JPH08333368A - New imide derivative - Google Patents

Abstract

PURPOSE: To obtain a new imide derivative having psychotropic action and antianxiety action and useful as an agent for the treatment of schizophrenia, senile psychosis, circulatory psychosis, neurosis, etc. CONSTITUTION: This imide derivative is a compound expressed by formula I [Z is a group of formula II (B is carbonyl or sulfonyl; R<1> and R<2> together form a hydrocarbon ring having at least one hydroxyl substituent and R<3> is H or hydroxyl, etc.; R<4> is H or a lower alkyl; (n) is 0 or 1); A is a hydrocarbon ring, etc.; (l) and (m) are each 0, 1 or 2; G is N, CH or COH and Ar is an aromatic heterocyclic group, benzoyl, etc., or G is C atom and Ar is biphenylmethylidene] or its acid addition salt, e.g. the compound of formula III. The compound of formula I can be produced e.g. by reacting a compound of formula IV (X is an eliminable group) with a compound of formula ZH in the presence of a base.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a novel imide derivative useful as a psychotropic substance and an acid addition salt thereof. More specifically, the psychotropic substance of the present invention {a substance having an antipsychotic action and / or anxiolytic action} is schizophrenia,
It is useful as a remedy for senile psychiatric disorders, depression, neurosis, etc.

[0002]

2. Description of the Related Art As imide derivatives having a psychotropic effect, those shown in Tables 1 and 2 are known.

[0003]

[Table 1]

[Table 2]

However, these derivatives are characterized by a linear alkylene chain between the imide moiety and piperazine or piperidine. The only compound having an alkylene chain containing a hydrocarbon ring here is disclosed in JP-A 5-174.
It is not known other than the compound reported in JP-A-40. However, the above publication does not describe a compound in which an imide moiety is substituted with a hydroxyl group.

Conventional psychotropic substances having anxiolytic action and / or antipsychotic action have central side effects,
Peripheral side effects such as hypotension are accompanied, and clinically significant problems [The Pharmacologic Basis of
Therapeutics The Pharmacological basis of t
herapeutics, A.Goodman Gilman, LSGoodman et al, New
York (1985) P387, Contemporary Medicine, 22 , P22, (1990)].

[0006]

DISCLOSURE OF THE INVENTION The object of the present invention is to provide an excellent psychotropic substance with few side effects.

[0007]

As a result of intensive studies, the present inventors have found that the imide moiety is substituted with a hydroxyl group,
The inventors have found that a novel imide derivative having an alkylene chain containing a hydrocarbon ring has desired pharmacological actions, and completed the present invention.

The present invention has the general formula [I]

Embedded image {In the formula, Z- is a formula

[Chemical 9](In the formula, B represents carbonyl or sulfonyl.
R¹, R²And R³Is R ¹And R²Together,
Represents a hydrocarbon ring substituted with at least one hydroxyl group
Then R³Represents a hydrogen atom or a hydroxyl group, or R
¹And R³Together with at least one hydroxyl group
Represents a substituted hydrocarbon ring, R²Is hydrogen atom or water
Represents an acid group. The hydrocarbon ring has at least one hydroxyl group
Lower alkylene optionally substituted with or an oxygen atom
May be cross-linked. The hydrocarbon ring and lower
Rukilen is substituted with at least one alkyl
Good. R^FourRepresents a hydrogen atom or lower alkyl. n
Represents 0 or 1. ) Represents. A represents a hydrocarbon ring
And the hydrocarbon ring is a lower alkylene or an oxygen atom.
It may be crosslinked. In addition, the lower alkylene and
And the hydrocarbon ring is substituted with at least one alkyl
May be. l and m each represent 0, 1 or 2. G is
N, CH or COH, Ar is an aromatic heterocyclic group,
Aromatic hydrocarbon groups, benzoyl, phenoxy or phenoxy
Represents Nylthio or G is a carbon atom and Ar is a bif
Represents methylenylidene. The aromatic heterocyclic group, aromatic
Hydrocarbon groups, benzoyl, phenoxy, phenylthio,
And biphenylmethylidene are at least one lower
Substituted with a kill, lower alkoxy or halogen atom
May be. } The imide derivative represented by
Regarding salting.

The groups used in the present invention will be described in detail below.

Examples of the lower alkylene in Z and A include groups having 3 or less carbon atoms, and specific examples thereof include methylene, ethylene and trimethylene.

As the hydrocarbon ring in Z and A,
Examples thereof include cycloalkanes and cycloalkenes having 7 or less carbon atoms. Examples of the cycloalkane having 7 or less carbon atoms include cyclopropane, cyclobutane, cyclopentane, cyclohexane and cycloheptane. Examples of the cycloalkene having 7 or less carbon atoms include cyclopentene, cyclohexene, cycloheptene and the like.

Examples of the hydrocarbon ring bridged with a lower alkylene or oxygen atom in Z and A include a ring having 10 or less carbon atoms, specifically bicyclo [1.1.1] pentane, Bicyclo [2.1.1] hexane, bicyclo [2.1.1] hex-2-ene, bicyclo [2.2.1] heptane, bicyclo [2.2.1]
Hepta-2-ene, bicyclo [2.2.2] octane,
Bicyclo [2.2.2] oct-2-ene, Bicyclo [4.1.1] octane, Bicyclo [4.1.1] oct-2-ene, Bicyclo [4.1.1] oct-3- Ene, bicyclo [3.2.1] octane, bicyclo [3.
2.1] oct-2-ene, bicyclo [3.2.1] oct-3-ene, bicyclo [3.2.1] oct-6-
Ene, bicyclo [3.2.2] nonane, bicyclo [3.
2.2] nona-2-ene, bicyclo [3.2.2] non-3-ene, bicyclo [3.2.2] non-6-ene,
7-oxabicyclo [2.2.1] heptane, 7-oxabicyclo [2.2.1] hept-2-ene, 7-oxabicyclo [4.1.1] octane, 7-oxabicyclo [4. 1.1] oct-2-ene, 7-oxabicyclo [4.1.1] oct-3-ene, 8-oxabicyclo [3.2.1] octane, 8-oxabicyclo [3.
2.1] Oct-2-ene, 8-oxabicyclo [3.
2.1] oct-3-ene, 8-oxabicyclo [3.
2.1] Oct-6-ene and the like can be mentioned.

The bonding position of the hydrocarbon ring in A is, for example, -1,1-, -1,2-, -1,3-, -1,4.
-And the like.

Examples of the aromatic hydrocarbon group in Ar include groups having 10 or less carbon atoms, and specific examples thereof include phenyl and naphthyl. Examples of the aromatic heterocyclic group in Ar include a monocyclic aromatic heterocyclic group and a bicyclic aromatic heterocyclic group.

Examples of the monocyclic aromatic heterocyclic group include groups having 6 or less carbon atoms, containing 1 to 4 nitrogen atoms, oxygen atoms or sulfur atoms as hetero atoms, the same or different, Specific examples thereof include pyridyl, pyrimidinyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, furyl and imidazolyl.

Examples of the bicyclic aromatic heterocyclic group include groups containing 1 to 5 nitrogen atoms, oxygen atoms or sulfur atoms as hetero atoms having 10 or less carbon atoms, which are the same or different. Specifically, benzisothiazolyl, benzisoxazolyl, benzfuryl, quinolyl, isoquinolyl, indolyl, indazolyl, benzimidazolyl, aromatic heterocyclic group condensed with benzene ring such as benzoxazolyl, naphthyridinyl, pteridinyl, thienofuranyl, Examples thereof include imidazothiophen-yl and imidazofuranyl.

The alkyl includes, for example, groups having 6 or less carbon atoms, preferably lower alkyl having 4 or less carbon atoms, specifically methyl, ethyl, propyl,
2-propyl, butyl and the like can be mentioned. Examples of the lower alkyl include groups having 4 or less carbon atoms, and specific examples thereof include methyl, ethyl, propyl, 2-propyl and butyl.

Examples of the lower alkoxy include groups having 4 or less carbon atoms, such as methoxy, ethoxy,
Propoxy, 2-propoxy, butoxy and the like can be mentioned.

Examples of the halogen atom include fluorine, chlorine, bromine and iodine.

The acid addition salt is a pharmaceutically acceptable inorganic acid,
Examples thereof include addition salts with organic acids. Examples of the inorganic acid include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and the like. Examples of organic acids include acetic acid, oxalic acid, citric acid,
Examples thereof include malic acid, tartaric acid, maleic acid, fumaric acid and the like.

The compound [I] of the present invention has stereoisomers and / or optical isomers. In the present invention,
Includes mixtures of these isomers and isolated isomers.

The preferred group represented by Ar is a bicyclic aromatic heterocyclic group, naphthyl, benzoyl,
Phenoxy or phenylthio (where G is N, C
Represents H or COH. ) Or biphenylmethylidene (wherein G represents a carbon atom) (wherein the bicyclic aromatic heterocyclic group, naphthyl, benzoyl, phenoxy, phenylthio and biphenylmethylidene are at least 1).
It may be substituted with one lower alkyl, lower alkoxy or halogen atom. ) Is mentioned.

More preferred groups represented by Ar are aromatic heterocyclic groups fused with a benzene ring, naphthyl, benzoyl, phenoxy or phenylthio (aromatic heterocyclic groups fused with the benzene ring, naphthyl, benzoyl, phenoxy and Phenylthio may be substituted with at least one lower alkyl, lower alkoxy or halogen atom). At this time, G represents N, CH or COH.

More preferable groups represented by Ar include:
Specifically, benzisothiazolyl, benzisoxazolyl, isoquinolyl, benzfuranyl, indazolyl or indolyl (the benzisothiazolyl, benzisoxazolyl, isoquinolyl, benzfuranyl, indazolyl and indolyl are at least one lower alkyl, lower Optionally substituted with an alkoxy or halogen atom). At this time, G represents N, CH or COH. The most preferable group represented by Ar is 3-benzisothiazolyl, 3-benzisoxazolyl, 3-indazolyl or 3-indolyl (the 3-benzisothiazolyl, 3-benzisoxazolyl, 3-indazolyl and 3-indolyl may be substituted with at least one lower alkyl, lower alkoxy or halogen atom). At this time, G represents N, CH or COH.

A preferred group represented by Z-is the formula

[Chemical 10] (In the formula, L represents a single bond or a double bond. E represents a hydroxyl group or lower alkylene optionally substituted by lower alkyl or an oxygen atom. R ⁵ represents a hydroxyl group, R ^5
6 represents a hydrogen atom or lower alkyl. B represents the above meaning. ),formula

[Chemical 11] (In the formula, L, E, R ⁵ , R ⁶ and B have the above-mentioned meanings), Formula

[Chemical 12] (In the formula, R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ and R ¹² each represent a hydrogen atom, a hydroxyl group or a lower alkyl, or
Two adjacent to each other at ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ and R ¹² are bonded to each other to represent a double bond. However, R ⁷ , R ⁸ , R ⁹ , R
^At least one of ¹⁰ , R ¹¹ and R ¹² represents a hydroxyl group.
B represents the above meaning. ) Or expression

[Chemical 13] (In the formula, R ¹³ and R ¹⁴ each independently represent a hydrogen atom or a lower alkyl which may be substituted with at least one hydroxyl group, or R ¹³ and R ¹⁴ together represent at least one hydroxyl group. Represents a saturated hydrocarbon ring which may be substituted, and R ⁵ , R ⁶ and B have the above-mentioned meanings.)
And the like.

Examples of the saturated hydrocarbon ring formed by R ¹³ and R ¹⁴ together include a cycloalkane having 7 or less carbon atoms, specifically, cyclopropane, cyclobutane, cyclopentane, cyclohexane. , Cycloheptane and the like.

More preferred groups represented by Z- are:
formula

Embedded image (In the formula, B, E, R ⁵ and R ⁶ have the above meanings.)

[Chemical 15] (In the formula, E, R ⁵ , R ⁶ and B have the above-mentioned meanings), Formula

Embedded image (In the formula, R ^{7 ′} , R ^{8 ′} , R ^{9 ′} , R ^{10 ′} , R ^{11 ′} and R ^{12 ′} each represent a hydrogen atom, a hydroxyl group or a lower alkyl,
^{At least one of 7 '} , R8 ^' , R9 ^' , R10 ^' , R11 ^' and R12 ^' represents a hydroxyl group. B represents the above meaning. ) Or expression

[Chemical 17] (In the formula, B, R ⁵ , R ⁶ , R ¹³ and R ¹⁴ have the above-mentioned meanings).

The compound [I] of the present invention can be produced, for example, by the method represented by the following reaction formula.

Manufacturing method a)

Embedded image

Manufacturing method b)

[Chemical 19]

Manufacturing method c)

Embedded image

Manufacturing method d)

[Chemical 21]

[In the reaction formula, R ¹⁵ and R ¹⁶ together represent hydroxy, alkoxy or, together, represent an oxygen atom. R ¹⁷ represents a hydroxy protecting group. p and q each represent 0 or 1. X represents a leaving group. Examples of the leaving group include a halogen atom, alkylsulfonyloxy and arylsulfonyloxy. Examples of alkylsulfonyloxy include methanesulfonyloxy and the like.
Examples of arylsulfonyloxy include p-toluenesulfonyloxy and benzenesulfonyloxy. Examples of the hydroxy protecting group include benzyl, substituted benzyl, methoxymethyl, methoxyethoxymethyl, and tetrahydrofuranyl. Examples of the substituent of the substituted benzyl include a halogen atom, methoxy, nitro and the like. R ^{5 'represents} an inverted hydroxyl configurations with respect to ^{R 5, Z, A, l} , m, G, Ar, B,
E, R ⁵ and R ⁶ have the above-mentioned meanings. ]

Starting compounds [II], [III], [IV], [V], [VI], [VII] used in the production methods a to c
I], [IX], [XI], [XII], [XIII], [XIV
], [XV] and [XVI] are known compounds, or can be synthesized by the method described in JP-A-5-17440. The starting compound [VII] can be obtained by reacting the corresponding dicarboxylic acid or carboxysulfonic acid with urea. Dicarboxylic acids or carboxysulfonic acids are described, for example, in the literature (Anallen del Chemie An.
nalen der Chemie, 514, 91 (1935), Chemische Berichte, 67, 1811 (1934), etc.).

Production Method a) The compound of the formula [III] can be obtained by reacting the compound of the formula [II] with a reducing agent in an inert solvent. The reaction temperature is in the range of 0 ° C to the boiling point of the solvent. The amount of reducing agent is in the range of 1 to 10 times by mole with respect to the compound of the formula [II].
Here, as the inert solvent, an ether solvent, for example,
Examples include diethyl ether and tetrahydrofuran. Examples of the reducing agent include LiAlH ₄ , NaBH ₄ , and Ca.
(BH ₄ ) ₂ , LiAlH ₂ (OCH ₂ CH ₂ OCH ₃ ) _{2 and the} like.

The compound of the formula [IV] can be obtained by introducing a leaving group into the compound of the formula [III]. When the leaving group is a halogen atom (for example, when it is a chlorine atom) The compound of the formula [IV] can be obtained by reacting the compound of the formula [III] with thionyl chloride in the presence of a base, if necessary. Examples of the reaction solvent include pyridine, tetrahydrofuran, methylene chloride and the like. Examples of the base include pyridine and the like. 0 ℃ as the reaction temperature
The range of -30 degreeC is mentioned. The amount of thionyl chloride is in the range of 2 to 4 times by mole with respect to the compound of the formula [III].

When the leaving group is sulfonyloxy: The compound of formula [IV] can be obtained by reacting the compound of formula [III] with a sulfonyl chloride in the presence of a base, if necessary. Examples of the reaction solvent include pyridine, tetrahydrofuran, methylene chloride, chloroform and the like. Examples of the base include triethylamine and the like. The reaction temperature may be in the range of 0 ° C to 30 ° C. Examples of the sulfonyl chloride include alkylsulfonyl chloride such as methanesulfonyl chloride, arylsulfonyl chloride such as tosyl chloride, benzenesulfonyl chloride and the like. The amount of sulfonyl chloride is 2 to the compound of the formula [III].
A 4-fold molar range can be mentioned.

The compound of formula [VI] can be obtained by reacting the compound of formula [IV] with the compound of formula [V] in the presence of a base. Examples of the reaction solvent include alcohol, acetonitrile, dimethylformamide and the like. Examples of the reaction temperature include a range around the boiling point of the solvent. Examples of the base include potassium carbonate, sodium carbonate and the like. The amount of base is 0 with respect to the compound of formula (IV).
The range of 5 to 2 times mol is mentioned. The amount of the compound of the formula [V] is in the range of 1 to 1.5 times the mol of the compound of the formula [IV]. Examples of alcohols include methanol, ethanol, propanol, 2-propanol, butanol and the like.

The compound of the formula [Ia] is obtained by reacting the compound of the formula [VI] with the compound of the formula [VII] in the presence of a base and optionally a catalyst. Examples of the reaction solvent include aromatic solvents such as toluene, xylene and chlorobenzene. Examples of the reaction temperature include a range around the boiling point of the solvent. Examples of the base include potassium carbonate, sodium carbonate and the like. The amount of the base is in the range of 1- to 1.5-fold the molar amount of the compound of the formula [VII]. Examples of the catalyst include crown ethers such as dibenzo-18-crown-6-ether. The amount of the catalyst is 0.1 with respect to the compound of the formula [VI].
The range is from 10 to 10% by weight. The amount of the compound of the formula [VII] is in the range of 1 to 1.5 times mol with respect to the compound of the formula [VI].

Production Method b) The compound of the formula [IX] is prepared by converting the compound of the formula [III] into the compound of the formula [IV]
The compound can be obtained by introducing a leaving group into the compound of the formula [VIII] in the same manner as the method of obtaining the compound of. The compound of the formula [X] can be obtained by reacting the compound of the formula [IX] with the compound of the formula [VII] in the presence of a base and optionally a reaction aid. Examples of the reaction solvent include alcohol, dimethylformamide, acetonitrile and the like. Examples of the reaction temperature include a range around the boiling point of the solvent. Examples of the base include inorganic bases such as potassium carbonate and sodium carbonate. Examples of the reaction aid include alkali metal iodides such as potassium iodide and sodium iodide. The amount of the base may be in the range of 1 to 2 times the mol of the compound of the formula [IX]. The amount of the reaction aid may be in the range of 0.1 to 1 mol per mol of the compound of the formula [IX]. The amount of the compound of the formula [VII] is in the range of 0.1 to 1 mol per mol of the compound of the formula [IX].

The compound of the formula [I] can be obtained by reacting the compound of the formula [X] with the compound of the formula [V] in the presence of a base and optionally a reaction aid. Examples of the reaction solvent include alcohol, dimethylformamide, acetonitrile and the like. Examples of the reaction temperature include a range around the boiling point of the solvent. Examples of the base include potassium carbonate,
An inorganic base such as sodium carbonate can be used. Examples of the reaction aid include alkali metal iodides such as potassium iodide and sodium iodide. The amount of the base may be in the range of 1 to 2 times the mol of the compound of the formula [X]. The amount of the reaction aid is in the range of 0.1 to 1 mol per mol of the compound of the formula [X]. The amount of the compound of the formula [V] is in the range of 1 to 1.5 times the mol of the compound of the formula [X].

Production Method c) The compound of the formula [XI] can be prepared from the compound of the formula [VIII] by a conventional method, for example, “Protective Group in Organic Synthesis Protective group in Organic Sy”.
nthesis, Theodora W. Greene, John Wiley & Sone, 10 ~
It can be obtained by the method for introducing a protecting group described on page 39.

The compound of the formula [XII] can be obtained by oxidizing the compound of the formula [XI], forming an oxime, and further reducing the compound. Examples of the oxidizing agent include chromates such as chromic anhydride and dichromic acid. Hydroxylamine is mentioned as an oxime agent. Examples of the oxime forming solvent include alcohol. The oxime formation temperature may be in the range of 0 to 30 ° C. The amount of the oxime-forming agent is in the range of 1 to 2 times that of the compound of the formula [XI]. Examples of the reducing agent include LiAlH _{4 and the} like. Examples of the reduction temperature include a range around the boiling point of the solvent. The amount of the reducing agent is in the range of 1 to 2 moles based on the compound of the formula [XI].

The compound of formula [XIV] is obtained by reacting the compound of formula [XII] with the compound of formula [XIII] in the presence of a base.
Examples of the reaction solvent include alcohol, diglyme, toluene, chlorobenzene and the like. Examples of the reaction temperature include a range around the boiling point of the solvent. Examples of the base include inorganic bases such as potassium carbonate and sodium carbonate. The amount of the base may be in the range of 1 to 2 times the mol of the compound of the formula [XII]. The amount of the compound of the formula [XIII] is in the range of 1 to 1.5 times mol with respect to the compound of the formula [XII].

The compound of the formula [XV] can be prepared from the compound of the formula [XIV] by a conventional method, for example, “Protective group in organic synthesis Protective group in
Organic Synthesis, Theodora W. Greene, John Wiley &
Sons, pages 10 to 39 ”.

The compound of the formula [XVI] can be obtained by introducing a leaving group into the compound of the formula [XV]. -When the leaving group is a halogen atom (for example, when it is a chlorine atom) The compound of the formula [XVI] is obtained by reacting the compound of the formula [XV] with thionyl chloride in the presence of a base, if necessary. Examples of the reaction solvent include pyridine, tetrahydrofuran, methylene chloride and the like. Examples of the base include pyridine and the like. The reaction temperature may be in the range of 0 ° C to 30 ° C. The amount of thionyl chloride is in the range of 2 to 4 times by mole with respect to the compound of the formula [XV].

When the leaving group is a sulfonyloxy group: The compound of the formula [XVI] can be obtained by reacting the compound of the formula [XV] with a sulfonyl chloride in the presence of a base, if necessary. Examples of the reaction solvent include pyridine, tetrahydrofuran, methylene chloride, chloroform and the like. Examples of the base include triethylamine and the like. The reaction temperature may be in the range of 0 ° C to 30 ° C. Examples of the sulfonyl chloride include alkylsulfonyl chlorides such as methanesulfonyl chloride and arylsulfonyl chlorides such as tosyl chloride and benzenesulfonyl chloride. The amount of the sulfonyl chloride may be in the range of 2 to 4 times the mol of the compound of the formula [XV].

The compound of formula [I] is obtained by reacting the compound of formula [XVI] with the compound of formula [VII] in the presence of a base. Examples of the reaction solvent include alcohol, acetonitrile,
Examples thereof include dimethylformamide. Examples of the reaction temperature include a range around the boiling point of the solvent. Examples of the base include potassium carbonate, sodium carbonate and the like. The amount of the base is in the range of 0.5 to 2 times by mole with respect to the compound of the formula [XVI]. The amount of the compound of the formula [VII] is in the range of 1 to 1.5 times the mol of the compound of the formula [XVI].

Production Method d) The compound of the formula [Ic] can be prepared from the compound of the formula [Ib] by a conventional method, for example, “Buretan of the Chemical Society of Japan Bull. Chem. Soc. Ja
p., 40, 2380 (1967) ”.

The compound of the formula [Ic] is obtained by reacting the compound of the formula [Ib] with formic acid in the presence of triphenylphosphine and diethyl azodicarboxylate to give a base of an formic acid ester derivative. It is obtained by solvolysis in the presence of. As a reaction solvent for producing the formic acid ester derivative, for example, an ether solvent such as diethyl ether or tetrahydrofuran is desirable. The reaction temperature may be in the range of ice cooling to around the boiling point of the solvent.
The amount of triphenylphosphine may be in the range of 1 to 1.5 times the mol of the compound of the formula [Ib].
The amount of diethyl azodicarboxylate may be represented by the formula [I-
The range of 1-1.5 times the molar amount of the compound [b] is included. The amount of formic acid is 1 with respect to the compound of the formula [Ib].
The range of 10 to 10 times by mole is included. Examples of the base for the solvolysis include potassium carbonate, sodium carbonate, sodium hydroxide and the like. The amount of the base may be in the range of 1 to 1.5 times the molar amount of the formic acid ester derivative. Examples of the reaction solvent include alcohol solvents such as methanol and ethanol, and mixed solvents thereof with water.

Compounds [I-obtained by the production methods a) to d)
a], [Ic] and [I] can be purified by recrystallization in a crystallization solvent (for example, alcohol, diethyl ether, ethyl acetate, hexane or a mixed solvent thereof) or silica gel chromatography. The compounds [Ia], [Ic] and [I] are also purified by recrystallizing them in the crystallization solvent (eg acetone, diethyl ether, alcohol, etc.) after forming acid addition salts. it can.

As a usual method for introducing a protecting group, for example, when the protecting group is benzyl, substituted benzyl or methoxymethyl, one to two times as much halide of the corresponding protecting group as the starting compound is used as a base (eg, , An alkali metal hydride such as NaH and KH, an organic base such as triethylamine and dimethylaminopyridine) in the presence of an organic solvent (for example, tetrahydrofuran and dimethylformamide) at a temperature range of -10 ° C to 30 ° C. A protecting group is introduced.

As a usual method of deprotection, for example, when the protecting group is benzyl or substituted benzyl, a catalyst (eg,
In the presence of a noble metal catalyst such as Pd-C, PtO, Pt-C)
It can be deprotected by carrying out a hydrogenation reaction (for example, in the range of 1 to 3 atm). When the protecting group is benzyl, substituted benzyl or methoxymethyl, a strong acid (for example, CF
₃ COOH, HBr, HBr-CH ₃ COOH, etc.) can also be used for deprotection.

In the case of optically resolving the compound represented by the general formula [I], it can be carried out as follows. The compound of formula [I] is dissolved in an inert solvent (for example, acetonitrile, alcohol and the like), and an optically active acid (for example, L-tartaric acid,
D-tartaric acid, D-camphoric acid, L-mandelic acid, L-
Pyroglutamic acid, D-10-camphorsulfonic acid,
D-quinic acid, L-malic acid, dibenzoyl-L-tartaric acid and the like can be mentioned, preferably L-tartaric acid and D-tartaric acid. ) Is added to form a salt. The temperature at which the salt is formed can be in the range of room temperature to the boiling point of the solvent, but it is desirable to once heat it to near the boiling point of the solvent in order to improve the optical purity. The precipitated salt can be cooled if necessary before being collected by filtration to improve the yield. The amount of the optically active acid (resolving agent) used is appropriately in the range of 0.5 to 2.0 equivalents, preferably about 1 equivalent, relative to the substrate. If necessary, the obtained crystal can be recrystallized in a crystallization solvent (for example, alcohol and the like) to obtain a highly pure optically active salt. If necessary, the obtained salt is treated with a base by a usual method to obtain an optically active form of the compound represented by the general formula [I] as a free form.

When used as an antipsychotic, the compound of the present invention represented by the general formula [I] and its acid addition salt can be administered orally or parenterally. That is, it can be orally administered in a commonly used dosage form such as tablets, capsules, syrups, and suspensions. Alternatively,
Solution forms can be administered parenterally in the form of injections. It can also be administered rectally in the form of suppositories. Further, the above-mentioned suitable dosage form can be produced by blending the compound [I] of the present invention or an acid addition salt thereof with an acceptable conventional carrier, excipient, binder, stabilizer and the like. When used as an injection, an acceptable buffering agent, solubilizing agent, isotonic agent, etc. may be added.

The dose and frequency of administration are as follows: symptom / age / body weight /
Although it depends on the administration form, etc., it is usually about 1 to 500 mg, preferably 5 to 100 mg in the case of oral administration, and 0.1 to 100 mg, preferably 0.1 in the case of intravenous injection to an adult per day. 3 to 50 mg can be administered once or in several divided doses.

Experimental Example 1 <Experimental method> (1) Antipsychotic action (anti-D ₂ action) (in vitro) Generally, a correlation is observed between clinical antipsychotic action and D ₂ receptor blocking action. . A binding assay for the dopamine D ₂ receptor, an in vitro test of D ₂ receptor action, was used. Using [ ³ H] spiroperidol, Japan J. Pharmacol.,
53, 321-329 (1990), etc., [ ³ H] spiroperidol (spiroperi
The amount of dol) binding was measured to determine the Ki value. The results are shown in Table 3.
It was shown to.

[Table 3]

(2) Antipsychotic effect (in vivo) An anti-methamphetamine test, which is a typical in vivo test method for clinical antipsychotic effect, was carried out. The test drug was intravenously administered to male rats, and 10 minutes later, methamphetamine (1 mg / kg) was intraperitoneally administered. 10 minutes to 9 after administration
The locomotor activity of the rat was measured for 0 minutes using Automex, and the 50% inhibitory effective dose / ED ₅₀ value was determined. The results are shown in Table 4.

[Table 4]

(3) Side Effects The catalepsy-inducing action, which is a typical central side effect of antipsychotic drugs in clinical practice, was evaluated. The test drug is intravenously administered to male rats, and 1 hour later, the test drug is forcibly suspended three times on a horizontal iron bar having a diameter of 2.5 mm at a height of 9 cm. A catalepsy positive was obtained when an unnatural stretched state was held for 30 seconds or longer even once in three times.
The results are shown in Table 5.

[Table 5]

[0060]

INDUSTRIAL APPLICABILITY The compound (I) of the present invention and an acid addition salt thereof show excellent antipsychotic activity, and it is clear from the efficacy ratio of antipsychotic activity (anti-apomorphine action) and side effects that there are few central side effects. It was

[0061]

【Example】

Reference Example 1 (1RS, 2RS, 3SR, 4RS, 5S
R) -5-Hydroxy-2,3-bicyclo [2.2.
1. ] Synthesis of heptane dicarboxylic acid (2)

[Chemical formula 22] (In the formula, thick solid lines and broken lines represent relative arrangements. The same applies to the following structural formulas.) Bicyclo [2.2.1. ] Hepta-5-ene-2,3-
Di-exo-carboxylic acid anhydride (1) (50.0 g,
0.303 mol) was gradually added to a 50% sulfuric acid aqueous solution (500 g), and the mixture was stirred at 80 to 85 ° C for 3.5 hours. After cooling the reaction solution, the reaction solution was barium chloride dihydrate (62
2 g, 2.55 mol) and water (1.5 l) were added dropwise with stirring to the mixture. After standing overnight, the precipitate was separated by filtration, and the filtrate and the washing solution were combined and concentrated under reduced pressure to precipitate crystals. By filtering, washing and drying the crystals, (1RS, 2RS, 3SR, 4RS, 5SR) -5
-Hydroxy-2,3-bicyclo [2.2.1. ] Heptane dicarboxylic acid (2) (22.8g) was obtained. Melting point 196 to 198 ° C. ¹ H-NMR (DMSO-d6) δ: 4.65 (1 H, s),
3.60 (1H, d, J = 5Hz), 2.50 (1
H), 2.43 (1H), 2.35 (1H), 2.20.
(1H), 1.16 to 1.80 (4H).

Reference Example 2 (1RS, 2RS, 3SR, 4
RS, 5SR) -5-Hydroxy-2,3-bicyclo [2.2.1. ] Synthesis of heptane dicarboximide (3)

[Chemical formula 23] After mixing the compound (2) (2.00 g, 9.95 mmol) and urea (0.66 g, 10.9 mmol),
When heated at an oil bath temperature of 170 ° C for 1 hour, the desired (1
RS, 2RS, 3SR, 4RS, 5SR) -5-Hydroxy-2,3-bicyclo [2.2.1. ] Heptane dicarboximide (3) (1.93 g) was obtained. ¹ H-NMR (DMSO-d6) δ: 3.83 (1 H, d, J
= 6.9 Hz), 2.56 (3H, s), 2.46 (1
H, s), 1.79 (1H, ddd, J = 13.5,
6.9, 2.3 Hz), 1.65 (1H, d, J = 1)
1.2), 1.41 (1H, ddd, J = 13.5,
4.3, 2.3 Hz, 1.18 (1H, d, J = 1)
1.2). Similarly, 1-hydroxy-1,2-cyclohexanedicarboximide is obtained from 1-hydroxy-1,2-cyclohexanedicarboxylic acid.

Reference Example 3 Compound (6)

[Chemical formula 24] (In the formula, wedge-shaped solid lines and broken lines represent absolute configurations.
The same applies to the following structural formulas. ) References (Journal of Chemical Society: J. C.
hem. Soc., 1953, 389) (-)-(1
R, 2R) -1,2-bis (methanesulfonyloxymethyl) cyclohexane (4) (32.52 g, 108 mmol) and 3
-(1-Piperazinyl) -1,2-benzisothiazole (5) (18.24 g, 83.3 mmol) and sodium carbonate (17.25
A mixture of g, 125 mmol) and toluene (300 ml) was heated under reflux for 21 hours. After concentrating toluene, isopropyl alcohol was added and the mixture was heated under reflux and then filtered while hot, and the filtrate was evaporated. Acetone was added to the residue, dissolved under heat, and then cooled to give the desired compound (6) (23.0 g)
I got IR (nujol): 3490, 3450, 1655, 159
0,1560,1495,1425,1210,104
^{. 0cm -1 1 H-NMR (} DMSO-d6) δ: 7.96 (1H, d, J
= 7.9 Hz), 7.82 (1H, d, J = 8.3H)
z), 7.50 (1H, t, J = 8.3 Hz), 7.4
0 (1H, t, J = 7.9 Hz), 4.08 (2H, d
d, J = 11.5, 6.5 Hz), 3.39 (2H,
t, J = 11.5 Hz), 2.1-1.8 (8H, comp
lex-m), 1.4-1.25 (4H, complex-m).

Example 1 Synthesis of compound (7)

[Chemical 25] Compound (3) (0.642 g, 3.54 mmol) and powdery anhydrous potassium carbonate (0.489 g, 3.54 m)
mol) to the compound (6) (1.00 g, 2.36 mmo)
l) in DMF (15 ml) solution, oil bath temperature 12
The mixture was heated and stirred at 0 ° C for 10 hours. After cooling, the reaction solution was poured into water and extracted twice with ether. The extract solution was washed with water and dried. After evaporation, the obtained residue is purified by column chromatography to obtain the desired (1RS, 2RS,
3SR, 4RS, 5SR) -N-[(1R, 2R) -2
-[4- (1,2-benzisothiazol-3-yl)
-1-Piperazinylmethyl] -1-cyclohexylmethyl] -5-hydroxy-2,3-bicyclo [2.2.
1] Heptane dicarboximide (7) (1.08 g) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 7.91 (1 H, d,
J = 7.9 Hz), 7.80 (1H, d, J = 7.9H)
z), 7.46 (1H, t, J = 7.9 Hz), 7.3
5 (1H, t, J = 7.9 Hz), 3.96 (1H,
d, J = 8.9 Hz), 3.9 (1H, m), 3.5
2 (4H, t, J = 5.3Hz), 3.32 (1H, d
d, J = 10.2, 13.2 Hz), 2.55-2.7
5 (7H, complex-m), 2.51 (2H, s), 2.
23 (1H, dd, J = 6.6, 12.5 Hz), 1.
8-1.95 (2H, complex-m), 1-1.7 (13
H, complex-m). Melting point 155-160 ° C (hydrochloride)

Example 2 Synthesis of compound (9)

[Chemical formula 26] a) triphenylphosphine (0.787 g, 3.00 mmol) and formic acid (0.23) in THF (20 ml) of compound (7) (1.02 g, 2.00 mmol).
g, 5.00 mmol) and azodicarboxylic acid diethyl ester (DEAD) (0.522 g, 3.00 mm
ol) was added, and the mixture was stirred at room temperature for 1 day. After evaporation, chloroform was added to the residue, and the chloroform solution was washed with saturated aqueous sodium hydrogen carbonate and dried. The formyloxy compound (8) was obtained by separating the residue obtained by evaporating the chloroform solution by column chromatography.
A fraction (1.49 g) containing was obtained. ¹ H-NMR (CDCl ₃ ) δ: 7.91 (d, J =
7.9 Hz), 7.81 (d, J = 7.9 Hz), 5.
2 (m), 3.98 (dd), 3.52 (t), 3.3
5 (dd, J = 10.2, 13.2 Hz), 3.22
(D, J = 7.3 Hz), 2.93 (d, J = 4.3 H)
z), 2.75 (d, J = 5.1 Hz), 2.55-
2.7 (complex-m), 2.15-2.3 (complex-m)
m), 0.9-1.9 (complex-m). b) Powdered anhydrous potassium carbonate (0.400 g) was added to a solution of the fraction (1.49 g) containing the compound (8) in methanol (100 ml), and the mixture was stirred at room temperature for 4 hours. After evaporation, ethyl acetate was added to the residue, washed with water, dried and then evaporated. By separating the residue by column chromatography, the desired (1RS, 2RS, 3SR,
4RS, 5RS) -N-[(1R, 2R) -2- [4-
(1,2-Benzisothiazol-3-yl) -1-piperazinylmethyl] -1-cyclohexylmethyl] -5
-Hydroxy-2,3-bicyclo [2.2.1] heptanedicarboximide (9) (0.255 g) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 7.91 (1 H, d,
J = 7.9 Hz), 7.81 (1H, d, J = 7.9H)
z), 7.46 (1H, t, J = 7.3 Hz), 7.3
5 (1H, t, J = 7.3 Hz), 4.39 (1H,
m), 3.96 (1H, dd, J = 4.0, 13.5H
z), 3.52 (4H, t, J = 4.5Hz), 3.3.
-3.4 (2H, m), 2.6-2.8 (7H, comple
x-m), 2.05-2.3 (2H, complex-m), 1.
8-2.0 (1H, m), 0.95-1.7 (14H,
complex-m).

Claims (5)

[Claims] 1. A general formula [I]: {In the formula, Z- is the formula: (In the formula, B represents carbonyl or sulfonyl.
R ¹ , R ² and R ³ are the same as R ¹ and R ² together,
Represents a hydrocarbon ring substituted with at least one hydroxyl group, R ³ represents a hydrogen atom or a hydroxyl group, or R 3
¹ and R ³ together represent a hydrocarbon ring substituted with at least one hydroxyl group, and R ² represents a hydrogen atom or a hydroxyl group. The hydrocarbon ring may be bridged with a lower alkylene which may be substituted with at least one hydroxyl group or an oxygen atom. The hydrocarbon ring and lower alkylene may be substituted with at least one alkyl. R ⁴ represents a hydrogen atom or lower alkyl. n
Represents 0 or 1. ) Represents. A represents a hydrocarbon ring, and the hydrocarbon ring may be bridged with a lower alkylene or an oxygen atom. Further, the lower alkylene and the hydrocarbon ring may be substituted with at least one alkyl. l and m each represent 0, 1 or 2. G represents N, CH or COH, Ar represents an aromatic heterocyclic group, an aromatic hydrocarbon group, benzoyl, phenoxy or phenylthio, or G represents a carbon atom and Ar represents biphenylmethylidene. The aromatic heterocyclic group, aromatic hydrocarbon group, benzoyl, phenoxy, phenylthio and biphenylmethylidene may be substituted with at least one lower alkyl, lower alkoxy or halogen atom. } The imide derivative represented by these or its acid addition salt. 2. Ar represents a bicyclic aromatic heterocyclic group, naphthyl, benzoyl, phenoxy or phenylthio, G represents N, CH or COH, or Ar
Represents biphenylmethylidene and G represents a carbon atom (the bicyclic aromatic heterocyclic group, naphthyl, benzoyl, phenoxy, phenylthio and biphenylmethylidene are substituted with at least one lower alkyl, lower alkoxy or halogen atom). The imide derivative according to claim 1 or an acid addition salt thereof. 3. Ar represents an aromatic heterocyclic group condensed with a benzene ring, or naphthyl, benzoyl, phenoxy or phenylthio (aromatic heterocyclic group condensed with the benzene ring, naphthyl, benzoyl, phenoxy and phenylthio. Is optionally substituted by at least one lower alkyl, lower alkoxy or halogen atom), and G represents N, CH or COH, and the imide derivative or acid addition salt thereof according to claim 1. 4. Z- is of the formula: (In the formula, L represents a single bond or a double bond. E represents a hydroxyl group or lower alkylene optionally substituted by lower alkyl or an oxygen atom. R ⁵ represents a hydroxyl group, R ^5
6 represents a hydrogen atom or lower alkyl. B is claim 1
Indicates the meaning of the description. ), The formula: (In the formula, L, E, R ⁵ , R ⁶ and B have the above meanings.) (In the formula, R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ and R ¹² each represent a hydrogen atom, a hydroxyl group or a lower alkyl, or
Two adjacent to each other at ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ and R ¹² are bonded to each other to represent a double bond. However, R ⁷ , R ⁸ , R ⁹ , R
^At least one of ¹⁰ , R ¹¹ and R ¹² represents a hydroxyl group.
B represents the above meaning. ) Or the formula: (In the formula, R ¹³ and R ¹⁴ each independently represent a hydrogen atom or a lower alkyl which may be substituted with at least one hydroxyl group, or R ¹³ and R ¹⁴ together represent at least one hydroxyl group. Represents a saturated hydrocarbon ring which may be substituted, and R ⁵ , R ⁶ and B have the above-mentioned meanings.)
The imide derivative according to claim 1 or an acid addition salt thereof. 5. The formula: (In the formula, the wedge-shaped solid line and the broken line represent the absolute configuration,
The solid line and the broken line of thick lines represent relative arrangements), The imide derivative or acid addition salt thereof according to claim 1.