WO2011059048A1 - Nouveau dérivé d'amide - Google Patents

Nouveau dérivé d'amide Download PDF

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Publication number
WO2011059048A1
WO2011059048A1 PCT/JP2010/070171 JP2010070171W WO2011059048A1 WO 2011059048 A1 WO2011059048 A1 WO 2011059048A1 JP 2010070171 W JP2010070171 W JP 2010070171W WO 2011059048 A1 WO2011059048 A1 WO 2011059048A1
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Prior art keywords
methyl
methoxy
imidazol
benzamide
hydroxypiperidin
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PCT/JP2010/070171
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English (en)
Japanese (ja)
Inventor
聖司 岩間
義裕 加藤
知法 小林
暁 房野
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大日本住友製薬株式会社
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Publication of WO2011059048A1 publication Critical patent/WO2011059048A1/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
    • C07D401/04—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C07D233/60—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms with hydrocarbon radicals, substituted by oxygen or sulfur atoms, attached to ring nitrogen atoms
    • 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
    • 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
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 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
    • C07D405/02—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
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • 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
    • 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

Definitions

  • the present invention relates to a novel amide derivative useful as a medicament having a beta amyloid (A ⁇ ) production inhibitory action. More specifically, the present invention relates to a novel amide derivative useful as a therapeutic and / or prophylactic agent for neurodegenerative diseases involving A ⁇ such as Alzheimer's disease and Down's syndrome.
  • a ⁇ beta amyloid
  • Alzheimer's disease is a neurodegenerative disease characterized by senile plaque formation and neurofibrillary tangles as well as neuronal degeneration and loss, and is a type of dementia that causes cognitive decline and personality changes.
  • treatment of Alzheimer's disease is limited to symptomatic treatment with drugs aimed at symptom improvement using acetylcholinesterase inhibitors and the like, and there is no effective method for treatment and / or prevention of the cause of Alzheimer's disease .
  • a ⁇ aggregates to form senile plaques and causes neuronal degeneration and loss.
  • a ⁇ can be divided into several types depending on the number of amino acids. Among them, A ⁇ 40 with 40 amino acids and A ⁇ 42 with 42 amino acids are highly aggregated, and are easily deposited in the brain earlier than other species. Is known to be strong. In familial Alzheimer's disease, it is known that production of A ⁇ 42 with higher aggregation is enhanced. For these reasons, the expression of Alzheimer's disease is thought to be closely related to the production of A ⁇ . Therefore, it is considered that a drug that suppresses the production of A ⁇ 40 and A ⁇ 42 can be a therapeutic and / or prophylactic agent for Alzheimer's disease.
  • a ⁇ is considered as one of the causes of Down's syndrome or other diseases caused by A ⁇ (eg, cognitive impairment, memory impairment, learning impairment, mild cognitive impairment, cerebrovascular angiopathy, etc.).
  • a ⁇ is produced by amyloid precursor protein (APP) being first cleaved by beta secretase and then cleaved by gamma secretase having presenilin as a constituent factor. Therefore, a drug targeting beta and gamma secretase is expected to be a therapeutic and / or prophylactic agent for Alzheimer's disease by suppressing A ⁇ production.
  • APP amyloid precursor protein
  • Various compounds that suppress A ⁇ production have been known so far, but they have a structure such as an aryl-substituted thiazole derivative, and the chemical structure of the compound mainly composed of the amide of the present invention is They are different (for example, Patent Document 1).
  • SST receptor subtype 5 antagonists whose main structure is an amide shown below are known.
  • the use of the compound of the present invention, which is an A ⁇ production inhibitor, was completely different and the structure was also different (for example, Patent Document 2).
  • An object of the present invention is to provide a novel compound having a strong A ⁇ 42 production inhibitory effect and useful as a therapeutic and / or preventive agent for a neuropsychiatric disorder caused by A ⁇ represented by Alzheimer's disease.
  • an amide derivative represented by the following formula (I) or a pharmaceutically acceptable salt thereof (hereinafter also referred to as “the compound of the present invention”) is provided.
  • A represents aryl, saturated carbocycle or heteroaryl, wherein the aryl, saturated carbocycle or heteroaryl is halogen, CF 3 , CF 3 O, hydroxyl, cyano, nitro, aryl-C 0- 4 alkyl-, heteroaryl-C 0-4 alkyl-, C 1-6 alkyl, C 3-8 cycloalkyl-C 0-4 alkyl-, 4-8 membered saturated heterocycle-C 0-4 alkyl-, 1 to 5 identical or different substituents selected from the group consisting of C 1-6 alkoxycarbonyl, C 0-4 alkyl-aminocarbonyl-, aryloxy, C
  • X 1 is CQ 1 or a nitrogen atom
  • X 2 is CQ 2
  • X 3 is CQ 3 .
  • Item 12 The compound according to Item 1 or a pharmaceutically acceptable salt thereof.
  • A represents aryl, saturated carbocycle or heteroaryl, wherein the aryl, saturated carbocycle or heteroaryl is halogen, CF 3 , CF 3 O, hydroxyl, cyano, nitro, aryl-C 0- 4 alkyl-, heteroaryl-C 0-4 alkyl-, C 1-6 alkyl, C 3-8 cycloalkyl-C 0-4 alkyl-, 4-8 membered saturated heterocycle-C 0-4 alkyl-, 1 to 5 identical or different substituents selected from the group consisting of C 1-6 alkoxycarbonyl, C 0-4 alkyl-aminocarbonyl-, aryloxy,
  • X 1 , X 2 and X 3 are each CH.
  • Item 6 The compound according to any one of Items 1 or a pharmaceutically acceptable salt thereof.
  • W is — (CH 2 ) n —, —CO (CH 2 ) n —, or —CONR 4 (CH 2 ) n —.
  • Item 6 The compound according to any one of Items 1 to 5, or a pharmaceutically acceptable salt thereof.
  • n 0.
  • Item 7 The compound according to Item 6 or a pharmaceutically acceptable salt thereof.
  • Z is-(a divalent group of a 4- to 9-membered nitrogen-containing saturated heterocyclic ring) -W-, and W and a nitrogen atom of the nitrogen-containing saturated heterocyclic ring are bonded.
  • Item 8 The compound according to any one of Items 1 to 7, or a pharmaceutically acceptable salt thereof.
  • a divalent group of a 4- to 9-membered nitrogen-containing saturated heterocyclic group of Z is an azetidine divalent group, a morpholine divalent group, a pyrrolidine divalent group optionally cross-linked with C 1-4 alkylene, C A piperidine divalent group optionally bridged with 1-4 alkylene or a homopiperidine divalent group optionally bridged with C2-4 alkylene, Item 9.
  • [Item 10] Z is a single bond.
  • Item 6. The compound according to any one of Items 1 to 5, or a pharmaceutically acceptable salt thereof.
  • R 2 is a fluorine atom, a chlorine atom, C 1-3 alkyl, C 1-3 alkoxy or C 1-3 alkoxy-C 1-3 alkoxy-.
  • Item 11 The compound according to any one of Items 1 to 10, or a pharmaceutically acceptable salt thereof.
  • R 1 is C 1-3 alkyl.
  • Item 12 The compound according to any one of Items 1 to 11 or a pharmaceutically acceptable salt thereof.
  • R 1 is methyl positioned at the 4-position of the imidazole ring.
  • Item 13 The compound according to any one of Items 1 to 12, or a pharmaceutically acceptable salt thereof.
  • Y is C 0-4 alkylene which may be substituted with the same or different 1 to 3 substituents selected from the group consisting of a fluorine atom and C 1-3 alkoxy.
  • Item 15 The compound according to any one of Items 1 to 14, or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition comprising the compound according to any one of items 1 to 17 or a pharmaceutically acceptable salt thereof.
  • a therapeutic or prophylactic agent for a disease caused by beta amyloid which comprises the compound according to any one of items 1 to 17 or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the therapeutic or prophylactic agent according to item 19, wherein the disease caused by beta amyloid is Alzheimer's disease, Down's syndrome, cognitive impairment, memory impairment / learning impairment, mild cognitive impairment, or cerebrovascular angiopathy.
  • a beta amyloid comprising administering to a patient in need of treatment a therapeutically effective amount of the compound according to any one of items 1 to 17 or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition comprising the compound according to any one of items 1 to 17 or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of a disease caused by beta amyloid.
  • the compound of the present invention is a therapeutic agent and / or prophylaxis for Alzheimer's disease, Down's syndrome or other diseases caused by A ⁇ (for example, cognitive impairment, memory impairment / learning impairment, mild cognitive impairment, senile dementia, amyloidosis, cerebrovascular angiopathy, etc.) Useful as an agent.
  • a ⁇ for example, cognitive impairment, memory impairment / learning impairment, mild cognitive impairment, senile dementia, amyloidosis, cerebrovascular angiopathy, etc.
  • 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.
  • Alkyl means a linear or branched saturated hydrocarbon group.
  • C 0-4 alkyl or “C 1-6 alkyl” has 0 carbon atoms, ie, a single carbon atom. It means a bond or 1 to 4 or 1 to 6 alkyl, respectively. Specific examples thereof include “C 0-4 alkyl” such as a single bond, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl and the like, and “C 0-6 alkyl”.
  • C 3-8 cycloalkyl means a cyclic alkyl having 3 to 8 carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.
  • Alkoxy means a group in which a linear or branched saturated hydrocarbon group is bonded via an oxygen atom. For example, “C 1-3 alkoxy” or “C 1-6 alkoxy” "Means alkoxy having 1 to 3 or 1 to 6 carbon atoms, respectively.
  • alkylcarbonylamino means amino in which a straight chain or branched alkyl group directly bonded to carbonyl is bonded.
  • C 1-6 alkylcarbonylamino means that the total number of carbon atoms is 1 to 6 means alkylcarbonylamino.
  • Specific examples include acetylamino, propionylamino, butyrylamino, valerylamino, pivaloylamino 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, fluorenyl, 9,10-dihydroanthracene, 10,11-dihydro-5H-dibenzo [A, D] cycloheptene, and the like. Of these, phenyl is preferable.
  • the “saturated carbocycle” includes a 3- to 11-membered monocyclic or polycyclic saturated carbocyclic group, and the polycyclic saturated carbocyclic group includes a group that partially forms an aromatic ring. . Specifically, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, bornyl, pinanyl, noradamantyl, adamantyl, 2-indanyl, 2-indenyl, 5,6,7,8-tetrahydro-2-naphthyl, 3,4-ethylenedioxyphenyl, 3,4- (methylenedioxy) phenyl and the like can be mentioned.
  • Heteroaryl is a monocyclic 5- to 7-membered aromatic heterocyclic group containing 1 to 4 atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom. Examples thereof include an 11-membered aromatic heterocyclic group or a 3-ring 12-16 membered aromatic heterocyclic group.
  • Alkylene means a linear, branched or cyclic divalent saturated hydrocarbon group, or a linear or branched divalent saturated hydrocarbon group partially containing a cyclic chain.
  • C 1-4 alkylene means alkylene having 1 to 4 carbon atoms, and includes methylene, ethylene, propylene, butylene, 2-methylethylene, cyclopropylmethylene, 1,1-cyclopropylene, 1,3-cyclobutylene and the like can be mentioned.
  • C 0-6 alkylene means alkylene having 0 to 6 carbon atoms.
  • C 1-6 alkylene “C 2-4 alkylene”, “C 2-6 alkylene” and “C 0-4 alkylene” are also exemplified according to the number of carbon atoms.
  • the “4- to 8-membered saturated heterocyclic ring” means a saturated heterocyclic ring composed of 4 to 8 atoms including 1 to 2 nitrogen atoms, oxygen atoms or sulfur atoms in addition to carbon atoms. Examples include azetidine, pyrrolidine, piperidine, piperazine, morpholine, homopiperidine, tetrahydrofuran, tetrahydropyran and the like.
  • the “divalent group of a 4- to 9-membered nitrogen-containing saturated heterocyclic ring” is composed of 4 to 9 atoms containing at least 1 to 2 (preferably 1 to 2) nitrogen atoms in addition to the carbon atom.
  • the divalent linking atom may be a carbon atom constituting a heterocyclic ring or a nitrogen atom.
  • a nitrogen atom is preferably bonded to W.
  • Specific examples of the monocyclic saturated heterocyclic ring include structures represented by the following chemical formulas, that is, azetidine, pyrrolidine, piperidine, piperazine, morpholine, homopiperidine (for example, a-12 or a-13) and the like.
  • “Pyrrolidine divalent group optionally bridged with C 1-4 alkylene” means that any two carbon atoms or nitrogen atoms constituting the pyrrolidine ring are bonded with C 1-4 alkylene to form a bridge. Means good.
  • “piperidine divalent group optionally bridged with C 1-4 alkylene” and “homopiperidine divalent group optionally bridged with C2-4 alkylene” also represent a piperidine ring or a homopiperidine ring, respectively. It means that any two carbon atoms or nitrogen atoms constituting the carbon atom may be bonded to the corresponding alkylene and bridged.
  • divalent group of the bicyclic nitrogen-containing saturated heterocyclic ring include the following groups in addition to the divalent group of the specific examples of the monocyclic saturated heterocyclic ring.
  • C 3-8 cycloalkyl -C 0-4 alkyl - A, C 1-4 1 of the hydrogen atoms are C 3-8 group substituted with a cycloalkyl or C 3-8 cycloalkyl alkyl (C 0 -4 alkyl means C0 alkyl, ie in the case of a single bond.
  • the position to be replaced is not limited to the end but is an arbitrary position.
  • each hydrogen atom of each latter substituent is Means a substituted group.
  • X 1 to X 3 , Q 1 to Q 3 , Y, Z, W, A, R 1 to R 4 and n are preferable as follows.
  • the technical scope of the present invention is not limited to the scope of the compounds listed below.
  • X 1, X 2 and X 3 is a benzene ring or X 1 is CQ 1, CQ 2 and CQ 3 is a nitrogen atom, is X 2 and X 3 Examples include pyridine rings which are CQ 2 and CQ 3 respectively.
  • Q 1 , Q 2 and Q 3 are preferably the same or different and include a hydrogen atom, halogen or C 1-6 alkyl. More preferred is a hydrogen atom or halogen, and most preferred is a hydrogen atom.
  • Y is preferably unsubstituted or C 0-6 alkylene substituted with 1 to 3 identical or different substituents selected from the group consisting of halogen and C 1-3 alkoxy.
  • the preferred halogen here is a fluorine atom or a chlorine atom, more preferably a fluorine atom. More preferred is unsubstituted C 0-4 alkylene. Most preferred is unsubstituted C0-2 alkylene.
  • Z is a single bond or — (a divalent group of a 4- to 9-membered nitrogen-containing saturated heterocyclic ring) —W—, and more preferably, a single bond or — (a 4- to 7-membered nitrogen-containing saturated heterocyclic ring 2 Valent group) -W-.
  • a preferable bonding position of the nitrogen-containing saturated heterocyclic ring with Y any carbon atom on the nitrogen-containing saturated heterocyclic ring can be mentioned, and more preferable is a carbon atom not bonded to the nitrogen atom.
  • Examples of the preferred bonding position of the nitrogen-containing saturated heterocyclic ring with W include the bonding position with the nitrogen atom of the nitrogen-containing saturated heterocyclic ring.
  • the divalent group of the 4- to 9-membered nitrogen-containing saturated heterocyclic group of Z is preferably an azetidine divalent group, a morpholine divalent group, a pyrrolidine divalent group optionally bridged with C 1-4 alkylene, C 0-
  • Examples thereof include a piperidine divalent group which may be cross-linked with 4- alkylene or a homopiperidine divalent group which may be cross-linked with C2-4 alkylene. More preferably, it is a pyrrolidine divalent group which may be cross-linked with C 1-4 alkylene or a piperidine divalent group which may be cross-linked with C 0-4 alkylene.
  • W is preferably — (CH 2 ) n — or —CO (CH 2 ) n —. More preferred is — (CH 2 ) n —. Most preferably, a single bond, a methylene, or ethylene is mentioned.
  • A is preferably phenyl, naphthyl or a saturated carbocycle. More preferably, mention may be made of phenyl, 1-naphthyl, 2-naphthyl, 5,6,7,8-tetrahydro-2-naphthyl, fluorenyl, bornyl, adamantyl or cyclohexyl, more preferably phenyl or fluorenyl. Most preferably, phenyl is mentioned.
  • the substituent is preferably halogen, CF 3 , cyano, nitro, aryl-C 0-4 alkyl, C 1-6 alkyl, C 3-8 saturated heterocycle-C 0-4 Examples include alkyl, C 1-6 alkoxycarbonyl, aryloxy or C 1-6 alkoxy. More preferred is halogen, CF 3 , cyano, aryl, C 1-6 alkyl, aryloxy or C 1-6 alkoxy. Most preferably, halogen, CF 3 , aryl or aryloxy is used.
  • R 1 is preferably halogen or C 1-6 alkyl. More preferred is C 1-6 alkyl, still more preferred is C 1-3 alkyl, and most preferred is methyl.
  • R 1 is bonded to the bondable 2 to 5 position on the imidazole ring, preferably bonded to the 4 position.
  • R 2 is preferably halogen, C 1-6 alkyl or C 1-6 alkoxy. More preferred is C 1-6 alkyl or C 1-6 alkoxy. More preferred is C 1-3 alkoxy, and most preferred is methoxy.
  • R 3 is preferably a hydrogen atom or C 1-3 alkyl. More preferably, a hydrogen atom or methyl is mentioned, Most preferably, a hydrogen atom is mentioned.
  • R 4 is preferably a hydrogen atom or C 1-3 alkyl. More preferably, a hydrogen atom or methyl is mentioned, Most preferably, a hydrogen atom is mentioned. n is preferably 0, 1 or 2, more preferably 0 or 1, and most preferably 1.
  • 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.
  • the compound of the present invention represented by the formula (I) can be produced by the following production methods A, B, C, D, E, or F.
  • the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof is a novel compound, and can be produced, for example, by the method described below, the examples described later and a method analogous thereto.
  • the compound used in the following production method may form a salt as long as the reaction is not hindered.
  • the compound of the formula (I) can be produced by the following production method. (Wherein X 1 , X 2 , X 3 , Y, Z, A, R 1 , R 2 and R 3 are the same as defined in item 1).
  • Compound (I) is obtained by performing a condensation reaction between compound (II) and compound (III).
  • This reaction can be performed according to a conventional method.
  • this reaction is achieved by converting compound (II) into a reactive derivative (eg, lower alkyl ester, active ester, acid anhydride, acid halide, etc.) and reacting with compound (III).
  • the starting compound (III) is commercially available or synthesized by a method according to a known method.
  • Specific examples of the active ester include p-nitrophenyl ester, N-hydroxysuccinimide ester, pentafluorophenyl ester and the like.
  • Specific examples of the acid anhydride include mixed acid anhydrides with ethyl chlorocarbonate, isobutyl chlorocarbonate, isovaleric acid, pivalic acid and the like.
  • Compound (I) can also be produced by reacting compound (II) and compound (III) in the presence of a condensing agent.
  • a condensing agent include N, N′-dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide monohydrochloride, N, N′-carbonyldiimidazole, benzotriazol-1-yl -Oxytris (pyrrolidino) phosphonium-hexafluorophosphate, hexafluorophosphate 2- (7-aza-1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium (HATU), etc.
  • the reaction between compound (II) and compound (III) is carried out in a solvent or without a solvent.
  • the solvent should be selected according to the type of raw material compound, etc., and include, for example, toluene, THF, 1,4-dioxane, DME, dichloromethane, chloroform, ethyl acetate, acetone, acetonitrile, DMF, DMSO and the like. Can be used alone or as a mixed solvent.
  • Compound (III) may be used in the form of an acid addition salt such as a free amine or hydrochloride, and a free base may be generated in the reaction system. This reaction is usually carried out in the presence of a base.
  • the base used include inorganic bases such as potassium carbonate and sodium hydrogen carbonate, triethylamine, ethyldiisopropylamine, N-methylmorpholine, pyridine. And organic bases such as 4-dimethylaminopyridine. While the reaction temperature varies depending on the kind of raw material compound used, it is generally about ⁇ 30 ° C. to about 150 ° C., preferably about ⁇ 10 ° C. to about 70 ° C.
  • Z is — (divalent group of a 4- to 9-membered nitrogen-containing saturated heterocyclic ring) —W—, and W is —CO (CH 2 ) n — or —COO (CH 2 ) n —. , —CONR 4 (CH 2 ) n — [compound of the following formula (Ia)] can also be produced by the following production method.
  • X 1 , X 2 , X 3 , Y, A, R 1 , R 2 , R 3 , R 4 and n are the same as defined in Item 1, and Z 1 is 4 to 9 membered.
  • a divalent group of a nitrogen-containing saturated heterocyclic ring, and W 1 is — (CH 2 ) n —, —O (CH 2 ) n —, — or —NR 4 (CH 2 ) n —.
  • Compound (Ia) is obtained by conducting a condensation reaction between compound (IV) and a carbonyl derivative such as various corresponding carboxylic acids.
  • This reaction can be performed according to a conventional method.
  • this reaction can be achieved by reacting compound (IV) in the presence of various corresponding carboxylic acids and a condensing agent in a suitable solvent or in the absence of a solvent.
  • the condensing agent include N, N′-dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide monohydrochloride, N, N′-carbonyldiimidazole, dimethylaminosulfonic acid chloride.
  • the solvent should be selected according to the type of raw material compound, etc., and examples include dichloromethane, chloroform, dichloroethane, THF, 1,4-dioxane, DME, acetonitrile, DMF, DMA, NMP, DMSO and the like. Can be used alone or as a mixed solvent.
  • Compound (IV) is usually used in the form of an acid addition salt such as a free amine or hydrochloride, and a free base may be generated in the reaction system. This reaction is usually carried out in the presence of a base.
  • the base used include inorganic bases such as potassium carbonate and sodium hydrogen carbonate, triethylamine, ethyldiisopropylamine, N-methylmorpholine, pyridine. And organic bases such as 4-dimethylaminopyridine. While the reaction temperature varies depending on the raw material compound used and the type of reagent, etc., it is generally ⁇ 20 to 200 ° C., preferably 0 to 100 ° C.
  • compound (Ia) is reacted with a reactive derivative such as various corresponding acid chlorides, acid anhydrides, chloroformates, carbamoyl chlorides, isocyanates and the like in a suitable solvent or in the absence of a solvent.
  • a reactive derivative such as various corresponding acid chlorides, acid anhydrides, chloroformates, carbamoyl chlorides, isocyanates and the like in a suitable solvent or in the absence of a solvent.
  • a suitable solvent or in the absence of a solvent.
  • the solvent should be selected according to the type of raw material compound, etc., and examples include dichloromethane, chloroform, dichloroethane, THF, 1,4-dioxane, DME, acetonitrile, DMF, DMA, NMP, DMSO and the like.
  • Compound (IV) is usually used in the form of an acid addition salt such as a free amine or hydrochloride, and a free base may be generated in the reaction system.
  • This reaction is usually carried out in the presence of a base.
  • the base used include inorganic bases such as potassium carbonate and sodium hydrogen carbonate, triethylamine, ethyldiisopropylamine, N-methylmorpholine, pyridine. And organic bases such as 4-dimethylaminopyridine.
  • the reaction temperature varies depending on the raw material compound used and the type of reagent, etc., it is generally ⁇ 20 to 200 ° C., preferably 0 to 100 ° C.
  • Z is — (a divalent group of a 4- to 9-membered nitrogen-containing saturated heterocyclic ring) —W—, W is — (CH 2 ) n —, and n is an integer of 1 to 4.
  • the compound [compound of the following formula (Ib)] can be produced by the following production method. Wherein X 1 , X 2 , X 3 , Y, A, R 1 , R 2 and R 3 are the same as defined in item 1, and Z 1 is a 4- to 9-membered nitrogen-containing saturated heterocyclic ring And n is an integer of 1 to 4.
  • Compound (Ib) is obtained by performing a reductive amination reaction from compound (IV).
  • This reaction can be performed according to a conventional method.
  • this reaction can be achieved by reacting compound (IV) in the presence of various corresponding carbonyl derivatives such as ketones or aldehydes, reducing agents, and the like, in a suitable solvent or in the absence of a solvent.
  • the reducing agent include sodium borohydride, lithium aluminum hydride, sodium triacetoxyborohydride, sodium cyanoborohydride and the like.
  • the solvent should be selected according to the type of raw material compound, etc., for example, dichloromethane, chloroform, dichloroethane, THF, 1,4-dioxane, DME, acetonitrile, DMF, DMA, NMP, DMSO, acetic acid, Water or alcohols such as methanol, ethanol, isopropanol and the like can be mentioned, and these can be used alone or as a mixed solvent. While the reaction temperature varies depending on the raw material compound used and the type of reagent, etc., it is generally ⁇ 20 to 200 ° C., preferably 0 to 100 ° C.
  • Compound (Ib) can also be obtained by reacting compound (IV) with a derivative having an appropriate leaving group such as various corresponding benzyl halides and phenethyl halides in an appropriate solvent or in the absence of a solvent.
  • a solvent should be selected according to the type of raw material compound, etc., and examples include dichloromethane, chloroform, dichloroethane, THF, 1,4-dioxane, DME, acetonitrile, DMF, DMA, NMP, DMSO and the like. Can be used alone or as a mixed solvent.
  • Compound (IV) is usually used in the form of an acid addition salt such as a free amine or hydrochloride, and a free base may be generated in the reaction system.
  • This reaction is usually carried out in the presence of a base.
  • the base used include inorganic bases such as potassium carbonate and sodium hydrogen carbonate, triethylamine, ethyldiisopropylamine, N-methylmorpholine, pyridine. And organic bases such as 4-dimethylaminopyridine.
  • the reaction temperature varies depending on the raw material compound used and the type of reagent, etc., it is generally ⁇ 20 to 200 ° C., preferably 0 to 100 ° C.
  • Compound (Ic) is obtained by coupling compound (IV) with a derivative having an appropriate leaving group such as various corresponding substituted phenyl halides.
  • This reaction can be performed according to a conventional method.
  • the compound (Ic) is a transition metal such as a palladium catalyst typified by tetrakistriphenylphosphine palladium and trisdibenzylideneacetone dipalladium in a suitable solvent by replacing the compound (IV) with various corresponding substituted phenyl halides.
  • It can be obtained by conducting a coupling reaction in the presence of a catalyst and a ligand typified by 2- (di-t-butylphosphino) biphenyl.
  • inorganic bases such as alkali metal carbonates (for example, sodium carbonate, potassium carbonate, cesium carbonate) and potassium phosphate, or alkali metal alkoxides (for example, sodium-t-butoxide)
  • the reaction can be carried out in the presence of an organic base such as triethylamine or diisopropylethylamine, or an inorganic salt such as lithium chloride or cesium fluoride.
  • organic base such as triethylamine or diisopropylethylamine
  • an inorganic salt such as lithium chloride or cesium fluoride.
  • Specific examples of the solvent should be selected according to the type of raw material compound and the type of reagent used.
  • reaction temperature varies depending on the raw material compound used and the type of reagent, etc., it is generally 0 to 200 ° C, preferably 60 to 150 ° C.
  • Compound (I) is obtained by reacting compound (V) with the corresponding substituted or unsubstituted imidazole.
  • This reaction can be performed according to a conventional method.
  • compound (I) is represented by compound (V) and the corresponding substituted or unsubstituted imidazole in a suitable solvent, or represented by cuprous halide, cuprous oxide or cupric oxide.
  • Copper catalyst, ⁇ -ketoesters typified by 2-oxocyclohexanecarboxylate, diamines typified by trans-1,2-cyclohexanediamine or 8-hydroxyquinoline, 4,7-dimethoxy-1,8-phenant It can be obtained by conducting a coupling reaction in the presence of a ligand such as helical.
  • inorganic metals such as alkali metal carbonates (for example, sodium carbonate, potassium carbonate, cesium carbonate, etc.), sodium alkoxides (for example, sodium methoxide, sodium ethoxide, etc.), potassium phosphate, etc. It can also be carried out in the presence of a base or an organic base such as triethylamine or diisopropylethylamine, or an inorganic salt such as lithium chloride or cesium fluoride.
  • alkali metal carbonates for example, sodium carbonate, potassium carbonate, cesium carbonate, etc.
  • sodium alkoxides for example, sodium methoxide, sodium ethoxide, etc.
  • potassium phosphate etc. It can also be carried out in the presence of a base or an organic base such as triethylamine or diisopropylethylamine, or an inorganic salt such as lithium chloride or cesium fluoride.
  • the solvent should be selected according to the type of raw material compound and the type of reagent used, and examples thereof include DMF, DMSO, NMP, acetonitrile, 1,4-dioxane, xylene, ionic liquid, and the like. It can be used alone or as a mixed solvent. While the reaction temperature varies depending on the raw material compound used and the type of reagent, etc., it is generally 0 to 200 ° C, preferably 60 to 150 ° C.
  • compound (Id) When compound (I ′) is coupled with various corresponding substituted phenylboronic acids, compound (Id) is obtained.
  • Compound (Id) can be obtained by using boron reagent such as compound (I ′) and various corresponding substituted phenylboronic acids [PhB (OH) 2 ], organometallic reagents such as various corresponding substituted phenyl zinc chlorides in an appropriate solvent, etc.
  • boron reagent such as compound (I ′) and various corresponding substituted phenylboronic acids [PhB (OH) 2 ]
  • organometallic reagents such as various corresponding substituted phenyl zinc chlorides in an appropriate solvent, etc.
  • inorganic bases such as alkali metal carbonates (for example, sodium carbonate, potassium carbonate, cesium carbonate, etc.) and potassium phosphate
  • organic bases such as triethylamine, diisopropylethylamine, and chloride It can also be carried out in the presence of an inorganic salt such as lithium or cesium fluoride.
  • the various boron reagents or organometallic reagents used in the coupling reaction with the compound (I ′) are commercially available, or are prepared from commercially available reagents according to known methods.
  • Specific examples of the solvent should be selected according to the type of raw material compound and the type of reagent used. For example, toluene, THF, dioxane, DME, ethyl acetate, acetone, acetonitrile, DMF or methanol, ethanol, isopropanol, t -Alcohols such as butanol and water can be mentioned, and these can be used alone or as a mixed solvent. While the reaction temperature varies depending on the raw material compound used and the type of reagent, etc., it is generally 0 to 200 ° C, preferably 60 to 150 ° C.
  • the compounds of the formula (I), (Ia), (Ib), (Ic) and (Id) produced by the above production method A, B, C, D, E or F are usually used for chromatography, recrystallization and the like. It can be isolated and purified by a method.
  • the raw material compounds used in the above production methods A, B, C, D, E or F are commercially available, or are prepared according to known methods from commercially available reagents, or produced by the following methods. Can do.
  • Compound (IV) used in the above production methods B, C and D is produced according to the method represented by the following reaction formula.
  • X 1 , X 2 , X 3 , Y, R 1 , R 2 and R 3 are the same as defined in Item 1, and Z 1 is a 2 to 9-membered nitrogen-containing saturated heterocyclic ring.
  • P is an amino protecting group such as t-butoxycarbonyl, benzyloxycarbonyl, etc.
  • Compound (IV) is obtained by deprotecting compound (VI).
  • This reaction can be performed according to a conventional method. For example, this reaction can be achieved by reacting compound (VI) with an acid or a base in an appropriate solvent or without a solvent.
  • Raw material compound (VI) can be produced by a method according to production method A using the corresponding raw material compound.
  • Specific examples of the acid include hydrochloric acid, sulfuric acid, trifluoroacetic acid, p-toluenesulfonic acid, boron trichloride and the like.
  • the base include sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate, barium carbonate, sodium t-butoxide, potassium t-butoxide and the like.
  • Specific examples of the solvent should be selected according to the type of the raw material compound, etc., for example, dichloromethane, chloroform, dichloroethane, THF, 1,4-dioxane, DME, acetonitrile, DMF, DMA, NMP, DMSO, water or Alcohols such as methanol, ethanol and isopropanol can be mentioned, and these can be used alone or as a mixed solvent.
  • reaction temperature varies depending on the raw material compound used and the type of reagent, etc., it is generally ⁇ 20 to 200 ° C., preferably 0 to 120 ° C.
  • This deprotection reaction can also be achieved by catalytic reduction using a palladium catalyst or the like under a hydrogen stream depending on the protecting group.
  • the compound (V) used in the production method E is produced according to the method represented by the following reaction formula. (In the formula, X 1 , X 2 , X 3 , Y, Z, A, R 2 and R 3 are the same as defined in Item 1. Hal is halogen.)
  • Compound (V) is obtained by performing a condensation reaction between compound (VII) and compound (VIII).
  • This reaction can be performed according to a conventional method.
  • this reaction can be achieved by reacting compound (VII) and compound (VIII) in the presence of a condensing agent or the like in a suitable solvent or without solvent.
  • the starting compound (VII) is commercially available or synthesized by a method according to a known method.
  • this reaction is achieved by converting compound (VII) into a reactive derivative (eg, lower alkyl ester, active ester, acid anhydride, acid halide, etc.) and reacting with compound (VIII).
  • the active ester include p-nitrophenyl ester, N-hydroxysuccinimide ester, pentafluorophenyl ester and the like.
  • Specific examples of the acid anhydride include mixed acid anhydrides with ethyl chlorocarbonate, isobutyl chlorocarbonate, isovaleric acid, pivalic acid and the like.
  • Compound (V) can also be produced by reacting compound (VII) and compound (VIII) in the presence of a condensing agent.
  • a condensing agent include N, N′-dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide monohydrochloride, N, N′-carbonyldiimidazole, benzotriazol-1-yl -Oxytris (pyrrolidino) phosphonium-hexafluorophosphate, hexafluorophosphate 2- (7-aza-1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium (HATU), etc.
  • the reaction between compound (VII) and compound (VIII) is carried out in a solvent or without a solvent.
  • the solvent should be selected according to the type of raw material compound, etc., and include, for example, toluene, THF, 1,4-dioxane, DME, dichloromethane, chloroform, ethyl acetate, acetone, acetonitrile, DMF, DMSO and the like. Can be used alone or as a mixed solvent.
  • Compound (VIII) may be used in the form of an acid addition salt such as a free amine or hydrochloride, and a free base may be generated in the reaction system. This reaction is usually carried out in the presence of a base.
  • the base used include inorganic bases such as potassium carbonate and sodium hydrogen carbonate, triethylamine, ethyldiisopropylamine, N-methylmorpholine, pyridine. And organic bases such as 4-dimethylaminopyridine. While the reaction temperature varies depending on the kind of raw material compound used, it is generally about ⁇ 30 ° C. to about 150 ° C., preferably about ⁇ 10 ° C. to about 70 ° C.
  • the optical isomers can be separated by performing a known separation step such as a method using an optically active column or a fractional crystallization method in an appropriate step of the production method.
  • An optically active substance can also be used as a starting material.
  • the pharmaceutically acceptable salt of compound (I) may be purified as it is when the salt of compound (I) is obtained by the above production method.
  • compound (I) may be dissolved or suspended in a suitable solvent, and an acid may be added to form a salt.
  • the compound of the present invention can be a useful therapeutic agent for various neuropsychiatric diseases including Alzheimer's therapeutic agents.
  • 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.
  • the compound of the present invention is usually administered in the form of a preparation prepared by mixing with a pharmaceutical carrier when used for pharmaceutical use as described above.
  • a pharmaceutical carrier a non-toxic substance that is commonly used in the pharmaceutical field and does not react with the compound of the present invention is used.
  • citric acid glutamic acid, glycine, lactose, inositol, glucose, mannitol, dextran, sorbitol, cyclodextrin, starch, partially pregelatinized starch, sucrose, methyl paraoxybenzoate, propyl paraoxybenzoate, and aluminum metasilicate
  • Magnesium sulfate, synthetic aluminum silicate crystalline cellulose, sodium carboxymethylcellulose, hydroxypropyl starch, carboxymethylcellulose calcium, ion exchange resin, methylcellulose, gelatin, gum arabic, pullulan, hydroxypropylcellulose, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose , Polyvinylpyrrolidone, polyvinyl alcohol, alginic acid, sodium alginate Light anhydrous silicic acid, magnesium stearate, talc, tragacanth, bentonite, bee gum, carboxyvinyl polymer, titanium
  • 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 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.
  • 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, the measurement conditions used for the measurement are indicated by A to F.
  • Reference example 1 3-Methoxy-4- (4-methyl-1H-imidazol-1-yl) -N- (piperidin-3-yl) benzamide hydrochloride
  • Step 1 3-methoxy-4- (4-methyl-1H-imidazol-1-yl) benzoic acid (500 mg), 1-Boc-3-aminopiperidine (440 mg), 1-ethyl-3- (3 -Dimethylaminopropylcarbodiimide) hydrochloride (422 mg), 1-hydroxybenzotriazole monohydrate (297 mg) and triethylamine (596 ⁇ l) in DMF (5 ml) were stirred at room temperature overnight.
  • Step 2 The compound (703 mg) obtained in Reference Example 1 [Step 1] was dissolved in dioxane (5 ml), and a 4M HCl / dioxane solution (5 ml) was added dropwise. After stirring at room temperature for 5 hours, the reaction mixture was concentrated under reduced pressure to give 3-methoxy-4- (4-methyl-1H-imidazol-1-yl) -N- (piperidin-3-yl) benzamide hydrochloride (878 mg). Obtained as a light brown solid.
  • Reference Example 2-13 The corresponding starting materials were used and reacted and treated in the same manner as in Reference Example 1 to obtain the compounds shown in Table 1.
  • Step 2 The compound (1.06 g) obtained in [Step 1] was dissolved in dioxane (15 ml), and a 4M HCl / dioxane solution (15 ml) was added dropwise. After stirring at room temperature for 2 hours, the reaction solution was concentrated under reduced pressure to obtain a white solid.
  • Example 1 N- (biphenyl-3-ylmethyl) -3-methoxy-4- (4-methyl-1H-imidazol-1-yl) benzamide 3-methoxy-4- (4-methyl-1H-imidazol-1-yl) benzoic acid (100 mg), m-phenyl-benzylamine (95 mg), 1-ethyl-3- (3-dimethylaminopropylcarbodiimide) hydrochloric acid A solution of salt (100 mg), 1-hydroxybenzotriazole monohydrate (70 mg), N, N-diisopropylethylamine (120 ml) in DMF (4 ml) was stirred at room temperature overnight.
  • Example 2-63 The corresponding starting materials were used and reacted and treated in the same manner as in Example 1 to obtain the compounds shown in Table 3.
  • Examples 64-68 The corresponding starting materials were used and reacted and treated in the same manner as in Example 1 to obtain the compounds shown in Table 4.
  • Example 69 3-Methoxy-4- (4-methyl-1H-imidazol-1-yl) -N- [1- (phenylcarbonyl) piperidin-3-yl ⁇ benzamide After desalting 3-methoxy-4- (4-methyl-1H-imidazol-1-yl) -N- (piperidin-3-yl) benzamide hydrochloride (24 mg) obtained in Reference Example 1 [Step 2] , Dissolved in DMF (1 ml), benzoic acid (13 mg), 1-ethyl-3- (3-dimethylaminopropylcarbodiimide (36 ⁇ l), 1-hydroxy-7-azabenzotriazole (28 mg) and triethylamine (29 ⁇ l).
  • Examples 70-85 The corresponding starting materials were used and reacted in the same manner as in Example 69 to obtain the compounds shown in Table 5.
  • Example 86 N-( ⁇ 1-[(3-Fluorophenyl) acetyl] piperidin-4-yl ⁇ methyl) -3-methoxy-4- (4-methyl-1H-imidazol-1-yl) benzamide 3-methoxy-4- (4-methyl-1H-imidazol-1-yl) -N- (piperidin-4-ylmethyl) benzamide (33 mg), 3-fluorophenylacetic acid (15 mg) obtained in Reference Example 4 Hexafluorophosphate 2- (7-aza-1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium (HATU) (46 mg), triethylamine (20 mg) in DMF (1 ml) Was stirred at room temperature overnight.
  • HATU 7-aza-1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium
  • reaction mixture was diluted with ethyl acetate and washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine.
  • Examples 87-91 Reaction and treatment were carried out in the same manner as in Example 86 using the corresponding starting compounds, and the compounds shown in Table 6 were obtained.
  • Example 92 N- (2-chlorobenzyl) -3- ⁇ [3-methoxy-4- (4-methyl-1H-imidazol-1-yl) phenyl] carbonylamino ⁇ piperidine-1-carboxamide After desalting 3-methoxy-4- (4-methyl-1H-imidazol-1-yl) -N- (piperidin-3-yl) benzamide hydrochloride (24 mg) obtained in Reference Example 1 [Step 2] The solution was dissolved in THF (1 ml), 2-chlorobenzyl isocyanate (14 mg) was added, and the mixture was stirred at room temperature for 3 hours. Methanol (1 ml) was added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes.
  • Examples 93-116 Reaction and treatment were carried out in the same manner as in Example 92 using the corresponding starting compounds, and the compounds shown in Table 7 were obtained.
  • Examples 118-133 The corresponding starting materials were used and reacted and treated in the same manner as in Example 117 to obtain the compounds shown in Table 8.
  • Examples 177-198 Reaction and treatment were performed in the same manner as in Example 117 using the corresponding starting compounds, and the compounds shown in Table 12 were obtained.
  • Example 199-262 Reaction and treatment were performed in the same manner as in Example 117 using the corresponding starting compounds, and the compounds shown in Table 13 were obtained.
  • Example 263-264 The corresponding starting materials were used and reacted and treated in the same manner as in Example 117 to obtain the compounds shown in Table 14.
  • Example 283 N- ⁇ [1- (4-Fluorophenyl) piperidin-4-yl] methyl ⁇ -3-methoxy-4- (4-methyl-1H-imidazol-1-yl) benzamide 3-methoxy-4- (4-methyl-1H-imidazol-1-yl) -N- (piperidin-4-ylmethyl) benzamide (33 mg), 4-fluorobenzaldehyde (12 mg), sodium obtained in Reference Example 4 A solution of triacetoxyborohydride (32 mg) and acetic acid (9 mg) in THF (1 ml) was stirred at room temperature overnight.
  • Examples 284-285 Reaction and treatment were carried out in the same manner as in Example 283 using the corresponding starting compounds, and the compounds shown in Table 16 were obtained.
  • Example 286 3-Methoxy-4- (4-methyl-1H-imidazol-1-yl) -N- ⁇ 1- [3- (trifluoromethyl) phenyl] piperidin-3-yl ⁇ benzamide 3-methoxy-4- (4-methyl-1H-imidazol-1-yl) -N- (piperidin-3-yl) benzamide (92 mg), 1-bromo-3 obtained in Reference Example 1 [Step 2] -(Trifluoromethyl) benzene (65 mg), tris (dibenzylideneacetone) dipalladium (27 mg), 2- (di-t-butylphosphino) biphenyl (17 mg), sodium-t-butoxide (42 mg) in toluene (42 mg) 1 ml) The solution was stirred at 40 ° C.
  • Examples 287-289 Reaction and treatment were carried out in the same manner as in Example 286 using the corresponding starting compounds, and the compounds shown in Table 17 were obtained.
  • Examples 290-304 Reaction and treatment were carried out in the same manner as in Example 286 using the corresponding starting compounds, and the compounds shown in Table 18 were obtained.
  • Examples 328-336 Reaction and treatment were carried out in the same manner as in Example 286 using the corresponding starting compounds, and the compounds shown in Table 21 were obtained.
  • Example 371 N- (biphenyl-3-yl-methyl) -3- (2-methoxyethoxy) -4- (4-methyl-1H-imidazol-1-yl) benzamide N- (biphenyl-3-yl-methyl) -4-bromo-3- (2-methoxyethoxy) benzamide (0.43 g), 4-methylimidazole (0.14 g), bromide obtained in Reference Example 14 Cuprous (0.03 g), cesium carbonate (0.39 g), and ethyl 2-cyclohexanone carboxylate (0.08 g) were suspended in DMSO (1 ml) and stirred at 100 ° C. overnight under a nitrogen stream.
  • Example 372 N-[(4′-fluorobiphenyl-3-yl) methyl] -6-methoxy-5- (4-methyl-1H-imidazol-1-yl) pyridine-2-carboxamide N- (3-bromobenzyl) -6-methoxy-5- (4-methyl-1H-imidazol-1-yl) pyridine-2-carboxamide (75 mg, 0.2 mmol), p-fluorophenylboronic acid (1. 2 eq.), Potassium carbonate (442 mg, 1.1 mmol), Pd (dppf) Cl 2 (14 mg, 0.02 mmol) in 1,4-dioxane (3 mL), H 2 O (1 mL) at 100 ° C.
  • Example 373-483 Reaction and treatment were carried out in the same manner as in Example 372 using the corresponding starting compounds, and the compounds shown in Table 24 were obtained.
  • Example 484-525 Reaction and treatment were carried out in the same manner as in Example 372 using the corresponding starting compounds, and the compounds shown in Table 25 were obtained.
  • Test Examples The pharmacological test results of the representative compounds of the present invention are shown below, but the present invention is not limited to these test examples.
  • Rat embryo-derived primary cultured neurons Cells from cerebral cortex were removed from Wistar rats (Charles RiverJapan, Yokohama, Japan) aged 16-17 days Isolated and subjected to culture. Specifically, fetuses were removed from pregnant rats euthanized by CO 2 inhalation, and fetal brains were removed in ice-cold Hepes buffer. Next, cerebral cortex is collected under a stereomicroscope and shaken in a 0.3 mg / ml papain (papain, Sigma-aldrich, cat # P4762, St. Louis, MO, USA) solution at 37 ° C. for 5 minutes. And distributed the organization.
  • papain papain, Sigma-aldrich, cat # P4762, St. Louis, MO, USA
  • the dispersion reaction was stopped by exchanging the culture solution with 10% fetal bovine serum, and the tissue was physically dispersed by pipetting after washing with Hepes buffer, and nylon mesh (cell strainer, cat # 352350, Becton Dickinson Labware, Franklin Lakes, NJ, USA) was used to remove the cell mass and obtain a neuronal cell suspension. The suspension was centrifuged at 1000 rpm for 4 minutes, and the supernatant was removed.
  • the number of cells was counted, and the neurons were diluted with a medium to 1 ⁇ 10 5 per well, and coated with poly-D-lysine 96 Well plates (cat # 356461, Becton Dickinson Labware, Franklin Lakes, NJ, USA) were seeded.
  • the medium includes 0.5 mM L-glutamine (cat # 25030-081, Invitrogen, Carlsbad, CA, USA), penicillin streptomycin (cat # 15140-122, Invitrogen, Carlsbad, CA, USA) and 2% B27 Supplement (cat # Neurobasal medium (cat # 21103-049, Invitrogen, Carlsbad, CA, USA) including 17504-044, Invitrogen, Carlsbad, CA, USA) was used.
  • the seeded cells were cultured for 3-4 days in a 37 ° C. incubator under 5% CO 2 .
  • test compounds were added as follows. A DMSO solution of the test compound was prepared at a concentration 100 times the final concentration. This solution was diluted 100 times with the medium. The whole amount of the cell culture medium was removed, and 100 or 200 ⁇ l / well of a medium containing the test compound was added. To the control group, a medium containing DMSO containing no test compound was added. After culturing for 1 to 3 days after compound addition, the medium was collected and used as a sample for A ⁇ measurement by ELISA. Further, the cells after recovering the culture medium were evaluated for survival using Cell Counting Kit-8 (cat # 347-07621, Dojindo, Kumamoto, Japan).
  • % control (A450_sample-A450_bkg) / (A450_ctrl-A450_bkg) x 100
  • a ⁇ ELISA Quantification of A ⁇ by ELISA was carried out according to the manufacturer's recommended protocol (method described in the package insert) using Human / Rat ⁇ amyloid (42) ELISA kit, High-Sensitive (cat # 292-64501) from Wako Pure Chemical Industries, Ltd. I went. The measurement results were expressed as a percentage of the inhibitory activity of each test compound, with the A ⁇ concentration in the medium of the control group being 100%.
  • Table 26 shows data on the A ⁇ production inhibitory action of typical compounds.
  • the compound of the present invention exhibits a strong beta amyloid production inhibitory effect. Therefore, the compound of the present invention is a therapeutic agent for Alzheimer's disease, Down's syndrome or other diseases caused by beta amyloid (for example, cognitive impairment, memory impairment / learning impairment, mild cognitive impairment, senile dementia, amyloidosis, cerebrovascular angiopathy, etc.) And / or useful as a preventive agent.
  • beta amyloid for example, cognitive impairment, memory impairment / learning impairment, mild cognitive impairment, senile dementia, amyloidosis, cerebrovascular angiopathy, etc.

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Abstract

La présente invention a pour objet un nouveau composé qui possède une forte activité inhibitrice de la production de la protéine bêta-amyloïde 42 et est utile en tant qu'agent thérapeutique et/ou prophylactique pour les maladies psychonévrotiques qui sont provoquées par la protéine bêta-amyloïde et modélisées par la maladie d'Alzheimer.
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EP2491026A1 (fr) * 2009-10-20 2012-08-29 Pfizer Inc. Nouveaux hétéroaryl-imidazoles et hétéroaryl-triazoles à titre de modulateurs de gamma-sécrétase
US9403815B2 (en) 2010-06-24 2016-08-02 The Regents Of The University Of California Compounds and uses thereof in modulating levels of various amyloid beta peptide alloforms
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WO2017079641A1 (fr) * 2015-11-06 2017-05-11 Neurocrine Biosciences, Inc. Dérivés de n-[2-(1-benzylpipéridin-4-yl)éthyl]-4-(pyrazin-2-yl)-pipérazine-1-carboxamide et composés apparentés en tant qu'antagonistes du récepteur muscarinique 4 (m4) pour le traitement de maladies neurologiques
EA039638B1 (ru) * 2016-01-06 2022-02-21 Нейрокрин Байосайенсиз, Инк. Антагонисты мускаринового рецептора 4 и способы их применения
CN109563071A (zh) * 2016-06-08 2019-04-02 葛兰素史密斯克莱知识产权发展有限公司 作为atf4途径抑制剂的化学化合物
US11547704B2 (en) 2016-06-08 2023-01-10 Glaxosmithkline Intellectual Property Development Limited Chemical compounds
CN109563071B (zh) * 2016-06-08 2021-08-03 葛兰素史密斯克莱知识产权发展有限公司 作为atf4途径抑制剂的化学化合物
EP3558992A4 (fr) * 2016-12-15 2020-12-02 ONO Pharmaceutical Co., Ltd. Activateur de canaux trek (canaux k+ associés à twik)
US11046683B2 (en) 2016-12-15 2021-06-29 Ono Pharmaceutical Co., Ltd. Activator of TREK (TWIK RElated K+ channels) channels
WO2018110669A1 (fr) * 2016-12-15 2018-06-21 Ono Pharmaceutical Co., Ltd. Activateur de canaux trek (canaux k+ associés à twik)
US11851428B2 (en) 2016-12-15 2023-12-26 Ono Pharmaceutical Co., Ltd. Activator of TREK (TWIK RElated K+channels) channels

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