WO2012133509A1 - Dérivé inédit de benzimidazole - Google Patents

Dérivé inédit de benzimidazole Download PDF

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WO2012133509A1
WO2012133509A1 PCT/JP2012/058096 JP2012058096W WO2012133509A1 WO 2012133509 A1 WO2012133509 A1 WO 2012133509A1 JP 2012058096 W JP2012058096 W JP 2012058096W WO 2012133509 A1 WO2012133509 A1 WO 2012133509A1
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group
alkoxy
optionally substituted
alkyl
halogen
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PCT/JP2012/058096
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Japanese (ja)
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幸博 西尾
慶介 柿口
治 市川
貴士 ▲高▼田
山口　洋輝
嘉人 畳谷
裕介 澤山
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大日本住友製薬株式会社
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Publication of WO2012133509A1 publication Critical patent/WO2012133509A1/fr

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    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond
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    • A61K31/4164—1,3-Diazoles
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
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    • 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
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    • 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
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    • 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
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    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to a novel benzimidazole derivative which is a modulator of ⁇ 7 nicotinic acetylcholine receptor ( ⁇ 7 nAChR). Due to their pharmacological properties, the compounds of the present invention can be used for diseases related to cholinergic activity of the central nervous system (CNS) and / or peripheral nervous system (PNS), diseases related to smooth muscle contraction, endocrine diseases, diseases related to neurodegeneration, It may be useful for the treatment of diseases such as inflammation or pain and diseases related to withdrawal symptoms caused by addictive drug abuse.
  • CNS central nervous system
  • PNS peripheral nervous system
  • diseases related to smooth muscle contraction endocrine diseases
  • diseases related to neurodegeneration It may be useful for the treatment of diseases such as inflammation or pain and diseases related to withdrawal symptoms caused by addictive drug abuse.
  • ⁇ 7 nicotinic acetylcholine receptor represents a valid molecular target for neuroprotection.
  • neuroprotection can be achieved by developing an active agonist / positive modulator of the receptor (positive allosteric modulator: PAM).
  • PAM positive allosteric modulator
  • ⁇ 7 nicotinic receptor agonists have already been identified and evaluated as potential clues for the development of neuroprotective drugs.
  • the involvement of ⁇ 7 nicotinic acetylcholine receptors in inflammation has also been reported. From the above, the development of a novel modulator of the receptor is expected to be a novel treatment for nervous system diseases, psychiatric diseases and inflammatory diseases.
  • Patent Document 1 a modulator of ⁇ 7 nicotinic acetylcholine receptor ( ⁇ 7 nAChR), but the structure is different from the compound of the present invention (Patent Document 1 and Patent Document 2).
  • An object of the present invention is to provide a novel compound having a potent ⁇ 7 nicotinic acetylcholine receptor ( ⁇ 7 nAChR) regulating action and useful as a novel therapeutic and / or preventive agent for nervous system diseases, mental disorders and inflammatory diseases. Is to provide.
  • ⁇ 7 nAChR potent ⁇ 7 nicotinic acetylcholine receptor
  • a novel compound represented by the following formula (I) has a potent ⁇ 7 nicotinic acetylcholine receptor ( ⁇ 7 nAChR) regulating action, and completed the present invention.
  • ⁇ 7 nAChR potent ⁇ 7 nicotinic acetylcholine receptor
  • a benzimidazole derivative represented by the following formula (I) or a pharmaceutically acceptable salt thereof (hereinafter sometimes referred to as “the compound of the present invention”) is provided.
  • Optionally substituted C 1-6 alkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of halogen, hydroxyl, C 1-6 alkoxy and —NR 16 R 17 3-10 cycloalkyl; 4-10 membered saturated heterocycle; hydrogen atom; halogen; hydroxyl group; or C 1-6 alkoxy R 10 to R 17 are the same or different and each represents a hydrogen atom or C 1-6 alkyl; n represents 1 or 2] Or a pharmaceutically acceptable salt thereof.
  • A is CR 1D or a nitrogen atom
  • XYZ represents N-CO-NR 4A R 5 , CR 6 -CO-NR 4A R 5 , CR 6 -NR 7 -CONR 4A R 5 , CR 6 -NR 7 -COR 4B , CR 6 -NR 7 -aryl, CR 6 -NR 7 -heteroaryl or CR 6 -CR 8 R 9 -NR 4A R 5 , R 1A , R 1B , R 1C and R 1D are the same or different and are substituted with 1 to 5 substituents selected from the group consisting of halogen, hydroxyl group, C 1-6 alkoxy and —NR 10 R 11 An optionally substituted C 1-6 alkyl; a C 3-10 optionally substituted with 1 to 5 substituents selected from the group consisting of halogen, hydroxyl group, C 1-6 alkoxy and —NR 10 R 11 cycloalkyl; halogen
  • A is CR 1D
  • XYZ is N—CO—NR 4A R 5
  • R 1A , R 1C and R 1D are both hydrogen atoms, and one of R 4A and R 5
  • R 1B is fluorine
  • the other of R 4A and R 5 is phenyl, 2-methoxyphenyl, 4-ethoxyphenyl, cyclohexyl, 4-methoxyphenyl, 2-ethoxyphenyl, 4-chloro-3-trifluoro Phenyl, 3-methoxyphenyl, 2-trifluoromethylphenyl, 3-methylphenyl, 2-chlorophenyl, adamantyl, 2-methylphenyl, 2,4-difluorophenyl, 4-ethoxyphenyl, 3-fluorophenyl
  • XYZ represents N—CO—NR 4A R 5 , CR 6 —NR 7 —CONR 4A R 5 , CR 6 —NR 7 —COR 4B , CR 6 —NR 7 —aryl, CR 6 -NR 7 -heteroaryl or CR 6 -CR 8 R 9 -NR 4A R 5 Item 5.
  • XYZ is N—CO—NR 4A R 5 or CR 6 —NR 7 —COR 4B .
  • Item 5 The compound according to any one of Items 1 to 4 or a pharmaceutically acceptable salt thereof.
  • XYZ is CR 6 —NR 7 —COR 4B .
  • Item 5 The compound according to any one of Items 1 to 4 or a pharmaceutically acceptable salt thereof.
  • R 4B is substituted with 1 to 5 substituents independently selected from the group consisting of aryl, heteroaryl, hydroxyl group, fluorine, C 1-6 alkoxy and C 3-10 cycloalkyl.
  • C 1-6 alkyl which may be substituted; aryl, heteroaryl, hydroxyl group, fluorine, C 1-6 alkoxy optionally substituted with 1 to 5 fluorines and optionally substituted with 1 to 5 fluorines
  • C 3-10 cycloalkyl which may be substituted with 1 to 5 substituents independently selected from the group consisting of C 1-6 alkyl (the group may form a condensed ring with aryl)
  • a 4- to 10-membered saturated heterocycle optionally substituted with 1 to 5 identical or different C 1-6 alkyls; or halogen, C 1-6 alkoxy and C 1-6 alkyl (the alkoxy and alkyl are 1-5
  • Aryl or heteroaryl optionally substituted with 1 to 5 substituents independently selected from the group
  • R 4B may be substituted with 1 to 5 substituents independently selected from the group consisting of aryl, heteroaryl, fluorine, C 1-6 alkoxy and C 3-10 cycloalkyl.
  • C 1-6 alkyl; aryl, heteroaryl, fluorine, 1-5 fluorine may be substituted with an optionally substituted C 1-6 alkoxy and 1 to 5 fluorine by C 1-6 C 3-10 cycloalkyl which may be substituted with 1 to 5 substituents independently selected from the group consisting of alkyl (the group may form a condensed ring with aryl); the same or different A 4- to 10-membered saturated heterocycle optionally substituted with 1 to 5 C 1-6 alkyl; or halogen, C 1-6 alkoxy and C 1-6 alkyl (wherein the alkoxy and alkyl are 1-5 Replaced with one fluorine An aryl or heteroaryl optionally substituted with 1 to 5 substituents independently selected from the group consisting of: Item 8.
  • A is CR 1D .
  • Item 10 The compound according to any one of Items 1 to 9, or a pharmaceutically acceptable salt thereof.
  • R 2 is a hydrogen atom.
  • Item 11 The compound according to any one of Items 1 to 10, or a pharmaceutically acceptable salt thereof.
  • n is 1.
  • Item 12 The compound according to any one of Items 1 to 11, or a pharmaceutically acceptable salt thereof.
  • R 3A , R 3B , R 3C and R 3D are the same or different and each is a hydrogen atom, a halogen, a hydroxyl group or C 1-6 alkoxy.
  • Item 13 The compound according to any one of Items 1 to 12, or a pharmaceutically acceptable salt thereof.
  • R 1A , R 1B , R 1C and R 1D are the same or different and substituted with 1 to 5 substituents independently selected from the group consisting of halogen, hydroxyl group and C 1-6 alkoxy C 1-6 alkyl which may be substituted; C 3-10 cycloalkyl which may be substituted with 1 to 5 substituents independently selected from the group consisting of halogen, hydroxyl group and C 1-6 alkoxy ; halogen, hydroxyl, C 1-6 alkoxy and C 3-6 optionally substituted by one to five substituents independently selected from the group consisting of cycloalkyl C 1-6 alkoxy; hydrogen atom; Independently from the group consisting of hydroxyl group; halogen; halogen, C 1-6 alkyl optionally substituted with 1 to 5 fluorines and C 1-6 alkoxy optionally substituted with 1 to 5 fluorines Selected That 1-5 phenyl optionally substituted with a substituent; a halogen, optionally
  • R 1A , R 1B , R 1C and R 1D are the same or different and substituted with 1 to 5 substituents independently selected from the group consisting of halogen, hydroxyl group and C 1-6 alkoxy C 1-6 alkyl which may be substituted; C 3-7 cycloalkyl which may be substituted with 1 to 5 substituents independently selected from the group consisting of halogen, hydroxyl group and C 1-6 alkoxy ; halogen, hydroxyl, C 1-6 alkoxy and C 3-6 optionally substituted by one to five substituents independently selected from the group consisting of cycloalkyl C 1-6 alkoxy; hydrogen atom; Halogen; 4-7 membered saturated heterocycle; cyano; —COOR 10 ; or —CONR 10 R 11 Item 14.
  • R 4A , R 5 and R 7 are the same or different and are substituted with 1 to 5 substituents independently selected from the group consisting of aryl, halogen, hydroxyl group and C 1-6 alkoxy.
  • R 6 , R 8, and R 9 are the same or different and each represents C 1-6 alkyl, a hydroxyl group, or a hydrogen atom.
  • Item 18 The compound according to any one of Items 1 to 16, or a pharmaceutically acceptable salt thereof.
  • R 4B is substituted with 1 to 5 substituents independently selected from the group consisting of aryl, heteroaryl, hydroxyl group, fluorine, C 1-6 alkoxy and C 3-10 cycloalkyl.
  • C 1-6 alkyl which may be substituted; aryl, heteroaryl, hydroxyl group, fluorine, C 1-6 alkoxy optionally substituted with 1 to 5 fluorines and optionally substituted with 1 to 5 fluorines
  • C 3-10 cycloalkyl which may be substituted with 1 to 5 substituents independently selected from the group consisting of C 1-6 alkyl (the group may form a condensed ring with aryl)
  • a 4- to 10-membered saturated heterocycle optionally substituted with 1 to 5 identical or different C 1-6 alkyls; or halogen, C 1-6 alkoxy and C 1-6 alkyl (the alkoxy and alkyl are 1 An aryl or heteroaryl optionally substituted with 1 to 5 substituents independently selected from the group consist
  • R 4A and R 5 are the same or different, and aryl (the group is 1 to 5 Halogen, hydroxyl, optionally substituted with C 1-6 alkyl or C 1-6 alkoxy), heteroaryl (the group consists of halogen, hydroxyl, C 1-6 alkyl and C 1-6 alkoxy) Independently substituted from the group consisting of halogen, hydroxyl, C 1-6 alkoxy, C 3-10 cycloalkyl and —NR 14 R 15 , optionally substituted with 1 to 5 substituents selected from the group C 1-6 alkyl optionally substituted with 1 to 5 selected substituents; aryl (the group is independent of the group consisting of halogen, hydroxyl, C 1-6 alkyl and C 1-6 alkoxy) 1 to 5 selected May be substituted with substituent), heteroaryl (in which, halogen, hydroxyl, 1 to 5 substituents
  • C 3-10 cycloalkyl (the group may form a condensed ring with aryl or heteroaryl); halogen, hydroxyl group, C 1-6 alkoxy and C 1-6 alkyl (the group is Heteroaryl optionally substituted with 1 to 5 substituents independently selected from the group consisting of 1 to 5 fluorines), or a hydrogen atom, Item 19.
  • A is CR 1D , R 1A , R 1C and R 1D are both hydrogen atoms, R 1B is a fluorine atom or methyl, and XYZ is N—CO—NR 4A R 5.
  • R 4A and R 5 are the same or different and are aryl (the group is independently selected from the group consisting of halogen, hydroxyl, C 1-6 alkyl and C 1-6 alkoxy) Optionally substituted with 1 substituent), heteroaryl (wherein the group is independently selected from the group consisting of halogen, hydroxyl, C 1-6 alkyl and C 1-6 alkoxy) 1 to 5 substituents independently selected from the group consisting of halogen, hydroxyl group, C 1-6 alkoxy, C 3-10 cycloalkyl and —NR 14 R 15.
  • aryl in an optionally substituted C 1 6 alkyl; aryl (said groups, halogen, optionally substituted with one to five substituents independently selected from the group consisting of hydroxyl and C 1-6 alkoxy), heteroaryl (said group , Optionally substituted with 1 to 5 substituents independently selected from the group consisting of halogen, hydroxyl, C 1-6 alkyl and C 1-6 alkoxy), C 3-9 cycloalkyl (including The group may form a condensed ring with aryl or heteroaryl, and is independently selected from the group consisting of halogen, hydroxyl group, C 1-6 alkoxy, C 1-6 alkyl and —NR 14 R 15.
  • a 4-10 membered saturated heterocycle optionally substituted with C 1-6 alkyl; halogen, C 1-6 alkoxy and C 1-6 alkyl 1-5 groups 1-5 may be substituted with a substituent aryl independently selected from the group consisting of Tsu may be substituted with hydrogen); halogen, hydroxyl, C 1-6 alkoxy and C 1-6 A heteroaryl optionally substituted with 1 to 5 substituents independently selected from the group consisting of alkyl (the group may be optionally substituted with 1 to 5 fluorines); or a hydrogen atom Is, Item 21.
  • A is CR 1D, R 1A, R 1C and R 1D are both hydrogen atoms, R 1B is a fluorine atom or a -NR 10 R 11, X-Y -Z is N-CO-
  • R 4A R 5 , R 4A and R 5 are the same or different and are independently selected from the group consisting of aryl (halogen, hydroxyl, C 1-6 alkyl and C 1-6 alkoxy) Independently selected from the group consisting of heteroaryl, halogen, hydroxyl, C 1-6 alkoxy, C 3-10 cycloalkyl and —NR 14 R 15.
  • C 1-6 alkyl optionally substituted with 1 to 5 substituents of C 1-6 alkyl; aryl (wherein the group is selected from the group consisting of halogen, hydroxyl group and C 1-6 alkoxy) Substituted with a group Good), heteroaryl, or hydroxyl, C 1-6 alkoxy, C 1-6 alkyl, -NR 14 R 15 or the same or different one to five good C 3-10 cycloalkyl optionally substituted with halogen (However, unsubstituted cyclohexyl, except said groups, aryl or may form a heteroaryl and fused); C 1-6 saturated heterocyclic ring may 4-10 membered optionally substituted with alkyl; halogen Substituted with 1 to 5 substituents independently selected from the group consisting of C 1-6 alkoxy and C 1-6 alkyl, which group may be substituted with 1 to 5 fluorines Item 22.
  • aryl wherein the group is selected from the group consisting
  • XYZ is CR 6 —NR 7 —COR 4B , n is 1, and the 1- and 4-positions of the cyclohexane ring formed are in a cis relationship.
  • Item 23 The compound according to any one of Items 1 to 22, or a pharmaceutically acceptable salt thereof.
  • R 7 is a hydrogen atom.
  • Item 24 The compound or a pharmaceutically acceptable salt thereof according to any one of Items 1 to 23.
  • XYZ is CR 6 —CR 8 R 9 —NR 4A R 5
  • one of R 4A and R 5 is (1) halogen, C 1-6 alkoxy and C 1-6 alkyl ( The alkoxy and alkyl are aryl or heteroaryl optionally substituted with 1 to 5 substituents independently selected from the group consisting of 1 to 5 fluorines)
  • the other is (2) a combination of hydrogen atoms, Item 25.
  • a pharmaceutical composition comprising the compound according to any one of items 1 to 27 or a pharmaceutically acceptable salt thereof.
  • a therapeutic agent for diseases caused by abnormal intracellular signaling involving acetylcholine comprising the compound according to any one of items 1 to 27 or a pharmaceutically acceptable salt thereof as an active ingredient Or a preventive agent.
  • CIAS cognitive impairment associated with schizophrenia
  • Alzheimer's disease Down's syndrome
  • cognitive impairment memory impairment / learning impairment
  • mild cognitive impairment Item 30.
  • An acetylcholine characterized by administering a therapeutically effective amount of the compound according to any one of items 1 to 27 or a pharmaceutically acceptable salt thereof to a patient in need of treatment.
  • the compound of the present invention is useful as a novel therapeutic agent and / or preventive agent for nervous system diseases, psychiatric diseases, and inflammatory diseases (for example, senile dementia, attention deficit disorder, Alzheimer's disease, and schizophrenia).
  • the compound of the present invention is useful for the treatment and / or prevention of nervous system diseases such as schizophrenia and mental disorders as a concomitant drug with drugs classified as atypical antipsychotic drugs.
  • the compounds of the present invention may exist in the form of hydrates and / or solvates, these hydrates and / or solvates are also included in the compounds of the present invention.
  • the compound of formula (I) may have one or more asymmetric carbon atoms and may cause geometric isomerism and axial chirality, and therefore exist as several stereoisomers. There is. In the present invention, these stereoisomers, mixtures thereof and racemates are included in the compound represented by the formula (I) of the present invention.
  • the compound represented by the general formula (I) includes a deuterium converter obtained by converting any one or two or more 1 H of the compound represented by the general formula (I) to 2 H (D). Is done.
  • a solvate such as a hydrate of the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof or an ethanol solvate is also represented by the general formula (I). Included in the compound.
  • Alkyl means a linear or branched saturated hydrocarbon group.
  • C 1-6 alkyl means an alkyl having 1 to 6 carbon atoms. Specific examples thereof include “C 1-6 alkyl” such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl and the like.
  • Cycloalkyl means a monocyclic or polycyclic saturated hydrocarbon. For example, “C 3-6 cycloalkyl” or “C 3-10 cycloalkyl” means 3 to 6 or 3 to C carbon atoms.
  • cyclic alkyls and those having a partially bridged structure or those formed a condensed ring with aryl or heteroaryl are also included.
  • C 3-6 cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
  • C 3-10 cycloalkyl in addition to the above, cycloheptyl, cyclooctyl, adamantyl and the like can be mentioned.
  • Alkoxy means a group in which a linear or branched saturated hydrocarbon group is interposed via an oxygen atom.
  • C 1-6 alkoxy means a group having 1 to 6 carbon atoms. Means alkoxy. Specific examples of “C 1-6 alkoxy” include methoxy, ethoxy, propoxy, isopropoxy, butyloxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy and the like.
  • Halogen means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. Among them, preferred is a fluorine atom or a chlorine atom.
  • aryl include phenyl, 1-naphthyl, 2-naphthyl, anthracene and the like. Of these, phenyl is preferable.
  • Heteroaryl is a monocyclic 5- to 7-membered aromatic heterocyclic group or bicyclic ring containing 1 to 4 atoms independently selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom And an 8- to 11-membered aromatic heterocyclic group or a 3-ring 12- to 16-membered aromatic heterocyclic group.
  • the “4- to 10-membered saturated heterocyclic ring” means 4 to 10 atoms including 1 to 2 atoms independently selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom. Means a composed heterocycle.
  • azetidine, pyrrolidine, piperidine, piperazine, morpholine, homopiperidine, tetrahydrofuran, tetrahydropyran and the like can be mentioned.
  • the “4- to 10-membered nitrogen-containing saturated heterocyclic ring” means a saturated heterocyclic ring composed of 4 to 10 atoms containing 1 to 2 nitrogen atoms in addition to carbon atoms.
  • azetidine, pyrrolidine, piperidine, piperazine, homopiperidine and the like can be mentioned.
  • CR 6 -NR 7 -aryl refers to a group in which aryl is substituted on the nitrogen atom of CR 6 -NR 7 . Like the - "aryl CR 6 -NR 7" - it means "CR 6 -NR 7 heteroaryl” etc. was also replaced with the latter group.
  • A is preferably CR 1D .
  • X—Y—Z is preferably N—CO—NR 4A R 5 , CR 6 —NR 7 —CONR 4A R 5 , CR 6 —NR 7 —COR 4B , CR 6 —NR 7 —aryl, CR 6 —NR 7 -heteroaryl or CR 6 -CR 8 R 9 -NR 4A R 5 may be mentioned, more preferably N-CO-NR 4A R 5 , CR 6 -NR 7 -COR 4B , CR 6 -NR 7 -aryl. Or CR 6 -NR 7 -heteroaryl.
  • N—CO—NR 4A R 5 or CR 6 —NR 7 —COR 4B is used.
  • R 1A to R 1D are preferably the same or different and may be substituted with 1 to 5 substituents independently selected from the group consisting of halogen, C 1-6 alkoxy and —NR 10 R 11.
  • C 1-6 alkyl, hydrogen atom, halogen, C 3-10 cycloalkyl, C 1-6 alkoxy, C 3-10 cycloalkoxy, —NR 10 R 11 , cyano, —COOR 10 , —CONR 10 R 11 , —NR 10 COR 11 , —SO 2 NR 10 R 11, or —NR 10 SO 2 R 11 may be mentioned. More preferably, C 1-6 alkyl, hydrogen atom, halogen, C 3-10 which may be substituted with 1 to 5 substituents independently selected from the group consisting of halogen and C 1-6 alkoxy Examples include cycloalkyl, C 1-6 alkoxy or C 3-10 cycloalkoxy.
  • R 2 is preferably C 1-6 alkyl which may be substituted with 1 to 5 substituents independently selected from the group consisting of halogen, hydroxyl group and —NR 12 R 13 , a hydrogen atom, C 1 -6 alkoxy or a 4- to 10-membered saturated heterocyclic ring can be mentioned, and more preferable examples include C 1-6 alkyl, hydrogen atom or C 1-6 alkoxy optionally substituted with 1 to 5 halogens. . Most preferably, a hydrogen atom is mentioned.
  • R 3A , R 3B , R 3C and R 3D are preferably the same or different and may be substituted with 1 to 5 substituents independently selected from the group consisting of halogen and —NR 14 R 15 Good C 1-6 alkyl, a hydrogen atom or halogen is preferable, and C 1-6 alkyl, a hydrogen atom or halogen is more preferable.
  • R 4A preferably as R 5 and R 7, which may be identical or different, halogen, optionally substituted with 1 to 5 substituents selected from the group consisting of hydroxyl and C 1-6 alkoxy C 1- 6 alkyl; C 3-10 cycloalkyl optionally substituted with 1 to 5 substituents selected from the group consisting of halogen, hydroxyl group and C 1-6 alkoxy; 4- to 10-membered saturated heterocycle or hydrogen Atoms, and more preferably, a C 3-10 cycloalkyl which may be substituted with 1 to 5 substituents selected from the group consisting of halogen, hydroxyl group and C 1-6 alkoxy, or a hydrogen atom. It is done.
  • R 4B is preferably substituted with 1 to 5 substituents independently selected from the group consisting of aryl, heteroaryl, hydroxyl group, fluorine, C 1-6 alkoxy and C 3-10 cycloalkyl.
  • C 1-6 alkyl; aryl, heteroaryl, hydroxyl, fluorine, 1-5 fluorine may be substituted with C 1-6 alkoxy and 1 to 5 substituents
  • C 1 be substituted by fluorine C 3-10 cycloalkyl which may be substituted with 1 to 5 substituents independently selected from the group consisting of -6 alkyl (the group may form a condensed ring with aryl); Or a 4- to 10-membered saturated heterocycle optionally substituted with 1 to 5 different C 1-6 alkyls; or halogen, C 1-6 alkoxy and C 1-6 alkyl (the alkoxy and alkyl are And aryl or heteroaryl optionally substituted with 1 to 5 substituents independently selected from the group consisting of 1 to 5
  • aryl, heteroaryl, hydroxyl, fluorine, C 1-6 alkoxy and C 3-10 cycloalkyl 1 to 5 substituents independently selected from the group consisting of aryl, heteroaryl, hydroxyl, fluorine, C 1-6 alkoxy and C 3-10 cycloalkyl.
  • 1-6 alkyl; aryl, heteroaryl, hydroxyl, fluorine, optionally substituted with 1-5 optionally substituted by fluorine C 1-6 alkoxy and 1 to 5 fluorine C 1-6 C 3-10 cycloalkyl which may be substituted with 1 to 5 substituents independently selected from the group consisting of alkyl (which may form a condensed ring with aryl); or the same or Examples thereof include a 4- to 10-membered saturated heterocyclic ring which may be substituted with 1 to 5 different C 1-6 alkyls.
  • fluorine, C 1-6 alkoxy and C 3-10 ⁇ 1 are independently selected from the group consisting of cycloalkyl 5 substituents optionally substituted by C 1-6 alkyl; fluorine, 1 to 1 to 5 selected 5 substituents are fluorine substituted C 1-6 alkoxy and 1 to 5 fluorine independently from the group consisting of C 1-6 alkyl optionally substituted C 3-10 cycloalkyl optionally substituted with one substituent; or a 4-10 membered saturated heterocycle.
  • R 6 , R 8 and R 9 are preferably the same or different and include a hydrogen atom, halogen, hydroxyl group, C 1-6 alkyl or C 1-6 alkoxy, and more preferably a hydrogen atom or halogen.
  • R 10 to R 17 are the same or different and include a hydrogen atom or C 1-6 alkyl, preferably a hydrogen atom.
  • n 1 or 2 is mentioned, Preferably 1 is mentioned.
  • the pharmaceutically acceptable salt of the compound represented by the formula (I) is a pharmaceutically acceptable acid addition of the compound of the formula (I) having a group capable of forming an acid addition salt in the structure.
  • Means salt Specific examples of acid addition salts include hydrochloride, hydrobromide, hydroiodide, sulfate, perchlorate, phosphate and other inorganic acid salts, oxalate, malonate, maleate Acid, fumarate, lactate, malate, citrate, tartrate, benzoate, trifluoroacetate, acetate, methanesulfonate, p-toluenesulfonate, trifluoromethanesulfonate And organic acid salts such as glutamic acid salts and aspartic acid salts.
  • compound represented by a formula (I) has acidic functional groups, such as a carboxyl group
  • various bases and salts can be formed.
  • the pharmaceutically acceptable salt in this case include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt, and ammonium salt. These salts can be obtained by a conventional method such as recrystallization after mixing the compound of the present invention represented by formula (I) with a base.
  • the method for producing the compound of the present invention is described below.
  • the compound of the present invention represented by the formula (I) can be produced, for example, by the following production methods A to D.
  • a compound represented by the formula A1 in which XYZ is N—CO—NR 4A R 5 (hereinafter also referred to as the compound A1) is, for example, the following production method Can be manufactured.
  • A, R 1A to R 1D , R 2 , R 3A to R 3D , R 4A , R 5 and n are as defined in Item 1, P is an amino-protecting group, and X is halogen. Etc., R means a methyl group or a phenyl group)
  • 2-halonitrobenzene in which A is a compound a1 having CR 1D is, for example, Bioorganic & Medicinal Chemistry Letters 2003, 13 (10), 1725-1728, Tetrahedron 1999, 55 (25), 7725-7738, Synth. Commun. 1998, 28 (23), 4295-4301, etc., or can be synthesized as a commercial product.
  • 2-halonitropyridine in which A is a nitrogen atom compound a1 is, for example, Bioorganic & Medicinal Chemistry Letters 2003, 13 (10), 525-527, J. Heterocyclic Chem. 2000, 37 (5), 1253. -1256, Tetrahedron Lett. 1993, 34 (18), 2937-2940, J. Heterocyclic Chem. 1996, 33 (6), 1815-1821, J. Org. Chem. 1991, 56 (9), 3006-3009, etc. Or can be purchased as a commercial product.
  • Step A-1 This step is a step of obtaining compound a2 by reacting compound a1 with compound a6 in a suitable solvent in the presence of various bases.
  • the base used in this step is selected from the bases exemplified below, and is preferably diisopropylethylamine or potassium carbonate.
  • the solvent used in this step is selected from the solvents exemplified below, and preferably dimethylformamide or tetrahydrofuran.
  • the methods described in Tetrahedron Lett. 1994, 35 (31), 5649-5652, Tetrahedron Lett. 2002, 43 (43), 7707-7710, etc. are known and synthesized in the same manner. Can do.
  • Step A-2 compound a3 can be obtained by reducing compound a2 obtained in step A-1 in the presence or absence of a catalyst.
  • a catalyst formic acid salts such as ammonium formate, hydrazine, zinc, iron, and tin dichloride can be used.
  • the catalyst include those supported on a carrier such as a transition metal such as palladium, nickel, rhodium, cobalt or platinum, a salt thereof, a complex thereof, or a polymer.
  • the solvent used in this step is selected from the solvents exemplified below, and is preferably tetrahydrofuran or methanol. Similar reactions include, for example, Org. Lett.
  • Step A-3 Compound a4 in which R 2 is a hydrogen atom can be obtained by reacting compound a3 obtained in step A-2 with trimethoxymethane, triethoxyethane, or formic acid in a suitable solvent.
  • trimethoxymethane triethoxyethane
  • formic acid formic acid
  • the methods described in Tetrahedron Lett. 2006, 47 (30), 5359-5361, International Publication No. 2010/012121, International Publication No. 2010/027500, etc. are known, Can be synthesized.
  • the compound a4 in which R 2 is bonded to the benzimidazole ring with carbon-carbon is obtained by reacting the compound a3 obtained in the above step A-2 with the corresponding carboxylic acid (R 2 CO 2 H) or acid in an appropriate solvent.
  • Step A-4 This step is a step of obtaining a compound a5 by deprotecting the amino-protecting group P of the compound a4 obtained in the step A-3.
  • This step can be carried out according to the method described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter G. M. Wuts, John Wiley & Sons, Inc., 1999).
  • Step A-5 This step is a step of obtaining compound A1 by reacting compound a5 obtained in step A-4 with compound a7, a8 or a9 in an appropriate solvent in the presence of various bases.
  • the base used in this step is selected from the bases exemplified below, and is preferably diisopropylethylamine or triethylamine.
  • the solvent used in this step is selected from the solvents exemplified below, and is preferably tetrahydrofuran or ethanol.
  • Step A-6 This step is a step of introducing a leaving group L into the compound a5 obtained in the above step A-4.
  • a1 is obtained by reacting 1,1′-carbonyldiimidazole or substituted or unsubstituted phenyl chloroformate in an appropriate solvent in the presence of various bases.
  • the base used in this step is selected from the bases exemplified below, and is preferably diisopropylethylamine or triethylamine.
  • the solvent used in this step is selected from the solvents exemplified below, and preferably methylene chloride or dichloroethane. As a similar reaction, for example, it can be synthesized by a method described in International Publication No. 2003/103669 pamphlet.
  • Step A-7 This step is a step of obtaining compound A1 by reacting compound a10 obtained in the above step A-6 with an amine in an appropriate solvent in the presence of various bases.
  • the solvent used in this step is selected from the solvents exemplified below, and is preferably tetrahydrofuran or dimethylformamide. As a similar reaction, for example, it can be synthesized by a method described in International Publication No. 2003/103669 pamphlet.
  • a compound represented by the formula [B1] in which XYZ is CR 6 —CO—NR 4A R 5 (hereinafter also referred to as compound B1) is, for example, It can be produced by the following production method.
  • A, R 1A to R 1D , R 2 , R 3A to R 3D , R 4A , R 5 , R 6 and n are as defined in Item 1, and Rx is a C 1-4 alkyl group.
  • X means a leaving group such as halogen
  • Step B-1 This step is a step of obtaining compound b1 by reacting compound b1 with compound b5 under the conditions according to the above step A-1.
  • Compound b5 can be synthesized, for example, by the method described in International Publication No. 2007/127382 pamphlet, or can be purchased as a commercial product.
  • Step B-2 This step is a step of converting the compound b1 obtained in the step B-1 into the compound b2 under the conditions according to the step A-2.
  • Step B-3 This step is a step of converting the compound b2 obtained in the step B-2 to the compound b3 under the conditions according to the step A-3.
  • Step B-4 This step is a step of converting the ester compound b3 obtained in the step B-3 to the corresponding carboxylic acid compound b4.
  • This step can be carried out according to the method described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter G. M. Wuts, John Wiley & Sons, Inc., 1999).
  • Step B-5 This step is a step of obtaining compound B1 by reacting compound b6 obtained in step B-4 with compound b6 in a suitable solvent in the presence of various condensing agents.
  • the condensing agent used in this step is preferably EDCI (including hydrochloride) or HBTU.
  • the solvent used in this step is selected from the solvents exemplified below.
  • a compound represented by the formula [C1] wherein XYZ is CR 6 -CR 8 R 9 -NR 4A R 5 (hereinafter also referred to as the compound C1) Can be produced, for example, by the following production method.
  • A, R 1A to R 1D , R 2 , R 3A to R 3D , R 4A , R 5 , R 6 , R 8 , R 9 and n are as defined in Item 1; , C 1-4 alkyl group)
  • Step C-1 This step is a step of converting the ester compound b3 obtained in the step B-3 to the corresponding aldehyde compound c1 using a reducing agent such as diisobutylaluminum hydride, sodium borohydride or lithium borohydride.
  • a reducing agent such as diisobutylaluminum hydride, sodium borohydride or lithium borohydride.
  • Similar reactions include, for example, Chem. Pharm. Bull. 1993, 41 (5), 882-888, Tetrahedron Lett. 1996, 37 (14), 2467-2470, Chem. Lett. 2007, 36 (7), 886- The methods described in 887, Tetrahedron 2001, 57 (14), 2701-2710 and the like are known and can be synthesized in the same manner.
  • the same conversion can also be performed by converting to an alcohol compound using a reducing agent such as lithium aluminum hydride and then converting to an aldehyde by Swern oxidation or the like.
  • a reducing agent such as lithium aluminum hydride
  • a similar reaction for example, a method described in Bioorg. Med. Chem. Lett. 2001, 11 (16), 2177-2180, Bioorg. Med. Chem. Lett. 1998, 8 (24), 3615-3620, etc. Are known and can be synthesized similarly.
  • Step C-2 the corresponding aldehyde compound C1 is obtained by reductive amination of the compound c2 in the presence of a reducing agent such as NaBH (OAc) 3 or NaBH 3 CN with respect to the aldehyde compound c1 obtained in the step C-1. It is the process of converting into. Similar reactions include, for example, J. Org. Chem. 1996, 61 (11), 3849-3862, J. Org. Chem. 1991, 56 (17), 5192-5196, Carbohydr. Res. 1999, 315 (3- 4), 339-344 and the like are known and can be synthesized in the same manner.
  • a reducing agent such as NaBH (OAc) 3 or NaBH 3 CN
  • XYZ is the formula [D1, D2], which is CR 6 —NR 7 —COR 4B , or the formula, which is CR 6 —NR 7 —CONR 4A R 5
  • the compounds represented by [D3, D4] (hereinafter also referred to as compounds D1, D2, D3, and D4) can be produced, for example, by the following production method.
  • A, R 1A to R 1D , R 2 , R 3A to R 3D , R 4B , R 5 to R 7 and n are as defined in Item 1, P is an amino-protecting group, X means a leaving group such as halogen)
  • Step D-1 This step is a step of obtaining compound d1 by reacting compound d1 with compound d6 under the same conditions as in step A-1.
  • Compound d6 can be synthesized, for example, by the method described in International Publication No. 2010/022159 pamphlet or International Publication No. 2007/08669 pamphlet, or can be purchased as a commercial product.
  • Step D-2 This step is a step of converting the compound d1 obtained in the step D-1 into the compound d2 under the conditions according to the step A-2.
  • Step D-3 This step is a step of converting the compound d2 obtained in the step D-2 to the compound d3 under the conditions according to the step A-3.
  • Step D-4 This step is a step of obtaining the compound d4 by deprotecting the amino-protecting group P of the compound d3 obtained in the step D-3.
  • This step can be carried out according to the method described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter G. M. Wuts, John Wiley & Sons, Inc., 1999).
  • Step D-5 This step is a step of obtaining compound D1 by reacting compound d4 obtained in step D-4 with compound d7 or d8 in a suitable solvent in the presence of various condensing agents or bases.
  • the condensing agent used in this step is preferably EDCI (including hydrochloride) or HBTU.
  • the base used is selected from the bases exemplified below, and is preferably diisopropylethylamine or triethylamine.
  • the solvent used in this step is selected from the solvents exemplified below, and preferably dimethylformamide or tetrahydrofuran.
  • Step D-6 This step is a step of converting the compound d4 obtained in the step D-4 to the compound d5.
  • R 7 is alkyl or cycloalkyl
  • Compound d5 can be synthesized. Similar transformations include, for example, Chem. Commun. 2004, 353-359, J. Comb. Chem. 2006, 8 (6), 834-840, J. Org. Chem. 1994, 59 (7), 1771-1778 , J. Org. Chem. 1995, 60 (10), 2989-2999, Bioorg. Med.
  • Step D-7 This step is a step of converting the compound d5 obtained in the step D-6 to the compound D2 by reacting the compound d7 or d8 under the conditions according to the step D-5.
  • R 1A to R 1D , R 2 , R 3A to R 3D , R 4A , R 5 to R 7 and n are as defined in Item 1;
  • X is a leaving group such as halogen;
  • R means a methyl group or a phenyl group
  • Step D-8 This step is a step of converting the compound d4 obtained in the step D-4 to the compound D3 under the conditions according to the step A-5.
  • Step D-9 This step is a step of converting the compound d5 obtained in the step D-6 to the compound D4 under the conditions according to the step A-5.
  • alkali bicarbonates such as sodium bicarbonate and potassium bicarbonate, sodium carbonate and potassium carbonate
  • Alkali carbonates such as sodium hydride, metal hydrides such as sodium hydride and potassium hydride, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metals such as sodium methoxide and sodium t-butoxide Alkoxides, organometallic bases such as butyllithium and lithium diisopropylamide, triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine (DMAP), 1,8-diazabicyclo [5.4.0] -7-undecene ( Organic bases such as DBU) That.
  • DMAP 4-dimethylaminopyridine
  • DBU 1,8-diazabicyclo [5.4.0] -7-undecene
  • the solvent used in each of the above steps should be appropriately selected depending on the reaction and the type of raw material compound.
  • alcohols such as methanol, ethanol and isopropanol
  • ketones such as acetone and methyl ketone
  • Halogenated hydrocarbons such as methylene and chloroform
  • ethers such as tetrahydrofuran (THF) and dioxane
  • aromatic hydrocarbons such as toluene and benzene
  • aliphatic hydrocarbons such as hexane and heptane
  • ethyl acetate Esters such as propyl acetate
  • amides such as N, N-dimethylformamide (DMF), N-methyl-2-pyrrolidone
  • sulfoxides such as dimethyl sulfoxide (DMSO)
  • nitriles such as acetonitrile.
  • the compound of the present invention represented by the formula (I) or an intermediate thereof can be separated and purified by methods known to those skilled in the art.
  • extraction, distribution, reprecipitation, column chromatography (for example, silica gel column chromatography, ion exchange column chromatography or preparative liquid chromatography) or recrystallization may be mentioned.
  • the recrystallization solvent include alcohol solvents such as methanol, ethanol and 2-propanol, ether solvents such as diethyl ether, ester solvents such as ethyl acetate, aromatic hydrocarbon solvents such as benzene and toluene, acetone and the like.
  • Ketone solvents such as dichloromethane or chloroform
  • hydrocarbon solvents such as hexane
  • aprotic solvents such as dimethylformamide or acetonitrile
  • water or a mixed solvent thereof.
  • the methods described in Experimental Chemistry Course (The Chemical Society of Japan, Maruzen) vol. 1 can be used.
  • the molecular structure of the compound of the present invention is determined by referring to the structure derived from each raw material compound, spectroscopic techniques such as nuclear magnetic resonance, infrared absorption, and circular two-spectrum spectroscopy, and mass. It can be easily done by analytical methods.
  • the compounds of the present invention represented by the formula (I) or pharmaceutically acceptable salts thereof may have asymmetry or may have a substituent having an asymmetric carbon.
  • Has optical isomers The compounds of the present invention include mixtures of these isomers and isolated ones, which can be produced according to ordinary methods. Examples of the production method include a method using a raw material having an asymmetric point, or a method of introducing asymmetry at an intermediate stage. For example, in the case of optical isomers, optical isomers can be obtained by using optically active raw materials or by performing optical resolution at an appropriate stage of the production process.
  • the optical resolution method for example, when the compound represented by the formula (I) or an intermediate thereof has a basic functional group, it is an inert solvent (for example, an alcohol solvent such as methanol, ethanol or 2-propanol).
  • An ether solvent such as diethyl ether, an ester solvent such as ethyl acetate, a hydrocarbon solvent such as toluene, an aprotic solvent such as acetonitrile, or a mixed solvent thereof
  • an optically active acid for example, mandelic acid, N-benzyloxyalanine or monocarboxylic acid such as lactic acid, tartaric acid, dicarboxylic acid such as o-diisopropylidene tartaric acid or malic acid, or sulfonic acid such as camphorsulfonic acid or bromocamphorsulfonic acid
  • camphorsulfonic acid or bromocamphorsulfonic acid camphorsulfonic acid or bromocamphorsul
  • Stereomer method can be mentioned.
  • an optically active amine for example, 1-phenylethylamine, quinine, quinidine, cinchonidine, cinchonine, strychnine, etc.
  • the optical resolution can also be carried out by forming a salt using an organic amine).
  • the temperature for forming the salt is selected from the range from room temperature to the boiling point of the solvent. In order to improve the optical purity, it is desirable to raise the temperature once to near the boiling point of the solvent. When the precipitated salt is collected by filtration, it can be cooled as necessary to improve the yield.
  • the amount of the optically active acid or amine used is suitably in the range of about 0.5 to about 2.0 equivalents, preferably in the range of about 1 equivalent, relative to the substrate.
  • Crystals in an inert solvent as necessary for example, alcohol solvents such as methanol, ethanol or 2-propanol, ether solvents such as diethyl ether, ester solvents such as ethyl acetate, hydrocarbon solvents such as toluene, acetonitrile, etc.
  • a high-purity optically active salt can be obtained.
  • the optically resolved salt can be treated with an acid or base by a conventional method to obtain a free form.
  • an optical resolution is achieved by forming an amide using a chemically active amine (eg, 1-phenylethylamine). Can also be performed.
  • the compound of the present invention can be a novel therapeutic agent and / or preventive agent for nervous system diseases, psychiatric diseases, and inflammatory diseases (for example, senile dementia, attention deficit disorder, Alzheimer's disease, and schizophrenia).
  • the administration route of the compound of the present invention may be any of oral administration, parenteral administration and rectal administration, and the daily dose varies depending on the type of compound, administration method, patient symptom / age and the like.
  • oral administration usually about 0.01 to 1000 mg, more preferably about 0.1 to 500 mg per kg body weight of a human or mammal can be administered in 1 to several divided doses.
  • parenteral administration such as intravenous injection, usually, for example, about 0.01 mg to 300 mg, more preferably about 1 mg to 100 mg per kg body weight of a human or mammal can be administered.
  • Examples of the dosage form include tablets, capsules, granules, powders, syrups, suspensions, injections, suppositories, eye drops, ointments, coatings, patches, inhalants and the like.
  • These preparations can be prepared according to a conventional method. In the case of a liquid preparation, it may be dissolved or suspended in water, an appropriate aqueous solution or other appropriate medium at the time of use. Tablets and granules may be coated by a known method. In addition, these formulations may contain other therapeutically valuable ingredients.
  • the compound of the present invention can be used in combination with drugs classified as atypical antipsychotic drugs.
  • atypical antipsychotics include olanzapine, risperidone, paliperidone, quetiapine, ziprasidone, aripiprazole, asenapine, iloperidone, clozapine, sertindole, blonanserin and lurasidone.
  • LCMS measurement conditions are as follows, and the observed mass spectrometry value [MS (m / z)] is represented by MH +, and the retention time is represented by Rt (min, min). In each actual measurement value, measurement conditions used for the measurement are denoted by A to G.
  • Reference example 3 cis-4- (5-Methyl-1H-benzimidazol-1-yl) cyclohexanecarbaldehyde Lithium aluminum hydride (1.5 g) was added to a THF solution (20 ml) of C2 (8.2 g) obtained by the same method as in Reference Example 2 under ice cooling. The resulting suspension was stirred overnight at room temperature and then quenched with saturated aqueous ammonium chloride and then filtered through celite. THF was removed from the solution after filtration, and the mixture was extracted twice with chloroform and washed with saturated brine. The chloroform layer was dried over sodium sulfate and concentrated under reduced pressure to obtain a solid (3.5 g).
  • Example 1 N-cyclohexyl-4- (5-fluoro-1H-benzimidazol-1-yl) piperidine-1-carboxamide Reference Example 1 (300 mg) was dissolved in formic acid (10 ml), and the resulting solution was stirred at 60 ° C. for 3 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted 3 times with 2% methanol-containing chloroform. The obtained organic layer was dried over sodium sulfate and evaporated under reduced pressure.
  • Example 2 cis-N-cyclohexyl-4- (5-methyl-1H-benzimidazol-1-yl) cyclohexanecarboxamide Triethylamine (150 mg) and cyclohexylamine (150 mg) were added to a suspension of THF (3 ml) in Reference Example 2 (110 mg), EDCI hydrochloride (152 mg) and HOBt (110 mg). Stir overnight. After THF was removed under reduced pressure, ethyl acetate was added, and the mixture was washed with a saturated aqueous ammonium chloride solution and saturated brine.
  • Example 3 trans-N-cyclohexyl-4- (5-methyl-1H-benzimidazol-1-yl) cyclohexanecarboxamide
  • trans-4- (5-methyl-1H-benzoimidazol-1-yl) cyclohexanecarboxylic acid formate (60 mg) obtained by the same method as in Reference Example 2.
  • Example 3 was synthesized (42 mg).
  • Example 4 4-chloro-N- ⁇ [cis-4- (5-methyl-1H-benzimidazol-1-yl) cyclohexyl] methyl ⁇ aniline 4-Chloroaniline (30 mg) and acetic acid (0.1 ml) were added to the methanol solution of Reference Example 3 (0.2 ml, 1.0 M) and stirred for 1 hour, and then NaBH 3 CN (15 mg) was added at room temperature. Stir overnight. A saturated aqueous ammonium chloride solution was added to the reaction solution, extracted with chloroform, and washed with saturated brine. The obtained chloroform solution was dried over sodium sulfate and concentrated.
  • Example 5 N- [cis-4- (5-methyl-1H-benzimidazol-1-yl) cyclohexyl] cyclohexanecarboxamide Triethylamine (37.8 ⁇ l), HOAt (13.5 mg) and EDCI hydrochloride (17.3 mg) were added to a DMF solution (1.0 ml) of Reference Example 4 (20 mg), and after stirring at room temperature for 1 hour, cyclohexanecarboxylic acid ( 13 ⁇ l) was added and stirred overnight at room temperature. After THF was removed under reduced pressure, ethyl acetate was added, and the mixture was washed with a saturated aqueous ammonium chloride solution and saturated brine.
  • Example 6 to 79 (Example 1 analogs) The corresponding starting materials were used and reacted in the same manner as in Example 1 to obtain the compounds shown in Table 1.
  • Example 80 to 91 (Example 2 analogs) The corresponding starting materials were used and reacted in the same manner as in Example 2 to obtain the compounds shown in Table 2.
  • Example 414 trans-4- (5-Methyl-1H-benzimidazol-1-yl) cyclohexanamine dihydrochloride was prepared in the same manner as in Reference Example 4 using tert-butyl (trans-4-aminocyclohexyl) carbamate.
  • the compounds shown in Table 5 were obtained by synthesizing and subjecting the corresponding carboxylic acid to the same reaction and treatment as in Example 5.
  • the following compounds are envisaged. These include various amines (cis-4- [5- (cyclopropoxy) -1H-benzoimidazol-1-yl] cyclohexaneamine, cis-4- [5- (cyclobutoxy) -1H-benzimidazole-1- Yl] cyclohexanamine or cis-4- [5- (difluoromethoxy) -1H-benzimidazol-1-yl] cyclohexanamine) and the corresponding carboxylic acid, the same reaction and treatment as in Example 5. Can be synthesized.
  • the various amines can be synthesized by alkylating 4-fluoro-3-nitrophenol and reacting and treating the resulting 4-alkoxy-1-fluoro-2-nitrobenzene in the same manner as in Reference Example 4.
  • As a similar reaction of the above cyclopropylation for example, it is synthesized in the same manner by the method described in International Publication No. 2011/079102, Pamphlet of International Publication No. 2010/105179, Pamphlet of International Publication No. 2008/101939, etc. can do.
  • Test Examples The pharmacological test results of the representative compounds of the present invention are shown below, and the pharmacological actions of the compounds are described. However, the present invention is not limited to these test examples.
  • Test Example 1 PAM activity evaluation using human ⁇ 7 nACh receptor stable expression cells
  • Human ⁇ 7 nAChR stable expression cells Human ⁇ 7 nAChR stable expression cells were prepared and subjected to culture. Specifically, rat pituitary-derived GH4C1 cells (cat # CCL-82.2, ATCC, USA) were used as host cells.
  • Aequorin by introducing pcDNA3.1Zeo vector into which the nucleotide sequence encoding the protein of GenBank BAC81731 was inserted and pcDNA3.1 vector (cat # V790-20, invitrogen, Carlsbad, CA, USA) into which the human ⁇ 7 nAChR gene was inserted And human ⁇ 7 nAChR stably expressing cells were obtained.
  • Zeocin catalog # R25001, invitrogen, Carlsbad, CA, USA
  • Geneticin catalog # 10131-027, invitrogen, Carlsbad, CA, USA
  • the medium includes 2.5% fetal bovine serum (cat # 2917354, ICN Biomedicals, Inc, USA), 15% inactivated horse serum (cat # 26050-088, invitrogen, Carlsbad, CA, USA), 1 ⁇ g / mL Geneticin, Collagen Type 1 using F-10 Nutrient Mixture (Ham) medium (cat # 11550-043, invitrogen, Carlsbad, CA, USA) containing 5 ⁇ g / mL Puromycin (cat # 14861-84, invitrogen, Carlsbad, CA, USA) Culturing was performed in a coat dish (cat # 4030-010, iwaki, Tokyo, Japan).
  • the medium was changed every 2-3 days, and cells were collected by TrypLE Express (cat # 45604-021, invitrogen, Carlsbad, CA, USA) treatment every 7 days and subcultured. Seven days after passage, cells were collected by TrypLE Express treatment in a state of about 80% confluence, and Hanks (cat # 14065-056, invitrogen, Carlsbad, CA, USA) / 20 mM Hepes (cat # 15630-080, invitrogen , Carlsbad, CA, USA) Suspended in a reaction medium consisting of Buffer (pH 7.4), F-10 Nutrient Mixture (Ham), 0.1 mg / mL Geneticin to 20000 cells / 25 ⁇ L / well, and a 384-well plate ( cat # 781090, Greiner, Germany).
  • Viviren (cat # E649X, Promega, Madison, WI, USA) was added to a final concentration of 4 ⁇ M (15 ⁇ L / well), and the mixture was allowed to stand for 4 hours at room temperature in the dark after centrifugation.
  • test compound A DMSO solution having a concentration 1000 times the final concentration was prepared as a test compound, and this solution was added to Hanks / 20 mM HEPES / 0.2% BSA (cat # A3803, Sigma, St. Louis, MO, USA). The final concentration was adjusted to 6 times the final concentration.
  • PAM activity evaluation FDSS7000 (Hamamatsu Photonics) was used for the detection of the luminescent signal by ⁇ 7 nAChR stimulation. Test compounds were added to the plates to which cells and luminescent substrate had been added, and ACh at a concentration indicative of EC 20 was added alone after 150 seconds. The luminescence signal (center wavelength: 465 nm) was measured for 138 seconds after addition of ACh to calculate RLU (Max-Min), and the ratio of RLU (Max-Min) between the control well and the test compound added well was defined as PAM activity. . Table 7 shows data of ⁇ 7 PAM activity of representative compounds.
  • the compound of the present invention had ⁇ 7 nAChR PAM activity in the PAM activity evaluation test.
  • Examples 2, 5, 6, 9, 20, 36, 54, 103, 106, 108, 137, 150, 157, 159, 168, 172, 174, 180, 181, 202, 212, 217, 221, 222, 224, 244, 245, 247, 280, 282, 283 showed stronger PAM activity.
  • Example 3 Evaluation of improvement of cognitive impairment using rat Y-shaped maze test (hereinafter referred to as Y-maze test)
  • Y-maze test In a Y-shaped maze test using 280-300 g Slc: Wistar rats (male, SLC), memory impairment was caused by subcutaneous administration of 0.6 mg / kg Scopolamine HBr (cat # S0929, Sigma Aldrich, Japan)
  • the compound of the present invention is pretreated and the memory impairment improving action is evaluated.
  • Example 9 and Example 192 a significant memory impairment improving action was confirmed at 3 or 10 mg / kg (oral), respectively.
  • the derivative represented by the formula (I), or a pharmaceutically acceptable salt thereof has a strong ⁇ 7 nicotinic acetylcholine receptor ( ⁇ 7hnAChR) modulating action, and the central nervous system ( CNS) and / or peripheral nervous system (PNS) cholinergic diseases, smooth muscle contraction diseases, endocrine diseases, neurodegenerative diseases, diseases such as inflammation or pain, and withdrawal symptoms caused by addictive drug abuse Useful for treatment of diseases and the like.
  • ⁇ 7hnAChR central nervous system
  • PNS peripheral nervous system

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Abstract

La présente invention concerne un agent thérapeutique destiné au traitement des maladies associées aux propriétés cholinergiques du système nerveux central (SNC) et/ou du système nerveux périphérique (SNP), des maladies associées à la contraction des muscles lisses, des maladies endocrines, des maladies associées à la dégénérescence nerveuse et équivalent. Ledit agent comprend un composé de formule (I) [dans laquelle A représente CR1D ou un atome d'azote ; X-Y-Z représente N-CO-NR4AR5 ou équivalent ; R1A, R1B, R1C et R1D peuvent être identiques ou différents et représentent indépendamment les uns des autres un groupe alkyle en C1-C6 qui peut être substitué, ou équivalent ; R2 représente un atome d'hydrogène ou équivalent ; R4A, R4B, R5 et R7 peuvent être identiques ou différents et représentent indépendamment les uns des autres un groupe cycloalkyle en C3-C10 qui peut être substitué, ou équivalent ; R6, R8 et R9 peuvent être identiques ou différents et représentent indépendamment les uns des autres un atome d'hydrogène ou équivalent ; R10 à R17 peuvent être identiques ou différents et représentent indépendamment les uns des autres un atome d'hydrogène ou équivalent ; et n est égal à 1 ou 2] ou un sel pharmaceutiquement acceptable de celui-ci. Ledit agent présente une puissante activité de modulation des récepteurs nicotiniques à l'acétylcholine α7 (α7 nAChR).
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WO2014054634A1 (fr) * 2012-10-02 2014-04-10 大日本住友製薬株式会社 Dérivé pyrimidine
WO2014054635A1 (fr) 2012-10-02 2014-04-10 大日本住友製薬株式会社 Dérivé d'imidazole
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WO2015152253A1 (fr) * 2014-04-01 2015-10-08 大日本住友製薬株式会社 Dérivé 4-aryl imidazole
EP3331530A4 (fr) * 2015-08-03 2018-12-19 Raze Therapeutics Inc. Inhibiteurs de mthfd2 et utilisation desdits inhibiteurs
US10696666B2 (en) 2016-10-18 2020-06-30 CellCentric Limited Pharmaceutical compounds
US11453662B2 (en) 2018-04-18 2022-09-27 Cellcentric Ltd Process for preparing modulators of p300 and/or CBP

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WO2014054634A1 (fr) * 2012-10-02 2014-04-10 大日本住友製薬株式会社 Dérivé pyrimidine
JP2015096495A (ja) * 2013-10-08 2015-05-21 大日本住友製薬株式会社 新規１位置換インダゾール誘導体からなる医薬
WO2015152253A1 (fr) * 2014-04-01 2015-10-08 大日本住友製薬株式会社 Dérivé 4-aryl imidazole
EP3331530A4 (fr) * 2015-08-03 2018-12-19 Raze Therapeutics Inc. Inhibiteurs de mthfd2 et utilisation desdits inhibiteurs
US10696666B2 (en) 2016-10-18 2020-06-30 CellCentric Limited Pharmaceutical compounds
US11377443B2 (en) 2016-10-18 2022-07-05 CellCentric Limited Pharmaceutical compounds
US11453662B2 (en) 2018-04-18 2022-09-27 Cellcentric Ltd Process for preparing modulators of p300 and/or CBP

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