JPH07252219A - Piperazine derivative - Google Patents

Abstract

PURPOSE:To obtain a new piperazine derivative useful as an active ingredient of an antipsychotic and a therapeutic agents for ischemic cerebropathy without inducing side effects of extrapyramidal symptoms. CONSTITUTION:This compound is expressed by formula I or II [R<1> is a l-12C alkyl, a substitutive phenyl or a substitutive phenylalkyl; (k) is 1 or 2; Q is expressed by formula III (G<1> and G<2> each is H or a lower alkyl; Z is H, a 1-18C alkyl, a substituted acyl, a substituted carbamoyl, a substitutive phenyl, a substitutive phenylalkyl or substituted heterocyclic group)] or its salt, e.g.1-(3- trifluoromethylphenyl)-3-(4-phenylpiperazin-1-ylmethyl)-2-pyrrolidinone. The compound expressed by formula I is obtained by condensing an amine derivative with gamma-butyrolactone, then introducing an alkoxycarbonyl group into the resultant compound, reducing the prepared compound, mesylating the reduction product and reacting the obtained mesylate with a cyclic amine. The compound expressed by formula II is prepared by condensing the amine derivative with itaconic acid, esterifying the resultant condensate, reducing the prepared ester, mesylating the reduction product and reacting the obtained mesylate with the cyclic amine.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel piperazine derivative, an antipsychotic agent containing the derivative and a therapeutic agent for ischemic brain disease.

[0002]

BACKGROUND OF THE INVENTION Schizophrenia occurs at a high rate of 1 in 130 and frequently occurs during adolescence. If left unattended, the personality is progressively dismantled, and the human-like self-development function is completely destroyed, which is a major social problem. Abnormal dopamine transmission in the brain has been pointed out as the cause of this disease. The fact that dopamine antagonists such as chlorpromazine and haloperidol are effective as antipsychotics supports this theory. However, dopamine antagonists are also associated with extrapyramidal side effects such as acute dystonia and parkinsonism,
Alternatively, it is known to cause tardive dyskinesia and the like to occur at a high rate, which is a big problem. On the other hand, in recent years, approaches have been attempted from the aspect different from the conventional mechanism of action of drugs. The sigma receptor agonist is one of them. SKF-1, a sigma receptor agonist
Since 0047 has been shown to induce a psychotic-like effect in humans, it is expected that this sigma receptor antagonist will be an antipsychotic drug without extrapyramidal side effects. . Rimcazole is known as a drug of this type, but its affinity and specificity for sigma receptors are still insufficient.

For pharmaceutical use, the compound of formula I is described in JP-A-51-95079 and reported to have analgesic and anti-diarrheal properties.

[0004]

[Chemical 5] [Wherein R is selected from the group consisting of H, lower alkyl, benzyl; R ¹ is selected from the group consisting of H, Cl, Br, F, trifluoromethyl, lower alkoxy; R 1
² is selected from the group consisting of H, Cl, Br, F; A is selected from the group consisting of hydroxy, lower alkylcarbonyloxy, lower alkoxycarbonyl; n is an integer 1, 2 or 3. As another pharmaceutical use, the compound represented by the formula II has been clinically studied as an anti-dementia agent, and as a typical document,
Butler et al., Journal of Medici
nal Chemistry, 27 , 684-691.
(1984).

[0005]

[Chemical 6] A compound having a structure corresponding to Formula III

[0006]

[Chemical 7] [In formula III, X is generally a C _2-4 substituted or unsubstituted alkylene, Y is carbonyl or methylene, A is a bridging moiety such as alkylene, alkanoyl, alkyleneamidoalkylene, W is nitrogen, B is pyrimidinyl, pyridinyl. , Benzoisothiazolyl ring system] is an antipsychotic,
It is reported to have anti-anxiety, anti-nausea, cognitive enhancement, and anti-dementia activity. 4,668,687, same No. Three
717, 634, the same No. 4,423,049, same N
o. 4, 524, 206. Compound of formula IV

[0007]

[Chemical 8] [Wherein X is hydrogen or chlorine in the formula IV] shows an analgesic property and a weak anti-inflammatory effect at the same time as Malawska.
"Synthesis and Pharmacological Properties of 2-Pyrrolidinone Mannich Bases", Polish Journal of Phar
macology, 34 , 373-382 (1982).
Are described in. See also Mattson et al., US Pat. 4,826,843, compounds of formula V have been shown to have cognitive and memory enhancing activity.

[0008]

[Chemical 9] [In the formula V, X is an ethylene chain or a 1,2-benzo ring, Y
Is carbonyl (only when X is a 1,2-benzo ring) or methylene, R ¹ is hydrogen or lower alkyl, Z is R ² , R ³ selected from pyridazine, pyrimidine and pyrazine ring systems.
A di-substituted diazinyl ring, wherein R ² and R ³ are each independently hydrogen, a lower alkyl group having 1 to 4 carbon atoms, a lower alkoxy group, a lower alkylthio group, a cyano group, a trifluoromethyl group, pentafluoromethyl And halogen. In addition, compounds of formula VI as monoamine oxidase-B inhibitors include Silverman et al. (Journa).
l of Medicinal Chemistry,
36 , 3606-3610 (1993)).

[0009]

[Chemical 10] Also, US Pat. 4,767,759 describes that the compound of formula VII has anti-dementia activity.

[0010]

[Chemical 11] [In Formula VII, R ¹ represents hydrogen or a methyl group, and R ² is mono- or di-substituted by alkoxy having 1 to 2 carbons, fluorine, chlorine, bromine, trifluoromethyl or alkyl having 1 to 4 carbons. Optionally represent a phenyl group or a pyridyl group, R ³ and R ⁴ may be the same or different and represent hydrogen or an alkyl group having 1 to 2 carbon atoms, or two groups R ³ and R ⁴ Represents, together with the nitrogen atom, a saturated 5- or 6-membered ring which may further contain O or N as another heteroatom and which may be optionally substituted by a methyl group, Alternatively, these groups form an imidazole ring and the aminoalkyl group is in the 4- or 5-position. However, there is no description that any of the above compounds has a high affinity for sigma receptors and exhibits an antipsychotic effect.

[0011]

DISCLOSURE OF THE INVENTION The object of the present invention is to provide a compound having an antipsychotic effect without causing extrapyramidal side effects.

[0012]

Means for Solving the Problems The inventors of the present invention have diligently studied a compound having a piperazine skeleton in order to solve these problems. As a result, a novel piperazine derivative having a specific and high affinity for a sigma receptor has been found. Found and completed the present invention. That is, the present invention provides the following general formula (1)

[0013]

[Chemical 12] (1) [In the formula (1), R ¹ is an alkyl group having 1 to 12 carbon atoms,
It represents a substituted or unsubstituted phenyl group or a substituted or unsubstituted phenylalkyl group. k represents an integer of 1 to 2. Q
Represents the following structure,

[0014]

[Chemical 13] Here, G ¹ and G ² represent hydrogen and a lower alkyl group, Z represents a hydrogen atom, an alkyl group having 1 to 18 carbon atoms, a substituted acyl group, a substituted carbamoyl group, a phenyl group, a substituted phenyl group, a phenylalkyl group, It represents a substituted phenylalkyl group or a substituted heterocyclic group. ] The piperazine derivative shown by these, or its salt. And the following general formula (2)

[0015]

[Chemical 14] (2) [In the formula (2), R ¹ is an alkyl group having 1 to 12 carbon atoms,
Represents a phenyl group and a substituted phenyl group. k represents an integer of 1 to 2. Q represents the following structure,

[0016]

[Chemical 15] Here, G ¹ and G ² represent hydrogen and a lower alkyl group, Z represents a hydrogen atom, an alkyl group having 1 to 18 carbon atoms, a substituted acyl group, a substituted carbamoyl group, a phenyl group, a substituted phenyl group, a phenylalkyl group, It represents a substituted phenylalkyl group or a substituted heterocyclic group. ] The piperazine derivative or its salt shown by these are provided.

Here, the alkyl group having 1 to 18 carbon atoms means a linear or branched alkyl group having 1 to 18 carbon atoms, and the substituted acyl group is substituted with a lower alkyl group, a phenyl group or a halogen atom-substituted phenyl group. Represents an acyl group.
The substituted carbamoyl group refers to a carbamoyl group substituted with a lower alkyl group or a halogen atom-substituted phenyl group.

The substituted phenyl group means a halogen atom, a lower alkyl group, a lower alkoxy group, an alkylenedioxy group,
A phenyl group having 1 to 3 groups selected from the group consisting of a lower perfluoroalkyl group, a phenyl group, a hydroxyl group, a carbamoyl group, an amino group, a nitro group, an acetyl group and a cyano group is shown. The phenylalkyl group means a phenyl lower alkyl group, and the substituted phenylalkyl group means a halogen atom, lower alkyl group, lower alkoxy group, lower perfluoroalkyl group, phenyl group, hydroxyl group, carbamoyl group, amino group, nitro group, acetyl group. A lower alkyl group substituted with a phenyl group having 1 to 3 groups selected from the group consisting of a group and a cyano group.

The substituted heterocyclic group has 1 to 3 hetero atoms.
A 5- to 6-membered ring having 1 to 6 rings and a benzolog thereof, and 1 to 2 groups selected from the group consisting of a halogen atom, a lower alkyl group and a perfluoro lower alkyl group as a substituent.
May contain one.

The present invention will be described in detail below. In the present invention, the alkyl group having 1 to 12 carbon atoms of R ¹ is
A linear or branched alkyl group having 1 to 5 carbon atoms, a cyclopropyl group, a cyclopropylmethyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a 2-methylcyclohexyl group, a 3-methylcyclohexyl group, 4- Methylcyclohexyl group, cyclooctyl group, 1-adamantyl group, 2-adamantyl group,
A cyclododecyl group and the like.

The halogen atom means fluorine, chlorine, bromine and iodine. The lower alkyl group is, for example, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-pentyl group, an isopentyl group, a butyl group or the like. The lower alkoxy group is, for example, a methoxy group, an ethoxy group, a propoxy group, a 2-methylethoxy group, a butoxy group, a 2-methylpropoxy group, a pentoxy group, a 2-methylbutoxy group,
A 2-ethylpropoxy group and the like are shown. The lower alkylenedioxy group is, for example, a methylenedioxy group, an ethylenedioxy group or the like. The lower perfluoroalkyl group is, for example, a trifluoromethyl group, a pentafluoroethyl group or the like.

The heterocyclic group means, for example, a group having 1 to 3 nitrogen atoms such as a pyridyl group, a pyrrolyl group, a pyrimidinyl group, an indolyl group, an isoindolyl group, a quinolyl group, a piperidyl group and a piperazyl group, and a thienyl group. Having 1 to 3 sulfur atoms, having an oxygen atom such as furyl group, isobenzofuryl group, nitrogen atom such as isothiazolyl group, isoxazolyl group, morpholinyl group, two or more kinds of sulfur atom, oxygen atom The thing etc. which are contained are mentioned. The phenyl lower alkyl group is, for example, a benzyl group, a phenethyl group or the like. The compound of the present invention can be produced, for example, by the method shown in the following reaction formula-1.

[0023]

Embedded image Reaction formula-1 [Wherein R ¹ , G ¹ , G ² and Z are the same as defined above. R ² represents a methyl group or an ethyl group, and L represents a halogen atom, a tosyloxy group or a mesyloxy group. ] The compound (4) is obtained by reducing the compound (3). The reaction temperature is −75 to 200 ° C., preferably 0 to 100 ° C. for 1 to 20 hours, preferably 5 to 15 hours. Examples of the solvent used include aromatic hydrocarbons such as benzene and toluene, alcohols such as methanol and ethanol, ethers such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, and ethylene glycol dimethyl ether, alone or It can be used as a mixed solvent. Examples of reduction reaction reagents include:
Aluminum hydride, lithium aluminum hydride, lithium aluminum hydride-aluminum chloride, sodium borohydride, sodium borohydride-calcium chloride, sodium borohydride-aluminum chloride and the like can be used.

Compound (4) is converted to the corresponding halomethyl compound with thionyl chloride or phosphorus halide, or to the corresponding tosyl or mesyl ester with tosyl or mesyl halide. This reaction is chloroform,
Preference is given to using an inert organic solvent such as dichloromethane, tetrahydrofuran or dimethylformamide, between room temperature and the boiling point of the solvent used. The compound (5) produced as an intermediate, that is, the halomethyl compound or the tosyl or mesyl ester may be isolated or may be further reacted as it is.

The reaction of these products with the amines of the general formula (6) gives the corresponding target compounds of the general formula (1). This reaction can be carried out in tetrahydrofuran, dioxane, acetonitrile, dimethyl cellosolve or dimethylformamide. Reaction temperature is 50-1
50 ° C., individual conditions depending on the basicity and boiling point of the amine. The reaction can also be carried out in excess of amine without the use of solvents. Examples of the base include inorganic bases such as potassium carbonate, sodium carbonate, sodium hydroxide, sodium hydrogen carbonate, sodium amide, sodium hydride, triethylamine, tripropylamine, pyridine, 1,8-diazabicyclo [5.
4.0] Organic base such as undecene-7 (DBU) can be used. In the above reaction, if necessary, an alkali metal iodide compound such as potassium iodide or sodium iodide can be added as a reaction accelerator. The ratio of the compound represented by the general formula (5) to the compound represented by the general formula (6) in the above reaction is not particularly limited,
Usually, the latter may be used in an equimolar to excess amount, and preferably in an equimolar to 5-fold molar amount with respect to the former. Here, the compound represented by the general formula (3) is synthesized, for example, as follows.

[0026]

Embedded image Reaction formula-2 The 3-substituted pyrrolidinone (9) is synthesized as follows. The amine derivative represented by the general formula (7) and γ-butyrolactone are solvent-free at 50 to 250 ° C., preferably 1
The intermediate (8) is obtained by dehydration condensation for 5 to 20 hours, preferably 10 to 15 hours under the temperature condition of 50 to 200 ° C.
At this time, an acid catalyst such as hydrochloric acid may be added if necessary. The compound (8) thus obtained is introduced into an inert solvent in the presence of a base to introduce an alkoxycarbonyl group to obtain a compound (9). The reaction temperature is 30 to 200 ° C., preferably 70 to 15
The reaction is carried out at 0 ° C. for 3 to 20 hours, preferably 5 to 15 hours. Examples of the inert solvent used include benzene,
Toluene, aromatic hydrocarbons such as xylene, tetrahydrofuran, dioxane, butyl ether, ethers such as ethylene glycol dimethyl ether, ethanol,
Examples include alcohols such as propanol. Examples of the reaction reagent for introducing an alkoxycarbonyl group include esters such as dimethyl carbonate, diethyl carbonate, ethyl phosphonoformate and ethyl oxalate. Examples of the base include inorganic bases such as potassium carbonate, sodium carbonate, sodium amide, sodium hydride, potassium tert.
-Butoxide, triethylamine, tripropylamine, pyridine, 1,8-diazabicyclo [5.4.0]
Organic bases such as undecene-7 (DBU) can be used.

The 4-substituted pyrrolidinone (11) is produced by dehydration condensation of the compound (7) and itaconic acid. This reaction is carried out without a solvent for 5 hours to 20 hours, preferably 10 to 15 hours under the temperature condition of 50 to 250 ° C, preferably 150 to 200 ° C. At this time, an acid catalyst such as hydrochloric acid may be added if necessary. The obtained compound (10) is refluxed in an alcohol solvent such as methanol or ethanol in the presence of a catalyst such as sulfuric acid to obtain a pyridine 4-position substitution product (11).

The compounds of the general formulas (1) and (2) of the present invention can easily form salts with usual pharmacologically acceptable acids. Examples of the acid include sulfuric acid, nitric acid, hydrochloric acid, phosphoric acid,
Inorganic acids such as hydrobromic acid, organic acids such as acetic acid, tartaric acid, fumaric acid, maleic acid, citric acid, benzoic acid, trifluoroacetic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid Is mentioned.
These salts can also be used as the active ingredient compound of the present invention in the same manner as the compound of the general formula (1) in the free form.

The derivative of the present invention represented by the above general formula has one or more asymmetric carbon atoms. Thus, the derivative can exist in different stereoisomeric forms or as a mixture of stereoisomeric forms, including racemic forms. Thus, the present invention includes various forms as defined above, and these can be used as the active ingredient compound as well. The target compound represented by each of the above reaction formulas can be separated from the reaction system by a conventional separation means and further purified. As the separation and purification means, for example, distillation method, recrystallization method, column chromatography, ion exchange chromatography, gel chromatography, affinity chromatography, preparative thin layer chromatography, solvent extraction method and the like can be used.

The compounds of the present invention are specifically listed below (Table-1) [Tables 1 to 7] and (Table-2) [Tables 8 to 12]. The present invention is not limited to these examples.

[0031]

[Table 1] Table-1

[0032]

[Table 2] Continuation 1 of Table-1

[0033]

[Table 3] Continuation 2 of Table-1

[0034]

[Table 4] Continuation of Table-1 3

[0035]

[Table 5] Continuation 4 of Table-1

[0036]

[Table 6] Continuation of Table-1 5

[0037]

[Table 7] Continuation of Table-1 6

[0038]

[Table 8] Table-2

[0039]

[Table 9] Continuation of Table-2 1

[0040]

[Table 10] Continuation 2 of Table-2

[0041]

[Table 11] Continuation 3 of Table-2

[0042]

[Table 12] Continuation 4 of Table-2 The active ingredient compounds thus obtained are effective as sigma receptor antagonists, and they are used in the form of general pharmaceutical preparations. Formulations are commonly used fillers, fillers,
It is prepared using a diluent or excipient such as a binder, a moisturizer, a disintegrant, a surface active agent, a lubricant, etc. Various forms of this pharmaceutical preparation can be selected according to the therapeutic purpose, and typical examples thereof include tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, suppositories, and injections ( Solutions, suspensions and the like).

When molding into tablets, various carriers well known in the art can be widely used as carriers. Examples thereof include lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, excipients such as silicic acid, water, ethanol, propanol, simple syrup, glucose solution, starch solution, Gelatin solution, carboxymethylcellulose, shellac, methylcellulose,
Binders such as potassium phosphate and polyvinylpyrrolidone, dry starch, sodium alginate, agar powder, sodium hydrogen carbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, disintegrants such as lactose , Sucrose, stearic acid, cocoa butter, disintegration inhibitors such as hydrogenated oil, quaternary ammonium base, absorption promoters such as sodium lauryl sulfate, humectants such as glycerin and starch, starch, lactose, kaolin, bentonite, colloid Adsorbents such as silicic acid, talc, stearates, boric acid powders, lubricants such as polyethylene glycol and the like can be used. Further, the tablets are tablets coated with a usual coating as necessary, for example, sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets,
It may be a film-coated tablet, a double-layer tablet, or a multi-layer tablet.

In the case of molding in the form of pills, various carriers conventionally known in this field can be widely used. Examples thereof include excipients such as glucose, lactose, starch, cocoa butter, hardened vegetable oil, kaolin, talc, etc., gum arabic powder, tragacanth powder, gelatin, binders such as ethanol, carmellose calcium, disintegration of agar, etc. Agents can be used. In the case of molding in the form of suppositories, conventionally known carriers can be widely used. Examples thereof include polyethylene glycol, cocoa butter, higher alcohols, esters of higher alcohols, gelatin, and semisynthetic glycerides. Capsules are usually prepared by mixing the active ingredient compound with various carriers exemplified above and filling hard gelatin capsules, soft capsules and the like.

When prepared as an injection, the solution, emulsion and suspension are preferably sterilized and isotonic with blood, and when molded into these forms, they are commonly used as diluents in this field. All of the above can be used, and for example, water, ethanol, macrogol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters and the like can be used. In this case, a sufficient amount of salt, glucose or glycerin for preparing an isotonic solution may be contained in the pharmaceutical preparation, and a usual solubilizing agent, buffer, soothing agent, etc. are added. You may. Further, if necessary, a coloring agent, a preservative, a flavoring agent, a flavoring agent, a sweetening agent and the like and other pharmaceuticals may be contained in the pharmaceutical preparation.

The amount of the active ingredient compound to be contained in these pharmaceutical preparations of the present invention is not particularly limited and may be appropriately selected from a wide range.
It should be 70% by weight, preferably about 5 to 50% by weight. The administration method of these pharmaceutical preparations of the present invention is not particularly limited, and they are administered according to various preparation forms, patient age, sex and other conditions, and degree of disease. For example, tablets, pills, solutions, suspensions, emulsions, granules and capsules are orally administered. In the case of an injection, it may be administered intravenously alone or in a mixture with a normal replacement fluid such as glucose or amino acid, and may be administered intramuscularly, subcutaneously or intraperitoneally alone if necessary. In the case of suppositories, it will be administered rectally.

The dose of these pharmaceutical preparations of the present invention is appropriately selected depending on the usage, age of the patient, sex and other conditions, and degree of disease. Usually, the amount of the active ingredient compound is about 0 per 1 kg of body weight per day. It is preferable that the amount is about 0.0001 to 50 mg. Further, it is desirable that the active ingredient compound is contained in the dosage unit form in the range of about 0.001 to 1000 mg. The compounds of the present invention have a high affinity for sigma receptors and exhibit antipsychotic activity without extrapyramidal side effects. In addition, an effect of a therapeutic drug for ischemic brain disease is expected.

[0048]

[Examples] The production examples of the compounds of the present invention will be described below, followed by formulation examples of pharmaceutical preparations and test examples, which will be described in detail. The present invention is not limited to the following examples.

Production Example of Compound No. 37 [37-1] 32.0 g of m-aminobenzotrifluoride and 17 ml of γ-butyrolactone were mixed.
Then 5 ml of hydrochloric acid was added. The reaction was continued under reflux for 4 hours. Furthermore, gradually increase the internal temperature while removing the reflux liquid,
The reaction was carried out at 190 ° C for 4 hours. After cooling, it was dissolved in ethyl acetate, washed with dilute hydrochloric acid, water, aqueous sodium hydrogencarbonate solution and water in that order, dried over magnesium sulfate, hexane was added for crystallization, and the precipitated crystals were collected by filtration and washed with hexane to give 1- (3 -Trifluoromethylphenyl) -2-pyrrolidinone (37
-1) 38g was obtained. Melting point 66-68 [deg.] C.

[37-2] 10.0 g of sodium hydride (60% oil) was mixed with 100 ml of benzene and 28 g of diethyl carbonate was added. Then, under reflux, a solution of 20.0 g of compound (37-1) in 60 ml of benzene was added dropwise over about 2 hours. After refluxing for 3 hours, it was cooled and carefully poured into ice water. Make it weakly alkaline with diluted hydrochloric acid, extract with 300 ml of ethyl acetate, and extract with water.
It was washed with aqueous sodium hydrogen carbonate and water in that order, dried over magnesium sulfate, and concentrated to give an oil. Add hexane to crystallize, collect by filtration,
It was washed with hexane to obtain 20.0 g of 1- (3-trifluoromethylphenyl) -3-ethoxycarbonyl-2-pyrrolidinone (37-2). Melting point 76.5-77.
5 ° C.

[37-3] 18.8 g of the compound (37
-2) was dissolved in 150 ml of methanol, and 10.5 g of anhydrous calcium chloride was added and dissolved. Then, under ice cooling, 3.85 g of sodium borohydride was added little by little. After concentrating, water and ethyl acetate were added, acidified with dilute hydrochloric acid, and stirred well. The organic layer is taken, washed with water, dried and concentrated, crystallized with hexane, collected by filtration and washed with hexane to give 1- (3-trifluoromethylphenyl) -3-
Hydroxymethyl-2-pyrrolidinone (37-3) 1
5.3 g was obtained. Melting point 62.5-64 [deg.] C.

[37-4] 1.5 g of the compound (37-
Dissolve 3) in 30 ml of dichloromethane and add 0.95 m
1 of triethylamine was added. Then, under ice cooling, 0.
51 ml of methanesulfonyl chloride was added dropwise. After reacting for 2 hours, washed with water, dried over magnesium sulfate, and concentrated to give an oily 1- (3-trifluoromethylphenyl)-
3- (mesyloxymethyl) -2-pyrrolidinone (37
-4) was obtained.

[37-5] The compound (37-
To 4) was added 4.0 g of 1-phenylpiperazine and 10
The reaction was carried out at 0 ° C for 1 hour. After cooling, add ice water to crystallize,
It was filtered and washed with water. Then, it was dissolved in ethyl acetate, washed with water, dried over magnesium sulfate, and a large amount of crystals were precipitated during the concentration. Chloroform: methanol = 30:
It refine | purified by the silica gel column chromatography using the mixed solvent of 1. After concentrating the target fraction, methanol was added to crystallize and collect by filtration to obtain 1- (3-trifluoromethylphenyl) -3- (4-phenylpiperazin-1-ylmethyl) -2-pyrrolidinone (Compound No. 3
7) 2.1 g was obtained. Melting point 163-168 [deg.] C.

Production Example of Compound No. 95 [95-1] 30.0 g of itaconic acid and 28.4 g of p-anisidine were mixed and reacted at 120 ° C. for 2 hours. The solid obtained after cooling was washed with methanol to obtain 55.6 g of 1- (4-methoxyphenyl) -2-oxo-4-pyrrolidinecarboxylic acid (95-1). Melting point 171-17
2 ° C.

[95-2] Compound (95-1) 7.0
g in ethanol 60 ml, concentrated sulfuric acid 0.5 ml
Was added and the mixture was refluxed for 2 hours. The solvent was evaporated, the residue was dissolved in ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate. The solution was dried and the solvent was distilled off again to give 1- (4-methoxyphenyl) -4.
-Ethoxycarbonyl-2-pyrrolidinone (95-2)
7.2 g was obtained. Melting point 79-80 [deg.] C.

[95-3] Compound (95-2) 5.0
g was dissolved in 50 ml of methanol, and 2.7 g of anhydrous calcium chloride was added and dissolved. Then, 2.2 g of sodium borohydride was gradually added. Ice water and ethyl acetate were added, acidified with diluted hydrochloric acid, and stirred well. The organic layer was taken, washed with water and dried to remove the solvent. Thereafter, ether was added to crystallize, and the crystals were collected by filtration and 1- (4-methoxyphenyl) -4-hydroxymethyl-2-pyrrolidinone (95
-3) 3.9 g was obtained.

[95-4] Compound (95-3) 1.7
g was dissolved in 50 ml of dichloromethane, and 1.5 ml of triethylamine was added. Then, 0.81 ml of methanesulfonyl chloride was added dropwise under ice cooling. After reacting for 1 hour at room temperature, it was washed with water, dried and concentrated. Ether was added to the residue to crystallize and collect by filtration to obtain 1- (4-methoxyphenyl) -4-mesyloxymethyl-2-pyrrolidinone (9
5-4) 1.7 g was obtained. Melting point 83-85 [deg.] C.

[95-5] Compound (95-4) 2.0
g was added to 3.5 g of 1-benzylpiperazine and refluxed with 6 ml of xylene for 2 hours. The reaction mixture was poured into water, extracted with ethyl acetate, dried and the solvent was distilled off. It was purified by silica gel chromatography (chloroform / methanol = 20/1). After the desired fraction was concentrated, ether / hexane was added to the residue for crystallization to give 1- (4-methoxyphenyl) -4- (4-benzylpiperazin-1-ylmethyl) -2-pyrrolidinone (Compound No. 95). 1.4 g was obtained. Melting point 101-102 [deg.] C.

Prepared in the same manner as Compound No. 37 or 95, melting point (mp) and NMR of each compound.
The results are shown in (Table 3) [Table 13 to Table 20].

[0060]

[Table 13] Table-3

[0061]

[Table 14] Continuation of Table-3 1

[0062]

[Table 15] Continuation 2 of Table-3

[0063]

[Table 16] Continuation 3 of Table-3

[0064]

[Table 17] Continuation 4 of Table-3

[0065]

[Table 18] Continuation of Table-3 5

[0066]

[Table 19] Continuation of Table-3 6

[0067]

[Table 20] Continuation of Table-3 7

Formulation Example 1 1- (3-trifluoromethylphenyl) -3- (4-butylpiperazin-1-ylmethyl) -2-pyrrolidinone dihydrochloride 130 g citric acid 1 g lactose 35 g dicalcium phosphate 72 g Pluronic F-68 30 g Sodium lauryl sulfate 20 g Polyvinylpyrrolidone 14 g Polyethylene glycol (Carbowax 1500) 5 g Polyethylene glycol (Carbowax 6000) 45 g Corn starch 33 g Dry sodium stearate 3 g Dry magnesium stearate 3 g Ethanol Appropriate amount The active ingredient compound of the present invention, citric acid, lactose, dicalcium phosphate, Pluronic F-68 and sodium lauryl sulfate are mixed.

The above mixture was added to No. Sieve through a 60 screen, wet granulate with an alcoholic solution containing polyvinylpyrrolidone, Carbowax 1500 and 6000. Alcohol is added as needed to make the powder a pasty mass. Add corn starch and continue mixing until uniform particles are formed. The mixture was Pass through 10 screens, place in trays and dry in oven at 100 ° C for 12-15 hours. The dried particles were Sieve through 16 screen, add dry sodium lauryl sulfate and dry magnesium stearate, mix and compress into tablets into desired shape on a tablet machine.

The uncoated tablets obtained are treated with varnish and sprinkled with talc to prevent absorption of moisture. The plain tablet is coated with an undercoat layer. Apply the varnish a sufficient number of times for internal use.
Further subbing layers and smooth coatings are applied in order to make the tablets completely round and smooth. Color coating is carried out until the desired coating is obtained. After drying, the coated tablets are polished into tablets of uniform gloss.

Formulation Example 2 1- (3-Trifluoromethylphenyl) -3- (4-methylpiperazin-1-ylmethyl) -2-pyrrolidinone dihydrochloride 5 g Polyethylene glycol (molecular weight: 4000) 0.3 g Sodium chloride 1.0 g Polyoxyethylene-sorbitan monooleate 0.5 g Sodium metabisulfite 0.1 g Methyl-paraben 0.2 g Distilled water for injection 10.0 ml While stirring the above methyl-paraben, sodium metabisulfite and sodium chloride Dissolve in about half of the above distilled water at 80 ° C. The obtained solution is cooled to 40 ° C., and the active ingredient compound of the present invention, and then polyethylene glycol and polyoxyethylene sorbitan monooleate are dissolved in the above solution. Distilled water for injection is added to the solution to adjust to the final volume, and then sterilized by filtration using an appropriate filter paper to prepare an injection.

Pharmacological test 1 Method of Vilner et al. (BJ Vilner and
W. D. Bowen, in Multiple Si
gma and PCP Receptor Ligan
ds: Mechanisms for Neurom
odula-tion and Neuroprote
action? , NPP Books: pp 341
(1992)) and a radioreceptor assay for the σ ₁ receptor was performed. Rat whole brain homogenate (10 mg / ml) excluding cerebellum and medulla oblongata was used as a test drug and
³ H-ligand (5 nM ³ H-(+) pentaz
cine (NEN)) at room temperature for 2 hours. Brain tissue as cell harvester (Brand
EL company, LL-12) glass fiber filter paper (Wh
atman, GF / B) with suction filtration and 3 ml of buf
It was washed twice with fer. Put the glass fiber filter paper in a vial and put it in a scintillator (Amersham, AC
SII) was added in an amount of 3.5 ml and allowed to stand for 10 hours, and then ³ H bound to the receptor by a liquid scintillation counter.
The amount of ligand was measured. In addition, (+)-pentazocine (10 μM) was used for the measurement of blank.

³ H-ligand at each test drug concentration
The binding rate to the receptor was 100 when the test drug was not added.
%, Create a graph with 0% for blank substances,
The concentration of the test drug at which the binding rate was 50% was determined and used as the IC ⁵⁰ value. From this, the Ki value was obtained from the following equation.

[0074] K _D is the dissociation constant between ³ H-ligand and the receptor,
^The binding to the receptor when the ³ H-ligand concentration was changed was determined by Scatchard plot. The results are shown in (Table-4).

(Table-4) ─────────────────────────── Test drug Ki (nM) ────────── ────────────────── Compound No. 37 Compound 15 Compound No. 41 Compound 13 Compound No. 95 Compound 11 Compound No. 97 Compound 25 Compound No. 98 Compound 30 Compound No. 44 compound 18 compound No. 46 compound 7 compound No. 48 compound 12 compound No. 49 compound 9 compound No. 50 compound 5 compound No. 51 compound 6 compound No. 53 compound 8 ─────────── ───────────────

Pharmacological test 2 Antipsychotic activity was measured by using mouse
It was examined by amine-induced hyperactivity. For the experiment, 10 5-week-old male ddy mice (Japan slc) were used per group. Immediately after intraperitoneal administration of the test drug (all 10 mg / kg), place the mouse in the photocell cage for measurement,
The amount of exercise was measured for 30 minutes (this was regarded as the effect of the test drug on the spontaneous movement). Then take it out of the cage once, and
Thamphetamine 1.5 mg / kg was subcutaneously administered, and the rats were returned to their original cages and their motility was measured for 30 minutes. Inhibition of hypermotility of methamphetamine%
Was calculated from the following formula.

% Inhibition = 100-[{(test drug administration group-normal group) / (control group-normal group)} × 100] test drug administration group: sample + methamphetam
ine control group; vehicle + methamphetam
ine normal group; vehicle + saline results are shown in (Table-5).

(Table-5) ────────────────────────────── Test drug mAMP hyperactivity suppression (%) ─── ─────────────────────────── Compound No. 37 Compound 40 Compound No. 38 Compound 68 Compound No. 40 Compound 45 Compound No. 41 Compound 78 Compound No. 94 Compound 43 Compound No. 95 Compound 26 Compound No. 43 Compound 43 Compound No. 100 Compound 49 Compound No. 97 Compound 47 Compound No. 44 Compound 70 Compound No. 46 Compound 82 Compound No. 49 Compound 34 Compound Compound No. 53 64 ────────────────────────────

Pharmacological test 3 Anti-cerebral ischemic action Koizumi et al. (Jinichi Koizumi: Experimental study of ischemic cerebral edema (1st report) Cerebral infarction model in which blood flow can be restarted in rats, stroke, 8 , 1 -8 (1986)) (Koizumi method MCAo).

No. 0.8 nylon thread (diameter 0.148 m
The tip of m. Gossen Co., Ltd. was brought close to the soldering iron to form a ball having a diameter of 0.2 to 0.3 mm, which was used as a stopper when inserting an embolus. The end of the nylon thread on the opposite side of the ball is coated with a waterproof filler (Vascoke, Cemedine Co., Ltd.) and has a diameter of 0.2.
~ 0.3mm, 5mm long embroidery with thread (total length 16m
m) was prepared.

SD male rats (Japan SLC, Inc.) 10 to 12 weeks old, body weight of about 330 g is 1.5%.
A median cervical incision was made under halothane anesthesia, and the left carotid bifurcation was reached, paying attention to the preservation of the vagus nerve. The common carotid artery and the external carotid artery were separated from the surrounding connective tissue centering on the left carotid artery bifurcation and ligated with a thread. Furthermore, a thread was applied to the origin of the internal carotid artery to prepare for ligation and fixation after embolization. Subsequently, the common carotid artery was incised, and an embolus was inserted from the same portion toward the internal carotid artery by about 15 to 16 mm, and the nylon thread proximal end (spherical portion) of the embolus was ligated and fixed to the internal carotid artery with a thread. By the above operation, the tip of the embolus crossed the middle cerebral artery bifurcation and entered the anterior cerebral artery to occlude the entrance of the middle cerebral artery at the body of the embolus. Since hemiplegia of the forelimb on the opposite side appears due to middle cerebral artery occlusion, individuals who did not appear hemiplegia were excluded as an index.

The drug was 0.5% CMC / saline.
Was dissolved or suspended in and was administered intraperitoneally immediately after occlusion of the middle cerebral artery. The control group contained 0.5% C immediately after middle cerebral artery occlusion.
MC / saline was intraperitoneally administered.

Cerebral edema was determined from the increase in cerebral hemisphere water content on the ischemic side. Two hours after occlusion of the middle cerebral artery, the animal was decapitated under anesthesia, the brain (dissected in the olfactory brain and cerebellum) was rapidly collected, and the wet weight of the left and right cerebral hemispheres was measured. Each of these hemispheres was dried in a hot air dryer at 110 ° C. for 48 to 72 hours, and then the dry weight was measured. The water content of each cerebral hemisphere was calculated by the formula shown below.

Dehydrated content (%) = [(wet weight)-(dry weight)] / (wet weight) × 100 Increase rate of dehydrated content (%) = [(left cerebral hemisphere water content)- (Right cerebral hemisphere water content)] / (Right cerebral hemisphere water content) × 100 The results are shown in (Table-6).

(Table 6) ──────────────────────────────── Test drug Koizumi method MCAo Anti-cerebral edema action ( %) ──────────────────────────────── Compound No. 36 Compound 16.4 Compound No. 98 Compound 16.1 Compound of Compound No. 55 15.2 ────────────────────────────────── Among the compounds of the present invention, pharmacological test Preliminary acute toxicity tests were conducted for those that showed high efficacy in. That is, 100 mg / kg was intraperitoneally administered using 3 mice per group, but no death was observed.

[0086]

Industrial Applicability According to the present invention, it can be expected to provide an antipsychotic drug which does not induce the extrapyramidal side effects, which have been a problem in the past. Further, the compound of the present invention is expected to be effective as a therapeutic agent for ischemic brain disease.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location A61K 31/495 AAM 31/55 C07D 207/267 207/27 Z 401/06 207 401/14 207 405 / 14 207 409/14 207 // (C07D 401/06 207: 26 211: 44) (C07D 401/06 207: 26 211: 08) (C07D 401/14 207: 26 211: 08) (C07D 405/14 207: 26 211: 44 307: 36) (C07D 409/14 207: 26 211: 44 333: 10) 207: 26 211: 44 317: 48 (72) Inventor Norio Oto 1144, Togo, Mobara-shi, Chiba Mitsui Higashi Pressure Chemical Co., Ltd. (72) Inventor Kazutoshi Horigo 1 1900, Togo, Mobara-shi, Chiba Prefecture Mitsui Toatsu Chemical Co., Ltd. (72) Inventor Mitsutaka City, 1900, 1900, Togo, Mobara-shi, Chiba Prefecture Mitsui Toatsu Chemical Co., Ltd. (72) Inventor Ken Kamioka 1-3, 1900, Togo, Mobara-shi, Chiba (72) Inventor, Shoji Kawashima, 1900, Togo, Mobara-shi, Chiba 1 Mitsui Toatsu Chemical Co., Ltd.

Claims (7)

[Claims] 1. The following general formula (1): [In the formula (1), R ¹ is an alkyl group having 1 to 12 carbon atoms,
It represents a substituted or unsubstituted phenyl group or a substituted or unsubstituted phenylalkyl group. k represents an integer of 1 to 2. Q
Represents the following structure: Here, G ¹ and G ² represent hydrogen and a lower alkyl group, Z represents a hydrogen atom, an alkyl group having 1 to 18 carbon atoms, a substituted acyl group, a substituted carbamoyl group, a phenyl group, a substituted phenyl group, a phenylalkyl group, It represents a substituted phenylalkyl group or a substituted heterocyclic group. ] The piperazine derivative shown by these, or its salt. 2. The following general formula (2): [In the formula (2), R ¹ is an alkyl group having 1 to 12 carbon atoms,
A phenyl group, a substituted phenyl group, and k represents an integer of 1 to 2. Q represents the following structure: Here, G ¹ and G ² represent hydrogen and a lower alkyl group, Z represents a hydrogen atom, an alkyl group having 1 to 18 carbon atoms, a substituted acyl group, a substituted carbamoyl group, a phenyl group, a substituted phenyl group, a phenylalkyl group, It represents a substituted phenylalkyl group or a substituted heterocyclic group. ] The piperazine derivative shown by these, or its salt. 3. In the general formula (1), R ¹ represents a phenyl group substituted with halogen or a trifluoromethyl group. k represents an integer of 1 to 2. G ¹ and G ² represent hydrogen or a lower alkyl group, Z represents a hydrogen atom, a lower alkyl group, a lower acyl group, a lower alkyl-substituted carbamoyl group, a phenyl group, a substituted phenyl group, a benzyl group, a substituted benzyl group, or a substituted hetero group. Represents a ring group. ] The piperazine derivative or its salt of Claim 1 shown by these. 4. Production of a piperazine derivative and a salt thereof according to claim 1, which comprises condensing an amine derivative with γ-butyrolactone, introducing an alkoxycarbonyl group into the condensed derivative, reducing it, mesylating it, and reacting it with a cyclic amine. Method. 5. The process for producing a piperazine derivative and a salt thereof according to claim 2, which comprises condensing an amine derivative and itaconic acid, esterifying, reducing, mesylating, and reacting with a cyclic amine. 6. An antipsychotic drug comprising the compound according to any one of claims 1 to 3 as an active ingredient. 7. A therapeutic agent for ischemic brain disease, which comprises the compound according to any one of claims 1 to 3 as an active ingredient.