WO2023249105A1 - Agent thérapeutique ou agent préventif pour des troubles myocardiques d'origine médicamenteuse - Google Patents

Agent thérapeutique ou agent préventif pour des troubles myocardiques d'origine médicamenteuse Download PDF

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Publication number
WO2023249105A1
WO2023249105A1 PCT/JP2023/023262 JP2023023262W WO2023249105A1 WO 2023249105 A1 WO2023249105 A1 WO 2023249105A1 JP 2023023262 W JP2023023262 W JP 2023023262W WO 2023249105 A1 WO2023249105 A1 WO 2023249105A1
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mmol
atom
tetrahydroquinolin
hydrogen atom
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PCT/JP2023/023262
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Japanese (ja)
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雄大 高橋
英樹 成見
系裕 大信田
美樹人 平形
こずえ 高垣
裕之 目黒
将史 山本
絢ヌネッツ 浅場
摩利菜 野上
理一郎 辻
直哉 請川
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東レ株式会社
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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure

Definitions

  • the present invention relates to a therapeutic or preventive agent for drug-induced myocardial damage.
  • Drug-induced myocardial damage is a so-called side effect of anticancer drugs, and is also considered a problem in cancer chemotherapy treatment.
  • Drug-induced myocardial injury is a disease whose basic condition is cardiomyopathy caused by damage to the myocardium caused by drugs, and patients who develop this disease may develop intractable heart failure and die.
  • Non-Patent Document 1 Non-Patent Document 1
  • Non-Patent Document 2 The development of drug-induced myocardial damage caused by anthracycline anticancer drugs including doxorubicin involves inhibition of topoisomerase 2 ⁇ activity expressed in cardiomyocytes, resulting in DNA damage, mitochondrial dysfunction, and increased production of reactive oxygen species. Guidance is considered to be important (Non-Patent Document 2).
  • Ferroptosis is a phenomenon in which various stimuli cause a decrease in antioxidant function such as a decrease in the amount of intracellular glutathione and glutathione peroxidase 4 (GPX4), and as a result of divalent iron-dependent reactions progressing, intracellular lipid peroxide becomes lethal. This is a reaction in which the amount of cells increases to a certain level, resulting in cell death.
  • Non-Patent Documents 3 and 5 Aniline derivatives such as Ferrostatin-1 are known as compounds that exhibit a ferroptosis inhibitory effect. Furthermore, it has been disclosed that tetrahydroquinoxaline derivatives and 3,4-dihydro-2H-benzo-[1,4]oxazine derivatives also have ferroptosis inhibiting effects (Patent Documents 1 and 2).
  • Non-Patent Document 6 It has been reported that radical scavenging action is important for the expression of ferroptosis inhibitory action. Furthermore, it has been disclosed that the tetrahydroquinoxaline derivative described in Patent Document 1 has a strong radical scavenging effect and, as a result, exhibits a ferroptosis inhibiting effect (Non-patent Documents 7 and 8).
  • an object of the present invention is to provide a compound that has a ferroptosis inhibiting effect and exhibits a therapeutic or preventive effect on drug-induced cardiomyopathy.
  • R 1x is a hydrogen atom, an aryl group, or a 5- or 6-membered heteroaryl group containing 1 or 2 heteroatoms selected from nitrogen atoms, oxygen atoms, and sulfur atoms (excluding pyridyl groups)
  • 1 or 2 arbitrary hydrogen atoms of the aryl group and the 5- or 6-membered heteroaryl group are each independently a halogen atom
  • 1 to 3 arbitrary hydrogen atoms are each independently a hydroxy group or
  • R 1x and R 1y are both hydrogen atoms
  • the combination of R 2 , R 4 and R 5 is such that R 2 , R 4 and R 5 are all hydrogen atoms, Or, one of R 2 , R 4 and R 5 is a halogen atom, a methoxy group, or a methyl group in which one hydrogen atom may be substituted with a hydroxy group, and the other two are hydrogen atoms, R 3 is a hydrogen atom, a halogen atom, an alkyl group having 1 to 3 carbon atoms in which 1 to 3 arbitrary hydrogen atoms may each be independently substituted with a hydroxy group or a fluorine atom, 3-hydroxyoxetane- 3-yl group, hydroxy group, alkoxy group having 1 to 3 carbon atoms in which 1 to 3 arbitrary hydrogen atoms may be substituted with fluorine atoms, -NR 9 R 10 , -CH 2 NR 11 R 12 or -CH 2 CONR 13 represents R 14
  • R 13 and R 14 are combined and one or two arbitrary hydrogen atoms are a fluorine atom, methyl group, hydroxy group, or methoxy group, or one arbitrary CH 2 group is an oxygen atom, a nitrogen atom or -(CH 2 ) k - which may be substituted with -CONH-, k represents an integer from 3 to 5,
  • R 15 represents an alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, or -NHR 16 ;
  • R 16 represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms,
  • R v represents a hydrogen atom, a methyl group in which one arbitrary hydrogen atom may be substituted with a hydroxy group or a methoxycarbonyl group, or
  • tetrahydroquinoline derivative or a pharmacologically acceptable salt thereof is selected from the following group: 2-phenyl-1,2,3,4-tetrahydroquinoline, 4-(1,2,3,4-tetrahydroquinolin-2-yl)benzenesulfonamide, and 4-(6-methyl-1,2,3,4-tetrahydroquinolin-2-yl)benzenesulfonamide, or its pharmacologically acceptable salts;
  • the present invention includes a ferroptosis inhibitor containing a tetrahydroquinoline derivative represented by the following general formula (I) or a pharmacologically acceptable salt thereof as an active ingredient. .
  • R 1x is a hydrogen atom, an aryl group, or a 5- or 6-membered heteroaryl group containing 1 or 2 heteroatoms selected from nitrogen atoms, oxygen atoms, and sulfur atoms (excluding pyridyl groups)
  • 1 or 2 arbitrary hydrogen atoms of the aryl group and the 5- or 6-membered heteroaryl group are each independently a halogen atom
  • 1 to 3 arbitrary hydrogen atoms are each independently a hydroxy group or
  • R 1x and R 1y are both hydrogen atoms
  • the combination of R 2 , R 4 and R 5 is such that R 2 , R 4 and R 5 are all hydrogen atoms, Or, one of R 2 , R 4 and R 5 is a halogen atom, a methoxy group, or a methyl group in which one hydrogen atom may be substituted with a hydroxy group, and the other two are hydrogen atoms, R 3 is a hydrogen atom, a halogen atom, an alkyl group having 1 to 3 carbon atoms in which 1 to 3 arbitrary hydrogen atoms may each be independently substituted with a hydroxy group or a fluorine atom, 3-hydroxyoxetane- 3-yl group, hydroxy group, alkoxy group having 1 to 3 carbon atoms in which 1 to 3 arbitrary hydrogen atoms may be substituted with fluorine atoms, -NR 9 R 10 , -CH 2 NR 11 R 12 or -CH 2 CONR 13 represents R 14
  • R 13 and R 14 are combined and one or two arbitrary hydrogen atoms are a fluorine atom, methyl group, hydroxy group, or methoxy group, or one arbitrary CH 2 group is an oxygen atom, a nitrogen atom or -(CH 2 ) k - which may be substituted with -CONH-, k represents an integer from 3 to 5,
  • R 15 represents an alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, or -NHR 16 ;
  • R 16 represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms,
  • R v represents a hydrogen atom, a methyl group in which one arbitrary hydrogen atom may be substituted with a hydroxy group or a methoxycarbonyl group, or
  • the present invention includes the use of the above-mentioned tetrahydroquinoline derivative (I) or a pharmacologically acceptable salt thereof in the production of a ferroptosis inhibitor.
  • the present invention includes the use of the above-mentioned tetrahydroquinoline derivative (I) or a pharmacologically acceptable salt thereof in the production of a therapeutic or preventive agent for drug-induced myocardial damage.
  • the present invention includes the above-mentioned tetrahydroquinoline derivative (I) or a pharmacologically acceptable salt thereof for use in the treatment or prevention of drug-induced myocardial damage.
  • the present invention provides a method for treating or preventing drug-induced myocardial damage, which comprises administering an effective amount of the above tetrahydroquinoline derivative (I) or a pharmacologically acceptable salt thereof. and administering to a subject in need thereof.
  • R 1x is a hydrogen atom, an aryl group, or a 5- or 6-membered heteroaryl group containing 1 or 2 heteroatoms selected from nitrogen atoms, oxygen atoms, and sulfur atoms (excluding pyridyl groups)
  • 1 or 2 arbitrary hydrogen atoms of the aryl group and the 5- or 6-membered heteroaryl group are each independently a halogen atom
  • 1 to 3 arbitrary hydrogen atoms are each independently a hydroxy group or
  • R 1y represents a hydrogen atom, a phenyl group, a 4-hydroxymethylphenyl group, a 4-aminocarbonylphenyl group, a 4-acetamidophenyl group, a 4-aminosulfonylphenyl group, a 4-methylsulfonylphenyl group, or a 3-pyridyl group.
  • R 1x and R 1y are both hydrogen atoms
  • the combination of R 2 , R 4 and R 5 is such that R 2 , R 4 and R 5 are all hydrogen atoms, Or, one of R 2 , R 4 and R 5 is a halogen atom, a methoxy group, or a methyl group in which one hydrogen atom may be substituted with a hydroxy group, and the other two are hydrogen atoms, R 3 is a hydrogen atom, a halogen atom, an alkyl group having 1 to 3 carbon atoms in which 1 to 3 arbitrary hydrogen atoms may each be independently substituted with a hydroxy group or a fluorine atom, 3-hydroxyoxetane- 3-yl group, hydroxy group, alkoxy group having 1 to 3 carbon atoms in which 1 to 3 arbitrary hydrogen atoms may be substituted with fluorine atoms, -NR 9 R 10 , -CH 2 NR 11 R 12 or -CH 2 CONR 13 represents R 14
  • R 13 and R 14 are combined and one or two arbitrary hydrogen atoms are a fluorine atom, methyl group, hydroxy group, or methoxy group, or one arbitrary CH 2 group is an oxygen atom, a nitrogen atom or -(CH 2 ) k - which may be substituted with -CONH-, k represents an integer from 3 to 5,
  • R 15 represents an alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, or -NHR 16 ;
  • R 16 represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms,
  • R v represents a hydrogen atom, a methyl group in which one arbitrary hydrogen atom may be substituted with a hydroxy group or a methoxycarbonyl group, or
  • Halogen atom means a fluorine atom, chlorine atom, bromine atom, or iodine atom.
  • Alkyl group having 1 to 3 carbon atoms means a methyl group, ethyl group, propyl group or isopropyl group.
  • Alkyl group having 1 to 5 carbon atoms means a linear or branched hydrocarbon group having 1 to 5 carbon atoms, such as methyl group, ethyl group, propyl group, isopropyl group, butyl group, Examples include isobutyl group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group, sec-pentyl group, tert-pentyl group and neopentyl group.
  • Alkyl group having 1 to 3 carbon atoms in which 1 to 3 arbitrary hydrogen atoms may be independently substituted with a hydroxy group or a fluorine atom refers to the above-mentioned "alkyl group having 1 to 3 carbon atoms”.
  • '' means a group in which 1 to 3 arbitrary hydrogen atoms may each be independently substituted with a hydroxy group or a fluorine atom, such as a methyl group, a hydroxymethyl group, an ethyl group, a 1-hydroxy Ethyl group, 2-hydroxyethyl group, 1,2-dihydroxyethyl group, propyl group, 1-hydroxypropyl group, 2-hydroxypropyl group, 3-hydroxypropyl group, 1,2-dihydroxypropyl group, 1,3- Dihydroxypropyl group, 2,3-dihydroxypropyl group, isopropyl group, 2-hydroxypropan-2-yl group, 1-hydroxypropan-2-yl group, 1,2-dihydroxy-1-methylethyl group, fluoromethyl group , difluoromethyl group, trifluoromethyl group, 1,1-difluoroethyl group, 2,2,2-trifluoroethyl group, 1,1-difluoropropyl group, 2,2-di
  • Alkyl group having 1 to 3 carbon atoms in which 1 to 3 arbitrary hydrogen atoms may be substituted with fluorine atoms means 1 to 3 of the above-mentioned "alkyl group having 1 to 3 carbon atoms” Refers to a group in which any hydrogen atom may be substituted with a fluorine atom, such as methyl group, fluoromethyl group, difluoromethyl group, trifluoromethyl group, ethyl group, 1,1-difluoroethyl group, 2, 2,2-trifluoroethyl group, propyl group, 1,1-difluoropropyl group, 2,2-difluoropropyl group, 3,3,3-trifluoropropyl group, isopropyl group, 2-fluoropropan-2-yl or 1,1,1-trifluoropropan-2-yl group.
  • a fluorine atom such as methyl group, fluoromethyl group, difluoromethyl group, trifluoro
  • Alkyl group having 1 to 3 carbon atoms in which 1 to 3 arbitrary hydrogen atoms are substituted with fluorine atoms means any 1 to 3 alkyl group having 1 to 3 carbon atoms of the above "alkyl group having 1 to 3 carbon atoms”
  • a hydrogen atom is substituted with a fluorine atom, such as a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a 1,1-difluoroethyl group, a 2,2,2-trifluoroethyl group, , 1-difluoropropyl group, 2,2-difluoropropyl group, 3,3,3-trifluoropropyl group, 2-fluoropropan-2-yl group or 1,1,1-trifluoropropan-2-yl group can be mentioned.
  • Alkyl group having 1 to 3 carbon atoms, in which one arbitrary hydrogen atom may be substituted with a hydroxy group means one arbitrary hydrogen atom of the above-mentioned "alkyl group having 1 to 3 carbon atoms” means a group which may be substituted with a hydroxy group, such as a methyl group, a hydroxymethyl group, an ethyl group, a 1-hydroxyethyl group, a 2-hydroxyethyl group, a propyl group, a 1-hydroxypropyl group, a 2- Examples include hydroxypropyl group, 3-hydroxypropyl group, isopropyl group, 2-hydroxypropan-2-yl group, and 1-hydroxypropan-2-yl group.
  • a C1-C3 alkyl group in which one arbitrary hydrogen atom is substituted with a hydroxy group refers to the above "C1-C3 alkyl group” in which one arbitrary hydrogen atom is substituted with a hydroxy group. means a group substituted with a group, such as hydroxymethyl group, 1-hydroxyethyl group, 2-hydroxyethyl group, 1-hydroxypropyl group, 2-hydroxypropyl group, 3-hydroxypropyl group, 2-hydroxy Examples include propan-2-yl group and 1-hydroxypropan-2-yl group.
  • Alkyl group having 1 to 3 carbon atoms in which 1 to 3 arbitrary hydrogen atoms may be substituted with a fluorine atom or 1 arbitrary hydrogen atom with a hydroxy group means the above-mentioned “1 to 3 carbon atoms "an alkyl group having 1 to 3 carbon atoms in which any hydrogen atom may be substituted with a fluorine atom” or "an alkyl group having 1 to 3 carbon atoms in which one arbitrary hydrogen atom may be substituted with a hydroxy group" "alkyl group”.
  • a methyl group in which one hydrogen atom may be substituted with a hydroxy group means a methyl group or a hydroxymethyl group.
  • Alkoxy group having 1 to 3 carbon atoms means a methoxy group, ethoxy group, propoxy group or isopropoxy group.
  • Alkoxy group having 1 to 5 carbon atoms means a monovalent substituent in which a linear or branched hydrocarbon group having 1 to 5 carbon atoms is bonded to an oxygen atom, such as a methoxy group, an ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group, sec-butoxy group, tert-butoxy group, pentyloxy group, isopentyloxy group, sec-pentyloxy group, tert-pentyloxy group or neopentyloxy group can be mentioned.
  • Alkoxy group having 1 to 3 carbon atoms in which 1 to 3 arbitrary hydrogen atoms may be substituted with fluorine atoms means 1 to 3 of the above-mentioned "alkoxy group having 1 to 3 carbon atoms” Refers to a group in which any hydrogen atom may be substituted with a fluorine atom, such as a methoxy group, a fluoromethoxy group, a difluoromethoxy group, a trifluoromethoxy group, an ethoxy group, a 1,1-difluoroethoxy group, 2, 2,2-trifluoroethoxy group, propoxy group, 1,1-difluoropropoxy group, 2,2-difluoropropoxy group, 3,3,3-trifluoropropoxy group, isopropoxy group, (2-fluoropropane-2 -yl)oxy group or (1,1,1-trifluoropropan-2-yl)oxy group.
  • a methoxy group in which 1 to 3 arbitrary hydrogen atoms are substituted with fluorine atoms means a fluoromethoxy group, a difluoromethoxy group, or a trifluoromethoxy group.
  • a methoxy group in which 1 to 3 arbitrary hydrogen atoms may be substituted with fluorine atoms refers to the above-mentioned "methoxy group in which 1 to 3 arbitrary hydrogen atoms are substituted with fluorine atoms" or Means a methoxy group.
  • Alkylsulfonyl group having 1 to 3 carbon atoms means a methylsulfonyl group, an ethylsulfonyl group, a propylsulfonyl group, or an isopropylsulfonyl group.
  • Aryl group means a monocyclic or bicyclic aromatic hydrocarbon group, and includes, for example, a phenyl group or a naphthyl group (1-naphthyl group or 2-naphthyl group).
  • pyrimidinyl group e.g. 2-pyrimidinyl group, 4-pyrimidinyl group
  • 5-pyrimidinyl group or 6-pyrimidinyl group pyridazinyl group
  • pyridazinyl group eg, 3-pyridazinyl group or 4-pyridazinyl group
  • pyrazinyl group eg, 2-pyridazinyl group.
  • 5- and 6-membered lactam ring means a pyrrolidin-2-one ring and a piperidin-2-one ring.
  • a fused ring in which a phenyl group is fused with one ring selected from the group consisting of a 5- and 6-membered lactam ring and a 5- and 6-membered saturated heterocycle containing 1 or 2 oxygen atoms as ring constituent atoms.
  • group is selected from the group consisting of a phenyl group, the above-mentioned “5- and 6-membered lactam ring", and the above-mentioned “5- and 6-membered saturated heterocycle containing 1 or 2 oxygen atoms as ring constituent atoms" 3-oxoisoindolin-4-yl group, 3-oxoisoindolin-5-yl group, 1-oxoisoindolin-5 -yl group, 1-oxoisoindolin-4-yl group, 2-oxoindolin-4-yl group, 2-oxoindolin-5-yl group, 2-oxoindolin-6-yl group, 2-oxoindolin- 7-yl group, 2,3-dihydrobenzofuran-4-yl group, 2,3-dihydrobenzofuran-5-yl group, 2,3-dihydrobenzofuran-6-yl group, 2,3-dihydrobenzofuran-7-yl
  • Azetidine ring in which one arbitrary hydrogen atom may be substituted with a hydroxy group together with the nitrogen atom to which R 13 and R 14 are bonded means, for example, an azetidine ring or a 3-hydroxyazetidine ring. Examples include rings.
  • Azetidine ring in which two arbitrary hydrogen atoms may be substituted with a methyl group or a fluorine atom, or one arbitrary hydrogen atom may be substituted with a hydroxy group or a methoxy group means an azetidine ring, 2,2-dimethylazetidine ring, Zine ring, 2,3-dimethylazetidine ring, 2,4-dimethylazetidine ring, 3,3-dimethylazetidine ring, 3,3-difluoroazetidine ring, 3-hydroxyazetidine ring or 3-methoxyazetidine ring Examples include the Jin ring.
  • a cycloalkyl group having 3 or 4 carbon atoms in which one arbitrary carbon atom may be substituted with an oxygen atom means, for example, a cyclopropyl group, a cyclobutyl group, an oxiran-2-yl group, or an oxetane-3 -yl group is mentioned.
  • a methyl group in which one arbitrary carbon atom is substituted with a cycloalkyl group having 3 or 4 carbon atoms which may be substituted with a nitrogen atom or an oxygen atom means, for example, a cyclopropylmethyl group, a cyclobutyl Examples include methyl group, oxiran-2-ylmethyl group, oxetan-2-ylmethyl, oxetan-3-ylmethyl, aziridin-2-ylmethyl, azetidin-2-ylmethyl group and azetidin-3-ylmethyl group.
  • R 1x is a substituted phenyl group, it is preferable that the hydrogen atom at the para position is substituted.
  • R 1x is a phenyl group (one arbitrary hydrogen atom of the phenyl group is a halogen atom).
  • R 1x is a hydrogen atom, a phenyl group (any hydrogen atom of one of the phenyl groups).
  • the atom is an alkyl group having 1 to 3 carbon atoms in which one arbitrary hydrogen atom is substituted with a hydroxy group, -CONR 6 R 7 , an aminosulfonyl group, a methylsulfonylamino group, an aminosulfonylamino group, or an alkyl group having 1 carbon number ⁇ 3 alkylsulfonyl groups, or one hydrogen atom at the meta position of the phenyl group is substituted with a cyano group, or the hydrogen atom at the para position of the phenyl group is substituted with a trifluoromethoxy group.
  • 1-methyl-1H-pyrazol-4-yl group or 6-methoxypyridin-3-yl group, or phenyl group and pyrrolidin-2-one, piperidin-2-one and 1 , 3-dioxolane is preferably a fused ring group (one arbitrary hydrogen atom of the fused ring group may be substituted with a methyl group).
  • R 1y is preferably a hydrogen atom, a phenyl group, a 4-hydroxymethylphenyl group, a 4-aminocarbonylphenyl group, a 4-acetamidophenyl group, a 4-aminosulfonylphenyl group, a 4-methylsulfonylphenyl group, and -Hydroxymethylphenyl group, 4-aminocarbonylphenyl group, 4-acetamidophenyl group, 4-aminosulfonylphenyl group or 4-methylsulfonylphenyl group, more preferably 4-aminocarbonylphenyl group, 4-aminosulfonyl group. More preferably, it is a phenyl group or a 4-methylsulfonylphenyl group.
  • R 1x and R 1y are not both hydrogen atoms.
  • R 2 is preferably a hydrogen atom, a fluorine atom, a chlorine atom, a hydroxymethyl group or a methyl group, and more preferably a hydrogen atom.
  • R 5 is a hydrogen atom.
  • R 6 and R 7 are each independently a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, or R 6 and R 7 together with the nitrogen atom bonded thereto are a piperidine ring, a morpholine It is preferable that a ring, a piperazine ring or an N-methylpiperazine ring may be formed, and it is more preferable that R 6 and R 7 are both hydrogen atoms.
  • R 8 is preferably a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, and more preferably a methyl group.
  • R 9 is a hydrogen atom
  • R 10 is a hydrogen atom, -COR 15 , or an alkylsulfonyl group having 1 to 3 carbon atoms, or R 9 and R 10 taken together are -(CH 2 ) n -, n is preferably 4 or 5, R 9 is a hydrogen atom, and R 10 is more preferably -COR 15 .
  • R 15 is preferably an alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, or -NHR 16 .
  • R 16 is preferably a hydrogen atom or an alkyl group having 1 to 5 carbon atoms.
  • R v is preferably a hydrogen atom.
  • R w is a hydrogen atom.
  • tetrahydroquinoline derivative (I) or a pharmacologically acceptable salt thereof can be used not only as a single stereoisomer but also as a mixture of stereoisomers such as a racemate and a diastereomer mixture (e.g., an enantiomer). (mixtures of) are also included.
  • Stepoisomer refers to compounds that have the same chemical structure but different configurations in three-dimensional space, such as conformers, rotamers, tautomers, enantiomers, or diastereomers. etc.
  • the above tetrahydroquinoline derivative (I) may have the following general formulas (I-1) to (I-8).
  • R 1x , R 1y , R 2 , R 3 , R 4 , R 5 , R v and R w have the same meanings as the above definitions. ]
  • R 1x is a phenyl group (one arbitrary hydrogen atom of the phenyl group is a fluorine atom, a chlorine atom, and 1 to 3 arbitrary hydrogen atoms are a fluorine atom). or an alkyl group having 1 to 3 carbon atoms in which one arbitrary hydrogen atom may be substituted with a hydroxy group, or an alkyl group having 1 to 3 carbon atoms in which 1 to 3 arbitrary hydrogen atoms may be substituted with fluorine atoms.
  • tetrahydroquinoline derivative (I) includes, for example, a tetrahydroquinoline derivative represented by the following general formula (II-a) or a pharmacologically acceptable salt thereof.
  • R 9 is a hydrogen atom
  • R 10 is -COR 15
  • R 15 is preferably an alkoxy group having 1 to 5 carbon atoms
  • A is a hydrogen atom
  • R 9 is a hydrogen atom
  • R 10 is -COR 15
  • R 15 is an alkoxy group having 1 to 5 carbon atoms. More preferably, A is a hydrogen atom, R 9 is a hydrogen atom, R 10 is -COR 15 , and R 15 is a tert-butoxy group.
  • the above tetrahydroquinoline derivative (II-a) or a pharmacologically acceptable salt thereof contains the above tetrahydroquinoline derivative (II-a) or a pharmacologically acceptable salt thereof as an active ingredient.
  • tetrahydroquinoline derivative (I) includes, for example, a tetrahydroquinoline derivative represented by the following general formula (II-b) or a pharmacologically acceptable salt thereof.
  • R 1y is a phenyl group, 4-hydroxymethylphenyl group, 4-aminocarbonylphenyl group, 4-acetamidophenyl group, 4-aminosulfonylphenyl group, 4-methylsulfonylphenyl or 3-pyridyl group;
  • R 3 is a hydrogen atom or a halogen atom, and
  • R 4 is a hydrogen atom or a halogen atom (excluding 3-phenyl-1,2,3,4-tetrahydroquinoline).
  • the above tetrahydroquinoline derivative (II-c) or a pharmacologically acceptable salt thereof contains the above tetrahydroquinoline derivative (II-c) or a pharmacologically acceptable salt thereof as an active ingredient. It can be used as a therapeutic or preventive agent for amyotrophic lateral sclerosis.
  • the above tetrahydroquinoline derivative (II-c) or a pharmacologically acceptable salt thereof contains the above tetrahydroquinoline derivative (II-c) or a pharmacologically acceptable salt thereof as an active ingredient.
  • the present invention also includes prodrugs of the above-mentioned tetrahydroquinoline derivative (I).
  • the prodrug of the above-mentioned tetrahydroquinoline derivative (I) is a compound that is enzymatically or chemically converted into the above-mentioned tetrahydroquinoline derivative (I) in vivo.
  • the active substance of the prodrug of the above tetrahydroquinoline derivative (I) is the above tetrahydroquinoline derivative (I), but the prodrug of the above tetrahydroquinoline derivative (I) itself may have activity.
  • organic acid salts such as glutamate or cinnamate.
  • the above tetrahydroquinoline derivative (I) or a pharmacologically acceptable salt thereof may be anhydrous or may form a solvate such as a hydrate.
  • each isomer can be obtained as a single compound by a known method or a method analogous thereto.
  • Known methods include, for example, crystallization, enzymatic resolution or chiral chromatography.
  • a general method for producing the above tetrahydroquinoline derivative (I) is illustrated below. Note that the compounds in the following schemes may also form salts, and examples of such salts include those similar to the salts in the above-mentioned tetrahydroquinoline derivative (I).
  • the manufacturing method of the present invention is not limited to the examples shown below.
  • Examples of the base used in the coupling reaction include organic bases such as triethylamine or N,N-diisopropylethylamine, inorganic bases such as sodium carbonate, potassium carbonate, or cesium carbonate, and lithium bases such as lithium hexamethyldisilazide or lithium diisopropylamide. Mention may be made of amides, metal alkoxides such as sodium tert-butoxide or potassium tert-butoxide, or mixtures thereof, but inorganic bases such as sodium carbonate, potassium carbonate or cesium carbonate are preferred.
  • organic bases such as triethylamine or N,N-diisopropylethylamine
  • inorganic bases such as sodium carbonate, potassium carbonate, or cesium carbonate
  • lithium bases such as lithium hexamethyldisilazide or lithium diisopropylamide. Mention may be made of amides, metal alkoxides such as sodium tert-butoxide or potassium
  • the amount of the base used in the coupling reaction is preferably 0.5 to 10 equivalents, more preferably 1 to 4 equivalents, relative to the 2-haloquinoline derivative (III).
  • reaction time of the coupling reaction is appropriately selected depending on conditions such as reaction temperature, but is preferably 1 to 30 hours.
  • the 2-haloquinoline derivative (III) and boronic acid derivative (IV) used in the coupling reaction can be purchased or produced by a known method or a method analogous thereto.
  • the quinoline derivative (IX) can be obtained by a cycloaddition reaction between the 2-aminobenzyl alcohol derivative (V) and the ketone derivative (VI) in the presence of a base.
  • a cycloaddition reaction between the 2-aminobenzyl alcohol derivative (V) and the ketone derivative (VI) in the presence of a base.
  • it can be carried out according to the method described in (Tetrahedron Letters, 2008, pp. 6893-6895) or a method analogous thereto.
  • the amount of the ketone derivative (VI) used in the cycloaddition reaction is preferably 0.5 to 10 equivalents, more preferably 0.8 to 5 equivalents, relative to the 2-aminobenzyl alcohol derivative (V).
  • Examples of the base used in the cycloaddition reaction include inorganic bases such as sodium hydroxide, potassium hydroxide, or cesium hydroxide, metal alkoxides such as sodium ethoxide, sodium tert-butoxide, or potassium tert-butoxide, sodium hydride, Mention may be made of metal hydrides such as potassium hydride or calcium hydride, or mixtures thereof, with metal alkoxides such as sodium ethoxide, sodium tert-butoxide or potassium tert-butoxide being preferred.
  • the amount of the base used in the cycloaddition reaction is preferably 0.5 to 10 equivalents, more preferably 1 to 3 equivalents, based on the 2-aminobenzyl alcohol derivative (V).
  • the reaction solvent used in the cycloaddition reaction is appropriately selected depending on the type of reagent used, but is not particularly limited as long as it does not inhibit the reaction.
  • THF 1,4-dioxane
  • DME 1,4-dioxane
  • examples include ether solvents such as benzene or toluene, aromatic hydrocarbon solvents such as benzene or toluene, aprotic polar solvents such as DMF, DMA or DMSO, or mixed solvents thereof; Ether solvents are preferred.
  • the reaction temperature of the cycloaddition reaction is preferably 0 to 200°C, more preferably 50 to 150°C.
  • reaction time for the cycloaddition reaction is appropriately selected depending on conditions such as reaction temperature, but is preferably 1 to 24 hours.
  • the quinoline derivative (IX) is produced by an oxidative cyclization reaction between the aniline derivative (VII) and an allyl alcohol derivative (VIII-a) or an ⁇ , ⁇ unsaturated aldehyde derivative (VIII-b) in an oxygen atmosphere in the presence of a metal catalyst. It can be obtained by For example, it can be carried out according to the method described in (RSC Advances, 2017, pp. 36242-36245) or a method analogous thereto.
  • the amount of the allyl alcohol derivative (VIII-a) or ⁇ , ⁇ unsaturated aldehyde derivative (VIII-b) used in the oxidative cyclization reaction is preferably 0.5 to 10 equivalents relative to the aniline derivative (VII), and 0. .8 to 2 equivalents is more preferred.
  • the amount of the metal catalyst used in the oxidative cyclization reaction is preferably 0.01 to 5 equivalents, more preferably 0.025 to 1 equivalent, relative to the aniline derivative (VII).
  • the pressure of oxygen used in the oxidative cyclization reaction is preferably about 1 to about 20 atm, more preferably about 1 to about 5 atm.
  • the reaction solvent used in the oxidative cyclization reaction is appropriately selected depending on the type of reagent used, but is not particularly limited as long as it does not inhibit the reaction.
  • THF, 1,4-dioxane, or DME examples include ether solvents such as benzene or toluene, aromatic hydrocarbon solvents such as benzene or toluene, aprotic polar solvents such as DMF, DMA or DMSO, or mixed solvents thereof; Polar solvents are preferred.
  • the reaction temperature of the oxidative cyclization reaction is preferably 0 to 300°C, more preferably 70 to 200°C.
  • reaction time of the oxidative cyclization reaction is appropriately selected depending on conditions such as reaction temperature, but is preferably 1 to 24 hours.
  • the aniline derivative (VII), allyl alcohol derivative (VIII-a), and ⁇ , ⁇ unsaturated aldehyde derivative (VIII-b) used in the oxidative cyclization reaction can be purchased or prepared using a known method or similar method. It can be manufactured by the method.
  • Tetrahydroquinoline derivative (Ia) can be obtained by hydrogenation reaction of quinoline derivative (IX) in a hydrogen atmosphere in the presence of a metal catalyst. Alternatively, it can be obtained by a hydrogen transfer reduction reaction between a 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid ester derivative and a quinoline derivative (IX).
  • metal catalysts used in the hydrogenation reaction include palladiums such as palladium on carbon, palladium(II) hydroxide on carbon and palladium(II) oxide, nickel such as developed nickel catalysts, platinum(IV) oxide or platinum on carbon, etc.
  • palladiums such as palladium on carbon, palladium(II) hydroxide on carbon and palladium(II) oxide
  • nickel such as developed nickel catalysts
  • platinum(IV) oxide or platinum on carbon etc.
  • platinums such as , rhodiums such as rhodium carbon, and platinum (IV) oxide is preferred.
  • the amount of the metal catalyst used in the hydrogenation reaction is preferably 0.001 to 1 equivalent, more preferably 0.01 to 0.5 equivalent, relative to the quinoline derivative (IX).
  • the reaction solvent used in the hydrogenation reaction is appropriately selected depending on the type of reagent used, but is not particularly limited as long as it does not inhibit the reaction, such as methanol, ethanol, isopropyl alcohol, or tert-butyl alcohol.
  • alcohol solvents such as toluene or xylene, chlorine solvents such as dichloromethane, chloroform or 1,2-dichloroethane, ether solvents such as diethyl ether, THF, DME or 1,4-dioxane , ester solvents such as ethyl acetate or propyl acetate, aprotic polar solvents such as DMF, DMA or DMSO, carboxylic acid solvents such as formic acid or acetic acid, water or a mixed solvent thereof, but methanol, ethanol, A mixed solvent of an alcohol solvent such as isopropyl alcohol or tert-butyl alcohol and a carboxylic acid solvent such as formic acid or acetic acid is
  • the reaction temperature of the hydrogenation reaction is preferably 0 to 200°C, more preferably 10 to 100°C.
  • the reaction time of the hydrogenation reaction is appropriately selected depending on conditions such as reaction temperature, but is preferably 0.5 to 40 hours.
  • the amount of the 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid ester derivative used in the hydrogen transfer reduction reaction is preferably 1 to 10 equivalents, and 1.7 to 10 equivalents relative to the quinoline derivative (IX). 3 equivalents is more preferred.
  • the reaction solvent used in the hydrogen transfer reduction reaction is appropriately selected depending on the type of reagent used, but is not particularly limited as long as it does not inhibit the reaction.
  • methanol, ethanol, isopropyl alcohol, or tert-butyl Alcohol solvents such as alcohol, aromatic hydrocarbon solvents such as toluene or xylene, chlorine solvents such as dichloromethane, chloroform or 1,2-dichloroethane, ether solvents such as diethyl ether, THF, DME or 1,4-dioxane
  • Solvents include ester solvents such as ethyl acetate or propyl acetate, aprotic polar solvents such as DMF, DMA or DMSO, or mixed solvents thereof, and chlorine solvents such as dichloromethane, chloroform or 1,2-dichloroethane; Ether solvents such as diethyl ether, THF, DME or 1,4-dioxane are preferred.
  • the reaction temperature of the hydrogen transfer reduction reaction is preferably 0 to 100°C, more preferably 10 to 50°C.
  • the reaction time for the hydrogen transfer reduction reaction is appropriately selected depending on conditions such as reaction temperature, but is preferably 1 to 24 hours.
  • the aminoquinoline derivative (XI) can be obtained by a coupling reaction between a 6-haloquinoline derivative (IX-a) and a secondary amine derivative (X) in the presence of a metal catalyst and a base.
  • the amount of the secondary amine derivative (X) used in the coupling reaction is preferably 0.5 to 20 equivalents, more preferably 0.8 to 10 equivalents, relative to the 6-haloquinoline derivative (IX-a).
  • metal catalyst used in the coupling reaction examples include 1,1'-bis(diphenylphosphino)ferrocene dichloropalladium(II) dichloromethane adduct, palladium(II) chloride, palladium(II) acetate, bis(dibenzylideneacetone) ) palladium(0), tris(dibenzylideneacetone)dipalladium(0), tetrakistriphenylphosphinepalladium(0) or dichlorobistriphenylphosphinepalladium(0), and palladium(II) acetate is preferred.
  • the amount of the metal catalyst used in the coupling reaction is preferably 0.001 to 5 equivalents, more preferably 0.02 to 0.5 equivalents, based on the 6-haloquinoline derivative (IX-a).
  • the coupling reaction may further use a ligand.
  • ligand examples include triphenylphosphine, tert-butylphosphine, 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, 2-(dicyclohexylphosphino)-2',4' , 6'-triisopropyl-1,1'-biphenyl or 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene.
  • the amount of the ligand is preferably 0.001 to 5 equivalents, more preferably 0.02 to 1 equivalent, relative to the 6-haloquinoline derivative (IX-a).
  • Examples of the base used in the coupling reaction include organic bases such as triethylamine or N,N-diisopropylethylamine, inorganic bases such as sodium carbonate, potassium carbonate, or cesium carbonate, and lithium bases such as lithium hexamethyldisilazide or lithium diisopropylamide. Mention may be made of amides, metal alkoxides such as sodium tert-butoxide or potassium tert-butoxide, or mixtures thereof, but inorganic bases such as sodium carbonate, potassium carbonate or cesium carbonate are preferred.
  • organic bases such as triethylamine or N,N-diisopropylethylamine
  • inorganic bases such as sodium carbonate, potassium carbonate, or cesium carbonate
  • lithium bases such as lithium hexamethyldisilazide or lithium diisopropylamide. Mention may be made of amides, metal alkoxides such as sodium tert-butoxide or potassium
  • the amount of the base used in the coupling reaction is preferably 0.8 to 10 equivalents, more preferably 1 to 5 equivalents, relative to the 6-haloquinoline derivative (IX-a).
  • the reaction solvent used in the coupling reaction is appropriately selected depending on the type of reagent used, but is not particularly limited as long as it does not inhibit the reaction, such as methanol, ethanol, isopropyl alcohol, or tert-butyl alcohol.
  • alcoholic solvents such as THF, 1,4-dioxane or DME, aromatic hydrocarbon solvents such as benzene or toluene, nitrile solvents such as acetonitrile or propionitrile, DMF, DMA or DMSO, etc.
  • Examples include aprotic polar solvents, chlorine solvents such as dichloromethane, chloroform or 1,2-dichloroethane, and mixed solvents thereof, and ether solvents such as THF, 1,4-dioxane or DME are preferred.
  • the reaction temperature of the coupling reaction is preferably 0 to 200°C, more preferably 50 to 150°C.
  • reaction time of the coupling reaction is appropriately selected depending on conditions such as reaction temperature, but is preferably 1 to 30 hours.
  • the 6-haloquinoline derivative (IX-a) used in the coupling reaction can be purchased or manufactured by the methods described in Steps 1-1 to 1-3, a known method, or a method analogous thereto. Can be done.
  • the secondary amine derivative (X) used in the coupling reaction can be purchased or manufactured by a known method or a method analogous thereto.
  • Tetrahydroquinoline derivative (Ib) can be obtained by hydrogenation reaction or hydrogen transfer reduction reaction of aminoquinoline derivative (XI).
  • the selection conditions of the reagent, catalyst, hydrogen pressure, reaction solvent, and reaction temperature in this step are the same as in Step 1-4.
  • Y represents an alkyl group having 1 to 5 carbon atoms, and each of the other symbols has the same meaning as the above definition.
  • the quinoline-6-carboxylic acid derivative (XII) can be obtained by a hydrolysis reaction of the quinoline-6-carboxylic acid ester derivative (IX-b) in the presence of a base.
  • Examples of the base used in the hydrolysis reaction include lithium hydroxide, potassium hydroxide, sodium hydroxide, and sodium tert-butoxide, with potassium hydroxide or sodium hydroxide being preferred.
  • the amount of base used in the hydrolysis reaction is preferably 0.5 to 100 equivalents, more preferably 0.8 to 30 equivalents, relative to the quinoline-6-carboxylic acid ester derivative (IX-b). .
  • the reaction solvent used in the hydrolysis reaction is appropriately selected depending on the type of reagent used, but is not particularly limited as long as it does not inhibit the reaction.
  • an ether solvent such as THF, 1,4-dioxane, or DME Solvents
  • chlorinated solvents such as dichloromethane, chloroform or 1,2-dichloroethane
  • aromatic hydrocarbon solvents such as benzene or toluene
  • aprotic polar solvents such as DMF, DMA or DMSO
  • ketone solvents such as acetone or methyl ethyl ketone
  • alcoholic solvents such as methanol, ethanol, or 2-propanol, water, or a mixed solvent thereof, preferably a mixed solvent of an alcoholic solvent such as methanol, ethanol, or 2-propanol, and water.
  • the reaction temperature for the hydrolysis reaction is preferably -50°C to 150°C, more preferably -20°C to 100°C.
  • reaction time of the hydrolysis reaction is appropriately selected depending on conditions such as reaction temperature, but is preferably 1 to 30 hours.
  • the quinoline-6-carboxylic acid ester derivative (IX-b) used in the hydrolysis reaction can be purchased, or can be obtained by the method described in Steps 1-1 to 1-3, a known method, or a method similar thereto. It can be manufactured in
  • Step 3-2 The quinoline-6-carbamate ester derivative (XIV) is obtained by alcoholysis of the isocyanate derivative produced by the rearrangement reaction of the acid azide produced by using diphenylphosphoric acid azide for the quinoline-6-carboxylic acid derivative (XII). It can be obtained by reaction.
  • the amount of diphenylphosphoric acid azide used in the rearrangement reaction is preferably 1 to 10 equivalents, more preferably 1 to 3 equivalents, relative to the quinoline-6-carboxylic acid derivative (XII).
  • Examples of the base used in the rearrangement reaction include inorganic bases such as sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, magnesium hydroxide, or calcium hydroxide, or organic bases such as triethylamine or N,N-diisopropylethylamine. Examples include bases, and organic bases such as triethylamine or N,N-diisopropylethylamine are preferred.
  • the amount of the base used in the rearrangement reaction is preferably 1 to 10 equivalents, more preferably 1 to 3 equivalents, relative to the quinoline-6-carboxylic acid derivative (XII).
  • the reaction solvent used in the rearrangement reaction is appropriately selected depending on the type of reagent used, but is not particularly limited as long as it does not inhibit the reaction.
  • ethers such as THF, 1,4-dioxane, or DME are used.
  • ester solvents such as ethyl acetate or propyl acetate, chlorine solvents such as dichloromethane, chloroform or 1,2-dichloroethane, aromatic hydrocarbon solvents such as benzene or toluene, nitrile solvents such as acetonitrile or propionitrile Solvents include aprotic polar solvents such as DMF, DMA, or DMSO, or mixed solvents thereof.
  • Examples of the alcohol (XIII) used in the alcoholysis reaction include methanol, ethanol, isopropyl alcohol, and tert-butyl alcohol.
  • the amount of alcohol (XIII) used in the alcoholysis reaction may be 1 to 20 equivalents relative to the quinoline-6-carboxylic acid derivative (XII), or a reaction solvent may be used instead of the reaction solvent used in the rearrangement reaction. It may also be used as
  • the reaction temperature of the rearrangement reaction and alcoholysis reaction is preferably 30 to 200°C, more preferably 50 to 150°C.
  • reaction time for the rearrangement reaction and the alcoholysis reaction is appropriately selected depending on conditions such as reaction temperature, but is preferably 1 to 30 hours.
  • the above-mentioned reactive functional groups include, for example, acid chlorides, mixed acid anhydrides with chlorocarbonate esters (e.g. methyl chlorocarbonate, ethyl chlorocarbonate, isobutyl chlorocarbonate), symmetrical acid anhydrides, activation with imidazole.
  • chlorocarbonate esters e.g. methyl chlorocarbonate, ethyl chlorocarbonate, isobutyl chlorocarbonate
  • symmetrical acid anhydrides activation with imidazole.
  • activation with imidazole e.g. amides.
  • Tetrahydroquinoline derivative (Ic) can be obtained by hydrogenation reaction or hydrogen transfer reduction reaction of quinoline-6-carbamate ester derivative (XIV).
  • the selection conditions of the reagent, catalyst, hydrogen pressure, reaction solvent, and reaction temperature in this step are the same as in Step 1-4.
  • L each independently represents a leaving group
  • Z represents an alkyl group having 1 to 3 carbon atoms
  • each of the other symbols has the same meaning as the above definition.
  • Examples of the leaving group represented by L include a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom, an alkylthio group having 1 to 12 carbon atoms such as a methylthio group, an ethylthio group, or a dodecylthio group, or a phenoxy group.
  • a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom
  • an alkylthio group having 1 to 12 carbon atoms such as a methylthio group, an ethylthio group, or a dodecylthio group, or a phenoxy group.
  • aryloxy groups such as methanesulfonyloxy groups, ethanesulfonyloxy groups, trifluoromethanesulfonyloxy groups, and alkylsulfonyloxy groups in which the hydrogen atom may be substituted with a halogen atom, and alkylsulfonylamino groups, such as trifluoromethanesulfonylamino groups. or an azolyl group such as an imidazol-1-yl group or a pyrazol-1-yl group.
  • Step 4-1 The diphenylmethanimine derivative (XV) can be obtained by a coupling reaction between the 6-haloquinoline derivative (IX-a) and diphenylmethanimine in the presence of a metal catalyst and a base.
  • the selection conditions of the reagent, catalyst, hydrogen pressure, reaction solvent, and reaction temperature in this step are the same as in Step 2-1.
  • the 6-haloquinoline derivative (IX-a) used in the coupling reaction can be purchased or manufactured by the methods described in Steps 1-1 to 1-3, a known method, or a method analogous thereto. Can be done.
  • Step 4-2 The aminoquinoline derivative (XVI) can be obtained by deprotection of the diphenylmethanimine derivative (XV).
  • Examples of the acid used in the deprotection reaction include hydrochloric acid, a 10% by weight hydrogen chloride/methanol solution, a 4 mol/L hydrogen chloride/ethyl acetate solution, trifluoroacetic acid, or hydrofluoric acid, with hydrochloric acid being preferred.
  • the amount of acid used in the deprotection reaction is preferably 0.5 to 100 equivalents, more preferably 1 to 10 equivalents, relative to the diphenylmethanimine derivative (XV).
  • the reaction solvent for the deprotection reaction is appropriately selected depending on the type of reagent used, but is not particularly limited as long as it does not inhibit the reaction.
  • ether solvents such as diethyl ether, THF, DME, 1,4-dioxane, etc.
  • ester solvents such as ethyl acetate or propyl acetate
  • chlorine solvents such as dichloromethane, chloroform or 1,2-dichloroethane
  • alcohol solvents such as methanol or ethanol, or mixed solvents thereof.
  • Ester solvents such as ethyl or propyl acetate or chlorine solvents such as dichloromethane, chloroform or 1,2-dichloroethane are preferred.
  • the reaction temperature for the deprotection reaction is preferably 0 to 200°C, more preferably 0 to 100°C.
  • the reaction time for the deprotection reaction varies depending on the reaction conditions, but is preferably 1 to 48 hours.
  • the amidoquinoline derivative (XVIII) can be obtained by an acylation reaction between the aminoquinoline derivative (XVI) and the acylating agent (XVII).
  • the amount of the acylating agent (XVII) used in the acylation reaction is preferably 0.5 to 10 equivalents, more preferably 1 to 3 equivalents, relative to the aminoquinoline derivative (XVI).
  • a base may be used in the acylation reaction if desired.
  • the base used include organic bases such as triethylamine, N,N-diisopropylethylamine, or pyridine, alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, or lithium hydroxide, sodium hydrogen carbonate, potassium hydrogen carbonate, etc.
  • Alkali metal carbonates such as alkali metal hydrogen carbonates, sodium carbonate, potassium carbonate, and mixtures thereof can be mentioned, and alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, and lithium hydroxide are preferred.
  • the reaction solvent used in the acylation reaction is appropriately selected depending on the type of reagent used, but is not particularly limited as long as it does not inhibit the reaction.
  • nitrile solvents such as acetonitrile or propionitrile, DMF , aprotic polar solvents such as DMA or DMSO, ether solvents such as diethyl ether, THF, DME or 1,4-dioxane, ester solvents such as ethyl acetate or propyl acetate, ketone solvents such as acetone or methyl ethyl ketone
  • Examples include water or a mixed solvent thereof, and a mixed solvent of water and an ether solvent such as diethyl ether, THF, DME or 1,4-dioxane is preferred.
  • the reaction temperature of the acylation reaction is preferably -78°C to 100°C, more preferably -20°C to 50°C.
  • the reaction time for the acylation reaction varies depending on the reaction conditions, but is preferably 1 to 30 hours.
  • the acylating agent (XVII) used in the acylation reaction can be purchased or manufactured by a known method or a method analogous thereto.
  • Step 4-4 The tetrahydroquinoline derivative (I-d) can be obtained by hydrogenation reaction or hydrogen transfer reduction reaction of the amidoquinoline derivative (XVIII).
  • the selection conditions of the reagent, catalyst, hydrogen pressure, reaction solvent, and reaction temperature in this step are the same as in Step 1-4.
  • the ureaquinoline derivative (XX) can be obtained by a ureation reaction between the aminoquinoline derivative (XVI) and the ureation agent (XIX).
  • the amount of the ureating agent (XIX) used in the ureating reaction is preferably 0.5 to 10 equivalents, more preferably 1 to 3 equivalents, relative to the aminoquinoline derivative (XVI).
  • a base may be used in the ureation reaction if desired.
  • the base used include organic bases such as triethylamine, N,N-diisopropylethylamine, or pyridine, alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, or lithium hydroxide, sodium hydrogen carbonate, potassium hydrogen carbonate, etc.
  • alkali metal carbonates such as alkali metal bicarbonates, sodium carbonate, potassium carbonate, and mixtures thereof
  • organic bases such as triethylamine, N,N-diisopropylethylamine, or pyridine are preferred.
  • the reaction solvent used in the ureation reaction is appropriately selected depending on the type of reagent used, but is not particularly limited as long as it does not inhibit the reaction.
  • nitrile solvents such as acetonitrile or propionitrile, DMF , aprotic polar solvents such as DMA or DMSO, ether solvents such as diethyl ether, THF, DME or 1,4-dioxane, ester solvents such as ethyl acetate or propyl acetate, ketone solvents such as acetone or methyl ethyl ketone, Water or a mixed solvent thereof may be used, but ether solvents such as diethyl ether, THF, DME or 1,4-dioxane are preferred.
  • the reaction temperature for the ureation reaction is preferably -78°C to 100°C, more preferably -20°C to 50°C.
  • the reaction time for the ureation reaction varies depending on the reaction conditions, but is preferably 1 to 30 hours.
  • the ureating agent (XIX) used in the ureating reaction can be purchased or produced by a known method or a method analogous thereto.
  • Tetrahydroquinoline derivative (Ie) can be obtained by hydrogenation reaction or hydrogen transfer reduction reaction of ureaquinoline derivative (XX).
  • the selection conditions of the reagent, catalyst, hydrogen pressure, reaction solvent, and reaction temperature in this step are the same as in Step 1-4.
  • the sulfonylamidoquinoline derivative (XXII) can be obtained by a sulfonylation reaction between the aminoquinoline derivative (XVI) and the sulfonylating agent (XXI).
  • the amount of the sulfonylating agent (XXI) used in the sulfonylation reaction is preferably 0.5 to 10 equivalents, more preferably 1 to 3 equivalents, relative to the aminoquinoline derivative (XVI).
  • a base may be used in the sulfonylation reaction if desired.
  • the base used include organic bases such as triethylamine, N,N-diisopropylethylamine, or pyridine, alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, or lithium hydroxide, sodium hydrogen carbonate, potassium hydrogen carbonate, etc.
  • alkali metal carbonates such as alkali metal bicarbonates, sodium carbonate, potassium carbonate, and mixtures thereof
  • organic bases such as triethylamine, N,N-diisopropylethylamine, or pyridine are preferred.
  • the reaction solvent used in the sulfonylation reaction is appropriately selected depending on the type of reagent used, but is not particularly limited as long as it does not inhibit the reaction.
  • nitrile solvents such as acetonitrile or propionitrile, DMF , aprotic polar solvents such as DMA or DMSO, ether solvents such as diethyl ether, THF, DME or 1,4-dioxane, ester solvents such as ethyl acetate or propyl acetate, ketone solvents such as acetone or methyl ethyl ketone, Water or a mixed solvent thereof may be used, but ether solvents such as diethyl ether, THF, DME or 1,4-dioxane are preferred.
  • the reaction temperature of the sulfonylation reaction is preferably -78°C to 100°C, more preferably -20°C to 50°C.
  • the reaction time for the sulfonylation reaction varies depending on the reaction conditions, but is preferably 1 to 30 hours.
  • the sulfonylating agent (XXI) used in the sulfonylation reaction can be purchased or produced by a known method or a method analogous thereto.
  • Step 4-8 The tetrahydroquinoline derivative (If) can be obtained by hydrogenation reaction or hydrogen transfer reduction reaction of the sulfonylamidoquinoline derivative (XXII).
  • the selection conditions of the reagent, catalyst, hydrogen pressure, reaction solvent, and reaction temperature in this step are the same as in Step 1-4.
  • Step 5-1 The methoxycarbonyltetrahydroquinoline derivative (XXIII) can be obtained by hydrogenation reaction or hydrogen transfer reduction reaction of the quinoline-6-carboxylic acid ester derivative (IX-b).
  • the selection conditions of the reagent, catalyst, hydrogen pressure, reaction solvent, and reaction temperature in this step are the same as in Step 1-4.
  • the quinoline-6-carboxylic acid ester derivative (IX-b) used in the hydrogenation reaction or hydrogen transfer reduction reaction can be purchased, or can be prepared by the methods described in Steps 1-1 to 1-3 or by known methods. Alternatively, it can be manufactured by a method similar to that method.
  • Step 5-2 Hydroxymethyltetrahydroquinoline derivative (XXIV) can be obtained by reduction reaction of methoxycarbonyltetrahydroquinoline derivative (XXIII).
  • Examples of the reducing agent used in the reduction reaction include aluminum-based reducing agents such as lithium aluminum hydride and diisobutyl aluminum hydride, and boron-based reducing agents such as sodium borohydride and lithium borohydride.
  • Aluminum-based reducing agents such as aluminum or diisobutylaluminum hydride are preferred.
  • the amount of the reducing agent used in the reduction reaction is preferably 0.3 to 100 equivalents, more preferably 0.5 to 20 equivalents, relative to the methoxycarbonyltetrahydroquinoline derivative (XXIII).
  • the reaction solvent used in the reduction reaction is appropriately selected depending on the type of reagent used, but is not particularly limited as long as it does not inhibit the reaction.
  • a reaction solvent used in the reduction reaction is appropriately selected depending on the type of reagent used, but is not particularly limited as long as it does not inhibit the reaction.
  • Alcohol solvents such as DMF, DMA or DMSO, ether solvents such as diethyl ether, THF, DME or 1,4-dioxane, chlorine solvents such as dichloromethane, chloroform or 1,2-dichloroethane, Examples include aromatic hydrocarbon solvents such as toluene or xylene, or mixed solvents thereof; ether solvents such as diethyl ether, THF, DME or 1,4-dioxane, or aromatic hydrocarbon solvents such as toluene or xylene. Solvents are preferred.
  • the reaction temperature of the reduction reaction is preferably -100°C to 200°C, more preferably -50°C to 50°C.
  • the reaction time for the reduction reaction varies depending on the reaction conditions, but is preferably 1 to 30 hours.
  • the tetrahydroquinoline derivative (Ig) can be obtained by a substitution reaction between a hydroxymethyltetrahydroquinoline derivative (XXIV) and a secondary amine derivative (XXV) in the presence of a phosphine derivative and iodine.
  • the amount of the secondary amine derivative (XXV) used in the substitution reaction is preferably 0.5 to 100 equivalents, more preferably 1 to 20 equivalents, relative to the hydroxymethyltetrahydroquinoline derivative (XXIV).
  • Examples of the phosphine derivative used in the substitution reaction include triphenylphosphine, trimethylphosphine, and tri-n-butylphosphine, with triphenylphosphine being preferred.
  • the amount of the phosphine derivative used in the substitution reaction is preferably 0.5 to 20 equivalents, more preferably 1 to 5 equivalents, relative to the hydroxymethyltetrahydroquinoline derivative (XXIV).
  • the amount of iodine used in the substitution reaction is preferably 0.5 to 20 equivalents, more preferably 1 to 5 equivalents, relative to the hydroxymethyltetrahydroquinoline derivative (XXIV).
  • the reaction solvent used in the substitution reaction is not particularly limited as long as it does not inhibit the reaction, and examples include aprotic polar solvents such as DMF, DMA or DMSO, ketone solvents such as acetone or methyl ethyl ketone, ethyl acetate or acetic acid.
  • aprotic polar solvents such as DMF, DMA or DMSO
  • ketone solvents such as acetone or methyl ethyl ketone, ethyl acetate or acetic acid.
  • Ester solvents such as propyl, ether solvents such as diethyl ether, THF, DME or 1,4-dioxane, chlorine solvents such as dichloromethane, chloroform or 1,2-dichloroethane, aromatic hydrocarbons such as toluene or xylene Examples include solvents or mixed solvents thereof, and chlorinated solvents such as dichloromethane, chloroform, or 1,2-dichloroethane are preferred.
  • the reaction temperature of the substitution reaction is preferably 0 to 150°C, more preferably 10 to 70°C.
  • the reaction time for the substitution reaction varies depending on the reaction conditions, but is preferably 1 to 24 hours.
  • Step 6-1 The nitrile derivative (XXVI) can be obtained by Mitsunobu reaction of the hydroxymethyltetrahydroquinoline derivative (XXIV) and acetone cyanohydrin using an azodicarboxylic acid ester derivative in the presence of a phosphine derivative.
  • Examples of the azodicarboxylic acid ester derivatives used in the Mitsunobu reaction include diethyl azodicarboxylate, diisopropyl azodicarboxylate, 1,1'-(azodicarbonyl)dipiperidine, and 1,1'-(azodicarbonyl) Dipiperidine is preferred.
  • the amount of the azodicarboxylic acid ester derivative used in the Mitsunobu reaction is preferably 0.5 to 30 equivalents, more preferably 1 to 10 equivalents, relative to the hydroxymethyltetrahydroquinoline derivative (XXIV).
  • Examples of the phosphine derivative used in the Mitsunobu reaction include triphenylphosphine, trimethylphosphine, and tri-n-butylphosphine, with tri-n-butylphosphine being preferred.
  • the amount of the phosphine derivative used in the Mitsunobu reaction is preferably 0.5 to 30 equivalents, more preferably 1 to 10 equivalents, relative to the hydroxymethyltetrahydroquinoline derivative (XXIV).
  • the amount of acetone cyanohydrin used in the Mitsunobu reaction is preferably 0.5 to 50 equivalents, more preferably 1 to 20 equivalents, relative to the hydroxymethyltetrahydroquinoline derivative (XXIV).
  • the reaction solvent used in the Mitsunobu reaction is not particularly limited as long as it does not inhibit the reaction, and examples include aprotic polar solvents such as DMF, DMA or DMSO, ketone solvents such as acetone or methyl ethyl ketone, ethyl acetate or acetic acid.
  • aprotic polar solvents such as DMF, DMA or DMSO
  • ketone solvents such as acetone or methyl ethyl ketone, ethyl acetate or acetic acid.
  • Ester solvents such as propyl, ether solvents such as diethyl ether, THF, DME or 1,4-dioxane, chlorine solvents such as dichloromethane, chloroform or 1,2-dichloroethane, aromatic hydrocarbons such as toluene or xylene Examples include solvents or mixed solvents thereof, and ether solvents such as diethyl ether, THF, DME, or 1,4-dioxane are preferred.
  • the reaction temperature of the Mitsunobu reaction is preferably -20°C to 200°C, more preferably -10°C to 100°C.
  • the reaction time for the Mitsunobu reaction varies depending on the reaction conditions, but is preferably 1 to 12 hours.
  • Step 6-2 The tetrahydroquinoline derivative (Ih) can be obtained by a hydrolysis reaction with a nitrile derivative (XXVI) in the presence of hydrogen peroxide and a base.
  • the amount of hydrogen peroxide used in the hydrolysis reaction is preferably 0.5 to 100 equivalents, more preferably 1 to 30 equivalents, relative to the nitrile derivative (XXVI).
  • Examples of the base used in the hydrolysis reaction include lithium hydroxide, potassium hydroxide, sodium hydroxide, and sodium tert-butoxide, with potassium hydroxide or sodium hydroxide being preferred.
  • the amount of base used in the hydrolysis reaction is preferably 0.5 to 100 equivalents, more preferably 0.8 to 20 equivalents, relative to the nitrile derivative (XXVI).
  • the reaction solvent used in the hydrolysis reaction is appropriately selected depending on the type of reagent used, but is not particularly limited as long as it does not inhibit the reaction.
  • an ether solvent such as THF, 1,4-dioxane, or DME Solvents, chlorinated solvents such as dichloromethane, chloroform or 1,2-dichloroethane, aromatic hydrocarbon solvents such as benzene or toluene, aprotic polar solvents such as DMF, DMA or DMSO, ketone solvents such as acetone or methyl ethyl ketone , alcoholic solvents such as methanol, ethanol or 2-propanol, or mixed solvents thereof; aprotic polar solvents such as DMF, DMA or DMSO; and ethereal solvents such as THF, 1,4-dioxane or DME.
  • a mixed solvent with is preferred.
  • the reaction temperature for the hydrolysis reaction is preferably -50°C to 150°C, more preferably -20°C to 100°C.
  • reaction time of the hydrolysis reaction is appropriately selected depending on conditions such as reaction temperature, but is preferably 1 to 30 hours.
  • the carboxylic acid derivative (XXVII) can be obtained by hydrolyzing the tetrahydroquinoline derivative (Ih) in the presence of a base.
  • Examples of the base used in the hydrolysis reaction include lithium hydroxide, potassium hydroxide, sodium hydroxide, and sodium tert-butoxide, with potassium hydroxide or sodium hydroxide being preferred.
  • the amount of base used in the hydrolysis reaction is preferably 0.5 to 100 equivalents, more preferably 0.8 to 30 equivalents, relative to the tetrahydroquinoline derivative (Ih).
  • the reaction solvent used in the hydrolysis reaction is appropriately selected depending on the type of reagent used, but is not particularly limited as long as it does not inhibit the reaction.
  • an ether solvent such as THF, 1,4-dioxane, or DME Solvents
  • chlorinated solvents such as dichloromethane, chloroform or 1,2-dichloroethane
  • aromatic hydrocarbon solvents such as benzene or toluene
  • aprotic polar solvents such as DMF, DMA or DMSO
  • ketone solvents such as acetone or methyl ethyl ketone
  • alcoholic solvents such as methanol, ethanol, or 2-propanol, water, or a mixed solvent thereof, preferably a mixed solvent of an alcoholic solvent such as methanol, ethanol, or 2-propanol, and water.
  • the reaction temperature of the hydrolysis reaction is preferably 0 to 200°C, more preferably 20 to 100°C.
  • reaction time of the hydrolysis reaction is appropriately selected depending on conditions such as reaction temperature, but is preferably 1 to 30 hours.
  • Tetrahydroquinoline derivative (I-i) can be obtained by a condensation reaction between a carboxylic acid derivative (XXVII) and an amine derivative (XXVIII) in the presence of a condensing agent.
  • the amount of the amine derivative (XXVIII) used in the condensation reaction is preferably 0.1 to 10 equivalents, more preferably 0.5 to 5 equivalents, relative to the carboxylic acid derivative (XXVII).
  • condensing agents used in the condensation reaction include N,N'-dicyclohexylcarbodiimide, N-ethyl-N'-3-dimethylaminopropylcarbodiimide hydrochloride, N,N'-carbodiimidazole, ⁇ [(1- Cyano-2-ethoxy-2-oxoethylidene)amino]oxy ⁇ -4-morpholinomethylene ⁇ dimethylammonium hexafluorophosphate, O-(7-azabenzotriazol-1-yl)-1,1,3,3 -tetramethyluronium hexafluorophosphate or O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; Benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is preferred.
  • the amount of the condensing agent used in the condensation reaction is preferably 0.5 to 10 equivalents, more preferably 1 to 3 equivalents, relative to the carboxylic acid derivative (XXVII).
  • Examples of the base used in the condensation reaction include organic bases such as triethylamine or diisopropylethylamine, inorganic bases such as sodium hydrogen carbonate or potassium carbonate, metal hydrides such as sodium hydride, potassium hydride, or calcium hydride, methyllithium, etc.
  • organic bases such as triethylamine or diisopropylethylamine
  • inorganic bases such as sodium hydrogen carbonate or potassium carbonate
  • metal hydrides such as sodium hydride, potassium hydride, or calcium hydride
  • methyllithium etc.
  • alkyllithiums such as butyllithium
  • lithium amides such as lithium hexamethyldisilazide or lithium diisopropylamide, or mixtures thereof
  • organic bases such as triethylamine or diisopropylethylamine are preferable.
  • the amount of the base used in the condensation reaction is preferably 0.5 to 10 equivalents, more preferably 1 to 5 equivalents, relative to the carboxylic acid derivative (XXVII).
  • the amine derivative (XXVIII) may be used as a base for the condensation reaction, and when the amine derivative (XXVIII) is used as the base for the condensation reaction, the amount of the amine derivative (XXVIII) is the same as that of the carboxylic acid derivative (XXVII).
  • the amount is preferably 0.6 to 20 equivalents, more preferably 1 to 10 equivalents.
  • the reaction solvent used in the condensation reaction is appropriately selected depending on the type of reagent used, but is not particularly limited as long as it does not inhibit the reaction.
  • an ether solvent such as THF, 1,4-dioxane, or DME Solvents include chlorinated solvents such as dichloromethane, chloroform or 1,2-dichloroethane, aprotic polar solvents such as DMF or DMSO, or nitrile solvents such as acetonitrile or propionitrile; -Chlorinated solvents such as dichloroethane or aprotic polar solvents such as DMF or DMSO are preferred.
  • the reaction temperature of the condensation reaction is preferably 0 to 200°C, more preferably 20 to 100°C.
  • the reaction time of the condensation reaction is appropriately selected depending on conditions such as reaction temperature, but is preferably 1 to 30 hours.
  • the amine derivative (XXVIII) used in the condensation reaction may be a free form or a salt such as a hydrochloride.
  • the amine derivative (XXVIII) used in the condensation reaction can be purchased or produced by a known method or a method analogous thereto.
  • the optically active forms (I-j') and (I-j'') of the tetrahydroquinoline derivative (I) are 1,4-dihydro-2,6-dimethyl-3,5- It can be obtained by an asymmetric hydrogen transfer reduction reaction between a pyridine dicarboxylic acid ester derivative and a quinoline derivative (XXIX). For example, it can be carried out according to the method described in (Tetrahedron: Asymmetry, 2015, pp. 1174-1179) or a method analogous thereto.
  • the quinoline derivative (XXIX) used in the asymmetric hydrogen transfer reduction reaction can be purchased or used in steps 1-1 to 1-3, step 2-1, step 3-1, step 3-2, step It can be produced by the methods described in Steps 4-1 to 4-3, Steps 4-5 and 4-7, known methods, or methods analogous thereto.
  • Examples of the asymmetric phosphoric acid catalyst used in the asymmetric hydrogen transfer reduction reaction include hydrogen phosphate (S)-1,1'-binaphthalene-2,2'-diyl, hydrogen phosphate (R)-1,1' -binaphthalene-2,2'-diyl, hydrogen phosphate (S)-3,3'-bis(3,5-bis(trifluoromethyl)phenyl)-1,1'-binaphthyl-2,2'-diyl , hydrogen phosphate (R)-3,3'-bis(3,5-bis(trifluoromethyl)phenyl)-1,1'-binaphthyl-2,2'-diyl, hydrogen phosphate (S)-3 , 3'-bis(triphenylsilyl)-1,1'-binaphthyl-2,2'-diyl, hydrogen phosphate (R)-3,3'-bis(triphenylsilyl)-1,1'-bina
  • Step 8-1 The quinoline derivative (XXXII) can be obtained by a coupling reaction between a 3-haloquinoline derivative (XXX) and a boronic acid derivative (XXXI) in the presence of a metal catalyst and a base.
  • the selection conditions of the reagent, catalyst, hydrogen pressure, reaction solvent, and reaction temperature in this step are the same as in Step 1-1.
  • the 3-haloquinoline derivative (XXX) and boronic acid derivative (XXXI) used in the coupling reaction can be purchased or manufactured by a known method or a method analogous thereto.
  • Tetrahydroquinoline derivative (Ik) can be obtained by hydrogenation reaction or hydrogen transfer reduction reaction of quinoline derivative (XXXII).
  • the selection conditions of the reagent, catalyst, hydrogen pressure, reaction solvent, and reaction temperature in this step are the same as in Step 1-4.
  • optically active forms (Ik') and (Ik'') of the tetrahydroquinoline derivative (Ik) in which R 1x , R v and R w are all hydrogen atoms ) can be obtained, for example, by the method described in Scheme 9.
  • Step 9-1 Optically active forms (Ik') and (Ik'') of the tetrahydroquinoline derivative (Ik) can be obtained by HPLC fractionation using a chiral column.
  • One embodiment of the present invention has a ferroptosis inhibiting effect and can be used to treat or prevent drug-induced myocardial damage.
  • Ferroptosis inhibition means inhibiting ferroptosis (cell death controlled in a divalent iron-dependent manner).
  • the ferroptosis inhibitor of the present invention can be used for diseases, disorders, or syndromes in which improvement of pathological conditions or remission of symptoms can be expected by inhibiting ferroptosis.
  • Drug-induced myocardial damage is a so-called side effect of anticancer drugs, and is also considered a problem in cancer chemotherapy treatment.
  • Drug-induced myocardial injury is a disease whose basic condition is cardiomyopathy caused by damage to the myocardium caused by drugs, and patients who develop this disease may develop intractable heart failure and die.
  • anthracyclines such as doxorubicin, a typical drug widely used as an anticancer drug, cause myocardial damage early after administration, but even if the damage is minor, myocardial remodeling occurs in the chronic phase. may progress and cause irreversible and progressive drug-induced cardiomyopathy.
  • the tetrahydroquinoline derivative (I) or a pharmacologically acceptable salt thereof of the present invention is a ferroptosis inhibitor containing the tetrahydroquinoline derivative (I) or a pharmacologically acceptable salt thereof as an active ingredient. It can also be used as a therapeutic or preventive agent for certain drug-induced myocardial disorders.
  • the above-mentioned ferroptosis inhibitor includes tetrahydroquinoline derivative (I) or a pharmacologically acceptable salt thereof, 2-phenyl-1,2,3,4-tetrahydroquinoline or a pharmacologically acceptable salt thereof. Salt can be used.
  • ferroptosis inhibitor refers to a compound that has the effect of improving cell survival rate and improving and maintaining cell function by inhibiting ferroptosis, and a composition containing such a compound as an active ingredient.
  • Patent Document 1 and Non-Patent Document 7 disclose that tetrahydroquinoxaline derivatives have a strong radical scavenging effect.
  • Non-Patent Document 7 reports that tetrahydroquinoline derivatives have an extremely weak radical scavenging effect. Nevertheless, the tetrahydroquinoline derivative (I) of the present invention or a pharmacologically acceptable salt thereof exhibits a ferroptosis inhibiting effect, and therefore can be used as a new pharmaceutical for treating or preventing drug-induced myocardial damage. Can be used.
  • the ferroptosis inhibitory effect of the tetrahydroquinoline derivative (I) or a pharmacologically acceptable salt thereof can be evaluated using an in vitro test. For example, by treating established cell lines such as human fibrosarcoma cells (HT-1080 cells), primary cultured cells, iPS cells, etc. with ferroptosis inducers such as Erastin, RSL3, FIN56, or buthionine sulfoximine. The inhibitory effect on cell death that occurs can be used as an index for evaluation.
  • ferroptosis inducers such as Erastin, RSL3, FIN56, or buthionine sulfoximine.
  • the radical scavenging effect of a test compound can be evaluated using an in vitro test. For example, it can be evaluated by a method using 1,1-Diphenyl-2-picrylhydrazyl (DPPH), which is a stable radical (Antioxidants, Vol. 258, 2019).
  • DPPH 1,1-Diphenyl-2-picrylhydrazyl
  • the effectiveness of the tetrahydroquinoline derivative (I) or a pharmacologically acceptable salt thereof in the treatment or prevention of drug-induced myocardial damage can be evaluated using a pathological model.
  • pathological models include the doxorubicin-induced myocardial injury model (Journal of Clinical Investigation Insight, 2020, Vol. 5, e132747) as a drug-induced myocardial injury model.
  • the doxorubicin-induced myocardial injury model is an animal model in which myocardial damage such as decreased heart weight, decreased left ventricular diameter shortening, and decreased ejection fraction is induced by administering the anticancer drug doxorubicin to experimental animals. be.
  • the above-mentioned pathological model is widely used to examine the efficacy of therapeutic or preventive agents for drug-induced myocardial damage due to the similarity of its symptoms and pathological findings to humans.
  • the effectiveness in treating or preventing drug-induced myocardial damage can be evaluated using the above-mentioned doxorubicin-induced myocardial damage model using, for example, body weight, heart weight, left ventricular diameter shortening rate, and ejection fraction as indicators. .
  • Tetrahydroquinoline derivative (I) or a pharmacologically acceptable salt thereof has a ferroptosis inhibitory effect, and therefore is suitable for use in mammals (e.g., mice, rats, hamsters, rabbits, cats, dogs, cows, sheep, monkeys, or humans). ) can be used as a useful therapeutic or preventive use for drug-induced myocardial damage.
  • mammals e.g., mice, rats, hamsters, rabbits, cats, dogs, cows, sheep, monkeys, or humans.
  • the tetrahydroquinoline derivative (I) or its pharmacologically acceptable salt is used clinically as a therapeutic or preventive agent for drug-induced myocardial damage
  • the tetrahydroquinoline derivative (I) or its pharmacologically acceptable salt is The salts can be administered orally, parenterally, or locally as such or in combination with a pharmacologically acceptable carrier.
  • the therapeutic or preventive agent for drug-induced myocardial damage described above may include excipients, binders, lubricants, disintegrants, sweeteners, stabilizers, corrigents, fragrances, coloring agents, and fluidizers, as necessary.
  • Additives such as agents, preservatives, buffers, solubilizing agents, emulsifiers, surfactants, suspending agents, diluents, or tonicity agents may be mixed as appropriate.
  • pharmacologically acceptable carriers include these additives.
  • the therapeutic or preventive agent for drug-induced myocardial damage described above can be produced by a conventional method using these pharmacologically acceptable carriers as appropriate.
  • the administration forms of the therapeutic or preventive agents for drug-induced myocardial damage include, for example, oral preparations in the form of tablets, pills, capsules, granules, powders, syrups, emulsions, suspensions, etc., inhalants, and injections.
  • parenteral preparations such as tablets, suppositories, and liquid preparations, as well as ointments, creams, and patches for local administration.
  • a suitable base for example, a polymer of butyric acid, a polymer of glycolic acid, a copolymer of butyric acid-glycolic acid, a mixture of a polymer of butyric acid and a polymer of glycolic acid, or a polyglycerol fatty acid ester. Therefore, it is also effective to formulate a sustained release formulation.
  • the above formulation containing the above tetrahydroquinoline derivative (I) or a pharmacologically acceptable salt thereof can be prepared according to a known manufacturing method commonly used in the pharmaceutical field.
  • Tablets can be prepared by containing, for example, excipients, binders, disintegrants, lubricants, etc.
  • Pills and granules can be prepared by containing, for example, excipients, binders, disintegrants, and lubricants.
  • Capsules and powders can be prepared by containing excipients, etc.
  • syrups can be prepared by containing, for example, sweeteners, etc.
  • Emulsions and suspensions can be prepared by adding, for example, surfactants, suspending agents, emulsifying agents, and the like.
  • excipients examples include lactose, glucose, starch, sucrose, microcrystalline cellulose, licorice powder, mannitol, sodium bicarbonate, calcium phosphate, and calcium sulfate.
  • binders examples include starch paste, gum arabic, gelatin, tragacanth, carboxymethyl cellulose, sodium alginate, and glycerin.
  • disintegrants examples include starch and calcium carbonate.
  • Examples of the above-mentioned lubricants include magnesium stearate, calcium stearate, polyethylene glycol, purified talc, and silica.
  • sweeteners examples include glucose, fructose, invert sugar, sorbitol, xylitol, glycerin, or simple syrup.
  • surfactants examples include sodium lauryl sulfate, polysorbate 80, sorbitan monofatty acid ester, and polyoxyl stearate 40.
  • suspending agents examples include gum arabic, sodium alginate, sodium carboxymethylcellulose, methylcellulose, and bentonite.
  • emulsifiers examples include gum arabic, tragacanth, gelatin, and polysorbate 80.
  • a therapeutic or preventive agent for drug-induced myocardial damage containing the tetrahydroquinoline derivative (I) or a pharmacologically acceptable salt thereof it is generally used in the pharmaceutical field.
  • Coloring agents, preservatives, fragrances, flavoring agents, stabilizers, thickening agents, etc. can be added as appropriate.
  • the therapeutic or preventive agent for drug-induced myocardial damage described above preferably contains 0.00001 to 90% by weight, and preferably 0.01 to 70% by weight of the tetrahydroquinoline derivative (I) or a pharmacologically acceptable salt thereof. % is more preferable.
  • the daily dosage is appropriately selected depending on the patient's condition, body weight, age, route of administration, etc., but for example, the amount of active ingredient for an adult (body weight approximately 60 kg) is 1 mg to 1000 mg for oral formulation, and 1 mg to 1000 mg for injection. In the case of a drug, it is preferable to administer 0.01 to 100 mg, and each dose can be administered once or in divided doses.
  • the therapeutic or preventive agent for drug-induced myocardial damage described above may be used in combination or in combination with other drugs in appropriate amounts in order to supplement or enhance its therapeutic or preventive effects or to reduce the dosage. It may be administered simultaneously with other drugs or sequentially in any order.
  • Other drugs include, but are not limited to, ACE (angiotensin converting enzyme) inhibitors, ARBs (angiotensin II receptor antagonists), beta blockers, statins, or Dexrazoxane.
  • Room temperature in the following Examples and Reference Examples usually refers to about 10 to about 35°C.
  • the solvent name shown in the NMR data indicates the solvent used in the measurement.
  • the 400 MHz NMR spectrum was measured using a JNM-ECS400 type nuclear magnetic resonance apparatus or a JNM-ECZ400S type nuclear magnetic resonance apparatus (JEOL Ltd.). The chemical shift is expressed in ⁇ (unit: ppm) based on tetramethylsilane, and the signals are s (singlet), d (doublet), t (triplet), q (quartet), and quint, respectively.
  • silica gel 60 As the silica gel, Silica Gel 60 (Merck & Co., Ltd.) was used, as amino silica gel, (Fuji Silysia Chemical Co., Ltd.) was used, and for flash chromatography, YFLCW-prep2XY (Yamazensha) was used. Silica gel 60 (Merck & Co.) was used for preparative thin layer chromatography (hereinafter referred to as preparative TLC).
  • preparative TLC preparative thin layer chromatography
  • the obtained crude product was purified by column chromatography (silica gel, hexane/ethyl acetate) to obtain the title compound (hereinafter, the compound of Example 2) (95.0 mg, 0.457 mmol, yield 95%, enantioexcess rate). 98.5% ee) was obtained as a colorless transparent oil.
  • Example 8 7-methoxy-2-(4-methoxyphenyl)quinoline (62.0 mg, 0.234 mmol) synthesized in Reference Example 4, the title compound (hereinafter referred to as Example 8) was synthesized in the same manner as in Example 4. Compound) (62.3 mg, 0.234 mmol, yield 99%) was obtained as a white solid.
  • Example 10 2-(2-(trifluoromethyl)phenyl)quinoline (62.0 mg, 0.227 mmol) synthesized in Reference Example 6, the title compound (hereinafter referred to as Example 10) was synthesized in the same manner as in Example 4. Compound) (52.2 mg, 0.188 mmol, yield 83%) was obtained as a colorless transparent oil.
  • the obtained crude product was purified by column chromatography (silica gel, chloroform/methanol) and column chromatography (amino silica gel, hexane/ethyl acetate) to obtain the title compound in the upper row (hereinafter, the compound of Example 14) (4 .1 mg, 0.019 mmol, yield 15%) was obtained as a colorless transparent oil.
  • Example 15 2-(6-methoxypyridin-3-yl)quinoline (50.0 mg, 0.212 mmol) synthesized in Reference Example 8, the title compound (hereinafter referred to as Example 15) was synthesized in the same manner as in Example 4. Compound) (11.0 mg, 0.0458 mmol, yield 22%) was obtained as a colorless transparent oil.
  • Methyl 4-(1,2,3,4-tetrahydroquinolin-2-yl)benzoate (50.0 mg, 0.187 mmol) synthesized in Example 17 was dissolved in THF (1.9 mL), and then poured on ice. A methyllithium THF solution (0.56 mL, 0.65 mmol) was added dropwise under cooling, and the mixture was stirred for 2 hours under ice cooling. After the reaction was completed, water was added to the reaction mixture, and the reaction mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure.
  • the title compound (hereinafter referred to as the compound of Example 18) (13.1 mg, 0.0490 mmol, yield 26%) was obtained as a colorless product by purifying the obtained crude product by column chromatography (silica gel, hexane/ethyl acetate). Obtained as a clear oil.
  • Example Compound No. 21 N-(4-(quinolin-2-yl)phenyl)acetamide (40.0 mg, 0.152 mmol) synthesized in Reference Example 13, the title compound (hereinafter referred to as Example Compound No. 21) (6.60 mg, 24.8 ⁇ mol, yield 16%) was obtained as a white amorphous.
  • Example 23 Using 3',4'-dihydro-[2,6'-biquinolin]-2'(1'H)-one (118 mg, 0.431 mmol) synthesized in Reference Example 15, the same method as in Example 4 was carried out.
  • the title compound (hereinafter referred to as the compound of Example 23) (80.6 mg, 0.290 mmol, yield 67%) was obtained as a white solid.
  • Example Compound No. 25 5-(quinolin-2-yl)isoindolin-1-one (61.6 mg, 0.237 mmol) synthesized in Reference Example 17, the title compound (hereinafter referred to as Example Compound No. 25) (35.7 mg, 0.135 mmol, yield 57%) was obtained as a white solid.
  • Example 29 2-(4-(trifluoromethyl)phenyl)quinoline (80.0 mg, 0.293 mmol) synthesized in Reference Example 21, the title compound (hereinafter referred to as Example 29) was synthesized in the same manner as in Example 26.
  • Compound) (77.0 mg, 0.278 mmol, yield 95%) was obtained as a colorless transparent oil.
  • Example 30 2-(3-(trifluoromethyl)phenyl)quinoline (40.0 mg, 0.146 mmol) synthesized in Reference Example 22, the title compound (hereinafter referred to as Example 30) was synthesized in the same manner as in Example 26. Compound) (39.1 mg, 0.141 mmol, yield 96%) was obtained as a colorless transparent oil.
  • Example 32 4-(quinolin-2-yl)benzenesulfonamide (70.0 mg, 0.246 mmol) synthesized in Reference Example 24, the title compound (hereinafter referred to as the compound of Example 32) was synthesized in the same manner as in Example 26. ) (36.1 mg, 0.125 mmol, yield 51%) was obtained as a white solid.
  • Example 35 Using 4-(quinolin-2-yl)benzonitrile (95.0 mg, 0.413 mmol) synthesized in Reference Example 25, the title compound (hereinafter referred to as the compound of Example 35) was prepared in the same manner as in Example 26. (94.9 mg, 0.405 mmol, yield 98%) was obtained as a white solid.
  • the obtained crude product was purified by column chromatography (silica gel, hexane/ethyl acetate) to obtain the title compound (hereinafter, the compound of Example 46) (115 mg, 0.454 mmol, yield 76%) as a white solid. Obtained.
  • Example 47 Using (2-(quinolin-2-yl)phenyl)methanol (139 mg, 0.592 mmol) synthesized in Reference Example 30, the title compound (hereinafter referred to as the compound of Example 47) was prepared in the same manner as in Example 26. (56.6 mg, 0.237 mmol, yield 40%) was obtained as a pale yellow oil.
  • Example 48 Using (3-(quinolin-2-yl)phenyl)methanol (143 mg, 0.607 mmol) synthesized in Reference Example 31, the title compound (hereinafter referred to as the compound of Example 48) was prepared in the same manner as in Example 26. (133 mg, 0.554 mmol, yield 94%) was obtained as a pale yellow oil.
  • Example 49 Using (4-(quinolin-2-yl)phenyl)methanol (136 mg, 0.576 mmol) synthesized in Reference Example 32, the title compound (hereinafter referred to as the compound of Example 49) was prepared in the same manner as in Example 26. (77.3 mg, 0.323 mmol, yield 56%) was obtained as a pale yellow oil.
  • Methyl 2-phenylquinoline-5-carboxylate (60.0 mg, 0.228 mmol) was dissolved in toluene (1 mL) under an argon atmosphere, and a 1.0 mol/L diisobutylaluminum hydride/hexane solution (0.0 mol/L diisobutylaluminum hydride/hexane solution) was dissolved at -78°C. 912 mL, 0.912 mmol) was added thereto, and the mixture was stirred at -78°C for 1.5 hours.
  • Methyl 2-chloroquinoline-6-carboxylate (100 mg, 0.451 mmol) was dissolved in THF (2 mL), and a 1 mol/L methylmagnesium bromide/THF solution (1.35 mL, 1.35 mmol) was dissolved in -78 mL under an argon atmosphere. C. and stirred at room temperature for 3 hours. After the reaction was completed, a saturated aqueous ammonium chloride solution was added to the reaction mixture until the pH reached 6-7, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and then the filtrate was concentrated under reduced pressure.
  • Methyl 2-phenyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (25.0 mg, 93.5 ⁇ mol) synthesized in Example 56 was dissolved in THF (1 mL), and 1 mol/L methylmagnesium bromide was added. /THF solution (0.374 mL, 0.374 mmol) was added at 0° C. under an argon atmosphere and stirred at room temperature for 16 hours. After the reaction was completed, water was added to the reaction mixture and extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and then the filtrate was concentrated under reduced pressure.
  • the obtained crude product was purified by thin layer preparative chromatography (hexane/ethyl acetate), and the title compound (hereinafter referred to as the compound of Example 57) (3.70 mg, 13.8 ⁇ mol, yield 15%) was purified in a pale layer. Obtained as yellow amorphous.
  • Methyl 2-phenylquinoline-6-carboxylate (0.279 g, 1.06 mmol) synthesized in Reference Example 38 was dissolved in THF/methanol solution (10 mL), and 1 mol/L sodium hydroxide aqueous solution (2.12 mL, 2 .12 mmol) was added thereto, and the mixture was stirred at room temperature for 17 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. 1 mol/L hydrochloric acid (4 mL) was added to the obtained crude product, and the precipitated solid was collected by filtration. The solid was washed with water and dried under vacuum to give the title compound (0.246 g, 0.988 mmol, 93% yield) as a white solid.
  • Example Compound No. 63 tert-butyl (2-phenylquinolin-6-yl)carbamate (29.0 mg, 0.0895 mmol, yield 40%) was obtained as a white solid.
  • the title compound (hereinafter referred to as the compound of Example 71) (49.2 mg, 0.174 mmol, yield 69%) was obtained as a colorless product by purifying the obtained crude product by column chromatography (silica gel, hexane/ethyl acetate). Obtained as a clear oil.
  • 6-bromo-2-phenylquinoline synthesized in Reference Example 49 (60.0 mg, 0.211 mmol), cesium carbonate (241 mg, 0.739 mmol), palladium (II) acetate (4.74 mg, 21.1 ⁇ mol), 2 ,2'-bis(diphenylphosphino)-1,1'-binaphthyl (26.3 mg, 42.2 ⁇ mol) was suspended in 1,4-dioxane (2.10 mL), and piperidine (69.7 ⁇ L, 0.2 ⁇ L) was suspended in 1,4-dioxane (2.10 mL). 633 mmol) was added thereto, and the mixture was stirred at 100° C. for 15 hours under an argon atmosphere.
  • diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate 50.4 mg, 0.199 mmol was added, and the mixture was stirred at room temperature under an argon atmosphere for 3 hours. Furthermore, iodine (2.40 mg, 9.46 ⁇ mol) and diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate (50.4 mg, 0.199 mmol) were added, and the mixture was heated at 40°C for 19 hours. Stirred. After the reaction was completed, the reaction mixture was concentrated under reduced pressure.
  • the obtained crude product was purified by column chromatography (silica gel, hexane/ethyl acetate) to obtain the title compound (hereinafter referred to as the compound of Example 72) (6.00 mg, 20.5 ⁇ mol, yield 22%) as a brown solid. obtained as.
  • 1,1-diphenyl-N-(2-phenylquinolin-6-yl)methanimine (108 mg, 0.280 mmol) synthesized in Reference Example 52 was dissolved in THF (1.0 mL), and 2 mol/L hydrochloric acid (0.28 mg, 0.280 mmol) was dissolved in THF (1.0 mL). 420 mL, 0.840 mmol) was added thereto, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, a saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layers were combined and dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure.
  • Example 73 N-(2-phenylquinolin-6-yl)acetamide (15.5 mg, 59.1 ⁇ mol) synthesized in Reference Example 54, the title compound (hereinafter referred to as Example 73) was synthesized in the same manner as in Example 4. Compound) (12.1 mg, 45.4 ⁇ mol, yield 77%) was obtained as a colorless amorphous.
  • Example 74 N-(2-phenylquinolin-6-yl)pivalamide (64.8 mg, 0.213 mmol) synthesized in Reference Example 55, the title compound (hereinafter referred to as Example 74) was synthesized in the same manner as in Example 26. Compound) (62.6 mg, 0.203 mmol, yield 95%) was obtained as a white solid.
  • 2-phenylquinolin-6-amine (40.0 mg, 0.182 mmol) synthesized in Reference Example 53 was dissolved in dichloromethane (1.8 mL), cooled to 0°C, and triethylamine (38.0 ⁇ L, 0.272 mmol) and Methanesulfonyl chloride (14.1 ⁇ L, 0.182 mmol) was added, and the mixture was stirred at 0° C. for 2 hours under an argon atmosphere. Next, triethylamine (25.3 ⁇ L, 0.182 mmol) and methanesulfonyl chloride (16.9 ⁇ L, 0.218 mmol) were added, and the mixture was stirred at room temperature under an argon atmosphere for 18 hours.
  • Example Compound No. 75 (20.2 mg, 66.8 ⁇ mol, yield 41%) was obtained as a white solid.
  • Example 77 1-(2-phenylquinolin-6-yl)urea (47.9 mg, 0.182 mmol) synthesized in Reference Example 58, the title compound (hereinafter referred to as Example 77) was synthesized in the same manner as in Example 4. Compound) (40.6 mg, 0.152 mmol, yield 84%) was obtained as a white amorphous.

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Abstract

Le but de la présente invention est de fournir un agent thérapeutique ou un agent préventif pour des troubles myocardiques d'origine médicamenteuse et ayant une action inhibitrice sur la ferroptose.　La présente invention concerne un agent thérapeutique ou un agent préventif pour des troubles myocardiques d'origine médicamenteuse, comprenant, en tant que principe actif, un dérivé de tétrahydroquinoline représenté par le composé suivant, ou un sel pharmacologiquement acceptable de celui-ci.
PCT/JP2023/023262 2022-06-24 2023-06-23 Agent thérapeutique ou agent préventif pour des troubles myocardiques d'origine médicamenteuse WO2023249105A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013011930A1 (fr) * 2011-07-15 2013-01-24 浜理薬品工業株式会社 Procédé de production d'une tétrahydroquinoléine optiquement active
WO2019106434A1 (fr) * 2017-12-01 2019-06-06 Collaborative Medicinal Development Pty. Ltd. Dérivés aromatiques hétérocycliques pour le traitement de troubles liés à la ferroptose
JP2022523860A (ja) * 2019-03-11 2022-04-26 コラボレイティブ メディシナル デベロップメント， エルエルシー フェロトーシス関連障害の処置のための複素芳香族およびヘテロ二環式芳香族誘導体
WO2022138888A1 (fr) * 2020-12-25 2022-06-30 東レ株式会社 Dérivé de tétrahydroquinoline et son utilisation médicale

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Publication number Priority date Publication date Assignee Title
WO2013011930A1 (fr) * 2011-07-15 2013-01-24 浜理薬品工業株式会社 Procédé de production d'une tétrahydroquinoléine optiquement active
WO2019106434A1 (fr) * 2017-12-01 2019-06-06 Collaborative Medicinal Development Pty. Ltd. Dérivés aromatiques hétérocycliques pour le traitement de troubles liés à la ferroptose
JP2022523860A (ja) * 2019-03-11 2022-04-26 コラボレイティブ メディシナル デベロップメント， エルエルシー フェロトーシス関連障害の処置のための複素芳香族およびヘテロ二環式芳香族誘導体
WO2022138888A1 (fr) * 2020-12-25 2022-06-30 東レ株式会社 Dérivé de tétrahydroquinoline et son utilisation médicale

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FANG XUEXIAN, WANG HAO, HAN DAN, XIE ENJUN, YANG XIANG, WEI JIAYU, GU SHANSHAN, GAO FENG, ZHU NALI, YIN XIANGJU, CHENG QI, ZHANG P: "Ferroptosis as a target for protection against cardiomyopathy", PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES, NATIONAL ACADEMY OF SCIENCES, vol. 116, no. 7, 12 February 2019 (2019-02-12), pages 2672 - 2680, XP055905845, ISSN: 0027-8424, DOI: 10.1073/pnas.1821022116 *
LIU X., ET AL.: "Highly regio-, diastereo- and enantioselective one-pot gold/chiral Bronsted acid-catalyzed cascade synthesis of bioactive diversely substituted tetrahydroquinolines", ORGANIC & BIOMOLECULAR CHEMISTRY, ROYAL SOCIETY OF CHEMISTRY, vol. 10, no. 35, 1 January 2012 (2012-01-01), pages 7208 - 7219, XP055944584, ISSN: 1477-0520, DOI: 10.1039/C2OB25753J *
TADOKORO TOMONORI, IKEDA MASATAKA, IDE TOMOMI, DEGUCHI HIROKO, IKEDA SOICHIRO, OKABE KOSUKE, ISHIKITA AKIHITO, MATSUSHIMA SHOUJI, : "Mitochondria-dependent ferroptosis plays a pivotal role in doxorubicin cardiotoxicity", JCI INSIGHT, vol. 5, no. 9, 7 May 2020 (2020-05-07), XP093119987, ISSN: 2379-3708, DOI: 10.1172/jci.insight.132747 *

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