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WO1996014297A1 - Nouveaux derives de lactame - Google Patents

Nouveaux derives de lactame Download PDF

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Publication number
WO1996014297A1
WO1996014297A1 PCT/JP1995/002256 JP9502256W WO9614297A1 WO 1996014297 A1 WO1996014297 A1 WO 1996014297A1 JP 9502256 W JP9502256 W JP 9502256W WO 9614297 A1 WO9614297 A1 WO 9614297A1
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WO
WIPO (PCT)
Prior art keywords
alkyl
lower alkylene
substituted
hydrocarbon ring
compound
Prior art date
Application number
PCT/JP1995/002256
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English (en)
Japanese (ja)
Inventor
Atsuyuki Kojima
Fujio Antoku
Mayumi Yoshigi
Norihiko Tanno
Toshio Nishihara
Tomohiro Toyoda
Yukihiro Ohno
Original Assignee
Sumitomo Pharmaceuticals Company, Limited
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 Sumitomo Pharmaceuticals Company, Limited filed Critical Sumitomo Pharmaceuticals Company, Limited
Priority to JP51519696A priority Critical patent/JP3948744B2/ja
Publication of WO1996014297A1 publication Critical patent/WO1996014297A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/08—Bridged systems

Definitions

  • the present invention relates to a novel lactam derivative useful as a psychotropic substance and an acid addition salt thereof. More specifically, the compounds of the present invention have, for example, psychotropic effects such as antipsychotic effects, anxiety-relieving effects, and antidepressant effects, and include, for example, schizophrenia, senile psychiatric disorders, depression, It is useful as a remedy for the symptom and accompanying symptoms of senile dementia.
  • psychotropic effects such as antipsychotic effects, anxiety-relieving effects, and antidepressant effects
  • schizophrenia, senile psychiatric disorders, depression It is useful as a remedy for the symptom and accompanying symptoms of senile dementia.
  • Lactam derivatives having a psychotropic effect are disclosed in Journal of Medicinal Chemistry (J. Med. Chem., H 1068 (1991)) and JP-T-Hei 7-5303723. Things are known.
  • An object of the present invention is to provide a new and excellent psychotropic substance.
  • the present invention has the general formula (I)
  • R l, R 2, R 3, R 4 each represents a hydrogen atom or a lower alkyl an if, R 1 and R 2, R 3 and R 4, R 1 and R 3 or R 2 and R 4
  • the hydrocarbon ring may be linked with a lower alkylene or an oxygen atom, and the lower alkylene and the hydrocarbon ring may be combined with each other.
  • n 0 or 1).
  • A represents lower alkylene, lower alkenylene or a hydrocarbon ring.
  • the lower alkylene, lower alkenylene and hydrocarbon ring may be substituted with at least one alkyl or hydroxyl group.
  • the hydrocarbon ring may also be bridged with a lower alkylene or oxygen atom optionally substituted with at least one alkyl or hydroxyl group.
  • p and q represent 0, 1 or 2, respectively.
  • G represents N (nitrogen atom) or CH
  • Ar represents an aromatic heterocyclic group or an aromatic hydrocarbon group
  • G represents CH and Ar represents phenoxy.
  • the aromatic heterocyclic group, aromatic hydrocarbon group and phenoxy may be substituted with at least one lower alkyl, lower alkoxy or halogen atom) or an acid addition salt thereof.
  • the lower alkyl includes, for example, a linear or branched alkyl group having 1 to 4 carbon atoms, and specific examples include methyl, ethyl, propyl, 2-propyl, and petyl.
  • the alkyl includes, for example, a linear or branched alkyl group having 1 to 6 carbon atoms, preferably a lower alkyl having 1 to 4 carbon atoms, and specifically, methyl, ethyl, propyl, 2- Propyl, butyl and the like.
  • the hydrocarbon ring include cycloalkanes having 3 to 7 carbon atoms and cycloalkenes having 5 to 7 carbon atoms.
  • Examples of cyclohexane include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane and the like.
  • Examples of the cycloalkene having 5 to 7 carbon atoms include cyclopentene, cyclohexene, and cycloheptene.
  • hydrocarbon ring bridged with a lower alkylene or the hydrocarbon ring bridged with an oxygen atom examples include a ring having 5 to 10 carbon atoms.
  • Examples of the lower alkylene for example, an group having 1-3 carbons, specifically methylene, ethylene, and trimethylene like force f.
  • Examples of the lower alkenylene include groups having 2 or 3 carbon atoms, and specific examples include ethenylene and propenylene.
  • Examples of the bonding position of the hydrocarbon ring in A include, for example, 1,1,1,1,1,2-1, -1,3, -1,1,4 and the like.
  • aromatic hydrocarbon group examples include groups having 6 to 10 carbon atoms, and specific examples include phenyl and naphthyl.
  • aromatic heterocyclic group examples include a monocyclic aromatic heterocyclic group and a bicyclic aromatic heterocyclic group.
  • Examples of the monocyclic aromatic heterocyclic group include a group having 5 to 6 carbon atoms and a group having 1 to 4 nitrogen atoms, oxygen atoms or sulfur atoms as hetero atoms, and specific examples thereof include pyridyl, pyrimidinyl, Thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, furyl, imidazolyl and the like.
  • bicyclic aromatic heterocyclic group examples include a group having 6 to 10 carbon atoms and 1 to 5 nitrogen atoms, oxygen atoms or sulfur atoms as a hetero atom.
  • Aromatic heterocyclic groups condensed with benzene rings such as benzoisothiazolyl, benzisoxazolyl, benzofuryl, benzothenyl, quinolyl, isoquinolyl, indolyl, indazolyl, benzimidazolyl, benzoxazolyl, naphthyridinyl , Pteridinyl, chenofuranyl, imidazo thiophenyl, imidazofuranyl and the like.
  • the lower alkoxy includes, for example, a straight-chain or branched-chain alkoxy group having 1 to 4 carbon atoms, and specific examples include methoxy, ethoxy, propoxy, 2-propoxy, butoxy and the like.
  • Examples of the halogen atom include fluorine, chlorine, bromine, and iodine.
  • Examples of the acid addition salts include addition salts with pharmaceutically acceptable inorganic acids and organic acids.
  • Examples of the inorganic acid include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, and the like.
  • Can be Examples of the organic acid include acetic acid, oxalic acid, citric acid, lingic acid, tartaric acid, maleic acid, fumaric acid and the like.
  • the compound [I] of the present invention includes stereoisomers and / or optical isomers.
  • the present invention includes a mixture of these isomers and an isolated isomer.
  • the compound [I] of the present invention may exist as a hydrate or a solvate. In the present invention, these hydrates or solvates are included.
  • A is a group of compounds having a hydrocarbon ring
  • Z is a group of compounds having a hydrocarbon ring bridged by lower alkylene or a hydrocarbon ring bridged by an oxygen atom
  • Z is a bridged group.
  • a group of compounds having an unsubstituted hydrocarbon ring is a group of compounds having an unsubstituted hydrocarbon ring.
  • L represents a single bond or a double bond.
  • E represents a lower alkylene which may be substituted with a lower alkyl, an oxygen atom or two hydrogen atoms which are not bonded to each other.
  • N represents 0 or 1.
  • L represents a single bond or a double bond.
  • E represents a lower alkylene or an oxygen atom which may be substituted with a lower alkyl.
  • N represents 0 or 1.
  • the group represented by Ar include a bicyclic aromatic heterocyclic group, naphthyl (where G represents N or CH) or a phenoxy group (where G represents CH). , '.
  • the bicyclic aromatic heterocyclic group, naphthyl and phenoxy may be substituted with at least one lower alkyl, lower alkoxy or halogen atom.
  • the group represented by Ar is a bicyclic aromatic heterocyclic group condensed with a benzene ring, naphthyl (G represents N or CH), and phenoxy (G Represents CH).
  • the aromatic heterocycle, naphthyl and phenoxy fused to the benzene ring may be substituted with at least one lower alkyl, lower alkoxy or halogen atom.
  • More specific examples of the bicyclic aromatic heterocyclic group condensed with a benzene ring include benzisothiazolyl, benzoisoxazolyl, isoquinolyl, benzofuranyl, benzochenyl, indazolyl, and indolyl.
  • G represents N or CH.
  • the benzisothiazolyl, benzisoxazolyl, isoquinolyl, benzofuranyl, benzophenyl, indazolyl and indolyl may be substituted with at least one lower alkyl, lower alkoxy or halogen atom. More specifically, there may be mentioned benzisothiazole-1-yl, benzisoxazo-l-yl 3-yl and indazo-l-yl 3-yl.
  • the compound [I] of the present invention can be produced, for example, by a method represented by the following reaction formula. Production method a)
  • X represents a leaving group (for example, a halogen atom such as chlorine, bromine or iodine, or a sulfonyloxy group such as methanesulfonyloxy or balatruenesulfonyloxy).
  • R i, R 2, R 3, R 4 and n are the same as above.
  • the starting compounds of the production methods a) to c) are known compounds or can be synthesized by the methods described in the following documents.
  • the compound of [II] is described in Journal of Medicinal, Chemistry (J. Med. Chem., 12, 876 (1969); J. Med. Chem., L ⁇ 477 (1972); J. Med. Chem., 26, 14 (1983); J. Med.
  • JP-A-5-17440 The production method of the compound [III] is disclosed in Chemical 'Pharmatical' Viuretin (Chem. Pharm. Bull., 2288 (1991)) and the like.
  • the production method of the compound [V] is disclosed in, for example, JP-A-5-17440.
  • the compound of [VII] is described in the journal “OB” Medicinal ”Chemistry (J. Med. Chem., 2 ⁇ , 761 (1985); J. Med. Chem., 29, 359 (1986); J. Med. Chem., 32, 1147 (1983); J. Med. Chem., 31, 2712 (1986)), JP-A-63-83085, and the like. Have been.
  • the compound of the formula [III] can be synthesized. That is, the compound of the formula [III] is obtained by reacting the compound of the formula [II] with a reducing agent in an inert solvent.
  • the reducing agent for example, NaBH 4, Ca (BH 4 ) 2, UA1H 4,
  • the amount of the reducing agent is 1 to 10 times the molar amount of the compound of the formula [II]
  • the inert solvent is an alcohol-based solvent.
  • Solvents e.g., methanol, ethanol, isopropanol, tertiary butanol, etc.Halogenated hydrocarbon solvents, e.g., dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, etc., or a mixture thereof
  • the amount of the reducing agent is 1 to 10 times the amount of the compound of the formula (II), and is used as an inert solvent.
  • the reaction is carried out using an ether-based solvent such as getyl ether, tetrahydrofuran or the like, or a hydrocarbon-based solvent such as n-hexane, cyclohexane, benzene, toluene or the like, or a mixed solvent thereof. It is desirable to carry out the reaction within the range from room temperature to room temperature.
  • the compound of the formula [I] can be synthesized. That is, the compound of the formula [I] is obtained by reacting a compound of the formula [III] with a trialkylsilane (for example, triethylsilane) in an inert solvent in the presence of an organic acid.
  • a trialkylsilane for example, triethylsilane
  • the amount of the trialkylsilane is 1 to 10 times the molar amount of the compound of the formula [III]
  • the organic acid is in the presence of a large excess of a strong acid such as trifluoroacetic acid.
  • a hydrocarbon solvent such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane and the like, it is desirable to carry out the reaction at a reaction temperature of 130 to the reflux temperature of the solvent.
  • the compound of the formula [I] is obtained by reacting the compound of the formula [IV] and the compound of the formula [V] in the presence of a base and / or a catalyst, if necessary.
  • the amount of the compound of the formula [IV] is in the range of 1 to 1.5 times the mol of the compound of the formula [V]
  • the base is, for example, sodium hydride, sodium amide, carbonate
  • a crown ether such as dibenzo-18-crown-16-ether in the presence of platinum, sodium carbonate or the like is used in an amount of 0.1 to 10% by weight based on the compound of the formula [V].
  • the reaction is performed at a temperature near the boiling point of the solvent using an aromatic solvent such as toluene, xylene, or benzene as a reaction solvent.
  • the compound of the formula [I] is obtained by reacting the compound of the formula [VI] and the compound of the formula [VII] in the presence of a base and, if necessary, a reaction auxiliary.
  • the amount of the compound of the formula (VI) is in the range of 1 to 1.5 times the mol of the compound of the formula (VII), and the base is, for example, sodium hydride, sodium amide, potassium carbonate, Sodium carbonate or the like is used in an amount of 1 to 2 moles relative to the compound of the formula [VII].
  • the reaction aid include iodine such as potassium iodide and sodium iodide.
  • the alkali metal halide is used in the range of 0.1 to 1 mol with respect to the compound of the formula [VII], and the reaction solvent is, for example, dimethylformamide, acetonitrile, toluene, xylene, or benzene. Is it desirable to perform the reaction at a temperature near the boiling point of the solvent?
  • the compound [I] obtained in the production processes a) to c) is purified by recrystallization in a crystallization solvent (for example, alcohol, getyl ether, ethyl acetate, hexane or a mixed solvent thereof), or silica gel chromatography.
  • a crystallization solvent for example, alcohol, getyl ether, ethyl acetate, hexane or a mixed solvent thereof
  • silica gel chromatography silica gel chromatography.
  • Compound [I] can also be purified by converting it into an acid addition salt and recrystallizing it in a crystallization solvent (for example, acetone, dimethyl ether, alcohol, etc.).
  • a crystallization solvent for example, acetone, dimethyl ether, alcohol, etc.
  • the compound of the formula [I] is dissolved in an inert solvent (for example, acetonitrile, alcohol, etc.), and an optically active acid (for example, L-tartaric acid, D-tartaric acid, D-camphoric acid, L-mandelic acid, L-mandelic acid, L- Pyroglutamic acid, D-10-camphorsulfonic acid, D-quinic acid, L-lin: ⁇ , dibenzoyl-L-tartaric acid and the like, and preferably L-tartaric acid and D-tartaric acid).
  • an inert solvent for example, acetonitrile, alcohol, etc.
  • an optically active acid for example, L-tartaric acid, D-tartaric acid, D-camphoric acid, L-mandelic acid, L-mandelic acid, L- Pyroglutamic acid, D-10-camphorsulfonic acid, D-quinic acid, L-lin: ⁇ , dibenzoyl-L-tartaric
  • the temperature at which the salt is formed is preferably within a range from room temperature to the boiling point of the solvent. In order to improve the optical purity, it is desirable to temporarily heat the solvent to near the boiling point. Before the precipitated salt is collected by filtration, the salt can be cooled if necessary to improve the yield.
  • the amount of the optically active acid (resolving agent), the substrate pair to 0.5 to 2.0 equivalents, preferably force of 1 equivalent before and after? Appropriate. If necessary, a high-purity optically active salt can be obtained by recrystallizing the obtained crystal in a crystallization solvent (for example, alcohols and the like).
  • the optically active form of the compound represented by [I] can be obtained as a free form.
  • the compounds of the present invention include dopamine receptors such as dopamine D, dopamine D 2 , dopamine D 3 and dopamine D 4 , serotonin 5-HT 1 A , serotonin 5-HT 2 and the like. Serotonin receptors,. A high affinity for one or more of a variety of receptors one Sabutipu of Norua de Renarin system receptors, such as have o 2.
  • D4 antagonism a subtype of other dopamine receptors, does not cause extrapyramidal side effects during schizophrenia maintenance therapy (Seeman et al. Nature.350.610 (1991). ), Seeman et al., Nature, 358.149 (1992)).
  • the compounds of the present invention have, for example, psychotropic effects such as antipsychotic effects, anxiolytic effects, antidepressant effects, etc., for example, schizophrenia, senile psychiatric disorders, depression, neuropathy. It is useful as a therapeutic drug for accompanying symptoms of senile dementia
  • the compound of the present invention represented by the general formula [I] and the acid addition salt thereof can be administered orally or parenterally when used as a psychotropic drug. That is, it can be orally administered in the form of commonly used dosage forms such as tablets, capsules, syrups and suspensions. Alternatively, solutions in liquid form can be administered parenterally in the form of injections. It can also be administered rectally in the form of suppositories.
  • the above-mentioned appropriate dosage form can be produced by mixing the compound (I) of the present invention or an acid addition salt thereof with an acceptable usual carrier, excipient, binder, stabilizer and the like.
  • an acceptable usual carrier excipient, binder, stabilizer and the like.
  • acceptable buffering agents, solubilizing agents, isotonic agents and the like can also be added.
  • the dosage and number of doses vary depending on the symptoms 'age' weight and dosage form, but are usually about 1 to 50 Omg per day orally, preferably about 5 to 10 per day, for adults.
  • Omg can be administered at about 0.1 to 100 mg, preferably about 0.3 to 5 Omg in the case of intravenous injection, in one or several doses.
  • the in vitro activity of the compound was determined by the method described in Molecular 'Pharm-Macol., 21301 (1982), using [3H] ketanserin as a serotonin 5-HT 2 receptor radioligand. The ratio of inhibition of the binding of [3H] ketanserin to rat whole brain (excluding cerebellum) membrane fractions at a given concentration of the test compound was determined. Table 1 shows the measurement results of the inhibition rate when the concentration of the test compound was 0.01.
  • the compound (I) of the present invention and an acid addition salt thereof have excellent properties as a psychotropic drug and are clearly useful as a therapeutic drug for schizophrenia, senile psychiatric disorders, depression, neurosis and the like.
  • Reference example -1
  • Trifluoroacetic acid (0.69 ml) was added to a solution of compound (5) (0.095 g, 0.19 mmol) in dichloromethane (10 ml), and then triethylsilane was added.

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Abstract

L'invention concerne un dérivé de lactame représenté par la formule générale (A), ou un sel d'addition d'acide de celui-ci, présentant d'excellentes caractéristiques comme médicament psychotrope et pouvant être utilisé comme remède contre la schizophrénie, les troubles psychiques de la démence sénile, la psychose maniaco-dépressive, la névrose, etc. Dans ladite formule (I), R?1, R2, R3 et R4¿ représentent chacun hydrogène ou alkyle inférieur, à condition qu'une paire de groupes comprise parmi R?1 et R2, R3 et R4, R1 et R3¿, ou bien R2 et R4 puissent former un cycle hydrocarbure qui peut être ponté avec alkylène inférieur ou oxygène, et que l'alkylène inférieur et le cycle hydrocarbure puissent être substitués par au moins un groupe alkyle; n vaut 0 ou 1; A représente alkylène inférieur, alcénylène inférieur ou un cycle hydrocarbure qui peut être ponté avec alkylène inférieur (qui peut être substitués par au moins un groupe alkyle ou hydroxy) ou oxygène, l'alkylène inférieur, l'alcénylène inférieur et le cycle hydrocarbure pouvant être chacun substitués par au moins un alkyle ou un groupe hydroxy; p et q valent chacun 0, 1 ou 2; et G représente N ou CH et Ar représente un groupe hétéroaryle ou hydrocarbure aromatique, ou bien G représente CH et Ar représente phénoxy, à condition que le groupe hétéroaryle, le groupe hydrocarbure aromatique et le groupe phénoxy puissent être chacun substitués par au moins un groupe alkyle inférieur, alcoxy ou halogéno.
PCT/JP1995/002256 1994-11-04 1995-11-06 Nouveaux derives de lactame WO1996014297A1 (fr)

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JP29560194 1994-11-04
JP6/295601 1994-11-04

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Cited By (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998037893A1 (fr) * 1997-02-26 1998-09-03 Sumitomo Pharmaceuticals Co., Ltd. Antagoniste du recepteur dopaminergique d4
WO2004113333A1 (fr) * 2003-06-23 2004-12-29 Dainippon Sumitomo Pharma Co., Ltd. Agent therapeutique pour la demence senile
WO2009088997A1 (fr) * 2008-01-07 2009-07-16 Vitae Pharmaceuticals, Inc. Inhibiteurs lactames de la 11-bêta-hydroxystéroïde déshydrogénase 1
JP2010523567A (ja) * 2007-04-04 2010-07-15 メルク・シャープ・エンド・ドーム・コーポレイション 治療薬
US7820817B2 (en) 2004-05-28 2010-10-26 Vertex Pharmaceuticals Incorporated Modulators of muscarinic receptors
WO2011002103A2 (fr) 2009-07-02 2011-01-06 Dainippon Sumitomo Pharma Co., Ltd. Dérivé de cycloalcane
WO2011062284A1 (fr) * 2009-11-17 2011-05-26 Dainippon Sumitomo Pharma Co., Ltd. Dérivé de cycloalcane
JP4847320B2 (ja) * 2004-02-20 2011-12-28 大日本住友製薬株式会社 統合失調症の記憶・学習機能障害治療薬のｉｎｖｉｖｏスクリーニング方法
US8258139B2 (en) 2010-11-08 2012-09-04 Dainippon Sumitomo Pharma Co., Ltd. Method of treatment for mental disorders
CN102731512A (zh) * 2011-04-12 2012-10-17 天津药物研究院 一种鲁拉西酮中间体及鲁拉西酮的制备方法
US8487094B2 (en) 2008-07-25 2013-07-16 Boehringer Ingelheim International Gmbh Synthesis of inhibitors of 11β-hydroxysteroid dehydrogenase type 1
US8552212B2 (en) 2009-11-05 2013-10-08 Boehringer Ingelheim International Gmbh Chiral phosphorus ligands
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JP2011508783A (ja) * 2008-01-07 2011-03-17 ヴァイティー ファーマシューティカルズ，インコーポレイテッド １１β−ヒドロキシステロイドデヒドロゲナーゼ１型のラクタム阻害剤
WO2009088997A1 (fr) * 2008-01-07 2009-07-16 Vitae Pharmaceuticals, Inc. Inhibiteurs lactames de la 11-bêta-hydroxystéroïde déshydrogénase 1
US8846668B2 (en) 2008-07-25 2014-09-30 Vitae Pharmaceuticals, Inc. Inhibitors of 11beta-hydroxysteroid dehydrogenase 1
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US8754076B2 (en) 2008-07-25 2014-06-17 Vitae Pharmaceuticals, Inc./Boehringer-Ingelheim Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1
US8637505B2 (en) 2009-02-04 2014-01-28 Boehringer Ingelheim International Gmbh Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1
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US8883778B2 (en) 2009-07-01 2014-11-11 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11 beta-hydroxysteroid dehydrogenase 1
WO2011002103A2 (fr) 2009-07-02 2011-01-06 Dainippon Sumitomo Pharma Co., Ltd. Dérivé de cycloalcane
US8552212B2 (en) 2009-11-05 2013-10-08 Boehringer Ingelheim International Gmbh Chiral phosphorus ligands
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