WO1995011239A1 - Nouveau derive de phenoxyalkylpiperazine - Google Patents

Nouveau derive de phenoxyalkylpiperazine Download PDF

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Publication number
WO1995011239A1
WO1995011239A1 PCT/JP1994/001720 JP9401720W WO9511239A1 WO 1995011239 A1 WO1995011239 A1 WO 1995011239A1 JP 9401720 W JP9401720 W JP 9401720W WO 9511239 A1 WO9511239 A1 WO 9511239A1
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WO
WIPO (PCT)
Prior art keywords
compound
group
present
receptor
affinity
Prior art date
Application number
PCT/JP1994/001720
Other languages
English (en)
Japanese (ja)
Inventor
Yoichi Kawashima
Junzo Matsumoto
Kiyoshi Matsuno
Toshihiko Senda
Keiko Hirano
Original Assignee
Santen Pharmaceutical Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Santen Pharmaceutical Co., Ltd. filed Critical Santen Pharmaceutical Co., Ltd.
Publication of WO1995011239A1 publication Critical patent/WO1995011239A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • 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
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • the present invention relates to a novel phenoxyalkyl useful as a therapeutic agent for cerebral nerve dysfunction such as dementia, schizophrenia and anxiety disorder, diseases associated with immune disorders and endocrine disorders, and gastrointestinal ulcers. It relates to a piperazine derivative.
  • this novel compound not only has an affinity for the sigma receptor, but also has an improving effect on learning impairment due to cerebrovascular disorders and an amount of acetylcholine in the brain. It also has an increasing effect on the brain, and was found to be useful as a therapeutic agent for brain neurological dysfunction. Disclosure of the invention
  • the present invention provides a compound represented by the following general formula [I] and a salt thereof (hereinafter, referred to as the compound of the present invention).
  • R represents one or more groups selected from a hydrogen atom, a hydroxy group, a lower alkoxy group, and a lower alkylenedioxy group.
  • ⁇ represents a lower alkylene group.
  • lower alkoxy refers to those having 1 to 6 carbon atoms such as methoxy, ethoxy, propoxy, hexyloxy, isopropoxy, t-butoxy, etc.
  • a lower or higher alkylene is a straight or branched chain having 1 to 6 carbon atoms such as methylene, ethylene, propylene, butylene, (dimethyl) methylene, and (getyl) methylene;
  • a lower alkylenedioxy group refers to an alkylenedioxy group having 1 to 6 carbon atoms between two oxygen atoms, such as methylenedioxy and ethylenedioxy.
  • salts include pharmaceutically acceptable salts such as hydrochloride, sulfate, maleate and fumarate.
  • X represents a reactive group such as a halogen atom or a lower alkane sulfonyloxy group.
  • a compound of the formula [III] is reacted with diethanolamine to give a compound of the formula [III], which is then reacted with thionyl chloride or methansulfonyl chloride to give a compound of the formula [III]
  • the compound of the formula [IV] is led to a compound of the formula [IV], which is then reacted with cyclohexylamine to obtain the compound [I] of the present invention.
  • the compound obtained by the above method can be converted into a salt as described above by a conventional method.
  • the compound represented by the general formula [I] may have optical isomers, and they are all included in the present invention.
  • Representative examples of the compounds of the present invention include 1-cyclohexyl 4- (3-phenoxypropyl) piperazine, 1-cyclohexyl-14- (2-phenoxicetyl) piperazine, 1-six mouth hexyl 4 -— [2-[(3,4-methylenedioxy) phenyl] ethyl] piperazine or salts thereof.
  • Pulsinelli et al. (Strokeil, 267 (1979)), which is a learning impairment model due to ischemia, which is known as a disease model of dementia due to cerebrovascular disorders.
  • the compound of the present invention had an improving effect on learning disabilities.
  • a compound that increases the amount of acetylcholine in the brain is useful as a therapeutic agent for dementia and the like (The New England Journal of Medicine, 315, 1241-1245 (1986) ), Based on the literature of Matsuno et al. (Brain Research, 575, 315-319 (1992)), the acetylcholine content in rat brain was measured. Indicated.
  • the compound of the present invention has a strong affinity for biceptors, and further has an improving effect on learning disorders due to cerebrovascular disorders and an effect of increasing the amount of acetylcholine in the brain. It is useful as a remedy for cerebral nerve dysfunction such as dementia, schizophrenia, anxiety, immune disorders and endocrine disorders, diseases associated with digestive system ulcers, etc. all right.
  • the method of administration of the compound of the present invention may be oral or parenteral.
  • the dosage form include tablets, capsules, soft capsules, granules, and injections. It can be formulated using commonly used techniques.
  • oral preparations such as tablets, capsules, soft capsules, and granules may be used, if necessary, in the form of bulking agents such as lactose, starch, microcrystalline cellulose, vegetable oil, etc., lubricants such as magnesium stearate, talc, etc.
  • binders such as hydroxypropylcellulose and polyvinylpyrrolidone, disintegrants such as calcium carboxymethylcellulose, coating agents such as hydroxypropylmethylcellulose, macrogol and silicone resin, and coating agents such as gelatin film.
  • the dosage is appropriately selected depending on the condition, dosage form, etc., but it is usually sufficient to administer lmg to: LOOO mg once or several times a day.
  • the membrane preparation was prepared by the following method according to the paper by Tam et al. (Proc. Natl. Acad. Sci. USA O, 6703-6707 (19)).
  • the brain was isolated from a Hartley guinea pig (body weight: 300 to 400 g), and tris-HCl buffer (50 mM, pH 7.7, 0.3 After homogenization (containing 2 M sucrose), the mixture was centrifuged to obtain a supernatant. The supernatant was ultracentrifuged for 20 minutes, and the resulting pellet was suspended in Tris-HCl buffer (50 mM, pH 7.7; the same applies hereinafter). I got
  • the specific binding amount of [ a H] (+) — SKF — 10047 was determined in advance by the following method. Doo Risu membrane specimen suspended in HCl buffer, was dissolved in Application Benefits sous-HCl buffer [3 H] (+) - SKF - 1 0 0 4 7 a (5 n M) was added (test compound Was added) and reacted at 25 ° C. for 30 minutes. After completion of the reaction, the reaction solution was subjected to suction filtration with a glass filter, and the radioactivity on the filter was measured with a liquid scintillation counter to determine the total binding amount. In addition, [ 3 H] (+)-SKF-100 4 7 (5 nM), which has no radioactivity (+) — SKF — 100 4 7 Two one
  • the amount of binding between the membrane sample and [ 3 H] (+) — SKF—10747 was measured in the presence of the test compound, and was determined earlier by changing the concentration of the test compound.
  • the (I c 50) was determined.
  • the present compound has a strong affinity to fine receptors both, for example, IC 5 Q of compound 1 1. was 3 n M.
  • the compound phenoxyalkylpiperazine derivative of the present invention has an affinity for a sigma receptor. It is useful as a therapeutic agent for gastrointestinal ulcers.

Abstract

Nouveau composé de formule générale (I), dans laquelle R représente au moins un groupe choisi parmi hydrogène, hydroxy, alkoxy inférieur et alkylènedioxy inférieur, et A représente alkylène inférieur. Ledit composé est utile en tant que remède contre les troubles de la fonction des nerfs crâniens tels que la démence, la schizophrénie et l'anxiété, les maladies accompagnant la perte de l'immunité et la dyscrinie, les ulcères de l'appareil digestif, etc.
PCT/JP1994/001720 1993-10-22 1994-10-13 Nouveau derive de phenoxyalkylpiperazine WO1995011239A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP5/287659 1993-10-22
JP05287659A JP3104005B2 (ja) 1993-10-22 1993-10-22 新規フェノキシアルキルピペラジン誘導体

Publications (1)

Publication Number Publication Date
WO1995011239A1 true WO1995011239A1 (fr) 1995-04-27

Family

ID=17720071

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1994/001720 WO1995011239A1 (fr) 1993-10-22 1994-10-13 Nouveau derive de phenoxyalkylpiperazine

Country Status (2)

Country Link
JP (1) JP3104005B2 (fr)
WO (1) WO1995011239A1 (fr)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS55124766A (en) * 1979-03-20 1980-09-26 Otsuka Pharmaceut Co Ltd Antihistaminic
JPS55127371A (en) * 1980-02-14 1980-10-02 Otsuka Pharmaceut Co Ltd Carbostyril derivative
JPS55162774A (en) * 1979-06-06 1980-12-18 Otsuka Pharmaceut Co Ltd Carbostyril derivative
JPS5646812A (en) * 1979-09-27 1981-04-28 Otsuka Pharmaceut Co Ltd Central nervous system depressant
JPS62116557A (ja) * 1985-11-15 1987-05-28 Takeda Chem Ind Ltd 置換ベンジルラクタム類

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS55124766A (en) * 1979-03-20 1980-09-26 Otsuka Pharmaceut Co Ltd Antihistaminic
JPS55162774A (en) * 1979-06-06 1980-12-18 Otsuka Pharmaceut Co Ltd Carbostyril derivative
JPS5646812A (en) * 1979-09-27 1981-04-28 Otsuka Pharmaceut Co Ltd Central nervous system depressant
JPS55127371A (en) * 1980-02-14 1980-10-02 Otsuka Pharmaceut Co Ltd Carbostyril derivative
JPS62116557A (ja) * 1985-11-15 1987-05-28 Takeda Chem Ind Ltd 置換ベンジルラクタム類

Also Published As

Publication number Publication date
JP3104005B2 (ja) 2000-10-30
JPH07118249A (ja) 1995-05-09

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