JPH0940667A - Pyrrolidinone derivative and its optical resolution - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a derivative having affinity to a sigma-acceptor and useful as an active component of an antipsychotic agent. SOLUTION: This optically active derivative (or its salt) is expressed by formula I [ R<1> and R<2> are each H, a halogen, a 1-6C alkyl, a 1-6C alkoxy, a 1-3C perfluoroalkyl or a 1-3C perfluoroalkoxy; R<3> is H, OH, a 1-6C alkyl, a 1-6C alkoxy, a 1-3C perfluoroalkyl, etc.; (n) is an integer of 4-7[, e.g. (R)-1-(4- chlorophenyl)-3-(hexamethyleneimin-1-ylmethyl)-2-pyrrolidinone hydrochloride. A racemic modification of the derivative is obtained by dehydrationcondensing an aniline derivative of formula II with γ-butyrolactone to obtain a compound of formula III, introducing an alkoxycarbonyl group into the resultant compound, reducing, obtaining a compound of formula IV (L is a halogen, tosyloxy or mesyloxy) by using thionyl, etc., then reacting with an amine of formula V.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an optically active pyrrolidinone derivative having a (R) configuration as a substituent at the 3-position of the pyrrolidinone ring, which is useful as an active ingredient of an antipsychotic drug, and an optical resolution method thereof.

[0002]

2. Description of the Related Art In modern society, central nervous system diseases such as dementia, schizophrenia, anxiety, depression, and neuronal cell death due to cerebral ischemia have become major problems. There is a particularly strong demand for establishment of preventive methods.

For example, schizophrenia occurs at a high rate of 1 in 130 and tends to occur frequently in adolescents, which is a major social problem. As one of the causes of schizophrenia, an abnormality in dopamine transmission in the brain has been pointed out, and the fact that dopamine antagonists such as chlorpromazine and haloperidol are effective as antipsychotic agents can be said to support this point.

[0004] However, dopamine antagonists are known to be effective as antipsychotics and to cause extrapyramidal side effects such as acute dystonia, parkinsonism and tardive dyskinesia, which is a problem. ing.

On the other hand, in recent years, approaches have been attempted from the aspect different from the conventional mechanism of action.

For example, SKF, a sigma receptor agonist
It has been revealed that -10047 induces a psychotic-like action in humans, and an antagonist to this agonist can be expected to have an action as an antipsychotic drug. Moreover, since the action on this sigma receptor is utilized, it is expected that the risk of concomitant extrapyramidal side effects can be significantly reduced. In addition, such sigma receptor agonists are not only used for other central nervous system diseases such as dementia, anxiety, depression, and neuronal cell death due to cerebral ischemia, but also for digestive system diseases, immune system diseases, or asthma. It is expected to have a therapeutic effect on the above.

[0007]

[Problems to be Solved by the Invention] As an antagonist of a sigma receptor agonist, rimcazole
However, the affinity and specificity for sigma receptors are still insufficient.

The present inventors have conducted various studies on compounds useful as sigma receptor agonists, and have found that pyrrolidinone derivatives having a specific structure have excellent properties as sigma receptor agonists. Furthermore, an optical isomer obtained by optically resolving the racemic form of this pyrrolidinone derivative, in which the substituent at the 3-position of the pyrrolidinone ring has the (R) configuration, has high affinity for sigma receptors and efficacy as a drug. Then, it was found that it would be further improved, and the present invention was completed.

An object of the present invention is to provide a sigma receptor agonist which is further improved in its affinity for sigma receptors and its effectiveness as a drug.

Another object of the present invention is to provide a method capable of efficiently optically resolving a racemate of a pyrrolidinone derivative useful as a sigma receptor agonist.

[0011]

The optically active pyrrolidinone derivative of the present invention has the following formula (1):

[0012]

Embedded image [In the above formula (1), R ¹ and R ² are each independently a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, and perfluoro having 1 to 3 carbon atoms. An alkyl group or a perfluoroalkoxy group having 1 to 3 carbon atoms is shown, and R ³ is a hydrogen atom, a hydroxyl group, or 1 to 6 carbon atoms.
Alkyl group, C1-6 alkoxy group, C1
A perfluoroalkyl group having 3 to 3 carbon atoms, a perfluoroalkoxy group having 1 to 3 carbon atoms, an alkenyloxy group having 2 to 5 carbon atoms or an alkynyloxy group having 3 to 5 carbon atoms,
n represents an integer of 4 to 7].

The optically active substance can also be used for desired purposes in the form of its pharmaceutically acceptable salt. This optically active substance and its pharmaceutically acceptable salt,
It is useful as a remedy for central nervous system diseases such as dementia, schizophrenia, anxiety, depression, nerve cell death due to cerebral ischemia,
Further, it is expected to be effective as a therapeutic drug for digestive system diseases, immune system diseases, or respiratory system diseases such as asthma.

For this optically active substance, a step of obtaining a mixture of diastereomeric salts from the racemate and an optical resolving agent, and a diastereomeric salt containing the optically active substance is separated from the mixture of diastereomeric salts. It can be obtained by an optical resolution method having a step and a step of separating and collecting this isomer from the separated diastereomeric salt.

[0015]

BEST MODE FOR CARRYING OUT THE INVENTION Examples of the halogen atom represented by R ¹ and R ² in the above formula (1) include fluorine, chlorine, bromine,
Iodine can be mentioned.

Examples of the alkyl group having 1 to 6 carbon atoms for R ¹ and R ² include a methyl group, an ethyl group, an n-propyl group,
Examples thereof include n-butyl group, n-pentyl group, n-hexyl group, isopropyl group, isobutyl group, tert-butyl group, isopentyl group, neopentyl group, isohexyl group and 3-methylpentyl group. Among these, those having 1 to 4 carbon atoms are preferable.

Examples of the alkoxy group having 1 to 6 carbon atoms of R ¹ and R ² include methoxy group, ethoxy group, propoxy group, 2-methylethoxy group, butoxy group, 2-methylpropoxy group, pentoxy group, 2 -Methylbutoxy group, 2
-Ethylpropoxy group and the like can be mentioned. Among these, those having 1 to 4 carbon atoms are preferable.

Examples of the perfluoroalkyl group having 1 to 3 carbon atoms for R ¹ and R ² include a trifluoromethyl group, a perfluoroethyl group, a perfluoropropyl group and a perfluoroisopropyl group. Among these, those having 1 to 2 carbon atoms are preferable.

Examples of the perfluoroalkoxy group having 1 to 3 carbon atoms for R ¹ and R ² include a trifluoromethoxy group, a perfluoroethoxy group, a perfluoropropoxy group and a perfluoroisopropoxy group. . Among these, those having 1 to 2 carbon atoms are preferable.

The alkyl group having 1 to 6 carbon atoms R ^3, the alkoxy group having 1 to 6 carbon atoms, perfluoroalkyl group having 1 to 3 carbon atoms, a perfluoroalkoxy group having 1 to 3 carbon atoms, R ¹ , R ² can be similarly exemplified.

Examples of the alkenyloxy group having 2 to 5 carbon atoms for R ³ include, for example, vinyloxy group, allyloxy group,
1-propenyloxy group, isopropenyloxy group, 2
-Butenyloxy group, 1,3-butadienyloxy group,
A 2-pentenyloxy group etc. can be mentioned. Of these, those having 3 carbon atoms are preferable.

Examples of the alkynyloxy group having 3 to 5 carbon atoms for R ³ include a 2-propynyloxy group, a 3-butynyloxy group and a 4-pentynyloxy group. Of these, those having 3 carbon atoms are preferable.

Preferred compounds of the formula (1) include compounds represented by the following formulas (2) to (4).

[0024]

Embedded image [In the formula (2), R ⁴ is a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a perfluoroalkyl group having 1 to 2 carbon atoms, or 1 carbon atom.
2 shows a perfluoroalkoxy group, and n shows the integer of 4-7. ]

[0025]

Embedded image [In the formula (3), R ⁴ is a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a perfluoroalkyl group having 1 or 2 carbon atoms, or 1 carbon atom.
~ 2 is a perfluoroalkoxy group, and R ⁵ is a hydroxyl group, an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a perfluoroalkyl group having 1 to 2 carbon atoms, or an alkyl group having 1 to 2 carbon atoms. A perfluoroalkoxy group, an alkenyloxy group having 2 to 5 carbon atoms or an alkynyloxy group having 3 to 5 carbon atoms is shown. As the compound of the formula (3), R ⁴ is a halogen atom, an alkyl group having 1 to 4 carbon atoms or a perfluoroalkyl group having 1 to 2 carbon atoms, and R ⁵ is an alkyl group having 1 to 4 carbon atoms, A compound having an alkoxy group having 1 to 4 carbon atoms, a perfluoroalkyl group having 1 to 2 carbon atoms or a perfluoroalkoxy group having 1 to 2 carbon atoms, R ⁴ being a halogen atom, an alkyl group having 1 to 4 carbon atoms, or Preferable ones are compounds having a perfluoroalkyl group having 1 to 4 carbon atoms and R ⁵ is a 2-propynyloxy group or a 2-propenyloxy group. Among them, compounds in which R ⁴ is a halogen atom or a trifluoromethyl group and R ⁵ is a methoxy group, a trifluoromethyloxy group or a 2-propynyloxy group are particularly preferable.

[0026]

[Chemical 12] [In the formula (4), R ⁶ and R ⁷ are each independently a halogen atom, an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a perfluoroalkyl group having 1 to 2 carbon atoms or a carbon atom. R represents a perfluoroalkoxy group represented by the formula
⁸ is a hydrogen atom, a hydroxyl group, an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a perfluoroalkyl group having 1 to 2 carbon atoms, a perfluoroalkoxy group having 1 to 2 carbon atoms, and 2 carbon atoms Is an alkenyloxy group having 5 to 5 carbon atoms or an alkynyloxy group having 3 to 5 carbon atoms. ] Specific examples of the optically active pyrrolidinone derivative of the present invention are listed below.

[0027]

[Table 1] Table 1

[0028]

[Table 2]

[0029]

[Table 3] Next, a method for producing the optically active pyrrolidinone derivative of the present invention will be described. First, the racemate of the compound of formula (5) can be obtained, for example, by using the following Reaction Route-1.

Reaction route-1

[0031]

Embedded image [In the formula, R ^{1 to} R ³ and n are defined as in formula (1), A represents a methyl group or an ethyl group, and L represents a halogen atom, a tosyloxy group or a mesyloxy group. The compound (10) is produced by dehydration condensation of the aniline derivative represented by the formula (9) and γ-butyrolactone. This reaction is solvent-free at 50 to 250 ° C., preferably 150 to 250 ° C.
5 hours to 20 hours under the temperature condition of 200 ° C., preferably 1
React for 0 to 15 hours. At this time, an acid catalyst such as hydrochloric acid may be added if necessary.

When synthesizing 1- (4-trifluoromethylphenyl) -2-pyrrolidinone, for example,
4-bromo-α, α, α-trifluorotoluene and 2-
It is possible to use a method in which pyrrolidone is used as a starting material, copper powder is added in an equimolar to several times molar amount with respect to 2-pyrrolidone, and the same reaction is performed.

A compound (11) is obtained by introducing an alkoxycarbonyl group into the obtained compound (10) in the presence of a base in an inert solvent. The temperature of this reaction can be 30 to 200 ° C., preferably 70 to 150 ° C., and the reaction time can be 3 to 20 hours, preferably 5 to 15 hours. Examples of the inert solvent used include aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as tetrahydrofuran, dioxane, butyl ether and ethylene glycol dimethyl ether, and alcohols such as methanol, ethanol and propanol. Examples of the reaction agent for introducing an alkoxycarbonyl group include esters such as dimethyl carbonate, diethyl carbonate, ethyl phosphonoformate, and ethyl oxalate. Examples of the base include potassium carbonate, sodium carbonate, sodium amide, sodium hydride, triethylamine, tripropylamine, pyridine, 1,8-diazabicyclo [5.4.0] undecene-7 (DBU), potassium tert-butoxide. Organic bases such as and the like can be used.

The compound (12) can be obtained by reducing the compound (11) in an inert solvent. The reaction temperature is -75 to 200 ° C, preferably 0 to 100 ° C, and the reaction time can be 1 to 20 hours, preferably 5 to 15 hours. Examples of the inert solvent used include aromatic hydrocarbons such as benzene and toluene, diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, ethers such as ethylene glycol dimethyl ether, dichloromethane, chloroform, and 1,2. -Halogenated hydrocarbons such as dichloroethane and alcohols such as methanol and ethanol can be used alone or in combination. Examples of the reaction agent for the reduction reaction include aluminum hydride, lithium aluminum hydride, sodium borohydride, a combination of lithium aluminum hydride and aluminum chloride, a combination of sodium borohydride and calcium chloride, and sodium borohydride. A combination of aluminum chloride and the like can be used.

Next, compound (12) is converted to its halomethyl compound using thionyl or phosphorus halide, or compound (12) is converted to its tosyl or mesyl ester using tosyl or mesyl halide. The conversion reaction to these intermediates is preferably carried out using an inert organic solvent such as chloroform, dichloromethane, tetrahydrofuran or dimethylformamide between room temperature and the boiling point of the solvent used. These intermediates may be used for the next reaction after being isolated from the reaction system, or may be used for the next reaction as they are in the reaction system.

The racemate of the pyrrolidinone derivative represented by the formula (5) can be obtained by reacting the compound (13) with the amine represented by the formula (14). This reaction can be carried out in tetrahydrofuran, dioxane, acetonitrile or dimethylformamide. The reaction temperature is 50 to 1
The temperature is in the range of 50 ° C., and individual conditions may be selected depending on the basicity of the amine, the boiling point of the solvent used as the reaction solvent, and the like. The reaction can also be carried out in the excess of amine without the use of solvents. Examples of the base used in this reaction include potassium carbonate, sodium carbonate, sodium hydroxide, sodium hydrogen carbonate, sodium amide, sodium hydride, triethylamine, tripropylamine, pyridine, 1,8-diazabicyclo [5.4. 0] Organic bases such as undecene-7 (DBU) and the like can be mentioned. In addition, an alkali metal iodide compound such as potassium iodide or sodium iodide can be added to the above reaction as a reaction accelerator, if necessary. A compound of formula (13) in the above reaction,
The ratio of the amine of formula (14) to be used is not particularly limited, but usually the latter can be equimolar to excess amount, preferably equimolar to 5 times the molar amount of the former.

From the racemate obtained as described above,
By using an optical resolving agent, an objective optically active substance in which the substituent at the 3-position of the pyrrolidinone ring has the (R) configuration can be obtained. In this optical resolution, a racemate of a pyrrolidinone derivative is reacted with an optical resolution agent to form a diastereomeric salt, and a difference in solubility of each diastereomeric salt is used to obtain an objective optically active pyrrolidinone derivative. It can be carried out. As the optical resolving agent used here, optically active dibenzoyl tartaric acid, optically active 10-camphorsulfonic acid, optically active di-p-toluoyl tartaric acid, optically active thiazolidine-4-carboxylic acid, optically active 3-phenyl lactic acid, optically active Mandelic acid, optically active camphoric acid, optically active camphanic acid, optically active pyroglutamic acid, optically active 2'-nitrotartranylic acid, optically active N-acetylphenylglycine, optically active 3-bromocamphor-8-sulfonic acid, Examples thereof include optically active malic acid, optically active tartaric acid, and optically active N-acetylphenylalanine. Among these, optically active carboxylic acids such as optically active mandelic acid, optically active dibenzoyl tartaric acid, and optically active camphanic acid can be mentioned as more preferable ones.

In the case of resolution of the optically active pyrrolidinone derivative of the formula (2), when R ⁴ is a halogen atom, n is 5 or 6, preferably R ⁴ is a chlorine atom, and n is 6, An optically active mandelic acid is particularly suitable as the optical resolving agent. Further, in the compound of formula (2), R ⁴ has 1 to 2 carbon atoms.
The optically active dibenzoyltartaric acid is particularly suitable for the resolution of the optically active substance having a perfluoroalkyl group of and n is 5 or 6.

In the resolution of the optically active substance of the formula (3),
R ⁴ is a halogen atom, R ⁵ is an alkoxy group having 1 to 4 carbon atoms or a perfluoroalkyl group having 1 to 2 carbon atoms,
When R ⁴ is preferably a chlorine atom or a trifluoromethyl group and R ⁵ is a methoxy group, an optically active mandelic acid is particularly preferred. In the formula (3), R ⁴ is a perfluoroalkyl group having 1 to 2 carbon atoms, R ⁵ is an alkoxy group having 1 to 4 carbon atoms, preferably R ⁴ is a trifluoromethyl group and R ⁵ is When it is a methoxy group,
Optically active dibenzoyl tartaric acid is particularly preferred.

In the resolution of the optically active compound of formula (4), R
⁶And R⁷Is a halogen atom, and R ⁸Is a hydrogen atom or
An alkoxy group having 1 to 4 carbon atoms, preferably R⁶And R⁷But
Chlorine atom, R⁸Is a methoxy group, the
Scientifically active camphanic acid is particularly preferred.

The amount of the optical resolving agent used may be 0.1 to 5.0 times mol, preferably 0.5 to 2.0 times mol, of the racemate of the pyrrolidinone derivative. Examples of the solvent include acetone, methyl ethyl ketone, acetonitrile, dioxane, ethyl acetate, methyl acetate, propyl acetate, methanol, ethanol, isopropyl alcohol and the like. Crystal of diastereomeric salt is 0 ° C to 5 ° C.
It can be performed in a temperature range of 0 ° C, preferably 10 ° C to 30 ° C.

The crystals of the diastereomeric salt thus produced can be filtered to obtain the (R) form or the (S) form having a high optical purity, but if it is desired to further increase the optical purity, recrystallization can be performed. Just repeat it. The recrystallization solvent is not particularly limited, but ethyl acetate, ethanol and the like are preferable. Furthermore, the optical purity can be increased by the preferential crystallization method.

To obtain a desired optically active substance from a diastereomer salt, the diastereomer salt is dissolved or suspended in water, and a base such as sodium hydroxide, potassium hydroxide, sodium carbonate or sodium hydrogen carbonate is added. It can be easily carried out by allowing it to act for desalting and collecting or extracting the resulting optically active pyrrolidinone derivative.

The present invention relates to the optical resolution of racemates.
The affinity for racemic sigma receptors.
While improving the affinity for dopamine receptors
By not doing this, we have achieved improved selectivity.
You. As shown in the pharmacological test example described later,
The (R) form obtained from the above has high activation (E) of antipsychotic activity.
D ₅₀(Smaller value) can be achieved, and some racemates
The observed side effects such as convulsions disappeared. Spasm in Table 6 below
Although an example of convulsion induction is described, the corresponding compound of the present invention
Semi-body develops antipsychotic activity dose and side effects
Since there is a large difference in the doses,
It can be used as an antipsychotic drug even if it remains a semi-body
However, the optical resolution eliminates the division of activity and side effects.
And improved safety. That is, the optical activity of the present invention
The (R) form has improved affinity / selectivity for sigma receptors,
It has increased antipsychotic activity and further improved safety.
You. This is important for the development of sigma receptor agonists.
It is a great effect.

The optically active pyrrolidinone derivative of the present invention is
It can easily form salts with usual pharmacologically acceptable acids.
Examples of the acid include inorganic acids such as sulfuric acid, nitric acid, hydrochloric acid, phosphoric acid and hydrobromic acid, acetic acid, tartaric acid, fumaric acid, maleic acid, citric acid, succinic acid, benzoic acid, trifluoroacetic acid, methanesulfonic acid, Organic acids such as ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, optically active mandelic acid, optically active camphanic acid, optically active camphoric acid, optically active benzoyl tartaric acid, optically active dibenzoyl tartaric acid, and amino acids can be given. These salts can also be used as an active ingredient of sigma agonists such as antipsychotic agents.

The drug containing the optically active pyrrolidinone derivative of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient is
It can be used in the form of a general pharmaceutical preparation. The preparation can be prepared by using a diluent or an excipient such as a filler, a filler, a binder, a moisturizer, a disintegrant, a surface active agent and a lubricant which are usually used. Various forms can be selected as the pharmaceutical preparation depending on the purpose of treatment, and typical examples are tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, suppositories and injections ( Liquid, suspension, etc.)
Is mentioned.

In the case of 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, carriers conventionally known in this field can be widely used. Examples thereof include excipients such as glucose, lactose, starch, cacao butter, hardened vegetable oil, kaolin, talc, etc., gum arabic powder, tragacanth powder, binders such as gelatin, carmellose calcium, disintegrating agents such as agar. 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 semi-synthetic glycerides.

Capsules are usually prepared by mixing the active ingredient compounds with the 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. What you have, 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 can 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.

There are no particular restrictions on the method of administration of these pharmaceutical preparations of the present invention, and they may be administered according to various dosage forms, patient age, sex and other conditions, and the degree of disease. For example, tablets, pills, solutions, suspensions, emulsions, granules and capsules are orally administered. Further, in the case of an injection, it is administered alone or mixed with a normal replenisher such as glucose or amino acid, and then intravenously administered. Further, if necessary, it is intramuscularly, subcutaneously or intraperitoneally administered alone. Suppositories are administered rectally.

The dose of these pharmaceutical preparations of the present invention is appropriately selected according to the usage, the age of the patient, the sex and other conditions, and the degree of the 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.

[0056]

EXAMPLES The present invention will be described in more detail with reference to production examples, formulation examples, pharmacological test examples and the like.

Production Example 1 Production of (R) -1- (4-chlorophenyl) -3- (hexamethyleneimine-1-ylmethyl) -2-pyrrolidinone hydrochloride (1) Production of racemate (1-1) Preparation of 1- (4-chlorophenyl) -2-pyrrolidinone [compound (1-a)] 372 g (2.916 mol) of p-chloroaniline and γ
-Butyrolactone 251 g (2.916 mol) were mixed, then hydrochloric acid 75 ml (0.9 mol) was added. The mixture was gradually heated and refluxed at an internal temperature of 110 to 115 ° C for 9 hours. Furthermore, gradually increase the internal temperature while removing the reflux liquid,
The reaction was carried out at 140 ° C. for 8 hours, and the reflux liquid (about 80 ml) was distilled off. After cooling to an internal temperature of 70 ° C, ethyl acetate 2000m
It was dissolved in 1 l, washed with water, an aqueous solution of sodium carbonate and water in this order, dried over magnesium sulfate and concentrated to about 1000 ml, and the precipitated crystals were collected by filtration. The filtrate was concentrated to about 200 ml, and the precipitated crystals were combined with the above product and washed with ethyl acetate to give 1
347 g of-(4-chlorophenyl) -2-pyrrolidinone [compound (1-a)] was obtained.

(1-2) 1- (4-chlorophenyl)-
Preparation of 3-ethoxycarbonyl-2-pyrrolidinone [compound (1-b)] 25 g (0.625 m) of sodium hydride (60% oily)
ol) is mixed with 100 ml of THF and diethyl carbonate 3
4.0 g (0.288 mol) was added and the mixture was refluxed. Then, 52.0 g (0.26) of the compound (1-a) was refluxed.
A solution of 6 mol) in 150 ml of THF is about 1.
It was added dropwise over 5 hours. After refluxing for 4.5 hours, it was cooled and carefully poured into ice water. The mixture was made weakly alkaline with diluted hydrochloric acid, extracted with 300 ml of ethyl acetate, washed successively with water, aqueous sodium hydrogen carbonate and water, dried over magnesium sulfate, and concentrated to give an oil. 200 ml of hexane was added to crystallize, collected by filtration, washed with hexane, and 1- (4-chlorophenyl).
60 g of -3-ethoxycarbonyl-2-pyrrolidinone [compound (1-b)] was obtained.

(1-3) 1- (4-chlorophenyl)-
3-hydroxymethyl-2-pyrrolidinone [compound (1
-C)] Preparation 30.0 g (0.112 mol) of compound (1-b) was dissolved in 150 ml of methanol to prepare anhydrous calcium chloride 15
g was added and dissolved. Then, under ice cooling, 3.9 g (0.103 mol) of sodium borohydride was separately charged. After confirming the disappearance of the raw materials, the mixture was concentrated, water and ethyl acetate were added, acidified with dilute hydrochloric acid, and stirred well. The organic layer was taken, washed with water, dried, concentrated and crystallized from hexane-ether. The crystals were collected by filtration and washed with hexane-ether to give 1- (4-chlorophenyl) -3-hydroxymethyl-2-pyrrolidinone [compound (1-c)] 23.
3 g were obtained.

(1-4) 1- (4-chlorophenyl)-
Production of 3-mesyloxymethyl-2-pyrrolidinone [compound (1-d)] 23.2 g (0.103 mol) of compound (1-c) was dissolved in 200 ml of dichloromethane, and triethylamine 1 was added.
2.5 g (0.124 mol) was added. Then, under ice cooling, 14.2 g (0.124 g) of methanesulfonyl chloride
mol) was added dropwise. After reacting for 2 hours, it was washed with water, dried over magnesium sulfate, concentrated, and crystallized. Add ether to sludge, filter, wash with ether,
(4-chlorophenyl) -3-mesyloxymethyl-2
-29.8 g of pyrrolidinone [compound (1-d)] was obtained.

(1-5) 1- (4-chlorophenyl)-
3- (hexamethyleneimine-1-ylmethyl) -2-
Preparation of racemic pyrrolidinone 20.0 g (65.8 mmol) of compound (1-d) was dissolved in 80 ml of dimethyl cellosolve to give hexahydro-1.
18.0 g (0.181 mol) of H-azepine was added,
Refluxed for 3.5 hours. After concentration, ice water was added to crystallize, and the crystals were collected by filtration and washed with water. Then dissolve in ethyl acetate,
It was washed with water, dried over magnesium sulfate, and concentrated to precipitate crystals. Sludge with hexane and collect by filtration. Wash with ethyl acetate-hexane to give 1- (4-chlorophenyl)-
3- (hexamethyleneimine-1-ylmethyl) -2-
16.5 g of racemic pyrrolidinone was obtained. Melting point: 98-101 ° C. ¹ H-NMR (CDCl ₃ , δppm): 1.64 (8
H, br), 2.13 (1H, m), 2.33 (1H,
m), 2.70 (6H, m), 3.08 (1H, m),
3.77 (2H, m), 7.31 (2H, d), 7.5
9 (2H, d) (2) Production of optically active hydrochloride salt 1- (4-chlorophenyl) -3-obtained in (1) above
(Hexamethyleneimine-1-ylmethyl) -2-pyrrolidinone racemate 15.0 g (48.9 mmol)
Was dissolved in 150 ml of ethyl acetate, and (R)-(-)-
Mandelic acid 7.44 g (48.9 mmol) was added,
The crystals precipitated in the mixed solution were collected by filtration. The crystals were dissolved in 250 ml of ethyl acetate under heating, and the solvent amount was about 1
It was concentrated to 20 ml. The crystals precipitated by this concentration were collected by filtration. This crystal was reused in 150m ethyl acetate.
1 g, and mixed with 100 ml of an aqueous solution in which 4.0 g of sodium carbonate was dissolved. The organic layer was separated and washed with water, and then the solvent was distilled off. 70 ml of ethanol was added to the residue to dissolve it, and 4N hydrochloric acid / dioxane was added to this to acidify it. The solution was concentrated, and the precipitated crystals were collected by filtration. It was dried under reduced pressure to give 4.1 g (1
1.9 mmol) was obtained. Melting point 218 ° C. Enantiomeric excess 98% ee or more ¹ H-NMR (DMSO-d ₆ , δppm): 1.61-
3.54 (17H, m), 3.78-3.83 (2H,
m), 7.43-7.49 (2H, m), 7.69-
7.74 (2H, m), 10.35 (1H, brs) The enantiomeric excess rate was calculated by liquid chromatography using a column for measuring optical activity. The same applies to the following.

Preparation Comparative Example 1 Preparation of (S) -1- (4-chlorophenyl) -3- (hexamethyleneimin-1-ylmethyl) -2-pyrrolidinone hydrochloride 1 obtained in (1) of Preparation Example 1 -(4-chlorophenyl) -3- (hexamethyleneimine-1-ylmethyl)
-2-Pyrrolidinone racemate 15.0 g (48.9
mmol) in 150 ml of ethyl acetate,
(S)-(+)-Mandelic acid 7.44 g (48.9 m)
mol) was added, and the crystals precipitated in the mixed solution were collected by filtration.
This was heated and dissolved in 250 ml of ethyl acetate, and concentrated until the amount of solvent was about 120 ml. The precipitated crystals were collected by filtration. This was dissolved in 150 ml of ethyl acetate and mixed with 100 ml of an aqueous solution in which 4.0 g of sodium carbonate was dissolved. The organic layer was washed with water and the solvent was evaporated. 70 ml of ethanol was added to the residue to dissolve it, and 4N hydrochloric acid / dioxane was added to this to acidify it. The solution was concentrated, and the precipitated crystals were collected by filtration. White crystals dried under reduced pressure
5.5 g (16.0 mmol) was obtained. Melting point 218 ° C. Enantiomeric excess 98% ee or more ¹ H-NMR (DMSO-d ₆ , δppm): 1.60-
3.53 (17H, m), 3.78-3.83 (2H,
m), 7.42-7.48 (2H, m), 7.69-
7.74 (2H, m), 10.39 (1H, brs) Production Example 2 of (R) -1- (4-chlorophenyl) -3- (4-methoxypiperidin-1-ylmethyl) -2-pyrrolidinone Production (1) Production of racemate (1-1) Production of 4-methoxypiperidine hydrochloride Hydroxypiperidine (475 g, 4.696 mol) was suspended in dioxane (3000 ml). The-tert-
A solution of 1100 g (5.04 mol) of butyl dicarbonate in 1000 ml of dioxane was added dropwise over 5 hours. It was stirred at room temperature for 1 hour and left overnight. The mixture was concentrated under reduced pressure, the concentrate was dissolved in 1000 ml of n-hexane, cooled to 5 to 10 ° C, and seeded with crystal seeds while stirring. Precipitated crystals were collected by filtration and washed with 500 ml of hexane to obtain 912.3 g of 4-hydroxy-1-tert-butoxycarbonylpiperidine.

100 g of sodium hydride (60% oily)
(2.5 mol) was suspended in 1000 ml of THF and gently refluxed, to which 4-hydroxy-1-tert was added.
-Butoxycarbonylpiperidine 480 g (2.38 m
ol) in THF 1500 ml was added dropwise over 1 hour. The internal temperature was lowered to 55 ° C, and methyl iodide 40 was added.
8 g (2.88 mol) was added dropwise over 1.5 hours.
After dropping, the mixture was refluxed for 2 hours, cooled to room temperature, and the reaction product was cooled with ice water.
Pour into 00 ml and 200 ml of ethyl acetate, stir well and separate, separate the organic layer and 300 ml of ethyl acetate in the aqueous layer.
2 times, and the organic layer was combined, washed with water and then with saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure to obtain 553.4 g of 4-methoxy-1-tert-butoxycarbonylpiperidine. .

675 g of 4-methoxy-1-tert-butoxycarbonylpiperidine was heated to 35-40 ° C., and 850 ml of 4N hydrochloric acid / dioxane was added dropwise thereto over 3 hours. After dropping, stir at room temperature for 2 hours and
It was cooled to 0 ° C. and the precipitated crystals were collected by filtration. The crystals were washed twice with 500 ml of isopropyl ether to obtain 283 g of 4-methoxypiperidine hydrochloride.

(1-2) 20 g (65.9 mmol) of the compound (1-d) obtained in (1-4) of Preparation Example 1 and 15 g (98.9 mmo) of 4-methoxypiperidine hydrochloride.
l) was mixed with 50 ml of acetonitrile, 20 g (197.3 mmol) of triethylamine was added, and the mixture was refluxed for 10 hours. The mixture was gradually cooled to 5 to 10 ° C with stirring, the precipitated crystals were collected by filtration, sludged twice with 50 ml of water, washed with 10 ml of isopropyl ether, and dried under reduced pressure.
15.2 g of racemic 1- (4-chlorophenyl) -3- (4-methoxypiperidin-1-ylmethyl) -2-pyrrolidinone was obtained. Melting point: 110-111 ° C. ¹ H-NMR (CDCl ₃ , δppm): 1.61 (2
H, m), 1.9-2.1. (4H, m), 2.2-
2.5 (2H, m), 2.62 (1H, m), 2.7-
3.0 (3H, m), 3.26 (1H, m), 3.32
(3H, s), 3.78 (2H, m), 7.32 (2
H, d), 7.60 (2H, d) (2) Production of optically active substance 1- (4-chlorophenyl) -3-obtained in the above (1)
2.74 g (8.49 mmo) of racemic body of (4-methoxypiperidin-1-ylmethyl) -2-pyrrolidinone
l) is dissolved in 45 ml of ethyl acetate, and (R)-
(−)-Mandelic acid 1.29 g (8.49 mmol)
Was added, and the crystals precipitated in the mixed solution were collected by filtration. The crystals were dissolved in 50 ml of ethanol under heating and recrystallized. The precipitated crystals were collected by filtration and recrystallized again from 50 ml of ethanol. 100 ml of ethyl acetate and 50 ml of sodium carbonate aqueous solution were added to this, and it stirred at room temperature. The organic layer was separated, washed with water and then concentrated, and the precipitated crystals were collected by filtration. Dry under reduced pressure to give white crystals 620
mg (1.92 mmol) was obtained. Melting point 133-134 ° C. Enantiomeric excess 99% ee or more ¹ H-NMR (CDCl ₃ , δppm): 1.48-1.
64 (2H, m), 1.83-1.98 (2H, m),
1.99-2.40 (4H, m), 2.55-2.64
(1H, m), 2.68-2.86 (4H, m), 3.
18-3.26 (1H, m), 3.34 (3H, s),
3.73-3.81 (2H, m), 7.29-7.33
(2H, m), 7.56-7.72 (2H, m) Production Comparative Example 2 (S) -1- (4-chlorophenyl) -3- (4-methoxypiperidin-1-ylmethyl) -2-pyrrolidinone Preparation of 1- (4-chlorophenyl) -obtained in (2) of Example 2
3- (4-methoxypiperidin-1-ylmethyl) -2
-2.74 g (8.49 mm) of racemic pyrrolidinone
ol) is dissolved in 45 ml of ethyl acetate, and (S)-
(+)-Mandelic acid 1.29 g (8.49 mmol)
Was added, and the crystals precipitated in the mixed solution were collected by filtration. Then, this was dissolved in 50 ml of ethanol under heating, recrystallized and collected by filtration. Further, it was recrystallized again from ethanol. This was suspended in 50 ml of ethyl acetate, 30 ml of an aqueous solution in which 1.0 g of sodium carbonate was dissolved was added, and the mixture was stirred to dissolve the crystals. The organic layer was separated, washed with water and then concentrated, and the precipitated crystals were collected by filtration. It was dried under reduced pressure to obtain 500 mg (1.55 mmol) of white crystals. Melting point 133 to 134 ° C. Enantiomeric excess rate 98% ee or more ¹ H-NMR (CDCl ₃ , δppm): 1.49-1.
64 (2H, m), 1.84-1.97 (2H, m),
2.02-2.41 (4H, m), 2.51-2.64.
(1H, m), 2.68-2.89 (4H, m), 3.
16-3.25 (1H, m), 3.34 (3H, s),
3.74-3.80 (2H, m), 7.30-7.33
(2H, m), 7.56-7.71 (2H, m) Production Example 3 (R) -1- (4-chlorophenyl) -3- (4-methoxypiperidin-1-ylmethyl) -2-pyrrolidinone Preparation of (R) -mandelate salt of 1- (4-chlorophenyl) -obtained in (2) of Example 2
3- (4-methoxypiperidin-1-ylmethyl) -2
-Pyrrolidinone racemate 726g (2.249mo
l) was dissolved in 7500 ml of ethanol while heating at 40 to 45 ° C., 2500 ml of ethanol was distilled off under reduced pressure, and while keeping at 40 to 45 ° C., 342 g (2.248 mol) of (R)-(−)-mandelic acid. Was added. The mixture was gradually cooled to 10 to 15 ° C, the precipitated crystals were collected by filtration and washed with 500 ml of ethanol. This is ethanol 200
Recrystallized from 0 ml. White crystals dried under reduced pressure
424 g (0.893 mol) was obtained. Melting point 142.5-143.5 ° C. Enantiomeric excess 99% ee or more ¹ H-NMR (DMSO-d ₆ , δppm): 1.40-
1.45 (2H, m), 1.81-2.27 (6H,
m), 2.50-2.88 (5H, m), 3.16-
3.22 (1H, m), 3.22 (3H, s), 3.7
3-3.79 (2H, m), 4.96 (1H, s),
7.28-7.44 (7H, m), 7.68-7.72
(2H, m) Production Example 4 (R) -1- (4-trifluoromethylphenyl) -3
-(4-Methoxypiperidin-1-ylmethyl) -2-
Production of pyrrolidinone (1) Production of racemate 4-bromo-α, α, α-trifluorotoluene 17
Copper powder 176.6 with 6.6 g (0.785 mol) and 2-methylpyrrolidone 55.7 g (0.654 mol)
In the presence of g, the mixture was heated and stirred at 160 to 170 ° C. for 10 hours, chloroform was added to the reaction product, copper was filtered off, washed with water and then concentrated.
There was obtained 38.9 g (21.6%) of-(4-trifluoromethylphenyl) -2-pyrrolidinone.

Thereafter, (1-) of (1) of Manufacturing Example 1
2), (1-3), (1-4)
19.4 g of (4-trifluoromethylphenyl) -3-mesyloxymethyl-2-pyrrolidinone was obtained.

Then, 19.4 g (57.4 mmol) of 1- (4-trifluoromethylphenyl) -3-mesyloxymethyl-2-pyrrolidinone, 17.5 g (115.4 mmol) of 4-methoxypiperidine hydrochloride and acetonitrile. 50 ml, triethylamine 17.4 g (17
2 mmol), and (1-) of (1) of Production Example 2 was used.
The same operation as in 2) was carried out to obtain 16.0 g of racemic 1- (4-trifluoromethylphenyl) -3- (4-methoxypiperidin-1-ylmethyl) -2-pyrrolidinone. Melting point: 106 to 108 ° C. ¹ H-NMR (CDCl ₃ , δppm): 1.59-1.
67 (2H, m), 1.90 (2H, m), 2.00-
2.60 (4H, m), 2.71 (1H, m), 2.7
6 (1H, m), 2.85 (3H, m), 3.23-
3.29 (1H, m), 3.34 (3H, s), 3.8
0-3.87 (2H, m), 7.62 (2H, d, J =
8.1 Hz), 7.77 (2H, d, J = 8.8 Hz) (2) Production of optically active substance 1- (4-trifluoromethylphenyl) -3- (4-) obtained in (1) above. 9.2 g (25.8 g) of racemic methoxypiperidin-1-ylmethyl) -2-pyrrolidinone
mmol) and (2R, 3R)-(−)-dibenzoyl-
L-Tartaric acid (9.7 g, 25.8 mmol) was mixed with ethyl acetate (46 ml), ethanol (23 ml) and ether (70 ml).
Was dissolved in water and cooled with ice, and the precipitated crystals were collected by filtration. The obtained crystals (6.7 g) were dissolved by heating in ethanol (50 ml), allowed to cool with stirring, and the precipitated crystals were collected by filtration. The same recrystallization operation was repeated twice to obtain 2.8 g of a crystal having an enantiomeric excess of 60.6% ee. It was made alkaline with an aqueous solution of sodium carbonate, the organic layer was taken, washed with water, and dried. Crystals were precipitated by concentrating and collected by filtration. White crystals (780 mg) were obtained by the preferential crystallization method. Melting point: 121.2 to 122.0 ° C. Enantiomeric excess: 90% ee or more ¹ H-NMR (CDCl ₃ , δppm): 1.53-1.
65 (2H, m), 1.89-2.91 (11H,
m), 3.17-3.26 (1H, m), 3.34 (3
H, s), 3.76-3.90 (2H, m), 7.61
(2H, d, J = 8.8Hz), 7.78 (2H, d,
J = 8.8 Hz) Production Comparative Example 3 (S) -1- (4-trifluoromethylphenyl) -3
-(4-Methoxypiperidin-1-ylmethyl) -2-
Preparation of Pyrrolidinone The first filtrate of Preparation Example 4 (2) was concentrated, dissolved in ethyl acetate and water and made alkaline with sodium carbonate,
The organic layer was taken, washed with water and dried. Crystals were precipitated by concentrating, sludged with hexane, and the crystals were filtered. White crystals (380 mg) were obtained by the preferential crystallization method. Melting point: 123.0 to 123.6 ° C. Enantiomeric excess: 85% ee or more ¹ H-NMR (CDCl ₃ , δppm): 1.50-1.
65 (2H, m), 1.85-2.95 (11H,
m), 3.15-3.25 (1H, m), 3.34 (3
H, s), 3.75-3.90 (2H, m), 7.61.
(2H, d, J = 8.8Hz), 7.78 (2H, d,
J = 8.8 Hz) Preparation Example 8 Preparation of (R) -1- (4-chlorophenyl) -3- (4-methoxypiperidin-1-ylmethyl) -2-pyrrolidinone fumarate Sodium carbonate 90 g (0.842 mol) ) Water 4
It was dissolved in 500 ml and ethyl acetate (3600 ml) was added, and (R) -1- (4-chlorophenyl) -3- (4-methoxypiperidin-1-ylmethyl) -2-pyrrolidinone (R)-obtained in Example 3 was added thereto. Mandelate 4
00 g (0.842 mol) was added. 3 with stirring
The mixture was heated to 5 to 40 ° C. to dissolve it, the organic layer was collected, washed with 3% aqueous sodium hydrogencarbonate (750 ml) and water (750 ml) and dried over anhydrous sodium sulfate. The desiccant was removed, and the filtrate was heated to 60 ° C., and 97.7 g of fumaric acid (0.842 mo
A solution prepared by dissolving l) in 2000 ml of ethanol by heating at 50 ° C. was added. The mixture was gradually cooled to 10 to 15 ° C., the precipitated crystals were collected by filtration, 500 ml of ethyl acetate and 2 parts of ethanol.
It was washed with 50 ml of mixed solvent. It was dried under reduced pressure to obtain 338.3 g (0.771 mol) of white crystals. Melting point 160-165.5 ° C. Enantiomeric excess 99% ee or more ¹ H-NMR (DMSO-d ₆ , δppm): 1.41-
1.49 (2H, m), 1.81-1.94 (3H,
m), 2.12-2.32 (3H, m), 2.51-
2.59 (1H, m), 2.66-2.89 (4H,
m), 3.15-3.20 (1H, m), 3.22 (3
H, s), 3.73-3.79 (2H, m), 6.61.
(2H, s), 7.41-7.44 (2H, m), 7.
68-7.71 (2H, m) Production Example 9 (R) -1- (3,4-dichlorophenyl) -3- (4)
-Methoxypiperidin-1-ylmethyl) -2-pyrrolidinone (1) Production of racemic compound (1-1) of (1) of Production Example 1, except that 3,4-dichloroaniline was used as a starting material. (1-2), (1-
3), (1-4) and (1-) of (1) of Production Example 2.
The same operation as in 2) was performed to obtain 32 g of 1- (3,4-dichlorophenyl) -3- (4-methoxypiperidin-1-ylmethyl) -2-pyrrolidinone racemate. Melting point: 110-111 ° C. ¹ H-NMR (CDCl ₃ , δppm): 1.50-1.
63 (2H, m), 1.87-2.88 (13H,
m), 2.00-2.59 (4H, m), 2.71 (1
H, m), 2.76 (1H, m), 2.85 (3H,
m), 3.17-3.25 (1H, m), 3.34 (3
H, s), 3, 69-3, 81 (2H, m), 7.32
(1H, d, J = 9Hz), 7.55 (1H, dd, J
= 11,3 Hz), 7.81 (1H, d, J = 3 Hz) (2) Production of optically active substance 1- (3,4-dichlorophenyl) -obtained in the above (1)
3- (4-methoxypiperidin-1-ylmethyl) -2
-Pyrrolidinone racemate 23.22 g (65.0 m
(mol) was dissolved in 400 ml of ethyl acetate, and (1
S)-(-)-Camphanic acid 12.90 g (65.1)
mmol) was added, and the crystals precipitated in the mixed solution were collected by filtration,
The crystals were recrystallized three times with 150 ml, 80 ml and 80 ml of ethanol. To this crystal, 200 ml of ethyl acetate and 100 ml of water in which 3 g of sodium carbonate was dissolved were added, and
Stir for minutes. The organic layer was separated and concentrated, and the precipitated crystals were collected by filtration. Dried under reduced pressure, white needles 5.8g
(16.2 mmol) was obtained. Melting point 132-133 ° C. Enantiomeric excess 99% ee or more ¹ H-NMR (CDCl ₃ , δppm): 1.52-1.
60 (2H, m), 1.81-1.99 (2H, m),
2.02-2.23 (2H, m), 2.24-2.42
(2H, m), 2.51-2.63 (1H, m), 2.
69-2.78 (1H, m), 2.80-2.88 (3
H, m), 3.17-3.24 (1H, m), 3.34.
(3H, s), 3.73-3.79 (2H, m), 7.
40 (1H, d, J = 8.8Hz), 7.54 (1H,
dd, J = 2.2, 8.8 Hz, 7.81 (1H,
d, J = 2.2 Hz) Production Comparative Example 4 (S) -1- (3,4-dichlorophenyl) -3- (4)
Preparation of -methoxypiperidin-1-ylmethyl) -2-pyrrolidinone 1- (3,4-dichlorophenyl) -3- (4-methoxypiperidin-1-ylmethyl) -2-pyrrolidinone obtained in (1) of Example 6 800 mg (2.
24 mmol) in 15 ml of ethyl acetate,
(1R)-(+)-camphanic acid 444 mg (2.2
4 mmol) was added, and the crystals precipitated in the mixed solution were collected by filtration and recrystallized twice with 7 ml and 7 ml of ethanol. Add 30 ml of ethyl acetate and 100 mg of sodium carbonate.
15 ml of water in which was dissolved was added, and the mixture was stirred for 5 minutes. The organic layer was separated and concentrated, and the precipitated crystals were collected by filtration. Dry under reduced pressure, 120 mg (0.34 mmol) of white needle crystals.
I got Melting point 132-133 ° C. Enantiomeric excess 98% ee or more ¹ H-NMR (CDCl ₃ , δppm): 1.49-1.
64 (2H, m), 1.87-1.89 (2H, m),
1.99-2.40 (4H, m), 2.51-2.60
(1H, m), 2.63-2.88 (4H, m), 3.
16-3.28 (1H, m), 3.34 (3H, s),
3.73-3.79 (2H, m), 7.40 (1H,
d, J = 8.8 Hz), 7.55 (1H, dd, J =
2.9, 8.8 Hz), 7.80 (1H, d, J = 2.
2 Hz) Production Example 10 (R) -1- (4-trifluoromethylphenyl) -3
-(4-Methoxypiperidin-1-ylmethyl) -2-
Preparation of Pyrrolidinone In (2) of Preparation Example 4, using (2R, 3R)-(-)-dibenzoyl-L-tartaric acid, crystals first obtained were made alkaline with an aqueous sodium carbonate solution (R). Body-rich crystals (28.9% ee) 0.84 g (2.36)
mmol) and 0.72 g of (R)-(−)-mandelic acid
(4.72 mmol) was heated and dissolved in 10 ml of ethanol. After cooling to room temperature, crystal seeds (99% ee or more) collected by the HPLC optical resolution column were inoculated and left for 2 hours. The precipitated crystal was filtered to obtain 0.1 g of white crystal. Melting point: 121.2 to 122.0 ° C. Enantiomeric excess: 98% ee or more ¹ H-NMR (CDCl ₃ , δppm): 1.53-1.
65 (2H, m), 1.89-2.91 (11H,
m), 3.17-3.26 (1H, m), 3.34 (3
H, s), 3.76-3.90 (2H, m), 7.61
(2H, d, J = 8.8Hz), 7.78 (2H, d,
J = 8.8 Hz) Production Comparative Example 5 280 mg of racemic 1- (4-chlorophenyl) -3- (4-hexamethyleneimin-1-ylmethyl) -2-pyrrolidinone obtained in (1) of Production Example 1 (0.9
1 mmol) was dissolved in 10 ml of acetone, and (2S,
3S)-(+)-di-p-toluoyl-D-tartaric acid 36
0 mg (0.93 mmol) was added. The precipitated crystals were collected by filtration. Although 578 g of white crystals were obtained, the enantiomeric excess was almost 0% ee.

Formulation Examples Tablets were prepared using the following ingredients.

[0069]

[Table 4] First, the fumaric acid salt of the pyrrolidinone derivative, citric acid, lactose, dicalcium phosphate, Pluronic F
-68 and sodium lauryl sulfate were mixed. The resulting mixture was designated No. 60 screen sieving, polyvinylpyrrolidone, carbowax 1500 and 600
Wet granulation with an alcoholic solution containing 0. that time,
Alcohol was added as needed to make the powder a pasty mass. Further cornstarch was added to the granulate thus obtained and mixing was continued until uniform particles were formed. The mixture was no. No. 10 after passing through a screen, placed in a tray, and dried in an oven at 100 ° C. for 12 to 15 hours. After sieving with a 16 screen, dry sodium lauryl sulfate and dry magnesium stearate were added and mixed, and compressed into a desired shape with a tableting machine to obtain a core.

The core was treated with a varnish and treated with talc to prevent moisture absorption, and then the undercoat layer (varnish coating layer) was coated on the periphery thereof. This undercoat layer was formed by applying varnish a sufficient number of times for internal use. A further subbing layer and a smooth coating were made with varnish to make the tablets completely round and smooth. Further color coating was applied until the desired coating was obtained and after drying the coated tablets were polished to give tablets of uniform gloss.

Pharmacological Test Example 1 (Radio Receptor Assay for σ ₁ Receptor) Method of Vilner et al. (BJ Vilner and
W. D. Bowen, in Multiple Si
gma and PCP Receptor Ligan
ds: Mechanisms for Neurom
odulation and Neuroprotec
section? , NPP Books: pp 341 (19)
92)) was modified to perform a radioreceptor assay for the σ ₁ receptor.

The P ₂ fraction (20 mg / ml) prepared from the whole brain of the guinea pig excluding the cerebellum and medulla oblongata was treated with the test drug and ³ H.
^{-Ligand (3nM 3 H - (+} ) pentazo
Incubated with cine (NEN) for 2 hours at room temperature. Brain tissue as a cell harvester
Company LL-12), glass fiber filter paper (Wha
tman, GF / B) with suction filtration and 3 with buffer
ml, washed twice. Put glass fiber filter paper in a vial and put it in a scintillator (Amersham, ACSI
After adding 3.5 ml of I) and leaving it for 10 hours, ³ H-1 bound to the receptor by a liquid scintillation counter.
The amount of igand was measured. In addition, (+)-pentazocine (10 μM) was used for blank measurement.

³ H-ligand at each test drug concentration
Binding rate to the receptor was 100 when no test drug was added.
%, The time of the blank substance is 0%, and a graph is created.
The test drug concentration at which the binding ratio was 50% was determined and defined as an IC ₅₀ value. From this, the Ki value was obtained from the following equation.

[0074]

[Equation 1] 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. Table 5 shows the results.

The compounds listed in Table 5 or Table 6 are as follows.

Compound I: 1- (4-chlorophenyl)-
3- (hexamethyleneimine-1-ylmethyl) -2-
Pyrrolidinone

[0077]

Embedded image Compound II: 1- (4-chlorophenyl) -3- (4-methoxypiperidin-1-ylmethyl) -2-pyrrolidinone

[0078]

Embedded image Compound III: 1- (3,4-dichlorophenyl) -3-
(4-Methoxypiperidin-1-ylmethyl) -2-pyrrolidinone

[0079]

Embedded image Pharmacological Test Example 2 (D ₂ Receptor Radioreceptor Assay) Method of Burt et al. (DR Burt et al.,
Proc. Natl. Acad. Sci. U. S. A.
72: 4655 (1975)), ³ H-spi
Perone (Amersham) and the test drug were incubated with rat brain striatal site homogenate, and the Ki value was calculated in the same manner as in the σ ₁ radioreceptor assay described above. Table 5 shows the results.

[0080]

[Table 5] *) It does not form a salt. The same applies to Table 6.

Pharmacological test example 3 (antipsychotic activity test: anti-SK
F action) The antipsychotic activity was examined in mice using the sigma receptor agonist SKF-10047-induced head weaving behavior. For the experiment, 5 week-old male ddy mice (Japan slc) were used in groups of 10
Used. One hour before the start of the test, they were placed in a measurement cage and allowed to rest. 60 minutes after oral administration of the test drug, SKF-10
047 was subcutaneously administered at a dose of 20 mg / kg,
After 10 minutes, the number of head weaving was measured for 10 minutes. The drug efficacy was evaluated by controlling the average value of the scores of each group from 20 minutes after administration of SKF-10047 to 10 minutes.
The inhibition rate for the group was determined and the ED ₅₀ value was calculated.
Table 6 shows the results.

Pharmacological test example 4 (antipsychotic activity: anti-mAMP
Action) antipsychotic activity in mice using methamphet
It was examined by mine (mAMP) -induced hyperactivity. For the experiment, 1 week old male ddy mouse (Japan slc) was used.
A group of 10 animals was used. 30 minutes after oral administration of the test drug, p for measurement
The mouse was placed in a photocell cage, and the amount of exercise was measured for 30 minutes (this was defined as the effect of the test drug on the spontaneous movement). Then take it out of the cage once,
Ethamine 1.5 mg / kg was subcutaneously administered, and the animals were returned to their original cages and the amount of exercise was measured for 30 minutes. Efficacy evaluation is based on the average value of the exercise amount of each group for 30 minutes after administration of mAMP
The inhibition rate for the ontrol group was determined and the ED ₅₀ was calculated. Table 6 shows the results.

[0083]

[Table 6]

[0084]

Industrial Applicability According to the method of the present invention, an optically active pyrrolidinone derivative which is a sigma receptor agonist having excellent affinity and selectivity and high efficacy can be easily obtained with high purity.

─────────────────────────────────────────────────── ───

[Procedure amendment]

[Submission date] June 19, 1996

[Procedure amendment 1]

[Document name to be amended] Statement

[Correction target item name] 0065

[Correction method] Change

[Correction contents]

(1-2) 20 g (65.9 mmol) of the compound (1-d) obtained in (1-4) of Preparation Example 1 and 15 g (98.9 mmo) of 4-methoxypiperidine hydrochloride.
l) was mixed with 50 ml of acetonitrile, 20 g (197.3 mmol) of triethylamine was added, and the mixture was refluxed for 10 hours. The mixture was gradually cooled to 5 to 10 ° C with stirring, the precipitated crystals were collected by filtration, sludged twice with 50 ml of water, washed with 10 ml of isopropyl ether, and dried under reduced pressure.
15.2 g of racemic 1- (4-chlorophenyl) -3- (4-methoxypiperidin-1-ylmethyl) -2-pyrrolidinone was obtained. Melting point: 110-111 ° C. ¹ H-NMR (CDCl ₃ , δppm): 1.61 (2
H, m), 1.9-2.1 (4H, m), 2.2-2.
5 (2H, m), 2.62 (1H, m), 2.7-3.
0 (3H, m), 3.26 (1H, m), 3.32 (3
H, s), 3.78 (2H, m), 7.32 (2H,
d), 7.60 (2H, d) (2) Production of optically active substance 1- (4-chlorophenyl) -3-obtained in the above (1)
2.74 g (8.49 mmo) of racemic body of (4-methoxypiperidin-1-ylmethyl) -2-pyrrolidinone
l) is dissolved in 45 ml of ethyl acetate, and (R)-
(−)-Mandelic acid 1.29 g (8.49 mmol)
Was added, and the crystals precipitated in the mixed solution were collected by filtration. The crystals were dissolved in 50 ml of ethanol under heating and recrystallized. The precipitated crystals were collected by filtration and recrystallized again from 50 ml of ethanol. 100 ml of ethyl acetate and 50 ml of sodium carbonate aqueous solution were added to this, and it stirred at room temperature. The organic layer was separated, washed with water and then concentrated, and the precipitated crystals were collected by filtration. Dry under reduced pressure to give white crystals 620
mg (1.92 mmol) was obtained. Melting point 133-134 ° C. Enantiomeric excess 99% ee or more ¹ H-NMR (CDCl ₃ , δppm): 1.48-1.
64 (2H, m), 1.83-1.98 (2H, m),
1.99-2.40 (4H, m), 2.55-2.64
(1H, m), 2.68-2.86 (4H, m), 3.
18-3.26 (1H, m), 3.34 (3H, s),
3.73-3.81 (2H, m), 7.29-7.33
(2H, m), 7.56-7.72 (2H, m) Production Comparative Example 2 (S) -1- (4-chlorophenyl) -3- (4-methoxypiperidin-1-ylmethyl) -2-pyrrolidinone Preparation of 1- (4-chlorophenyl) -obtained in (2) of Example 2
3- (4-methoxypiperidin-1-ylmethyl) -2
-2.74 g (8.49 mm) of racemic pyrrolidinone
ol) is dissolved in 45 ml of ethyl acetate, and (S)-
(+)-Mandelic acid 1.29 g (8.49 mmol)
Was added, and the crystals precipitated in the mixed solution were collected by filtration. Then, this was dissolved in 50 ml of ethanol under heating, recrystallized and collected by filtration. Further, it was recrystallized again from ethanol. This was suspended in 50 ml of ethyl acetate, 30 ml of an aqueous solution in which 1.0 g of sodium carbonate was dissolved was added, and the mixture was stirred to dissolve the crystals. The organic layer was separated, washed with water and then concentrated, and the precipitated crystals were collected by filtration. It was dried under reduced pressure to obtain 500 mg (1.55 mmol) of white crystals. Melting point 133-134 ° C. Enantiomeric excess rate 98% ee or more 1H-NMR (CDCl3, δppm): 1.49-
1.64 (2H, m), 1.84-1.97 (2H,
m), 2.02-2.41 (4H, m), 2.51-
2.64 (1H, m), 2.68-2.89 (4H,
m), 3.16-3.25 (1H, m), 3.34 (3
H, s), 3.74-3.80 (2H, m), 7.30.
-7.33 (2H, m), 7.56-7.71 (2H,
m) Production Example 3 Production of (R) -mandelate salt of (R) -1- (4-chlorophenyl) -3- (4-methoxypiperidin-1-ylmethyl) -2-pyrrolidinone (1) of Example 2 )-(4-chlorophenyl)-
3- (4-methoxypiperidin-1-ylmethyl) -2
-Pyrrolidinone racemate 726g (2.249mo
l) was dissolved in 7500 ml of ethanol while heating at 40 to 45 ° C., 2500 ml of ethanol was distilled off under reduced pressure, and while keeping at 40 to 45 ° C., 342 g (2.248 mol) of (R)-(−)-mandelic acid. Was added. The mixture was gradually cooled to 10 to 15 ° C, the precipitated crystals were collected by filtration and washed with 500 ml of ethanol. This is ethanol 200
Recrystallized from 0 ml. White crystals dried under reduced pressure
424 g (0.893 mol) was obtained. Melting point 142.5-143.5 ° C Enantiomeric excess 99% ee or more 1H-NMR (DMSO-d6, δppm): 1.40
-1.45 (2H, m), 1.81-2.27 (6H,
m), 2.50-2.88 (5H, m), 3.16-
3.22 (1H, m), 3.22 (3H, s), 3.7
3-3.79 (2H, m), 4.96 (1H, s),
7.28-7.44 (7H, m), 7.68-7.72
(2H, m) Production Example 4 (R) -1- (4-trifluoromethylphenyl) -3
-(4-Methoxypiperidin-1-ylmethyl) -2-
Production of pyrrolidinone (1) Production of racemate 4-bromo-α, α, α-trifluorotoluene 17
Copper powder 176.6 with 6.6 g (0.785 mol) and 2-methylpyrrolidone 55.7 g (0.654 mol)
In the presence of g, the mixture was heated and stirred at 160 to 170 ° C. for 10 hours, chloroform was added to the reaction product, copper was filtered off, washed with water and then concentrated.
There was obtained 38.9 g (21.6%) of-(4-trifluoromethylphenyl) -2-pyrrolidinone.

[Procedure amendment 2]

[Document name to be amended] Statement

[Correction target item name] 0067

[Correction method] Change

[Correction contents]

Then, 19.4 g (57.4 mmol) of 1- (4-trifluoromethylphenyl) -3-mesyloxymethyl-2-pyrrolidinone, 17.5 g (115.4 mmol) of 4-methoxypiperidine hydrochloride and acetonitrile. 50 ml, triethylamine 17.4 g (17
2 mmol), and (1-) of (1) of Production Example 2 was used.
The same operation as in 2) was carried out to obtain 16.0 g of racemic 1- (4-trifluoromethylphenyl) -3- (4-methoxypiperidin-1-ylmethyl) -2-pyrrolidinone. Melting point: 106-108 ° C 1H-NMR (CDCl3, δppm): 1.59-
1.67 (2H, m), 1.90 (2H, m), 2.0
0-2.60 (4H, m), 2.71 (1H, m),
2.76 (1H, m), 2.85 (3H, m), 3.2
3-3.29 (1H, m), 3.34 (3H, s),
3.80-3.87 (2H, m), 7.62 (2H,
d, J = 8.1 Hz), 7.77 (2H, d, J = 8.
8 Hz) (2) Production of optically active substance 1- (4-trifluoromethylphenyl) -3- (4-methoxypiperidin-1-ylmethyl) -2-pyrrolidinone racemic body 9.2 g obtained in the above (1) (25.8
mmol) and (2R, 3R)-(−)-dibenzoyl-
L-Tartaric acid (9.7 g, 25.8 mmol) was mixed with ethyl acetate (46 ml), ethanol (23 ml) and ether (70 ml).
Was dissolved in water and cooled with ice, and the precipitated crystals were collected by filtration. The obtained crystals (6.7 g) were dissolved by heating in ethanol (50 ml), allowed to cool with stirring, and the precipitated crystals were collected by filtration. The same recrystallization operation was repeated twice to obtain 2.8 g of a crystal having an enantiomeric excess of 60.6% ee. It was made alkaline with an aqueous solution of sodium carbonate, the organic layer was taken, washed with water, and dried. Crystals were precipitated by concentrating and collected by filtration. White crystals (780 mg) were obtained by the preferential crystallization method. Melting point: 121.2 to 122.0 ° C. Enantiomeric excess: 90% ee or more ¹ H-NMR (CDCl ₃ , δppm): 1.53-1.
65 (2H, m), 1.89-2.91 (11H,
m), 3.17-3.26 (1H, m), 3.34 (3
H, s), 3.76-3.90 (2H, m), 7.61
(2H, d, J = 8.8Hz), 7.78 (2H, d,
J = 8.8 Hz) Production Comparative Example 3 (S) -1- (4-trifluoromethylphenyl) -3
-(4-Methoxypiperidin-1-ylmethyl) -2-
Preparation of Pyrrolidinone The first filtrate of Preparation Example 4 (2) was concentrated, dissolved in ethyl acetate and water and made alkaline with sodium carbonate,
The organic layer was taken, washed with water and dried. Crystals were precipitated by concentrating, sludged with hexane, and the crystals were filtered. White crystals (380 mg) were obtained by the preferential crystallization method. Melting point: 123.0 to 123.6 ° C. Enantiomeric excess: 85% ee or more ¹ H-NMR (CDCl ₃ , δppm): 1.50-1.
65 (2H, m), 1.85-2.95 (11H,
m), 3.15-3.25 (1H, m), 3.34 (3
H, s), 3.75-3.90 (2H, m), 7.61.
(2H, d, J = 8.8Hz), 7.78 (2H, d,
J = 8.8 Hz) Preparation Example 5 Preparation of (R) -1- (4-chlorophenyl) -3- (4-methoxypiperidin-1-ylmethyl) -2-pyrrolidinone fumarate Sodium carbonate 90 g (0.842 mol) ) Water 4
It was dissolved in 500 ml and ethyl acetate (3600 ml) was added, and (R) -1- (4-chlorophenyl) -3- (4-methoxypiperidin-1-ylmethyl) -2-pyrrolidinone (R)-obtained in Example 3 was added thereto. Mandelate 4
00 g (0.842 mol) was added. 3 with stirring
The mixture was heated to 5 to 40 ° C. to dissolve it, the organic layer was collected, washed with 3% aqueous sodium hydrogencarbonate (750 ml) and water (750 ml) and dried over anhydrous sodium sulfate. The desiccant was removed, and the filtrate was heated to 60 ° C., and 97.7 g of fumaric acid (0.842 mo
A solution prepared by dissolving l) in 2000 ml of ethanol by heating at 50 ° C. was added. The mixture was gradually cooled to 10 to 15 ° C., the precipitated crystals were collected by filtration, 500 ml of ethyl acetate and 2 parts of ethanol.
It was washed with 50 ml of mixed solvent. It was dried under reduced pressure to obtain 338.3 g (0.771 mol) of white crystals. Melting point 160-165.5 ° C. Enantiomeric excess 99% ee or more ¹ H-NMR (DMSO-d ₆ , δppm): 1.41-
1.49 (2H, m), 1.81-1.94 (3H,
m), 2.12-2.32 (3H, m), 2.51-
2.59 (1H, m), 2.66-2.89 (4H,
m), 3.15-3.20 (1H, m), 3.22 (3
H, s), 3.73-3.79 (2H, m), 6.61.
(2H, s), 7.41-7.44 (2H, m), 7.
68-7.71 (2H, m) Production Example 6 (R) -1- (3,4-dichlorophenyl) -3- (4)
-Methoxypiperidin-1-ylmethyl) -2-pyrrolidinone (1) Production of racemic compound (1-1) of (1) of Production Example 1, except that 3,4-dichloroaniline was used as a starting material. (1-2), (1-
3), (1-4) and (1-) of (1) of Production Example 2.
The same operation as in 2) was performed to obtain 32 g of 1- (3,4-dichlorophenyl) -3- (4-methoxypiperidin-1-ylmethyl) -2-pyrrolidinone racemate. Melting point: 110-111 ° C. ¹ H-NMR (CDCl ₃ , δppm): 1.50-1.
63 (2H, m), 1.87-2.88 (13H,
m), 2.00-2.59 (4H, m), 2.71 (1
H, m), 2.76 (1H, m), 2.85 (3H,
m), 3.17-3.25 (1H, m), 3.34 (3
H, s), 3, 69-3, 81 (2H, m), 7.32
(1H, d, J = 9Hz), 7.55 (1H, dd, J
= 11,3 Hz), 7.81 (1H, d, J = 3 Hz) (2) Production of optically active substance 1- (3,4-dichlorophenyl) -obtained in the above (1)
3- (4-methoxypiperidin-1-ylmethyl) -2
-Pyrrolidinone racemate 23.22 g (65.0 m
(mol) was dissolved in 400 ml of ethyl acetate, and (1
S)-(-)-Camphanic acid 12.90 g (65.1)
mmol) was added, and the crystals precipitated in the mixed solution were collected by filtration,
The crystals were recrystallized three times with 150 ml, 80 ml and 80 ml of ethanol. To this crystal, 200 ml of ethyl acetate and 100 ml of water in which 3 g of sodium carbonate was dissolved were added, and
Stir for minutes. The organic layer was separated and concentrated, and the precipitated crystals were collected by filtration. Dried under reduced pressure, white needles 5.8g
(16.2 mmol) was obtained. Melting point 132-133 ° C. Enantiomeric excess 99% ee or more ¹ H-NMR (CDCl ₃ , δppm): 1.52-1.
60 (2H, m), 1.81-1.99 (2H, m),
2.02-2.23 (2H, m), 2.24-2.42
(2H, m), 2.51-2.63 (1H, m), 2.
69-2.78 (1H, m), 2.80-2.88 (3
H, m), 3.17-3.24 (1H, m), 3.34.
(3H, s), 3.73-3.79 (2H, m), 7.
40 (1H, d, J = 8.8Hz), 7.54 (1H,
dd, J = 2.2, 8.8 Hz, 7.81 (1H,
d, J = 2.2 Hz) Production Comparative Example 4 (S) -1- (3,4-dichlorophenyl) -3- (4)
Production of -methoxypiperidin-1-ylmethyl) -2-pyrrolidinone 1- (3,4-dichlorophenyl) -3- (4-methoxypiperidin-1-ylmethyl) -2-obtained in Production Example 6 (1) 800 mg of racemic pyrrolidinone
(2.24 mmol) was dissolved in 15 ml of ethyl acetate, and (1R)-(+)-camphanic acid 444 mg.
(2.24 mmol) was added, and the crystals precipitated in the mixed solution were collected by filtration and recrystallized twice with 7 ml and 7 ml of ethanol. Add 30 ml of ethyl acetate and 10 parts of sodium carbonate.
15 ml of water in which 0 mg was dissolved was added, and the mixture was stirred for 5 minutes.
The organic layer was separated and concentrated, and the precipitated crystals were collected by filtration. Dried under reduced pressure, 120 mg of white needles (0.34 mm
ol). Melting point 132-133 ° C Enantiomeric excess 98% ee or more 1H-NMR (CDCl3, δppm): 1.49-
1.64 (2H, m), 1.87-1.89 (2H,
m), 1.99-2.40 (4H, m), 2.51-
2.60 (1H, m), 2.63- 2.88 (4H,
m), 3.16-3.28 (1H, m), 3.34 (3
H, s), 3.73-3.79 (2H, m), 7.40.
(1H, d, J = 8.8Hz), 7.55 (1H, d
d, J = 2.9, 8.8 Hz), 7.80 (1H, d,
J = 2.2 Hz) Production Example 7 (R) -1- (4-trifluoromethylphenyl) -3
-(4-Methoxypiperidin-1-ylmethyl) -2-
Preparation of Pyrrolidinone In (2) of Preparation Example 4, using (2R, 3R)-(-)-dibenzoyl-L-tartaric acid, crystals first obtained were made alkaline with an aqueous sodium carbonate solution (R). Body-rich crystals (28.9% ee) 0.84 g (2.36)
mmol) and 0.72 g of (R)-(−)-mandelic acid
(4.72 mmol) was heated and dissolved in 10 ml of ethanol. After cooling to room temperature, crystal seeds (99% ee or more) collected by the HPLC optical resolution column were inoculated and left for 2 hours. The precipitated crystal was filtered to obtain 0.1 g of white crystal. Melting point: 121.2 to 122.0 ° C Enantiomeric excess: 98% ee or more 1H-NMR (CDCl3, δppm): 1.53-
1.65 (2H, m), 1.89-2.91 (11H,
m), 3.17-3.26 (1H, m), 3.34 (3
H, s), 3.76-3.90 (2H, m), 7.61
(2H, d, J = 8.8Hz), 7.78 (2H, d,
J = 8.8 Hz) Production Comparative Example 5 280 mg of racemic 1- (4-chlorophenyl) -3- (4-hexamethyleneimin-1-ylmethyl) -2-pyrrolidinone obtained in (1) of Production Example 1 (0.9
1 mmol) was dissolved in 10 ml of acetone, and (2S,
3S)-(+)-di-p-toluoyl-D-tartaric acid 36
0 mg (0.93 mmol) was added. The precipitated crystals were collected by filtration. Although 578 g of white crystals were obtained, the enantiomeric excess was almost 0% ee.

[Procedure 3]

[Document name to be amended] Statement

[Correction target item name]

[Correction method] Change

[Correction contents]

Pharmacological test example 4 (antipsychotic activity: anti-mAMP
Action) antipsychotic activity in mice using methamphet
It was examined by mine (mAMP) -induced hyperactivity. For the experiment, 1 week old male ddy mouse (Japan slc) was used.
A group of 10 animals was used. 30 minutes after oral administration of the test drug, p for measurement
The mouse was placed in a photocell cage, and the amount of exercise was measured for 30 minutes (this was defined as the effect of the test drug on the spontaneous movement). Then take it out of the cage once,
Ethamine 1.5 mg / kg was subcutaneously administered, and the animals were returned to their original cages and the amount of exercise was measured for 30 minutes. C efficacy evaluation from the average value of the momentum of each group 30 minutes after mAMP administration
The inhibition rate for the ontrol group was determined, and the ED50 was calculated. Table 6 shows the results.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Office reference number FI Technical indication location A61K 31/445 AED A61K 31/445 AED 31/55 AAE 31/55 AAE C07B 57/00 350 7419- 4H C07B 57/00 350 C07D 403/06 207 C07D 403/06 207 223 223 225 225 // C07M 7:00 (72) Inventor Norio Oto 1 Mitsui Toatsu Chemical Co., Ltd. 1900, Togo, Mobara-shi, Chiba ( 72) Inventor Hori Tori Mitsui Toatsu Chemical Co., Ltd., 1900 Togo, Mobara, Chiba Prefecture (72) Inventor Miwa Takashi 1 Mitsui Toatsu Chemical Co., Ltd., 1900, Togo, Mobara City, Chiba Prefecture (72 ) Inventor Ken Kamioka 1 1900 Togo, Mobara-shi, Chiba Mitsui Toatsu Chemical Co., Ltd. (72) Inventor Shoji Kawashima Shigeru Chiba City Togo 1900 address of 1 Mitsui Toatsu in the Chemical Co., Ltd.

Claims (20)

[Claims] 1. The following formula (1): [In the above formula (1), R ¹ and R ² are each independently a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, or a perfluoro group having 1 to 3 carbon atoms. An alkyl group or a perfluoroalkoxy group having 1 to 3 carbon atoms, R ³ represents a hydrogen atom, a hydroxyl group, an alkyl group having 1 to 6 carbon atoms,
Alkoxy group having 1 to 6 carbon atoms, perfluoroalkyl group having 1 to 3 carbon atoms, perfluoroalkoxy group having 1 to 3 carbon atoms, alkenyloxy group having 2 to 5 carbon atoms or alkynyloxy group having 3 to 5 carbon atoms And n is an integer of 4 to 7]. An optically active pyrrolidinone derivative and a pharmaceutically acceptable salt thereof. 2. The following formula (2): [In the formula (2), R ⁴ is a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a perfluoroalkyl group having 1 to 2 carbon atoms, or 1 carbon atom.
Or more and 2 is a perfluoroalkoxy group, and n is an integer of 4 to 7.] The optically active pyrrolidinone derivative and the pharmaceutically acceptable salt thereof according to claim 1. 3. The following formula (3): [In the formula (3), R ⁴ is a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a perfluoroalkyl group having 1 or 2 carbon atoms, or 1 carbon atom.
~ 2 is a perfluoroalkoxy group, R ⁵ is a hydroxyl group, an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a perfluoroalkyl group having 1 to 2 carbon atoms, and 1 to 2 carbon atoms. A perfluoroalkoxy group, an alkenyloxy group having 2 to 5 carbon atoms or an alkynyloxy group having 3 to 5 carbon atoms], or the pharmaceutically acceptable salt thereof. . 4. R ⁴ is a halogen atom, an alkyl group having 1 to 4 carbon atoms or a perfluoroalkyl group having 1 to 2 carbon atoms, and R ⁵ is an alkyl group having 1 to 4 carbon atoms, 1 to 1 carbon atoms.
4. An optically active pyrrolidinone derivative and a pharmaceutically acceptable salt thereof according to claim 3, which is an alkoxy group having 4 carbon atoms, a perfluoroalkyl group having 1 to 2 carbon atoms or a perfluoroalkoxy group having 1 to 2 carbon atoms. 5. The following formula (4): [In the formula (4), R ⁶ and R ⁷ are each independently a halogen atom, an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a perfluoroalkyl group having 1 to 2 carbon atoms or a carbon atom. Represents a perfluoroalkoxy group having 1 to 2 carbon atoms, R ⁸ represents a hydrogen atom, a hydroxyl group, an alkyl group having 1 to 4 carbon atoms,
Alkoxy group having 1 to 4 carbon atoms, perfluoroalkyl group having 1 to 2 carbon atoms, perfluoroalkoxy group having 1 to 2 carbon atoms, alkenyloxy group having 2 to 5 carbon atoms or alkynyloxy group having 3 to 5 carbon atoms The optically active pyrrolidinone derivative according to claim 1 and a pharmaceutically acceptable salt thereof. 6. An antipsychotic drug containing the optically active pyrrolidinone derivative or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 5 as an active ingredient. 7. The following formula (5): [In the formula (5), R ¹ and R ² are each independently a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, or a perfluoro group having 1 to 3 carbon atoms. An alkyl group or a perfluoroalkoxy group having 1 to 3 carbon atoms, R ³ represents a hydrogen atom, a hydroxyl group, an alkyl group having 1 to 6 carbon atoms,
Alkoxy group having 1 to 6 carbon atoms, perfluoroalkyl group having 1 to 3 carbon atoms, perfluoroalkoxy group having 1 to 3 carbon atoms, alkenyloxy group having 2 to 5 carbon atoms or alkynyloxy group having 3 to 5 carbon atoms And n represents an integer of 4 to 7], a step of obtaining a mixture of diastereomeric salts from a racemic body of a pyrrolidinone derivative represented by the formula and an optical resolving agent, and (b) from the mixture of diastereomeric salts, It has the process of isolate | separating the diastereomer salt of the optically active pyrrolidinone derivative of Claim 1, and the process of isolate | separating and collecting the said optically active pyrrolidinone derivative from the separated diastereomeric salt. Optical resolution method. 8. The racemate is represented by the following formula (6): [In the formula (6), R ⁴ is a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a perfluoroalkyl group having 1 or 2 carbon atoms, or 1 carbon atom.
Is a racemic body of the pyrrolidinone derivative represented by the formula (1) to (2) and n represents an integer of 4 to 7, and the optically active pyrrolidinone derivative according to claim 2 is resolved. Optical resolution method. 9. The optical resolution method according to claim 8, wherein R ⁴ is a halogen atom, n is 5 or 6, and the optical resolution agent is an optically active mandelic acid. 10. The production method according to claim 9, wherein R ⁴ is a chlorine atom and n is 6. 11. The optical resolution method according to claim 8, wherein R ⁴ is a perfluoroalkyl group having 1 to 2 carbon atoms, n is 5 or 6, and the optical resolution agent is optically active dibenzoyltartaric acid. 12. The racemate is represented by the following formula (7): [In the formula (7), R ⁴ is a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a perfluoroalkyl group having 1 or 2 carbon atoms, or 1 carbon atom.
~ 2 is a perfluoroalkoxy group, R ⁵ is a hydroxyl group, an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a perfluoroalkyl group having 1 to 2 carbon atoms, and 1 to 2 carbon atoms. A perfluoroalkoxy group, an alkenyloxy group having 2 to 5 carbon atoms or an alkynyloxy group having 3 to 5 carbon atoms], which is a racemic body of the pyrrolidinone derivative. The optical division method according to claim 7, wherein the optical division is performed. 13. R ⁴ is a halogen atom, an alkyl group having 1 to 4 carbon atoms or a perfluoroalkyl group having 1 to 2 carbon atoms, and R ⁵ is an alkyl group having 1 to 4 carbon atoms, and 1 carbon atom.
13. The optical resolution method according to claim 12, wherein the alkoxy group has 4 to 4 carbon atoms, a perfluoroalkyl group having 1 to 2 carbon atoms, or a perfluoroalkoxy group having 1 to 2 carbon atoms. 14. R ⁴ is a halogen atom or has 1 to 10 carbon atoms.
2 is a perfluoroalkyl group and R ⁵ has 1 to 1 carbon atoms.
13. The optical resolution method according to claim 12, wherein the alkoxy group is 4 and the optical resolution agent is an optically active mandelic acid. 15. The optical resolution method according to claim 14, wherein R ⁴ is a chlorine atom or a trifluoromethyl group, and R ⁵ is a methoxy group. 16. The method according to claim 13, wherein R ⁴ is a perfluoroalkyl group having 1 to 2 carbon atoms, R ⁵ is an alkoxy group having 1 to 4 carbon atoms, and the optical resolving agent is optically active dibenzoyltartaric acid. Optical resolution method. 17. R ⁴ is a trifluoromethyl group,
The optical resolution method according to claim 16, wherein R ⁵ is a methoxy group. 18. The racemate is represented by the following formula (8): [In the formula (8), R ⁶ and R ⁷ are each independently a halogen atom, an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a perfluoroalkyl group having 1 to 2 carbon atoms or a carbon atom. Shows a perfluoroalkoxy group of the number 1-2,
R ⁸ is a hydrogen atom, a hydroxyl group, an alkyl group having 1 to 4 carbon atoms,
Alkoxy group having 1 to 4 carbon atoms, perfluoroalkyl group having 1 to 2 carbon atoms, perfluoroalkoxy group having 1 to 2 carbon atoms, alkenyloxy group having 2 to 5 carbon atoms or alkynyloxy group having 3 to 5 carbon atoms The optical resolution method according to claim 7, wherein the optically active pyrrolidinone derivative according to claim 5 is a racemate of the pyrrolidinone derivative, and the optically active pyrrolidinone derivative according to claim 5 is resolved. 19. R ⁶ and R ⁷ are halogen atoms, and R <sup>6
8. 8</sup> is a hydrogen atom or an alkoxy group having 1 to 4 carbon atoms, and the optical resolving agent is an optically active camphanic acid.
8. The optical division method according to item 8. 20. The optical resolution method according to claim 19, wherein R ⁶ and R ⁷ are chlorine atoms, and R ⁸ is a methoxy group.