WO1996014297A1 - Novel lactam derivatives - Google Patents

Novel lactam derivatives 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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Prior art keywords
alkyl
lower alkylene
substituted
hydrocarbon ring
compound
Prior art date
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PCT/JP1995/002256
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French (fr)
Japanese (ja)
Inventor
Atsuyuki Kojima
Fujio Antoku
Mayumi Yoshigi
Norihiko Tanno
Toshio Nishihara
Tomohiro Toyoda
Yukihiro Ohno
Original Assignee
Sumitomo Pharmaceuticals Company, Limited
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Application filed by Sumitomo Pharmaceuticals Company, Limited filed Critical Sumitomo Pharmaceuticals Company, Limited
Priority to JP51519696A priority Critical patent/JP3948744B2/en
Publication of WO1996014297A1 publication Critical patent/WO1996014297A1/en

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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

A lactam derivative represented by general formula (A) or an acid-addition salt thereof, having excellent characteristics as a psychotropic drug, and being useful as a remedy for schizophrenia, senile psychosis, manic-depressive psychosis, neurosis, and so forth, wherein R?1, R2, R3 and R4¿ represent each hydrogen or lower alkyl, provided a pair of R?1 and R2, R3 and R4, R1 and R3, or R2 and R4¿ may form a hydrocarbon ring which may be bridged with lower alkylene or oxygen, and the lower alkylene and the hydrocarbon ring may be substituted by at least one alkyl group; n represents 0 or 1; A represents lower alkylene, lower alkenylene or a hydrocarbon ring which may be bridged with lower alkylene (which may be substituted by at least one alkyl or hydroxy group) or oxygen, and the lower alkylene, the lower alkenylene and the hydrocarbon ring may be each substituted by at least one alkyl or hydroxy group; p and q represent each 0, 1 or 2; and G represents N or CH and Ar represents a heteroaryl or aromatic hydrocarbon group, or alternatively G represents CH and Ar represents phenoxy, provided the heteroaryl group, the aromatic hydrocarbon group and the phenoxy group may be each substituted by at least one lower alkyl, lower alkoxy or halogeno.

Description

明 細 書  Specification
新規なラクタム誘導体  New lactam derivatives
技術分野 Technical field
本発明は向精神性物質として有用な新規ラクタム誘導体およびその酸付加 塩に関する。 さらに詳しくは、 本発明の化合物は、 たとえば、 抗精神性作 用、 不安解消作用、 抗うつ作用等の向精神性作用を有し、 例えば精神分裂 病、 老年性精神疾患、 そううつ病、 神経症、 老人性痴呆の随伴症状等の治療 薬として有用である。  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.
背景技術 Background art
向精神性作用を持つラクタム誘導体としては、 ジャーナル · ォブ · メディ シナル . ケミストリー （J. Med. Chem., H 1068 (1991) ) および特表平 7 - 5 0 3 7 2 3に開示されたものが知られている。  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.
発明の開示 Disclosure of the invention
本発明の目的は、 新規なしかも優れた向精神性物質を提供することにあ る。  An object of the present invention is to provide a new and excellent psychotropic substance.
本発明者らは、 鋭意検討を重ねた結果、 新規ラクタム誘導体が目的とした 生物活性作用を有することを見出し本発明を完成するに至った。  As a result of intensive studies, the present inventors have found that the novel lactam derivative has the desired biological activity, and have completed the present invention.
本発明は、 一般式 〔I〕  The present invention has the general formula (I)
/ ^ \  / ^ \
：一 (CH2)p— A一 (CH2) -N si G G-Ar : One (CH 2 ) p — A one (CH 2 ) -N si G G-Ar
\- [ I ]  \-[I]
〔式中、 Zは式  (Where Z is the formula
Figure imgf000003_0001
(式中、 R l、 R 2、 R 3、 R 4は各々水素原子または低級アルキルを表す if、 R 1と R 2、 R 3と R 4、 R 1と R 3もしくは R 2と R 4が一緒になつて炭 化水素環を形成してもよい。 該炭化水素環は低級アルキレンまたは酸素原子 で架橋されていてもよい。 該低級アルキレンおよび炭化水素環は少なくとも
Figure imgf000003_0001
(Wherein, 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.
1つのアルキルで置換されていてもよレ、。 nは 0または 1を表す） を表す。 May be substituted with one alkyl. n represents 0 or 1).
Aは低級アルキレン、 低級アルケニレンまたは炭化水素環を表す。 該低級 アルキレン、 低級アルケニレンおよび炭化水素環は少なくとも 1つのアルキ ルまたは水酸基で置換されていてもよい。 該炭化水素環はまた少なくとも 1 つのアルキルもしくは水酸基で置換されていてもよい低級アルキレンまたは 酸素原子で架橋されていてもよい。 p、 qは各々 0、 1または 2を表す。 G は N (窒素原子） もしくは C Hを、 A rは芳香族複素環基も しくは芳香族炭 化水素基を表すか、 または Gは C Hを、 A rはフエノキシを表す。 当該芳香 族複素環基、 芳香族炭化水素基およびフエノキシは少なく とも 1つの低級ァ ルキル、 低級アルコキシまたはハロゲン原子で置換されていてもよい） で表されるラクタム誘導体またはその酸付加塩に関する。  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, or 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.
以下 本発明で使われている官能基について詳しく説明する。  Hereinafter, the functional groups used in the present invention will be described in detail.
低級アルキルとしては例えば炭素数 1〜 4個の直鎖または分枝鎖アルキル 基が挙げられ、 具体的にはメチル、 ェチル、 プロピル、 2 _プロピル、 プチ ル等が挙げられる。  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.
アルキルとしては例えば炭素数 1〜 6個の直鎖または分枝鎖アルキル基が 挙げられ、 好ましくは炭素数 1 〜4個の低級アルキルが挙げられ、 具体的に はメチル、 ェチル、 プロピル、 2—プロピル、 ブチル等が挙げられる。 炭化水素環としては、 例えば炭素数 3〜 7個のシクロアルカンおよび炭素 数 5〜 7個のシクロアルゲンが挙げられる。 炭素数 3〜 7個のシクロアルカ ンとしては例えばシクロプロパン、 シクロブタン、 シクロペンタン、 シクロ へキサン、 シクロヘプタン等が挙げられる。 炭素数 5〜 7個のシクロアルケ ンとしては例えばシクロペンテン、 シクロへキセン、 シクロヘプテン等が挙 げられる。 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. Examples of the hydrocarbon ring include cycloalkanes having 3 to 7 carbon atoms and cycloalkenes having 5 to 7 carbon atoms. C3-C7 cycloalka 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.
低級アルキレンで架橋された炭化水素環または酸素原子で架橋された炭化 水素環と しては例えば炭素数 5〜 1 0個の環が挙げられ、 具体的にはビシク 口 〔1. 1. 1〕 ペンタン、 ビシクロ 〔2. 1. 1〕 へキサン、 ビシクロ Examples of the hydrocarbon ring bridged with a lower alkylene or the hydrocarbon ring bridged with an oxygen atom include a ring having 5 to 10 carbon atoms.Specifically, a bicyclic port (1.1.1) Pentane, bicyclo [2.1.1] hexane, bicyclo
〔2. 1. 1〕 へキサ一 2—ェン、 ビシクロ 〔2. 2. 1〕 ヘプタン、 ビシ クロ 〔2. 2. 1〕 ヘプタ一 2—ェン、 ビシクロ 〔2. 2. 2〕 オクタン、 ビシクロ 〔2. 2. 2〕 ォクタ一 2—ェン、 ビシクロ 〔4. 1. 1〕 ォクタ ン、 ビシクロ 〔4. 1. 1〕 ォクタ一 2—ェン、 ビシクロ 〔4. 1. 1〕 ォ クタ一 3—ェン、 ビシクロ 〔3. 2. 1〕 オクタン、 ビシクロ 〔3. 2. 1〕 ォクタ一 2—ェン、 ビシクロ 〔3. 2. 1〕 ォクター 3—ェン、 ビシク 口 〔3. 2. 1〕 ォクター 6—ェン、 ビシクロ 〔3. 2. 2〕 ノナン、 ビシ クロ 〔3. 2. 2〕 ノナ一 2—ェン、 ビシクロ 〔3. 2. 2〕 ノナ一 3—ェ ン、 ビシクロ 〔3. 2. 2〕 ノナー6—ェン、 7—ォキサビシクロ 〔2. 2. 1〕 ヘプタン、 7—ォキサビシクロ 〔2. 2. 1〕 ヘプター 2—ェン、 7—ォキサビシクロ 〔4. 1. 1〕 オクタン、 7—ォキサビシクロ 〔4. 1. 1〕 ォクタ一 2—ェン、 7—ォキサビシクロ 〔4. 1. 1〕 ォクター 3 —ェン、 8—ォキサビシクロ 〔3. 2. 1〕 オクタン、 8—ォキサビシクロ[2.1.1] Hexa-2-ene, bicyclo [2.2.1] Heptane, bicyclo [2.2.1] Hepta-2-ene, bicyclo [2.2.2] octane , Bicyclo [2.2.2] octa-2-ene, bicyclo [4.1.1] octane, bicyclo [4.1.1] octa-2-ene, bicyclo [4.1.1] Octa-l-en, bicyclo [3.2.1] Octane, bicyclo [3.2.1] Octa-l-l-en, bicyclo [3.2.1] Octel 3-en, bisik mouth [ 3.2.1] Oct 6-Ben, Bicyclo [3.2.2] Nonane, Bicyclo [3.2.2] Nona-2-ene, Bicyclo [3.2.2] Nona 3- Ene, bicyclo [3.2.2] nona 6-ene, 7-oxabicyclo [2.2.1] heptane, 7-oxabicyclo [2.2.1] hepter 2-ene, 7-oxabicyclo [4 .1.1] Octane, 7-oxabicyclo [4. 1.1] Octa-1-ene, 7-oxabicyclo [4.1.1] Octa3-ene, 8-oxabicyclo [3.2.1] octane, 8-oxabicyclo
〔3. 2. 1〕 ォクタ一 2—ェン、 8—ォキサビシクロ 〔3, 2. 1〕 ォク ター 3—ェン、 8—ォキサビシクロ 〔3. 2. 1〕 ォクタ一 6—ェン等が挙 げられる。 [3.2.1] Octa-2-ene, 8-oxabicyclo [3.2.1] Octa3-ene, 8-oxabicyclo [3.2.1] Octa-1-ene Are listed.
低級アルキレンとしては、 例えば炭素数 1〜 3個の基が挙げられ、 具体的 にはメチレン、 エチレン、 トリメチレン等力 f挙げられる。 低級アルケニレンとしては例えば炭素数 2あるいは 3個の基が挙げられ、 具体的にはェテニレン、 プロぺニレン等が挙げられる。 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.
Aにおける炭化水素環の結合位置としては例えば一 1 , 1 一、 一 1 , 2 一、 — 1 , 3—、 — 1 , 4一等が挙げられる。  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.
芳香族炭化水素基としては例えば炭素数 6〜 1 0個の基が挙げられ、 具体 的にはフエニル、 ナフチル等が挙げられる。  Examples of the aromatic hydrocarbon group include groups having 6 to 10 carbon atoms, and specific examples include phenyl and naphthyl.
芳香族複素環基としては例えば単環の芳香族複素環基、 二環性の芳香族複 素現基が挙げられる。  Examples of the aromatic heterocyclic group include a monocyclic aromatic heterocyclic group and a bicyclic aromatic heterocyclic group.
単環の芳香族複素 ¾基としては例えば炭素数 5〜 6個の、 ヘテロ原子とし て窒素原子、 酸素原子または硫黄原子を 1 〜 4個含む基が挙げられ、 具体的 にはピリジル、 ピリミジニル、 チアゾリル、 ォキサゾリル、 イソォキサゾリ ル、 イソチアゾリル、 フリル、 イミダゾリル等が挙げられる。  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.
二環性の芳香族複素環基としては例えば炭素数 6〜 1 0個およびへテロ原 子として窒素原子、 酸素原子または硫黄原子 1 〜 5個を含む基が'挙げられ、 具体的にはべンズイソチアゾリル、 ベンズイソォキサゾリル、 ベンゾフリ ル、 ベンゾチェニル、 キノリル、 イソキノリル、 イン ドリル、 インダゾリ ル、 ベンズイミダゾリル、 ベンズォキサゾリル等のベンゼン環と縮合した芳 香族複素環基、 ナフチリジニル、 プテリジニル、 チェノフラニル、 イミダゾ チォフエニル、 イミダゾフラニル等が挙げられる。  Examples of the bicyclic aromatic heterocyclic group 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.
低級アルコキシとしては例えば炭素数 1 〜 4個の直鎖または分枝鎖アルコ キシ基が挙げられ、 具体的にはメ トキシ、 エトキシ、 プロボキシ、 2—プロ ポキシ、 ブトキシ等が挙げられる。  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.
ハロゲン原子としては例えばフッ素、 塩素、 臭素、 ヨウ素が挙げられる。 酸付加塩としては薬学上許される無機酸、 有機酸との付加塩が挙げられ る。 無機酸としては例えば塩酸、 臭化水素酸、 ヨウ化水素酸、 硫酸等が挙げ られる。 有機酸としては例えば酢酸、 シユウ酸、 クェン酸、 リ ンゴ酸、 酒石 酸、 マレイン酸、 フマール酸等が挙げられる。 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.
本発明化合物 〔I〕 には立体異性体および （または） 光学異性体が存在す る。 本発明においては、 これらの異性体の混合物および単離された異性体を 含む。  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.
本発明化合物 〔I〕 は水和物または溶媒和物として存在する場合がある。 本発明においては、 これらの水和物または溶媒和物を含む。  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.
本発明化合物 〔I〕 には、 Aが炭化水素環を有する化合物群、 Zが低級ァ ルキレンで架橋された炭化水素環または酸素原子で架橋された炭化水素環を 有する化合物群、 Zが架橋されていない炭化水素環を有する化合物群、 等が 含まれる。  In the compound (I) of the present invention, 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, and Z is a bridged group. And a group of compounds having an unsubstituted hydrocarbon ring.
Zで表される基としては、 具体的には式  As the group represented by Z, specifically, the formula
Figure imgf000007_0001
Figure imgf000007_0001
(式中、 Lは単結合または二重結合を表す。 Eは低級アルキルで置換されて いてもよい低級アルキレン、 酸素原子または互いに結合されない二つの水素 原子を表す。 nは 0または 1を表す） (In the formula, 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.)
で表される基等が挙げられる。 And the like.
また、 Zで表される基としては、 より具体的には式  Further, as the group represented by Z, more specifically, a group represented by the formula
Figure imgf000007_0002
(式中、 Lは単結合または二重結合を表す。 Eは低級アルキルで置換されて いてもよい低級アルキレンまたは酸素原子を表す。 nは 0または 1を表 す。 ）
Figure imgf000007_0002
(In the formula, 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.)
で表される基等が挙げられる。 And the like.
A rで表される基として具体的には、 二環性の芳香族複素環基、 ナフチル (この際、 Gは Nあるいは C Hを表す） あるいはフエノキシ基 （この際、 G は C Hを表す） 力、'挙げられる。 ただし、 当該二環性の芳香族複素環基、 ナフ チルおよびフエノキシは少なくとも 1つの低級アルキル、 低級アルコキシま たはハロゲン原子で置換されていてもよい。  Specific examples of 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). , '. However, the bicyclic aromatic heterocyclic group, naphthyl and phenoxy may be substituted with at least one lower alkyl, lower alkoxy or halogen atom.
A rで表される基としてより具体的にはベンゼン環と縮合した二環性の芳 香族複素環基、 ナフチル （この際、 Gは Nあるいは C Hを表す） およびフエ ノキシ （この際、 Gは C Hを表す） が挙げられる。 ただし、 当該ベンゼン環 と縮合した芳香族複素環、 ナフチルおよびフエノキシは少なくとも 1つの低 級アルキル、 低級アルコキシまたはハロゲン原子で置換されていてもよい。 ベンゼン環と縮合した二環性の芳香族複素環基のさらに具体的な例として は、 ベンズイソチアゾリル、 ベンズイソォキサゾリル、 イソキノリル、 ベン ゾフラニル、 ベンゾチェ二ル、 ィンダゾリルおよびィンドリル等が挙げら れ、 この際 Gは Nあるいは C Hを表す。 ただし、 当該べンズイソチアゾリ ル、 ベンズイソォキサゾリル、 イソキノリル、 ベンゾフラニル、 ベンゾチェ ニル、 インダゾリルおよびイン ドリルは少なくとも 1つの低級アルキル、 低 級アルコキシまたはハロゲン原子で置換されていてもよい。 より具体的に は、 ベンズイソチアゾール一 3—ィル、 ベンズイソォキサゾ一ルー 3—ィル およびィンダゾ一ルー 3—ィルが挙げられる。  More specifically, 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). However, 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. Where G represents N or CH. However, 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.
本発明化合物 〔I〕 は、 例えば、 以下の反応式で表される方法により製造 することができる。 製造法 a ) The compound [I] of the present invention can be produced, for example, by a method represented by the following reaction formula. Production method a)
：1一 (CH2)p— A_(CH2)q— N G-Ar : 1 (CH 2 ) p — A_ (CH 2 ) q — NG-Ar
N ^ f  N ^ f
[II]  [II]
Z^— (CH2)F5-A-(CH2)q— N G-Ar [I] Z ^ — (CH 2 ) F5-A- (CH 2 ) q — NG-Ar [I]
[III] [III]
製造法 b ) H Production method b) H
〔  [
A A
Γ Γ
Figure imgf000009_0001
Figure imgf000009_0001
[V] 製造法 c)  [V] Manufacturing method c)
Z— (CH2)p— A-(CH2)q— X [I] [VI] Z— (CH 2 ) p — A- (CH 2 ) q — X [I] [VI]
〔反応式中、 Z、 A、 p、 q、 Gおよび A rは前記と同じ。 Xは脱離基 （例 えば塩素、 臭素、 沃素等のハロゲン原子、 メタンスルホニルォキシ、 バラ ト ルエンスルホニルォキシ等のスルホニルォキシ基） を表す。 [In the reaction formula, Z, A, p, q, G and Ar are the same as described above. 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).
Z 1は式 Z 1 is the formula
Figure imgf000010_0001
Figure imgf000010_0001
(式中、 R i、 R 2、 R 3、 R 4および nは前記と同じ） Wherein R i, R 2, R 3, R 4 and n are the same as above.
を表す。 Represents
Z 2は式  Z 2 is the formula
Figure imgf000010_0002
Figure imgf000010_0002
(式中、 R i、 R 2、 R3、 R 4および nは前記と同じ） (Wherein, R i, R 2, R 3, R 4 and n are the same as above)
を表す〕 Represents
製造法 a) 〜 c) の原料化合物は公知化合物であるか、 または以下の文献 に記載の方法で合成することができる。 例えば、 〔II〕 の化合物は、 ジャー ナル · ォブ · メデイシナル ， ケミス トリ一 （J. Med. Chem., 12, 876 (1969) ； J. Med. Chem., l∑ 477 (1972) ； J. Med. Chem., 26, 1 4 (1983) ； J. Med.  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. For example, 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.
Chem., 29, 359 (1986) ； J. Med. Chem., IL 1382 (1988) ) 、 特開昭 58- 110576号公報、 特開昭 58-213455号公報、 特開昭 62-123179号公報、 特開平 5- 17440号公報、 等に製法が開示されている。 〔III〕 の化合物は、 ケミカル ' ファーマシュティカル ' ビユレチン （Chem. Pharm. Bull., 2288 (1991 ) ) 等に製法が開示されている。 〔V〕 の化合物は、 特開平 5-17440号公報 等に製法が開示されている。 〔VII〕 の化合物は、 ジャーナル 'ォブ ' メ ディ シナル ' ケミス トリ一 （J. Med. Chem., 2^,761 (1985) ； J. Med. Chem., 29, 359 (1986) ； J. Med. Chem., 32, 1147 (1983) ； J. Med. Chem., 31, 2712 ( 1986) ) 、 特開昭 63-83085号公報、 等に製法が開示されている。 Chem., 29, 359 (1986); J. Med.Chem., IL 1382 (1988)), JP-A-58-110576, JP-A-58-213455, and JP-A-62-123179. The production method is disclosed in, for example, 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.
以下に製造法 a) 〜 c) について詳しく説明する。  Hereinafter, the production methods a) to c) will be described in detail.
製造法 a )  Production method a)
一般的に、 環状酸ィミ ドを部分還元してヒドロキシラクタム体を合成する 方法は、 テトラへドロン （Tetrahedron, L 1437 (1975) ) およびジャーナ ル · ォブ · メディシナル · ケミス トリ一 （J. Med. Chem., 34, 1068 (1991 ) ) に開示されており、 それに準じて、 式 〔III〕 の化合物は合成できる。 即 ち、 式 〔III〕 の化合物は、 不活性溶媒中、 式 〔II〕 の化合物と還元剤を反応 させて得られる。 還元剤としては例えば、 NaBH4、 Ca(BH4)2、 UA1H4、 In general, a method of synthesizing a hydroxylactam by partially reducing a cyclic acid imid is described in Tetrahedron (L 1437 (1975)) and journal-of-medicinal chemistry (J. Med. Chem., 34, 1068 (1991)), and according to this, 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,
LiAlH 2 (OCH 2 CH 2 OCH 3 ) 2等が挙げられる。 NaBH 4および Ca(BH 4 ) 2を使 用した場合には、 還元剤の量は、 式 〔II〕 の化合物に対し、 1〜 1 0倍モル 使用し、 不活性溶媒としては、 アルコール系の溶媒例えば、 メ タノール、 ェ タノール、 イソプロパノール、 第 3級ブタノール等、 ハロゲン化炭化水素系 溶媒例えば、 ジクロロメタン、 クロ口ホルム、 四塩化炭素、 1,2-ジクロロェ タン等、 またはそれらの混合溶媒を使用し、 反応温度は、 0 〜溶媒の沸点 の範囲で反応を行うのが望ましい。 LiAlH4、 LiAlH2(OCH2CH2OCH3)2を 使用した場合には、 還元剤の量は、 式 〔II〕 の化合物に対し、 1〜 1 0倍モ ル使用し、 不活性溶媒としては、 エーテル系の溶媒例えば、 ジェチルエーテ ル、 テトラヒ ドロフラン等、 炭化水素系溶媒例えば、 n-へキサン、 シクロへ キサン、 ベンゼン、 トルエン等、 またはそれらの混合溶媒を使用し、 反応温 度は— 20でから室温の範囲で反応を行うのが望ましい。 LiAlH 2 (OCH 2 CH 2 OCH 3) 2 and the like. When NaBH 4 and Ca (BH 4) 2 are used, the amount of the reducing agent is 1 to 10 times the molar amount of the compound of the formula [II], and 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 However, it is desirable to carry out the reaction at a reaction temperature in the range of 0 to the boiling point of the solvent. When LiAlH 4 or LiAlH 2 (OCH 2 CH 2 OCH 3 ) 2 is used, 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.
ヒドロキシラクタム体を部分還元してラクタム体を合成する方法は、 ジャーナル ' ォブ ' メデイ シナル ' ケミス ト リー （J. Med. Chem., 1068 ( 1991) ) に開示されており、 それに準じて、 式 〔I〕 の化合物は合成でき る。 即ち、 式 〔I〕 の化合物は、 不活性溶媒中、 有機酸の存在下、 式 〔III〕 の化合物とトリアルキルシラン （例えばトリェチルシラン） を反応させて得 られる。 トリアルキルシランの量は、 式 〔III〕 の化合物に対し、 1 〜 1 0倍 モル使用し、 有機酸としては、 トリフルォロ酢酸等の強酸の大過剰の存在 下、 不活性溶媒としては、 ハロゲン化炭化水素系溶媒例えば、 ジクロロメタ ン、 クロ口ホルム、 四塩化炭素、 1 , 2—ジクロロェタン等の中、 反応温度 は、 一 3 0でから溶媒の還流温度の範囲で反応を行うのが望ましい。 A method for synthesizing lactams by partial reduction of hydroxylactams is described in the journal “Ob” “Medicinal” Chemistry (J. Med. Chem., 1068). (1991)), and according to this, 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. The amount of the trialkylsilane is 1 to 10 times the molar amount of the compound of the formula [III], and the organic acid is in the presence of a large excess of a strong acid such as trifluoroacetic acid. In 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.
製造法 b ) Production method b)
式 〔I〕 の化合物は、 式 〔IV〕 の化合物と式 〔V〕 の化合物を必要に応じ て、 塩基および/または触媒の存在下で反応して得られる。 式 〔IV〕 の化合 物の量としては、 式 〔V〕 の化合物に対して 1 〜1. 5倍モルの範囲を使用 し、 塩基としては例えば、 水素化ナトリウム、 ナトリウムアミ ド、 炭酸力リ ゥム、 炭酸ナトリウム等の存在下、 触媒としては例えばジベンゾ— 1 8—ク ラウン一 6—エーテル等のクラウンエーテルを式 〔V〕 の化合物に対して 0. 1 〜 1 0重量％の範囲で使用し、 反応溶媒として例えば、 トルエン、 キシレ ン、 クロ口ベンゼン等の芳香族溶媒を用いて、 溶媒の沸点付近の温度で反応 を行うのが望ましい。  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], and the base is, for example, sodium hydride, sodium amide, carbonate As a catalyst, for example, 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]. Preferably, 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.
製造法 c ) Production method c)
式 〔I〕 の化合物は式 〔VI〕 の化合物と式 〔VII〕 の化合物を塩基および 必要に応じて反応助剤の存在下で反応して得られる。 式 〔VI〕 の化合物の量 としては、 式 〔VII〕 の化合物に対して 1 〜1. 5倍モルの範囲を使用し、 塩 基としては例えば、 水素化ナトリウム、 ナトリウムアミ ド、 炭酸カリウム、 炭酸ナトリゥム等を式 〔VII〕 の化合物に対して 1 〜 2倍モルの範囲で用 レ、、 反応助剤としては例えば、 ヨウ化カリウム、 ヨウ化ナトリウム等のヨウ 化アルカリ金属塩を式 〔VII〕 の化合物に対して 0. 1 〜 1モルの範囲で用 レ、、 反応溶媒として例えば、 ジメチルホルムアミ ド、 ァセトニトリル、 トル ェン、 キシレン、 クロ口ベンゼン等を用いて、 溶媒の沸点付近の温度で反応 を行うのか *望ましい。 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]. Examples of 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?
製造法 a ) 〜 c ) で得られる化合物 〔I〕 は、 結晶化溶媒中 （例えば、 ァ ルコール、 ジェチルエーテル、 酢酸ェチル、 へキサンまたはこれらの混合溶 媒等 再結晶、 またはシリカゲルクロマトグラフィーによ り精製できる。 また 物 〔 I〕 は、 酸付加塩にし結晶化溶媒中 （例えば、 アセトン、 ジェ チル—一テル、 アルコール等） にて再結晶することによつても精製できる。 一般式 〔I〕 で表される化合物を光学分割する場合には以下の様にでき る。  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. 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.). When the compound represented by the formula (I) is optically resolved, the following method can be used.
式 〔I〕 の化合物を不活性溶媒 （例えばァセトニトリル、 アルコール等が 挙げられる） に溶解し、 光学活性な酸 （例えば L一酒石酸、 D—酒石酸、 D 一カンファー酸、 L—マンデル酸、 L—ピログルタミ ン酸、 D— 1 0—カン ファースルホン酸、 D—キナ酸、 L—リ ン:^^、 ジベンゾィルー L—酒石酸 等が挙げられ、 好ましくは L—酒石酸、 D—酒石酸が挙げられる） を加え塩 を形成させる。  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). Add salt to form.
塩を形成させる際の温度としては、 室温から溶媒の沸点までの範囲で行う ことができる力 光学純度を向上させるために、 一旦溶媒の沸点近くまで加 熱することが望ましい。 析出した塩をろ取する前に必要に応じ冷却し、 収率 を向上させることができる。 光学活性な酸 （分割剤） の使用量は、 基質に対 して 0. 5〜2. 0当量、 好ましくは 1当量前後の範囲力 ?適当である。 必要に応 じ、 得られた結晶を結晶化溶媒中 （例えば、 アルコール等が挙げられる） で 再結晶することにより、 高純度の光学活性な塩を得ることもできる。 必要に 応じ、 得られた塩を通常の方法で塩基と処理することによって、 一般式 〔I〕 で表される化合物の光学活性体をフリー体として得ることができる。 本発明の化合物は、 ドーパミ ン Dい ドーパミ ン D2、 ド一パミ ン D3、 ドーパミ ン D 4等のドーパミ ン系レセブター、 セロ トニン 5— HT 1 A、 セ ロ トニン 5—HT2等のセロ トニン系レセプター、 。 い o 2等のノルア ド レナリン系レセプターのうち 1つまたは複数の種々のレセプタ一サブタィプ に対する高い親和性を示す。 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). If necessary, the resulting salt is treated with a base in a usual manner to give a compound of the general formula 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.
ドーパミン系レセプターのサブタィプの D 2レセプター拮抗作用と抗精神 病作用との間には強い相関関係があることは、 以前からよく知られており （ Seeman, Pharmacol. Rev., 22,229 (1981) 等参照） 、 またセロトニン系レセプ ターのサブタイプの 5— HT2レセプタ一拮抗作用も抗精神病作用にとつて 望まれるものであることは提唱されている （ Janssenら， J. Pharm. Exper. Ther.,244,685 (1988) 等参照） 。 特に、 D 2レセプタ—拮抗作用は、 精神分 裂病の陽性の徴候 （例えば、 幻覚、 妄想） を制御しうる力、 5— HT2レセ プター拮抗作用は、 精神分裂病の陰性の徴候 （例えば、 無関心、 社会的ひき こもり） の改善に寄与する。 また、 5— HT2レセブター拮抗作用は、 D2 レセプター拮抗剤を用いた精神分裂病のメンテナンス療法の際にしばしば起 こることが知られている錐体外路の副作用を減少させることも示唆されてい る o That there is a strong correlation between D 2 receptor antagonism and antipsychotic disease effects of Sabutipu the dopamine system receptors are well known previously (Seeman, Pharmacol. Rev., reference, etc. 22,229 (1981) It has also been proposed that 5-HT 2 receptor antagonism of the serotonin receptor subtype is also desirable for antipsychotic effects (Janssen et al., J. Pharm. Exper. Ther., 244, 685 (1988), etc.). In particular, D 2 receptor - antagonism, signs of positive mental component裂病(e.g., hallucinations, delusions) force can control, 5-HT 2 receptacle Puta antagonism, symptoms of schizophrenia negative (e.g., , Indifference, social withdrawal). It has also been suggested that 5-HT 2 receptor antagonism reduces extrapyramidal side effects, which are known to frequently occur during schizophrenia maintenance therapy with D 2 receptor antagonists. O
また、 他のドーパミン系レセブターのサブタィブである D4拮抗作用は、 精神分裂病のメ ンテナンス療法の際の錐体外路の副作用を起こさないこと が、 最近示唆された (Seeman等. Nature.350.610 (1991) ， Seeman等， Nature, 358.149 (1992) 等参照） 。  It has also recently been suggested that 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)).
—方、 他のセロトニン系レセブターのサブタイプである 5— HT i Aレセ ブターの作動作用は、 抗不安作用との相関が報告されている （Titeler, Biochem. Pharmacol., 2 3265 (1987) 等参照） 。 —5—HT i A receptor, a subtype of other serotonin receptors The action of butter has been reported to correlate with anxiolytic action (see, for example, Titeler, Biochem. Pharmacol., 23265 (1987)).
それ故、 本発明の化合物は、 たとえば、 抗精神性作用、 不安解消作用、 抗 うつ作用等の向精神性作用を有し、 例えば精神分裂病、 老年性精神疾患、 そ ううつ病、 神経症、 老人性痴呆の随伴症状等の治療薬としての有用性があ る  Therefore, 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
一般式 〔 I〕 で表される本発明化合物及びその酸付加塩は、 向精神薬として 用いる場合、 経口的あるいは非経口的に投与することができる。 すなわち通 常用いられる投与形態例えば、 錠剤， カプセル剤， シロップ剤、 懸濁液等の 型で経口的に投与できる。 あるいは、 液剤の型にしたものを注射の型で非経 口的に投与できる。 また、 坐剤の型で直腸投与することもできる。 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.
また、 前記の適当な投与剤型は許容される通常の担体、 賦型剤、 結合剤、 安定剤等に本発明化合物 〔I〕 またはその酸付加塩を配合することにより製 造することができる。 また、 注射剤型として用いる場合には、 許容される緩 衝剤、 溶解補助剤、 等張剤等を添加することもできる。  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. . When used in the form of an injection, acceptable buffering agents, solubilizing agents, isotonic agents and the like can also be added.
投与量、 投与回数は、 症状 '年齢 '体重 ·投与形態等によって異なるが、 通常は成人に対し、 1日あたり、 経口の場合には約 1〜50 Omg、 好まし くは約 5〜 1 0 Omgを、 静注の場合には約 0.1〜 1 00mg、 好ましくは約 0.3〜 5 Omgを 1回または数回にわけて投与することができる。  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.
実験例 1 Experimental example 1
<実験方法〉  <Experimental method>
1 ) ドーパミ ン D2受容体結合活性 1) Dopami emissions D 2 receptor binding activity
化合物のインビトロ活性は、 ライフ 'サイエンス （LifeSci.) ,2 1781〜 1784, (1978) などに記載の方法に準じて、 ドーパミ ン D 2受容体ラジオリ ガンドとして 〔3 H〕 ラクロプライ ド （raclopride) を用いて、 被験化合物の 所定谩度のときの 〔3 H〕 ラクロプライ ドのラッ ト線条体膜への結合の阻害 率を求めた。 被験化合物の澳度が 0.0 1 のときの阻害率の測定結果を 表 1に示す。 In vitro activity of the compounds, Life 'Sciences (LifeSci.), 2 1781~ 1784 , (1978) according to the method described in such as Dopami emissions D 2 receptors Rajiori Using [3H] raclopride as a gand, the inhibition rate of the binding of [3H] raclopride to the rat striatal membrane at a predetermined concentration of the test compound was determined. Table 1 shows the measurement results of the inhibition rate when the test compound was 0.01.
2 ) セロトニン 5— HT 2受容体結合活性 2) Serotonin 5-HT 2 receptor binding activity
化合物のインビトロ活性は、 モレキュラー ' ファーマコロジ一 （Mol. Phar- macol.) ,21301 (1982) に記載の方法に準じて、 セロトニン 5— HT 2受 容体ラジオリガンドとして 〔3 H〕 ケタンセリン （ketanserin) を用いて、 被 験化合物の所定濃度のときの 〔3 H〕 ケタンセリ ンのラッ ト全脳 （小脳を除 いた） 膜画分への結合の阻害率を求めた。 被験化合物の瀵度が 0.0 1 のときの阻害率の測定結果を表 1に示す。 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.
3 ) ドーパミン D 4受容体結合活性 3) Dopamine D 4 receptor binding activity
化合物のインビトロ活性は、 ラジオリガンドとして 〔3 H〕 スピペロン （ spiperone) を用いて、 ヒト D 4.4受容体を発現させた C H 0細胞膜画分への In vitro activity of the compounds, used as the radioligand [3 H] spiperone (spiperone), human D 4. 4 to CH 0 cell membrane fraction was expressed receptor
[3H] スピペロン結合に対する各種濃度の被験薬物の濃度を求め評価し た。 これにより得られた 5 0 %阻害濃度 （I C 5 0値） から算出された被験 薬物の結合阻害定数 （K i値） を表 1に示す。 [3H] Various concentrations of the test drug for spiperone binding were determined and evaluated. Table 1 shows the binding inhibition constant (K i value) of the test drug calculated from the 50% inhibitory concentration (IC 50 value) obtained in this way.
4 ) セロトニン 5— HT I A受容体結合活性  4) Serotonin 5-HTIA receptor binding activity
化合物のインビトロ活性は、 ジャーナル ' ォブ 'ニューロケミストリ一 （J. Neurochem. ) ,44, 1685 (1985) に記載の方法に準じて、 セロトニン 5— HT 1 A受容体ラジオリガンドとして 〔3 H〕 8 -OH -D P AT (8- In vitro activity of the compounds, the journal 'O Bed' Neuro chemistry one (J. Neurochem.), According to the method described in 44, 1685 (1985), as serotonin 5-HT 1 A receptor radioligand [3 H] 8 -OH -DP AT (8-
Hydroxy-2- (di-n-propylamino) tetraline) を用いて、 被験化合物の所定濃度の ときの 〔3 H〕 8—OH— D P ATのラッ ト大脳皮質 （brain cortices) 膜画分 への結合の阻害率を求めることができる。 表 1 化合物番号 D 2結合阻害率 5— HT 2結合阻害率 D 4結合阻害 Binding of [3H] 8-OH-DPAT to rat brain cortices membrane fraction at a given concentration of test compound using Hydroxy-2- (di-n-propylamino) tetraline) Can be determined. Table 1 Compound No.D 2 binding inhibition rate 5—HT 2 binding inhibition rate D 4 binding inhibition
(%) (%) (Ki:nM)  (%) (%) (Ki: nM)
29 80 8 1 0.7329 80 8 1 0.73
30 90 5 1 30 90 5 1
3 1 59 24  3 1 59 24
32 95 66 6.82 33 76 4 1 1 7.7 効果  32 95 66 6.82 33 76 4 1 1 7.7 Effect
本発明化合物 （I) およびその酸付加塩は、 向精神薬としての優れた特性 を有し、 精神分裂病、 老年性精神病、 そううつ病、 神経症等の治療薬として 有用であることが明らかとなつた。 参考例 -1  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. And Reference example -1
化合物 （2) の合成  Synthesis of compound (2)
Figure imgf000017_0001
水素化リチウムアルミニウム 0.37 g (9.85 mmol) とテトラヒ ドロフ 'ン （42ml) の混合物に、 氷冷搜拌下、 （ 1 R， 2 S) — N— 〔4— 〔4 - ( 1 , 2—べンズイソチアゾ一ル一 3—ィル） 一 1—ピペラジニル〕 ブチ ル〕 一 1 , 2—シクロへキサンジカルボキシイ ミ ド （化合物 （ 1 ) ) 2.1g
Figure imgf000017_0001
A mixture of lithium aluminum hydride (0.37 g, 9.85 mmol) and tetrahydrofuran (42 ml) was added to a mixture of (1R, 2S) —N— [4— [4 -(1,2-Benzisothiazol-1-3-yl) -11-piperazinyl] butyl] 1-1,2-cyclohexanedicarboximide (compound (1)) 2.1 g
(4.92 mmol) のテトラヒドロフラン （ 2 1 ml) 溶液を滴下した。 氷冷 下、 1 0分間携拌を続けたのち、 水 （1.5ml) を加えて析出した沈澱を濾 別後、 濾液をエバポレート し、 残渣をカラムクロマトグラフィ一精製するこ とにより、 目的の化合物 （2) ( l.lg, 52%) を得た。 (4.92 mmol) in tetrahydrofuran (21 ml) was added dropwise. After stirring for 10 minutes under ice-cooling, water (1.5 ml) was added, the precipitated precipitate was separated by filtration, the filtrate was evaporated, and the residue was purified by column chromatography to give the desired compound ( 2) (l.lg, 52%) was obtained.
融点 （塩酸塩） 202 - 20 Melting point (hydrochloride) 202-20
iH-NMR (CDC13) δ： 7.89 (IH, d, J=8.0Hz)， 7.81 (IH, d, J=8.0Hz), 7.46 (IH, t, J=8.0Hz), 7.35 (IH, t, J=8.0Hz), 4.71 (IH, s), 3.30-3.65 (6H, m), 2.35- 2.81 (7H, m), 2.12-2.25 (1H， m), 1.81-2.09 (1H， m), 1.41-1.87 (8H, m)， 0.93- 1.32 (3H, m).  iH-NMR (CDC13) δ: 7.89 (IH, d, J = 8.0 Hz), 7.81 (IH, d, J = 8.0 Hz), 7.46 (IH, t, J = 8.0 Hz), 7.35 (IH, t, J = 8.0Hz), 4.71 (IH, s), 3.30-3.65 (6H, m), 2.35- 2.81 (7H, m), 2.12-2.25 (1H, m), 1.81-2.09 (1H, m), 1.41 -1.87 (8H, m), 0.93- 1.32 (3H, m).
参考例 2 Reference example 2
化合物 （4) および化合物 （5) の合成  Synthesis of compound (4) and compound (5)
Figure imgf000018_0001
Figure imgf000018_0001
水素化リチウムアルミニウム 0.077 g (2 mmol) とテトラヒ ドロフラ ン （1 0ml) の混合物に、 水冷携拌下、 （1 R, 2 S, 3 R, 4 S) 一 N— To a mixture of lithium aluminum hydride 0.077 g (2 mmol) and tetrahydrofuran (10 ml) was added (1 R, 2 S, 3 R, 4 S) 1 N—
[2 R*- 〔 〔4— (1, 2—ベンズイソチアゾール一 3—ィル） 一 1ーピ ペラジニル〕 メチル一 1 R*—シクロへキシル〕 メチル〕 一2， 3—ビシク 口 〔 2. 2. 1〕 へブタンジカルボキシイ ミ ド （化合物 （ 3 ) ) 0.5 g (1 mmol) のテトラヒドロフラン （5ml) 溶液を滴下した。 氷冷下、 1 0分間 报拌を続けたのち、 水を加えて析出した沈澱を濾別後、 濾液をエバポレート し、 残渣 （0.52g) を得た。 この残渣 （0.26g) をカラムクロマトグラ LI [2 R *-[[4- (1,2-benzisothiazol-1-yl) -11-piperazinyl] methyl-1R * -cyclohexyl] methyl] -12,3-bisic mouth [2 2.2.1] A solution of 0.5 g (1 mmol) of hebutanedicarboximide (compound (3)) in tetrahydrofuran (5 ml) was added dropwise. After stirring was continued for 10 minutes under ice-cooling, water was added, and the deposited precipitate was separated by filtration. The filtrate was evaporated to obtain a residue (0.52 g). This residue (0.26 g) is purified by column chromatography. LI
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Figure imgf000020_0001
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Figure imgf000020_0002
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Figure imgf000021_0001
Figure imgf000021_0001
L6ZPII960 A L6ZPII960 A
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Figure imgf000022_0001
Figure imgf000022_0001
寸
Figure imgf000023_0001
Dimension
Figure imgf000023_0001
実施例 1 Example 1
化合物 （2 9) の合成  Synthesis of compound (29)
Figure imgf000024_0001
化合物 （2) ( 0.55 g, 1.2 8 mmol) のジクロロメタン （ 70 ml) 溶液 中にトリフルォロ酢酸 （4.6 ml) を加え、 次いでトリェチルシラン （0.2 lml) を加えた。 6時間、 室温で攬拌を続けたのち、 エバポレートし、 残渣 をジクロロメタンに溶かし、 飽和重曹水および飽和食塩水にて洗浄後、 無水 硫酸マグネシウムで乾燥し、 エバポレートした。 その残渣をカラムクロマト グラフィー精製することにより、 目的の化合物 （29') ( 0.2 5 g, 4 7%) を得た。
Figure imgf000024_0001
To a solution of compound (2) (0.55 g, 1.28 mmol) in dichloromethane (70 ml) was added trifluoroacetic acid (4.6 ml), and then triethylsilane (0.2 lml). After the mixture was stirred at room temperature for 6 hours, the mixture was evaporated, the residue was dissolved in dichloromethane, washed with saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by column chromatography to give the desired compound (29 ') (0.25 g, 47%).
融点 （塩酸塩） 1 76— 1 77 Melting point (hydrochloride) 1 76— 1 77
iH-NMR (CDC13)5: 7.91 (1H, d, J=8.0Hz), 7.81 (1H, d, J=8.0Hz), 7.47 iH-NMR (CDC1 3) 5 : 7.91 (1H, d, J = 8.0Hz), 7.81 (1H, d, J = 8.0Hz), 7.47
(1H, t， J=8.0Hz), 7.36 (1H, t, J=8.0Hz), 3.56 (4H， t, J=5.0Hz), 3.28-3.41 (3H, m)， 2.89 (1H, d, J=10.0Hz), 2.39-2.52 (3H， m), 2.26-2.39 (1H, m), 1.98-2.09 (1H， m), 1.42-1.83 (8H， m), 1.12-1.32 (3H， m). (1H, t, J = 8.0Hz), 7.36 (1H, t, J = 8.0Hz), 3.56 (4H, t, J = 5.0Hz), 3.28-3.41 (3H, m), 2.89 (1H, d, J = 10.0Hz), 2.39-2.52 (3H, m), 2.26-2.39 (1H, m), 1.98-2.09 (1H, m), 1.42-1.83 (8H, m), 1.12-1.32 (3H, m) .
実施例 2 Example 2
化合物 （30) の合成  Synthesis of compound (30)
Figure imgf000024_0002
化合物 （4) ( 0.087 g, 0.1 8 mmol) のジクロロメタン （ 1 0 ml) 溶 液中にトリフルォロ酢酸 （0.63ml) を加え、 次いでトリェチルシラン (0.03ml) を加えた。 終夜、 室温で擾拌を続けたのち、 エバポレート し、 残渣をジクロロメタンに溶かし、 飽和重曹水および飽和食塩水にて洗诤 後、 無水硫酸マグネシウムで乾燥し、 エバポレートした。 その残渣を n-へキ サンから再結晶することにより、 目的の化合物 （30) (0.034g, 4 0%) を得た。
Figure imgf000024_0002
To a solution of compound (4) (0.087 g, 0.18 mmol) in dichloromethane (10 ml) was added trifluoroacetic acid (0.63 ml), and then triethylsilane (0.03 ml). After stirring at room temperature overnight, the mixture was evaporated, the residue was dissolved in dichloromethane, washed with saturated aqueous sodium hydrogencarbonate and saturated saline, dried over anhydrous magnesium sulfate, and evaporated. The residue was recrystallized from n-hexane to obtain the desired compound (30) (0.034 g, 40%).
融点 1 28— 1 2 9 Melting point 1 28— 1 2 9
JH-NMR (CDC13) S 7.90 (1H, d, J=8.0Hz), 7.81 (1H, d, J=8.0Hz), 7.3-7.5 JH-NMR (CDC1 3) S 7.90 (1H, d, J = 8.0Hz), 7.81 (1H, d, J = 8.0Hz), 7.3-7.5
(2H, m), 3.2-3.6 (7H， m), 2.96 (1H， dd, J=3 and 10.0Hz), 2.45-2.75 (6H, m), 2.42 (1H, d， J=9.0Hz), 1.85-2.25 (4H, m), 0.9-1.8 (15H, m). (2H, m), 3.2-3.6 (7H, m), 2.96 (1H, dd, J = 3 and 10.0Hz), 2.45-2.75 (6H, m), 2.42 (1H, d, J = 9.0Hz), 1.85-2.25 (4H, m), 0.9-1.8 (15H, m).
実施例 3 Example 3
化合物 （3 1) の合成  Synthesis of compound (3 1)
Figure imgf000025_0001
化合物 （5) (0.095g, 0.1 9 mmol) のジクロロメタン （ 1 0 ml) 溶 液中にトリフルォロ酢酸 （0.6 9ml) を加え、 次いでトリェチルシラン
Figure imgf000025_0001
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.
(0.03ml) を加えた。 8時間、 室温で拢拌を続けたのち、 エバポレート し、 残渣をジクロロメタンに溶かし、 飽和重曹水および飽和食塩水にて洗浄 後、 無水硫酸マグネシウムで乾燥し、 エバポレートした。 その残渣を酢酸ェ チルから再結晶することにより、 目的の化合物 （3 1 ：化合物 （3 0) のジ ァステレオマ一） （0.03 9g， 4 3 %) を得た。 融点 1 65— 1 66 (0.03 ml) was added. After stirring for 8 hours at room temperature, the mixture was evaporated, the residue was dissolved in dichloromethane, washed with saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous magnesium sulfate, and evaporated. The residue was recrystallized from ethyl acetate to obtain the desired compound (31: diastereomer of compound (30)) (0.039 g, 43%). Melting point 1 65— 1 66
iH-NMR (CDC13) δ： 7.90 (1H， d, J=8.0Hz), 7.81 (1H， d, J=8.0Hz), 7.33- iH-NMR (CDC1 3) δ : 7.90 (1H, d, J = 8.0Hz), 7.81 (1H, d, J = 8.0Hz), 7.33-
7.49 (2H, m), 3.35-3.65 (6H， m), 3.19 (1H, dd, J=9.0 and 13.0Hz), 2.88 (1H, dd, J=3.0 and 10.0Hz), 2.4-2.7 (6H, m), 2.42 (1H, d, J=9.0Hz), 2.0-2.3 (3H, m), 1.85-2.0 (1H, m), 1.0-1.8 (15H, m). 7.49 (2H, m), 3.35-3.65 (6H, m), 3.19 (1H, dd, J = 9.0 and 13.0Hz), 2.88 (1H, dd, J = 3.0 and 10.0Hz), 2.4-2.7 (6H, m), 2.42 (1H, d, J = 9.0Hz), 2.0-2.3 (3H, m), 1.85-2.0 (1H, m), 1.0-1.8 (15H, m).
実施例 4 Example 4
化合物 （32) の合成  Synthesis of compound (32)
Figure imgf000026_0001
化合物 （7) (0.24 5 g, 0.50 mmol) のジクロロメタン （ 20 ml) 溶 液中にトリフルォロ酢酸 （1.8ml) を加え、 次いでトリェチルシラン （0. 08ml) を加えた。 終夜、 室温で搜拌を続けたのち、 エバポレートし、 残渣 をジクロロメタンに溶かし、 飽和重曹水および飽和食塩水にて洗浄後、 無水 硫酸マグネシウムで乾燥し、 エバポレートした。 その残渣を n-へキサン一酢 酸ェチルから再結晶することにより、 目的の化合物 （32) (0.1 1 6 g, 48.5%) を得た。
Figure imgf000026_0001
To a solution of the compound (7) (0.245 g, 0.50 mmol) in dichloromethane (20 ml) was added trifluoroacetic acid (1.8 ml), and then triethylsilane (0.08 ml). After stirring overnight at room temperature overnight, the mixture was evaporated, the residue was dissolved in dichloromethane, washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was recrystallized from n-hexane-ethyl acetate to give the desired compound (32) (0.116 g, 48.5%).
融点 1 1 7— 1 1 8 Melting point 1 1 7— 1 1 8
iH-NMR (CDC13) δ： 7.90 (1H， d, J=8.0Hz)， 7.81 (1H, d, J=8.0Hz)， 7.33- iH-NMR (CDC1 3) δ : 7.90 (1H, d, J = 8.0Hz), 7.81 (1H, d, J = 8.0Hz), 7.33-
7.49 (2H, m), 3.2-3.7 (7H， m), 2.96 (1H, dd, J=3 and 8.0Hz), 2.5-2.75 (6H, m), 2.42 (1H, d, J=8.0Hz), 2.1-2.3 (3H, m), 1.9-2.05 (1H, m), 0.9-1.8 (15H, m). 実施例 5 7.49 (2H, m), 3.2-3.7 (7H, m), 2.96 (1H, dd, J = 3 and 8.0Hz), 2.5-2.75 (6H, m), 2.42 (1H, d, J = 8.0Hz) , 2.1-2.3 (3H, m), 1.9-2.05 (1H, m), 0.9-1.8 (15H, m). Example 5
化合物 （33) の合成  Synthesis of compound (33)
Figure imgf000027_0001
化合物 （8) (0.2 73 g, 0.5 5 mmol) のジクロロメタン （ 30 ml) 溶 液中にトリフルォロ酢酸 （1.9 7ml) を加え、 次いでトリェチルシラン (0.0 9ml) を加えた。 7.5時間、 室温で攪拌を続けたのち、 エバポレー 卜し、 残渣をジクロロメタンに溶かし、 飽和重曹水および飽和食塩水にて洗 浄後、 無水硫酸マグネシウムで乾燥し、 エバポレートした。 その残渣を酢酸 ェチルから再結晶することにより、 目的の化合物 （33 ：化合物 （3 2) の ジァステレオマー） （0.1 6 8g, 6 3. ) を得た。
Figure imgf000027_0001
To a solution of the compound (8) (0.273 g, 0.55 mmol) in dichloromethane (30 ml) was added trifluoroacetic acid (1.97 ml), and then triethylsilane (0.09 ml). After stirring at room temperature for 7.5 hours, the mixture was evaporated, the residue was dissolved in dichloromethane, washed with saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous magnesium sulfate, and evaporated. The residue was recrystallized from ethyl acetate to give the desired compound (33: diastereomer of compound (32)) (0.168 g, 63).
融点 1 75— 1 77 Melting point 1 75— 1 77
iH-NMR (CDC13 : 7.91 (1H, d, J=8.0Hz), 7.81 (1H, d, J=8.0Hz), 7.33- iH-NMR (CDC1 3: 7.91 (1H, d, J = 8.0Hz), 7.81 (1H, d, J = 8.0Hz), 7.33-
7.5 (2H -n), 3.4-3.6 (6H, m), 3.19 (1H, dd, J=9.0 and 10.0Hz), 2.88 (1H, dd, J=4.0 and 7.0Hz), 2.45-2.7 (6H, m), 2.21 (1H, d， J=9.0Hz), 2.1-2.25 (3H, m), 1.85-2.0 (1H, m), 0.9-1.75 (15H, m). 7.5 (2H -n), 3.4-3.6 (6H, m), 3.19 (1H, dd, J = 9.0 and 10.0Hz), 2.88 (1H, dd, J = 4.0 and 7.0Hz), 2.45-2.7 (6H, m), 2.21 (1H, d, J = 9.0Hz), 2.1-2.25 (3H, m), 1.85-2.0 (1H, m), 0.9-1.75 (15H, m).
実施例 6 Example 6
上記の実施例と同様にして、 対応するヒドロキシラクタム誘導体から、 以 下の表 5〜 7のラクタム誘導体を合成した。 91 In the same manner as in the above examples, lactam derivatives shown in Tables 5 to 7 below were synthesized from the corresponding hydroxylactam derivatives. 91
Figure imgf000028_0001
Figure imgf000028_0001
S峯  Smine
9SZZ0/S6dT/X3d L6ZPH96 OA LZ 9SZZ0 / S6dT / X3d L6ZPH96 OA LZ
Figure imgf000029_0001
Figure imgf000029_0001
9¾ 9¾
9SZZ0/S6df/XDd 6ひ 1/96 ΟΛλ 9SZZ0 / S6df / XDd 6 pcs 1/96 ΟΛλ
Figure imgf000030_0001
Figure imgf000030_0001

Claims

請 求 の 範 囲 The scope of the claims
1 . —般式 〔 I〕 f ~~ \  1. —General formula [I] f ~~ \
Z - (CH2)p— A - (CH2)q— N^^G-Ar Z-(CH 2 ) p — A-(CH 2 ) q — N ^^ G-Ar
〔式中、 Zは式 (Where Z is the formula
Figure imgf000031_0001
Figure imgf000031_0001
(式中、 R R 2、 R 3、 R 4は各々水素原子または低級アルキルを表す 、 R 1と R 2、 R 3と R 4、 R 1と R 3もしくは R 2と R 4がー緖になって炭 化水素環を形成してもよい。 該炭化水素環は低級アルキレンまたは酸素原子 で架棟されていてもよい。 該低級アルキレンおよび炭化水素環は少なくとも(Wherein, RR 2 , R 3, and R 4 each represent a hydrogen atom or lower alkyl; R 1 and R 2, R 3 and R 4, R 1 and R 3 or R 2 and R 4 are The hydrocarbon ring may be bridged by a lower alkylene or an oxygen atom The lower alkylene and the hydrocarbon ring may be at least
1つのアルキルで置換されていてもよい。 nは 0または 1 を表す） を表す。 It may be substituted with one alkyl. n represents 0 or 1).
Aは f氐級アルキレン、 低級アルケニレンまたは炭化水素環を表す。 該低級 アルキレン、 低級アルケニレンおよび炭化水素環は少なく とも 1つのアルキ ルまたは水酸基で置換されていてもよい。 該炭化水素環はまた少なくとも 1 つのアルキルもしくは水酸基で置換されていてもよい低級アルキレンまたは 酸素原子で架橋されていてもよい。 P、 qは各々 0、 1または 2を表す。 G は N (窒素原子） もしくは C Hを、 A rは芳香族複素環基もしくは芳香族炭 化水素基を表すか、 または Gは C Hを、 A rはフエノキシを表す。 当該芳香 族複素環基、 芳香族炭化水素基およびフエノキシは少なく とも 1つの低級ァ ルキル、 低級アルコキシまたはハロゲン原子で置換されていてもよい） で表されるラクタム誘導体またはその酸付加塩。 A represents a f 氐 alkylene, a 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, or 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 a acid addition salt thereof.
2 . Aが炭化水素環であって、 該炭化水素環は低級アルキレンまたは酸素原 子で架撟されていてもよく、 また該炭化水素環および低級アルキレンは少な くとも 1つのアルキルで置換されていてもよい、 請求項 1記載のラクタム誘 導体またはその酸付加塩。  2. A is a hydrocarbon ring, the hydrocarbon ring may be bridged by a lower alkylene or an oxygen atom, and the hydrocarbon ring and the lower alkylene are substituted by at least one alkyl. The lactam derivative according to claim 1, or an acid addition salt thereof.
3 . Aが低級アルキレンもしくは低級アルケニレンであって、 該低級アルキ レンおよび低級アルケニレンは少なくとも 1つのアルキルまたは水酸基で置 換されていてもよい、 請求項 1記載のラクタム誘導体またはその酸付加塩。 3. The lactam derivative or an acid addition salt thereof according to claim 1, wherein A is lower alkylene or lower alkenylene, and the lower alkylene and lower alkenylene may be substituted with at least one alkyl or hydroxyl group.
4 . Zが式 4. Z is the formula
Figure imgf000032_0001
Figure imgf000032_0001
(式中、 Lは単結合または二重結合を表す。 Eは低級アルキルで置換されて いてもよい低級アルキレン、 酸素原子または互いに結合されない二つの水素 原子を表す。 nは 0または 1を表す） (In the formula, 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.)
である請求項 1記載のラクタム誘導体またはその酸付加塩。 2. The lactam derivative or the acid addition salt thereof according to claim 1, which is:
5 . £カ?低級アルキルで置換されていてもよい低級アルキレンもしくは酸素 原子である請求項 4記載のラクタム誘導体またはその酸付加塩。 5. £ Ca? Lactam derivative or an acid addition salt according to claim 4, wherein the lower alkyl optionally substituted lower alkylene or an oxygen atom.
6 . Eが互いに結合されない二つの水素原子である請求項 4記載のラクタム 誘導体またはその酸付加塩。  6. The lactam derivative or the acid addition salt thereof according to claim 4, wherein E is two hydrogen atoms that are not bonded to each other.
7 . Aが炭化水素現であって、 該炭化水素環は低級アルキレンまたは酸素原 子で架棟されていてもよく、 また該炭化水素璨ぉよび低級アルキレンは少な くとも 1つのアルキルで置換されていてもよい、 請求項 6記載のラクタム誘 導体またはその酸付加塩。 7. A is a hydrocarbon radical, wherein the hydrocarbon ring may be bridged with a lower alkylene or oxygen atom, and wherein the hydrocarbon and lower alkylene are substituted with at least one alkyl. 7. The lactam derivative according to claim 6, or an acid addition salt thereof.
8 . Aが低級アルキレンもしくは低級アルケニレンであって、 該低級アルキ レンおよび低級アルケニレンは少なくとも 1つのアルキルまたは水酸基で置 換されていてもよい、 請求項 6記載のラクタム誘導体またはその酸付加塩。 8. The lactam derivative or acid addition salt thereof according to claim 6, wherein A is lower alkylene or lower alkenylene, and the lower alkylene and lower alkenylene may be substituted with at least one alkyl or hydroxyl group.
9 . 活性成分として治療上有効な量の請求項 1記載の化合物および薬理上許 容される担体または賦形剤を含有する医薬組成物。 9. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 1 as an active ingredient and a pharmacologically acceptable carrier or excipient.
1 0 . 治療上有効な量の請求項 1記載の化合物を患者に投与することからな る精神分裂病、 老年性精神疾患、 そううつ病、 神経症または老人性痴呆の随 伴症状を処置する方法。  10. Treating schizophrenia, senile psychiatric disorders, depression, neurosis or the accompanying symptoms of senile dementia comprising administering to a patient a therapeutically effective amount of the compound of claim 1. Method.
1 1 . 請求項 1記載の化合物からなる医薬。  11. A pharmaceutical comprising the compound according to claim 1.
1 2 . 請求項 1記載の化合物からなる向精神病薬。  12. A psychotropic drug comprising the compound according to claim 1.
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