JPS6383085A - Novel imide derivative - Google Patents

Abstract

NEW MATERIAL:A compound of formula I [A is group of formula II (E is methylene, ethylene or O), etc.; D is (substituted) monomethylene, (substituted) dimethylene, substituted trimethylene, substituted tetramethylene or substituted pentamethylene; Y is H, alkyl, alkoxy, etc.] or its salt. EXAMPLE:N-[4-{4-(1,2-benzisothiazol-3-yl)-1-piperazinyl}3-oxobutyl]bic yclo[2,2,1] heptane-2,3-di-exo-carboxyimide. USE:A remedy for central nervous system diseases. PREPARATION:The compound of formula I can be produced e.g. by reacting a dicarboxyimide compound of formula III with a piperazine derivative of formula IV in the presence of an acid scavenger such as potassium carbonate in a solvent such as benzene under heating.

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to novel imide derivatives, acid addition salts thereof, methods for producing the same, and therapeutic agents for central nervous system diseases containing them as active ingredients.

[Prior art/Problems to be solved by the invention] Conventionally, as antipsychotic drugs, bicyclic antipsychotic drugs such as chlorpromazine and butyrophenone antipsychotic drugs such as haloperidol have been used. They are accompanied by central side effects such as extrapyramidal system side effects (catalepsy, etc.) and peripheral side effects such as a drop in blood pressure, posing a major problem in terms of clinical application.

Chlorpromazine Haloperidol Therefore, an object of the present invention is to provide a compound that has excellent antipsychotic activity and has few side effects.

[Means for solving problems]

Under these circumstances, the present inventors have conducted intensive research and have discovered a novel imide derivative, which is the compound of the present invention, and have discovered that this product has the desired pharmacological actions.
The present invention has now been completed.

The present invention is based on the general formula (1) [wherein A represents the general formula (in the formula, E represents a methylene group, ethylene group or oxygen atom, and Uni represents a single bond or a double bond], the general formula (wherein R represents a hydrogen atom or an alkyl group, and Dini has the same meaning as above);
D represents a substituted or unsubstituted monomethylene fin, a substituted or unsubstituted dimethylene group, a substituted trimethylene group, a substituted tetramethylene group and a substituted pentamethylene group, and Y represents a hydrogen atom, an alkyl group, an alkoxy or a halogen atom. The present invention relates to imide derivatives and acid addition salts thereof.

The compound (1) of the present invention can be used as desired with various inorganic or organic acids, such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, acetic acid, oxalic acid, citric acid, malic acid, tartaric acid, fumaric acid, Acid addition salts can be formed with maleic acid or the like by means known per se. Alternatively, the salt can be converted into the corresponding base form by conventional treatment with a suitable alkali.

A detailed explanation of each symbol in general formula (1) is as follows.

Preferred examples of the substituent for D include an alkyl group, an oxo group, a hydroxyimino group, an alkanoyloxy group, and an alkoxy group. The alkyl group as a substituent here may be either linear or branched, and preferable examples include the lower alkyl group of CI-a, and more specifically, for example, methyl group, ethyl group, propyl group, isopropyl group. and butyl groups,
The alkanoyloxy group may be straight or branched (preferably a Cl-5 lower alkanoyloxy group, for example, an acetoxy group, a propanoyloxy group, a 2-methylpropanoyloxy group). basis,
Examples include a butanoyloxy group and a pentanoyloxy group, and the alkoxy group may be linear or branched, preferably a C1-4 lower alkoxy group, and specifically, for example, a methoxy group. , ethoxy group,
Mention may be made of propoxy, isopropoxy and butoxy groups.

Therefore, when D is a substituted monomethylene group, the substituent is preferably an alkyl group, and when D is a substituted dimethylene group, substituted trimethylene group, substituted tetramethylene group, or substituted pentamethylene group, the general formula Preferred examples of the substituent on the carbon adjacent to the group represented by the formula [wherein A has the same meaning as above] include an alkyl group.

In addition, as a substituent on the carbon adjacent to the group represented by the general formula [wherein Y represents the same meaning as above], an alkyl group or an oxo group is exemplified as a preferable substituent, and Preferred examples of the substituent include an alkyl group, an oxo group, a hydroxyimino group, an alkanoyloxy group, and an alkoxy group.

Y represents a hydrogen atom, an alkyl group, an alkoxy group, or a halogen atom. The alkyl group in Y may be linear or branched, preferably a C3-4 lower alkyl group, and more specifically, , for example, a methyl group,
Examples include ethyl group, propyl group, isopropyl group and butyl group. The alkoxy group may be straight-chain or branched, and preferable examples include CI-4 lower alkoxy groups, and more specifically, methoxy, ethoxy, propoxy, isopropoxy, and butoxy groups. Illustrated. Examples of the halogen atom include a fluorine atom, a chlorine atom, and a bromine atom.

The alkyl group in R may be linear or branched, preferably a C1-4 lower alkyl group, and more specifically, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, and a butyl group. For example,

The compound (1) of the present invention is produced, for example, by a method represented by the following reaction formula.

Production method a) (II) (III) Production method b) Production method C) (XI[l) (III) (In the reaction formula, A, Y and D represent the same meanings as above, and Do
represents a trimethylene group, a tetramethylene group and a pentamethylene group substituted with a hydroxy group or an oxo group, X represents a leaving group, and m represents an integer of 2 to 4.

) Regarding each symbol in the above reaction formula, Do represents a trimethylene group, a tetramethylene group, and a pentamethylene group substituted with a hydroxy group or an oxo group, and the substitution position of each functional group is determined by the general formula [A has the same meaning as above] represents.

] and a group represented by the general formula [wherein Y has the same meaning as above] is preferably on a carbon that is not adjacent to the group.

X represents a leaving group, for example, a halogen atom such as a chlorine atom, a bromine atom, an iodine atom, methanesulfonyloxy II
Examples include alkyl or arylsulfonyloxy groups such as s,p-)luenesulfonyloxy groups.

-IG Regarding D in formula (II), preferred examples of the substituent on the carbon adjacent to the group represented by -X include an alkyl group or an oxo group, and examples of substituents on other carbons include: Preferred examples include an alkyl group, an oxo group, a hydroxyimino group, an alkanoyloxy group, and an alkoxy group.

Next, each manufacturing method will be explained in detail.

By reacting the compound of the formula (II) with the piperazine derivative of the general formula (III) in the presence of an acid binder using an inert organic solvent. Preferred solvents include benzene, toluene, xylene, dimethylformamide, acetonitrile, n-
butyl alcohol, and in these solvents, alkali and alkaline earth metal carbonates, bicarbonates or hydrides such as potassium carbonate, sodium bicarbonate, sodium hydride, tertiary amines such as triethylamine, or pyridine. It is desirable to carry out the reaction in the presence of an acid binder such as at room temperature or under heating.

With the remains of the alliance (1) Among the compounds represented by general formula (IV), D.

When the substituent is an oxo group, the compound (1) of the present invention can be produced by reacting with hydroxylamine hydrochloride in an appropriate solvent in the presence of an acid binder to form an oxime. The acid binder is preferably an alkali metal carbonate such as potassium carbonate or sodium carbonate, and the solvent is preferably an alcoholic solvent such as methyl alcohol or ethyl alcohol, and if necessary, a buffer such as sodium acetate. may be added, and the reaction is preferably carried out at room temperature or under heating.

(ii) Among the compounds represented by general formula (IV),
When the substituent of D' is a hydroxy group, the compound (1) of the present invention can be produced by acylation in a suitable solvent. As the acylating agent, acid anhydrides such as acetic anhydride and propionic anhydride, and acid halides such as acetyl chloride and propionyl chloride are particularly effective. Preferable solvents include ether solvents such as ether and tetrahydrofuran, halogenated hydrocarbons such as dichloromethane and dichloroethane, and aromatic hydrocarbons such as benzene and toluene. Agents may be added, and the reaction is preferably carried out under water cooling or heating.

(iii) Among the compounds represented by general formula (IV),
D.

ii1! When the i group is a hydroxy group, the compound of the present invention can be produced by oxidation in a suitable solvent. Preferred solvents include benzene, toluene,
Examples include chloroform, acetic acid, trifluoroacetic acid, acetone, water, acetonitrile, dimethyl sulfoxide, pyridine, etc. In these solvents, potassium permanganate, manganese dioxide, chromic acid, dimethyl sulfoxide-dicyclohexylcarbodiimide Alternatively, it is preferable to carry out the reaction under cooling or heating in the presence of an oxidizing agent such as dimethyl sulfoxide-acetic anhydride.

Compounds represented by the general formula (Xl11) and the general formula (■)
The compound N) of the present invention can be produced by reacting the compound represented by the following in an appropriate solvent in the presence of an acid binder. As the acid binder, tertiary amine such as triethylamine or pyridine is preferable, and as the reaction solvent, V aromatic hydrocarbons such as benzene, toluene, xylene, ether solvents such as ether, tetrahydrofuran, dichloromethane, chloroform, etc. The 0 reaction in which halogenated hydrocarbons are preferable is carried out in their solvents,
It is desirable to carry out the reaction under cooling or heating.

Raw material compound (II) used in the above production method, (
I[l), (IV) and (Xlll) are compounds that are known per se or can be synthesized according to known synthesis methods. The synthesis method for each raw material compound will be explained below.

i) Production of raw material compound (n) (V) (Vr) (■)' (II) [In the formula, A, D and X represent the same meanings as above, and n
represents an integer of 1.2 or 3, D# represents a group represented by (in the formula, A represents the same meaning as above), and a general formula (in the formula, X represents the same meaning as above). represents a trimethylene group, a tetramethylene group, or a pentamethylene group in which a hydroxy group or an alkoxy group is substituted on a carbon atom not adjacent to the group represented by the above.

Here, the alkoxy group is preferably a linear or branched one as described above, 01-4. In other words, the compound (
II) is compound (Vl) and compound (
■) It can also be manufactured via '. If necessary, the compound (1) of the present invention can also be derived from the starting compound (■)'.

ii) Production of raw material compound (III) (■) (■) (IX) (X) (
III) [In the formula, Y represents the same meaning as above], that is,
Compound ([[[) is from compound (■), Chew.

According to the method described in Her, , 99.2566-71 (1966), compound (X) was obtained via compounds (■) and (IX), and then JP-A-58-11057
It is induced according to the method described in Publication No. 6.

iii) Production of raw material compound (rV) (V) (XI) [In the formula, A, D', Y and n represent the same meanings as above.] That is, raw material compound (IV) is a compound that is smaller than compound (V). (
XI) or compound (III)
is induced via compound (X II).

In addition, when the substituent of D' is oxo, it can also be synthesized according to the method of production method a).

iv) Synthesis of starting compound (Xll) (XrV) (XV) [In the formula, ASm and ).

[Action/Effect]

The compound (1) of the present invention and its acid addition salts exhibit excellent antipsychotic effects, and have extrapyramidal side effects that are commonly observed in conventional butyrophenone antipsychotics and phenothiazine antipsychotics. It is clear from the experiments shown below that central side effects such as catalepsy (catalepsy, etc.) and peripheral side effects such as hypotension were reduced.

Experimental Example 1 Experimental Method (1) Antipsychotic Effect Typical in vitro antipsychotic effects in clinical practice
A dopamine D□ receptor binding assay, which is a vjtro test method, was used.

The affinity of compounds for D2 receptors in both bovine brain striatal membranes was investigated using the following method.a (T, Kuno, K
.

5aijoh and T., Tanaka, J.
Neurochea+, 41+ 841 (1983)
Reference] Preparation of fal 111 fraction □ Fresh bovine brain striatum was mixed with 20 times the volume of Tris41CII p street solution (pH?, 4.0)
．． Homogenize in 05M), so,ooox g
The membrane fraction obtained by centrifugation for 10 minutes was washed twice with the same volume of buffer to obtain a membrane fraction preparation.

(bl displacement assembly (displa)
cementassay) □ The above membrane fraction (1■ containing protein) was mixed with (211) subiperone (19Ci/5nol)
1 nM, 120mM NaCl, 25mM
Tris-H (1 (pH 7, 4), and test compound 1
The membrane fraction was incubated at 37°C for 30 minutes in a buffer containing 0-9 to 10-'M, and the membrane fraction was purified by Whatman (Wha
tman) GF/B glass filter, and the amount of membrane-bound [3H]spiperone was measured using a liquid scintillation sun counter.

[3H] Spiperone paste at each test compound concentration.

The amount of specific binding to the receptor is determined from the following formula, and Hilb O
, plot (old 11 plot), IC50 value and Ki
I found the value.

Specific binding amount - total binding amount - non-specific binding! ”(”10-
"M Binding amount in the presence of subiperone) C50 C50Ki (n□ 1+J/KO <Experimental results> The results of the dopamine D8 receptor binding assay are shown in Table 1.

(The following is a blank space) Table 1 As is clear from the results shown in Table 1, the compounds of the present invention have high affinity for dopamine D2 receptors. In other words, it is clear that it has an antipsychotic effect equivalent to that of conventional antipsychotic drugs. In addition, research by the present inventors has shown that the compound of the present invention has very low extrapyramidal side effects, such as the effect of inducing cachlepsy, which are common in conventional antipsychotic drugs. It can be said to be a drug with a high safety margin and a wide safety margin, and it is thought that it can be used not only for general psychiatric patients but also for elderly patients with psychiatric disorders who are more likely to develop side effects.

The compound (1) of the present invention represented by the general formula (1) and its acid addition salt can be administered orally or parenterally when used as an antipsychotic. That is, it can be administered orally in commonly used dosage forms, such as tablets, capsules, syrups, suspensions, etc., or in the form of solutions, emulsions, suspensions, etc. It can be administered parenterally in the form of an injection.

It can also be administered rectally in the form of suppositories.

The appropriate dosage forms also include acceptable conventional carriers,
It can be produced by blending the compound (1) of the present invention or an acid addition salt thereof with an excipient, a binder, a stabilizer, and the like. Furthermore, when used in the form of an injection, acceptable buffers, solubilizing agents, isotonic agents, etc. may be added.

Dose and frequency of administration vary depending on symptoms, age, body weight, administration form, etc., but are usually about 0.5 to 100 mg per day for adults.
1000 μ, preferably 3 to 500 μ can be administered once or divided into several doses.

[Reference example/Example]

The present invention will be explained below using reference examples and examples.
The present invention is not limited to this.

(A) Synthesis of Compound (It) Reference Example 1 Synthesis of N-(3-butenyl)bicyclo(2,2,1)hebutane-2,3-di-exo-carboximidebicyclo(2,2,1) To a mixture of 1.65 g of hebutane-2,3-di-exo-carboximide and 5 d of dimethylformamide, add a solution of 1.62 g of 4-bromo-1-butene in dimethylformamide 3 in a room and while stirring,
Further, 2.07 g of powdered anhydrous potassium carbonate was added to the 0 reaction mixture, and the temperature was raised, and the reaction was carried out for 1 hour at an internal temperature of 90 to 100°C. After adding chloroform to the 0 reaction mixture, it was filtered, and the filtrate was depressurized. Top concentration was performed. The residual hedolene was added, washed with water and dried, and the solvent was distilled off under reduced pressure to obtain 2.22 g of the title compound as an oil.

I Rv 2Ai,” (cm-’): 305G
, 3000.2925.1485, the following compound was obtained according to the method of Reference Example 1.

・N-(3-butenyl)cyclohexane-1,2-di-
Carboximide I Rv LA'x"Ccm-'>: 2950
．． 2860.1780.1700, Reference Example 2 Synthesis of N-(4-bromo-3-hydroxybutyl)cyclohexane-1,2-di-carboximide N-(3-butenyl)cyclohexane-1,2-dicarboximide 1 g (4.8 mmol), N-phyromosuccinimide 0.86 g (4.8 mmol)
After the completion of the reaction in which the mixture of 2- and 2-water was stirred at room temperature for 4 hours, water was added to dissolve insoluble matter, and extraction was performed with benzene. The benzene layer was washed with saturated brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 1.4
g (95.8%) of the title compound were obtained.

IR Shinji A-1I (clI-1): 1760.1700
S1440.1400° According to the method of Reference Example 2, the following compound was obtained.

・N-(4-bromo-3-hydroxybutyl)bicyclo(2,2,1)hebutane-2,3-di-exo-carboximide IRI/2B (cm-'): 176
0. 1700, 1480, 1400 Reference example 3 N-(4-bromo-3-oxobutyl)bicyclo(2,
2,1) Synthesis of hebutane-2,3-di-exo-carboximide N-(4-bromo-3-hydroxybutyl)bicyclo(
2,2,1) Hebutane-2,3-di-exo-carboximide 2g (6,66 gu-ol) in acetone 20@1
Cool 5.5 g of Hedjon's reagent (26.7 g of chromium M, 23 af of concentrated sulfuric acid and water??dtS solution) in ice water for 1 hour.
The 0 reaction solution was added dropwise and stirred at the same temperature for 2 hours.
The mixture was poured into 0-water and extracted with chloroform. The chloroform layer was washed with 100@1 saturated aqueous sodium bicarbonate solution, further washed with saturated saline solution, and then dried over magnesium sulfate. The organic solvent was distilled off under reduced pressure, yield 1.24 g, yield 59.3%.
The title compound was obtained.

I RI/::4”(C1l-'): 1760.
1730.1680.1440° (b) Compound (Ill
) synthesis reference example 4 (■) (■) (IX) (X) (I[I
) Synthesis of 3-(1-piperazinyl)-1,2-benzisothiazole (III) ■ 2. Into 2'-dithiobenzoic acid (■) (23 g),
When thionyl chloride (100 aJ) was added and heated under reflux for 3.5 hours, the crystals were dissolved, and then heated under reflux for an additional 30 minutes. After cooling, excess thionyl chloride was distilled off, leaving an acid chloride (25.8 g).

30% methylamine in ethanol <15.5g)
, triethylamine (15,2 g) and ethanol (
80 m), the above acid chloride (25.8 g
) Dry tetrahydrofuran solution (160, d) was added dropwise, and stirring was continued at 25-30°C for 30 minutes. After adding water (15M) and stirring for 30 minutes, the precipitated crystals were collected by filtration, and the amide compound (■) (18.9 g
, melting point 217-219°C).

■ Add phosphorus pentachloride (18.8 g) to a dry benzene solution (60aZ) of the above amide compound (■) (Log),
The mixture was heated to reflux while stirring for 2 hours. After cooling, the precipitated crystals were collected by filtration to obtain crude quaternary salt ([X) (20 g
) was obtained.

■ After adding 〇-dichlorobenzene (40aO) to the above crude quaternary salt (tX) (20g), it was heated under reflux for 30 minutes. After cooling, insoluble matter was filtered off, and the tt& was subjected to vacuum distillation. By attaching, the benzisothiazole compound (X)
(5.4g, b, p, 125-133℃714m
1 l of mmm was obtained as an oil.

■ The above chlorobenzisothiazole (X) (4,8
g) After adding anhydrous piperazine (36.6 g) into
Stirring was continued for 12 hours at 120°C. Thereafter, excess piperazine was distilled off, diluted caustic soda water was added to the residue, and extraction with dichloromethane was performed. After washing the extract with saturated saline, drying, and condensing under reduced pressure, the residue was purified by chromatography to obtain the title compound (1 [1) (3.5 g, melting point 8).
7-91°C).

(c) Synthesis of compound (mV) Reference example 5 Reference example 5 'N-(3,4-engine, boxybutyl)bicyclo[2゜2
, l] Synthesis of hebutane-2,3-di-exo-carboximide Bicyclo(2,2,1)hebutane-2,3-di-exo-carboximide 2.3 g (14,2a++ao
l), 2 g of 4-bromo-1,2-epoxybutane (
14,2a+5ol), KzCO22,9g (21
, 3ms+ol) and acetone 35-.
After the reaction was completed by stirring under reflux for 5 hours, the reaction solution was cooled and the suspended matter was filtered off. The filtrate was concentrated under reduced pressure, and 100 parts of toluene and 50 parts of saturated brine were added to the residue for extraction. The aqueous layer was further extracted again with toluene 100aZ, and the organic layers were combined and dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue was subjected to column chromatography using silica gel to obtain 2.6 g (79.4%) of the title compound.

lRI/25-"(cs-')! 1765.1
700.1480.1440, the following compound was obtained according to the method of Reference Example 5.

Reference example 6 N-(4-(4-(1,2-benzisothiazole-3
-yl)-1-piperazinyl) 3-hydroxybutyl]bicyclo(2,2,1)hebutane-2゜3-di-exo-carboximide synthesis 2.1] Hepkun-2,3-di-
A mixture of 1.07 g of exo-carboximide, 1.0 g of 3-(1-piperazinyl)-1,2-benzisothiazole and 20 g of n-butyl alcohol was stirred under the method for 12 hours. The solvent was distilled off under reduced pressure, and the obtained crystals were washed with isopropyl alcohol and collected by filtration to obtain the title compound having a melting point of 169 to 170°C.

The following compound was obtained according to the method of Reference Example 6.

(III) (Xn)
3- (3,4-epoxybutyl-1-piperazinyl)
-Synthesis of 1,2-benzisothiazole 4-bromo-1
, 2-epoxybutane 1.06g (7,02snol)
, 3-(1-piperazinyl)-! .

2-Benzisothiazole 1.65 g (7,52+
uiol), potassium carbonate 1.6 g (11,3sn
ol) and acetone 20aZ was stirred for 19 hours. After confirming the disappearance of the raw materials, insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected to column chromatography using silica gel, yielding 11.5 g, yield 73.
8% of the title compound was obtained.

rR Shinji! L"(cm-'): 1590.15
60.1490.1460 Reference Example 8 N-(4-(4-(1,2-benzisothiazole-3
Synthesis of 2-hydroxybutyl]bicyclo(2,2,1)butane-2゜3-di-exo-carboximide 1-(3,4-epoxybutyl)-4-( 1°2-benzisothiazol-3-yl)piperazine 0.5 g (1,73 snol),
Bicyclo(2,2,1)hebutane-2,3-di-exo-carboximide 0,57 g (3,46 snol
), powdered potassium carbonate 0.72g (5,19ms+
After the reaction was completed, a mixture of 13d of n-butyl alcohol and 13d of ethyl acetate was stirred under reflux for 9 hours.
001m7 and washed twice with 50aZ of water. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography using silica gel to obtain 375 ml (47.5%) of the title compound (melting point 1
66-167°C).

The following compound was obtained according to the method of Reference Example 8.

(d) Synthesis of compound (XI[I) υ [In the formula, X represents the same meaning as above] Reference Example N-(3-carboxypropyl)bicyclo[2°2.1
] Synthesis of hebutane-2,3-di-exo-carboximide Anhydrous bicyclo(2,2,1)hebutane-2,3-di-exo-carboxylic acid 3.32 g (0.02 mol) and 4- Aminobutyric acid 2.06 g (0.02 mol)
was melted at 150°C for 30 minutes, cooled, and then recrystallized from toluene-isopropyl ether to obtain the title compound (melting point: 78-81°C).

The following compound was obtained according to the method of Reference Example 9.

・N-(3-carboxypropyl)bicyclo [2゜2.
2] Octane-2,3-di-carboximide melting point 12
1-123℃ ・N-(3-carboxypropyl)cyclohexane-1
,2-dicarboximide melting point 84-86°C Reference Example 1O N-(3-chloroformylpropyl)bicyclo(2,2
, 1) Synthesis of hebutane-2,3-di-exo-carboximide N-(3-carboxypropyl)bicyclo[2゜2,l
] Hebutane-2,3-di-exo-carboximide 1
After refluxing a low solution of g of thionyl chloride for 3 hours, the solvent was distilled off under reduced pressure to obtain the title compound (crude crystal melting point: 86
~92°C).

Example 1 Compound No. l N-(4-(4-(1,2-benzisothiazole-3
Synthesis of N-(4-bromo-3-oxobutyl)bicyclo(2,2,1)butane-2,3=di-exo-carboximide ,1) Hebutane-2,3-di-
1 g of exo-carboximide (3,18m+*o
l), 3-(1-piperazinyl)-1,2-benzisothiazole 0.69 g (3,18 mmol),
Potassium carbonate 0.53g (3,82111101)%
A mixture of 60 mm of potassium iodide (0.38 mmo+) and 30 II+7 of dry dimethylformamide was heated to a bath temperature of 90 mm.
Stirring was performed at 100° C. for 5.5 hours. The reaction solution was poured into 100 ml of toluene, washed three times with 50 ml of water, further washed with saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by chromatography using silica gel to obtain the title compound (yield: 420 ml, yield: 29%, melting point: 157-159°C).

According to the method of Example 1, the following compounds were obtained.

Compound number 5 N-(4-+4- (1,2-benzisothiazole-
3-yl)-1-piperazinyl)-4-methylbutyl]
Bicyclo(2,2,1)hebutane-2゜3-di-exo-carboximide Melting point 257-258℃ (hydrochloride) Compound No. 6 N-(2-(4-(1,2-benzisothiazole- 3
-yl)-1-piperazinyl)ethyl]bicyclo(2,
2,1) Hebutane-2,3-di-exo-carboximide Melting point 248-249°C (hydrochloride) Example 2 Compound No. 2 N-(4-(4-(1,2-benzisothiazole-3)
Synthesis of N-(4-+4- (1,
2-Benzisothiazol-3-yl)-1-piperazinyl) 3-hydroxybutyl]bicyclo(2,2,1
) Heplan-2,3-di-exocarboximide I
g (2.2 mmol), acetyl chloride 290 w
(3,74 mmol) and dichloroethane 25- was stirred and refluxed for 1 hour. The reaction solution was cooled to 0°C, and an aqueous sodium acetate solution was added to adjust the pH of the aqueous layer to about 8.
After that, the mixture was extracted with dichloromethane, washed with water, and further washed with saturated saline, and the organic layer was dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified using silica gel.
Chromatographic purification was performed to obtain 1.13 g of the title compound [melting point 150-153°C (hydrochloride)].

According to the method of Example 2, the following compounds were obtained.

Compound number 3 N-(4-(4-(1,2-benzisothiazole-3
-・yl)-1-piperazinyl) 2-acetoxybutylcocyclohexane-1,2-dicarboximide Melting point 114-117°C (oxalate) Example 3 Compound No. 4 N-(4-(4-(1,2 -Benzisothiazole-3
Synthesis of N-(4-+4-
1,2-Benzisothiazol-3-yl)-1-piperazinyl) 3-oxobutyl]bicyclo(2,2,1
) hebutane-2,3-di-exo-carboximide 0
．． 8g (1,771IIlol), sodium carbonate 1.
13 g (10.62 mmol), 10 ml of ethyl alcohol, 4 ml of water and 0.0 ml of hydroxylamine hydrochloride.
A mixed solution of 74 g (10,62++nol) was stirred under reflux for 4 hours. The reaction solution was extracted with water and ethyl acetate, and the organic layer was washed with saturated brine, dried over magnesium sulfate, and dried under reduced pressure. The solvent was distilled off. The crude crystals were recrystallized with methyl alcohol and subjected to thin layer chromatography (
420 ml of a polar substance was obtained in a developing solvent (3% methyl alcohol/chloroform) (melting point: 193-194°C).

In addition, the recrystallization mother liquor was distilled off under reduced pressure, and further chromatographic purification was performed using silica gel to obtain a nonpolar product 1r60■ (
Melting point 156-158°C) salt)].

Example 4 Compound No. 7 N-(4-(4-(1,2-benzisothiazole-3
-yl)-1-piperazinyl) 4-oxobutyl]bicyclo(2,2,1)hebutane-2,3-di-exo-
Synthesis of carboximide 3-(l-piperazinyl)-1
, 2-benzisothiazole 0.86 g (3,93
1) ,) ethylamine 0.8 g (7,9
A mixture of N-(3-chloroformylpropyl)bicyclo(2,2,1)butane-2,3
-di-exo-carboximide 1.06 g (3,
A solution of 93 mmol) in 10 ar of tetrahydrofuran was added dropwise thereto, followed by stirring at room temperature for 3 hours. The suspended matter was filtered off, the residue was concentrated under reduced pressure, and the obtained oil was purified by chromatography using silica gel, yielding 1.12
g, the title compound was obtained in 63% yield (melting point 133-13
5℃).

The following compounds were obtained according to the methods of Examples 1 to 4.

(Margin below)

Claims (4)

[Claims] (1) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, A is the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, E represents a methylene group, an ethylene group, or an oxygen atom, ■Represents a single bond or double bond.), general formula ▲Mathematical formula, chemical formula, table, etc.▼ (In the formula, F represents a methylene group or ethylene group, ■
represents the same meaning as above. ) or general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R represents a hydrogen atom or an alkyl group, ■ represents the same meaning as above.), and D represents a substituted or It represents an unsubstituted monomethylene group, a substituted or unsubstituted dimethylene group, a substituted trimethylene group, a substituted tetramethylene group, and a substituted pentamethylene group, and Y represents a hydrogen atom, an alkyl group, an alkoxy group, or a halogen atom. ] or its acid addition salt. (2) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, D, E, Y and
) has the same meaning as the term. ] An imide derivative or an acid addition salt thereof according to claim (1). (3) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, D, F, Y and
) has the same meaning as the term. ] An imide derivative or an acid addition salt thereof according to claim (1). (4) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R, D, Y and
) has the same meaning as the term. ] An imide derivative or an acid addition salt thereof according to claim (1).