WO2018139471A1 - Dérivé de dibenzodiazépine - Google Patents

Dérivé de dibenzodiazépine Download PDF

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Publication number
WO2018139471A1
WO2018139471A1 PCT/JP2018/002058 JP2018002058W WO2018139471A1 WO 2018139471 A1 WO2018139471 A1 WO 2018139471A1 JP 2018002058 W JP2018002058 W JP 2018002058W WO 2018139471 A1 WO2018139471 A1 WO 2018139471A1
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Prior art keywords
methyl
dibenzo
diazepine
tetrahydropyridin
optionally substituted
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PCT/JP2018/002058
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English (en)
Japanese (ja)
Inventor
渡辺　仁
磯部　義明
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大日本住友製薬株式会社
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Priority claimed from JP2017151063A external-priority patent/JP2020055752A/ja
Application filed by 大日本住友製薬株式会社 filed Critical 大日本住友製薬株式会社
Publication of WO2018139471A1 publication Critical patent/WO2018139471A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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

Definitions

  • the present invention relates to a dibenzodiazepine derivative having a dopamine D 1 receptor antagonistic action, a dopamine D 2 receptor antagonistic action, and a serotonin 5-HT 2A receptor antagonistic action, or a pharmaceutically acceptable salt thereof, and a derivative thereof.
  • the present invention relates to an agent for treating and / or preventing central nervous system diseases as an active ingredient.
  • Schizophrenia is a psychiatric disorder that is reported to have an estimated 45 million patients worldwide, with positive symptoms, negative symptoms, and cognitive impairment as main symptoms.
  • D 2 receptor dopamine D 2 receptor
  • 5-HT 2A receptor serotonin 5-HT 2A receptor
  • Non-Patent Document 1 clozapine, an atypical antipsychotic, is known to show high efficacy in patients with schizophrenia and is the only effective drug for patients with refractory schizophrenia. It has been reported (Non-Patent Document 1). However, 0.8% of clozapine patients have been reported to cause agranulocytosis, which is a serious side effect, and blood monitoring is required when taking clozapine. In addition, side effects such as epilepsy, digestive disorders, sedation, weight gain, and fluency have been reported, which makes it difficult to continue treatment with clozapine (Non-Patent Documents 2 and 3). Therefore, development of an antipsychotic drug that is safer and effective for treatment-resistant schizophrenic patients is an urgent issue.
  • Clozapine dopamine D 2 receptor antagonistic action, in addition to the serotonin 5-HT 2A receptor antagonistic action, dopamine D 1 receptor (hereinafter, D 1 receptors) are known to have antagonistic action against .
  • Clozapine has been reported to occupy the D 2 receptor and the D 1 receptor simultaneously and in a similar ratio in the PET test for schizophrenic patients (Non-Patent Documents 4, 5, and 6).
  • Patent Document 1 discloses a 1-piperazino-1,2-dihydroindene derivative as a substance having an antagonistic action on D 1 receptor, D 2 receptor, and 5-HT 2A receptor.
  • the dibenzodiazepine derivative has a different chemical structure in both the basic skeleton and the side chain.
  • Patent Document 2 discloses a dibenzoxazepine derivative useful as an antipsychotic drug, but the basic skeleton has a different chemical structure from the dibenzodiazepine derivative of the present invention.
  • An object of the present invention is to provide a compound for use in the prevention or treatment of a central nervous system disease characterized by D 1 receptor antagonism, D 2 receptor antagonism, and 5-HT 2A receptor antagonism, or a pharmaceutical product thereof It is to provide a salt that is chemically acceptable, a method for producing the same, a composition containing the compound, and the like.
  • the present inventors have shown that a compound having an antagonistic action on the D 1 receptor, D 2 receptor, and 5-HT 2A receptor has a strong medicinal effect on schizophrenia and other psychiatric disorders including treatment resistance.
  • the compound represented by the following formula (1) and a pharmaceutically acceptable salt thereof (hereinafter sometimes abbreviated as “the compound of the present invention” as necessary) are D 1. It has been found that it has a strong antagonistic action on the receptor, D 2 receptor, and 5-HT 2A receptor, and has completed the present invention.
  • ring Q 1 represents an optionally substituted benzene ring or an optionally substituted pyridine ring
  • Ring Q 2 represents an optionally substituted benzene ring or an optionally substituted pyridine ring
  • R a represents a hydrogen atom or C 1-6 alkyl optionally substituted with 1 to 3 halogen atoms of the same or different types
  • n represents 0, 1 or 2
  • m represents 1, 2, 3 or 4
  • Each of R b independently represents a hydrogen atom, a halogen atom, or C 1-6 alkyl optionally substituted with 1 to 3 halogen atoms of the same or different types.
  • the ring Q 1 is a benzene ring or a pyridine ring (the benzene ring or pyridine ring is optionally substituted by a halogen atom, cyano, the same or different 1 to 3 halogen atoms, C 1-6 From alkyl, C 1-6 alkoxy optionally substituted with 1 to 3 halogen atoms of the same or different types, and amino optionally substituted with 1 to 2 C 1-6 alkyls of the same or different types
  • Ring Q 2 is a benzene ring or a pyridine ring (wherein the benzene ring or pyridine ring is a C 1-6 alkyl which may be substituted with 1 to 3 halogen atoms, the same or different halogen atoms, the same or different Selected from the group consisting of C 1-6 alkoxy optionally substituted with 1 to 3 different
  • the ring Q 1 is a benzene ring (the ring is a halogen atom, cyano, a C 1-6 alkyl optionally substituted with 1 to 3 halogen atoms, and the same or different Optionally substituted with 1 to 4 groups of the same or different types selected from the group consisting of C 1-6 alkoxy optionally substituted with 1 to 3 halogen atoms;
  • Ring Q 2 is a benzene ring (the ring is a halogen atom, cyano, C 1-6 alkyl optionally substituted with 1 to 3 halogen atoms of the same or different species, and 1 to 3 of the same or different species) Item 1 or 2 which may be substituted with the same or different 1 to 4 groups selected from the group consisting of C 1-6 alkoxy optionally substituted with a halogen atom of A compound, or a pharmaceutically acceptable salt thereof.
  • each R b is independently a halogen atom, or C 1-6 alkyl optionally substituted with 1 to 3 halogen atoms of the same or different types. 5.
  • R a represents a hydrogen atom, or C 1-6 alkyl optionally substituted with 1 to 3 halogen atoms of the same or different types
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 are each independently a hydrogen atom, a halogen atom, cyano, the same or different, 1 to 3 halogen atoms C 1-6 alkyl optionally substituted with 1 to 3 C 1-6 alkoxy optionally substituted with 1 to 3 halogen atoms of the same or different type, or 1 to 2 C 1-of the same or different type
  • R 11 , R 12 , R 13 , and R 14 each independently represent a hydrogen atom, a halogen atom, or C 1-6 alkyl optionally substituted with 1 to 3 halogen atoms of the same or different types.
  • R 11, R 12, R 13 , and any one or more of the R 14 is a halogen atom or an optionally substituted with 1 to 3 halogen atoms same or different, C 1-6 Item 7.
  • R 2 and R 7 are each independently a hydrogen atom, a halogen atom, cyano, a C 1-6 alkyl optionally substituted with 1 to 3 halogen atoms of the same or different kinds, or the same Or the compound according to any one of Items 6 to 14, or a pharmaceutically acceptable salt thereof, which is C 1-6 alkoxy optionally substituted with 1 to 3 different halogen atoms.
  • R 2 and R 7 is halogen atom, cyano, same or different 1 to 3 C 1-6 alkyl optionally substituted by a halogen atom or a same or different, Item 15.
  • R 2 is a hydrogen atom, a fluorine atom, a chlorine atom, C 1-3 alkyl, or C 1-3 alkoxy; R 7 may be substituted with a hydrogen atom, a fluorine atom, a chlorine atom, cyano, C 1-3 alkyl optionally substituted with 1 to 3 fluorine atoms, or 1 to 3 fluorine atoms C 1-6 alkoxy, Item 15.
  • a pharmaceutical comprising the compound according to any one of items 1 to 20 or a pharmaceutically acceptable salt thereof as an active ingredient.
  • a therapeutic agent for central nervous system diseases comprising the compound according to any one of items 1 to 20 or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Central nervous system disease is schizophrenia, bipolar disorder, autism, ADHD, depression, anxiety disorder, sleep disorder, behavioral and psychological symptoms of dementia (BPSD (Behavioral and Psychological Symptoms of Dementia) Item 23.
  • BPSD Behavioral and Psychological Symptoms of Dementia
  • a central nervous system comprising administering to a patient in need of treatment a therapeutically effective amount of a compound according to any one of items 1 to 20, or a pharmaceutically acceptable salt thereof. For treating systemic diseases.
  • Item 21. A therapeutic agent comprising the compound according to any one of Items 1 to 20 or a pharmaceutically acceptable salt thereof as an active ingredient for treating a central nervous system disease in combination with a drug.
  • the compound of the present invention exhibits an antagonistic action on the D 1 receptor, D 2 receptor, and 5-HT 2A receptor.
  • the ability to migrate to the brain is excellent, and the amount of reactive metabolites that are responsible for agranulocytosis is also low.
  • histamine receptor, muscarinic receptor, serotonin 5-HT 2c receptor hereinafter referred to as 5-HT 2c receptor
  • Antagonism is weak. Therefore, the compound of the present invention is useful as a highly safe and excellent therapeutic agent and / or preventive agent for central nervous system diseases (for example, schizophrenia).
  • C 1-6 alkyl is synonymous with alkyl having 1 to 6 carbons.
  • halogen atom include fluorine atom, chlorine atom, bromine atom or iodine atom. Preferably, they are a fluorine atom and a chlorine atom.
  • C 1-6 alkyl means a straight or branched saturated hydrocarbon group having 1 to 6 carbon atoms. Preferred is “C 1-4 alkyl”. Specific examples of “C 1-6 alkyl” include, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, Examples thereof include 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl and the like.
  • C 1-6 alkyl part of “C 1-6 alkoxy” has the same meaning as the above “C 1-6 alkyl”. Preferred is “C 1-4 alkoxy”. Specific examples of “C 1-6 alkoxy” include, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like.
  • the R b group may be substituted with any carbon atom on the nitrogen-containing monocycle if possible, and the same or different 2 on the same carbon atom if possible.
  • One R b group may be substituted.
  • ring Q 1 and / or ring Q 2 is a pyridine ring, the four atoms indicated by the arrows shared by the ring to which they are condensed are carbon atoms. is there.
  • substituent in the “optionally substituted benzene ring” and the “optionally substituted pyridine ring” include, for example, (A) a halogen atom, (B) cyano, (C) C 1-6 alkyl (the group may be substituted with 1 to 3 groups of the same or different types selected from the group consisting of halogen atoms, hydroxy, and C 1-6 alkoxy), (D) C 1-6 alkoxy (the group may be substituted with 1 to 3 groups of the same or different types selected from the group consisting of halogen atoms, hydroxy, and C 1-6 alkoxy), (E) phenyl (the group may be substituted with 1 to 4 groups of the same or different types selected from the group consisting of halogen atoms, C 1-6 alkyl, and C 1-6 alkoxy), (F) 5-membered or 6-membered heteroaryl (the group is substituted with 1 to 4 groups of the same or different types selected from the group consisting of a
  • C 1-6 alkyl optionally substituted with 1 to 3 halogen atoms of the same or different halogen atom, cyano, optionally substituted with 1 to 3 halogen atoms of the same or different type C 1-6 alkoxy, and amino optionally substituted with the same or different 1-2 C 1-6 alkyl. More preferably, it may be substituted with a halogen atom, C 1-6 alkyl optionally substituted with the same or different 1 to 3 halogen atoms, and 1 or 3 halogen atoms of the same or different.
  • C 1-6 alkoxy is mentioned.
  • R a , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 11 , R 12 , R 13 , Preferred examples of R 14 and R 14 are as follows, but the technical scope of the present invention is not limited to the following compounds.
  • R a is preferably C 1-6 alkyl optionally substituted with 1 to 3 halogen atoms of the same or different types. More preferred is C 1-3 alkyl; even more preferred is methyl. Another example of R a is deuterated methyl (CD 3 ).
  • R 1 , R 3 , R 4 , R 5 , R 6 , and R 8 are preferably a hydrogen atom and a halogen atom. More preferably, it is a hydrogen atom.
  • R 2 and R 7 are preferably a hydrogen atom, a halogen atom, cyano, a C 1-6 alkyl optionally substituted with 1 to 3 halogen atoms of the same or different types, and 1 to 3 of the same or different types
  • C 1-6 alkoxy optionally substituted with a halogen atom. More preferably, it may be substituted with a halogen atom, C 1-6 alkyl optionally substituted with the same or different 1 to 3 halogen atoms, and 1 or 3 halogen atoms of the same or different.
  • C 1-6 alkoxy is mentioned.
  • R 11 , R 12 , R 13 , and R 14 are each independently a hydrogen atom, a halogen atom, or C 1-6 alkyl optionally substituted with 1 to 3 halogen atoms of the same or different types And any one or more of R 11 , R 12 , R 13 , and R 14 is a halogen atom, or a C 1-6 alkyl optionally substituted with 1 to 3 halogen atoms of the same or different types It is preferable that More preferably, any one or more of R 11 , R 12 , R 13 , and R 14 is C 1-6 alkyl.
  • R 11 , R 12 , and R 14 are preferably a hydrogen atom and C 1-6 alkyl. More preferably, it is a hydrogen atom.
  • R 13 preferably includes a hydrogen atom and C 1-6 alkyl. More preferred is C 1-4 alkyl; even more preferred is methyl.
  • R 11 , R 12 , R 13 , and R 14 are hydrogen atoms; R 13 is C 1-6 alkyl; R 14 is hydrogen atom, or C 1-6 alkyl.
  • R 11 , R 12 , R 13 , and R 14 are hydrogen atoms; R 13 is C 1-4 alkyl.
  • the compound represented by the formula (1) may exist as a tautomer. Therefore, this invention compound also includes the tautomer of the compound represented by Formula (1).
  • the compound represented by formula (1) may have at least one asymmetric carbon atom. Accordingly, the compound of the present invention includes not only the racemic form of the compound represented by the formula (1) but also optically active forms of these compounds. In addition, a deuterium converter obtained by converting any one or two or more 1 H of the compound represented by the formula (1) into 2 H (D) is also included in the compound represented by the formula (1). .
  • the compound represented by the formula (1) and a pharmaceutically acceptable salt thereof may exist in the form of a hydrate and / or a solvate, these hydrates or ethanol solvates. Solvates such as are also included in the compounds of the present invention. Further, the compounds of the present invention include all forms of crystal forms.
  • an alkali metal salt such as sodium salt or potassium salt
  • an alkaline earth such as calcium salt or magnesium salt
  • Metal salts inorganic metal salts such as zinc salts
  • organic base salts such as triethylamine, triethanolamine, trihydroxymethylaminomethane, and amino acids.
  • inorganic acid salts such as hydrochloride, hydrobromide, sulfate, phosphate, nitrate; and acetate, propionate Organics such as succinate, lactate, malate, tartrate, citrate, maleate, fumarate, methanesulfonate, p-toluenesulfonate, benzenesulfonate, ascorbate
  • succinate lactate
  • malate tartrate
  • citrate citrate
  • maleate fumarate
  • methanesulfonate p-toluenesulfonate
  • benzenesulfonate ascorbate
  • acid salts include acid salts.
  • the compound of the present invention is synthesized by a method combining the following production method and a known synthesis method.
  • the compounds in the reaction formula also include the case where each forms a salt, and examples of the salt include the same salts as the salt of the compound represented by the formula (1).
  • These reactions are merely examples, and the compounds of the present invention can also be produced by other methods as appropriate based on the knowledge of those skilled in organic synthesis.
  • protecting groups can be accomplished by methods commonly used in organic synthetic chemistry (eg, TW Greene and PMGM Wuts, “Protective Groups in Organic Synthesis”, 3rd Ed., John Wiley and Sons). , Inc., New York (1999)) or a similar method.
  • Examples of the amino-protecting group include tert-butoxycarbonyl, benzyloxycarbonyl, p-toluenesulfonyl, o-nitrobenzenesulfonyl and the like.
  • Step 1-1 Production Step of Compound (1-2)
  • a halogenating reagent in compound (1-1) in the presence or absence of a base in a suitable inert solvent. It is manufactured by.
  • the compound (1-1) a commercially available compound or one produced by a known method (for example, International Publication No. 2007/047776) can be used.
  • the halogenating reagent include 1-chloro-N, N, 2-trimethylpropenylamine, phosphorus oxychloride, phosphorus trichloride, thionyl chloride, phosphorus pentachloride and the like.
  • the base include N, N-dimethylaniline.
  • the inert solvent examples include toluene, dichloromethane and the like.
  • the reaction time is usually 5 minutes to 72 hours, preferably 30 minutes to 2 hours.
  • the reaction temperature is usually ⁇ 78 ° C. to 200 ° C., preferably 20 ° C. to 100 ° C.
  • Step 1-2 Production Step of Compound (1d)
  • Compound (1d) is prepared by coupling compound (1-2) and compound (1-3) in the presence of a palladium catalyst in a suitable inert solvent. Manufactured. This step can be performed in the presence of a base and / or a phosphorus ligand as necessary.
  • a commercially available compound or one produced by a known method for example, International Publication No. WO 2002/066470
  • what was manufactured by the postscript manufacturing method 4 can be used.
  • the palladium catalyst various palladium catalysts used in a conventional method can be used, and tetrakis (triphenylphosphine) palladium (0) is preferable.
  • Examples of the base include potassium carbonate and cesium carbonate.
  • Examples of the phosphorus ligand include triphenylphosphine and bis (diphenylphosphino) methane.
  • Examples of the inert solvent include 1,4-dioxane, tetrahydrofuran, water, and a mixed solvent thereof.
  • the reaction temperature is usually 0 ° C. to 200 ° C., preferably 20 ° C. to 150 ° C., and can be performed under microwave irradiation as necessary. While the reaction time varies depending on the reaction temperature, the palladium catalyst used, the raw materials, the solvent and the like, it is generally 5 minutes to 72 hours, preferably 30 minutes to 24 hours.
  • Step 1-3 Step of producing compound (1-5)
  • Compound (1-5) is produced from compound (1-2) and compound (1-4) according to the method described in step 1-2.
  • Step 1-4 Step of Producing Compound (1c)
  • Compound (1c) is obtained by reacting the protecting group Pro of the amino group of compound (1-5) with a known method (for example, Protective Group in Organic Synthesis 3rd Edition (Theodora W Green, Peter GM Wuts, published by John Wiley & Sons Inc, 1999).
  • Step 1-5 Production Step of Compound (1d)
  • Compound (1d) can also be produced by reacting compound (1c) with various alkyl aldehydes in the presence of a reducing agent in a suitable inert solvent.
  • a reducing agent include sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride and the like.
  • the inert solvent include toluene, THF, dichloroethane, methanol and the like.
  • the reaction time is usually 5 minutes to 48 hours, preferably 1 hour to 24 hours.
  • the reaction temperature is usually ⁇ 78 ° C. to 100 ° C., preferably 0 ° C. to 80 ° C.
  • Compound (1d) can also be produced by reacting compound (1c) with various alkyl halides in a suitable inert solvent in the presence of a base.
  • a suitable inert solvent examples include potassium carbonate, cesium carbonate, sodium hydride, lithium diisopropylamide and the like.
  • the inert solvent examples include DMF, dimethyl sulfoxide, THF, 1,4-dioxane and the like.
  • the reaction time is usually 5 minutes to 48 hours, preferably 1 hour to 24 hours.
  • the reaction temperature is usually ⁇ 78 ° C. to 100 ° C., preferably 0 ° C. to 80 ° C.
  • Manufacturing method 2 The compound represented by the formula (1-4) is produced, for example, by the method shown below. [Wherein, R b , m and n are as defined above in [Item 1]; X 1 represents halogen or triflate (trifluoromethanesulfonyloxy); Pro represents an amino-protecting group; Represents boronic acid or boronic ester. ]
  • Step 2-1 Step of producing compound (2-2)
  • Compound (2-2) is produced by reacting compound (2-1) with a triflating agent in the presence of a base in a suitable inert solvent.
  • a base for example, International Publication No. 2012/142668
  • the base include lithium diisopropylamide or sodium bis (trimethylsilyl) amide.
  • the triflating agent various triflating agents used in a conventional method can be used, and preferably N-phenylbis (trifluoromethanesulfonimide) is used.
  • the inert solvent include THF.
  • the reaction time is usually 5 minutes to 72 hours, preferably 30 minutes to 8 hours.
  • the reaction temperature is usually ⁇ 78 ° C. to 200 ° C., preferably ⁇ 78 ° C. to 20 ° C.
  • Step 2-2 Production Step of Compound (1-4)
  • Compound (1-4) is obtained by coupling compound (2-2) and a boronation reagent in the presence of a palladium catalyst in a suitable inert solvent.
  • This step can be performed in the presence of a base and / or a phosphorus ligand as necessary.
  • the base include potassium acetate.
  • the phosphorus ligand include triphenylphosphine and bis (diphenylphosphino) methane.
  • the boronation reagent various boronation reagents used in a conventional method can be used, and bis (pinacolate) diborane is preferable.
  • the palladium catalyst various palladium catalysts used in a conventional method can be used, and preferably 1,1′-bis (diphenylphosphino) ferrocene-palladium (II) dichloride is used.
  • the inert solvent include 1,4-dioxane, THF and the like.
  • the reaction temperature is usually 0 ° C. to 200 ° C., preferably 50 ° C. to 120 ° C., and can be performed under microwave irradiation as necessary. While the reaction time varies depending on the reaction temperature, the palladium catalyst used, the raw materials, the solvent and the like, it is generally 5 minutes to 72 hours, preferably 2 hours to 8 hours.
  • the compound represented by the formula (1e) is produced, for example, by the method shown below.
  • R a1 is optionally substituted by 1 to 3 halogen atoms the same or different Represents C 1-6 alkyl
  • X represents halogen
  • A represents boronic acid or boronic ester.
  • Step 3-1 Production Step of Compound (3-2)
  • Compound (3-2) is produced from compound (1-2) and compound (3-1) according to the method described in Step 1-2.
  • the As the compound (3-1) a commercially available compound or one produced by a known method (for example, International Publication No. 2011/119518) can be used.
  • Step 3-2 Production Step of Compound (1e)
  • Compound (1e) was reacted with compound (3-2) and compound (3-3) in a suitable inert solvent to form a quaternary ammonium cation. Thereafter, it is produced by acting a reducing agent.
  • the inert solvent include acetonitrile, THF, 1,4-dioxane and the like.
  • the reaction time in the alkylation step is usually 5 minutes to 48 hours, preferably 1 hour to 24 hours.
  • the reaction temperature in the alkylation step is 0 ° C to 100 ° C.
  • Examples of the reducing agent used in the subsequent reduction reaction step include sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride and the like.
  • Examples of the solvent used include toluene, THF, dichloroethane, methanol and the like.
  • the reaction time is usually 5 minutes to 48 hours, preferably 1 hour to 24 hours.
  • the reaction temperature is usually ⁇ 78 ° C. to 100 ° C., preferably ⁇ 78 ° C. to 20 ° C.
  • Manufacturing method 4 The compound represented by the formula (1-3) is also produced, for example, by the method shown below.
  • R b , m and n are as defined above in [Item 1];
  • R a1 represents C 1-6 alkyl optionally substituted with 1 to 3 halogen atoms of the same or different types;
  • X 1 represents halogen or triflate;
  • Pro represents an amino-protecting group;
  • A represents boronic acid or a boronic ester.
  • Step 4-1 Production Step of Compound (4-1)
  • the compound (4-1) is prepared by reacting the protecting group Pro of the amino group of the compound (2-2) with a known method (for example, Protective Group in Organic Synthesis 3). It is manufactured by deprotection in a plate (Theodora W. Green, by Peter GM Wuts, published by John Wiley & Sons Inc, 1999).
  • Step 4-2 Production Step of Compound (4-2)
  • Compound (4-2) is obtained by reacting compound (4-1) with various alkyl aldehydes in the presence of a reducing agent in a suitable inert solvent.
  • a reducing agent include sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride and the like.
  • the inert solvent include toluene, THF, dichloroethane, methanol and the like.
  • the reaction time is usually 5 minutes to 48 hours, preferably 1 hour to 24 hours.
  • the reaction temperature is usually ⁇ 78 ° C. to 100 ° C., preferably 0 ° C. to 80 ° C.
  • Compound (4-2) can also be produced by reacting compound (4-1) with various alkyl halides in a suitable inert solvent in the presence of a base.
  • a suitable inert solvent examples include potassium carbonate, cesium carbonate, sodium hydride, lithium diisopropylamide and the like.
  • the inert solvent examples include DMF, dimethyl sulfoxide, THF, 1,4-dioxane and the like.
  • the reaction time is usually 5 minutes to 48 hours, preferably 1 hour to 24 hours.
  • the reaction temperature is usually ⁇ 78 ° C. to 100 ° C., preferably 0 ° C. to 80 ° C.
  • Step 4-3 Production Step of Compound (1-3)
  • Compound (1-3) is obtained by coupling compound (4-2) and a boronation reagent in the presence of a palladium catalyst in a suitable inert solvent.
  • This step can be performed in the presence of a base and / or a phosphorus ligand as necessary.
  • the base include potassium acetate.
  • the phosphorus ligand include triphenylphosphine and bis (diphenylphosphino) methane.
  • the boronation reagent various boronation reagents used in a conventional method can be used, and bis (pinacolate) diborane is preferable.
  • the palladium catalyst various palladium catalysts used in a conventional method can be used, and preferably 1,1′-bis (diphenylphosphino) ferrocene-palladium (II) dichloride is used.
  • the inert solvent include 1,4-dioxane, THF and the like.
  • the reaction temperature is usually 0 ° C. to 200 ° C., preferably 50 ° C. to 120 ° C., and can be performed under microwave irradiation as necessary. While the reaction time varies depending on the reaction temperature, the palladium catalyst used, the raw materials, the solvent and the like, it is generally 5 minutes to 72 hours, preferably 2 hours to 8 hours.
  • the compound of the present invention having a desired substituent at a desired position can be obtained by appropriately combining the above production methods.
  • Isolation and purification of intermediates and products in the above production method may be performed by appropriately combining methods used in ordinary organic synthesis, for example, filtration, extraction, washing, drying, concentration, crystallization, various chromatography, and the like. it can.
  • the intermediate can be subjected to the next reaction without any particular purification.
  • some of the raw material compounds or intermediates in the above production method may exist in the form of a salt such as hydrochloride, but can be used as they are or in a free form.
  • a salt such as hydrochloride
  • these are dissolved or suspended in an appropriate solvent, and a base such as an aqueous sodium hydrogen carbonate solution is obtained. It can be converted to the free form by neutralizing with, for example.
  • tautomers such as keto enol, isomers such as positional isomer, geometric isomer or optical isomer. May be present, but all possible isomers including these and mixtures in any ratio of the isomers are also encompassed by the present invention.
  • 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 salt of the compound represented by the formula (1) may be purified as it is, and the compound represented by the formula (1) When obtained in a free form, the compound represented by the formula (1) may be dissolved or suspended in a suitable solvent, and an acid or base may be added to form a salt.
  • compound (1) or a pharmaceutically acceptable salt thereof may exist in the form of a solvate with water or various solvents, and these solvates are also encompassed in the present invention.
  • treatment refractory schizophrenia refers to schizophrenia in which two or more types of antipsychotic drugs are not sufficiently improved even when administered in sufficient amounts for a sufficient period.
  • two or more antipsychotic drugs are administered at a dose of 600 mg / day or more in chlorpromazine for 4 weeks or more, resulting in an overall function assessment (Global Assessment of Functioning: GAF) of 41 or more. It is defined that the corresponding state has never been reached.
  • GAF Global Assessment of Functioning
  • the compound of the present invention shows an antagonistic action on the D 2 receptor and 5-HT 2A receptor, schizophrenia, bipolar disorder, autism, ADHD, depression, anxiety disorder, sleep disorder, It is expected to be effective for behavioral and psychological symptoms of dementia (BPSD (Behavioral and Psychological Symptoms of Dementia)) and psychiatric symptoms of neurodegenerative diseases.
  • BPSD Behavioral and Psychological Symptoms of Dementia
  • the rat methamphetamine-induced hyperactivity test (Test Example 5), which is a model of positive symptoms of schizophrenia, is conducted to treat schizophrenia. It is considered that a drug effective for treatment-resistant schizophrenia can be searched by finding a drug and confirming that it has an antagonistic action on the aforementioned D 1 receptor and D 2 receptor.
  • a reactive metabolite which is toxic (agranulocytosis, hepatotoxicity, allergy, Tissue necrosis, mutagenicity, carcinogenicity, etc.) may occur.
  • prevention is an act of administering the active ingredient of the present invention to a healthy person who has not developed a disease, for example, for the purpose of preventing the onset of the disease. is there.
  • Treatment is an act of administering the active ingredient of the present invention to a person (patient) diagnosed as having developed a disease by a doctor.
  • the compound of the present invention can be formulated and administered by oral administration or parenteral administration, directly or using a suitable dosage form.
  • suitable dosage form include, but are not limited to, tablets, capsules, powders, granules, solutions, suspensions, injections, patches, and cataplasms.
  • the preparation is produced by a known method using a pharmaceutically acceptable additive.
  • Additives are excipients, disintegrants, binders, fluidizers, lubricants, coating agents, solubilizers, solubilizers, thickeners, dispersants, stabilizers, sweeteners depending on the purpose. Perfumes and the like can be used.
  • lactose lactose, mannitol, crystalline cellulose, low-substituted hydroxypropyl cellulose, corn starch, partially pregelatinized starch, carmellose calcium, croscarmellose sodium, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinyl alcohol, stearin
  • examples include magnesium acid, sodium stearyl fumarate, polyethylene glycol, propylene glycol, titanium oxide, and talc.
  • oral or parenteral such as intravenous, application, inhalation and instillation can be mentioned, but oral administration is preferable.
  • the dosage form include tablets and injections, and tablets are preferred.
  • the dosage and frequency of administration of these pharmaceutical compositions vary depending on the dosage form, the patient's disease and symptoms, the patient's age and weight, etc., and cannot be generally specified, but are usually effective for adults per day
  • the amount of ingredients ranges from about 0.0001 to about 5000 mg, preferably from about 0.001 to about 1000 mg, more preferably from about 0.1 to about 500 mg, particularly preferably from about 1 to about 300 mg. It can be administered once or several times a day, preferably 1 to 3 times a day.
  • the compound of the present invention can be used in combination with other drugs for the purpose of enhancing its effect and / or reducing side effects.
  • it can be used in combination with an antipsychotic such as aripirazole, olanzapine, quetiapine, risperidone, bronanserin, perospirone, paliperidone, ziprasidone, asenapine, iloperidone, sertindole, lurasidone, or a pharmaceutically acceptable salt thereof.
  • an antipsychotic such as aripirazole, olanzapine, quetiapine, risperidone, bronanserin, perospirone, paliperidone, ziprasidone, asenapine, iloperidone, sertindole, lurasidone, or a pharmaceutically acceptable salt thereof.
  • a drug that can be used in combination with the compound of the present invention is abbreviated as a concomitant drug.
  • the administration period of the compound of the present invention and the concomitant drug is not limited, and these may be administered simultaneously to the administration subject or may be administered with a time difference. Moreover, it is good also as a mixture of this invention compound and a concomitant drug.
  • the dose of the concomitant drug can be appropriately selected based on the clinically used dose.
  • the compounding ratio of the compound of the present invention and the concomitant drug can be appropriately selected depending on the administration subject, administration route, target disease, symptom, combination and the like. For example, when the administration subject is a human, the concomitant drug may be used in an amount of 0.01 to 100 parts by weight per 1 part by weight of the compound of the present invention. Moreover, it can be used in combination with drugs (concomitant drugs) such as antiemetics, sleep-inducing agents, and anticonvulsants for the purpose of suppressing the side effects.
  • drugs concomitant drugs
  • Symbols used in NMR include: s is a single line, d is a double line, dd is a double line double line, t is a triple line, td is a triple line double line, q is a quadruple line, m Is a multiple line, br is broad, brs is a wide single line, brm is a wide multiple line, and J is a coupling constant.
  • Reference example 1 8-Chloro-2-fluoro-5,10-dihydro-11H-dibenzo [b, e] [1,4] diazepin-11-one a) Preparation of 2-[(4-chloro-2-nitrophenyl) amino] -5-fluorobenzoic acid (Compound W1) 4-Chloro-1-fluoro-2-nitrobenzene (5.0 g) in DMF (29 mL) To the solution were added 2-amino-5-fluorobenzoic acid (4.4 g) and cesium carbonate (28 g), and the mixture was stirred at 120 ° C. overnight.
  • 2-amino-5-fluorobenzoic acid 4.4 g
  • cesium carbonate 28 g
  • Reference examples 2-8 According to the method described in Reference Example 1, using the corresponding starting material compounds, the compounds shown in the table below were obtained. LC-MS in the above table was measured using measurement condition (1).
  • the solvent of the organic layer after drying was distilled off under reduced pressure, and then purified by silica gel column chromatography (elution solvent; chloroform / methanol) and NH 2 silica gel column chromatography (elution solvent; hexane / ethyl acetate) to obtain substance A ( 1.7 g, a mixture of isomers).
  • N-phenylbis (trifluoromethanesulfonimide) 22 g was added at ⁇ 78 ° C. After stirring at ⁇ 78 ° C. for 10 minutes, the mixture was further stirred at room temperature for 3 hours. Saturated aqueous ammonium chloride solution was added at room temperature, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over sodium sulfate.
  • the obtained organic layer was washed with saturated brine, and dried over sodium sulfate. After the solvent of the organic layer after drying was distilled off under reduced pressure, the compound was purified by silica gel column chromatography (elution solvent; chloroform / ethyl acetate) and NH 2 silica gel column chromatography (elution solvent; chloroform / ethyl acetate). W11 (3.9 g) was obtained.
  • Example 1 8-Chloro-2-fluoro-11- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) -5H-dibenzo [b, e] [1,4] diazepine a) Preparation of 8,11-dichloro-2-fluoro-5H-dibenzo [b, e] [1,4] diazepine (Compound W9) N in a solution of the compound of Reference Example 1 (1.0 g) in toluene (20 mL) , N-dimethylaniline (2.3 g) and phosphorus oxychloride (1.8 g) were added. The mixture was stirred at 95 ° C. for 2 hours and then cooled.
  • Examples 2 to 6 In accordance with the method described in Example 1, the compounds of Examples 2 to 6 were obtained using the compounds of the corresponding reference examples and the raw material compounds. LC-MS in the above table was measured using measurement condition (1).
  • Example 7 and Example 8 8-chloro-2-fluoro-11- (6-methyl-1,2,3,6-tetrahydropyridin-4-yl) -5H-dibenzo [b, e] [1,4] diazepine
  • Example 7 8-chloro-2-fluoro-11- (2-methyl-1,2,3,6-tetrahydropyridin-4-yl) -5H-dibenzo [b, e] [1,4] diazepine
  • a) tert-Butyl 4- (8-chloro-2-fluoro-5H-dibenzo [b, e] [1,4] diazepin-11-yl) -6-methyl-3,6-dihydropyridine-1 (2H) -Carboxy
  • Example 8 8-chloro-2-fluoro-11- (6-methyl-1,2,3,6-tetrahydropyridin-4-yl) -5H-dibenzo [b, e] [1,4] diazepine (Examples) 7) and 8-chloro-2-fluoro-11- (2-methyl-1,2,3,6-tetrahydropyridin-4-yl) -5H-dibenzo [b, e] [1,4] diazepine
  • Trifluoroacetic acid (1 mL) was added to a solution of substance B (0.17 g) in dichloromethane (4 mL), and the mixture was stirred at room temperature for 1 hour.
  • Examples 9 to 16 In accordance with the methods described in Example 7 and Example 8, the compounds of Examples 9 to 16 were obtained using the compounds and starting compounds of the corresponding reference examples. LC-MS in the above table was measured using measurement condition (1).
  • Example 17 and Example 18 8-chloro-11- (1,6-dimethyl-1,2,3,6-tetrahydropyridin-4-yl) -2-fluoro-5H-dibenzo [b, e] [1,4] diazepine
  • Example 17) 8-chloro-11- (1,2-dimethyl-1,2,3,6-tetrahydropyridin-4-yl) -2-fluoro-5H-dibenzo [b, e] [1,4] diazepine (Examples) 18)
  • Examples 19-21 According to the methods described in Example 17 and Example 18, the compounds of Examples 19 to 21 were obtained using the compounds and starting compounds of the corresponding reference examples. LC-MS in the above table was measured using measurement condition (1).
  • Example 22 8-Chloro-2-fluoro-11- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) -5H-dibenzo [b, e] [1,4] diazepine a) Preparation of 8-chloro-2-fluoro-11- (pyridin-4-yl) -5H-dibenzo [b, e] [1,4] diazepine (W10) Compound W9 (107 mg) in THF / water (4 / 1) To the (5 mL) solution was added pyridine-4-boronic acid (94 mg), potassium carbonate (0.16 g) and tetrakis (triphenylphosphine) palladium (0) (88 mg).
  • Examples 23-31 According to the method described in Example 22, the compounds of Examples 23 to 31 were obtained using the compounds of the corresponding reference examples and raw material compounds. LC-MS in the above table was measured using measurement condition (1).
  • Example 32-89 According to the methods described in Example 1, Example 7 and Example 8, Example 17 and Example 18, the compounds of Examples 32 to 89 were obtained using the compounds and starting compounds of the corresponding reference examples.
  • Test Examples The pharmacological test results of the 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 human D 1 receptor, human D 2 receptor antagonist activity evaluation test human D 1 receptor for human 5-HT 2A receptor, human D 2 receptors, human 5-HT The antagonist activity against the 2A receptor was measured using the intracellular calcium concentration as an index.
  • Aequorin and G ⁇ 16 protein and their respective receptors were transiently expressed in CHO-K1 cells (Chinese hamster ovary), seeded in 384-well plates, and cultured overnight at 37 ° C. in a CO 2 incubator.
  • the inhibition rate at 1 ⁇ mol / L of the compound of the present invention was calculated when the luminescence amount of wells added only with DMSO was inhibited by 100%, and the luminescence amount of wells added only with dopamine or serotonin was inhibited by 0%. .
  • Test Example 2 Dansylated glutathione (dGSH) trapping assay
  • the compound of the present invention was metabolized in liver microsomes, and reactive metabolites that react with dansylated glutathione (dGSH) were detected and quantified from the metabolites generated.
  • the metabolic reaction was measured using a screening robot (manufactured by Tecan), and the metabolite-dGSH conjugate concentration was measured using a fluorescence detection UPLC system (manufactured by Waters).
  • the compound of the present invention was dissolved in DMSO to prepare a 10 mmol / L test substance solution.
  • a microsome solution was prepared by mixing 7.6 mL of potassium phosphate buffer (500 mmol / L, pH 7.4), 1.9 mL of human liver microsome (Xenotech, 20 mg protein / mL), and 1.27 mL of pure water. .
  • a microsome (dGSH ( ⁇ )) solution was prepared by adding 0.67 mL of pure water to 3.78 mL of the microsome solution.
  • dGSH (+) dGSH (+)
  • a cofactor solution was prepared by dissolving 80.9 mg of NADPH in 30 mL of pure water.
  • a reaction stopping solution was prepared by dissolving 33 mg of Tris (2-carboxyethyl) phosphine (TECP) in 115 mL of methanol.
  • TECP Tris (2-carboxyethyl) phosphine
  • reaction 12 ⁇ L of the test substance solution was mixed with 388 ⁇ L of pure water, and 50 ⁇ L each was dispensed into 6 wells in a 96-well plate. The 6 wells were divided into 3 groups of 2 wells, which were designated as “reaction group”, “unreacted group” and “dGSH non-added group”, respectively.
  • the microsome (dGSH (+)) solution was added to the “reaction group” and the “unreacted group”, and 50 ⁇ L of the microsome (dGSH ( ⁇ )) solution was added to the “dGSH non-addition group”.
  • the cofactor solution was added to the “reaction group” and “dGSH non-addition group”, and 50 ⁇ L of pure water was added to the “non-reaction group”. After incubation at 37 ° C. for 60 minutes, 450 ⁇ L of reaction stop solution was added to stop the reaction. Purified water was added to the “reaction group” and “dGSH non-added group”, and 50 ⁇ L of cofactor solution was added to the “unreacted group”. The plate was cooled at ⁇ 20 ° C. for 1 hour, and then centrifuged (4000 rpm, 10 minutes) went. The supernatant was collected on a separate plate and subjected to analysis.
  • the metabolite-dGSH conjugate concentration in the “reaction group” was calculated by subtracting the fluorescence peaks detected in the “unreacted group” and “dGSH non-added group” from the fluorescence peak detected in the “reaction group”. By measuring the concentration of the “reaction group” metabolite-dGSH conjugate, the risk of the reactive metabolite of the test substance can be evaluated.
  • the concentration of dGSH conjugate in the “unreacted group” is subtracted from the fluorescence peak detected in the “unreacted group” from the fluorescence peak detected in the “dGSH non-added group”. was calculated.
  • concentration of the dGSH conjugate in the “unreacted group” it is possible to evaluate the covalent binding property of the test substance that is considered to be related to cytotoxicity or immunotoxicity.
  • the result of the dGSH conjugate concentration of the “unreacted group” of the compound of the present invention is shown in the table below.
  • Test Example 3 Human Liver Microsome Metabolic Stability Test
  • Human liver microsomal metabolic stability (MS) of the compound of the present invention was evaluated by the following method. Human liver microsomes manufactured by Xenontech were used. Human liver microsomes, NADPH, and a test substance were mixed in 125 mmol / L phosphate buffer (pH 7.4) to the following concentrations and incubated at 37 ° C. for 30 minutes.
  • Human liver microsome 0.1 mg / mL NAPDH: 3.2 mmol / L
  • Test substance 0.1 ⁇ mol / L
  • the results are shown in the table below.
  • Test Example 4 Rat Brain Translocation Test
  • the brain translocation of the compound of the present invention can be evaluated.
  • the SD compound 7-week-old rat is subcutaneously administered with the compound of the present invention in 0.01 mol / L hydrochloric acid aqueous solution, and plasma and brain are collected 1 hour after the administration, and the plasma and brain are collected by LC-MS.
  • Drug concentration was measured.
  • Serum and brain protein binding rates of the compounds of the present invention were measured using equilibrium dialysis. By fitting the plasma and brain compound concentrations and serum and brain protein binding rates obtained by the above test to the following equations, Kp, uu, brain (brain / plasma non-binding drug concentration ratio) Can be calculated.
  • Kp, uu, brain (Brain compound concentration ⁇ (100 ⁇ protein binding rate in brain (%)) / 100) / (plasma compound concentration ⁇ (100 ⁇ protein binding rate in serum (%)) / 100) The results are shown in the table below.
  • Test Example 5 Evaluation for Positive Symptoms by Rat Methamphetamine-Induced Momentum Increase Test
  • the motility enhancement effect by methamphetamine administration to rats is used as an evaluation system for positive symptoms of schizophrenia, and the inhibitory action when the present compound is administered Can be evaluated.
  • the compound of the present invention is administered to 6-10 week old rats, the amount of exercise for 90 minutes is measured immediately after methamphetamine administration.
  • SuperMex Moromachi Machine Co., Ltd.
  • the inhibition rate when the momentum of the solvent administration group is 100% is calculated.
  • Test Example 6 Evaluation of efficacy for schizophrenia patients
  • PANSS Positive and Negative Syndrome Scale
  • CGI-S Clinical Global Impression Severity scale
  • the effectiveness is evaluated using the above-mentioned evaluation scale.
  • Test Example 7 Cyano Trapping Assay
  • reactive metabolites that cannot be captured by dansylated glutathione can be detected.
  • Reactive metabolites are detected and quantified by metabolizing the compound of the present invention in human liver microsomes and reacting with radioactive potassium cyanide (K 14 CN).
  • Human liver microsomes manufactured by Xenontech are used, and the reaction is performed at 37 ° C. for 60 minutes under the following concentration conditions.
  • Concentration conditions / phosphate buffer solution 100 mM ⁇ Human liver microsomes: 1 mg / mL ⁇ K 14 CN: 0.1 mM
  • Test substance 50 ⁇ M NADPH: 0 mM or 1 mM Reactive metabolites that react with K 14 CN are collected by solid phase extraction, and the radioactivity concentration is measured using a liquid scintillation counter.
  • the production clearance of the reactive metabolite is calculated by subtracting the measurement value obtained under the condition where NADPH is not added from the measurement value obtained under the condition where NADPH is added.
  • Test Example 8 Human type 5-HT 2C receptor, human type histamine H 1 receptor (hereinafter referred to as H 1 receptor), human type muscarinic M 1 receptor (hereinafter referred to as M 1 receptor), human type muscarinic M 2 receptor (hereinafter, M 2 receptors), human muscarinic M 3 receptor (hereinafter, M 3 receptors) and human muscarinic M 4 receptor (hereinafter, M 4 receptor) antagonist activity evaluation test human against 5 -Intracellular calcium concentration for antagonist activity against HT 2C receptor, human H 1 receptor, human M 1 receptor, human M 2 receptor, human M 3 receptor and human M 4 receptor was used as an index.
  • H 1 receptor human type histamine H 1 receptor
  • M 1 receptor human type muscarinic M 1 receptor
  • M 2 receptors human type muscarinic M 2 receptor
  • M 3 receptors human muscarinic M 3 receptor
  • M 4 receptor human muscarinic M 4 receptor
  • Aequorin, G ⁇ 16 protein and each receptor were transiently expressed in CHO-K1 cells (Chinese hamster ovary), seeded in a 384-well plate, and cultured overnight at 37 ° C. in a CO 2 incubator. After adding coelenterazine, a DMSO suspension of the compound of the present invention was added using FDSS (manufactured by Hamamatsu Photonics), and then the corresponding ligands shown in the table below were added, and the change in the amount of luminescence was measured. The following table shows the ligands used for evaluating the antagonist activity of each receptor and the concentrations used.
  • Antagonist activity is defined as 100% inhibition of luminescence in wells to which only DMSO has been added, and 0% inhibition of luminescence in wells to which only the corresponding ligand has been added. The inhibition rate in the case of was calculated.
  • Test Example 9 Human type 5-HT 2A receptor, human type D 1 receptor, human type D 2 receptor, human type 5-HT 2C receptor, human type H 1 receptor, human type M 1 receptor, Evaluation of binding activity to human type M 2 receptor, human type M 3 receptor and human type M 4 receptor
  • human type 5-HT 2A receptor, human type D 1 receptor, human type of the compound of the present invention were used. Binding to D 2 receptor, human 5-HT 2C receptor, human H 1 receptor, human M 1 receptor, human M 2 receptor, human M 3 receptor and human M 4 receptor Affinity can be measured.
  • a test compound dissolved in DMSO various receptor membrane samples diluted with a buffer, and these receptors RI (Radio Isotope) labeled ligands are mixed and incubated at room temperature for 30 or 60 minutes, respectively.
  • RI labeled ligand for a receptor can be appropriately selected by the test conditions, for the 5-HT 2A receptor [3H] Ketanserin, for the D 2 receptor [3H] spiperone, for D 1 receptor may be used [3H] SCH23390.
  • Non-specific binding to the receptor is determined by competitive binding test in the presence of Mianserin for 5-HT 2A receptor, Dopamine for D 2 receptor, SCH 23390 for D 1 receptor, etc. More demanded. After measuring the radioactivity bound to the receptor using a liquid scintillation counter, calculate the 50% inhibitory concentration, evaluate the Ki value from the dissociation constant calculated from the saturation binding test, and the substrate concentration, and use it as the binding affinity. To do.
  • binding affinity for human type 5-HT 2C receptor human type H 1 receptor, human type M 1 receptor, human type M 2 receptor, human type M 3 receptor and human type M 4 receptor Can also be measured according to the above method.
  • the RI-labeled ligand for these receptors can be appropriately selected depending on the test conditions and the like.
  • human type H 1 receptor against it is [3H] Pyrilamine, human M 1 receptor, human M 2 receptor, for the human M 3 receptor and human M 4 receptor be used [3H] N-Methylscopolamine etc. it can.
  • non-specific binding to these receptors is Mianserin for the human 5-HT 2C receptor, Pyrilamine for the human H 1 receptor, human M 1 receptor, human M 2 For the receptor, human M 3 receptor, and human M 4 receptor, it is determined by a competitive binding test in the presence of Atropine or the like.
  • the compound of the present invention exhibits an antagonistic action on dopamine D 1 receptor, dopamine D 2 receptor, and serotonin 5-HT 2A receptor, it is useful as a therapeutic and / or prophylactic agent for central nervous system diseases. is there.

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Abstract

La présente invention concerne un dérivé de dibenzodiazépine représenté par la formule (1), qui est utile en tant qu'agent thérapeutique et/ou prophylactique pour des maladies du système nerveux central, et un sel pharmaceutiquement acceptable de celui-ci. (Dans la formule, chacun des cycles Q1 et Q2 représente indépendamment un cycle benzène éventuellement substitué ou un cycle pyridine éventuellement substitué ; Ra représente un atome d'hydrogène ou un groupe alkyle en C1-6 qui peut être substitué par 1 à 3 atomes d'halogène identiques ou différents ; n représente 0, 1 ou 2 ; m représente 1, 2, 3 ou 4 ; et si plusieurs fractions Rb sont présentes, chacune des fractions Rb représente indépendamment un atome d'hydrogène, un atome d'halogène, ou un groupe alkyle en C1-6 qui peut être substitué par 1 à 3 atomes d'halogène identiques ou différents.)
PCT/JP2018/002058 2017-01-25 2018-01-24 Dérivé de dibenzodiazépine WO2018139471A1 (fr)

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Cited By (2)

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Publication number Priority date Publication date Assignee Title
WO2019163865A1 (fr) * 2018-02-22 2019-08-29 大日本住友製薬株式会社 Dérivé de dibenzazépine ayant un cycle hétérocyclique contenant de l'azote
CN110922421A (zh) * 2019-12-17 2020-03-27 蚌埠中实化学技术有限公司 一种n-甲基-1,2,5,6-四氢吡啶-4-硼酸频哪醇酯的合成方法

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US4045445A (en) * 1975-12-14 1977-08-30 American Cyanamid Company 11-(4-Piperidyl)dibenzo-diazepines
JP2007534656A (ja) * 2003-12-22 2007-11-29 アカディア ファーマシューティカルズ，インコーポレーテッド ムスカリンアゴニストとしてのアミノ置換ジアリール［ａ，ｄ］シクロヘプテン類似体および精神神経疾患の治療方法
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