WO2012108490A1 - Dérivé isoquinoléine d'amide - Google Patents

Dérivé isoquinoléine d'amide Download PDF

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WO2012108490A1
WO2012108490A1 PCT/JP2012/052936 JP2012052936W WO2012108490A1 WO 2012108490 A1 WO2012108490 A1 WO 2012108490A1 JP 2012052936 W JP2012052936 W JP 2012052936W WO 2012108490 A1 WO2012108490 A1 WO 2012108490A1
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isoquinoline
compound
carboxamide
chloro
trifluorophenyl
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PCT/JP2012/052936
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English (en)
Japanese (ja)
Inventor
▲はま▼口　渉
陽平 小金丸
竜一 関岡
統 金子
加藤　浩二
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アステラス製薬株式会社
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Publication of WO2012108490A1 publication Critical patent/WO2012108490A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
    • C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems

Definitions

  • the present invention relates to a pharmaceutical, particularly an isoquinolinamide derivative having a 5-HT 5A receptor modulating action and useful as a therapeutic or prophylactic agent for dementia, schizophrenia and the like.
  • 5-HT 5A receptor which is one of serotonin receptor subtypes, plays an important role in dementia and schizophrenia.
  • 5-HT 5A receptor increases, also, overactive by LSD is a 5-HT 5A receptor knockout mice have been reported to be inhibited (Neuron, 22, 581-591, 1999).
  • 5-HT 5A receptor is highly expressed in human and rodent brains, and in hippocampal CA1 and CA3 pyramidal cells, which are involved in memory, and schizophrenia It has been reported that there is a lot of expression in the frontal cortex (cerebral cortex) that is deeply related to the disease (Molecular Brain Research, 56, 1-8, 1998).
  • 5-HT 5A receptor polymorphism is associated with schizophrenia (Neuroreport 11, 2017-2020, 2000; Mol. Psychiatr. 6, 217-219, 2001; J. Psychiatr. Res. 38, 371-376, 2004).
  • regulating the function of 5-HT 5A receptor leads to improvement of dementia and schizophrenia, and a compound having such a function is desired.
  • a tricyclic compound represented by the following formula (a) binds to a 5-HT 5A receptor and is used for the treatment of dementia, schizophrenia and the like (Patent Document 1).
  • A means a benzene, thiophene, furan, cyclohexene or tetrahydropyridine ring
  • B means a benzene, cyclohexene or tetrahydropyridine ring.
  • This publication relates to tricyclic compounds and is different from the isoquinolinamide derivatives of the present invention.
  • a bicyclic acylguanidine compound represented by the following formula (b) binds to a 5-HT 5A receptor and is used for the treatment of dementia, schizophrenia and the like (Patent Document 2).
  • A is phenyl
  • R 1 , R 2 and R 3 are H, lower alkyl, halogen, etc.
  • R 7 and R 8 are H, lower alkyl, etc.
  • X is O
  • R 9a and R 9b are H, etc.
  • dotted line is bonded or absent
  • m is 0, 1 or 2
  • L 1 and L 2 are bonded, etc.
  • R 4 , R 5 and R 6 are H
  • This publication relates to a compound in which the bicyclic ring group moiety is chroman or benzothiophene and is different from the isoquinolinamide derivative of the present invention.
  • a naphthoylguanidine compound substituted with a cyclic group represented by the following formulas (c) and (d) binds to a 5-HT 5A receptor and is useful for the treatment of dementia, schizophrenia and the like.
  • a naphthoylguanidine compound substituted with a cyclic group represented by the following formulas (c) and (d) binds to a 5-HT 5A receptor and is useful for the treatment of dementia, schizophrenia and the like.
  • A represents various ring groups including phenyl, pyridyl, etc.
  • This publication relates to naphthalene compounds and is different from the isoquinolinamide derivative of the present invention.
  • a quinoline or isoquinoline compound substituted with a cyclic group represented by the following formula (e) binds to 5-HT 5A receptor and is useful for the treatment of dementia, schizophrenia, etc. It is disclosed in Document 7.
  • A represents a cyclic group, and any one of Z 1 , Z 2 , Z 3 , Z 4 and Z 5 is a nitrogen atom and the other is a carbon atom.
  • This publication relates to acylguanidino derivatives and is different from the isoquinolinamide derivatives of the present invention.
  • a tetrahydroisoquinoline compound represented by the following formula (g) has been reported as a 5-HT 1B and 5-HT 1D receptor regulator (Patent Document 6).
  • R 1 represents alkyl, halogen or the like
  • R 2 represents aryl, heterocycle or carboxamide
  • W represents a linking group such as —C (O) — or —C (O) NR a —
  • Ring X means an optionally substituted aryl or an optionally substituted heterocycle (see the publication for details)
  • the compound disclosed in the publication relates to a tetrahydroisoquinoline derivative and is different from the isoquinoline amide derivative of the present invention.
  • isoquinoline derivatives in which a ring group is bonded to the 1-position of the isoquinoline ring and a further ring group is bonded to the 7-position via a bonding group such as an amide group have been known as 5-HT 5A receptor modulators. Not.
  • An object of the present invention is to provide an excellent therapeutic or preventive agent for dementia, schizophrenia and the like based on a 5-HT 5A receptor modulating action.
  • the present inventors have shown that the ring group is bonded to the 1-position of the isoquinoline ring represented by the formula (I) and the amide group is located at the 7-position. It was found that isoquinoline derivatives to which a further ring group or the like is bonded via a linking group have a potent 5-HT 5A receptor modulating action and an excellent pharmacological action based on this, such as dementia and schizophrenia.
  • the present invention was completed by discovering that it is useful as a therapeutic or prophylactic agent.
  • the compound of the formula (I) is an isoquinolinamide derivative characterized in that a ring group is bonded to the 1-position of the isoquinoline ring and a further ring group or the like is bonded to the 7-position via a bonding group such as an amide group. . That is, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • A aryl, heteroaryl or cycloalkyl
  • R 1 ⁇ R 3 different same or mutually, H, halogen, halogeno lower alkyl, -CN, -OH, -OR 0, -O- ( halogeno-lower alkyl), - R 00 -OH, -R 00 - OR 0 , cycloalkyl or lower alkylene
  • R 4 H, halogen, halogeno-lower alkyl, R 0, -CN, -OH, -OR 0, -O- ( halogeno-lower alkyl), - R 00 -OH, -R 00 -OR 0, or cycloalkyl
  • R 5 H or R 0 , L: a single bond, -R 00 -O -, - R 00 -S -, - R 00 -SO 2 -, - R 00 -NH
  • the compound of the formula (I) has an advantage of having a potent 5-HT 5A receptor modulating action and a good pharmacological action based thereon.
  • the pharmaceutical composition of the present invention is used for the treatment or prevention of diseases involving 5-HT 5A receptor, particularly for the treatment or prevention of dementia, schizophrenia, bipolar disorder, attention deficit hyperactivity disorder and mood disorder. Useful.
  • the term “5-HT 5A receptor modulator” refers to a compound that suppresses 5-HT 5A receptor activation by antagonizing an endogenous ligand (5-HT 5A antagonist), and 5- It is a general term for compounds (5-HT 5A agonists) that exert their actions by activating the HT 5A receptor.
  • An embodiment of the “5-HT 5A receptor modulator” is, for example, a 5-HT 5A antagonist.
  • “Lower alkyl” means a linear or branched alkyl group having 1 to 6 carbon atoms (hereinafter abbreviated as C 1-6 ), specifically, methyl, ethyl, n-propyl.
  • Another embodiment is C 1-4 alkyl, and yet another embodiment is methyl, ethyl, or n-propyl.
  • the “lower alkylene” means a divalent substituent formed by removing any hydrogen atom from the lower alkyl.
  • methylene, ethylene, 1,2-propylene, or trimethylene is used.
  • methylene, ethylene, or trimethylene is used.
  • methylene or ethylene is used.
  • Halogen means F, Cl, Br, I.
  • One embodiment is F or Cl.
  • Halogeno lower alkyl means lower alkyl substituted with one or more halogens, such as F or Cl, and in some embodiments is trifluoromethyl or difluoromethyl.
  • the “aryl” is a C 6-14 monocyclic to tricyclic aromatic hydrocarbon ring group, and in one embodiment, phenyl or naphthyl, and in another embodiment, phenyl.
  • Heteroaryl is a 5- to 14-membered ring having 1 to 5 heteroatoms selected from O, N and S as atoms forming the ring, and in another embodiment, a 5- to 10-membered ring.
  • monocyclic to tricyclic and in another embodiment are monocyclic to bicyclic aromatic ring groups, which may be condensed.
  • One embodiment is a 5- to 6-membered monocyclic heteroaryl, such as pyridyl, pyrimidinyl, pyridazinyl, pyrrolyl, imidazolyl, thiazolyl, oxadiazolyl and the like.
  • monocyclic nitrogen-containing heteroaryl those having a nitrogen atom as a ring-constituting atom are referred to as “monocyclic nitrogen-containing heteroaryl”.
  • Another embodiment is a 9-10 membered bicyclic heteroaryl, such as quinolyl, isoquinolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl and the like.
  • Cycloalkyl is a C 3-10 saturated hydrocarbon ring group, which may be bridged or condensed.
  • cyclopropyl is a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl group or the like, and as another aspect, a C 3-6 cycloalkyl group, and as another aspect, C A 3-7 cycloalkyl group, and in yet another embodiment, cyclopropyl or cyclobutyl.
  • the condensed ring is a 5- to 6-membered monocyclic heteroaryl.
  • Heterocycloalkyl is a saturated or partially unsaturated 3- to 14-membered ring group having 1 to 6 heteroatoms as atoms constituting the ring, and is bridged and / or condensed. May be.
  • An embodiment is a monocyclic heterocycloalkyl having 1 to 4 heteroatoms selected from O, N, or S, such as acetylidinyl, pyrrolidyl, piperidyl, piperazyl, pyranyl, morpholyl, thiopyranyl, etc. .
  • the monocyclic thing which has a nitrogen atom as an atom which comprises a ring is set as "monocyclic nitrogen-containing heterocycloalkyl.”
  • Another embodiment is a bicyclic ring group in which a monocyclic heterocycloalkyl having 1 to 4 heteroatoms selected from O, N, or S is condensed with a benzene ring, such as benzopyran- 2-yl, benzopyran-3-niyl and benzopyran-4-yl.
  • a bridged heterocycloalkyl group such as quinuclidyl or 8-azabicyclo [3.2.1] oct-3-yl.
  • “It may be substituted” means unsubstituted or having 1 to 5 substituents. In one embodiment, there are 1 to 2 unsubstituted or substituted groups, in another embodiment, one substituent, and in another embodiment, two substituents. When it has a plurality of substituents, these substituents may be the same or different from each other.
  • substituent in the “optionally substituted lower alkylene” examples include —OH, —OR 0 , —N (R 0 ) 2 , —CO 2 H, —CO 2 R 0 , —CN, phenyl, cyclopropyl, And another group selected from the group consisting of —OH, —N (R 0 ) 2 , —CN, cyclopropyl, and oxo, and Another embodiment is -OH. In one embodiment, it is unsubstituted, in another embodiment, 1 or 2 substituents, in another embodiment, 1 substituent, and in another embodiment, 2 substituents. is there. When there are two substituents, these may be the same or different from each other.
  • heterocycloalkyl, heteroaryl, cycloalkyl, or aryl “optionally substituted, heterocycloalkyl or heteroaryl”, “optionally substituted, respectively” , "Monocyclic nitrogen-containing heterocycloalkyl or monocyclic nitrogen-containing heteroaryl”, “optionally substituted phenyl, piperidyl, imidazolyl or pyridyl”, and "optionally substituted piperidyl” -R 0 , -R 00 -OH, -R 00 -OR 0 , -R 00 -CN, -R 00 -N (R 0 ) 2 , -R 00 -COR 0 , -R 00 -CONH 2 , -COR 0 , -CO 2 H, -CO 2 R 0 , -CONH 2 , -CN, -OH, -OR 0 , -NH 2 , -SR
  • A is aryl, heteroaryl or cycloalkyl;
  • R 1 to R 3 are the same or different from each other, and are H, halogen, halogeno lower alkyl, -O- (lower alkyl), or lower alkyl;
  • R 4 is H, halogen, halogeno lower alkyl, lower alkyl, -O- (lower alkyl), or cycloalkyl;
  • R 5 is H or lower alkyl, L is a single bond, lower alkylene,-(lower alkylene) -O-,-(lower alkylene) -S-,-(lower alkylene) -NH-,-(lower alkylene) -NR 0 -,-(lower alkylene) ) —SO 2 —, cycloalkylene, or optionally substituted lower alkylene
  • B is -OH, -OR 0 , -SR 0 , -N (R 0
  • (B) A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein L is a single bond, cycloalkylene or optionally substituted lower alkylene.
  • L is, -R 00 -O -, - R 00 -S -, - R 00 -NH -, - R 00 -NR 0 - or -R 00 -SO 2 - and is, B is, -R 00 —OR 0 , —CONH 2 or —CO 2 R 0 , or each optionally substituted heterocycloalkyl, heteroaryl, cycloalkyl or aryl, a compound of formula (I) or a pharmaceutically acceptable salt thereof Acceptable salt.
  • this invention includes the following.
  • A is phenyl, pyridyl or C 3-7 cycloalkyl, and in one embodiment, phenyl, in another embodiment, monocyclic nitrogen-containing heteroaryl, and in another embodiment, pyridyl.
  • Yet another embodiment is a compound of formula (I), which is C 3-7 cycloalkyl.
  • R 1 to R 3 are the same or different from each other, and in one embodiment, are halogen or H, in another embodiment, a group selected from F, Cl and H, and in another embodiment, A compound of formula (I) which is F or H.
  • R 4 is halogen, C 1-3 alkyl, —O— (C 1-3 alkyl) or cyclopropyl, and in one embodiment, F or Cl, and in another embodiment, lower alkyl.
  • the compound of formula (I) is methyl or ethyl.
  • the substitution position of R 4 is, in one embodiment, the 4-position of the isoquinoline ring.
  • R 5 is H.
  • the compound of the formula (I), wherein L is a single bond or lower alkylene, and in one embodiment is a single bond, and in another embodiment, is a single bond, methylene, ethylene or trimethylene.
  • B is an optionally substituted heterocycloalkyl or heteroaryl, and in another embodiment, each may be substituted, a monocyclic nitrogen-containing heterocycloalkyl or monocyclic nitrogen-containing In the formula (I), which is heteroaryl, and in yet another embodiment is phenyl, piperidyl, imidazolyl or pyridyl, which may each be substituted, and in another embodiment is optionally substituted piperidyl Compound.
  • B is -R 0 , -R 00 -OH, -R 00 -OR 0 , -R 00 -CN, -R 00 -N (R 0 ) 2 , -COR 0 , -CO 2 R 0 , -CONH 2 , -CN, -OH, -OR 0 , -NH 2 , -SR 0 , halogen, -R 00- (phenyl), halogeno lower alkyl, cycloalkyl, -R 00- (cyclopropyl ), - R 00 - (cyclohexyl), - CO- (cyclopropyl), - R 00 - (morpholyl), - R 00 - (piperidyl), pyrrolidyl, piperidyl, -R 00 - (pyridyl), and pyrimidinyl
  • -R 0 , -R 00 -NH 2, -R 00 Phenyl, piperidyl, quinucidyl, imidazolyl, or pyridyl each optionally substituted with a group selected from -OH and -R 00 -OR 0
  • -R 0 , -R 00 A compound of formula (I) which is piperidyl optionally substituted with a group selected from -CO-NH 2 and -R 00 -OR 0 , and in another embodiment is imidazolyl.
  • the present invention includes compounds in which the embodiments of the substituents shown in the above (1) to (6) and (A) to (C) are arbitrarily combined, for example, the following compounds.
  • A is phenyl, pyridyl or C 3-7 cycloalkyl
  • R 1 to R 3 are the same or different from each other and are selected from F, Cl and H
  • R 4 is halogen, C 1-3 alkyl, —O— (C 1-3 alkyl) or cyclopropyl
  • R 5 is H
  • L is a single bond or lower alkylene
  • B is lower alkyl, —R 00 —NH 2
  • a compound of formula (I) which is a monocyclic nitrogen-containing heterocycloalkyl or monocyclic nitrogen-containing heteroaryl, each optionally substituted with a group selected from -R 00 -OH.
  • A is phenyl
  • R 1 to R 3 are F or H
  • R 4 is F or Cl
  • R 5 is H
  • L is a single bond, methylene, ethylene or trimethylene
  • B is phenyl, piperidyl, imidazolyl, or pyridyl, each optionally substituted with a group selected from lower alkyl, -R 00 -NH 2, -R 00 -OH and -R 00 -OR 0 Compound (I).
  • A is phenyl
  • R 1 to R 3 are F or H
  • R 4 is F or Cl
  • R 5 is H
  • L is a single bond
  • B is phenyl, piperidyl, quinucidyl, imidazolyl, or pyridyl, each optionally substituted with a group selected from lower alkyl, -R 00 -NH 2, -R 00 -OH and -R 00 -OR 0
  • A is phenyl, R 1 to R 3 are F or H, R 4 is Cl or methyl, R 5 is H, L is a single bond, B is lower alkyl, A compound of formula (I) which is piperidyl optionally substituted with a group selected from -R 00 -CO-NH 2 and -R 00 -OR 0 .
  • A is phenyl, R 1 to R 3 are F or H, R 4 is Cl, R 5 is H, and L is ethylene that may be substituted with -OH;
  • the present application includes the following (13) to (26).
  • (13) A pharmaceutical composition comprising the compound of the above formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
  • (16) The pharmaceutical composition according to the above (13), which is used for prevention or treatment of dementia or schizophrenia.
  • a preventive or therapeutic agent for dementia, schizophrenia, bipolar disorder, or attention deficit / hyperactivity disorder comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient.
  • a preventive or therapeutic agent for dementia or schizophrenia comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient.
  • (19) Use of the compound of the above formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a preventive or therapeutic agent for dementia, schizophrenia, bipolar disorder, or attention deficit hyperactivity disorder .
  • (20) Use of the compound of the above formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a preventive or therapeutic agent for dementia or schizophrenia.
  • the above schizophrenia includes positive symptoms, negative symptoms, cognitive impairment, and mood disorders.
  • the present invention includes pharmaceutically acceptable prodrugs of the compound of formula (I).
  • Pharmaceutically acceptable prodrugs are compounds having groups that can be converted to amino groups, OH, CO 2 H, etc. by solvolysis or under physiological conditions. Examples of groups that form prodrugs include those described in Prog. Med., 5, 2157-2161 (1985) and “Development of Pharmaceuticals” (Yodogawa Shoten, 1990), Volume 7, Molecular Design 163-198. Can be mentioned.
  • the compound of the formula (I) may form an acid addition salt or a salt with a base depending on the kind of the substituent, and as long as such a salt is a pharmaceutically acceptable salt, the compound of the present invention is used.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid
  • Acid addition salts with organic acids such as lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, aspartic acid or glutamic acid, sodium, potassium, magnesium, calcium, aluminum, etc.
  • Inorganic bases salts with organic bases such as methylamine, ethylamine, ethanolamine, lysine, ornithine, ammonium salts, and the like.
  • the compound of formula (I) and pharmaceutically acceptable salts thereof include various hydrates, solvates and polymorphic substances.
  • the compounds of formula (I) and pharmaceutically acceptable salts thereof include compounds labeled with various radioactive or non-radioactive isotopes.
  • the compound of the formula (I) and pharmaceutically acceptable salts thereof can be produced by applying various known synthetic methods utilizing characteristics based on the basic skeleton or the type of substituent.
  • an appropriate protecting group a group that can be easily converted into the functional group
  • Examples of such a functional group include an amino group, a hydroxyl group, and a carboxyl group
  • examples of protective groups thereof include, for example, “Greene's Protective Groups in Organic Synthesis (No. 4) by PGM Wuts and Green (TW Greene)”. Edition, 2006) ”, and these may be appropriately selected depending on the reaction conditions.
  • a desired compound can be obtained by introducing the protecting group and carrying out the reaction, and then removing the protecting group as necessary.
  • the prodrug of the compound of the formula (I) introduces a specific group at the stage from the raw material to the intermediate as in the case of the protective group, or further reacts with the obtained compound of the formula (I).
  • the reaction can be carried out by applying a method known by those skilled in the art, such as ordinary esterification, amidation, dehydration and the like.
  • typical production methods of the compound of the formula (I) will be described. Each manufacturing method can also be performed with reference to the reference attached to the said description.
  • the manufacturing method of this invention is not limited to the example shown below.
  • the compound of formula (I) can be produced by reacting compound (II) with compound (III) or a salt thereof. The reaction can be carried out using an equal amount of compound (II) and compound (III) or an excess amount of compound (III).
  • Aromatic hydrocarbons such as benzene, toluene or xylene, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane or chloroform, ethers such as diethyl ether, tetrahydrofuran (THF), dioxane or dimethoxyethane (DME), Under cooling in a solvent inert to the reaction such as N, N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N-methylpyrrolidone (NMP), ethyl acetate, acetonitrile or water, or a mixture thereof.
  • the heating can be performed preferably at -20 ° C to 80 ° C.
  • the reaction is preferably performed in the presence of a condensing agent.
  • a condensing agent N, N'-dicyclohexylcarbodiimide (DCC), 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide (WSC), 1,1'-carbonyldiimidazole (CDI) 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU), diphenyl phosphate azide (DPPA), phosphorus oxychloride and the like.
  • DCC N, N'-dicyclohexylcarbodiimide
  • WSC 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide
  • CDI 1,1'-carbonyldiimidazole
  • HBTU 1- (1H-benzotriazol-1-yl) -1
  • an additive for example, N-hydroxysuccinimide (HONSu) or 1-hydroxybenzotriazole (HOBt)
  • the condensing agent is used in an equivalent amount or an excess amount relative to the carboxylic acid.
  • organic bases such as base (triethylamine (TEA), diisopropylethylamine (DIPEA), N-methylmorpholine, pyridine or 4- (N, N-dimethylamino) pyridine, or sodium bicarbonate, etc. It may be advantageous to carry out the reaction in the presence of an inorganic base, etc.) in order to allow the reaction to proceed smoothly.
  • Pyridine can also serve as a solvent.
  • the reaction is preferably carried out at room temperature to heating under reflux.
  • X 1 represents a trifluoromethanesulfonyloxy group, a halogen, a methanesulfonyloxy group, or a p-toluenesulfonyloxy group
  • X 2 represents —B (OH) 2 , —B (OY) OW, etc.
  • Compound (II) can be produced by a coupling reaction with compound (IV) and compound (V) and then deprotection of the carboxyl group.
  • X 2 is an active group such as -B (OH) 2 or -B (OY) OW
  • compounds (IV) and (V) are used in an equal amount, or one of them is used in excess, and a mixture thereof is reacted.
  • an inert solvent usually in the presence of a base and a palladium catalyst at room temperature to heating under reflux, usually by stirring for 0.1 hour to 5 days. This reaction is preferably performed in an inert gas atmosphere.
  • the solvent used here are not particularly limited, but include aromatic hydrocarbons, ethers, halogenated hydrocarbons, alcohols such as methanol and ethanol, DMF, DMSO, and mixed solvents thereof. It is done.
  • inorganic bases such as sodium carbonate, potassium carbonate, sodium hydroxide and the like are preferable.
  • the palladium catalyst include tetrakis (triphenylphosphine) palladium, dichlorobis (triphenylphosphine) palladium, palladium chloride-1,1′-bis (diphenylphosphino) ferrocene, and tris (dibenzylideneacetone) dipalladium.
  • the palladium ligand tert-butylphosphine, cyclohexylphosphine, 2-dicyclohexylphosphinobiphenyl derivative and the like can also be used.
  • the compound (V) when X 2 is halogen, the compound (V) is converted into an organolithium compound using n-butyllithium or LDA (lithium diisopropylamide), and then zinc chloride is allowed to act. It can be converted into an organic zinc compound.
  • Compound (II) can be produced by reacting the obtained organic zinc compound with compound (IV) in the presence of a base and a palladium catalyst in a solvent inert to the reaction.
  • a base and a palladium catalyst As the reaction solvent, base, and palladium catalyst used here, the same reaction as in the case where X 2 is an active group such as —B (OH) 2 or —B (OY) OW can be used.
  • the manufacturing method of the compound used as a raw material is described as a manufacture example.
  • the manufacturing method of the compound of a formula (I) is not limited only to the manufacturing method of the specific Example shown below, It can manufacture also by the combination of these manufacturing methods, or a well-known manufacturing method.
  • the concentration [M] means [mol / L], and “rel” means relative configuration.
  • Example 1 4-Chloro-1- (2,4,6-trifluorophenyl) isoquinoline-7-carboxylic acid (90 mg), 2- (1-methyl-1H-imidazol-2-yl) ethanamine dihydrochloride (58 mg ), HOBt (40 mg), WSC hydrochloride (56 mg), DIPEA (0.12 mL) and DMF (5 mL) were stirred at room temperature for 4 hours. A saturated aqueous sodium bicarbonate solution and ethyl acetate were added to the reaction solution, and a liquid separation operation was performed.
  • Example 2 4-chloro-1- (2,4,6-trifluorophenyl) isoquinoline-7-carboxylic acid (80 mg), trans-4-aminocyclohexanol (33 mg), HOBt (38 mg), WSC hydrochloride ( 54 mg) and DMF (2.7 mL) were stirred at room temperature for 3 days. A saturated aqueous sodium bicarbonate solution and ethyl acetate were added to the reaction solution, and a liquid separation operation was performed. The organic layer was washed with saturated brine, dried and concentrated under reduced pressure.
  • Example 3 tert-Butyl [trans-3-( ⁇ [4-Chloro-1- (2,4,6-trifluorophenyl) isoquinolin-7-yl] carbonyl ⁇ amino) cyclobutyl] carbamate (500 mg), methanol (5 mL ) And ethyl acetate (5 mL) were added 4M hydrogen chloride / ethyl acetate (1.5 mL), and the mixture was stirred at room temperature for 3 days. Chloroform and saturated sodium bicarbonate water were sequentially added to the reaction solution, and a liquid separation operation was performed. The organic layer was washed and dried, and concentrated under reduced pressure.
  • Example 4 4-chloro-N- [2- (1H-imidazol-2-yl) ethyl] -1- (2,4,6-trifluorophenyl) isoquinoline-7-carboxamide (60 mg), 2-iodopropane (170 mg) and DMF (2 mL) were added with DIPEA (30 mg), stirred at an oil temperature of 90 ° C. for 2 days, and then cooled to room temperature. Ethyl acetate and water were added to the reaction solution to carry out a liquid separation operation. The organic layer was washed successively with water and saturated brine, dried and concentrated under reduced pressure.
  • Example 6 To a methanol solution (1.74 mL) of tert-butyl 4-( ⁇ [4-chloro-1- (2,4-difluorophenyl) isoquinolin-7-yl] carbonyl ⁇ amino) piperidine-1-carboxylate (173 mg) 4M Hydrogen chloride / dioxane (1.3 mL) was added, and the mixture was stirred at room temperature for 1 day. The reaction solution was concentrated under reduced pressure to obtain 4-chloro-1- (2,4-difluorophenyl) -N- (piperidin-4-yl) isoquinoline-7-carboxamide dihydrochloride (80 mg).
  • Example 7 4-Chloro-N- (piperidin-4-yl) -1- (2,4,6-trifluorophenyl) isoquinoline-7-carboxamide dihydrochloride (100 mg), cyclopropanecarbaldehyde (374 mg), acetic acid (0.058 mL) and TEA (0.085 mL) in dichloromethane (8.6 mL) were added sodium triacetoxyborohydride (64 mg), and the mixture was stirred at room temperature for 18 hours. A 1M aqueous sodium hydroxide solution and ethyl acetate were added to the reaction solution to carry out a liquid separation operation.
  • Example 9 4-chloro-1- (2,4,6-trifluorophenyl) isoquinoline-7-carboxylic acid (80 mg), tetrahydro-2H-pyran-4-amine (29 mg), HOBt (32 mg), TEA ( To a mixture of 0.1 ml) and DMF (2.7 mL), WSC hydrochloride (68 mg) was added and stirred at room temperature for 20 hours. A 1M aqueous sodium hydroxide solution and ethyl acetate were added to the reaction solution, and a liquid separation operation was performed.
  • Example 10 4-chloro-N- (piperidin-4-yl) -1- (2,4,6-trifluorophenyl) isoquinoline-7-carboxamide dihydrochloride (62 mg), 2,2-difluoroethyl trifluoromethanesulfonate ( A mixture of 54 mg), TEA (0.07 mL) and DMF (6.2 mL) was stirred at 60 ° C. overnight and then cooled to room temperature. A saturated aqueous sodium bicarbonate solution and ethyl acetate were added to the reaction solution, and a liquid separation operation was performed.
  • Example 13 4-Chloro-N- (piperidin-4-yl) -1- (2,4,6-trifluorophenyl) isoquinoline-7-carboxamide dihydrochloride (80 mg), TEA (82 mg) and dichloromethane (4 mL ) was added to the mixture and stirred at room temperature overnight. A 1M aqueous sodium hydroxide solution and ethyl acetate were added to the reaction solution, and a liquid separation operation was performed.
  • Example 14 tert-butyl 4-( ⁇ [4-chloro-1- (2,4,6-trifluorophenyl) isoquinolin-7-yl] carbonyl ⁇ amino) piperidine-1-carboxylate (169 mg) and ethyl acetate (10 4M hydrogen chloride / ethyl acetate (10 mL) was added to the mixture, and the mixture was stirred at room temperature for 1 day, and then the reaction mixture was concentrated under reduced pressure. The residue was washed with ethyl acetate to obtain 4-chloro-N- (piperidin-4-yl) -1- (2,4,6-trifluorophenyl) isoquinoline-7-carboxamide dihydrochloride (161 mg) .
  • Example 16 To a mixture of 6-[( ⁇ [4-chloro-1- (2,4,6-trifluorophenyl) isoquinolin-7-yl] carbonyl ⁇ amino) methyl] nicotinic acid (50 mg) and DMF (10 mL) , CDI (25 mg) was added, and the mixture was stirred at room temperature for 1 hr, 28% aqueous ammonia (5 mL) was added, and the mixture was stirred at an oil temperature of 60 ° C. for 16 hr. The reaction solution was cooled to room temperature and concentrated under reduced pressure.
  • Example 17 4-Chloro-N-[(2S) -piperidin-2-ylmethyl] -1- (2,4,6-trifluorophenyl) isoquinoline-7-carboxamide hydrochloride (70 mg), DIPEA (57 mg), iodine A mixture of methyl chloride (28 mg) and ethanol (1 mL) was stirred at 120 ° C. for 30 minutes under microwave irradiation.
  • Example 19 A mixture of 6-nitroimidazo [1,2-a] pyridine (584 mg), methanol (41 mg) and 10% palladium / carbon (905 mg) was stirred at room temperature for 3 hours in a hydrogen gas atmosphere. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure.
  • Example 20 To a mixture of 4-chloro-1- (2-fluorophenyl) -N- (1H-imidazol-2-ylmethyl) isoquinoline-7-carboxamide (88 mg) and DMF (20 mL) was added 1-chloropyrrolidine-2, 5-dione (34 mg) was added, and the mixture was stirred at room temperature for 1 day. Water and ethyl acetate were added to the reaction liquid, and liquid separation operation was performed.
  • Example 21 Under an argon gas atmosphere, N-[(6-chloropyridin-3-yl) methyl] -1- (2-fluorophenyl-l) -4-methylisoquinoline-7-carboxamide (269 mg), trimethylboroxine (210 mg ), Potassium phosphate (422 mg), toluene (6 mL) and water (0.4 mL), palladium acetate (15 mg) and tricyclohexylphosphine (37 mg) are added, and the oil temperature is 100 ° C. for 1 day. Stir. The reaction mixture was cooled to room temperature, ethyl acetate and water were added, and the mixture was filtered through Celite.
  • Example 22 4-Chloro-1- (2-fluorophenyl) -N- (1H-imidazol-2-ylmethyl) isoquinoline-7-carboxamide (60 mg), 2-bromoethyl methyl ether (24 mg), cesium carbonate (128 mg ) And N-methylpyrrolidone (1 mL) were stirred at 120 ° C. for 15 minutes under microwave irradiation. The reaction solution was ice-cooled, and water and ethyl acetate were added to carry out a liquid separation operation.
  • Example 23 4-chloro-1- (2-fluorophenyl) -N- (1H-imidazol-2-ylmethyl) isoquinoline-7-carboxamide (60 mg), 2-bromoacetamide (24 mg), cesium carbonate (128 mg) and A mixture of DMF (10 mL) was stirred at an oil temperature of 60 ° C. for 15 hours. After the reaction solution was cooled to room temperature, ethyl acetate and water were added to carry out a liquid separation operation. The organic layer was washed successively with water and saturated brine, dried and concentrated under reduced pressure.
  • Example 24 4-chloro-1- (2-fluorophenyl) -N- (1H-imidazol-2-ylmethyl) isoquinoline-7-carboxamide (52 mg), DIPEA (35 mg), 1M oxirane / THF solution (1.4 mL), A mixture of methanol (1 mL) and N-methylpyrrolidone (1 mL) was stirred at 60 ° C. for 30 minutes under microwave irradiation, and further stirred at 150 ° C. for 15 minutes. After allowing to cool to room temperature, ethyl acetate and water were added to the reaction solution to carry out a liquid separation operation. The organic layer was washed successively with water and saturated brine, dried and concentrated under reduced pressure.
  • Example 25 Under an argon gas atmosphere, a mixture of 4-chloro-1- (2,4,6-trifluorophenyl) isoquinoline-7-carboxylic acid (60 mg) and dichloromethane (1 mL) was added to oxalyl chloride (25 mg) and DMF (0.01 mL) were added sequentially, and the solution stirred at room temperature for 1.5 hours was added to a mixture of pyrimidine-2-amine (20 mg), TEA (18 mg) and dichloromethane (1 mL) in a separate container with ice. The solution was added dropwise under cooling and stirred at room temperature for 2 hours. Methanol was added to the reaction mixture and the mixture was concentrated under reduced pressure.
  • Example 26 Ethyl-2-[( ⁇ [4-chloro-1- (2,4,6-trifluorophenyl) isoquinolin-7-yl] carbonyl ⁇ amino) methyl] -1,3-thiazole-4-carboxylate (50 mg), ethanol (0.5 mL) and THF (0.5 mL) were added 1M aqueous sodium hydroxide solution (0.5 mL), and the mixture was stirred at an oil temperature of 50 ° C. for 0.5 hr. The reaction solution was concentrated under reduced pressure, and water and diethyl ether were added to carry out a liquid separation operation. The aqueous layer was weakly acidified with 1M hydrochloric acid, and chloroform was added to carry out a liquid separation operation.
  • Example 27 2-[( ⁇ [4-Chloro-1- (2,4,6-trifluorophenyl) isoquinolin-7-yl] carbonyl ⁇ amino) methyl] -1,3-thiazole-4-carboxylic acid (30 mg) , HOBt (13 mg), WSC hydrochloride (18 mg), and DMF (1.2 mL) were stirred at room temperature for 1 hour, 28% aqueous ammonia (0.04 mL) was added, and the mixture was further stirred at room temperature for 16 hours. . Water and ethyl acetate were added to the reaction liquid, and liquid separation operation was performed. The organic layer was washed with saturated brine, dried and concentrated under reduced pressure.
  • Example 28 Under an argon gas atmosphere, N-[(4-carbamoyl-1,3-thiazol-2-yl) methyl] -4-chloro-1- (2,4,6-trifluorophenyl) isoquinoline-7-carboxamide (10 mg) and pyridine (0.13 mL) were added phosphoryl chloride (2.5 ⁇ L) under ice-cooling and stirred at room temperature for 1 hour. Water and ethyl acetate were added to the reaction liquid, and liquid separation operation was performed. The organic layer was washed with saturated brine, dried, and concentrated under reduced pressure.
  • Example 29 4-Chloro-N- ⁇ [4- (hydroxymethyl) -1,3-thiazol-2-yl] methyl ⁇ -1- (2,4,6-trifluorophenyl) isoquinoline-7-carboxamide (14 mg) And methanol (720 mL) were added trimethyl orthoformate (640 mg) and sulfuric acid (31 mg), and the mixture was stirred with heating under reflux for 3 hours.
  • Example 30 4-Chloro-N- [2-hydroxy-2- (1-trityl-1H-imidazol-2-yl) ethyl] -1- (2,4,6-trifluorophenyl) isoquinoline-7-carboxamide (120 mg ) And dioxane (3.5 mL), 1M hydrochloric acid (2 mL) was added, and the mixture was stirred with heating at an oil temperature of 60 ° C. for 2 hours and cooled to room temperature. The reaction mixture was neutralized with 1M aqueous sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried and concentrated under reduced pressure.
  • Example 31 1,2,2,6,6-pentamethylpiperidin-4-amine (4.3 mg) and 4-chloro-1- (2,4,6-trifluorophenyl) isoquinoline-7-carboxylic acid (8.4 mg) , DIPEA (19.2 ⁇ l) in DMF (400 ⁇ l), and N-[(dimethylamino) (3H- [1,2,3] triazolo [4,5-b] pyridin-3-yloxy) methylene] -N -Methylmethananium Hexafluorophosphoric acid (11.4 mg) in DMF (100 ⁇ l) was added and stirred at room temperature overnight.
  • Example 360 4-Chloro-1- (2-fluorophenyl) -N-[(2S) -piperidin-2-ylmethyl] isoquinoline-7-carboxamide monohydrochloride (63 mg) in DMF (2 mL) was added to potassium carbonate ( mg) and methyl iodide (11 ⁇ L) were sequentially added, and the mixture was stirred at room temperature for 5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed successively with saturated brine, dried and concentrated under reduced pressure.
  • Example compounds shown in the table below were produced using the corresponding raw materials in the same manner as in the above examples.
  • the structural formulas, physicochemical data and production methods of the example compounds are shown in the table below.
  • HEK293 cells Human embryonic kidney-derived cell line HEK293 cells (ATCC) are seeded, and the expression plasmid (1 ⁇ g) obtained above is added together with LIPOFECTAMINE 2000 (Invitrogen; 2 ⁇ l). After introducing the gene into HEK293 cells, An expression cell was selected with a certain geneticin (G418 sulfate 500 ⁇ g / ml; Kanto Chemical).
  • Recombinant cells expressing the gene thus produced were D-MEM (Dulbecco's Modified Eagle Medium, Sigma), 10% FCS (Fetal calf serum), 1% Pc./Sm (penicillin / Culturing was performed with streptomycin (Invitrogen) and 500 ⁇ g / ml G418 medium for 3 days.
  • D-MEM Dulbecco's Modified Eagle Medium, Sigma
  • FCS Fetal calf serum
  • Pc./Sm penicillin / Culturing was performed with streptomycin (Invitrogen) and 500 ⁇ g / ml G418 medium for 3 days.
  • the above experimental procedures are described in the instruction manual attached to the genetic manipulation experiment manuals and reagents such as known methods (Sambrook, J. et al, “Molecular Cloning-A Laboratory Manual”, Cold Spring Harabor laboratory, NY, 1989). I followed.
  • Test Example 2 Human 5-HT 5A receptor binding inhibition test (1) were cultured in F500 plates membrane preparation Human 5-HT 5A receptor forced expression HEK293 cells from human 5-HT 5A receptor forced expression HEK293 cells, scraper I've written it. After centrifugation, the precipitate was collected, and incubation buffer (50 mM Tris (HCl) PH7.4, 10 mM MgSO 4 , 0.5 mM EDTA (ethylenediaminetetraacetic acid)) was added. After homogenization, the mixture was further centrifuged, and an incubation buffer was added to the precipitate to suspend well. After repeating this operation, the protein concentration was measured and the membrane preparation was completed.
  • incubation buffer 50 mM Tris (HCl) PH7.4, 10 mM MgSO 4 , 0.5 mM EDTA (ethylenediaminetetraacetic acid)
  • the radioactivity remaining on the GF / C filter plate was measured using a top count.
  • the following table shows the Ki values of some example compounds.
  • Ex indicates an example number, and “-” indicates not evaluated.
  • the compound of formula (I) has 5-HT 5A receptor affinity, and 5-HT 5A receptor than 5-HT 7 receptor which is another 5-HT subtype receptor It has been confirmed that it has excellent subtype selectivity for.
  • Test Example 3 Evaluation of various drugs against a drug that increases mouse momentum (MK-801) (Measurement method of infrared radiation momentum) The improvement effect of the compound of formula (I) on schizophrenia was evaluated by measuring the amount of exercise suppressed under the administration of the compound in a model in which symptoms were induced by MK-801.
  • Animal species Male ICR mouse
  • Operating procedure The animal was removed from the breeding cage, and the test compound was orally administered and placed in the breeding cage. After 30 minutes, the test compound alone was measured for momentum in a measurement cage.
  • the compounds of Examples 32, 39, 42, 62, 63, 85, 106 and 158 caused MK-801-induced overactivity by 1.0 mg / kg, 0.1 mg / kg, 0.3 mg / kg, respectively.
  • the dose was significantly suppressed at 0.3 mg / kg, 0.3 mg / kg, 0.3 mg / kg, 0.03 mg / kg and 0.3 mg / kg. From this, it was confirmed that the compound of Formula (I) has an improvement effect with respect to the increase in exercise amount (overactivity) which is a symptom of schizophrenia.
  • a mouse was placed in one end of a maze (Y-maze) arm with the same length of arm in three directions, and allowed to explore freely for 8 minutes, and the number of entries into the arm during this period was counted. Moreover, the case where it entered into three different arms continuously was made into the spontaneous alternation behavior (Spontaneous alternation behavior), and the ratio with respect to the total number of entries of this behavior number was computed as the spontaneous alternation rate (Alternation rate) by the following formula
  • Spontaneous turnover rate (%) number of spontaneous turnover actions / (total number of entries -2) x 100 (3)
  • Data analysis When a significant difference (Student T test) was found between the normal group and the control group in the spontaneous alternation rate (%), it was judged that learning disability was established by scopolamine administration. The presence or absence of the learning disorder effect of the test compound was determined by conducting a Dunnett test of the test compound administration group with respect to the control group. In each test, p ⁇ 0.10 was a trend, and p ⁇ 0.05 was a significant difference.
  • the compound of the formula (I) suppressed spontaneous alternation behavior of mice induced by scopolamine.
  • the compounds of Examples 39, 62, 63, 85 and 106 show that scopolamine-induced spontaneous alternation behavior was 0.03 mg / kg, 0.03 mg / kg, 0.3 mg / kg, 1.0 mg / kg and 0.01 mg, respectively. It was significantly suppressed at a dose of / kg. Thus, it was confirmed that the compound of formula (I) has an effect on cognitive impairment in dementia and schizophrenia.
  • Test Example 5 Improving effect on disorder of PCP-induced prepulse inhibition (PPI) in rats
  • the ameliorating effect of the compound of formula (I) on schizophrenia is evaluated by a known PCP-induced prepulse inhibition disorder model as a disease state model. be able to. Specifically, the method described in “Neuropsychopharmacology, 1989; 2: 61-66, Mansbach, RS and Geyer, MA” and Brain Research (1998; 781: 227-235) is followed.
  • Test Example 6 Evaluation of Drugs in Water Maze Learning Disorders of Aged Rats The improvement effect of the compound of formula (I) on dementia can be evaluated by a known water maze learning disorder model as a disease state model. Specifically, the method described in “J Pharmacol Exp Ther, 1996; 279: 1157-73, Yamazaki M. et al.” Is followed.
  • Test Example 7 Evaluation of Drug in Forced swimming Test of DBA / 2 Mice
  • the improvement effect of the compound of formula (I) on depression can be evaluated by a known forced swimming test as an evaluation model. Specifically, the method described in “Behav Brain Res. 2005; 156 (1): 153-162, Ducottet C. et al.)” Is followed.
  • Test Example 8 Phototoxic effect evaluation test [Day 1]: Cell culture (96-well plate) 1) Remove BALB / 3T3 from the culture flask and count the number of cells. 2) Adjust the cell concentration to 0.7 ⁇ 10 5 cells / ml and spread 100 ⁇ l / well in a 96-well plate. Add 100 ⁇ l of PBS to each side of the hole that does not cover cells. 3) Incubate in a CO2 incubator for 2 days. [Day 2]: Addition of compound and UV irradiation (non-irradiation) 1) The minimum weight of the test compound is 0.8 mg.
  • MPE is a value indicating a mean photo effect, that is, an average light effect.
  • MPE can be calculated according to Equation 2 in the following document. ATLA (2002), 30, 415-432
  • Test Example 9 Solubility test 1 mL of Japanese Pharmacopoeia disintegration test solution 2 was accurately added to 13 ⁇ L of a 10 mM DMSO solution of a test substance prepared in advance, and shaken at 25 ° C. for 20 hours to obtain a sample stock solution. Next, a sample stock solution of 200 ⁇ L was filtered and moistened in advance, a sample stock solution of 200 ⁇ ⁇ ochL was newly added and filtered, and the resulting solution was used as a sample solution.
  • the inhibitory activity with respect to the CYP1A2 metabolic enzyme was evaluated about some compounds of Formula (I).
  • the CYP1A2 metabolic enzyme inhibitory activities of the compounds of Examples 15, 32, 39, 42, 58, 62, 63, 91, 106 and 158 all have an IC 50 value of 20 ⁇ M or more and do not inhibit the metabolic enzyme. It was confirmed to be a compound.
  • the compound of formula (I) of the present invention is used for the treatment or prevention of diseases involving 5-HT 5A , particularly dementia, schizophrenia (positive symptoms, negative symptoms, cognitive impairment). , Including symptoms such as mood disorder), bipolar disorder, attention deficit / hyperactivity disorder, and mood disorder (anxiety disorder, depressive disorder).
  • Formulations containing one or more of the compounds of formula (I) or salts thereof as active ingredients are generally used methods using pharmaceutical carriers, excipients and the like that are usually used in the art Can be prepared. Administration is orally by tablets, pills, capsules, granules, powders, solutions, etc., or injections such as intra-articular, intravenous, intramuscular, suppositories, eye drops, ophthalmic ointments, transdermal solutions, Any form of parenteral administration such as an ointment, a transdermal patch, a transmucosal liquid, a transmucosal patch, and an inhalant may be used.
  • solid composition for oral administration tablets, powders, granules and the like are used.
  • one or more active ingredients are combined with at least one inert excipient such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone. And / or mixed with magnesium aluminate metasilicate.
  • the composition may contain an inert additive, for example, a lubricant such as magnesium stearate, a disintegrant such as sodium carboxymethyl starch, a stabilizer, and a solubilizing agent according to a conventional method. .
  • Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs and the like, and commonly used inert diluents such as purified water. Or contains ethanol.
  • the liquid composition may contain solubilizers, wetting agents, auxiliaries such as suspending agents, sweeteners, flavors, fragrances and preservatives in addition to the inert diluent.
  • Injections for parenteral administration contain sterile aqueous or non-aqueous solutions, suspensions or emulsions. Examples of the aqueous solvent include distilled water for injection or physiological saline.
  • water-insoluble solvents examples include propylene glycol, polyethylene glycol or vegetable oils such as olive oil, alcohols such as ethanol, or polysorbate 80 (a pharmacopeia name).
  • Such compositions may further contain isotonic agents, preservatives, wetting agents, emulsifying agents, dispersing agents, stabilizing agents, or solubilizing agents. These are sterilized by, for example, filtration through a bacteria-retaining filter, blending with a bactericide or irradiation. These can also be used by producing a sterile solid composition and dissolving or suspending it in sterile water or a sterile solvent for injection before use.
  • External preparations include ointments, plasters, creams, jellies, poultices, sprays, lotions, eye drops, eye ointments and the like.
  • ointment bases include commonly used ointment bases, lotion bases, aqueous or non-aqueous solutions, suspensions, emulsions, and the like.
  • ointments or lotion bases include polyethylene glycol, propylene glycol, white petrolatum, white beeswax, polyoxyethylene hydrogenated castor oil, glyceryl monostearate, stearyl alcohol, cetyl alcohol, lauromacrogol, sorbitan sesquioleate, etc. Can be mentioned.
  • Transmucosal agents such as inhalants and nasal agents are used in solid, liquid or semi-solid form and can be produced according to conventionally known methods.
  • known excipients, and further pH adjusters, preservatives, surfactants, lubricants, stabilizers, thickeners and the like may be appropriately added.
  • an appropriate device for inhalation or insufflation can be used.
  • a known device such as a metered dose inhalation device or a nebulizer
  • the compound is administered alone or as a powder in a formulated mixture or as a solution or suspension in combination with a pharmaceutically acceptable carrier. be able to.
  • the dry powder inhaler or the like may be for single or multiple administration, and a dry powder or a powder-containing capsule can be used. Alternatively, it may be in the form of a pressurized aerosol spray using a suitable gas such as a suitable propellant such as chlorofluoroalkane, hydrofluoroalkane or carbon dioxide.
  • a suitable gas such as a suitable propellant such as chlorofluoroalkane, hydrofluoroalkane or carbon dioxide.
  • the appropriate daily dose is about 0.0001 to 100 mg / kg, preferably 0.0001 to 10 mg / kg, more preferably 0.0001 to 1 mg / kg per body weight.
  • Administer in 4 to 4 divided doses When administered intravenously, the appropriate daily dosage is about 0.00001 to 1 mg / kg per body weight, and is administered once a day or divided into multiple times.
  • an external preparation or transmucosal agent As an external preparation or transmucosal agent, about 0.0001 to 10 mg / kg per body weight is administered once to several times a day. The dose is appropriately determined according to individual cases in consideration of symptoms, age, sex, and the like. The content of the active ingredient in the preparation is 0.0001 to 50%, more preferably 0.001 to 50%.
  • the compound of the formula (I) can be used in combination with various therapeutic agents or preventive agents for diseases for which the compound of the formula (I) is considered to be effective.
  • the combination may be administered simultaneously, separately separately, or at desired time intervals.
  • the simultaneous administration preparation may be a combination drug or may be separately formulated.
  • the compound of the formula (I) has an advantage of having a potent 5-HT 5A receptor modulating action and a good pharmacological action based thereon.
  • the pharmaceutical composition of the present invention is used for the treatment or prevention of diseases involving 5-HT 5A receptor, particularly for the treatment or prevention of dementia, schizophrenia, bipolar disorder, attention deficit hyperactivity disorder and mood disorder. Useful.

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Biomedical Technology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Neurosurgery (AREA)
  • Medicinal Chemistry (AREA)
  • Neurology (AREA)
  • Psychiatry (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Hospice & Palliative Care (AREA)
  • Pain & Pain Management (AREA)
  • Anesthesiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Other In-Based Heterocyclic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention a pour but de proposer un excellent agent thérapeutique ou prophylactique pour la démence, la schizophrénie et similaires, qui est basé sur une action de modulation des récepteurs 5-HT5A de la sérotonine. A cet effet, la présente invention a été réalisée par la découverte qu'un dérivé isoquinoléine, dans lequel un groupe cyclique est lié à la position 1 du noyau isoquinoléine et un groupe cyclique ou similaire est en outre lié à la position 7 du noyau d'isoquinoléine par l'intermédiaire d'un groupe de liaison ayant un groupe amide, a une action puissante de modulation des récepteurs 5-HT5A et une excellente action pharmacologique sur la base de cette action, et par la découverte que le dérivé est efficace en tant qu'agent prophylactique ou thérapeutique pour la démence, la schizophrénie et similaires.
PCT/JP2012/052936 2011-02-09 2012-02-09 Dérivé isoquinoléine d'amide WO2012108490A1 (fr)

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JP2011025539A JP2014076948A (ja) 2011-02-09 2011-02-09 イソキノリンアミド誘導体
JP2011-025539 2011-02-09

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JP2016517876A (ja) * 2013-05-03 2016-06-20 エフ．ホフマン−ラ ロシュ アーゲーＦ． Ｈｏｆｆｍａｎｎ−Ｌａ Ｒｏｃｈｅ Ａｋｔｉｅｎｇｅｓｅｌｌｓｃｈａｆｔ 神経新生刺激イソキノリン誘導体
WO2016198937A1 (fr) 2015-06-08 2016-12-15 Suven Life Sciences Limited Modulateurs allostériques positifs du récepteur muscarinique m1
US10183938B2 (en) 2014-12-16 2019-01-22 Axovant Sciences Gmbh Geminal substituted quinuclidine amide compounds as agonists of α-7 nicotonic acetylcholine receptors
US10370370B2 (en) 2015-06-10 2019-08-06 Axovant Sciences Gmbh Aminobenzisoxazole compounds as agonists of α7-nicotinic acetylcholine receptors
US10428062B2 (en) 2015-08-12 2019-10-01 Axovant Sciences Gmbh Geminal substituted aminobenzisoxazole compounds as agonists of α7-nicotinic acetylcholine receptors

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WO2018228452A1 (fr) * 2017-06-16 2018-12-20 成都先导药物开发有限公司 Composé inhibiteur de rock et utilisations correspondantes
TW202031644A (zh) * 2018-11-06 2020-09-01 日商第一三共股份有限公司 苯并咪唑衍生物
CN110372612B (zh) * 2019-08-17 2021-06-25 西安都创医药科技有限公司 一种硼替佐米衍生物的制备方法

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JP2008515907A (ja) * 2004-10-07 2008-05-15 エピックス デラウェア， インク． チエノピリジノン化合物およびその処置方法
WO2010090305A1 (fr) * 2009-02-09 2010-08-12 アステラス製薬株式会社 Dérivé d'acylguanidine substitué
WO2010090304A1 (fr) * 2009-02-09 2010-08-12 アステラス製薬株式会社 Dérivé d'acylguanidine
WO2011016504A1 (fr) * 2009-08-06 2011-02-10 アステラス製薬株式会社 Dérivé d'acylguanidine à noyau azoté

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JP2008515907A (ja) * 2004-10-07 2008-05-15 エピックス デラウェア， インク． チエノピリジノン化合物およびその処置方法
WO2010090305A1 (fr) * 2009-02-09 2010-08-12 アステラス製薬株式会社 Dérivé d'acylguanidine substitué
WO2010090304A1 (fr) * 2009-02-09 2010-08-12 アステラス製薬株式会社 Dérivé d'acylguanidine
WO2011016504A1 (fr) * 2009-08-06 2011-02-10 アステラス製薬株式会社 Dérivé d'acylguanidine à noyau azoté

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2016517876A (ja) * 2013-05-03 2016-06-20 エフ．ホフマン−ラ ロシュ アーゲーＦ． Ｈｏｆｆｍａｎｎ−Ｌａ Ｒｏｃｈｅ Ａｋｔｉｅｎｇｅｓｅｌｌｓｃｈａｆｔ 神経新生刺激イソキノリン誘導体
KR101757100B1 (ko) * 2013-05-03 2017-07-26 에프. 호프만-라 로슈 아게 신경발생-자극성 이소퀴놀린 유도체
US10183938B2 (en) 2014-12-16 2019-01-22 Axovant Sciences Gmbh Geminal substituted quinuclidine amide compounds as agonists of α-7 nicotonic acetylcholine receptors
WO2016198937A1 (fr) 2015-06-08 2016-12-15 Suven Life Sciences Limited Modulateurs allostériques positifs du récepteur muscarinique m1
US10370370B2 (en) 2015-06-10 2019-08-06 Axovant Sciences Gmbh Aminobenzisoxazole compounds as agonists of α7-nicotinic acetylcholine receptors
US10428062B2 (en) 2015-08-12 2019-10-01 Axovant Sciences Gmbh Geminal substituted aminobenzisoxazole compounds as agonists of α7-nicotinic acetylcholine receptors

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