WO2008047839A1 - 5-ht1a receptor agonist - Google Patents

5-ht1a receptor agonist Download PDF

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Publication number
WO2008047839A1
WO2008047839A1 PCT/JP2007/070276 JP2007070276W WO2008047839A1 WO 2008047839 A1 WO2008047839 A1 WO 2008047839A1 JP 2007070276 W JP2007070276 W JP 2007070276W WO 2008047839 A1 WO2008047839 A1 WO 2008047839A1
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Prior art keywords
mmol
pharmaceutically acceptable
added
acceptable salt
tetrahydronaphthalene
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PCT/JP2007/070276
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French (fr)
Japanese (ja)
Inventor
Tomohiro Toyoda
Masashi Tanaka
Nao Fujibayashi
Megumi Maruyama
Ikutaro Saji
Fujio Antoku
Masayuki Muto
Mayumi Oda
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Dainippon Sumitomo Pharma Co., Ltd.
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Publication of WO2008047839A1 publication Critical patent/WO2008047839A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/46—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C215/48—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C217/74—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with rings other than six-membered aromatic rings being part of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/58—[b]- or [c]-condensed
    • C07D209/72—4,7-Endo-alkylene-iso-indoles
    • C07D209/76—4,7-Endo-alkylene-iso-indoles with oxygen atoms in positions 1 and 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/06—Peri-condensed systems

Definitions

  • the present invention includes an amino compound having a cyclic imide skeleton, a tetrahydronaphthalene skeleton, a tetrahydrodiazabenzazulenone skeleton, or a phenylpyridyl skeleton, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Receptor agonist serotonin 1A agonist
  • G Specifically, it relates to a therapeutic or prophylactic agent for anxiety, depression, Parkinson's disease, or schizophrenia.
  • 5-HT receptor a subtype of 5-HT receptor, is localized in the cell body
  • statin 1 A body agonists are generally used as anxiolytics, and typical examples include tandospirone citrate having a cyclic imide skeleton (see Patent Document 1, etc.).
  • Patent Document 3 International Publication No. 98/011068 Pamphlet
  • Non-Patent Document 1 Bioorganic & Medicinal Chemistry Letters 9 (1999) 2167-2172 Disclosure of Invention
  • the subject of the present invention is useful as a therapeutic or prophylactic agent for anxiety disorders, mood disorders such as depression, psychotic disorders such as schizophrenia, developmental disorders, or motor disorders such as Parkinson's disease.
  • HT receptor agonist serotonin 1A agonist
  • an amino compound having a cyclic imide skeleton, a tetrahydronaphthalene skeleton, a tetrahydrodiazabenzazolenen skeleton, or a phenylpyridyl skeleton or a pharmaceutically acceptable salt thereof is a 5-HT receptor agonist. Functions as a serotonin 1A agonist
  • R 1 represents a hydrogen atom or a methyl group
  • R 2 and R 3 both represent a hydrogen atom
  • R 2 and R 3 combine to represent a methylene group.
  • R 4 represents a hydrogen atom or a methyl group. Or a pharmaceutically acceptable salt thereof;
  • a therapeutic agent for anxiety, depression, Parkinson's disease, or schizophrenia comprising the compound of any one of [1] to [5] or any of the above or a pharmaceutically acceptable salt thereof as an active ingredient Or preventive drugs;
  • a 5-HT receptor agonist comprising an amino compound having a cyclic imide skeleton, a tetrahydronaphthalene skeleton, a tetrahydrodiazabenzoazulenone skeleton, or a phenylpyridyl skeleton, or a pharmaceutically acceptable salt thereof.
  • a 5-HT receptor agonist comprising an amino compound having a cyclic imide skeleton, a tetrahydronaphthalene skeleton, a tetrahydrodiazabenzoazulenone skeleton, or a phenylpyridyl skeleton, or a pharmaceutically acceptable salt thereof.
  • the 5-HT receptor agonist (serotonin 1A agonist) of the present invention is
  • Parkinson's disease Applicable to patients with disabilities, mood disorders such as depression, psychotic disorders such as schizophrenia, developmental disorders, or movement disorders such as Parkinson's disease.
  • the compounds of the present invention represented by the general formula (1) are the compounds shown in Examples 1 to 4, and can be produced by, for example, the methods described in Examples 1 to 4.
  • the compound of the present invention represented by the general formula (2) is the compound shown in Example 5, and can be produced, for example, by the method described in Example 5.
  • the compounds of the present invention represented by the general formula (3) are the compounds shown in Examples 6 to 7, and can be produced by, for example, the methods described in Examples 6 to 7.
  • the compound of the present invention represented by the general formula (4) is the compound shown in Example 8, and can be produced, for example, by the method described in Example 8.
  • the compound of the present invention represented by the general formula (5) is the compound shown in Example 9, and can be produced, for example, by the method described in Example 9.
  • the raw material compounds used in the production methods described in the examples can be appropriately prepared by using commercially available products or using methods known to those skilled in the art.
  • the compound of the present invention can be converted into a pharmaceutically acceptable inorganic acid or organic acid addition salt or alkali addition salt as necessary.
  • acid addition salt for example, salts with inorganic acids such as hydrochloride, hydrobromide, sulfate, phosphate, formate, acetate, fumarate, maleate, oxalate, kenate, Salts with organic carboxylic acids such as malate, tartaric acid, aspartate, glutamate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, hydroxybenzenesulfonate, dihydroxybenzenesulfonate
  • salt with sulfonic acid such as ammonium salt include ammonium salt, lithium salt, sodium salt, potassium salt, calcium salt, magnesium salt and the like.
  • the present invention also includes solvates such as hydrates and ethanol hydrates of the compounds of the present invention or pharmaceutically acceptable salts thereof.
  • the present invention includes stereoisomers such as all optical isomers of the compound of the present invention, and crystal forms of all embodiments. These can be appropriately purified using methods such as silica gel column chromatography, HPLC, ion exchange chromatography, and recrystallization well known to those skilled in the art. In order to obtain the optical isomer purely, an optical resolution method known to those skilled in the art may be used. Specifically, when the compound of the present invention or an intermediate thereof has a basic functional group such as an amino group, an optically active acid (for example, mandelic acid, N-benzyloxylanine) in an inert solvent.
  • an optically active acid for example, mandelic acid, N-benzyloxylanine
  • Lactic acid and other monostrengths such as rubonic acids, tartaric acid, o-diisopropylidenetartaric acid, dicarboxylic acids such as malic acid, and sulfonic acids such as camphorsulfonic acid).
  • the intermediate of the compound of the present invention has an acidic functional group such as a carboxyl group, it forms a salt with optically active organic amines (for example, ⁇ -phenethylamine, cun, quinidine, cinchonidine, cinchonine, strychnine, etc.).
  • optically active organic amines for example, ⁇ -phenethylamine, cun, quinidine, cinchonidine, cinchonine, strychnine, etc.
  • the temperature at which the salt is formed include the range of the boiling point of the room temperature solvent.
  • An amino compound having a cyclic imide skeleton, a tetrahydronaphthalene skeleton, a tetrahydrodiazabenzazulenone skeleton, or a phenylpyridyl skeleton of the present invention, or a pharmaceutically acceptable salt thereof, is a 5- ⁇ ⁇ receptor agonist (serotonin 1A Anagonist) as an anxiety disorder
  • the therapeutic agent or preventive agent can be used as a therapeutic or preventive agent for mood disorders such as psychiatric disorders such as schizophrenia, developmental disorders, or movement disorders such as Parkinson's disease.
  • the therapeutic agent or preventive agent is an ordinary pharmaceutically acceptable carrier, binder, stabilizer, excipient, diluent, pH Capable of adding various formulation ingredients such as buffers, disintegrants, solubilizers, solubilizers, and isotonic agents.
  • These therapeutic agents or preventive agents can be administered orally or parenterally. That is, orally, it can be administered orally in a commonly used dosage form such as tablets, pills, powders, granules, capsules, syrups, emulsions and suspensions.
  • preparations in the form of intravenous injection instillation
  • intramuscular injection subcutaneous injection
  • coating agent for example, suppository
  • transdermal agent for example, nasal drop, eye drop, eye ointment, etc.
  • Solid preparations such as tablets contain active ingredients as usual pharmacologically acceptable carriers or excipients such as lactose, sucrose and corn starch, binders such as hydroxypropyl cellulose, polypyrrolopyrrolidone, hydroxypropylmethylcellulose, It is prepared by mixing with a disintegrant such as sodium carboxymethyl cellulose or sodium starch glycolate, a lubricant such as stearic acid or magnesium stearate, or a preservative.
  • active ingredients as usual pharmacologically acceptable carriers or excipients such as lactose, sucrose and corn starch, binders such as hydroxypropyl cellulose, polypyrrolopyrrolidone, hydroxypropylmethylcellulose, It is prepared by mixing with a disintegrant such as sodium carboxymethyl cellulose or sodium starch glycolate, a lubricant such as stearic acid or magnesium stearate, or a preservative.
  • the active ingredient is dissolved or suspended in a physiologically acceptable carrier such as water, saline, oil, aqueous dextrose, etc., and this may be used as an emulsifier, stabilizer, osmotic pressure adjusting salt. Or you may contain a buffering agent as needed.
  • Additives for eye drops include isotonic agents such as glycerin and sodium chloride, buffering agents such as phosphoric acid and citrate, pH regulators such as hydrochloric acid and sodium hydroxide, and hydroxypropylmethylcellulose and poly (bull alcohol). A preservative such as a sticking agent, benzethonium chloride, or a solubilizing agent may be contained as necessary.
  • the eye ointment additive include petrolatum, polyethylene glycol, purified lanolin, and liquid paraffin.
  • the dose and frequency of administration vary depending on the administration method and the age, weight, medical condition, etc. of the patient, but a method of local administration to the bed part is preferred.
  • Dosage can be several tens of g to 2 g, preferably 1 to several hundred mg, more preferably tens of mg or less as the amount of active ingredient per adult patient, and can be used once or several times a day. It can be administered separately. For parenteral administration, doses of 0.;! To l OOmg / day, more preferably 0.3 to 50 mg / day per adult patient, include once or several times a day Can be administered separately. Sustained-release preparations can be used to reduce the number of administrations.
  • Example 1 47% hydrobromic acid was added to 11 (8 methoxy-1, 2, 3, 4 tetrahydronaphthalene 2 yl) piperazine (16.1 g, 65 mmol) obtained by the method of [1]. In addition, the mixture was stirred under reflux. The solvent was distilled off under reduced pressure, and the resulting solid was recrystallized from methanol to give 21.4 g of 1 (8 hydroxy 1, 2, 3, 4 tetrahydronaphthalene-2-inole) piperazine dihydrobromide Salt was obtained. Yield 84%. Melting point 280 ° C or higher.
  • Acetonitrile solution (4.0 mL) of 3- (4 fluorophenyl) 5- (2 methoxyvininole) pyridine (200.0 mg, 0.876 mmol) was prepared, and 2N hydrochloric acid (4 mL) was added.
  • the reaction mixture was stirred at 50 ° C. for 1 hour and diluted with water and ethyl acetate.
  • the mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate.
  • buffer B containing each test substance 10- 5 M (20mM HEPES, 100 mM NaCl, 10 mM MgSO, 1 M GDP, 0.1 mM DTT) in, the 0.05 nM [3] GTP ⁇ S ( de
  • 1A agonist activity was expressed as the rate of increase (5-HT receptor agonist activity) when the increase in [ 3 ] GTP y S binding by 10 and 1 M serotonin (5-HT) was 100%.
  • the tolerated salt can be used as a therapeutic or prophylactic agent for anxiety disorders, mood disorders such as depression, psychotic disorders such as schizophrenia, developmental disorders, or movement disorders such as Parkinson's disease.

Abstract

Disclosed is a compound represented by the formula (1) or a pharmaceutically acceptable salt thereof, which can act as a 5-HT1A receptor agonist (serotonin 1A agonist) and is useful as a therapeutic or prophylactic agent for a mood disorder such as anxiety disorder and depression, a psychotic disorder such as schizophrenia, a developmental disorder or a movement disorder such as Parkinson's disease. Also disclosed is a 5-HT1A receptor agonist comprising the compound or the pharmaceutically acceptable salt thereof as an active ingredient. (1) wherein R1 represents a hydrogen atom or amethyl group; and R2 and R3 independently represent a hydrogen atom, or R2 and R3 may together form a methylene group.

Description

明 細 書  Specification
5-HT 受容体作動薬  5-HT receptor agonist
1A  1A
技術分野  Technical field
[0001] 本発明は、環状イミド骨格、テトラヒドロナフタレン骨格、テトラヒドロジァザべンゾァ ズレノン骨格、又はフエニルピリジル骨格を有するァミノ化合物又はその薬学的に許 容される塩を有効成分として含有する 5— HT 受容体作動薬 (セロトニン 1Aァゴニス  [0001] The present invention includes an amino compound having a cyclic imide skeleton, a tetrahydronaphthalene skeleton, a tetrahydrodiazabenzazulenone skeleton, or a phenylpyridyl skeleton, or a pharmaceutically acceptable salt thereof as an active ingredient. Receptor agonist (serotonin 1A agonist)
1A  1A
ト）に関する。具体的には、不安、うつ、パーキンソン病、又は統合失調症の治療薬又 は予防薬に関する。  G). Specifically, it relates to a therapeutic or prophylactic agent for anxiety, depression, Parkinson's disease, or schizophrenia.
背景技術  Background art
[0002] 5— HT受容体のサブタイプの一つである 5— HT 受容体は、細胞体に局在する  [0002] 5-HT receptor, a subtype of 5-HT receptor, is localized in the cell body
1 1A  1 1A
シナプス自己受容体で、セロトニン神経活動を抑制し、振戦や異常運動などの行動 変化、いわゆるセロトニン症候群に関連していることが知られている。 5-HT 受容  It is known to be a synaptic autoreceptor that inhibits serotonergic activity and is related to behavioral changes such as tremor and abnormal movement, so-called serotonin syndrome. 5-HT acceptance
1A 体作動薬 (セロトニン 1 Aァゴニスト）は一般に抗不安薬として用いられており、代表的 な薬剤としては例えば、環状イミド骨格を有するクェン酸タンドスピロン等が挙げられ る (特許文献 1等参照)。  1A body agonists (serotonin 1 A agonist) are generally used as anxiolytics, and typical examples include tandospirone citrate having a cyclic imide skeleton (see Patent Document 1, etc.).
(R)— 2—アミノー 5—メトキシテトラリン誘導体がドーパミン D2A受容体のアンタゴ 二ストやインバースァゴニストとして作用することが報告されている力 3—フエニルプ 口ピルアミノ基を側鎖に有するテトラヒドロナフタレン誘導体につ!/、ては開示されてレヽ ない (非特許文献 1参照)。  (R) —The ability of 2-amino-5-methoxytetralin derivatives to act as antagonists and inverse agonists of dopamine D2A receptors. To the tetrahydronaphthalene derivatives having 3-phenylpropyl pyramino groups in the side chain. It has not been disclosed (see Non-Patent Document 1).
国際出願 PCT国際公開第 90/015058号には、中枢神経系活性を有する三環 式窒素原子含有化合物が開示されている力 テトラヒドロジァザベンゾァズレノン骨 格を有するァミノ化合物にっレ、ては開示されて!/、な!/、（特許文献 2参照）。  In the international application PCT International Publication No. 90/015058, a tricyclic nitrogen atom-containing compound having a central nervous system activity is disclosed. An amino compound having a tetrahydrodiazabenzazulenone skeleton is disclosed. Is disclosed! /, NA! / (See Patent Document 2).
また国際出願 PCT国際公開第 98/011068号には、ドーパミン D4受容体の選択 的リガンドであるピぺラジン誘導体が報告されている力 フエニルピリジル基とのリンカ 一としてエチレン鎖を有する誘導体につ!/、ては開示されて!/、な!/、（特許文献 3参照） 特許文献 1：特開昭 58 - 126865 特許文献 2 :国際公開第 90/015058号パンフレット In addition, in international application PCT WO 98/011068, piperazine derivatives, which are selective ligands for the dopamine D4 receptor, have been reported. Derivatives having an ethylene chain as a linker with the phenylpyridyl group! / It is disclosed! /, NA! /, (See Patent Document 3) Patent Document 1: JP-A-58-126865 Patent Document 2: International Publication No. 90/015058 Pamphlet
特許文献 3 :国際公開第 98/011068号パンフレット  Patent Document 3: International Publication No. 98/011068 Pamphlet
非特許文献 1 : Bioorganic & Medicinal Chemistry Letters 9 (1999) 2167-2172 発明の開示  Non-Patent Document 1: Bioorganic & Medicinal Chemistry Letters 9 (1999) 2167-2172 Disclosure of Invention
発明が解決しょうとする課題  Problems to be solved by the invention
[0003] 本発明の課題は、不安障害、うつ等の気分障害、統合失調症等の精神病性障害、 発達障害、又はパーキンソン病等の運動障害の治療薬又は予防薬として有用である 新規な 5— HT 受容体作動薬 (セロトニン 1Aァゴニスト)を提供することにある。 The subject of the present invention is useful as a therapeutic or prophylactic agent for anxiety disorders, mood disorders such as depression, psychotic disorders such as schizophrenia, developmental disorders, or motor disorders such as Parkinson's disease. — To provide an HT receptor agonist (serotonin 1A agonist).
1A  1A
課題を解決するための手段  Means for solving the problem
[0004] 本発明者らは、環状イミド骨格、テトラヒドロナフタレン骨格、テトラヒドロジァザベン ゾァズレノン骨格、又はフエニルピリジル骨格を有するァミノ化合物又はその薬学的 に許容される塩が、 5 -HT 受容体作動薬 (セロトニン 1Aァゴニスト）として機能する [0004] The present inventors have found that an amino compound having a cyclic imide skeleton, a tetrahydronaphthalene skeleton, a tetrahydrodiazabenzazolenen skeleton, or a phenylpyridyl skeleton or a pharmaceutically acceptable salt thereof is a 5-HT receptor agonist. Functions as a serotonin 1A agonist
1A  1A
ことを見出した。  I found out.
即ち本発明は、  That is, the present invention
〔1〕式 (1 ) :  (1) Formula (1):
Figure imgf000004_0001
Figure imgf000004_0001
[式中、 R1は、水素原子又はメチル基を表し、 R2及び R3は、ともに水素原子を表すか 、あるいは R2及び R3は結合して、メチレン基を表す。 ] [Wherein, R 1 represents a hydrogen atom or a methyl group, and R 2 and R 3 both represent a hydrogen atom, or R 2 and R 3 combine to represent a methylene group. ]
で表される化合物、又はその薬学的に許容される塩；  Or a pharmaceutically acceptable salt thereof;
〔2〕式 (2) : [0006]
Figure imgf000005_0001
(2) Equation (2): [0006]
Figure imgf000005_0001
で表される化合物、又はその薬学的に許容される塩； 〔3〕式 (3) :  Or a pharmaceutically acceptable salt thereof; [3] Formula (3):
[0007]
Figure imgf000005_0002
[0007]
Figure imgf000005_0002
[式中、 R4は、水素原子又はメチル基を表す。 ] で表される化合物、又はその薬学的に許容される塩;[Wherein, R 4 represents a hydrogen atom or a methyl group. Or a pharmaceutically acceptable salt thereof;
〔4〕式 (4) : (4) Equation (4):
Figure imgf000005_0003
Figure imgf000005_0003
で表される化合物、又はその薬学的に許容される塩; 〔5〕式 (5) :  Or a pharmaceutically acceptable salt thereof; (5) Formula (5):
Figure imgf000005_0004
Figure imgf000005_0004
で表される化合物、又はその薬学的に許容される塩; 〔6〕〔1〕〜〔5〕の!/、ずれかに記載の化合物又はその薬学的に許容される塩を有効成 分として含有する 5— HT 受容体作動薬； Or a pharmaceutically acceptable salt thereof; [6] 5-HT receptor agonist containing as an active ingredient the compound according to [1] to [5] or any one of the above or a pharmaceutically acceptable salt thereof;
1A  1A
〔7〕〔1〕〜〔5〕の!/、ずれかに記載の化合物又はその薬学的に許容される塩を有効成 分として含有する不安、うつ、パーキンソン病、又は統合失調症の治療薬又は予防 薬；  [7] A therapeutic agent for anxiety, depression, Parkinson's disease, or schizophrenia comprising the compound of any one of [1] to [5] or any of the above or a pharmaceutically acceptable salt thereof as an active ingredient Or preventive drugs;
に関する。  About.
発明の効果  The invention's effect
[0010] 本発明により、環状イミド骨格、テトラヒドロナフタレン骨格、テトラヒドロジァザベンゾ ァズレノン骨格、又はフエニルピリジル骨格を有するァミノ化合物又はその薬学的に 許容される塩を含む 5— HT 受容体作動薬 (セロトニン 1Aァゴニスト）が提供される  [0010] According to the present invention, a 5-HT receptor agonist (serotonin) comprising an amino compound having a cyclic imide skeleton, a tetrahydronaphthalene skeleton, a tetrahydrodiazabenzoazulenone skeleton, or a phenylpyridyl skeleton, or a pharmaceutically acceptable salt thereof. 1A agonist)
1A  1A
。本発明の 5— HT 受容体作動薬 (セロトニン 1Aァゴニスト）は、具体的には、不安  . The 5-HT receptor agonist (serotonin 1A agonist) of the present invention is
1A  1A
障害、うつ等の気分障害、統合失調症等の精神病性障害、発達障害、又はパーキン ソン病等の運動障害等の患者に適用可能である。  Applicable to patients with disabilities, mood disorders such as depression, psychotic disorders such as schizophrenia, developmental disorders, or movement disorders such as Parkinson's disease.
発明を実施するための最良の形態  BEST MODE FOR CARRYING OUT THE INVENTION
[0011] 一般式（1)で表される本発明化合物は、実施例 1〜4に示した化合物であり、例え ば実施例 1〜4に記した方法によって製造することができる。 The compounds of the present invention represented by the general formula (1) are the compounds shown in Examples 1 to 4, and can be produced by, for example, the methods described in Examples 1 to 4.
一般式（2)で表される本発明化合物は、実施例 5に示した化合物であり、例えば実 施例 5に記した方法によって製造することができる。  The compound of the present invention represented by the general formula (2) is the compound shown in Example 5, and can be produced, for example, by the method described in Example 5.
一般式（3)で表される本発明化合物は、実施例 6〜7に示した化合物であり、例え ば実施例 6〜7に記した方法によって製造することができる。  The compounds of the present invention represented by the general formula (3) are the compounds shown in Examples 6 to 7, and can be produced by, for example, the methods described in Examples 6 to 7.
一般式 (4)で表される本発明化合物は、実施例 8に示した化合物であり、例えば実 施例 8に記した方法によって製造することができる。  The compound of the present invention represented by the general formula (4) is the compound shown in Example 8, and can be produced, for example, by the method described in Example 8.
一般式（5)で表される本発明化合物は、実施例 9に示した化合物であり、例えば実 施例 9に記した方法によって製造することができる。  The compound of the present invention represented by the general formula (5) is the compound shown in Example 9, and can be produced, for example, by the method described in Example 9.
実施例に記した製造方法において用いられる原料化合物は、市販品を用いるか、 当業者に公知の方法を用いることにより、適宜調製することができる。  The raw material compounds used in the production methods described in the examples can be appropriately prepared by using commercially available products or using methods known to those skilled in the art.
[0012] また、本発明化合物は、必要に応じて医薬として薬学的に許容される無機酸もしく は有機酸との酸付加塩、又はアルカリ付加塩とすることができる。当該酸付加塩とし ては、例えば、塩酸塩、臭化水素酸塩、硫酸塩、リン酸塩等の無機酸との塩、ギ酸塩 、酢酸塩、フマル酸塩、マレイン酸塩、シユウ酸塩、クェン酸塩、リンゴ酸塩、酒石酸 塩、ァスパラギン酸塩、グルタミン酸塩等の有機カルボン酸との塩、メタンスルホン酸 塩、ベンゼンスルホン酸塩、 p—トルエンスルホン酸塩、ヒドロキシベンゼンスルホン酸 塩、ジヒドロキシベンゼンスルホン酸塩等のスルホン酸との塩力 また当該アルカリ付 加塩としては、アンモニゥム塩、リチウム塩、ナトリウム塩、カリウム塩、カルシウム塩、 マグネシウム塩等が挙げられる。 In addition, the compound of the present invention can be converted into a pharmaceutically acceptable inorganic acid or organic acid addition salt or alkali addition salt as necessary. As the acid addition salt For example, salts with inorganic acids such as hydrochloride, hydrobromide, sulfate, phosphate, formate, acetate, fumarate, maleate, oxalate, kenate, Salts with organic carboxylic acids such as malate, tartaric acid, aspartate, glutamate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, hydroxybenzenesulfonate, dihydroxybenzenesulfonate Examples of the salt with sulfonic acid such as ammonium salt include ammonium salt, lithium salt, sodium salt, potassium salt, calcium salt, magnesium salt and the like.
また、本発明には、本発明化合物又はその薬学的に許容される塩の水和物、エタ ノール和物等の溶媒和物も含まれる。  The present invention also includes solvates such as hydrates and ethanol hydrates of the compounds of the present invention or pharmaceutically acceptable salts thereof.
さらに、本発明には、本発明化合物のあらゆる光学異性体などの立体異性体、及 びあらゆる態様の結晶形のものも包含されている。これらは、当業者に良く知られて いるシリカゲルカラムクロマトグラフィー、 HPLC、イオン交換クロマトグラフィー、再結 晶等の方法を用いて、適宜精製すること力 Sできる。当該光学異性体を純粋に得るた めには、当業者に公知の光学分割法を用いればよい。具体的には、本発明化合物 もしくはその中間体がアミノ基等の塩基性官能基を有する場合には、不活性溶媒中 、光学活性な酸（例えば、マンデル酸、 N—べンジルォキシァラニン、乳酸等のモノ力 ルボン酸類、酒石酸、 o—ジイソプロピリデン酒石酸、リンゴ酸等のジカルボン酸類、 カンファースルホン酸等のスルホン酸類）と塩を形成させること力 Sできる。また本発明 化合物の中間体がカルボキシル基等の酸性官能基を有する場合には、光学活性な 有機アミン類（例えば、 α—フエネチルァミン、キュン、キニジン、シンコニジン、シン コニン、ストリキニーネ等）と塩を形成させることができる。塩を形成させる温度としては 、室温力 溶媒の沸点の範囲が挙げられる。  Furthermore, the present invention includes stereoisomers such as all optical isomers of the compound of the present invention, and crystal forms of all embodiments. These can be appropriately purified using methods such as silica gel column chromatography, HPLC, ion exchange chromatography, and recrystallization well known to those skilled in the art. In order to obtain the optical isomer purely, an optical resolution method known to those skilled in the art may be used. Specifically, when the compound of the present invention or an intermediate thereof has a basic functional group such as an amino group, an optically active acid (for example, mandelic acid, N-benzyloxylanine) in an inert solvent. , Lactic acid and other monostrengths such as rubonic acids, tartaric acid, o-diisopropylidenetartaric acid, dicarboxylic acids such as malic acid, and sulfonic acids such as camphorsulfonic acid). Further, when the intermediate of the compound of the present invention has an acidic functional group such as a carboxyl group, it forms a salt with optically active organic amines (for example, α-phenethylamine, cun, quinidine, cinchonidine, cinchonine, strychnine, etc.). Can be made. Examples of the temperature at which the salt is formed include the range of the boiling point of the room temperature solvent.
本発明の、環状イミド骨格、テトラヒドロナフタレン骨格、テトラヒドロジァザべンゾァ ズレノン骨格、又はフエニルピリジル骨格を有するァミノ化合物又はその薬学的に許 容される塩は、 5 -ΗΤ 受容体作動薬 (セロトニン 1Aァゴニスト）として、不安障害、う  An amino compound having a cyclic imide skeleton, a tetrahydronaphthalene skeleton, a tetrahydrodiazabenzazulenone skeleton, or a phenylpyridyl skeleton of the present invention, or a pharmaceutically acceptable salt thereof, is a 5- 作 動 receptor agonist (serotonin 1A Anagonist) as an anxiety disorder
1A  1A
つ等の気分障害、統合失調症等の精神病性障害、発達障害、又はパーキンソン病 等の運動障害等に対する治療剤又は予防剤として使用できる。当該治療剤又は予 防剤は、薬学的に許容される通常の担体、結合剤、安定化剤、賦形剤、希釈剤、 pH 緩衝剤、崩壊剤、可溶化剤、溶解補助剤、等張剤などの各種調剤用配合成分を添 カロすること力 Sできる。またこれら治療剤又は予防剤は、経口的又は非経口的に投与 すること力 Sできる。すなわち経口的には、通常用いられる投与形態、例えば錠剤、丸 剤、粉末、顆粒、カプセル剤、シロップ剤、乳剤、懸濁液等の剤型で経口的に投与す ること力 Sできる。非経口的には、例えば、静脈内注射 (点滴剤)、筋注射剤、皮下注射 剤、塗布剤、座剤、経皮剤、点鼻剤、点眼剤、眼軟膏剤等の形態の製剤とすることが できる。 It can be used as a therapeutic or preventive agent for mood disorders such as psychiatric disorders such as schizophrenia, developmental disorders, or movement disorders such as Parkinson's disease. The therapeutic agent or preventive agent is an ordinary pharmaceutically acceptable carrier, binder, stabilizer, excipient, diluent, pH Capable of adding various formulation ingredients such as buffers, disintegrants, solubilizers, solubilizers, and isotonic agents. These therapeutic agents or preventive agents can be administered orally or parenterally. That is, orally, it can be administered orally in a commonly used dosage form such as tablets, pills, powders, granules, capsules, syrups, emulsions and suspensions. For parenteral use, for example, preparations in the form of intravenous injection (instillation), intramuscular injection, subcutaneous injection, coating agent, suppository, transdermal agent, nasal drop, eye drop, eye ointment, etc. can do.
錠剤のような固体製剤は有効成分を、乳糖、ショ糖、トウモロコシ澱粉などの通常の 薬理的に許容し得る担体又は賦形剤、ヒドロキシプロピルセルロース、ポリビュルピロ リドン、ヒドロキシプルピルメチルセルロースなどの結合剤、カルボキシメチルセルロー スナトリウムや澱粉グリコール酸ナトリウムなどの崩壊剤、ステアリン酸やステアリン酸 マグネシウムなどの滑沢剤、あるいは保存剤等と混合して調製される。  Solid preparations such as tablets contain active ingredients as usual pharmacologically acceptable carriers or excipients such as lactose, sucrose and corn starch, binders such as hydroxypropyl cellulose, polypyrrolopyrrolidone, hydroxypropylmethylcellulose, It is prepared by mixing with a disintegrant such as sodium carboxymethyl cellulose or sodium starch glycolate, a lubricant such as stearic acid or magnesium stearate, or a preservative.
非経口投与には、有効成分は水、生理食塩水、油、ブドウ糖水溶液などの生理的 に許容し得る担体に溶解又は懸濁し、これは補助剤として乳化剤、安定化剤、浸透 圧調整用塩、又は緩衝剤を必要に応じて含有してもよい。点眼剤の添加物としては、 グリセリンや塩化ナトリウムなどの等張化剤、リン酸やクェン酸などの緩衝剤、塩酸や 水酸化ナトリウムなどの pH調節剤、ヒドロキシプルピルメチルセルロースやポリビュル アルコールなどの増粘剤、塩化べンゼトニゥムなどの保存剤、あるいは可溶化剤を必 要に応じて含有してもよい。また、眼軟膏剤の添加剤としては、ワセリン、ポリエチレン グリコール、精製ラノリン、流動パラフィン等が例示される。  For parenteral administration, the active ingredient is dissolved or suspended in a physiologically acceptable carrier such as water, saline, oil, aqueous dextrose, etc., and this may be used as an emulsifier, stabilizer, osmotic pressure adjusting salt. Or you may contain a buffering agent as needed. Additives for eye drops include isotonic agents such as glycerin and sodium chloride, buffering agents such as phosphoric acid and citrate, pH regulators such as hydrochloric acid and sodium hydroxide, and hydroxypropylmethylcellulose and poly (bull alcohol). A preservative such as a sticking agent, benzethonium chloride, or a solubilizing agent may be contained as necessary. Examples of the eye ointment additive include petrolatum, polyethylene glycol, purified lanolin, and liquid paraffin.
投与量及び投与回数は、投与法と患者の年齢、体重、病状等によって異なるが、 病床部位に局所的に投与する方法が好ましい。また、一日あたり一回又は二回以上 投与することが好ましレ、。二回以上投与するときは連日あるレ、は適当な間隔をおレ、て 繰り返し投与することが望ましレ、。  The dose and frequency of administration vary depending on the administration method and the age, weight, medical condition, etc. of the patient, but a method of local administration to the bed part is preferred. In addition, it is preferable to administer once or twice a day. If it is administered more than once, it should be repeated every day, and should be repeated at appropriate intervals.
投与量は、成人患者一人一回当たり有効成分の量として数十 g〜2g、好ましくは 1〜数百 mg、更に好ましくは数十 mg以下を用いることができ、一日一回又は数回に わけて投与すること力できる。非経口投与では、成人患者一人あたり 0. ；!〜 l OOmg /日、さらに好ましくは 0. 3〜50mg/日の投与量が挙げられ、一日一回又は数回 に分けて投与すること力できる。投与回数を減らすために徐放性製剤を用いることも できる。 Dosage can be several tens of g to 2 g, preferably 1 to several hundred mg, more preferably tens of mg or less as the amount of active ingredient per adult patient, and can be used once or several times a day. It can be administered separately. For parenteral administration, doses of 0.;! To l OOmg / day, more preferably 0.3 to 50 mg / day per adult patient, include once or several times a day Can be administered separately. Sustained-release preparations can be used to reduce the number of administrations.
[0015] 以下、実施例および試験例により本発明をさらに詳細に説明するが、本発明の技 術的範囲はこれら実施例に限定されるものではない。  [0015] Hereinafter, the present invention will be described in more detail with reference to Examples and Test Examples, but the technical scope of the present invention is not limited to these Examples.
実施例 1  Example 1
[0016] 2—{4 [4 （8 メトキシ 1 , 2, 3, 4 テトラヒドロナフタレンー2 ィノレ）ピペラジ ン 1 ィル]ブチル }へキサヒドロイソインドールー 1 , 3 ジオン · 2塩酸塩  [0016] 2— {4 [4 (8 Methoxy 1, 2, 3, 4 tetrahydronaphthalene-2-inole) piperazine 1-yl] butyl} hexahydroisoindole 1,3 dione dihydrochloride
[0017] 〔1〕1一（8 メトキシー 1 , 2, 3, 4 テトラヒドロナフタレン 2 ィノレ）ピぺラジン [0017] [1] 1 (8 Methoxy-1, 2, 3, 4 Tetrahydronaphthalene 2 Inole) Piperazine
Figure imgf000009_0001
Figure imgf000009_0001
P. A. Robinsらの方法（J. Chem. So 、 1958年、 409— 421頁に記載）により合成さ れた 8 メトキシ一 2 テトラロン（5.00 g、 0.03 mol)、をベンゼン（125 mL)に溶解し、 ピぺラジン（7.87 g、 0.09 mmol)およびパラトルエンスルホン酸 · 1水和物（0.57 g、 0.0 03 mmol)を加え、ディーンシュターク型脱水装置を用いて、 10時間加熱還流した。 室温に戻した後、減圧下溶媒を留去し、残渣にエタノール（125 mL)を加えた。この 懸濁液中に水素化シァノホウ素ナトリウム（4.5 g、 0.072 mol)を加え、 4時間半加熱還 流した。室温に戻した後、不溶物を濾別し、濾液を減圧下濃縮した。得られた残渣に クロ口ホルム（400 mL)を加え、水で洗浄（200 mL X 2回）した後、無水硫酸マグネシ ゥムで乾燥し、濾過後、減圧下で溶媒を留去した。得られた残渣をシリカゲルカラムク 口マトグラフィ一で精製して、 4.2 gの 1— (8 メトキシ一 1 , 2, 3, 4 テトラヒドロナフ タレン一 2 ィル)ピぺラジンを得た。収率 64%。  8 methoxy-12 tetralone (5.00 g, 0.03 mol) synthesized by the method of PA Robins et al. (J. Chem. So, 1958, described on pages 409-421) was dissolved in benzene (125 mL). Piperazine (7.87 g, 0.09 mmol) and paratoluenesulfonic acid monohydrate (0.57 g, 0.0 03 mmol) were added, and the mixture was heated to reflux for 10 hours using a Dean-Stark type dehydrator. After returning to room temperature, the solvent was distilled off under reduced pressure, and ethanol (125 mL) was added to the residue. Sodium cyanoborohydride (4.5 g, 0.072 mol) was added to this suspension, and the mixture was heated to reflux for 4 and a half hours. After returning to room temperature, insoluble matters were filtered off, and the filtrate was concentrated under reduced pressure. To the resulting residue was added black mouth form (400 mL), washed with water (2 × 200 mL), dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 4.2 g of 1- (8 methoxy-1,2,3,4, tetrahydronaphthalene-2-yl) piperazine. Yield 64%.
:H NMR (CDCl ): δ 1.50-1.67 (1Η， m)， 1.78—1.90 (1Η， m)， 2.05-2.20 (1Η， m)， 2.4 : H NMR (CDCl): δ 1.50-1.67 (1Η, m), 1.78—1.90 (1Η, m), 2.05-2.20 (1Η, m), 2.4
0-3.10 (13Η， m)， 3.81 (3Η， s)， 6.68 (2Η， m)， 7.08 (1Η， t). 0-3.10 (13mm, m), 3.81 (3mm, s), 6.68 (2mm, m), 7.08 (1mm, t).
[0019] 〔2〕2— {4— [4— (8 メトキシ一 1 , 2, 3, 4 テトラヒドロナフタレン一 2 ィノレ）ピぺ ラジン 1 ィル]ブチル }へキサヒドロイソインドールー 1 , 3—ジオン · 2塩酸塩
Figure imgf000010_0001
[0019] [2] 2— {4— [4— (8-methoxy-1,2,3,4-tetrahydronaphthalene-2-inole) piperazine-1-yl] butyl} hexahydroisoindole-1,3- Dione dihydrochloride
Figure imgf000010_0001
1一（8 メトキシー 1 , 2, 3, 4 テトラヒドロナフタレン 2—ィノレ）ピぺラジン（1.50 g、 6.1 mmol)をジメチルホルムアミド（DMF、 15 mL)に溶解し、 2—（4ーブロモブチノレ )へキサヒドロイソインドールー 1 , 3 ジオン (石墨ら、特開昭 60-087262に記載） (1.8 7 g、 6.5 mmol)、炭酸カリウム、および触媒量のヨウ化カリウムを加え、 90〜100°Cに加 熱撹拌した。得られた残渣に水（100 mL)を加え、酢酸ェチルにて抽出した（100 mL X 2回）。有機層を合わせて、水（100 mL)で洗浄後、無水硫酸マグネシウムで乾燥し 、濾過後、減圧下で溶媒を留去した。得られた固体をイソプロピルアルコールより再 結晶し、 2— {4— [4— (8 メトキシ一 1 , 2, 3, 4 テトラヒドロナフタレン一 2 ィル） ピぺラジン 1 ィル]ブチル }へキサヒドロイソインドールー 1 , 3—ジオンを得た。 更に、これを塩化水素のイソプロピルアルコール溶液を用いて塩酸塩化して、 1.12 gの表題化合物を得た。収率 35%。  1 (8 methoxy-1,2,3,4) tetrahydronaphthalene-2-inole) piperazine (1.50 g, 6.1 mmol) is dissolved in dimethylformamide (DMF, 15 mL) and 2- (4-bromobutinole) hexahydro Add isoindole 1,3 dione (described in Graphite et al., JP 60-087262) (1.87 g, 6.5 mmol), potassium carbonate, and catalytic amount of potassium iodide, and heat to 90-100 ° C. Stir. Water (100 mL) was added to the obtained residue, and the mixture was extracted with ethyl acetate (100 mL X 2 times). The organic layers were combined, washed with water (100 mL), dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The resulting solid was recrystallized from isopropyl alcohol to give 2— {4— [4— (8 methoxy-1,2,3,4, tetrahydronaphthalene-1,2 yl) piperazine 1 yl] butyl} hexahydro Isoindole-1,3-dione was obtained. This was further converted to hydrochloric acid using an isopropyl alcohol solution of hydrogen chloride to obtain 1.12 g of the title compound. Yield 35%.
:H NMR (CDCl ): δ 1.39-1.50 (4Η， m)， 1.53-1.80 (6Η， m)， 1.82-1.97 (4Η， m)， 2.5 : H NMR (CDCl): δ 1.39-1.50 (4Η, m), 1.53-1.80 (6Η, m), 1.82-1.97 (4Η, m), 2.5
3 (1Η， br.)， 2.80-3.06 (5Η， m)， 3.15-3.24 (2Η， m)， 3.37 (1Η， dd， J=3.5 and 16.0 Hz )， 3.48-3.70 (7H， m)， 3.81 (3H， s)， 4.10-4.24 (2H， m)， 6.68 (1H， d， J=7.3 Hz), 6.71 (1H， d， J=7.0 Hz), 7.15 (1H， t， J=7.8 Hz), 13.52 (1H， br.). 3 (1Η, br.), 2.80-3.06 (5Η, m), 3.15-3.24 (2Η, m), 3.37 (1Η, dd, J = 3.5 and 16.0 Hz), 3.48-3.70 (7H, m), 3.81 (3H, s), 4.10-4.24 (2H, m), 6.68 (1H, d, J = 7.3 Hz), 6.71 (1H, d, J = 7.0 Hz), 7.15 (1H, t, J = 7.8 Hz) , 13.52 (1H, br.).
実施例 2 Example 2
4 {4 [4 （8 メトキシ 1 , 2, 3, 4 テトラヒドロナフタレンー2 ィノレ）ピペラジ ン一 1—ィル]ブチル }— 4 ァザトリシクロ [5· 2. 1. 02'6]デカン一 3, 5 ジオン · 2塩 酸塩 4 {4 [4 (8 Methoxy 1, 2, 3, 4 Tetrahydronaphthalene-2-inole) piperazine 1-yl] butyl} — 4 Azatricyclo [5 2. 1. 0 2 ' 6 ] Decane 3, 5 Dione dihydrochloride
Figure imgf000010_0002
試薬として、 2—（4ーブロモブチル）へキサヒドロイソインドールー 1 , 3 ジオンに換 えて 4— (4 ブロモブチル）一4 ァザトリシクロ [5· 2. 1. 02'6]デカン一 3, 5 ジォ ン (石墨ら、特開昭 62-123179に記載）を用いた以外は実施例 1一〔2〕と同様に合成 し、 1.32 gの表題化合物を得た。収率 40%。
Figure imgf000010_0002
As a reagent, replace 2- (4-bromobutyl) hexahydroisoindole-1,3 dione with 4- (4 bromobutyl) -4-azatricyclo [5 · 2. 1. 0 2 ' 6 ] decane 1,3,5 dio Was synthesized in the same manner as in Example 1 [2] except that 1.32 g of the title compound was obtained. Yield 40%.
:H NMR (CDCl ): δ 1.07 (1Η， d， J=11.6 Hz), 1.26 (1H， d， J=10.8 Hz), 1.35 (2H， d， : H NMR (CDCl): δ 1.07 (1Η, d, J = 11.6 Hz), 1.26 (1H, d, J = 10.8 Hz), 1.35 (2H, d,
J=7.9 Hz), 1.55-1.75 (4H， m)， 1.82—2.02 (4H， m)， 2.53 (1H， br.), 2.69 (4H， d， J=10 • 4 Hz), 2.80-3.08 (3H， m)， 3.19 (2H， m)， 3.36 (1H， dd， J=5.0 and 16.5 Hz), 3.52 (2 H， t， J=6.5 Hz), 3.50-3.70 (5H， m)， 3.81 (3H， s)， 4.10-4.24 (2H， m)， 6.68 (1H， d， J =7.3 Hz), 6.71 (1H， d， J=7.0 Hz), 7.15 (1H， t， J=7.9 Hz), 13.50 (1H， br.). J = 7.9 Hz), 1.55-1.75 (4H, m), 1.82—2.02 (4H, m), 2.53 (1H, br.), 2.69 (4H, d, J = 10 • 4 Hz), 2.80-3.08 ( 3H, m), 3.19 (2H, m), 3.36 (1H, dd, J = 5.0 and 16.5 Hz), 3.52 (2 H, t, J = 6.5 Hz), 3.50-3.70 (5H, m), 3.81 ( 3H, s), 4.10-4.24 (2H, m), 6.68 (1H, d, J = 7.3 Hz), 6.71 (1H, d, J = 7.0 Hz), 7.15 (1H, t, J = 7.9 Hz), 13.50 (1H, br.).
実施例 3  Example 3
[0023] 2—{4 [4 （8 ヒドロキシ 1 , 2, 3, 4 テトラヒドロナフタレンー2 ィノレ）ピペラ ジン 1 ィル]ブチル }へキサヒドロイソインドールー 1 , 3—ジオン  [0023] 2— {4 [4 (8 Hydroxy 1, 2, 3, 4 tetrahydronaphthalene-2-inole) piperazine 1 yl] butyl} hexahydroisoindole 1, 3-dione
[0024] 〔1〕1ー（8—ヒドロキシー1 , 2, 3, 4 テトラヒドロナフタレンー2 ィノレ）ピぺラジン · 2 臭化水素酸塩  [0024] [1] 1- (8-Hydroxy-1, 2, 3, 4 tetrahydronaphthalene-2-inole) piperazine-2 hydrobromide
Figure imgf000011_0001
実施例 1一〔1〕の方法で得られた 1一（8 メトキシー 1 , 2, 3, 4 テトラヒドロナフタ レン 2 ィル）ピぺラジン（16.1 g、 65 mmol)に 47%臭化水素酸を加え、還流下撹 拌した。減圧下溶媒を留去し、得られた固体をメタノールより再結晶して、 21.4 gの 1 一（8 ヒドロキシ 1 , 2, 3, 4 テトラヒドロナフタレンー2 ィノレ）ピぺラジン · 2臭化 水素酸塩を得た。収率 84%。融点 280°C以上。
Figure imgf000011_0001
Example 1 47% hydrobromic acid was added to 11 (8 methoxy-1, 2, 3, 4 tetrahydronaphthalene 2 yl) piperazine (16.1 g, 65 mmol) obtained by the method of [1]. In addition, the mixture was stirred under reflux. The solvent was distilled off under reduced pressure, and the resulting solid was recrystallized from methanol to give 21.4 g of 1 (8 hydroxy 1, 2, 3, 4 tetrahydronaphthalene-2-inole) piperazine dihydrobromide Salt was obtained. Yield 84%. Melting point 280 ° C or higher.
[0026] 〔2〕2— {4 [4 （8 ヒドロキシ 1 , 2, 3, 4 テトラヒドロナフタレンー2 ィノレ）ピ ペラジン 1 ィル]ブチル }へキサヒドロイソインドールー 1 , 3—ジオン [0027] [0026] [2] 2— {4 [4 (8 Hydroxy 1, 2, 3, 4 tetrahydronaphthalene-2-inole) piperazine 1 yl] butyl} hexahydroisoindole 1,3-dione [0027]
Figure imgf000012_0001
Figure imgf000012_0001
試薬として、 1一（8 メトキシ 1 , 2, 3, 4 テトラヒドロナフタレンー2 ィノレ）ピぺ ラジンに換えて 1一（8 ヒドロキシ 1 , 2, 3, 4 テトラヒドロナフタレンー2 ィル）ピ ペラジン · 2臭化水素酸塩を用いた以外は実施例 1—〔2〕と同様に合成し、 0.69 gの 表題化合物を得た。収率 31 %。  1 1 (8 hydroxy 1, 2, 3, 4 tetrahydronaphthalene-2-yl) piperazine 2 instead of 1 (8 methoxy 1, 2, 3, 4 tetrahydronaphthalene-2-inole) piperazine The title compound was synthesized in the same manner as in Example 1- [2] except that the hydrobromide was used. Yield 31%.
:H NMR (DMSO-d ): δ 1.23—1.46 (4Η， m)， 1.47—1.82 (10Η, m)， 2.27 (1H， br.)， 2.5 : H NMR (DMSO-d): δ 1.23—1.46 (4Η, m), 1.47—1.82 (10Η, m), 2.27 (1H, br.), 2.5
6  6
-3.9 (18H， m)， 6.57 (1H， d， J=7.7 Hz), 6.66 (1H， d， J=7.7 Hz), 6.95 (1H， t， J=7.9 H z)， 9.60 (1H， s).  -3.9 (18H, m), 6.57 (1H, d, J = 7.7 Hz), 6.66 (1H, d, J = 7.7 Hz), 6.95 (1H, t, J = 7.9 H z), 9.60 (1H, s ).
実施例 4  Example 4
[0028] 4 {4 [4 （8 ヒドロキシ 1 , 2, 3, 4 テトラヒドロナフタレンー2 ィノレ）ピペラ ジン一 1—ィル]ブチル }— 4 ァザトリシクロ [5· 2. 1. 02'6]デカン一 3, 5 ジオン · 2 塩酸塩 [0028] 4 {4 [4 (8 Hydroxy 1, 2, 3, 4 tetrahydronaphthalene-2-inole) piperazine 1-yl] butyl} — 4 Azatricyclo [5 · 2. 1. 0 2 ' 6 ] decane 1, 3, dione 2 hydrochloride
Figure imgf000012_0002
Figure imgf000012_0002
試薬として、 2—（4ーブロモブチル）へキサヒドロイソインドールー 1 , 3 ジオンに換 えて 4— (4 ブロモブチル）一4 ァザトリシクロ [5· 2. 1. 02'6]デカン一 3, 5 ジォ ンを用いた以外は実施例 3—〔2〕と同様に合成し、 4— {4— [4— (8—ヒドロキシ— 1 , 2, 3, 4—テトラヒドロナフタレン一 2—ィノレ）ピぺラジン一 1—ィノレ]ブチル }— 4—ァ ザ 2. 1. 02'6]デカン 3, 5- 更に、これを塩化水素のイソプロピルアルコール溶液を用いて塩酸塩化して、 0.90 g の表題化合物を得た。収率 40%。 H NMR (CD OD): δ 1.08 (1H， d， J=10.8 Hz), 1.25 (1H， d， J=11.0 Hz), 1.34-1.42 (As a reagent, replace 2- (4-bromobutyl) hexahydroisoindole-1,3 dione with 4- (4 bromobutyl) -4-azatricyclo [5 · 2. 1. 0 2 ' 6 ] decane 1,3,5 dio The compound was synthesized in the same manner as in Example 3- [2] except that 4- (4-hydroxy- (4-hydroxy--1,2,3,4-tetrahydronaphthalene-2-inole) piperazine was used. 1-ynole] butyl}-4-aza 2. 1. 0 2 ' 6 ] decane 3, 5- Furthermore, this is hydrochloric acid-chlorinated with isopropyl alcohol solution of hydrogen chloride to obtain 0.90 g of the title compound. Obtained. Yield 40%. H NMR (CD OD): δ 1.08 (1H, d, J = 10.8 Hz), 1.25 (1H, d, J = 11.0 Hz), 1.34-1.42 (
2H， m)， 1.54-1.80 (8H， m)， 2.25 (1H， br.)， 2.55-3.35 (17H， m)， 3.42-3.55 (2H， m)， 6.59 (2H， d， J=7.9 Hz), 6.94 (1H， t， J=7.9 Hz). 2H, m), 1.54-1.80 (8H, m), 2.25 (1H, br.), 2.55-3.35 (17H, m), 3.42-3.55 (2H, m), 6.59 (2H, d, J = 7.9 Hz ), 6.94 (1H, t, J = 7.9 Hz).
実施例 5  Example 5
[0030] 4— {4— [ (7 ヒドロキシ一 1 , 2, 3, 4 テトラヒドロナフタレン一 2 ィルメチル）アミ ノコブチル }— 4 ァザトリシクロ [5· 2. 1. 02'6]デカン一 3, 5 ジオン [0030] 4— {4— [(7 Hydroxy 1, 2, 3, 4 Tetrahydronaphthalene, 1 2-methyl) aminocobutyl} — 4 Azatricyclo [5 · 2. 1. 0 2 ' 6 ] Decane, 1, 3 dione
[0031] 〔1〕 7 メトキシ 2—（4 トルエンスルホニルォキシ）メチルー 1 , 2, 3, 4 テトラヒド ロナフタレン
Figure imgf000013_0001
[0031] [1] 7 Methoxy 2- (4 toluenesulfonyloxy) methyl- 1, 2, 3, 4 tetrahydronaphthalene
Figure imgf000013_0001
R. E. Mewshawらの方法（J. Med. Chem.、 1997年、 40巻、 4235— 4256頁に記載）に より合成された（7 メトキシ 1 , 2, 3, 4 テトラヒドロナフタレン- 2-ィル）メタノール（ 2.00 g、 10.40 mmol)をピリジン（15 mL)に溶解し、塩化パラトルエンスルホニル（2.09 g、 10.93 mmol)を加え、室温で終夜撹拌した。反応混合物を 1規定塩酸水溶液に注 ぎ、酢酸ェチルより抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで 乾燥し、濾過後、減圧下で溶媒を留去した。得られた残渣をシリカゲルカラムクロマト グラフィ一で精製して（へキサン：酢酸ェチル = 9 : 1)、 2.78 gの 7 メトキシー2—（4 トルエンスルホニルォキシ）メチルー 1 , 2, 3, 4 テトラヒドロナフタレンを無色油状 物質として得た。収率 77%。  (7 methoxy 1, 2, 3, 4 tetrahydronaphthalen-2-yl) methanol synthesized by the method of RE Mewshaw et al. (J. Med. Chem., 1997, 40, 4235-4256) (2.00 g, 10.40 mmol) was dissolved in pyridine (15 mL), paratoluenesulfonyl chloride (2.09 g, 10.93 mmol) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into 1N aqueous hydrochloric acid and extracted from ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1) and 2.78 g of 7 methoxy-2- (4 toluenesulfonyloxy) methyl-1,2,3,4 tetrahydronaphthalene. Was obtained as a colorless oil. Yield 77%.
:H NMR (300 MHz, CDC1 ): δ 1.32-1.49 (1H， m)， 1.85—1.97 (1H， m)， 2.03-2.20 (1 : H NMR (300 MHz, CDC1): δ 1.32-1.49 (1H, m), 1.85—1.97 (1H, m), 2.03-2.20 (1
H， m)， 2.35-2.55 (1H， m)， 2.46 (3H， s)， 2.65—2.75 (2H， m)， 2.81 (1H， dd， J=4.9 and 16.4 Hz), 3.76 (3H， s)， 3.99 (2H， dd， J=2.2 and 6.6 Hz), 6.56 (1H， d， J=2.6 Hz), 6.6 8 (1H， dd， J=2.7 and 8.3 Hz), 6.96 (1H， d， J=4.2 Hz), 7.36 (2H， d， J=7.9 Hz), 7.81 ( 2H， d， J=8.4 Hz). H, m), 2.35-2.55 (1H, m), 2.46 (3H, s), 2.65—2.75 (2H, m), 2.81 (1H, dd, J = 4.9 and 16.4 Hz), 3.76 (3H, s) 3.99 (2H, dd, J = 2.2 and 6.6 Hz), 6.56 (1H, d, J = 2.6 Hz), 6.6 8 (1H, dd, J = 2.7 and 8.3 Hz), 6.96 (1H, d, J = 4.2 Hz), 7.36 (2H, d, J = 7.9 Hz), 7.81 (2H, d, J = 8.4 Hz).
[0033] 〔2〕4— (4 アミノブチル） 4 ァザトリシクロ [5· 2. 1. 02'6]デカン一 3, 5 ジオン
Figure imgf000014_0001
[0033] [2] 4- (4 Aminobutyl) 4 Azatricyclo [5 · 2. 1. 0 2 ' 6 ] Decane 3,5 dione
Figure imgf000014_0001
4— (4 クロロブチル） 4 ァザトリシクロ [5· 2. 1. 02'6]デカン一 3, 5 ジオン（2.0 0 g、 7.83 mmol)を DMF(10 mL)に溶角早し、アジ化ナトリウム（615 mg、 9.39 mmol)を 加え、 60°Cで 3時間撹拌した。室温に戻した後、反応混合物にエーテル（100 mL)お よび水（100 mL)を加え、撹拌後分液した。水層よりエーテル（100 mL)で再度抽出を 行った。有機層を合わせ、水（50 mL X 2回）、次!/、で飽和食塩水（50 mL)で洗浄後、 無水硫酸マグネシウムで乾燥した。濾過後、減圧下で溶媒を留去し、 4一（4 アジド ブチル）一4 ァザトリシクロ [5· 2. 1. 02'6]デカン一 3, 5 ジオン 2.78 gの 7 メトキ シ 2—（4 トルエンスルホニルォキシ）メチルー 1 , 2, 3, 4 テトラヒドロナフタレン を含む残渣 1.97 gを得た。 4— (4 chlorobutyl) 4 azatricyclo [5 · 2. 1. 0 2 ' 6 ] decane 1,5 dione (2.0 0 g, 7.83 mmol) was dissolved in DMF (10 mL) and sodium azide ( (615 mg, 9.39 mmol) was added, and the mixture was stirred at 60 ° C for 3 hours. After returning to room temperature, ether (100 mL) and water (100 mL) were added to the reaction mixture, and the mixture was separated after stirring. The aqueous layer was extracted again with ether (100 mL). The organic layers were combined, washed with water (50 mL x 2 times), then! /, With saturated brine (50 mL), and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure. 4 1 (4 Azidobutyl) 1 4 Azatricyclo [5 · 2. 1. 0 2 ' 6 ] Decane 1 3, 5 Dione 2.78 g 7 Methoxy 2— (4 1.97 g of a residue containing toluenesulfonyloxy) methyl-1,2,3,4 tetrahydronaphthalene was obtained.
この残渣全量を、テトラヒドロフラン (THF、 40 mL)と水（10 mL)の混合溶媒中に溶解 し、トリフエニルホスフィン（2.46 g、 9.40 mmol)を加え、 60°Cで 1時間撹拌した。室温 に戻した後、 THFを減圧下留去し、残渣に酢酸ェチル（10 mL)および 1規定塩酸（10 mL)を加え、撹拌後分液した。水層を減圧下濃縮し、飽和重曹水で中和した後に、 クロ口ホルムにて抽出した。有機層を無水硫酸ナトリウムで乾燥し、 1.32 gの 4一（4 アミノブチル） 4 ァザトリシクロ [5· 2. 1. 02'6]デカン一 3, 5 ジオンを白色固体と して得た。収率 71 %。 The entire amount of the residue was dissolved in a mixed solvent of tetrahydrofuran (THF, 40 mL) and water (10 mL), triphenylphosphine (2.46 g, 9.40 mmol) was added, and the mixture was stirred at 60 ° C for 1 hour. After returning to room temperature, THF was distilled off under reduced pressure. Ethyl acetate (10 mL) and 1N hydrochloric acid (10 mL) were added to the residue, and the mixture was separated after stirring. The aqueous layer was concentrated under reduced pressure, neutralized with saturated aqueous sodium hydrogen carbonate, and extracted with black mouth form. The organic layer was dried over anhydrous sodium sulfate to give 1.32 g of 4 (4 aminobutyl) 4 azatricyclo [5 · 2. 1. 0 2 ' 6 ] decane 3,5 dione as a white solid. Yield 71%.
[0035] 〔3〕4— {4— [ (7 メトキシ一 1 , 2, 3, 4 テトラヒドロナフタレン一 2 ィルメチル）ァ ミノ]ブチル }— 4 ァザトリシクロ [5· 2. 1. 02'6]デカン一 3, 5 ジオン [0035] [3] 4— {4— [(7 methoxy-1,2,3,4) tetrahydronaphthalene-2-ylmethyl) amino] butyl} —4azatricyclo [5 · 2. 1. 0 2 ' 6 ] decane 1, 3, dione
Figure imgf000014_0002
7 メトキシ 2—（4 トルエンスルホニルォキシ）メチルー 1 , 2, 3, 4 テトラヒドロ ナフタレン（346 mg、 1.00
Figure imgf000015_0001
、 1 mL)に溶解し、 4
Figure imgf000014_0002
7 Methoxy 2- (4 toluenesulfonyloxy) methyl- 1, 2, 3, 4 tetrahydronaphthalene (346 mg, 1.00
Figure imgf000015_0001
1 mL), 4
— (4 アミノブチル） 4 ァザトリシクロ [5· 2. 1. 02'。]デカン一 3, 5 ジオン（782 mg、 3.00 mmol)およびトリェチルァミン（0.56 mL、 4.00 mmol)を加え、 70〜80°Cで 2 時間撹拌した。反応混合物を室温に戻した後、水（5 mL)および酢酸ェチル (5 mL) を加え、撹拌後分液した。有機層を水洗し（5 mL X 5回）、無水硫酸ナトリウムで乾燥 して、濾過後、減圧下で溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグ ラフィ一で精製して（酢酸ェチルのみ、次いで 3%トリェチルァミン含有酢酸ェチル）、 36 mgの 4— {4— [ (7 メトキシ一 1 , 2, 3, 4 テトラヒドロナフタレン一 2 ィルメチ ル）ァミノ]ブチル }— 4 ァザトリシクロ [5· 2. 1. 02'6]デカン一 3, 5 ジオンを薄黄 色油状物質として得た。収率 9%。 — (4 aminobutyl) 4-azatricyclo [5 · 2. 1. 0 2 '. ] Decane 1 3,5 dione (782 mg, 3.00 mmol) and triethylamine (0.56 mL, 4.00 mmol) were added and stirred at 70-80 ° C for 2 hours. After returning the reaction mixture to room temperature, water (5 mL) and ethyl acetate (5 mL) were added, and the mixture was stirred and separated. The organic layer was washed with water (5 mL × 5 times), dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate only, then 3% triethylamine-containing ethyl acetate) to give 36 mg of 4- {4-— ((7 methoxy-1,2,3,4 tetrahydronaphthalene). 1- (2-methyl) amino] butyl} —4azatricyclo [5 · 2. 1. 0 2 ' 6 ] decane-1,3,5 dione was obtained as a pale yellow oil. Yield 9%.
:H NMR (300 MHz, CDCl ): δ 1.06—1.72 (10H, m)， 1.82—2.00 (2H， m)， 2.44 (1H， d d， J=10.5 and 16.4 Hz), 2.57-2.79 (10H, m)， 2.86 (1H， dd， J=4.6 and 16.1 Hz), 3.48 (2H， t， J=7.2 Hz), 3.77 (3H， s)， 6.62 (1H， d， J=2.8 Hz), 6.68 (1H， dd， J=2.8 and 8.4 Hz), 6.99 (1H， d， J=8.4 Hz). : H NMR (300 MHz, CDCl): δ 1.06—1.72 (10H, m), 1.82—2.00 (2H, m), 2.44 (1H, dd, J = 10.5 and 16.4 Hz), 2.57-2.79 (10H, m ), 2.86 (1H, dd, J = 4.6 and 16.1 Hz), 3.48 (2H, t, J = 7.2 Hz), 3.77 (3H, s), 6.62 (1H, d, J = 2.8 Hz), 6.68 (1H , Dd, J = 2.8 and 8.4 Hz), 6.99 (1H, d, J = 8.4 Hz).
[0037] 〔4〕4 {4 [ (7—ヒドロキシー1 , 2, 3, 4 テトラヒドロナフタレンー2 ィルメチル） ァミノ]ブチル }— 4 ァザトリシクロ [5· 2. 1. 02'6]デカン一 3, 5 ジオン [0037] [4] 4 {4 [(7-Hydroxy-1, 2, 3, 4 Tetrahydronaphthalene-2-ylmethyl) amino] butyl}-4 Azatricyclo [5 · 2. 1. 0 2 ' 6 ] 5 Zeon
Figure imgf000015_0002
Figure imgf000015_0002
4— {4— [ (7 メトキシ一 1 , 2, 3, 4 テトラヒドロナフタレン一 2 ィルメチル）ァミノ ]ブチル }— 4 ァザトリシクロ [5· 2. 1. 02'6]デカン一 3, 5 ジオン（36 mg、 0.09 mm ol)をジクロロメタン（1 mL)に溶解し、ドライアイス一アセトンバスで冷却した。この溶液 中に、三臭化ホウ素の 1.0Mジクロロメタン溶液（0.40 mL、 0.40 mmol)を滴下し、室温 に戻しながら撹拌した。反応溶液を氷冷し、メタノールを加えて撹拌後、減圧下で溶 媒を留去した。得られた残渣に飽和重曹水を加え、クロ口ホルムより抽出した。有機 層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、濾過後、減圧下で溶媒を 留去した。得られた残渣をシリカゲルカラムクロマトグラフィーで精製して、 22 mgの表 題化合物を薄茶色固体として得た。収率 63%。 4— {4— [(7-methoxy-1,2,3,4-tetrahydronaphthalene-2-ylmethyl) amino] butyl} —4-azatricyclo [5 · 2. 1. 0 2 ' 6 ] decane 1,3,5 dione (36 mg, 0.09 mmol) was dissolved in dichloromethane (1 mL) and cooled in a dry ice / acetone bath. To this solution, 1.0M boron tribromide in dichloromethane (0.40 mL, 0.40 mmol) was added dropwise and stirred while returning to room temperature. The reaction solution was ice-cooled, methanol was added and stirred, and then the solvent was distilled off under reduced pressure. Saturated aqueous sodium hydrogen carbonate was added to the resulting residue, and the mixture was extracted from black mouth form. Organic The layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 22 mg of the title compound as a light brown solid. Yield 63%.
:H NMR (300 MHz, CDC1 ): δ 1.05—1.70 (10Η, m)， 1.80—2.00 (2H， m)， 2.42 (1H， d d， J=10.1 and 15.8 Hz), 2.55-2.90 (12H， m)， 3.48 (2H， br.t), 6.53 (1H， s)， 6.59 (1H， d， J=7.9 Hz), 6.92 (1H， d， J=8.1 Hz). : H NMR (300 MHz, CDC1): δ 1.05—1.70 (10Η, m), 1.80—2.00 (2H, m), 2.42 (1H, dd, J = 10.1 and 15.8 Hz), 2.55-2.90 (12H, m ), 3.48 (2H, br.t), 6.53 (1H, s), 6.59 (1H, d, J = 7.9 Hz), 6.92 (1H, d, J = 8.1 Hz).
実施例 6  Example 6
[0039] (5 メトキシ一 1 , 2, 3, 4 テトラヒドロナフタレン一 2 ィル）（3 フエニルプロピル） ァミン  [0039] (5-methoxy-1,2,3,4-tetrahydronaphthalene-2-yl) (3-phenylpropyl) amine
Figure imgf000016_0001
Figure imgf000016_0001
文献記載の方法（Austr. J. Chem.、 1998年、 51巻、 386— 396頁）により合成された 5 —メトキシ一 2—テトラロン（100 mg、 0.57 mmol)にトノレェン（1 mL)、 3 フエ二ノレプロ ピルアミン（0.10 mL、 0.70 mmol)、パラトルエンスルホン酸 · 1水和物（11 mg、 0.06 m mol)を加えて、 2時間還流した。室温に戻した後に減圧下溶媒を留去し、得られた残 渣にエタノール（2 mL)および水素化ホウ素ナトリウム（215 mg、 5.7 mmol)を加えて 5 時間還流した。室温に戻した後、反応混合物を 5%炭酸カリウム水溶液中に注ぎ、酢 酸ェチルより抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し 、濾過後、減圧下で溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフ ィーで精製して（へキサン：酢酸ェチル= 1 : 1→1 : 0)、 109 mgの表題化合物を赤茶 色の油状物質として得た。収率 65%。  5-Methoxy-2-tetralone (100 mg, 0.57 mmol) synthesized by the method described in the literature (Austr. J. Chem., 1998, 51, 386-396) was added to tolylene (1 mL), 3 phenol. Ninolepropylamine (0.10 mL, 0.70 mmol) and p-toluenesulfonic acid monohydrate (11 mg, 0.06 mmol) were added and refluxed for 2 hours. After returning to room temperature, the solvent was distilled off under reduced pressure, ethanol (2 mL) and sodium borohydride (215 mg, 5.7 mmol) were added to the resulting residue, and the mixture was refluxed for 5 hours. After returning to room temperature, the reaction mixture was poured into 5% aqueous potassium carbonate solution and extracted from ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1 → 1: 0) to obtain 109 mg of the title compound as a red-brown oily substance. Yield 65%.
:H NMR (300 MHz, CDC1 ): δ 1.42-1.62 (1H， m)， 1.80—1.90 (2H， m)， 1.98—2.10 (1 : H NMR (300 MHz, CDC1): δ 1.42-1.62 (1H, m), 1.80—1.90 (2H, m), 1.98—2.10 (1
H， m)， 2.48-3.05 (9H， m)， 3.81 (3H， s)， 6.68 (2H， m)， 7.09 (1H， m)， 7.14-7.34 (5H， m). H, m), 2.48-3.05 (9H, m), 3.81 (3H, s), 6.68 (2H, m), 7.09 (1H, m), 7.14-7.34 (5H, m).
実施例 7  Example 7
(5 ヒドロキシ 1， 2， 3， 4ーテトラヒドロナフタレンー2 ィノレ） （3 フエ二ノレプロピ ル）ァミン (5 hydroxy 1, 2, 3, 4-tetrahydronaphthalene-2-inole) (3 phenolinopropi Le) Amin
Figure imgf000017_0001
Figure imgf000017_0001
実施例 6で合成された（5 メトキシ 1 , 2, 3, 4 テトラヒドロナフタレンー2 ィル ) (3 フエニルプロピル）ァミン（90 mg、 0.31 mmol)をジクロロメタン（1 mL)に溶解し、 ドライアイス アセトンバスで冷却した。この溶液中に、三臭化ホウ素の 1.0Mジクロロ メタン溶液 (0.76 mL、 0.760 mmol)を滴下し、室温に戻しながら撹拌した。反応溶液 を氷冷し、メタノールを加えて撹拌後、減圧下で溶媒を留去した。得られた残渣に飽 和重曹水を加え、クロ口ホルムより抽出した。有機層を飽和食塩水で洗浄後、無水硫 酸ナトリウムで乾燥し、濾過後、減圧下で溶媒を留去した。得られた残渣をシリカゲル カラムクロマトグラフィーで精製して（クロ口ホルム：メタノール = 100： 0→90 : 10) , 58 mgの表題化合物を茶褐色のアモルファスとして得た。収率 68%。  (5 methoxy 1, 2, 3, 4 tetrahydronaphthalene-2-yl) (3 phenylpropyl) amine (90 mg, 0.31 mmol) synthesized in Example 6 was dissolved in dichloromethane (1 mL) and dried ice Cooled in an acetone bath. To this solution, a 1.0 M dichloromethane solution of boron tribromide (0.76 mL, 0.760 mmol) was added dropwise and stirred while returning to room temperature. The reaction solution was ice-cooled, methanol was added and stirred, and then the solvent was distilled off under reduced pressure. Saturated aqueous sodium bicarbonate was added to the resulting residue, and the mixture was extracted from black mouth form. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (black mouth form: methanol = 100: 0 → 90: 10) to obtain 58 mg of the title compound as a brown amorphous. Yield 68%.
:H NMR (300 MHz, CDC1 ): δ 1.50—1.70 (1Η， m)， 1.80—1.95 (2Η， m)， 2.05-2.20 (1 : H NMR (300 MHz, CDC1): δ 1.50—1.70 (1Η, m), 1.80—1.95 (2Η, m), 2.05-2.20 (1
Η， m)， 2.50-3.03 (9Η， m)， 6.59 (1Η， d， J=7.9 Hz), 6.67 (1H， d， J=7.7 Hz), 6.99 (1H， t， J=7.7Hz), 7.14-7.34 (5H， m). Η, m), 2.50-3.03 (9Η, m), 6.59 (1Η, d, J = 7.9 Hz), 6.67 (1H, d, J = 7.7 Hz), 6.99 (1H, t, J = 7.7 Hz), 7.14-7.34 (5H, m).
実施例 8  Example 8
[0043] 8 プロピノレアミノー 6, 7, 8, 9 テトラヒドロー 2H— 2, 9a ジァザべンゾ [cd]ァズ レン 1一才ン  [0043] 8 Propinoleamino-6, 7, 8, 9 Tetrahydro 2H— 2, 9a Diazabenzo [cd] azulen 1 1 year old
[0044] 〔1〕1— (4 トルエンスルホニル）一 1 , 2, 4, 5 テトラヒドロべンゾ [b]ァゼピン一 3 一才ン才キシム  [0044] [1] 1— (4 Toluenesulfonyl) 1 1, 2, 4, 5 Tetrahydrobenzo [b] Azepine 1 3 1 year old Kissim
Figure imgf000017_0002
Figure imgf000017_0002
D. N. Guptaらの方法（J. Chem. Soc. (C)、 1970年、 2191— 2193頁に記載）により合 成された 1一（4一トルエンスルホニル）一 1 , 2, 4, 5 テトラヒドロベンゾ [b]ァゼピン —3 オン（6.0 g， 19 mmol)のエタノール溶液（60 mL)に、ピリジン（3.6 mL)、塩酸ヒ ドロキシルァミン（1.98 g， 29 mmol)を加え、加熱還流下で 3時間撹拌した。反応終了 後、クロ口ホルムにて希釈し、 0. 5規定塩酸水にて洗浄した。有機層を硫酸ナトリウム で乾燥し、濾過後、減圧下で溶媒を留去した。得られた残渣よりエタノール 酢酸ェ チル—へキサンの混合溶媒により晶析し、 4.01 gの 1— (4 トルエンスルホニル）― 1 , 2, 4, 5—テトラヒドロベンゾ [b]ァゼピンー3—オンォキシムを白色固体として得た 。収率 64%。 Synthesized by the method of DN Gupta et al. (Described in J. Chem. Soc. (C), 1970, pp. 2191-2193) 1 (4 monotoluenesulfonyl) 1 1, 2, 4, 5 tetrahydrobenzo [ b] Azepine — 3-one (6.0 g, 19 mmol) in ethanol (60 mL), pyridine (3.6 mL), hydrochloric acid Droxylamine (1.98 g, 29 mmol) was added, and the mixture was stirred for 3 hours with heating under reflux. After completion of the reaction, the reaction mixture was diluted with chloroform and washed with 0.5N hydrochloric acid. The organic layer was dried over sodium sulfate, filtered, and the solvent was distilled off under reduced pressure. The residue obtained was crystallized with a mixed solvent of ethanol / ethyl acetate / hexane to give 4.01 g of 1- (4 toluenesulfonyl) -1,2,4,5-tetrahydrobenzo [b] azepine-3-onoxime in white. Obtained as a solid. Yield 64%.
〔2〕（2, 3, 4, 5 テトラヒドロー 1H—ベンゾ [b]ァゼピンー3 ィノレ）力ルバミン酸べ ンジルエステル  [2] (2, 3, 4, 5 Tetrahydro-1H-benzo [b] azepine-3inole) strength rubamic acid benzyl ester
Figure imgf000018_0001
Figure imgf000018_0001
1一（4 トルエンスルホニル） 1 , 2, 4, 5 テトラヒドロベンゾ [b]ァゼピンー3— オンォキシム（1.50 g， 4.54 mmol)のエタノール溶液（50 mL)に、 10%パラジウム炭 素（50%含水、 1.0 g)およびギ酸アンモニゥム（3.0 g)を加え、 1時間加熱還流した。反 応系を一旦冷却後、 10%パラジウム炭素（50%含水、 0.30 mg)およびギ酸アンモニゥ ム（1.0 g)を加え、更に 1時間加熱還流した。この操作を 3回繰り返した。反応終了後 、セライトを用いて濾過し、濾液を減圧下濃縮して、 1一（4 トルエンスルフォニル） - 2, 3, 4, 5 テトラヒドロー 1H—ベンゾ [b]ァゼピンー3 ィルァミンを含む黄色ァ モルファスを 1.87 g得た。  1 (4 Toluenesulfonyl) 1, 2, 4, 5 Tetrahydrobenzo [b] azepine-3- ethanol solution (50 mL) of onoxime (1.50 g, 4.54 mmol) was added to 10% palladium carbon (50% water, 1.0% g) and ammonium formate (3.0 g) were added, and the mixture was heated to reflux for 1 hour. The reaction system was once cooled, 10% palladium carbon (containing 50% water, 0.30 mg) and ammonium formate (1.0 g) were added, and the mixture was further heated to reflux for 1 hour. This operation was repeated three times. After completion of the reaction, the reaction mixture was filtered using Celite, and the filtrate was concentrated under reduced pressure to obtain 1- (4-toluenesulfonyl) -2,3,4,5 tetrahydro-1H-benzo [b] azepine-3ylamine. 1.87 g was obtained.
このアモルファス全量をトリフルォロ酢酸（10 mL)に溶解し、メタンスルホン酸（1.0 mL )およびチオア二ソール（2.0 mL)を加え、室温で 15時間撹拌した。反応終了後、溶 媒を減圧下留去し、 2, 3, 4, 5 テトラヒドロー 1H—ベンゾ [b]ァゼピンー3 ィルァ ミンを含む茶色の油状物質を 2.12 g得た。  The total amount of this amorphous was dissolved in trifluoroacetic acid (10 mL), methanesulfonic acid (1.0 mL) and thioanisol (2.0 mL) were added, and the mixture was stirred at room temperature for 15 hours. After completion of the reaction, the solvent was distilled off under reduced pressure to obtain 2.12 g of a brown oily substance containing 2,3,4,5 tetrahydro-1H-benzo [b] azepine-3-ylamine.
この茶色の油状物質全量をジクロロメタン（50 mL)に溶解し、トリェチルァミン（12.7 m L、 91 mmol)およびべンジルクロ口ホルメート（0.819 mL、 5.45 mmol)を加え、室温に て 1時間撹拌した。反応終了後、クロ口ホルムにて希釈し、飽和重曹水、次いで食塩 水で洗浄した。有機層を硫酸ナトリウムで乾燥し、減圧下溶媒を留去した。得られた 残渣をシリカゲルカラムクロマトグラフィーで精製して（へキサン：酢酸ェチル = 7： 1→ 6 : 1 )、 242 mgの（2, 3, 4, 5—テトラヒドロ一 1H—ベンゾ [b]ァゼピン一 3—ィノレ）力 ノレバミン酸べンジルエステルを黄色油状物質として得た。収率 18%。 The whole amount of this brown oily substance was dissolved in dichloromethane (50 mL), triethylamine (12.7 mL, 91 mmol) and benzyl chloride formate (0.819 mL, 5.45 mmol) were added, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, dilute with black mouth form, saturated aqueous sodium bicarbonate, then salt Washed with water. The organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 7: 1 → 6: 1), and 242 mg of (2, 3, 4, 5-tetrahydro 1H-benzo [b] azepine 1-3-Inole) Norebamic acid benzyl ester was obtained as a yellow oily substance. Yield 18%.
[0048] 〔3〕（1ーメトキシカルバモイルー 2, 3, 4, 5 テトラヒドロー 1H—ベンゾ [b]ァゼピン [0048] [3] (1-methoxycarbamoyl-2, 3, 4, 5 tetrahydro-1H-benzo [b] azepine
3—ィル）力ルバミン酸べンジルエステル  3—yl) force rubamic acid benzyl ester
Figure imgf000019_0001
Figure imgf000019_0001
(2, 3, 4, 5—テトラヒドロー 1H—ベンゾ [b]ァゼピンー3—ィル）力ルバミン酸ベン ジルエステル（237 mg、 0.80 mmol)をテトラヒドロフラン（5.0 mL)に溶解し、トリェチル ァミン（0.167 mL、 1.20 mmol)を加えて氷冷した。氷冷下、トリホスゲンを加え、同温に て 1時間半撹拌した。次いで、 O メトキシヒドロキシルァミン塩酸塩（134 mg、 1.60 m mol)およびトリェチルァミン（0.279 mL、 2.00 mmol)を加え、室温にて 24時間撹拌し た。反応終了後、減圧下溶媒を留去した。得られた残渣をクロ口ホルムで希釈し、飽 和重曹水で洗浄した。有機層を硫酸ナトリウムで乾燥し、濾過後、減圧下溶媒を留去 した。得られた残渣をシリカゲルカラムクロマトグラフィーで精製して (へキサン:酢酸 ェチル = 1 : 1次いでクロ口ホルム：メタノール = 20 : 1)、 119 mgの（1—メトキシカノレ バモイル一 2, 3, 4, 5 テトラヒドロ一 1H—ベンゾ [b]ァゼピン一 3—ィル）カルバミ ン酸べンジルエステルを薄黄色アモルファスとして得た。収率 40%。  (2, 3, 4, 5-tetrahydro-1H-benzo [b] azepine-3-yl) rubamic acid benzyl ester (237 mg, 0.80 mmol) is dissolved in tetrahydrofuran (5.0 mL), and triethylamine (0.167 mL) is dissolved. , 1.20 mmol) was added and the mixture was ice-cooled. Triphosgene was added under ice cooling, and the mixture was stirred at the same temperature for 1.5 hours. Then, O methoxyhydroxylamine hydrochloride (134 mg, 1.60 mmol) and triethylamine (0.279 mL, 2.00 mmol) were added, and the mixture was stirred at room temperature for 24 hours. After completion of the reaction, the solvent was distilled off under reduced pressure. The resulting residue was diluted with black mouth form and washed with saturated aqueous sodium bicarbonate. The organic layer was dried over sodium sulfate and filtered, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1, then chloroform: methanol = 20: 1), and 119 mg of (1-methoxycanole vasoyl 1, 2, 3, 4, 5 Tetrahydro-1H-benzo [b] azepine-1-yl) carbamic acid benzyl ester was obtained as a pale yellow amorphous. Yield 40%.
[0050] 〔4〕（2 メトキシ 1 ォキソ 1 , 2, 6, 7, 8, 9 へキサヒドロー 2, 9a ジァザべ ンゾ [cd]ァズレン 8—ィル）力ルバミン酸べンジルエステル [0050] [4] (2 Methoxy 1-oxo 1, 2, 6, 7, 8, 9 Hexahydro 2, 9a Diazabenzo [cd] azulene 8-yl) Powered rubamic acid benzyl ester
Figure imgf000020_0001
Figure imgf000020_0001
〇——  〇——
(1ーメトキシカルバモイルー 2, 3, 4, 5 テトラヒドロー 1H—ベンゾ [b]ァゼピン 3 ィノレ）力ルバミン酸べンジルエステル（110 mg、 0.298 mmol)をジクロロメタン（15 m L)に溶解し、氷冷下、ビス（トリフルォロアセトキシ）ョードベンゼン（HI mg、 0.322 m mol)を加え、同温にて 3時間撹拌した。反応終了後、クロ口ホルムで希釈し、飽和重 曹水にて洗浄した。有機層を硫酸ナトリウムで乾燥し、濾過後、減圧下溶媒を留去し た。得られた残渣をシリカゲルカラムクロマトグラフィーで精製して (へキサン：酢酸ェ チル = 2 : 1→1 : 2)、 74 mgの（2 メトキシ一 1—ォキソ 1 , 2, 6, 7, 8, 9 へキサ ヒドロ 2, 9a ジァザべンゾ [cd]ァズレン 8 ィル）力ルバミン酸べンジルエステ ルを赤茶色の油状物質として得た。収率 68%。  (1-Methoxycarbamoyl-2, 3, 4, 5 tetrahydro-1H-benzo [b] azepine 3-inole) rubamic acid benzyl ester (110 mg, 0.298 mmol) is dissolved in dichloromethane (15 mL) and cooled with ice. Bis (trifluoroacetoxy) iodobenzene (HI mg, 0.322 mmol) was added and stirred at the same temperature for 3 hours. After completion of the reaction, the reaction mixture was diluted with chloroform and washed with saturated aqueous sodium hydrogen carbonate. The organic layer was dried over sodium sulfate and filtered, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1 → 1: 2), and 74 mg of (2 methoxy-1-oxo-1,2,6,7,8) 9 Hexahydro 2, 9a diazabenzo [cd] azulene 8 yl) benzil ester rubamate was obtained as a reddish brown oily substance. Yield 68%.
:H NMR (300 MHz, CDC1 ): δ 2.10—2.32 (2H， m)， 2.96—3.05 (2H， m)， 3.93 (1H， dd : H NMR (300 MHz, CDC1): δ 2.10—2.32 (2H, m), 2.96—3.05 (2H, m), 3.93 (1H, dd
)， 4.08 (3H， s)， 4.20 (1H， dd), 4.30-4.40 (1H， m)， 4.95—5.02 (1H， m)， 5.10 (2H， s)， 6.86 (1H， dd), 6.97 (1H， dd), 7.04 (1H， t)， 7.32-7.38 (5H， m). ), 4.08 (3H, s), 4.20 (1H, dd), 4.30-4.40 (1H, m), 4.95—5.02 (1H, m), 5.10 (2H, s), 6.86 (1H, dd), 6.97 ( 1H, dd), 7.04 (1H, t), 7.32-7.38 (5H, m).
[0052] 〔5〕 8 アミノー 6, 7, 8, 9 テトラヒドロー 2H— 2, 9a ジァザべンゾ [cd]ァズレン [0052] [5] 8 Amino-6, 7, 8, 9 Tetrahydro 2H— 2, 9a Diazabenzo [cd] azulene
Figure imgf000020_0002
Figure imgf000020_0002
(2 メトキシ一 1—ォキソ 1 , 2, 6, 7, 8, 9 へキサヒドロー 2, 9a ジァザベン ゾ [cd]ァズレン一 8—ィノレ）力ルバミン酸べンジルエステル（74 mg、 0.201 mmol)をェ タノール（10 mL)に溶解し、 10%パラジウム炭素（50%含水、 100 mg)およびギ酸アン モニゥム（250 mg)を加え、 1時間加熱還流した。反応終了後、セライトを用いて濾過 し、濾液を減圧下濃縮して、 8 アミノー 6, 7, 8, 9 テトラヒドロ一 2H— 2, 9a ジ ァザべンゾ [cd]ァズレン 1 オンを含む白色アモルファスを 34 mg得た。収率 83(2 Methoxy-1-oxo-1, 2, 6, 7, 8, 9 Hexahydro-2,9a Diazabenzo [cd] azulene-1-8-no-re) rubamic acid benzyl ester (74 mg, 0.201 mmol) Dissolved in ethanol (10 mL), 10% palladium carbon (containing 50% water, 100 mg) and ammonium formate (250 mg) were added, and the mixture was heated to reflux for 1 hour. After completion of the reaction, the reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain white color containing 8 amino-6, 7, 8, 9 tetrahydro-1H-2, 9a diazabenzo [cd] azulene 1-one. 34 mg of amorphous was obtained. Yield 83
%。 %.
[0054] 〔6〕 8 プロピノレアミノー 6, 7, 8, 9 テトラヒドロー 2H— 2, 9a ジァザべンゾ [cd] ァズレン 1一才ン  [0054] [6] 8 Propinoleamino-6, 7, 8, 9 Tetrahydro 2H— 2, 9a Diazabenzo [cd] Azulene 1
Figure imgf000021_0001
Figure imgf000021_0001
8 アミノー 6, 7, 8, 9 テトラヒドロー 2H— 2, 9a ジァザべンゾ [cd]ァズレン 1—オン（12 mg、 0.059 mmol)をメタノール（5 mL)に溶解し、酢酸 (0.5 mL),プロピオ ンァノレデヒド（5· 1 μ 、 0.071 mmol)、水素化シァノホウ素ナトリウム（19 mg, 0.295 m mol)を順次加え、室温にて 15時間撹拌した。反応終了後、反応混合物を飽和重曹 水中へ注ぎ、クロ口ホルムにて抽出した。有機層を硫酸ナトリウムで乾燥し、濾過後、 減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィーで精製し て（クロロホルム：メタノール= 100 : 1→10 : 1)、9.5 mgの表題化合物を薄黄色の油 状物質として得た。収率 66%。  8 Amino-6, 7, 8, 9 Tetrahydro-2H— 2, 9a Diazabenzo [cd] azulene 1-one (12 mg, 0.059 mmol) dissolved in methanol (5 mL), acetic acid (0.5 mL), propio Nanodehydride (5.1 μm, 0.071 mmol) and sodium cyanoborohydride (19 mg, 0.295 mmol) were sequentially added, and the mixture was stirred at room temperature for 15 hours. After completion of the reaction, the reaction mixture was poured into saturated sodium bicarbonate water and extracted with black mouth form. The organic layer was dried over sodium sulfate and filtered, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 100: 1 → 10: 1) to obtain 9.5 mg of the title compound as a pale yellow oily substance. Yield 66%.
:H NMR (300 MHz, CDCl ): δ 0.94 (3H， t)， 1.53 (2H， m)， 1.92—2.04 (1H， m)， 2.22 : H NMR (300 MHz, CDCl): δ 0.94 (3H, t), 1.53 (2H, m), 1.92—2.04 (1H, m), 2.22
-2.32 (1H， m)， 2.60—2.81 (2H， m)， 2.91-3.01 (1H， m)， 3.06-3.24 (2H， m)， 3.92 (1H: dd)， 4.13 (1H， dd)， 6.80-6.84 (1H， m)， 6.92-6.95 (2H， m)， 9.95 (1H， br.s). -2.32 (1H, m), 2.60—2.81 (2H, m), 2.91-3.01 (1H, m), 3.06-3.24 (2H, m), 3.92 (1H : dd), 4.13 (1H, dd), 6.80 -6.84 (1H, m), 6.92-6.95 (2H, m), 9.95 (1H, br.s).
実施例 9  Example 9
[0056] 1 - (2, 3 ジクロロフエ二ノレ）一 4— { 2— [ 5— (4 フノレオロフェニノレ）ピリジン一 3 ィノレ]ェチノレ }ピぺラジン  [0056] 1-(2, 3 dichloropheninole) 1 4-— {2— [5— (4 funoleolopheninole) pyridine 1 3-inore] echinore} piperazine
[0057] [1] 3 - (4 フルオロフェニル） 5— (2 メトキシビュル）ピリジン
Figure imgf000022_0001
[0057] [1] 3-(4 Fluorophenyl) 5— (2 Methoxybuyl) pyridine
Figure imgf000022_0001
氷冷下で臭化（メトキシメチル）トリフエニルホスホニゥムのナトリウムアミド複合体（2. 0 g， 4.6 mmol)のテトラヒドロフラン (10.0 mL)溶液を調製した。ここへ、 5— (4 フルォ 口フエニル）ピリジンー3 カルボアルデヒド（D. Dorschら、国際公開公報 WO 20010 98293に記載）（800 mg， 4.0 mmol)のテトロヒドロフラン溶液（5.0 mL)を氷冷下で滴 下した。反応混合物を室温にて 4時間撹拌した。反応混合物を水と酢酸ェチルで希 釈し、酢酸ェチルで抽出した。有機層を硫酸 乾燥し、溶媒を減圧下で 除去して得られた油状物質 一にて精製し、 3 - (4 ーフノレオロフェニノレ） 5—（2 メトキシビ- 8 mg, 3.9 mmol)を得た 。収率 98%。  A solution of sodium amide complex (2.0 g, 4.6 mmol) in (methoxymethyl) triphenylphosphonium bromide (10.0 mL) was prepared under ice cooling. To this, a tetrohydrofuran solution (5.0 mL) of 5- (4 fluoro-phenyl) pyridine-3 carbaldehyde (described in D. Dorsch et al., International Publication WO 20010 98293) (800 mg, 4.0 mmol) under ice cooling Drip with. The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with water and ethyl acetate and extracted with ethyl acetate. The organic layer was dried over sulfuric acid, and the solvent was removed under reduced pressure to purify the oily substance. 3-(4-Funoleorophenole) 5— (2 methoxybi-8 mg, 3.9 mmol) Obtained . Yield 98%.
[0059] 〔2] [5—（4 フルオロフェニル）ピリジン 3  [0059] [2] [5-(4 Fluorophenyl) pyridine 3
Figure imgf000022_0002
Figure imgf000022_0002
3 - (4 フルオロフェニル） 5— (2 メトキシビニノレ）ピリジン（200.0 mg, 0.876 m mol)のァセトニトリル溶液（4.0 mL)を調製し、 2規定塩酸 (4 mL)を加えた。反応混合 物を 50°Cにて 1時間撹拌し、水と酢酸ェチルで希釈した。飽和炭酸水素ナトリウム水 溶液で中和し、酢酸ェチルで抽出した。有機層を硫酸マグネシウムで乾燥し、乾燥 剤を除去後に減圧下で溶媒を除去して、 [5—（4 フルオロフェニル)ピリジンー3— ィル]ァセトアルデヒドを 187.7 mg (0.876 mmol)を得た。収率 99%。  Acetonitrile solution (4.0 mL) of 3- (4 fluorophenyl) 5- (2 methoxyvininole) pyridine (200.0 mg, 0.876 mmol) was prepared, and 2N hydrochloric acid (4 mL) was added. The reaction mixture was stirred at 50 ° C. for 1 hour and diluted with water and ethyl acetate. The mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and after removing the desiccant, the solvent was removed under reduced pressure to give 187.7 mg (0.876 mmol) of [5- (4 fluorophenyl) pyridine-3-yl] acetaldehyde. . Yield 99%.
[0061] 〔3〕 1ー（2, 3 ジクロ口フエ二ノレ）ー4 { 2— [ 5—（4ーフノレオロフェニ'  [0061] [3] 1- (2, 3 Diclonal Fuenore) -4 {2— [5— (4-Funoleorofeni '
3—ィル Ίェチル }ピ
Figure imgf000023_0001
3—il Ίtil
Figure imgf000023_0001
1— (2, 3 ジクロロフエニル）ピぺラジン · 1塩酸塩（262 mg， 0.98 mmol)をメタノー ル（ 10· 0 mL)に溶解し、 [5- (4-フルオロフェニル）ピリジン一 3 ィル]ァセトアル デヒド（210 mg， 0.98 mmol) ,酢酸（1 mL)，水素化シァノホウ素ナトリウム（246 mg， 3.9 2 mmol)を順次加えた。反応混合物を室温で 18時間撹拌した後、飽和重曹水を加え て pH = 8とした。酢酸ェチルで抽出し、飽和食塩水で洗浄し、硫酸マグネシウムで乾 燥した。乾燥剤を濾別した後、溶媒を減圧下で除去し、シリカゲルカラムクロマトダラ フィ一で精製して（クロ口ホルム：メタノール = 100： 1→60： 1)、 146 mgの表題化合物 を得た。収率 35%。  1— (2, 3 dichlorophenyl) piperazine monohydrochloride (262 mg, 0.98 mmol) is dissolved in methanol (10.0 mL) and [5- (4-fluorophenyl) pyridine Ru] acetoaldehyde (210 mg, 0.98 mmol), acetic acid (1 mL), sodium cyanoborohydride (246 mg, 3.9 2 mmol) were sequentially added. The reaction mixture was stirred at room temperature for 18 hours, and saturated aqueous sodium hydrogen carbonate was added to adjust to pH = 8. The mixture was extracted with ethyl acetate, washed with saturated brine, and dried over magnesium sulfate. After the desiccant was filtered off, the solvent was removed under reduced pressure and purified by silica gel column chromatography (black mouth form: methanol = 100: 1 → 60: 1) to give 146 mg of the title compound. . Yield 35%.
:H NMR (400 MHz, CDC1 ): δ 2.71-2.76 (6H， m)， 2.91 (2H， t， J=8.5 Hz), 3.10 (4H : H NMR (400 MHz, CDC1): δ 2.71-2.76 (6H, m), 2.91 (2H, t, J = 8.5 Hz), 3.10 (4H
3  Three
， br)， 6.97 (2H， dd， J=3.0, 6.6 Hz), 7.15-7.19 (4H， m)， 7.53-7.57 (2H， m)， 7.69 (1H ， t， J=2.1 Hz), 8.48 (1H， d， J=2.0 Hz), 8.65 (1H， d， J=2.2 Hz).  , Br), 6.97 (2H, dd, J = 3.0, 6.6 Hz), 7.15-7.19 (4H, m), 7.53-7.57 (2H, m), 7.69 (1H, t, J = 2.1 Hz), 8.48 ( 1H, d, J = 2.0 Hz), 8.65 (1H, d, J = 2.2 Hz).
[0063] 試験例 1 [0063] Test Example 1
[0064] 実施例 1ないし実施例 4の化合物の 5— HT 結合活性  [0064] 5-HT binding activity of the compounds of Examples 1 to 4
1A  1A
[0065] 文献記載の方法（Hall, M.ら、 J. Neurochem., 1985年、第 44巻、 1685— 1696頁に 記載）に従い雄ラットの脳皮質より調製した膜画分 0.4 mgに、 0.25 nMの [ ]ー8 ーヒドロキシ DPATを加えて、 22°Cで 60分間インキュベートした。フィルター濾過、 3回洗浄後に、フィルター上の [3H]— 8—ヒドロキシー DPATを測定した。各化合物 は、 10— 7 Mの濃度で用いた。 [0065] According to the method described in the literature (Hall, M. et al., J. Neurochem., 1985, 44, 1685-1696), 0.4 mg of membrane fraction prepared from the brain cortex of male rats nM [] -8-hydroxy DPAT was added and incubated at 22 ° C for 60 minutes. After filtering and washing 3 times, [3H] -8-hydroxy-DPAT on the filter was measured. Each compound was used at a concentration of 10- 7 M.
結果を表 1に示す。  The results are shown in Table 1.
[0066] [表 1] Entry 化合物 10— 7 M での結合0 /。 [0066] [Table 1] Entry Compound 10—The bond at 7 M 0 /.
1 実施例 1の化合物 54  1 Compound of Example 1 54
2 実施例 2の化合物 56  2 Compound of Example 2 56
3 実施例 3の化合物 63  3 Compound of Example 3 63
4 実施例 4の化合物 72  4 Compound of Example 4 72
[0067] 試験例 2 [0067] Test Example 2
[0068] 実施例 5ないし実施例 9の化合物の 5— HT 結合活性  [0068] 5-HT binding activity of the compounds of Examples 5 to 9
1A  1A
[0069] 文献記載の方法（Kato, T.ら、 Japan J Pharmacol, 1990年、第 54巻、 478-481頁に 記載）を参考に、雄ラットの海馬より調製した膜画分に 0.2nMの [3H] 8 ヒドロキシ DPATを加えて、室温で 20分間インキュベートした。フィルター濾過、 3回洗浄後 にフィルター上の [3H] 8 ヒドロキシ DPATを測定した。各化合物は、 10— 7Mの 濃度で用いた。 [0069] By referring to the method described in the literature (Kato, T. et al., Japan J Pharmacol, 1990, 54, 478-481), 0.2 nM of the membrane fraction prepared from the hippocampus of male rats was used. [ 3 H] 8 hydroxy DPAT was added and incubated at room temperature for 20 minutes. [ 3 H] 8 hydroxy DPAT on the filter was measured after filtering and washing 3 times. Each compound was used at a concentration of 10- 7 M.
結果を表 2に示す。  The results are shown in Table 2.
[0070] [表 2]  [0070] [Table 2]
Figure imgf000024_0001
Figure imgf000024_0001
[0071] 試験例 3 [0071] Test Example 3
[0072] 5 -HT 受容体作動試験  [0072] 5 -HT receptor agonist test
1A  1A
[0073] 3— 1 )使用細胞および膜標品の調製  [0073] 3—1) Preparation of cells and membrane preparation
実験にはヒト 5— HT 受容体発現チャイニーズ'ノ、ムスター卵巣（CHO)細胞（huma  Human 5-HT receptor-expressing Chinese, muster ovary (CHO) cells (huma)
1A  1A
n 5-HT /CHO)を用いた。細胞は、 5% COインキュベータ一中で、 10% FCS、 500 μ n 5-HT / CHO). Cells in a 5% CO incubator, 10% FCS, 500 μ
1Α 2 1Α 2
g/mL Geneticinお J:び 100 U/mL penicillin-100 μ g/mL streptmoycin^含む F12 (す ベてギブコ）にて培養し、膜標品はエー.ニューマン (A.Newman)らの方法（Eur. J. Ph armacol., 307， 107-111(1996))に従って調製した。すなわち、緩衝液 A (20mM HEPE S、 5mM MgSO )にて剥離 '採取した細胞を、テフロン (登録商標）グラスホモジナイザ  G / mL Geneticin and J: and 100 U / mL penicillin-100 μg / mL streptmoycin ^ in culture with F12 (Subete Gibco), and membrane preparation is the method of A. Newman et al. Eur. J. Pharmacol., 307, 107-111 (1996)). That is, exfoliate with buffer A (20 mM HEPE S, 5 mM MgSO 4) and collect the collected cells using a Teflon (registered trademark) glass homogenizer.
4  Four
一（Teflon-glass homogenizer)でホモジナイズした後、遠心操作（50，000 X g、 30min、 4°C)を行った。沈渣は適量の緩衝液 Aに再懸濁し、使用まで— 80°Cで保存した。膜 標品中のタンパク質量は、標準物質に牛血清アルブミン (Albumin Bovine, SIGMA) を用いて、ダイ'リエージェント 'コンセントレート（Dye Reagent Concentrate, BIO-RA D)により定量した。 Homogenize with one (Teflon-glass homogenizer), then centrifuge (50,000 X g, 30 min, 4 ° C). The sediment was resuspended in an appropriate amount of buffer A and stored at -80 ° C until use. The amount of protein in the membrane preparation was quantified by Dye Reagent Concentrate (BIO-RA D) using bovine serum albumin (Albumin Bovine, SIGMA) as a standard substance.
3— 2)実験方法 3— 2) Experimental method
ヒト 5— HT 受容体に対する [35S]GTP y S結合の測定は、上記の膜標品を用い、ェ The measurement of [ 35 S] GTP y S binding to the human 5-HT receptor was performed using the above membrane preparation.
1A  1A
一'ニューマン（A. Newman)らの方法（Eur. J. Pharmacol., 307， 107-111(1996))に準 じて行った。すなわち、 10— 5Mの各被験物質を含む緩衝液 B(20mM HEPES、 100 mM NaCl、 10 mM MgSO、 1 M GDP、 0.1 mM DTT)中に、 0.05 nMの [3 ]GTP γ S (デ This was performed according to the method of E. Newman et al. (Eur. J. Pharmacol., 307, 107-111 (1996)). That is, buffer B containing each test substance 10- 5 M (20mM HEPES, 100 mM NaCl, 10 mM MgSO, 1 M GDP, 0.1 mM DTT) in, the 0.05 nM [3] GTP γ S ( de
4  Four
ュポン NEN)および一定量（約 50 g/tube)の膜標品を加え、全量 1 mLの反応液 を 22ないし 30 °Cで 20分間インキュベートした。反応終了後、反応液を氷冷した 5mL の緩衝液 Bで希釈し、ガラス繊維ろ紙 (Whatman、 GF/B)を用いて速やかに吸引ろ過 することにより反応を終了させた。同緩衝液で 2回洗浄したガラス繊維ろ紙をバイアル に入れ、 4mLの ACS— IIを添加した。ろ紙上の [3 ]GTP γ Sの放射活性を液体シンチ レーシヨンカウンターで測定した。 10 \の GTP y S (Sigma)存在下で得られた非特 異的結合から [35S]GTP y Sの特異的結合を求めた。各被験物質の 5— HT 受容体 (Upon NEN) and a fixed amount (about 50 g / tube) of membrane preparation were added, and a total volume of 1 mL of the reaction solution was incubated at 22-30 ° C for 20 minutes. After completion of the reaction, the reaction solution was diluted with 5 mL of ice-cooled buffer B, and the reaction was terminated by rapid suction filtration using glass fiber filter paper (Whatman, GF / B). Glass fiber filter paper washed twice with the same buffer was placed in a vial and 4 mL of ACS-II was added. The radioactivity of [ 3 ] GTPγS on the filter paper was measured with a liquid scintillation counter. Specific binding of [ 35 S] GTP y S was determined from the non-specific binding obtained in the presence of 10 \ GTP y S (Sigma). 5-HT receptor for each test substance
1A 作動活性は、それぞれ 10 ,1 Mのセロトニン（5-HT)による [3 ]GTP y S結合増加を 10 0%としたときの増加率（5— HT 受容体作動活性）で表した。 1A agonist activity was expressed as the rate of increase (5-HT receptor agonist activity) when the increase in [ 3 ] GTP y S binding by 10 and 1 M serotonin (5-HT) was 100%.
1A  1A
結果を表 3に示す。  The results are shown in Table 3.
[表 3] [Table 3]
Figure imgf000025_0001
産業上の利用可能性
Figure imgf000025_0001
Industrial applicability
本発明の、環状イミド骨格、テトラヒドロナフタレン骨格、テトラヒドロジァザべンゾァ ズレノン骨格、又はフエニルピリジル骨格を有するァミノ化合物又はその薬学的に許 容される塩は、不安障害、うつ等の気分障害、統合失調症等の精神病性障害、発達 障害、又はパーキンソン病等の運動障害等の治療剤又は予防剤として利用できる。 The amino compound having a cyclic imide skeleton, a tetrahydronaphthalene skeleton, a tetrahydrodiazabenzazolenenone skeleton, or a phenylpyridyl skeleton of the present invention, or a pharmaceutically acceptable product thereof. The tolerated salt can be used as a therapeutic or prophylactic agent for anxiety disorders, mood disorders such as depression, psychotic disorders such as schizophrenia, developmental disorders, or movement disorders such as Parkinson's disease.

Claims

請求の範囲 The scope of the claims
[1] 式 (1) :  [1] Equation (1):
Figure imgf000027_0001
Figure imgf000027_0001
[式中、 R1は、水素原子又はメチル基を表し、 R2及び R3は、ともに水素原子を表すか 、あるいは R2及び R3は結合して、メチレン基を表す。 ] [Wherein, R 1 represents a hydrogen atom or a methyl group, and R 2 and R 3 both represent a hydrogen atom, or R 2 and R 3 combine to represent a methylene group. ]
で表される化合物、又はその薬学的に許容される塩。  Or a pharmaceutically acceptable salt thereof.
[2] 式 (2) :  [2] Equation (2):
Figure imgf000027_0002
Figure imgf000027_0002
で表される化合物、又はその薬学的に許容される塩。  Or a pharmaceutically acceptable salt thereof.
[3] 式 (3) :  [3] Equation (3):
Figure imgf000027_0003
Figure imgf000027_0003
[式中、 R4は、水素原子又はメチル基を表す。 ] [Wherein, R 4 represents a hydrogen atom or a methyl group. ]
で表される化合物、又はその薬学的に許容される塩。  Or a pharmaceutically acceptable salt thereof.
[4] 式 (4) :
Figure imgf000028_0001
[4] Equation (4):
Figure imgf000028_0001
で表される化合物、又はその薬学的に許容される塩。  Or a pharmaceutically acceptable salt thereof.
[5] 式 (5) :  [5] Equation (5):
Figure imgf000028_0002
Figure imgf000028_0002
で表される化合物、又はその薬学的に許容される塩。  Or a pharmaceutically acceptable salt thereof.
[6] 請求項 1〜5のいずれか一項に記載の化合物又はその薬学的に許容される塩を有 効成分として含有する 5— HT 受容体作動薬。  [6] A 5-HT receptor agonist comprising the compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof as an active ingredient.
1A  1A
[7] 請求項 1〜5のいずれか一項に記載の化合物又はその薬学的に許容される塩を有 効成分として含有する不安、うつ、パーキンソン病、又は統合失調症の治療薬又は 予防薬。  [7] A therapeutic or prophylactic agent for anxiety, depression, Parkinson's disease, or schizophrenia comprising the compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof as an active ingredient .
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