WO1993005036A1 - Derive de carbazole n-substitue - Google Patents

Derive de carbazole n-substitue Download PDF

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Publication number
WO1993005036A1
WO1993005036A1 PCT/JP1992/001129 JP9201129W WO9305036A1 WO 1993005036 A1 WO1993005036 A1 WO 1993005036A1 JP 9201129 W JP9201129 W JP 9201129W WO 9305036 A1 WO9305036 A1 WO 9305036A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
ethyl
group
present
carbazole derivative
Prior art date
Application number
PCT/JP1992/001129
Other languages
English (en)
Japanese (ja)
Inventor
Satoshi Hibino
Shigeru Okuyama
Atsuro Nakazato
Yutaka Kawashima
Original Assignee
Taisho 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 Taisho Pharmaceutical Co., Ltd. filed Critical Taisho Pharmaceutical Co., Ltd.
Publication of WO1993005036A1 publication Critical patent/WO1993005036A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the present invention relates to an N-substituted rubazole derivative having an antipsychotic effect.
  • Psychotic drugs are used not only in the treatment of schizophrenia but also in the treatment of problematic behaviors (aggression, mental agitation, wandering, delirium, etc.) in cerebrovascular disorders and senile dementia. Are severely affected by extrapyramidal disorders, which is a major problem.
  • a sigma receptor antagonist One of them is a sigma receptor antagonist.
  • the sigma receptor is considered to be a receptor involved in mental disorders such as hallucinations, and compounds having a specific affinity for this receptor show antipsychotic effects without causing extrapyramidal disorders.
  • An object of the present invention is to provide a compound having an antipsychotic effect without causing extrapyramidal disorders. Disclosure of the invention
  • the present inventors have conducted intensive studies on a compound having a carbazole skeleton, and as a result, have found a novel carbazole compound that is specific and has high affinity for sigma receptor and has completed the present invention.
  • the present invention is based on the formula 1
  • R 1 and R 3 are the same or different and are a hydrogen atom, a halogen atom, a hydroxyl group or an alkoxy group having 1 to 5 carbon atoms
  • R 2 is a hydrogen atom or a methyl group
  • R 4 is An alkyl group having 1 to 5 carbon atoms
  • n is an integer of 1 to 4.
  • the halogen atom is a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.
  • the alkoxy group is a linear or branched one, for example, a methoxy group, an ethoxy group, a broboxy group, an isopropoxy group, a butoxy group.
  • Alkyl groups are straight-chain or branched-chain, such as methyl, ethyl, bromo, isopropyl, butyl, and benzyl.
  • the salt of the compound represented by the formula 1 of the present invention means a pharmacologically acceptable salt, for example, a salt with a mineral acid such as sulfuric acid, hydrochloric acid, phosphoric acid, acetic acid, lactic acid, tartaric acid, and fumaric acid. Salts with organic acids such as sulfonic acid, maleic acid, trifluoroacetic acid, and methanesulfonic acid.
  • a mineral acid such as sulfuric acid, hydrochloric acid, phosphoric acid, acetic acid, lactic acid, tartaric acid, and fumaric acid.
  • Salts with organic acids such as sulfonic acid, maleic acid, trifluoroacetic acid, and methanesulfonic acid.
  • the compound of the present invention of the formula 1 has optical isomers (D-form and L-form), and the present invention includes both of them.
  • the compound of Formula 1 has the formula
  • R 4 and n are as defined above, and X is an arbitrary halogen atom.
  • a salt thereof e.g., hydrochloride.
  • This reaction is carried out in a solvent inert to the reaction (for example, benzene, chloroform, methylene chloride, tetrahydrofuran, ⁇ , ⁇ -dimethylformamide, dimethylsulfoxide, water, or a mixture thereof) or in a solvent-free solvent.
  • a solvent inert for example, benzene, chloroform, methylene chloride, tetrahydrofuran, ⁇ , ⁇ -dimethylformamide, dimethylsulfoxide, water, or a mixture thereof
  • a solvent inert for example, benzene, chloroform, methylene chloride, tetrahydrofuran, ⁇ , ⁇ -dimethylformamide, dimethylsulfoxide, water, or a mixture thereof
  • a basic compound for example, pyridine, triethylamine, sodium hydroxide, potassium hydroxide, sodium carbonate, carbonated carbonate, sodium hydride, etc.
  • a phase transfer catalyst
  • the desired product can be obtained by filtration. If no crystals are precipitated, the desired product can be obtained by extracting with an appropriate solvent (for example, benzene, chloroform, ethyl acetate, methanol, etc.) and treating it by a conventional method.
  • an appropriate solvent for example, benzene, chloroform, ethyl acetate, methanol, etc.
  • the compound of the present invention is mixed with a solid or liquid carrier and prepared into a pharmaceutical preparation suitable for oral or parenteral administration.
  • Pharmaceutical preparations include solid preparations such as tablets, pills, capsules and granules, liquid preparations such as injections, syrups and emulsions, and external preparations such as ointments and suppositories, which are commonly used. It is manufactured according to formulation technology.
  • each of the above preparations may contain commonly used additives such as excipients, binders, lubricants, stabilizers, wetting agents, emulsifiers and the like.
  • injectables include dissolving agents such as distilled water for injection, physiological saline, Ringer's solution, methyl paraoxybenzoate, and Palau. --
  • Preservatives such as propyl xyloxybenzoate may be included.
  • syrups and emulsions include sorbitol syrup, methylcellulose, glucose, sucrose tablets, hydroxyethyl cellulose, cooking oil, glycerin, ethanol, water, etc., as well as gum arabic and lecithin? It may contain an activator such as a preservative, a twin, or a span.
  • Solid preparations include excipients such as crystalline cellulose, lactose, corn starch, mannitol, lubricating agents such as magnesium stearate, talc, binders such as hydroxybutyl vircellulose and polyvinyl vilolidone, and calcium carboxymethyl cellulose.
  • a disintegrant, a fluid ft improver such as light gay anhydride, or the like can be used.
  • the dose of the compound of the present invention to a treated patient may vary depending on the patient's age, disease type and condition, etc., but usually 0.5 to 20 mg per day can be administered to an adult in one or several divided doses.
  • 6-Acetoxycarbazole was used instead of 6-methoxycarbazole, and reacted with N-methyl-2- (2-chloroethyl) pyrrolidine hydrochloride in the same manner as in Example 1.
  • 2-hydroxy-91 (N-methylpyrrolidinone 2-ethyl) carbazole was obtained.
  • the animals used were male Wistar rats.
  • Binding reactions using [ 3 H] -labeled ligands are described in Molecular Pharmacology, Vol. 32, p. 772 (1987), Journal of Pharmaceuticals and Pharmacology, Vol. 32, p. 820 (1987), respectively. Year)), the following methods (1) to (3) were used.
  • the reaction was carried out at 21 for 90 minutes.
  • the reaction was performed at 37 ° C for 10 minutes.
  • the solution was suction-filtered through a glass filter (GFZB), and the radioactivity of the filter paper was measured with a liquid scintillation vector meter.
  • GFZB glass filter
  • D 2 Resebuta is that is shown by the value for [3 H] Subiberon bond.
  • the compounds of the present invention are specific for sigma receptors and show high affinity. Therefore, the compound of the present invention exhibits an antipsychotic effect without causing extrapyramidal dysfunction, and thus is useful as a therapeutic agent for schizophrenia, cerebrovascular disorders, and problematic behavior associated with senile dementia.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un dérivé de carbazole N-substitué représenté par la formule générale (I) ainsi qu'un sel de celui-ci, dans laquelle R1 et R3 peuvent être identiques ou différents et représentent chacun hydrogène, halogène, hydroxy ou alkoxy contenant 1 à 5 atomes de carbone, R2 représente hydrogène ou méthyle, R4 représente alkyle contenant 1 à 5 atomes de carbone, et n représente un nombre entier compris entre 1 et 4. Ce composé est utile dans le traitement de la schizophrénie sans provoquer de troubles extrapyramidaux, et dans le traitement de comportements problématiques accompagnant des troubles cérébro-vasculaires ou la démence sénile.
PCT/JP1992/001129 1991-09-06 1992-09-03 Derive de carbazole n-substitue WO1993005036A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP22685891 1991-09-06
JP3/226858 1991-09-06

Publications (1)

Publication Number Publication Date
WO1993005036A1 true WO1993005036A1 (fr) 1993-03-18

Family

ID=16851677

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1992/001129 WO1993005036A1 (fr) 1991-09-06 1992-09-03 Derive de carbazole n-substitue

Country Status (2)

Country Link
AU (1) AU2511192A (fr)
WO (1) WO1993005036A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB809488A (en) * 1956-02-01 1959-02-25 Promonta Chem Fab Carbazole derivatives and process for the production thereof
GB822592A (en) * 1956-06-27 1959-10-28 Promonta Chem Fab Carbazole derivatives and process for the production thereof
US3093651A (en) * 1958-11-07 1963-06-11 Us Vitamin Pharm Corp Nu-alkyl-2-(2-[9-carbazolyl-ethyl])-piperidines

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB809488A (en) * 1956-02-01 1959-02-25 Promonta Chem Fab Carbazole derivatives and process for the production thereof
GB822592A (en) * 1956-06-27 1959-10-28 Promonta Chem Fab Carbazole derivatives and process for the production thereof
US3093651A (en) * 1958-11-07 1963-06-11 Us Vitamin Pharm Corp Nu-alkyl-2-(2-[9-carbazolyl-ethyl])-piperidines

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
ARZNEIM.-FORSCH., Vol. 9, No. 4, (1959), O. NIESCHULZ et al., "Pharmacological Studies on Some N-(Alkylpiperidyl) Carbazol Derivatives", p. 219-228. *
J. AMER. PHARM. ASSOC., Vol. 46, (July 1957), S.L. SHAPIRO et al., "Piperidines with Motor Depressor and Anti-Inflammatory Properties", p. 333-336. *

Also Published As

Publication number Publication date
AU2511192A (en) 1993-04-05

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