Tetrahydroquinoline derivative and medicinal use thereof

Patent metadata

Field	Value
Publication number	US-12570639-B2
Application number	US-202118268667-A
Country	US
Kind code	B2
Filing date	Dec 24, 2021
Priority date	Dec 25, 2020
Publication date	Mar 10, 2026
Grant date	Mar 10, 2026

Abstract

A compound has a tetra-hydroquinoline skeleton, the compound having inhibitory action against ferroptosis, and exerting therapeutic or preventive effect on diseases, disorders or syndromes related to ferroptosis inhibition, such as multiple sclerosis. This disclosure provides a tetrahydroquinoline derivative represented by the following formula or a pharmaceutically acceptable salt thereof:

First claim

The invention claimed is:

1 . A tetrahydroquinoline derivative represented by general formula (I) below or a pharmaceutically acceptable salt thereof,

wherein
for a 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, methoxy, or methyl in which one hydrogen atom is optionally replaced by a hydroxy group, and both the other and R 5 represent hydrogen; otherwise, both R 2 and R 4 represent hydrogen, and R 5 is fluorine or chlorine;
R v is hydrogen; and
R w is hydrogen;
when R 1x is phenyl in which any one hydrogen atom in the phenyl group is optionally replaced by one substituent selected from the group consisting of halogen, C 1 -C 3 alkyl in which any one to three hydrogen atoms are optionally replaced by 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, and —NHCOR 8 , provided that m-cyanophenyl and p-(trifluoromethoxy)phenyl are excluded, or 5- or 6-membered heteroaryl in which any one hydrogen atom in the 5- or 6-membered heteroaryl is optionally replaced by a C 1 -C 3 alkyl or C 1 -C 3 alkoxy group, provided that 1-methyl-1H-pyrazol-4-yl and 6-methoxypyridin-3-yl are excluded, R 3 is C 1 -C 3 alkyl in which any one to three hydrogen atoms are replaced by a fluorine atom(s), C 1 -C 3 alkyl in which any one hydrogen atom is replaced by a hydroxy group, ethyl, propyl, isopropyl, 3-hydroxyoxetan-3-yl, methoxy in which any one to three hydrogen atoms are replaced by a fluorine atom(s), methoxycarbonyl, —NR 9 R 10 , —CH 2 NR 11 R 12 , or —CH 2 CONR 13 R 14 wherein, when both R 2 and R 4 represent hydrogen and R 5 is fluorine or chlorine, R 3 is optionally hydrogen or fluorine, or when both R 2 and R 5 represent hydrogen and R 4 is fluorine or chlorine, R 3 is optionally fluorine, or when R 2 is methyl in which one hydrogen atom is optionally replaced by a hydroxy group, and both R 4 and R 5 represent hydrogen, R 3 is optionally hydrogen; or
when R 1x is hydrogen, phenyl in which any one hydrogen atom in the phenyl group is replaced by a C 1 -C 3 alkyl in which any one hydrogen atom is replaced by a hydroxy group, —CONR 6 R 7 , aminosulfonyl, methylsulfonylamino, aminosulfonylamino, or C 1 -C 3 alkylsulfonyl group; other-wise, the hydrogen atom at the meta-position of the phenyl group is replaced by a cyano group; otherwise, the hydrogen atom at the para-position of the phenyl group is replaced by a trifluoromethoxy group, or 1-methyl-1H-pyrazol-4-yl, or 6-methoxypyridin-3-yl, or
when R 1x is a fused ring group formed by fusing of a phenyl group and one ring selected from the group consisting of pyrrolidin-2-one, piperidin-2-one, and 1,3-dioxolane, wherein any one hydrogen atom in the fused ring group is optionally replaced by a methyl group,
R 3 is hydrogen, fluorine, chlorine, bromine, C 1 -C 3 alkyl in which any one to three hydrogen atoms are optionally replaced by a fluorine atom(s) or any one hydrogen atom is optionally replaced by a hydroxy group, 3-hydroxyoxetan-3-yl, hydroxy, methoxy 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 with the nitrogen atom which is bound to R 6 and R 7 , optionally form a piperidine ring, a morpholine ring, a piperazine ring, or an N-methylpiperazine ring;
R 8 is hydrogen or C 1 -C 3 alkyl;
R 9 is hydrogen;
R 10 is hydrogen, —COR 15 , or C 1 -C 3 alkylsulfonyl, or
R 9 and R 10 together represent —(CH 2 ) n —;
n is 4 or 5;
R 11 and R 12 together represent —(CH 2 ) m —;
m is 4 or 5, wherein any one of the methylene groups is optionally replaced by an oxygen atom;
R 13 is hydrogen or methyl;
R 14 is hydrogen, methyl, ethyl, isopropyl, tert-butyl, 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 with the nitrogen atom which is bound to R 13 and R 14 , optionally form a pyrrolidine ring, a piperidine ring, a piperazine ring, a morpholine ring, a piperazinone ring, or an azetidine ring in which any two hydrogen atoms are optionally replaced by a methyl group(s) and/or a fluorine atom(s) or in which any one hydrogen atom is optionally replaced by a hydroxy or methoxy group;
R 15 is C 1 -C 5 alkyl, C 1 -C 8 alkoxy, or —NHR 16 ;
R 16 is hydrogen or C 1 -C 5 alkyl provided that methyl 2-(4-methoxyphenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate and 2-(benzo[d][1,3]dioxol-5-yl)-1,2,3,4-tetrahydroquinoline are excluded; and
R 1y is hydrogen, 4-hydroxymethylphenyl, 4-aminocarbonylphenyl, 4-acetamidophenyl, 4-aminosulfonylphenyl, or 4-methylsulfonylphenyl, provided that Rly is a substituent other than hydrogen when R 1x is hydrogen, or that Rly is hydrogen when R 1x is a substituent other than hydrogen.

2 . The tetrahydroquinoline derivative or a pharmaceutically acceptable salt thereof according to claim 1 , wherein
for a 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, methoxy, or methyl in which one hydrogen atom is optionally replaced by a hydroxy group, and both the other and R 5 represent hydrogen; otherwise, both R 2 and R 4 represent hydrogen, and R 5 is fluorine or chlorine; R v is hydrogen; and R w is hydrogen; wherein, when R 1x is phenyl in which any one hydrogen atom in the phenyl group is optionally replaced by one substituent selected from the group consisting of halogen, C 1 -C 3 alkyl in which any one to three hydrogen atoms are optionally replaced by 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, and —NHCOR 8 , provided that m-cyanophenyl and p-(trifluoromethoxy)phenyl are excluded, or 5- or 6-membered heteroaryl in which any one hydrogen atom in the 5- or 6-membered heteroaryl is optionally replaced by a C 1 -C 3 alkyl or C 1 -C 3 alkoxy group, provided that 1-methyl-1H-pyrazol-4-yl and 6-methoxypyridin-3-yl are excluded, R 3 is C 1 -C 3 alkyl in which any one to three hydrogen atoms are replaced by a fluorine atom(s), C 1 -C 3 alkyl in which any one hydrogen atom is replaced by a hydroxy group, ethyl, propyl, isopropyl, 3-hydroxyoxetan-3-yl, methoxy in which any one to three hydrogen atoms are replaced by a fluorine atom(s), methoxycarbonyl, —NR 9 R 10 , —CH 2 NR 11 R 12 , or —CH 2 CONR 13 R 14 wherein, when both R 2 and R 4 represent hydrogen and R 5 is fluorine or chlorine, R 3 is optionally hydrogen or fluorine, or when both R 2 and R 5 represent hydrogen and R 4 is fluorine or chlorine, R 3 is optionally fluorine, or when R 2 is methyl in which one hydrogen atom is optionally replaced by a hydroxy group, and both R 4 and R 5 represent hydrogen, R 3 is optionally hydrogen; or when R 1x is phenyl in which any one hydrogen atom in the phenyl group is replaced by a C 1 -C 3 alkyl in which any one hydrogen atom is replaced by a hydroxy group, —CONR 6 R 7 , aminosulfonyl, or C 1 -C 3 alkylsulfonyl group; otherwise, the hydrogen atom at the meta-position of the phenyl group is replaced by a cyano group; otherwise, the hydrogen atom at the para-position of the phenyl group is replaced by a trifluoromethoxy group, or 1-methyl-1H-pyrazol-4-yl, or 6-methoxypyridin-3-yl, or when R 1x is a fused ring group formed

Assignees

• Toray Industries

Inventors

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

Classifications

• C07D417/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D413/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D401/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• C07D401/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D215/06 Primary

  having only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to the ring nitrogen atom · CPC title