THERAPEUTIC AGENT OR PREVENTIVE AGENT FOR AMYOTROPHIC LATERAL SCLEROSIS

Claims

1. A therapeutic or prophylactic agent for amyotrophic lateral sclerosis, consisting of a tetrahydroquinoline derivative represented by the general formula (I) below or a pharmaceutically acceptable salt thereof as an active ingredient, Where R 1x represents hydrogen, aryl, or a 5- or 6-membered heteroaryl having one or two heteroatoms selected from nitrogen, oxygen, and sulfur (any one or two hydrogen atoms in an aryl or 5- or 6-membered heteroaryl are each independently optionally substituted with a halogen atom(s), C1-C3 alkyl in which any one to three hydrogen atoms are each independently optionally substituted with a hydroxy group(s) or a fluorine atom(s), C1-C3 alkoxy in which any one to three hydrogen atoms are optionally substituted with a fluorine atom(s), cyano, methoxycarbonyl, -CONR 6 R 7 , -NHCOR 8, aminosulfonyl, C1-C3 alkylsulfonylamino, aminosulfonylamino or C1-C3 alkylsulfonyl group(s)), or in cases where the aryl group is phenyl, R 1x optionally represents a fused ring group formed by the fusion of a phenyl group and one ring selected from the group consisting of 5- or 6-membered lactam rings and 5- or 6-membered saturated heterocycles, each containing one or two oxygen atoms as a ring constituent atom (any one hydrogen atom in the fused ring group is optionally replaced by a methyl group); R 1y represents hydrogen, phenyl, 4-hydroxymethylphenyl, 4-aminocarbonylphenyl, 4-acetamidophenyl, 4-aminosulfonylphenyl, 4-methylsulfonylphenyl, or 3-pyridyl (except when both R 1x and R 1y represent hydrogen); for combination R 2 , R 4 and R 5 , all from R2 , R 4 and R 5 represent hydrogen, or one of the R 2 , R 4 and R 5 is halogen, methoxy or methyl in which one hydrogen atom is optionally replaced by a hydroxy group and both others are hydrogen; R 3 represents hydrogen, halogen, C1-C3 alkyl in which any one to three hydrogen atoms are each independently optionally substituted with hydroxy group(s) or fluorine atom(s), 3-hydroxyoxetan-3-yl, hydroxy, C1-C3 alkoxy in which any one to three hydrogen atoms are optionally substituted with fluorine atom(s), methoxycarbonyl, -NR 9 R 10 , -CH2NR 11 R 12 or -CH2CONR 13 R 14 ; R 6 and R 7 each independently represents hydrogen or C1-C3 alkyl, or R 6 and R 7 together represent -(CH2) h -; h is an integer from 3 to 5, where any one of the methylene groups is optionally substituted by an oxygen atom, -NH- or -N(CH3)-; R 8 represents hydrogen or C1-C3 alkyl; R 9 and R 10 each independently represents hydrogen, -COR 15 or C1-C3alkylsulfonyl, or R 9 and R 10 together represent -(CH2) n -; n is an integer from 3 to 6; R 11 and R 12 together represent -(CH2) m -; m is an integer from 3 to 5, where any one of the methylene groups is optionally substituted by an oxygen atom; R 13 and R 14each independently represents hydrogen, a C1-C5 alkyl group, 2-hydroxyethyl, C3 or C4 cycloalkyl in which any one carbon atom is optionally substituted by an oxygen atom, or methyl which is substituted by a C3 or C4 cycloalkyl group in which any one carbon atom is optionally substituted by a nitrogen or oxygen atom, or R 13 and R 14 together represent -(CH2) k -, in which any one or two hydrogen atoms are optionally substituted by a fluorine atom(s), a methyl group(s), a hydroxy group(s) or a methoxy group(s), or in which any one CH2 group is optionally substituted by an oxygen atom, a nitrogen atom or -CONH-; k is an integer from 3 to 5; R 15 is C1-C5 alkyl, C1-C5 alkoxy, or -NHR 16 ; R 16 represents hydrogen or C1-C5 alkyl; R vrepresents hydrogen, methyl in which any one hydrogen atom is optionally replaced by a hydroxy or methoxycarbonyl group, or methoxycarbonyl; and R w represents hydrogen, methyl, hydroxymethyl, or methoxycarbonyl.

2. A therapeutic or prophylactic agent for amyotrophic lateral sclerosis according to claim 1, comprising a tetrahydroquinoline derivative or a pharmaceutically acceptable salt thereof as an active ingredient, wherein R 1x represents hydrogen, phenyl (the hydrogen atom in the para-position of the phenyl group is optionally substituted by a fluorine atom, trifluoromethyl, trifluoromethoxy, cyano, aminocarbonyl, acetamide, aminosulfonyl, methylsulfonylmino or methylsulfonyl group); R 1y represents hydrogen or 4-aminosulfonylphenyl (where, in cases where R 1x represents hydrogen, R 1y is 4-aminosulfonylphenyl, or in cases where R 1xis phenyl (the hydrogen atom at the para-position of the phenyl group is optionally substituted by a fluorine atom, trifluoromethyl, trifluoromethoxy, cyano, aminocarbonyl, acetamide, aminosulfonyl, methylsulfonylmino or methylsulfonyl group), R 1y is hydrogen); for combination R 2 , R 4 and R 5 , all from R 2 , R 4 and R 5 represent hydrogen; otherwise, one of R 2 and R 4 represents fluorine, chlorine or methyl, and the other together with R 5 represent hydrogen; R 3 represents hydrogen, fluorine, chlorine, methyl, hydroxymethyl, trifluoromethoxy, or -CH2CONR 13 R 14 ; R 13 represents hydrogen or methyl; R 14 is tert-butyl, 2-hydroxyethyl, cyclopropyl, cyclobutyl or oxetan-3-yl, or R 13 and R 14together with the nitrogen atom to which they are bonded to R 13 and R 14 , optionally form a piperazine ring, a piperazin-2-one ring, an azetidine ring, a 3,3-difluoroazetidine ring, a 3,3-dimethylazetidine ring, a 3-hydroxyazetidine ring or a 3-methoxyazetidine ring; R v is hydrogen; and R w is hydrogen.

3. A therapeutic or prophylactic agent for amyotrophic lateral sclerosis according to claim 2, wherein the tetrahydroquinoline derivative or a pharmaceutically acceptable salt thereof is selected from the group consisting of: 2-phenyl-1,2,3,4-tetrahydroquinoline, 4-(1,2,3,4-tetrahydroquinolin-2-yl)benzenesulfonamide, 4-(1,2,3,4-tetrahydroquinolin-2-yl)benzamide, 1-(3-hydroxyazetidin-1-yl)-2-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)ethan-1-one, 4-(6-methyl-1,2,3,4-tetrahydroquinolin-2-yl)benzamide, 4-(6-methyl-1,2,3,4-tetrahydroquinolin-2-yl)benzenesulfonamide, 4-(7-methyl-1,2,3,4-tetrahydroquinolin-2-yl)benzenesulfonamide, 4-(7-methyl-1,2,3,4-tetrahydroquinolin-2-yl)benzamide, 4-(6-fluoro-1,2,3,4-tetrahydroquinolin-2-yl)benzenesulfonamide, 4-(5-methyl-1,2,3,4-tetrahydroquinolin-2-yl)benzenesulfonamide, 4-(6-chloro-1,2,3,4-tetrahydroquinolin-2-yl)benzenesulfonamide, 4-(7-fluoro-1,2,3,4-tetrahydroquinolin-2-yl)benzenesulfonamide, 4-(6-chloro-1,2,3,4-tetrahydroquinolin-2-yl)benzamide, 4-(6-fluoro-1,2,3,4-tetrahydroquinolin-2-yl)benzamide, 4-(5-chloro-1,2,3,4-tetrahydroquinolin-2-yl)benzenesulfonamide, 4-(5-fluoro-1,2,3,4-tetrahydroquinolin-2-yl)benzamide, 4-(5-chloro-1,2,3,4-tetrahydroquinolin-2-yl)benzamide, 1-(3-methoxyazetidin-1-yl)-2-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)ethan-1-one, N-(oxetan-3-yl)-2-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)acetamide, 1-(3,3-difluoroazetidin-1-yl)-2-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)ethan-1-one, N-(2-hydroxyethyl)-N-methyl-2-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)acetamide, 1-(azetidin-1-yl)-2-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)ethan-1-one, N-cyclopropyl-2-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)acetamide, N-cyclobutyl-2-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)acetamide, 2-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)-1-(piperazin-1-yl)ethan-1-one, and 4-(1,2,3,4-tetrahydroquinolin-3-yl)benzenesulfonamide and their pharmaceutically acceptable salts.

4. A therapeutic or prophylactic agent for amyotrophic lateral sclerosis according to claim 3, wherein the tetrahydroquinoline derivative or pharmaceutically acceptable salt thereof is 2-phenyl-1,2,3,4-tetrahydroquinoline.

5. A therapeutic or prophylactic agent for amyotrophic lateral sclerosis according to any one of claims 1 to 4, wherein the therapeutic or prophylactic agent is a ferroptosis inhibitor.