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WO2018101434A1 - Dérivé de chlorine e6 glycosylé ou son sel pharmaceutiquement acceptable, composition pharmaceutique, procédé de destruction de cible, et procédé de production d'un dérivé de chlorine e6 glycosylé ou d'un sel pharmaceutiquement acceptable de celui-ci - Google Patents

Dérivé de chlorine e6 glycosylé ou son sel pharmaceutiquement acceptable, composition pharmaceutique, procédé de destruction de cible, et procédé de production d'un dérivé de chlorine e6 glycosylé ou d'un sel pharmaceutiquement acceptable de celui-ci Download PDF

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WO2018101434A1
WO2018101434A1 PCT/JP2017/043144 JP2017043144W WO2018101434A1 WO 2018101434 A1 WO2018101434 A1 WO 2018101434A1 JP 2017043144 W JP2017043144 W JP 2017043144W WO 2018101434 A1 WO2018101434 A1 WO 2018101434A1
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chlorin
derivative
group
acceptable salt
pharmaceutically acceptable
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PCT/JP2017/043144
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English (en)
Japanese (ja)
Inventor
矢野　重信
洋望 片岡
裕忠 西江
卓志 城
圭介 福本
仲野　靖浩
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公立大学法人名古屋市立大学
矢野　重信
富士フイルム株式会社
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Priority to JP2018554260A priority Critical patent/JP7003057B2/ja
Publication of WO2018101434A1 publication Critical patent/WO2018101434A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/02—Acyclic radicals, not substituted by cyclic structures
    • C07H15/14—Acyclic radicals, not substituted by cyclic structures attached to a sulfur, selenium or tellurium atom of a saccharide radical

Definitions

  • the present invention is a glycosylated chlorin e6 derivative, or a pharmaceutically acceptable salt thereof, that can be suitably used in photodynamic therapy (PDT) and / or photodynamic diagnosis (PDD). Relating to salt.
  • the present invention also relates to a pharmaceutical composition, a method for destroying a target, and a method for producing a glycosylated chlorin e6 derivative, or a pharmaceutically acceptable salt thereof.
  • Photodynamic therapy involves administering a photosensitive substance to a patient having a target diseased tissue (hereinafter also referred to as “target tissue”), and the target tissue (cancer tissue, tumor tissue, skin lesion, and This is a treatment method that selectively destroys only a target tissue by irradiating light having an appropriate wavelength for exciting the photosensitive substance after the photosensitive substance is accumulated in the neovascularization.
  • target tissue a target diseased tissue
  • cancer tissue tumor tissue
  • skin lesion skin lesion
  • hematoporphyrin derivative for example, Photofrin (registered trademark)
  • Photofrin registered trademark
  • hematoporphyrin derivatives are known to cause temporary photosensitivity as a side effect when administered to the human body.
  • the selectivity of hematoporphyrin derivatives for cancer tissues is not sufficient, and accumulation in normal tissues is also observed. Therefore, the patient who received the drug is dark for a long time until it is excreted outside the body so that normal cells are not destroyed by the photosensitizing action of hematoporphyrin derivative (porfimer sodium) accumulated in normal tissues. It is necessary to stay in place.
  • phthalocyanine compounds having absorption in a longer wavelength region 650 nm to 800 nm
  • chlorin compounds, and the like have been proposed as second-generation drugs.
  • talaporfin sodium hereinafter also referred to as “TS” in the present specification, Rezaphyrin (registered trademark)
  • TS talaporfin sodium
  • Rezaphyrin registered trademark
  • Patent Document 1 proposes a compound obtained by binding chlorin e6, which is a chlorin compound, and folic acid.
  • Patent Document 2 proposes a compound in which a chlorin compound and galactosamine are bound to detect a galectin biomarker.
  • Non-Patent Document 1 synthesizes a compound in which a sugar is bound to a chlorin compound labeled with 124 iodine, and proposes to PET (Positron Emission Tomography) imaging and photodynamic therapy.
  • an object of the present invention is to provide a glycosylated chlorin e6 derivative or a pharmaceutically acceptable salt thereof that has excellent tumoricidal properties (phototoxicity) and excellent tumor tissue growth inhibitory effect.
  • Another object of the present invention is to provide a pharmaceutical composition, a method for destroying a target, and a method for producing a glycosylated chlorin e6 derivative, or a pharmaceutically acceptable salt thereof.
  • the present inventors have become a photosensitive substance useful as a photodynamic therapeutic drug, ensuring safety to the living body and exhibiting high phototoxicity in a small amount.
  • the present inventors have found a novel glycosylated chlorin e6 derivative and a method for producing the same, and have reached the present invention.
  • R 1 , R 2 and R 3 are each independently an acetoxyalkyl group having 1 to 6 carbon atoms or a hydrocarbon group having 1 to 6 carbon atoms, [1 Or a pharmaceutically acceptable salt thereof.
  • R 1 , R 2 and R 3 in the general formula (1) described later are methyl groups, or a pharmaceutically acceptable salt thereof Salt.
  • —X— is —X 3 —O—
  • X 3 is a group bonded to an anomeric carbon atom of R or a group bonded to a carbon atom adjacent to the anomeric carbon atom.
  • Glycosylated chlorin e6 derivative or a pharmaceutically acceptable salt thereof.
  • X 4 is an alkylene group represented by — (CH 2 ) n —, and n is an integer of 3 to 10. Or a pharmaceutically acceptable salt thereof.
  • the saccharide is any one of [1] to [9], wherein the saccharide is a monosaccharide, an oligosaccharide, a polysaccharide, a monosaccharide containing an amino group, an oligosaccharide containing an amino group, or a polysaccharide containing an amino group.
  • the glycosylated chlorin e6 derivative or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition comprising as an active ingredient.
  • a pharmaceutical composition comprising the glycosylated chlorin e6 derivative according to any one of [1] to [13] or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the glycosylated chlorin e6 derivative or a pharmaceutically acceptable salt thereof (hereinafter also simply referred to as “the present chlorin derivative”) according to an embodiment of the present invention has very low toxicity in the dark, In vitro and in vivo, the target virus, bacteria, or these infected cells, tumor cells, or After contacting with a tumorous tissue, irradiation with light having a wavelength that is absorbed by the present chlorin derivative or the like can be applied to destroy the target. Therefore, the present chlorin derivative and the like can be used as a medicament containing the present chlorin derivative or the like as an active ingredient, particularly as a photodynamic therapeutic agent for tumors or skin diseases, or a photodynamic diagnostic agent.
  • glycosylated chlorin e6 derivative and its production method
  • a glycosylated chlorin e6 derivative may be described as an example, but the description is pharmaceutically acceptable for the glycosylated chlorin e6 derivative unless otherwise specified.
  • X 1 and X 2 are each independently a group represented by H (hydrogen atom) or R—X— * (* represents a bonding position), and X 1 and At least one of X 2 is a group represented by R—X— *. Synthesis is easier viewpoint, i.e., from the viewpoint of having superior productivity, it is preferable that either one of X 1 and X 2 is a group represented by R-X- *, X 1 is More preferably, it is a group represented by R—X— *, and X 2 is H (hydrogen atom).
  • R represents a sugar residue (hereinafter referred to as “sugar residue”).
  • sugar residue means a residue obtained by removing one hydroxyl group bonded to a carbon atom of the sugar, and a residue obtained by removing a hemiacetal (anomeric) hydroxyl group of a sugar is preferable.
  • X is a divalent group bonded to any one of the carbon atoms constituting R, and R is C (carbon atom), N (nitrogen atom), O (oxygen atom), H (hydrogen atom), And a linear or branched divalent group consisting of at least one atom selected from the group consisting of S and sulfur (sulfur atom).
  • X is, for example, —S—, —O—, —NR x — (R x is a hydrogen atom or a hydrocarbon group which may have a hetero atom), a carbonyl group, an alkylene group, an alkenylene group, and And a combination thereof, preferably containing O (oxygen atom) and / or S (sulfur atom), and selected from the group consisting of —S—, —O—, and an alkylene group A group in which the above is combined is more preferable, and a group in which —S—, —O—, and an alkylene group are combined is more preferable.
  • the sugar of R is not particularly limited.
  • aldpentose ribose, arabinose, xylose, lyxose, etc.
  • aldohexose allose, altrose, glucose, mannose, gulose, idose, galactose, talose, etc.
  • Aldoheptose ketopentose (such as ribulose and xylulose), ketohexose (such as psicose, fructose, sorbose, and tagatose), ketoheptose (such as cedoheptulose and coliose), and derivatives thereof having an amino group, etc.
  • Monosaccharides Oligosaccharides such as sucrose, maltose, lactose, maltotriose, raffinose and maltotetraose, and derivatives thereof having an amino group; And polysaccharides such as starch, amylose and glycogen, and derivatives thereof having an amino group; Among these, monosaccharides are preferable, hexose or hexosamine is more preferable, hexose is more preferable, and glucose is particularly preferable.
  • the monosaccharide may be D-form or L-form, but D-form is preferred.
  • oligosaccharide means a compound containing 2 to 9 monosaccharide units
  • polysaccharide means a compound containing 10 or more monosaccharide units
  • the monosaccharides that are glycosidically linked may be the same or different.
  • the glycosidic bond between monosaccharides may be an ⁇ -bond or a ⁇ -bond.
  • hexose examples include glucose, galactose, mannose, allose, altrose, gulose, idose, and talose.
  • glucose is most preferable. This is because the phototoxicity of glucose is excellent.
  • hexosamine examples include glucosamine, galactosamine, mannosamine, daunosamine, and perosamine. Of these, glucosamine is most preferable. This is because the phototoxicity of glucosamine is excellent.
  • R 1 , R 2 and R 3 are each independently H (hydrogen atom), an acetoxyalkyl group having 1 to 6 carbon atoms or a hydrocarbon group having 1 to 6 carbon atoms, and R 1 , R 2 and R 3 are each an acetoxyalkyl group having 1 to 6 carbon atoms or a hydrocarbon group having 1 to 6 carbon atoms.
  • examples of the acetoxyalkyl having 1 to 6 carbon atoms include acetoxymethyl, acetoxyethyl, acetoxypropyl, and acetoxybutyl.
  • the hydrocarbon having 1 to 6 carbon atoms is a straight chain having 1 to 6 carbon atoms such as methyl, ethyl, n-propyl, n-butyl, sec-butyl, tert-butyl, pentyl, cyclopentyl, hexyl, and cyclohexyl. Examples include chain, branched chain, or cyclic alkyl.
  • R 1 , R 2 and R 3 are each independently an acetoxyalkyl group having 1 to 6 carbon atoms or 1 carbon atom in that a glycosylated chlorin e6 derivative having a better effect of the present invention can be obtained. It is preferably a hydrocarbon group of ⁇ 6. It is because the uptake
  • R 1 , R 2 and R 3 are each independently preferably a hydrocarbon group having 1 to 3 carbon atoms, more preferably a methyl group, from the viewpoint of water solubility.
  • the divalent group (linking group) X preferably contains O (oxygen atom), and O and S (sulfur atoms) ) Is more preferable.
  • the group represented by R—X— * includes a group represented by R—X 3 —O— * in that a glycosidated chlorin e6 derivative having a better effect of the present invention can be obtained.
  • X 3 is a linear or branched divalent group consisting of at least one selected from the group consisting of C, N, O, H, and S, and constitutes R It is bonded to any one of the carbon atoms.
  • the glycosylated chlorin e6 derivative is preferably represented by the following formula (2).
  • the form of the sugar residue R is as already described as R in the formula (1).
  • the group represented by R—X 3 —O— * is a group represented by R—L—S—X 4 —O— * in that a glycosidated chlorin e6 derivative having an excellent effect of the present invention can be obtained.
  • More preferred are the groups Here, L represents a single bond or a divalent group. Although it does not restrict
  • the group represented by R—X— * is a group represented by R—S—X 4 —O— *, in other words, the sugar residue R is directly linked to —S—X 4 —O—.
  • the groups are preferred.
  • the direct linkage refers to, for example, a structure (—C—S—X 4 —O—) in which C (carbon atom) at the anomeric position of a sugar and —S—X 4 —O— are linked.
  • S (sulfur atom) in the group represented by R—S—X 4 —O— * is a linking group bonded to the anomeric carbon atom of R (carbon atom at position 1), or the anomeric position from the viewpoint of synthesis.
  • a linking group bonded to a carbon atom adjacent to the carbon atom (2-position carbon atom) is preferable, and a linking group bonded to the anomeric carbon atom (1-position carbon atom) of R is more preferable.
  • X 4 is bonded to O (oxygen atom) and S (sulfur atom).
  • X 4 is a linear or branched divalent group having C (carbon atom) and H (hydrogen atom).
  • X 4 is not particularly limited, and examples thereof include an alkylene group, an oxyalkylene group, and an alkyleneoxy group. Among these, a linear or branched alkylene group having 1 to 16 carbon atoms may be used.
  • a linear alkylene group represented by — (CH 2 ) n— is more preferable.
  • n is preferably an integer of 1 to 16, more preferably n is an integer of 2 to 13, and further preferably n is an integer of 3 to 10. This is because the synthesis is easy and the water solubility of the compound is increased.
  • glycosylated chlorin e6 derivative is preferably represented by the following formula (4), (5), or (6) from the viewpoint of having particularly excellent effects of the present invention.
  • n represents an integer of 3 to 10, respectively.
  • glycosylated chlorin e6 derivative may be used alone, or two or more kinds may be used in combination.
  • Pharmaceutically acceptable salts include alkali metal salts (such as sodium and potassium salts), alkaline earth metal salts (such as magnesium and calcium salts), ammonium salts, mono-, di- or tri -Lower (alkyl or hydroxyalkyl) ammonium salts (eg ethanolammonium salt, diethanolammonium salt, triethanolammonium salt, tromethamine salt), hydrochloride, hydrobromide, hydroiodide, nitrate, phosphate, Sulfate, formate, acetate, citrate, oxalate, fumarate, maleate, succinate, malate, tartrate, trichloroacetate, trifluoroacetate, methanesulfonate, Benzene sulfonate, p-toluene sulfonate, mesitylene sulfonate and naphthalene Sulfonic acid salts.
  • the salt may be an anhydride or a solv
  • the present chlorin derivative having the above-described configuration does not show cytotoxicity in the dark, but shows strong cytotoxicity under light irradiation. And it is estimated that the absorption in a long wavelength is large compared with a porphyrin derivative (absorption maximum wavelength 650nm), and the compound has high cell affinity and / or cell permeability by the coupling
  • the method for producing a chlorin derivative or the like includes a step of linking chlorin e6 and a sugar via a linking group (glycosidation). More specifically, it includes a step of glycosylation by binding a 3-position double bond of chlorin e6 alkyl ester and a sugar via a linking group.
  • the procedure for binding the linking group may be to link the sugar and the linking group and then link to chlorin e6.
  • the linking group and chlorin e6 may be combined and then linked to the saccharide, depending on the purpose.
  • the manufacturing method may be selected.
  • the thiol sugar (R-SH) has a functional group that can be linked to the thiol sugar, such as a leaving group (E) such as a halogen, a tosyl group, and a mesyl group, and a hydroxyl group (-OH).
  • a linking group (EX 4 —OH) is introduced.
  • the sugar residue R of the thiol sugar (R-SH) used here is preferably protected with a protecting group such as an acyl group.
  • a protecting group such as an acyl group.
  • Protecting groups include acetyl and aliphatic acyl groups such as pivaloyl; aromatic acyl groups such as benzoyl group; and aralkyl groups such as benzyl group. Of these protecting groups, an acetyl group is particularly preferred.
  • Examples of the linking group (EX 4 —OH) linked to the thiol sugar (R—SH) include chloroalcohol, bromoalcohol, iodoalcohol, tosylalcohol, and mesylalcohol.
  • the solvent used in this reaction is not particularly limited as long as the reaction proceeds.
  • aromatic amines such as pyridine, lutidine, and quinoline; dichloromethane, chloroform, 1,2-dichloroethane, and carbon tetrachloride Halogenated hydrocarbons such as hexane, pentane, and cyclohexane; aromatic hydrocarbons such as benzene, toluene, xylene, and chlorobenzene; diethyl ether, diisopropyl ether, diphenyl ether, tetrahydrofuran, And ethers such as dioxane and 1,2-dimethoxyethane; amides such as N, N-dimethylformamide and N, N-dimethylacetamide; water; and mixtures thereof.
  • a particularly preferred solvent for the above reaction is chloroform or dichloromethane.
  • a base for example, basic salts such as sodium carbonate, potassium carbonate, and cesium carbonate; inorganic bases such as sodium hydroxide and potassium hydroxide; pyridine, lutidine, etc.
  • Aromatic amines such as: triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, and N-methylmorpholine Tertiary amines; Sodium hydrides and alkali metal hydrides such as potassium hydride; Metal amides such as sodium amide, lithium diisopropylamide and lithium hexamethyldisilazide; Sodium methoxide and sodium ethoxy Do And metal alkoxides such as potassium tert- butoxide; is selected from the like.
  • the final product obtained by this reaction can be isolated and purified from the reaction mixture by
  • chlorin e6 trimethyl ester hydrogen halide adduct is obtained by adding hydrogen halide to the double bond at the 3-position in the porphyrin ring 1-24 number method with respect to chlorin e6 trimethyl ester.
  • the hydrogen halide used include hydrogen chloride, hydrogen bromide, and hydrogen iodide.
  • hydrogen bromide is preferable from the viewpoint of the reactivity and stability of the chlorin e6 trimethyl ester hydrogen halide adduct.
  • the solvent used in this reaction is not particularly limited as long as the reaction proceeds, but formic acid, acetic acid, propionic acid and the like can be mentioned.
  • the resulting chlorin e6 trimethyl ester hydrogen halide adduct is allowed to act on a thiol sugar linking group conjugate (RS—X 4 —OH) to give a thiol sugar linking group conjugate (RS—X 4 —OH).
  • a chlorin e6 trimethyl ester hydrohalide to give a sugar-linked chlorin e6 trimethyl ester.
  • the thiol sugar linking group conjugate (RS—X 4 —OH) added in the above reaction is preferably added in an amount of 3 equivalents or more with respect to the chlorin e6 trimethyl ester hydrogen halide adduct. This is because the yield of sugar-linked chlorin e6 trimethyl ester is improved.
  • a base for example, basic salts such as sodium carbonate, potassium carbonate, and cesium carbonate; inorganic salts such as sodium hydroxide and potassium hydroxide; pyridine, and Aromatic amines such as lutidine; triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, and N-methylmorpholine Tertiary amines such as sodium hydride and alkali metal hydrides such as potassium hydride; metal amides such as sodium amide, lithium diisopropylamide and lithium hexamethyldisilazide; sodium methoxide, Sodium etoki De, and it is selected from metal alkoxides such as potassium tert- butoxide.
  • basic salts such as sodium carbonate, potassium carbonate, and cesium carbonate
  • the solvent used in this reaction is not particularly limited as long as the reaction proceeds.
  • aromatic amines such as pyridine, lutidine, and quinoline
  • Halogenated hydrocarbons such as hexane, pentane, and cyclohexane
  • aromatic hydrocarbons such as benzene, toluene, xylene, and chlorobenzene
  • amides such as N, N-dimethylformamide and N, N-dimethylacetamide, or a mixture of two or more of these.
  • Particularly preferred solvents for the above reaction are dichloromethane, chloroform and mixtures thereof from the viewpoint of reactivity.
  • the final product obtained by this reaction can be isolated and purified from the reaction mixture by known means such as concentration, solvent extraction, fractional distillation, crystallization, recrystallization, and chromatography.
  • the chlorin e6 trimethyl ester has a functional group capable of being linked to a sugar, for example, a linking group (E) having a leaving group (E) such as a halogen, a tosyl group, and a mesyl group, and a hydroxyl group (—OH).
  • a linking group (E) having a leaving group (E) such as a halogen, a tosyl group, and a mesyl group, and a hydroxyl group (—OH).
  • a chlorin e6 trimethyl ester hydrogen halide adduct is obtained by adding a hydrogen halide to the double bond at the 3-position in the porphyrin ring 1-24 number method.
  • the hydrogen halide used include hydrogen chloride, hydrogen bromide, and hydrogen iodide.
  • hydrogen bromide is preferable from the viewpoint of the reactivity and stability of the chlorin e6 trimethyl ester hydrogen halide adduct.
  • the solvent used in this reaction is not particularly limited as long as the reaction proceeds, and formic acid, acetic acid, propionic acid and the like can be mentioned.
  • the linking group (EX 4 -OH) added in the above reaction is preferably added in an amount of 10 equivalents or more with respect to the chlorin e6 trimethyl ester hydrogen halide adduct. This is because the yield of the linking group-bound chlorin e6 trimethyl ester is improved.
  • a base for example, basic salts such as sodium carbonate, potassium carbonate, and cesium carbonate; inorganic bases such as sodium hydroxide and potassium hydroxide; pyridine, lutidine, etc.
  • Aromatic amines such as: triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, and N-methylmorpholine Tertiary amines; Sodium hydrides and alkali metal hydrides such as potassium hydride; Metal amides such as sodium amide, lithium diisopropylamide and lithium hexamethyldisilazide; Sodium methoxide and sodium ethoxy Do And it is selected from metal alkoxides such as potassium tert- butoxide.
  • the solvent used in this reaction is not particularly limited as long as the reaction proceeds.
  • aromatic amines such as pyridine, lutidine, and quinoline
  • Halogenated hydrocarbons such as hexane, pentane, and cyclohexane
  • aromatic hydrocarbons such as benzene, toluene, xylene, and chlorobenzene
  • amides such as N, N-dimethylformamide and N, N-dimethylacetamide; and mixtures of two or more of these.
  • Particularly preferred solvents for the above reaction are dichloromethane, chloroform and mixtures thereof from the viewpoint of reactivity.
  • the final product obtained by this reaction can be isolated and purified from the reaction mixture by known means such as concentration, solvent extraction, fractional distillation, crystallization, recrystallization, and chromatography.
  • a thiol sugar (R-SH) is introduced into the linking group-bound chlorin e6 trimethyl ester.
  • thiol sugar As the thiol sugar (R-SH) used here, it is preferable to use a sugar in which a hydroxyl group in the sugar is protected with a protecting group such as an acyl group.
  • a protecting group such as an acyl group.
  • the protecting group include an acetyl group and an aliphatic acyl group such as a pivaloyl group; an aromatic acyl group such as a benzoyl group; an aralkyl group such as a benzyl group; Of these protecting groups, an acetyl group is particularly preferred.
  • the solvent used in this reaction is not particularly limited as long as the reaction proceeds.
  • aromatic amines such as pyridine, lutidine, and quinoline; dichloromethane, chloroform, 1,2-dichloroethane, and carbon tetrachloride
  • Halogenated hydrocarbons such as hexane, pentane, and cyclohexane
  • aromatic hydrocarbons such as benzene, toluene, xylene, and chlorobenzene
  • diethyl ether, diisopropyl ether, diphenyl ether, tetrahydrofuran Examples thereof include ethers such as dioxane and 1,2-dimethoxyethane; amides such as N, N-dimethylformamide and N, N-dimethylacetamide; water; a mixture of two or more of these.
  • Particularly preferred solvents for the above reaction are chloroform and dichloromethane.
  • a base for example, basic salts such as sodium carbonate, potassium carbonate and cesium carbonate; inorganic bases such as sodium hydroxide and potassium hydroxide; pyridine, lutidine and the like Aromatic amines; triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, etc.
  • Tertiary amines alkali metal hydrides such as sodium hydride and potassium hydride; metal amides such as sodium amide, lithium diisopropylamide and lithium hexamethyldisilazide; sodium methoxide, sodium ethoxide , And metal alkoxides such as potassium tert- butoxide; is selected from the like.
  • the final product obtained by this reaction can be isolated and purified from the reaction mixture by known means such as concentration, solvent extraction, fractional distillation, crystallization, recrystallization, and chromatography.
  • the protecting group is then eliminated and removed by alkali treatment or the like.
  • the protecting group is an acyl group, it may be hydrolyzed by adding an alkaline solution.
  • alkali metals such as sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, and potassium tert-butoxide in dichloromethane, methanol, ethanol, tetrahydrofuran, or a mixed solvent thereof
  • the protecting group is removed by treating the protected compound with an alkali such as an alkoxide.
  • the protecting group is an aralkyl group
  • it can be removed by hydrogenation using a palladium catalyst.
  • Deprotecting the hydroxyl group of the sugar residue R further promotes the transfer of the present chlorin derivative and the like into the cell, and is superior in cytotoxicity.
  • This chlorin derivative, etc. does not show cytotoxicity in the dark, but makes use of the fact that it exhibits strong cytotoxicity under irradiation with light, so that it is brought into contact with the target biological material in vitro or in vivo in the dark. It can be used for the purpose of destroying the target by irradiating with light having an absorption wavelength such as the present chlorin derivative after incorporation into the cell.
  • examples of the target include a target selected from the group consisting of viruses, microorganisms and their infected cells, tumor cells, tumorous tissues, and neovascularization. Therefore, it can be used for tumor destruction.
  • the present chlorin derivative and the like can be used as a therapeutic agent for cancer classified as a malignant tumor.
  • the malignant tumor include an epithelial malignant tumor and a malignant tumor having a non-epithelial tissue classified as a sarcoma as a development base.
  • the present chlorin derivative is particularly useful for the treatment of solid tumors in which tumor cells grow massively and solidly, and surface cancers that reach light, among tumor cells.
  • Specific examples include esophageal cancer, lung cancer, gastric cancer, cervical cancer, uterine cancer such as uterine cancer, skin cancer, prostate cancer, and kidney cancer.
  • Skin cancer includes primary (squamous cell carcinoma, basal cell carcinoma, and epidermis cancer), as well as skin metastasis of visceral cancer.
  • the present chlorin derivative has an affinity for benign tumors among tumor cells, photodynamics of skin diseases such as actinic keratosis, severe acne, and skin psoriasis can be obtained by local administration. It can also be used as a therapeutic drug and as a photodynamic therapeutic drug for eye diseases such as age-related macular degeneration.
  • the glycosylated chlorin e6 derivative of the present invention can be used for diagnosis of cancer in combination with PET or the like. Furthermore, the glycosylated chlorin derivative of the present invention can also be used for tumor detection by utilizing its tumor accumulation property and affinity for benign tumors.
  • the present chlorin derivative and the like can be applied to the method for destroying the above target.
  • the method for destroying a target according to an embodiment of the present invention includes a step of irradiating the target with light having a wavelength absorbed by the chlorin derivative or the like after contacting the target with the chlorin derivative or the like.
  • the said method can be implemented in a human individual and a non-human individual. That is, the method for destroying the target can be carried out in a human individual, and can be carried out in a form other than that in a human individual.
  • a pharmaceutical composition according to an embodiment of the present invention is for photodynamic treatment of tumors, skin diseases, eye diseases or age-related macular degeneration, and contains the glycosylated chlorin e6 derivative as an active ingredient. In particular, it has a better effect for photodynamic therapy of tumors.
  • the glycosylated chlorin e6 derivative which is an active ingredient, has excellent water solubility, excellent cell permeability, and high phototoxicity. Therefore, it is a drug for photodynamic treatment of tumors (particularly solid cancer). Can be suitably used.
  • the pharmaceutical composition can be administered by catheter, intravenous or intramuscular injection, and can be administered by other parenteral routes. Moreover, it may be a creamy pharmaceutical composition and can be administered transdermally. In addition, it can be locally injected directly into the tumor tissue deep inside the body.
  • the present pharmaceutical composition contains the present chlorin derivative and the like, it may contain other components as necessary.
  • other components include excipients.
  • Excipients include, for example, lactose, kaolin, sucrose, crystalline cellulose, corn starch, talc, agar, pectin, stearic acid, magnesium stearate, lecithin, and sodium chloride as solids, Examples thereof include glycerin, peanut oil, polyvinyl pyrrolidone, olive oil, ethanol, benzyl alcohol, propylene glycol, and water.
  • this pharmaceutical composition can be used as necessary, including bases, surfactants, preservatives, emulsifiers, colorants, flavoring agents, fragrances, stabilizers, preservatives, antioxidants, An agent, an antibacterial agent, a solubilizing agent, a suspending agent, a binder, and a disintegrating agent may be contained.
  • the dosage form of the pharmaceutical composition is not particularly limited, and examples thereof include tablets, powders, granules, capsules, troches, syrups, emulsions, soft gelatin capsules, gels, pastes, injectable preparations, creams and gels. , Lotions, patches and the like.
  • the carrier used in the present pharmaceutical composition is appropriately selected according to the type of preparation. When it is prepared as an injectable preparation, it can be formulated into a sterile aqueous solution or dispersion containing the present chlorin derivative or the like or a sterile lyophilized preparation containing the present chlorin derivative or the like.
  • the liquid carrier for example, water, physiological saline, ethanol, hydrous ethanol, glycerol, propylene glycol, vegetable oil and the like are preferable.
  • diluents such as lactose, sucrose, dicalcium phosphate and carboxymethylcellulose
  • lubricants such as magnesium stearate, calcium stearate and talc
  • starch glucose, molasses , Polyvinyl pyrrolidone, cellulose, and derivatives thereof, and the like.
  • the content of the active ingredient per preparation in the present embodiment can be appropriately determined according to the subject to be treated and the usage, but for example, the amount of glycosylated chlorin e6 derivative can be 1 to 2000 mg. -1000 mg is preferable, and 10-500 mg is more preferable.
  • the dose of the present chlorin derivative and the like varies depending on the subject to be treated and the purpose, but in general, the amount of the present chlorin derivative and the like is preferably 0.1 to 30 mg / kg for tumor diagnosis or detection and tumor treatment.
  • the standard is 0.2 to 20 mg / kg. Since the present chlorin derivative, which is an active ingredient, has high cytotoxicity, it can be expected to obtain an effect equal to or higher than that of conventional products (photofurin and resafirin). This means that the time required for metabolism and excretion is short, and the convenience of using photodynamic therapy is enhanced.
  • the region to be treated is irradiated with light containing the absorption band of the compound.
  • singlet oxygen can be generated by irradiation with light having a wavelength of 500 nm or more, and the desired cytotoxicity can be exhibited, but irradiation with light having a high ratio of light having the maximum absorption wavelength is preferable.
  • an LED Light Emitting Diode
  • a laser a halogen lamp, or the like
  • the laser a dye laser, a semiconductor laser, an argon laser, or the like may be used as long as it can obtain light having a wavelength necessary for excitation.
  • IC 50 (Half maximum (50%) inhibitory concentration) was used for the phototoxicity evaluation, and the measurement was performed according to the following procedure.
  • MKN45 obtained from JCRB cell bank and subcultured for 6 months
  • MKN28 obtained from Immunobiological Laboratories and subcultured for 6 months
  • IC 50 was used for the phototoxicity evaluation, and the measurement was performed according to the following procedure.
  • MKN45 obtained from JCRB cell bank and subcultured for 6 months
  • MKN28 obtained from Immunobiological Laboratories and subcultured for 6 months
  • each well is adjusted to a predetermined drug concentration, cultured for 4 hours, and then 100 ⁇ L of phosphate buffered saline (PBS). Washed once with Buffered Saline), 100 ⁇ L of PBS was added again. Then, light was irradiated for 8 minutes and 40 seconds (16 J / cm 2 ) using a 660 nm LED light source (30.8 mW / cm 2 , LEDR-660DL, OptoCode). After irradiation, PBS was removed, and 100 ⁇ L of RPMI 1640 medium containing 2% FBS was added and cultured for 24 hours.
  • PBS phosphate buffered saline
  • 0.1 ⁇ mol / L or more and less than 0.1 ⁇ mol / L is B, 0.1 ⁇ mol / L or more and less than 1 ⁇ mol / L is C, 1 ⁇ mol / L or more and less than 10 ⁇ mol / L is D, 10 ⁇ mol / L or more is E It was evaluated.
  • Tumor volume was calculated by 1/2 (4 ⁇ / 3) (L / 2) (W / 2) H (L: length of tumor, W: width, H: height).
  • 0.1 ml of physiological saline (control group) was added from the lateral tail vein of nude mice, and the drug concentration was 1 in physiological saline or 20% PEG aqueous solution.
  • 0.1 ml of drug solution dissolved at 25 mM was administered.
  • the tumor was irradiated with a diode laser (100 mW / cm 2 , CrystaLaser CL660) with a spot of 660 nm (15 Jcm ⁇ 2 ) and a diameter of 2 cm.
  • the tumor size is measured every 2 days, and the tumor growth inhibition rate (TGI%) is calculated from the tumor volume on the 24th day according to the following formula.
  • TGI% is less than 65%, D, 65% or more and 70 Less than% was evaluated as C, 70% or more and less than 75% was evaluated as B, and 75% or more was evaluated as A.
  • TGI% ((Tumor volume in control group) ⁇ (Tumor volume in treatment group)) / (Tumor volume in control group) ⁇ 100%
  • Example 1 Production and evaluation of 1- (3-hydroxy-propanethio) - ⁇ -D-glucose-linked chlorin e6 trimethyl ester (1-1) Synthesis of 1- (3-hydroxy-propanethio) - ⁇ -D-glucose tetraacetate Nitrogen atmosphere Then, 1-thio- ⁇ -D-glucose tetraacetate (2.73 g, 7.50 mmol) was dissolved in chloroform (5.0 ml), and triethylamine (2.08 ml, 15.00 mmol) was added. The resulting solution was cooled to 0 ° C.
  • the obtained compound was confirmed by 1 H-NMR (400 MHz, deuterated chloroform solvent) based on Photochemistry and Photobiology, 2007, 83, 1006-1015.
  • the obtained dichloromethane layer was washed with water (200 ml) and saturated brine (200 ml), and dried over anhydrous sodium sulfate.
  • the obtained dichloromethane solution was suction filtered, and the solvent was distilled off under reduced pressure.
  • the obtained crude product was packed in a silica gel column (High Flash column, manufactured by Yamazen Co., Ltd.) and eluted with a mixed solvent of ethyl acetate and dichloromethane.
  • the eluent was concentrated under reduced pressure to obtain 1- (3-hydroxy-propanethio) - ⁇ -D-glucose tetraacetate-linked chlorin e6 trimethyl ester (yield 0.42 g, yield 27%).
  • the solvent was distilled off from the resulting solution under reduced pressure, and the residue was loaded onto a PLC glass plate (silica gel 60 F254, manufactured by Merck & Co., Inc.) and eluted with a mixed solvent of dichloromethane and methanol.
  • the eluent was concentrated under reduced pressure, filled in reverse phase silica gel chromatography (Sep-Pak C18, manufactured by Waters), the salt was eluted with ion-exchanged water, and then eluted with methanol.
  • the obtained methanol solution was concentrated under reduced pressure to obtain 1- (3-hydroxy-propanethio) - ⁇ -D-glucose linked chlorin e6 trimethyl ester (yield 64 mg, yield 72%).
  • the obtained dichloromethane solution was suction filtered, and the solvent was distilled off under reduced pressure.
  • the obtained crude product was packed in a silica gel column (High Flash column, manufactured by Yamazen Co., Ltd.) and eluted with a mixed solvent of ethyl acetate and dichloromethane.
  • the eluent was concentrated under reduced pressure to obtain 1- (6-hydroxy-hexanethio) - ⁇ -D-glucose tetraacetate linked chlorin e6 trimethyl ester (yield 145 mg, yield 13%).
  • the solvent was distilled off from the resulting solution under reduced pressure, and the residue was loaded onto a PLC glass plate (silica gel 60 F254, manufactured by Merck & Co., Inc.) and eluted with a mixed solvent of dichloromethane and methanol.
  • the eluent was concentrated under reduced pressure, filled in reverse phase silica gel chromatography (Sep-Pak C18, manufactured by Waters), the salt was eluted with ion-exchanged water, and then eluted with methanol.
  • the obtained methanol solution was concentrated under reduced pressure to obtain 1- (6-hydroxy-hexanethio) - ⁇ -D-glucose linked chlorin e6 trimethyl ester (yield 75 mg, 67%).
  • the obtained dichloromethane solution was suction filtered, and the solvent was distilled off under reduced pressure.
  • the obtained crude product was packed in a silica gel column (High Flash column, manufactured by Yamazen Co., Ltd.) and eluted with a mixed solvent of ethyl acetate and dichloromethane.
  • the eluent was concentrated under reduced pressure to obtain 1- (10-hydroxy-decanthio) - ⁇ -D-glucose tetraacetate-linked chlorin e6 trimethyl ester (yield 285 mg, yield 22%).
  • the solvent was distilled off from the resulting solution under reduced pressure, and the residue was loaded onto a PLC glass plate (silica gel 60 F254, manufactured by Merck & Co., Inc.) and eluted with a mixed solvent of dichloromethane and methanol.
  • the eluent was concentrated under reduced pressure, filled in reverse phase silica gel chromatography (Sep-Pak C18, manufactured by Waters), the salt was eluted with ion-exchanged water, and then eluted with methanol.
  • the obtained methanol solution was concentrated under reduced pressure to obtain 1- (10-hydroxy-decanthio) - ⁇ -D-glucose linked chlorin e6 trimethyl ester (yield 149 mg, yield 65%).
  • the 1- (3-hydroxy-propanethio) - ⁇ -D-galactose-linked chlorin e6 trimethyl ester obtained based on the above production method was evaluated based on the phototoxicity evaluation method and the tumor growth inhibition rate evaluation method. Carried out. The results are shown in Table 1, Table 2 and Table 3. Further, it was confirmed that all nude mice were alive without weight loss within the evaluation period of the tumor growth inhibition rate, and no adverse effects on the nude mice due to drug administration and laser irradiation were observed.
  • Example 5 Production and evaluation of 1- (6-hydroxy-hexanethio) - ⁇ -D-galactose-linked chlorin e6 trimethyl ester 1- synthesized in (4-1) instead of 1-thio- ⁇ -D-glucose tetraacetate The same production method as in Example 2 was performed using thio- ⁇ -D-galactose tetraacetate to obtain 1- (6-hydroxy-hexanethio) - ⁇ -D-galactose-linked chlorin e6 trimethyl ester. .
  • the 1- (6-hydroxy-hexanethio) - ⁇ -D-galactose-linked chlorin e6 trimethyl ester obtained based on the above production method was evaluated based on the phototoxicity evaluation method and the tumor growth inhibition rate evaluation method. Carried out. The results are shown in Table 1, Table 2 and Table 3. Further, it was confirmed that all nude mice were alive without weight loss within the evaluation period of the tumor growth inhibition rate, and no adverse effects on the nude mice due to drug administration and laser irradiation were observed.
  • Example 6 Production and evaluation of 1- (10-hydroxy-decanthio) - ⁇ -D-galactose-linked chlorin e6 trimethyl ester 1- synthesized in (4-1) instead of 1-thio- ⁇ -D-glucose tetraacetate The same production method as in Example 3 was carried out using thio- ⁇ -D-galactose tetraacetate to obtain 1- (10-hydroxy-decanthio) - ⁇ -D-galactose-linked chlorin e6 trimethyl ester. .
  • the 1- (10-hydroxy-decanthio) - ⁇ -D-galactose-linked chlorin e6 trimethyl ester obtained based on the above production method was evaluated based on the phototoxicity evaluation method and the tumor growth inhibition rate evaluation method. Carried out. The results are shown in Table 1, Table 2 and Table 3. Further, it was confirmed that all nude mice were alive without weight loss within the evaluation period of the tumor growth inhibition rate, and no adverse effects on the nude mice due to drug administration and laser irradiation were observed.
  • the 1- (3-hydroxy-propanethio) - ⁇ -D-mannose-linked chlorin e6 trimethyl ester obtained based on the above production method was evaluated based on the phototoxicity evaluation method and the tumor growth inhibition rate evaluation method. Carried out. The results are shown in Table 1, Table 2 and Table 3. Further, it was confirmed that all nude mice were alive without weight loss within the evaluation period of the tumor growth inhibition rate, and no adverse effects on the nude mice due to drug administration and laser irradiation were observed.
  • Example 8 Production and evaluation of 1- (6-hydroxy-hexanethio) - ⁇ -D-mannose-linked chlorin e6 trimethyl ester 1-thio- synthesized in (4-1) instead of 1-thio- ⁇ -D-glucose tetraacetate The same production method as in Example 2 was carried out using ⁇ -D-mannose tetraacetate to obtain 1- (6-hydroxy-hexanethio) - ⁇ -D-mannose-linked chlorin e6 trimethyl ester. .
  • the 1- (6-hydroxy-hexanethio) - ⁇ -D-mannose-linked chlorin e6 trimethyl ester obtained based on the above production method was evaluated based on the phototoxicity evaluation method and the tumor growth inhibition rate evaluation method. Carried out. The results are shown in Table 1, Table 2 and Table 3. Further, it was confirmed that all nude mice were alive without weight loss within the evaluation period of the tumor growth inhibition rate, and no adverse effects on the nude mice due to drug administration and laser irradiation were observed.
  • Example 9 Production and evaluation of 1- (10-hydroxy-decanthio) - ⁇ -D-mannose linked chlorin e6 trimethyl ester 1-thio- synthesized in (4-1) instead of 1-thio- ⁇ -D-glucose tetraacetate The same production method as in Example 3 was carried out using ⁇ -D-mannose tetraacetate to obtain 1- (10-hydroxy-decanthio) - ⁇ -D-mannose-linked chlorin e6 trimethyl ester. .
  • Esophageal cancer cell line KYSE30 (No. 11D028; ECACC), OE21 (No. 11D028; ECACC), gastric cancer cell line: MKN45 (No. 0254; Japan Cancer Research Bank), and colon cancer cell line: HT29 (No. HTB-38 (ATCC) was used and cultured under the following conditions.
  • KYSE30 RPMI 1640 OE21: RPMI 1640 and half mixture of Ham's F12 MKN45: RPMI 1640 HT29: McCoy's 5A All cultures contained 10% fetal bovine serum, 100 U / ml penicillin and streptomycin, 0.25 mg / ml amphotericin B, and were cultured under the conditions of 5% CO 2 and 37 ° C.
  • Example 3 the 1- (3-hydroxy-propanethio) - ⁇ -D-glucose-linked chlorin e6 trimethyl ester of Example 1 (in Table 3) was prepared in the same manner as the “phototoxicity evaluation method” described above.
  • IC 50 50% cancer cell killing concentration
  • TS comparative example
  • TS comparative example
  • TS comparative example
  • a human gastric cancer cell line MKN45 (No. 0254; Japan Cancer Research Bank) and a colon cancer cell line: HT29 (No. HTB-38; ATCC) were used.
  • Culture conditions As the culture solution, RPMI 1640 was used for MKN45, and McCoy's 5A was used for HT29. All cultures contained 10% fetal bovine serum, 100 U / ml penicillin and streptomycin, 0.25 mg / ml amphotericin B, and were cultured under the conditions of 5% CO 2 and 37 ° C.
  • Test method Using a 6 cm culture plate, 2 ⁇ 10 5 cells / well of the above cancer cell lines were cultured under the above conditions for 28 hours. Next, the culture solution was removed, (1) only the culture solution (control), (2) a culture solution containing 5 ⁇ M of the glycosylated chlorin e6 derivative of Example 1, and (3) 5 ⁇ M Talaporfin Sodium (TS; (Registered trademark, Meiji Seika Pharma) was replaced with the culture solution, and further cultured for 4 hours. After culturing for 4 hours, the culture solution was removed, washed three times with phosphate-buffered saline (PBS), and cells were collected from the culture plate using TrypLE-Express (Invitrogen).
  • PBS phosphate-buffered saline
  • the MAA of TS (Comparative Example) was 235, the MAA of the compound of Example 1 was 17051, and the MAA of the compound of Example 1 was the MAA of TS. It was about 70 times higher.
  • the MAA of TS (Comparative Example) is 97, the MAA of the compound of Example 1 is 18669, and the MAA of the compound of Example 1 is about 190 times higher than TS. was.
  • Example 1 has about 70 to 190 times higher uptake into cells in vitro compared to TS (Comparative Example) which is clinically applied. From this, it can be inferred that, when this chlorin derivative or the like is used, strong tumor fluorescence is obtained, and therefore, when applied to photodynamic diagnosis (PDD), a superior sensitivity can be obtained.
  • PDT photodynamic diagnosis
  • the present chlorin derivative and the like have better uptake performance into cancer cell lines compared to TS, and from this, the present chlorin derivative and the like have a cell killing effect by PDT superior to TS. It was found that
  • Cell culture conditions are as follows. OE21: Mixture of half volume of RPMI 1640 and Ham's F12 Het-1A: BEGM Bullet kit was used as a culture solution. All culture solutions were 10% fetal bovine serum, 100 U / ml penicillin and streptomycin, 25 mg / ml Of amphotericin B and cultured under conditions of 5% CO 2 concentration and 37 ° C.
  • the mouse colon cancer cell line CT26 (No. CRL-2638; ATCC) was used as the cell line.
  • Cell culture conditions, animals used, and methods for preparing mouse subcutaneous tumor models are as follows.
  • DMEM Dulbecco's Modified Eagle Medium
  • fetal bovine serum 100 U / ml penicillin and streptomycin, 0.25 mg / ml amphotericin B, and cultured at 5% CO 2 concentration at 37 ° C. .
  • mice used: The mice were 8-10 weeks old, female, approximately 20 g body weight mice (BALB / c CrSlc). Mice were raised for 2 weeks and adapted to the environment.
  • mouse subcutaneous tumor model The hair was removed in a circular shape of about 10 mm around the back of the right thigh root of the mouse, and 1 ⁇ 10 6 CT26 were inoculated subcutaneously using a 27G needle. Seven days after inoculation, a subcutaneous tumor model with an average tumor size of 100 mm 3 (major axis (mm) ⁇ minor axis (mm) ⁇ minor axis (mm)) was prepared.
  • the prepared mouse subcutaneous tumor model was divided into three groups (untreated control group, treatment group with the compound of Example 1, Talaporfin Sodium (TS (comparative example); Rezaphyrin (registered trademark), Meiji Seika Pharma) treatment group) average tumor Ten animals were allocated so that the sizes were uniform.
  • the compound of Example 1 or TS at a concentration of 1.56 ⁇ mol / Kg was intravenously administered from the mouse tail vein, and 30 minutes later, a 664 nm red semiconductor laser (KOYO-PDL664, OK Fiber Technology) was used, for a total of 100 J / cm 2 (150 mW / cm 2 ) single irradiation was performed.
  • Tumor size after treatment was measured using electronic calipers every 3 days. The measurement results were compared between two groups using Welch's t-test. The results are shown in the graph of FIG.
  • Example 1 Single intravenous toxicity study using mice
  • mice Crl: CD1 (ICR), 5 males and 5 females / dose group
  • mice Crl: CD1 (ICR), 5 males and 5 females / dose group
  • the administration liquid volume was 10 ml / kg.
  • a pharmacological physiological saline containing 10% Cremophor + 5% ethanol was used as the administration liquid medium.
  • Results of administration In the 250 mg / kg group raised in light conditions, 3 males, 1 female died on the 2nd day, and 1 female died on the 3rd day. In the 250 mg / kg group kept in the dark, 2 males died on the 2nd and 5th days, and 3 females died on the 2nd to 4th days. In some of these animals, decreased locomotor activity, slow breathing, and decreased body temperature were observed. There was no difference between the light and dark conditions in the status of death.
  • Body weight measurement Weight loss was observed on the 4th or 8th day in the 125 and 250 mg / kg groups for both bright and dark conditions. Both were temporary and showed a tendency to recover. There was no difference between light and dark conditions in weight fluctuation.
  • Necropsy results Only the discoloration of the auricle, the defect, and the crust of the tail, which were recognized as general symptoms in the 250 mg / kg group, were observed.
  • the minimum lethal dose in the single intravenous administration of the compound of Example 1 was 250 mg / kg for both male and female in the light and dark breeding conditions. Moreover, under the light condition breeding, swelling of the tail and discoloration of the auricle were observed after administration of the 250 mg / kg group, and a difference depending on the lighting conditions was observed. From the above results, it was presumed that the compound of Example 1 could obtain sufficient effects of the present invention at a dose at which safety was recognized.
  • AUC 0-last is 30.42 ⁇ g eq h / ml
  • AUC 0- ⁇ is 31.89 ⁇ g eq. -H / ml.

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Abstract

Le problème décrit par la présente invention est de fournir un dérivé de chlorine E6 glycosylé qui a d'excellentes propriétés de destruction de cellules tumorales (propriété phototoxique) et un effet d'inhibition de croissance sur des tissus tumoraux et qui est utilisé pour une thérapie photodynamique. Le dérivé de chlorine E6 glycosylé selon la présente invention peut être utilisé dans le diagnostic photodynamique. La présente invention concerne un dérivé de chlorine E6 glycosylé représenté par la formule générale (1) ou un sel pharmaceutiquement acceptable de celui-ci.
PCT/JP2017/043144 2016-11-30 2017-11-30 Dérivé de chlorine e6 glycosylé ou son sel pharmaceutiquement acceptable, composition pharmaceutique, procédé de destruction de cible, et procédé de production d'un dérivé de chlorine e6 glycosylé ou d'un sel pharmaceutiquement acceptable de celui-ci WO2018101434A1 (fr)

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WO2023048233A1 (fr) * 2021-09-24 2023-03-30 株式会社PhotoQ3 Médicament destiné à tuer des cellules tumorales

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