Therapeutic agent or prophylactic agent for amyotrophic lateral sclerosis

Patent metadata

Field	Value
Publication number	US-2026083723-A1
Application number	US-202318877122-A
Country	US
Kind code	A1
Filing date	Jun 23, 2023
Priority date	Jun 24, 2022
Publication date	Mar 26, 2026
Grant date	—

Abstract

A therapeutic or preventive agent for amyotrophic lateral sclerosis has inhibitory action against ferroptosis. The therapeutic or preventive agent for amyotrophic lateral sclerosis contains a tetrahydroquinoline derivative or a pharmaceutically acceptable salt thereof as an active ingredient. Compositions for and methods of treating amyotrophic lateral sclerosis and inhibiting ferroptosis are also disclosed.

First claim

What is claimed is:

1 . A method of treating amyotrophic lateral sclerosis, comprising:
administering to a patient in need thereof, a therapeutic amount of a tetrahydroquinoline derivative represented by general formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient,

wherein
R 1x is hydrogen, aryl, or 5- or 6-membered heteroaryl having one or two heteroatoms selected from nitrogen, oxygen, and sulfur atoms (any one or two hydrogen atoms in the aryl or the 5- or 6-membered heteroaryl are each independently optionally replaced by a halogen atom(s), a C 1 -C 3 alkyl in which any one to three hydrogen atoms are each independently optionally replaced by a hydroxy group(s) or a fluorine atom(s), C 1 -C 3 alkoxy in which any one to three hydrogen atoms are optionally replaced by a fluorine atom(s), cyano, methoxycarbonyl, —CONR 6 R 7 , —NHCOR 8 , aminosulfonyl, C 1 -C 3 alkylsulfonylamino, aminosulfonylamino, or C 1 -C 3 alkylsulfonyl group(s)), or
in cases where the aryl group is phenyl, R 1x is optionally a fused ring group formed by fusing of the 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 the atom constituting the ring (any one hydrogen atom in the fused ring group is optionally replaced by a methyl group);
R 1y is hydrogen, phenyl, 4-hydroxymethylphenyl, 4-aminocarbonylphenyl, 4-acetamidophenyl, 4-aminosulfonylphenyl, 4-methylsulfonylphenyl, or 3-pyridyl (except that both R 1x and R 1y represent hydrogen);
for the combination of R 2 , R 4 , and R 5 , all of R 2 , R 4 , and R 5 represent hydrogen, or
one of 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 the other two are hydrogen;
R 3 is hydrogen, halogen, C 1 -C 3 alkyl in which any one to three hydrogen atoms are each independently optionally replaced by a hydroxy group(s) or a fluorine atom(s), 3-hydroxyoxetan-3-yl, hydroxy, C 1 -C 3 alkoxy in which any one to three hydrogen atoms are optionally replaced by a fluorine atom(s), methoxycarbonyl, —NR 9 R 10 , —CH 2 NR 11 R 12 , or —CH 2 CONR 13 R 14 ;
R 6 and R 7 each independently represent hydrogen or C 1 -C 3 alkyl, or
R 6 and R 7 together represent —(CH 2 ) h —;
h is an integer of 3 to 5, wherein any one of the methylene groups is optionally replaced by an oxygen atom, —NH—, or —N(CH 3 )—;
R 8 is hydrogen or C 1 -C 3 alkyl;
R 9 and R 10 each independently represent hydrogen, —COR 15 , or C 1 -C 3 alkylsulfonyl, or
R 9 and R 10 together represent —(CH 2 ) n —;
n is an integer of 3 to 6;
R 11 and R 12 together represent —(CH 2 ) m —;
m is an integer of 3 to 5, wherein any one of the methylene groups is optionally replaced by an oxygen atom;
R 13 and R 14 each independently represent hydrogen, C 1 -C 5 alkyl group, 2-hydroxyethyl, C 3 or C 4 cycloalkyl in which any one carbon atom is optionally replaced by an oxygen atom, or methyl which is substituted with a C 3 or C 4 cycloalkyl group in which any one carbon atom is optionally replaced by a nitrogen or oxygen atom, or
R 13 and R 14 together represent —(CH 2 ) k — in which any one or two hydrogen atoms are optionally replaced by a fluorine atom(s), a methyl group(s), a hydroxy group(s), or a methoxy group(s) or in which any one CH 2 group is optionally replaced by an oxygen atom, a nitrogen atom, or —CONH—;
k is an integer of 3 to 5;
R 15 is C 1 -C 5 alkyl, C 1 -C 5 alkoxy, or —NHR 16 ;
R 16 is hydrogen or C 1 -C 5 alkyl; or
R v is hydrogen, methyl in which any one hydrogen atom is optionally replaced by a hydroxy or methoxycarbonyl group, or methoxycarbonyl; and
R w is hydrogen, methyl, hydroxymethyl, or methoxycarbonyl.

2 . The method of treating amyotrophic lateral sclerosis, according to claim 1 , wherein
R 1x is hydrogen, phenyl (the hydrogen atom at the para-position of the phenyl group is optionally replaced by a fluorine atom, a trifluoromethyl, trifluoromethoxy, cyano, aminocarbonyl, acetamide, aminosulfonyl, methylsulfonylamino, or methylsulfonyl group); R 1y is hydrogen or 4-aminosulfonylphenyl (wherein, in cases where R 1x is hydrogen, R 1y is 4-aminosulfonylphenyl, or in cases where R 1x is phenyl (the hydrogen atom at the para-position of the phenyl group is optionally replaced by a fluorine atom, a trifluoromethyl, trifluoromethoxy, cyano, aminocarbonyl, acetamide, aminosulfonyl, methylsulfonylamino, or methylsulfonyl group), R 1y is hydrogen); for the combination of R 2 , R 4 , and R 5 , all of R 2 , R 4 , and R 5 represent hydrogen; otherwise, one of R 2 and R 4 is fluorine, chlorine, or methyl, and both the other and R 5 represent hydrogen; R 3 is hydrogen, fluorine, chlorine, methyl, hydroxymethyl, trifluoromethoxy, or —CH 2 CONR 13 R 14 ; R 13 is hydrogen or methyl; R 14 is tert-butyl, 2-hydroxyethyl, cyclopropyl, cyclobutyl, or oxetan-3-yl, or R 13 and R 14 , together with the nitrogen atom which is bound 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 . The method of treating amyotrophic lateral sclerosis, according to claim 1 , wherein the tetrahydroquinoline derivative or the 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 pharmaceutically acceptable salts thereof.

4 . The method of treating amyotrophic lateral sclerosis, according to claim 1 , wherein the tetrahydroquinoline derivative or the pharmaceutically acceptable salt thereof is 2-phenyl-1,2,3,4-tetrahydroquinoline.

5 . The method of

Assignees

• Toray Industries

Inventors

• Ogawa Mizue
• Takahashi Takehiro
• Takagaki Kozue
• Meguro Hiroyuki
• Asaba Ken Nunettsu
• Yamamoto Masashi
• Nogami Marina
• Tsuji Riichiro
• Ukegawa Naoya

Classifications

• A61K31/5377

  not condensed and containing further heterocyclic rings, e.g. timolol · CPC title

• A61K31/496

  Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin · CPC title

• A61P25/02

  for peripheral neuropathies · CPC title

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title

• A61P21/02 Primary

  Muscle relaxants, e.g. for tetanus or cramps · CPC title