 |
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WO2016143699A1 (ja) * | 2015-03-06 | 2016-09-15 | 国立研究開発法人科学技術振興機構 | ジピリンホウ素錯体及びこれを含有する医薬 |
WO2017164172A1 (ja) * | 2016-03-22 | 2017-09-28 | 国立研究開発法人科学技術振興機構 | クルクミンホウ素錯体及びこれを含有する医薬 |
WO2021145368A1 (ja) * | 2020-01-14 | 2021-07-22 | 国立大学法人 東京大学 | フェノチアジン骨格を有する光酸素化触媒化合物及びこれを含有する医薬 |
JP6950067B1 (ja) * | 2020-10-15 | 2021-10-13 | ユシロ化学工業株式会社 | 光触媒組成物、光触媒組成物溶液、光触媒部材、光触媒組成物の使用方法、及び空間除菌方法 |
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WO2016143699A1 (ja) * | 2015-03-06 | 2016-09-15 | 国立研究開発法人科学技術振興機構 | ジピリンホウ素錯体及びこれを含有する医薬 |
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CN108884112B (zh) * | 2016-03-22 | 2021-03-02 | 国立研究开发法人科学技术振兴机构 | 姜黄素硼配合物和含有该姜黄素硼配合物的药物 |
WO2021145368A1 (ja) * | 2020-01-14 | 2021-07-22 | 国立大学法人 東京大学 | フェノチアジン骨格を有する光酸素化触媒化合物及びこれを含有する医薬 |
JP6950067B1 (ja) * | 2020-10-15 | 2021-10-13 | ユシロ化学工業株式会社 | 光触媒組成物、光触媒組成物溶液、光触媒部材、光触媒組成物の使用方法、及び空間除菌方法 |
JP2022065439A (ja) * | 2020-10-15 | 2022-04-27 | ユシロ化学工業株式会社 | 光触媒組成物、光触媒組成物溶液、光触媒部材、光触媒組成物の使用方法、及び空間除菌方法 |
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EP3170820B1 (en) | 2019-02-20 |
EP3170820A4 (en) | 2017-12-06 |
JP6562361B2 (ja) | 2019-08-21 |
JPWO2016010092A1 (ja) | 2017-06-15 |
US20170197956A1 (en) | 2017-07-13 |
EP3170820A1 (en) | 2017-05-24 |
US9932333B2 (en) | 2018-04-03 |
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