Back to results
US 12,570,639 B2Granted
Tetrahydroquinoline derivative and medicinal use thereof
AssigneeToray Industries, Inc.
InventorsKen Nunettsu Asaba, Takehiro Takahashi, Masashi Yamamoto, Kozue Takagaki, Marina Nogami, Riichiro Tsuji, Hiroyuki Meguro, Naoya Ukegawa
Life of this patent
Estimating the term…
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:
Claims17
A tetrahydroquinoline derivative represented by general formula (I) below or a pharmaceutically acceptable salt thereof,
- wherein
- for a combination of R2, R4, and R5, all of R2, R4, and R5 represent hydrogen;
- otherwise, one of R2 and R4 is fluorine, chlorine, methoxy, or methyl in which one hydrogen atom is optionally replaced by a hydroxy group, and both the other and R5 represent hydrogen;
- otherwise, both R2 and R4 represent hydrogen, and R5 is fluorine or chlorine;
- Rv is hydrogen;
- and
- Rw is hydrogen;
- when R1x 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, C1-C3 alkyl in which any one to three hydrogen atoms are optionally replaced by a fluorine atom(s), C1-C3 alkoxy in which any one to three hydrogen atoms are optionally replaced by a fluorine atom(s), cyano, methoxycarbonyl, and —NHCOR8, 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 C1-C3 alkyl or C1-C3 alkoxy group, provided that 1-methyl-1H-pyrazol-4-yl and 6-methoxypyridin-3-yl are excluded, R3 is C1-C3 alkyl in which any one to three hydrogen atoms are replaced by a fluorine atom(s), C1-C3 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, —NR9R10, —CH2NR11R12, or —CH2CONR13R14 wherein, when both R2 and R4 represent hydrogen and R5 is fluorine or chlorine, R3 is optionally hydrogen or fluorine, or when both R2 and R5 represent hydrogen and R4 is fluorine or chlorine, R3 is optionally fluorine, or when R2 is methyl in which one hydrogen atom is optionally replaced by a hydroxy group, and both R4 and R5 represent hydrogen, R3 is optionally hydrogen;
- or
- when R1x is hydrogen, phenyl in which any one hydrogen atom in the phenyl group is replaced by a C1-C3 alkyl in which any one hydrogen atom is replaced by a hydroxy group, —CONR6R7, aminosulfonyl, methylsulfonylamino, aminosulfonylamino, or C1-C3 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 R1x 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,
- R3 is hydrogen, fluorine, chlorine, bromine, C1-C3 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, —NR9R10, —CH2NR11R12, or —CH2CONR13R14;
- R6 and R7 each independently represent hydrogen or C1-C3 alkyl, or
- R6 and R7, together with the nitrogen atom which is bound to R6 and R7, optionally form a piperidine ring, a morpholine ring, a piperazine ring, or an N-methylpiperazine ring;
- R8 is hydrogen or C1-C3 alkyl;
- R9 is hydrogen;
- R10 is hydrogen, —COR15, or C1-C3 alkylsulfonyl, or
- R9 and R10 together represent —(CH2)n—;
- n is 4 or 5;
- R11 and R12 together represent —(CH2)m—;
- m is 4 or 5, wherein any one of the methylene groups is optionally replaced by an oxygen atom;
- R13 is hydrogen or methyl;
- R14 is hydrogen, methyl, ethyl, isopropyl, tert-butyl, 2-hydroxyethyl, C3 or C4 cycloalkyl in which any one carbon atom is optionally replaced by an oxygen atom, or methyl which is substituted with a C3 or C4 cycloalkyl group in which any one carbon atom is optionally replaced by a nitrogen or oxygen atom, or
- R13 and R14, together with the nitrogen atom which is bound to R13 and R14, 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;
- R15 is C1-C5 alkyl, C1-C8alkoxy, or —NHR16;
- R16 is hydrogen or C1-C5 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
- R1y is hydrogen, 4-hydroxymethylphenyl, 4-aminocarbonylphenyl, 4-acetamidophenyl, 4-aminosulfonylphenyl, or 4-methylsulfonylphenyl, provided that Rly is a substituent other than hydrogen when R1x is hydrogen, or that Rly is hydrogen when R1x is a substituent other than hydrogen.
27 more elements
A pharmaceutical composition containing a tetrahydroquinoline derivative represented by general formula (I) below or a pharmaceutically acceptable salt thereof as an active ingredient,
- wherein
- R1x is hydrogen, aryl, or 5- or 6-membered heteroaryl having one or two heteroatoms selected from nitrogen, oxygen, and sulfur atoms, wherein 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 C1-C3 alkyl in which any one to three hydrogen atoms are each independently optionally replaced by a hydroxy group(s) or a fluorine atom(s), C1-C3 alkoxy in which any one to three hydrogen atoms are optionally replaced by a fluorine atom(s), cyano, methoxycarbonyl, —CONR6R7, —NHCOR8, aminosulfonyl, C1-C3 alkylsulfonylamino, aminosulfonylamino, or C1-C3 alkylsulfonyl group(s), or
- when the aryl group is phenyl, R1x 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, wherein any one hydrogen atom in the fused ring group is optionally replaced by a methyl group;
- R1y is hydrogen, phenyl, 4-hydroxymethylphenyl, 4-aminocarbonylphenyl, 4-aceta-midophenyl, 4-aminosulfonylphenyl, 4-methylsulfonylphenyl, or 3-pyridyl, except that both R1x and R1y represent hydrogen;
- for a combination of R2, R4, and R5, all of R2, R4, and R5 represent hydrogen, or
- one of R2, R4, and R5 is halogen, methoxy, or methyl in which one hydrogen atom is optionally replaced by a hydroxy group, and the other two are hydrogen;
- R3 is hydrogen, halogen, C1-C3 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, C1-C3 alkoxy in which any one to three hydrogen atoms are optionally replaced by a fluorine atom(s), methoxycarbonyl, —NR9R10, —CH2NR11R12, or —CH2CONR13R14,
- R6 and R7 each independently represent hydrogen or C1-C3 alkyl, or
- R6 and R7 together represent —(CH2)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(CH3)—;
- R8 is hydrogen or C1-C3 alkyl;
- R9 and R10 each independently represent hydrogen, —COR15, or C1-C3 alkylsulfonyl, or
- R9 and R10 together represent —(CH2)n—;
- n is an integer of 3 to 6;
- R11 and R12 together represent —(CH2)m—;
- m is an integer of 3 to 5, wherein any one of the methylene groups is optionally replaced by an oxygen atom;
- R13 and R14 each independently represent hydrogen, C1-C5 alkyl group, 2-hydroxyethyl, C3 or C4 cycloalkyl in which any one carbon atom is optionally replaced by an oxygen atom, or methyl which is substituted with a C3 or C4 cycloalkyl group in which any one carbon atom is optionally replaced by a nitrogen or oxygen atom, or
- R13 and R14 together represent —(CH2)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 CH2 group is optionally replaced by an oxygen atom, a nitrogen atom, or —CONH—;
- k is an integer of 3 to 5;
- R15 is C1-C5 alkyl, C1-C5 alkoxy, or —NHR16;
- R16 is hydrogen or C1-C8alkyl;
- Rv is hydrogen, methyl in which any one hydrogen atom is optionally replaced by a hydroxy or methoxycarbonyl group, or methoxycarbonyl;
- and
- Rw is hydrogen, methyl, hydroxymethyl, or methoxycarbonyl, provided that 2-phenyl-1,2,3,4-tetrahydroquinoline and 3-phenyl-1,2,3,4-tetrahydroquinoline are excluded.
21 more elements
Dependencies are inferred from the claim text.