JPH11335286A - Effect-reinforcing medicament for dopamine antagonist - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject medicament capable of reinforcing the effect of a dopamine antagonist and reducing a side effect, and useful for treating diseases, such as schizopherenia, mania and depression, for which the dopamine antagonist is used, by compounding a specific pyrrolidinone as an active ingredient. SOLUTION: This effect-reinforcing medicament for a dopamine antagonist contains 1-(4-chlorophenyl)-3-[4-(2-methoxyethyl) piperazin-1-yl] methyl-2- pyrrolidinone, its pharmacologically acceptable salt or a hydrate of the pharmacologically acceptable salt as an active ingredient. A blocking agent of D2 receptor, such as haloperidol, is preferably used as the target dopamine antagonist. The medicament is usually administered at a daily dose of about 0.001-1,000 mg for an adult as the active ingredient. The medicament is preferably prepared in the form of tablet, granule, powder, etc.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a dopamine antagonist effect enhancer and / or a side effect reducer.

[0002]

2. Description of the Related Art Dopamine antagonists include schizophrenia, mania, depression, mental retardation, geriatric psychiatry, neurosis, various symptoms associated with autism and mental retardation, gastric ulcer, duodenal ulcer,
It is a useful drug for the treatment of preoperative and postoperative nausea and vomiting, pain such as diabetic, and Meniere's syndrome.

However, by taking these drugs, for example, in the treatment of schizophrenia, extrapyramidal symptoms such as parkinsonism (catalepsy in behavioral pharmacology) are expressed in about 90% of patients who take the drug (Calev, Br.). .J.Psychiatry, 187,19
83) and causes drug discontinuation in more than 50% of patients (Casey, Int. Clin. Psychopharmacol., 207, 1995).

[0004] To prevent this, it is common to use an anti-cholinergic anti-Parkinson drug at the beginning of the treatment with an anti-psychotic drug. However, it has been pointed out that concomitant use of anti-Parkinson drugs may enhance chronic side effects such as constipation, dry mouth, digestive symptoms, and even late onset dyskinesia and macrocolon.

[0005] Further, it has been considered that dopamine antagonists such as chlorpromazine and haloperidol deteriorate cognitive functions (Cohen & Servan Schreiber, Schizoph.
r.Bull., 395,1993; Gallhofer, J.Pract.Psychiatr.Be
hav. Health, 16, 1996).

[0006] In addition, it has been reported that anticholinergic agents used for treating extrapyramidal side effects cause considerable memory impairment (Tune, Am. J. Psychiatry, 34, 1982; Calev, Br. J. Psych
iatry, 422, 1983).

[0007] These experiences have led to a desire to reduce the extrapyramidal side effects or to develop drugs that do not further exacerbate cognitive dysfunction, but there are still no effective drugs. U.S. Pat. No. 4,767,759, JP-A-7-2
JP-A-52219 and JP-A-9-40667 disclose pyrrolidinone derivatives, but do not describe the effect of enhancing dopamine antagonists or reducing side effects.

[0008]

An object of the present invention is to provide a drug which enhances the effect of a dopamine antagonist and reduces side effects.

[0009]

Means for Solving the Problems The present inventors have found compounds that reduce the side effects of dopamine antagonists and enhance the effects of dopamine antagonists, and provide more effective treatment for diseases using dopamine antagonists. The present invention as an agent has been completed.

That is, the present invention relates to [1] 1- (4-
Chlorophenyl) -3- [4- (2-methoxyethyl)
[Piperazin-1-yl] methyl-2-pyrrolidinone, or a pharmacologically acceptable salt thereof, and an enhanced effect of a dopamine antagonist comprising a hydrate of the pharmacologically acceptable salt thereof as an active ingredient And [2] 1
The dopamine antagonist effect enhancer according to the above [1], wherein the absolute configuration of-(4-chlorophenyl) -3- [4- (2-methoxyethyl) piperazin-1-yl] methyl-2-pyrrolidinone is R. And [3] the dopamine antagonist is the dopamine antagonist effect enhancer according to the above [2], wherein the dopamine antagonist is a D2 receptor blocker; and [4] the dopamine antagonist effect enhancer is a tablet, The effect of the dopamine antagonist according to the above [1] to [3], which is an oral administration preparation, injection, suppository or infusion for granules, powders, suspensions, emulsifiers, capsules or syrups, injections, suppositories or infusions. And [5] 1- (4-chlorophenyl)-
3- [4- (2-methoxyethyl) piperazin-1-yl] methyl-2-pyrrolidinone, or a pharmacologically acceptable salt thereof, or a hydrate of a pharmacologically acceptable salt thereof, as an active ingredient [6] 1- (4-Chlorophenyl) -3- [4- (2-methoxyethyl) piperazin-1-yl] methyl-2-pyrrolidinone Is a side effect reducer of the dopamine antagonist according to the above [5], wherein the absolute configuration of R is R, and [7] the side effect of the dopamine antagonist according to the above [6], wherein the dopamine antagonist is a D2 receptor blocker. [8] a dopamine antagonist, which is a side effect reducer; a tablet, granule, powder, suspension, emulsifier, capsule, or syrup for oral administration, injection, suppository, or infusion; for A isotonic solution relates agents to attenuate any adverse effects of dopamine antagonists [7], wherein the above [5].

[0011]

DETAILED DESCRIPTION OF THE INVENTION The present invention will be described in more detail.

The salts of the compound of the present invention are not particularly limited as long as they are pharmaceutically acceptable salts. Examples thereof include hydrochloride, sulfate, phosphate, hydrobromide, fumarate, and maleate. , Tartrate, methanesulfonate, benzenesulfonate, paratoluenesulfonate, oxalate,
Mandelate, citrate, lactate, succinic acid, and the like. In synthesizing these salts, when the acid used has an asymmetric carbon, an optically active substance can also be used.

The dopamine antagonist to be used for enhancing the effects of the compound of the present invention and reducing side effects is not particularly limited as long as it is a drug that antagonizes the action of dopamine. For example, risperidone, olanzapine (oranzapine, LY17)
0053), SM-9018, quetiapine (ICI-204, 63
6), aripirazole (aripirazole, OPC-14597), sertindole (sertindole, S-1991), AD-5423, ziprasidone (CP-88059, ziprasidone), SM-13496, fananserin (fananserin, RP-62,203) , Clozapine,
Chlorpromazine, fluphenazine (f
luphenazine), levomepromazine,
Perazine, perphenazine,
Prochlorperazine, Propericiazine, Trifluoperazine
razine), thioridazine, thiothixene
(thiothixene), bromperidol, floropipamide, haloperidol
dol), moperone (moperone), pimozide (pimozide), spiperone (spiperone), timiperone (timiperone), nemonapride (nemonapride), sulpiride (sulpiride), sultopride (sultopride), carpiramine (carpiramine), clocapramine (clocapramine), clocapramine clotiapin
e), mosapramine, oxypertin (oxyp
ertine), zotepine and the like.

[0014] Formulation can be performed by a known method.
As the dosage form, various forms can be selected according to the purpose of treatment, and representative examples thereof include solid preparations, liquid preparations, and other suppositories. Specifically, there are the following various preparations. That is, as solid preparations, tablets, pills, powders, granules, capsules, etc., as liquid preparations, in addition to injections as solutions, suspensions, syrups, emulsions, etc. Agent and the like.

[0015] In the case of molding into a tablet form, carriers well known in the art can be widely used as carriers. Examples include lactose, sucrose, glucose, urea, starch, calcium carbonate, kaolin,
Excipients such as crystalline cellulose and silicic acid, water, ethanol,
Propanol, simple syrup, glucose solution, starch solution,
Gelatin solution, shellac solution, methylcellulose solution, hydroxypropylcellulose solution, polyvinylpyrrolidone solution, binder such as carboxymethylcellulose solution, dried starch, sodium alginate, agar powder, sodium hydrogencarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, Disintegrators such as sodium lauryl, stearic acid glyceride, starch, lactose, disintegration inhibitors such as sucrose, stearic acid, cocoa butter, hydrogenated oil, quaternary ammonium bases, absorption promoters such as sodium lauryl sulfate, glycerin, starch Sorbents such as starch, lactose, kaolin, bentonite, colloidal silicic acid, crystalline cellulose, light anhydrous silicic acid, etc .; lubricants such as talc, stearate, boric acid powder, polyethylene glycol, etc. It is an agent, and the like.

Further, in the case of tablets, tablets which have been coated with a usual coating, if necessary, such as sugar-coated tablets, gelatin-encapsulated tablets, enteric-coated tablets, film-coated tablets or two-layer tablets or multilayer tablets, can be prepared.

In molding into the form of pills, a wide variety of carriers conventionally known in this field can be used. Examples include lactose, starch, microcrystalline cellulose,
Excipients such as cocoa butter, hardened vegetable oil, kaolin, talc,
Gum arabic powder, tragacanth powder, binders such as gelatin,
Disintegrators such as carmellose calcium, agar and the like can be mentioned.

Capsules are prepared by mixing the active ingredient compound with the various carriers exemplified above and filling the mixture into hard gelatin capsules, soft capsules and the like according to a conventional method.

When prepared as an injection, when it is formed into a liquid, emulsion or suspension, it is generally used as a diluent in the art, for example, water, ethanol, macrogol, propylene glycol, ethoxylated. Isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters, cottonseed oil, corn oil, peanut oil, olive oil and the like can be used. Further, water is added to the compound of the present invention, and a suspension of the compound in the presence of a suitable surfactant, or a polyoxyethylene hydrogenated castor oil (HCO
-60), and can be prepared as an emulsion using a surfactant such as polysorbate 80 and polyethylene glycol. In addition, salt, glucose or glycerin may be contained in the pharmaceutical preparation, and a usual solubilizer,
A buffer, a soothing agent and the like may be added.

In molding into a suppository, a wide variety of conventionally known carriers can be used. Examples include polyethylene glycol, cocoa butter, higher alcohols, higher alcohol esters, gelatin,
Semi-synthetic glycerides and the like can be mentioned. Further, if necessary, a coloring agent, a preservative, a flavor, a flavoring agent, a sweetening agent or the like and other pharmaceuticals can be contained in the pharmaceutical preparation.

The method of administering these pharmaceutical preparations of the present invention is not particularly limited, and the pharmaceutical preparations are administered according to various preparation forms, the age and sex of the patient, other conditions, and the degree of the disease. For example, tablets, pills, solutions, suspensions, emulsions, powders, granules,
Syrups and capsules are administered orally. In the case of an injection, it is administered intravenously, alone or as a mixture with a normal replenisher such as glucose or amino acid, and if necessary, intramuscularly, subcutaneously or intraperitoneally. Suppositories are administered rectally.

The dosage of these pharmaceutical preparations of the present invention is appropriately selected depending on the usage, age, sex, other conditions, and the degree of the disease of the patient. It is good to use about 0.001 to 1,000 mg. In addition, the active ingredient compound is contained in a dosage unit form in a formulation.
Desirably, it is contained in the range of 0.001 to 1,000 mg.

The active ingredient of the composition of the present invention includes:
Compounds specifically exemplified in the following production examples other than 1- (4-chlorophenyl) -3- [4- (2-methoxyethyl) piperazin-1-yl] methyl-2-pyrrolidinone can also be used.

[0024]

The production examples, preparation examples and evaluation examples of the present invention are described below, but the present invention is not limited to these examples. In the evaluation examples, (R)-(+)-1- (4-chlorophenyl) -3- [4- (2-methoxyethyl) piperazin-1-yl] methyl-2-pyrrolidinone L-tartrate was used as a test compound. Used as

Production Example 1 1- (4-chlorophenyl)-
3- [4- (2-methoxyethyl) piperazin-1-yl] methyl-2-pyrrolidinone (1) Synthesis of 1- (4-chlorophenyl) -2-pyrrolidinone 372 g of p-chloroaniline and γ-butyrolactone 25
1 g, and 75 ml of hydrochloric acid was added. The mixture was gradually heated and refluxed at an internal temperature of 110 to 115 ° C. for 9 hours. Further, the internal temperature was gradually raised while removing the reflux liquid, and the reaction was carried out at 140 ° C. for 8 hours, and the reflux liquid (about 80 ml) was distilled off. 7 internal temperature
After cooling to 0 ° C, dissolve in 2000 ml of ethyl acetate,
Washing was carried out in the order of water, aqueous sodium carbonate solution and water. After drying over magnesium sulfate, the mixture was concentrated to about 1000 ml and the precipitated crystals were collected by filtration. The filtrate was further concentrated to about 200 ml, and the precipitated crystals were combined with the previous one and washed with ethyl acetate.
This was dried under reduced pressure to obtain 347 g of the desired product. ¹ H NMR (CDCl ₃ , δ ppm): 2.17 (2
H, quintet), 2.61 (2H, t), 3.8
3 (2H, t), 7.32 (2H, d), 7.58 (2
H, d)

(2) 1- (4-chlorophenyl) -3
Synthesis of -ethoxycarbonyl-2-pyrrolidinone 37 g of diethyl carbonate was added to a suspension of 25 g of sodium hydride (60% oily) in tetrahydrofuran (100 ml), and 52.0 g of 1- (4-chlorophenyl) -2-pyrrolidinone was refluxed. A tetrahydrofuran (150 ml) solution was added dropwise over about 1.5 hours. After refluxing for 4.5 hours, it was cooled and carefully poured into ice water. The mixture was made weakly alkaline with dilute hydrochloric acid and extracted with 300 ml of ethyl acetate. The organic layer was washed with water, aqueous sodium hydrogen carbonate and water in that order, dried over anhydrous magnesium sulfate, and concentrated to obtain an oil. n-hexane 20
0 ml was added, and the precipitated crystals were collected by filtration. Next, the product was washed with n-hexane and dried under reduced pressure to obtain 60 g of the desired product. ¹ H NMR (CDCl ₃ , δ ppm): 1.32 (3
H, t), 2.35-2.61 (2H, m), 3.60.
-3.66 (1H, m), 3.75-3.86 (1H,
m), 3.89-4.07 (1H, m), 4.26 (2
H, q), 7.33 (2H, d), 7.58 (2H,
d)

(3) 1- (4-chlorophenyl) -3
Synthesis of 1- (4-chlorophenyl) -3-ethoxycarbonyl-2-pyrrolidinone 30.0 g and anhydrous calcium chloride 15 g in methanol (150 ml) under ice-cooling
3.9 g of sodium borohydride were charged in portions. After completion of the reaction, the mixture was concentrated, water and ethyl acetate were added, and the mixture was acidified with diluted hydrochloric acid. The organic layer obtained by liquid separation was washed with water and dried over anhydrous magnesium sulfate. After concentration, it was crystallized from n-hexane-ethyl ether. The crystals were collected by filtration, washed with a mixed solvent of n-hexane and diethyl ether, and dried under reduced pressure to obtain 23.3 g of the desired product. ¹ H NMR (CDCl ₃ , δ ppm): 1.94-2.
09 (1H, m), 2.23-2.35 (1H, m),
2.83-2.94 (1H, m), 2.99 (1H, b
s), 3.75-3.89 (3H, m), 3.94-
4.00 (1H, m), 7.33 (2H, dd), 7.
59 (2H, dd)

(4) 1- (4-chlorophenyl) -3
Synthesis of -mesyloxymethyl-2-pyrrolidinone 1- (4-chlorophenyl) -3-hydroxymethyl-
23.2 g of 2-pyrrolidinone and triethylamine 1
Methanesulfonyl chloride (14.0 g) was added dropwise to a solution of 2.5 g of dichloromethane (200 ml) under ice cooling.
After reacting for 2 hours, the mixture was washed with water and dried over anhydrous magnesium sulfate. The solution was concentrated to crystallize and sludged with diethyl ether. After filtration, the product was further washed with diethyl ether and dried under reduced pressure to obtain 29.8 g of the desired product. ¹ H NMR (CDCl ₃ , δ ppm): 2.16-2.
50 (2H, m), 2.87-3.18 (4H, m),
3.77-3.87 (2H, m), 4.43-4.67
(2H, m), 7.34 (2H, d), 7.58 (2
H, d)

(5) Synthesis of 1-formyl-4- (2-methoxyethyl) piperazine 53.15 g of methoxyethyl bromide was added to a solution of 37.1 g of N-formylpiperazine and 37.1 g of anhydrous sodium carbonate in 50 ml of methanol. The mixture was added dropwise and refluxed for 3.5 hours. After cooling to room temperature, insolubles were removed by filtration, and the filtrate was concentrated. Water and chloroform were added to the filtrate, and the mixture was separated to give an organic layer. The aqueous layer was extracted with chloroform, combined with the previous organic layer, dried over anhydrous magnesium sulfate, and concentrated to obtain 57.2 g of the desired product. ¹ H NMR (CDCl ₃ , δ ppm): 2.45-2.
54 (4H, m), 2.59-2.63 (2H, m),
3.35-3.43 (2H, m), 3.36 (3H,
s), 3.50-3.61 (4H, m), 8.02 (1
H, s)

(6) Synthesis of 1- (2-methoxyethyl) piperazine dihydrochloride 1-Formyl-4-methoxyethylpiperazine 57.2
g of methanol (100 ml) in 4N hydrochloric acid /
180 ml of 1,4-dioxane was added dropwise over 1.5 hours. After stirring at room temperature for 1 hour, the crystals were collected by filtration, washed with isopropyl ether, and dried under reduced pressure to obtain 68.8 g of the desired product.

(7) Synthesis of 1- (2-methoxyethyl) piperazine To an aqueous solution (50 ml) of 68.8 g of 1-methoxyethylpiperazine dihydrochloride, an aqueous solution (100 ml) of 33.0 g of sodium hydroxide was added dropwise. Extract with chloroform,
After drying over anhydrous magnesium sulfate, the solvent was distilled off to obtain 41.3 g of the desired product. ¹ H NMR (CDCl ₃ , δ ppm): 1.80 (1
H, s), 2.47-2.60 (6H, m), 2.90.
-2.94 (4H, m), 3.36 (3H, s), 3.
52 (2H, t)

(8) 1- (4-chlorophenyl) -3
Synthesis of-(4- (2-methoxyethyl) piperazin-1-yl) methyl-2-pyrrolidinone 1- (4-chlorophenyl) -3-mesyloxymethyl-2-pyrrolidinone 18.5 g and 1- (2-methoxy) Ethyl) piperazine 17.6 g of acetonitrile (5
(0 ml), 8.0 g of triethylamine was added to the solution, and the mixture was heated under reflux for 4 hours. After concentrating the reaction mixture, water was added, and the precipitated crystals were collected by filtration and dried under reduced pressure to obtain 18.5 g of the desired product. Melting point: 103-105 ° C ¹ H NMR (CDCl ₃ , δ ppm): 2.01-2.
12 (1H, m), 2.29-2.62 (12H,
m), 2.78-2.94 (2H, m), 3.35 (3
H, s), 3.51 (2H, t), 3.74-3.80.
(2H, m), 7.32 (2H, d), 7.59 (2
H, d)

Production Example 2 1- (4-chlorophenyl)-
3- (4- (2-methoxyethyl) piperazin-1-yl) methyl-2-pyrrolidinone dihydrochloride 1- (4-chlorophenyl) -3- (4- (2-methoxyethyl) piperazin-1-yl) To a solution of 1.41 g of methyl-2-pyrrolidinone in 10 ml of methanol was added 4
The mixture was acidified by addition of N hydrochloric acid / 1,4-dioxane. The precipitated crystals were collected by filtration, washed with diethyl ether, and dried under reduced pressure to obtain 1.62 g of the desired product. Melting point: 261-262 ° C. ¹ H NMR (DMSO, δ ppm): 2.00-2.
12 (1H, m), 2.55 (1H, m), 3.31
(3H, s), 3.31-3.84 (17H, m),
7.46 (2H, d), 7.72 (2H, d)

Production Example 3 (R) -1- (4-chlorophenyl) -3- (4- (2-methoxyethyl) piperazin-1-yl) methyl-2-pyrrolidinone (R)-(-)
-Mandelic acid salt heated 1- (4-chlorophenyl) -3- (4- (2
-Methoxyethyl) piperazin-1-yl) methyl-2
66.6 g of ethyl acetate of pyrrolidinone (350 ml)
To the solution was added a heated solution of (R)-(-)-mandelic acid in ethyl acetate (120 ml). After cooling, the precipitated crystals were collected by filtration, washed with ethyl acetate, and dried under reduced pressure to obtain the desired product 3.
6.4 g were obtained. Melting point: 137-138 ° C Enantiomeric excess 99% ee or more (calculated from HPLC area ratio) The enantiomeric excess was calculated from the peak area by liquid chromatography using a chiral column. The same applies to the following. ¹ H NMR (DMSO, δ ppm): 1.83-1.
97 (1H, m), 2.19-2.97 (14H,
m), 3.23 (3H, s), 3.41-3.48 (2
H, m), 3.70-3.81 (2H, m), 4.94.
(1H, s), 7.21-7.38 (5H, m), 7.
41 (2H, d), 7.69 (2H, d)

Production Example 4 (R) -1- (4-chlorophenyl) -3- (4- (2-methoxyethyl) piperazin-1-yl) methyl-2-pyrrolidinone Recrystallized from ethanol (100 ml) ( R) -1-
30.5 g of (4-chlorophenyl) -3- (4- (2-methoxyethyl) piperazin-1-yl) methyl-2-pyrrolidinone (R)-(-)-mandelate was added to water (30
0 ml), desalted with sodium carbonate, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated to obtain 19.5 g of the desired product. Melting point: 102-103 ° C. Optical rotation: + enantiomeric excess 99% ee or more ¹ H NMR (CDCl ₃ , δ ppm): 2.04 (1
H, m), 2.35 (1H, m), 2.4-2.7 (1
1H, m), 2.81 (1H, m), 2.91 (1H,
dd), 3.35 (3H, s), 3.51 (2H,
t), 3.77 (2H, m) 7.32 (2H, d),
7.59 (2H, d)

Production Example 5 Production of (R) -1- (4-chlorophenyl) -3- (4- (2-methoxyethyl) piperazin-1-yl) methyl-2-pyrrolidinone dihydrochloride (compound of Table 2) (R) -form of No. 50) (R) -1- (4-chlorophenyl) -3- (4- (2
-Methoxyethyl) piperazin-1-yl) methyl-2
-18.7 g of pyrrolidinone methanol (130 ml)
The solution was acidified by adding 4N hydrochloric acid / 1,4-dioxane. The precipitated crystals were collected by filtration, washed with diethyl ether, and dried under reduced pressure to obtain 22.6 g of the desired product. Melting point: 252 to 253 ° C. (decomposition) Optical rotation:-enantiomeric excess 99% ee or more ¹ H NMR (D ₂ O, δ ppm): 2.06 (1H,
m), 2.52 (1H, m), 3.41 (3H, s),
3.32-4.03 (17H, m), 7.48 (4H,
s)

Production Example 6 (R) -1- (4-chlorophenyl) -3- (4- (2-methoxyethyl) piperazin-1-yl) methyl-2-pyrrolidinone dihydrochloride dihydrate (R) -1- (4-chlorophenyl) -3- (4- (2
-Methoxyethyl) piperazin-1-yl) methyl-2
1.98 g of pyrrolidinone dihydrochloride at 75% relative humidity,
It was left in a thermostat maintained at a temperature of 25 ° C. for 24 hours to obtain 2.14 g of the desired product. Melting point: 264.6-265.1 ° C. (decomposition) Optical activity:-enantiomeric excess 99% ee or more ¹ H NMR (D ₂ O, δ ppm): 2.06 (1H,
m), 2.52 (1H, m), 3.41 (3H, s),
3.32-4.03 (17H, m), 7.48 (4H,
s) This compound can also be synthesized by the following method.

Under reflux, (R) -1- (4-chlorophenyl) -3- (4- (2-methoxyethyl) piperazine-
1-yl) methyl-2-pyrrolidinone dihydrochloride 100m
Water was added dropwise to a suspension of g (3 ml) of ethanol until the reaction system became homogeneous. After allowing to cool to room temperature, the precipitated solid was collected by filtration and dried to obtain 88.5 mg of the desired product.

Production Example 7 (R) -1- (4-chlorophenyl) -3- (4- (2-methoxyethyl) piperazin-1-yl) methyl-2-pyrrolidinone dihydrobromide 47% bromide Hydrogen acid aqueous solution 379 mg and ethanol (10
(R) -1- (4-chlorophenyl) -3- (4- (2-methoxyethyl) piperazine-
A solution of 352 mg of 1-yl) methyl-2-pyrrolidinone in ethanol (10 ml) was added. After stirring at room temperature and cooling, the precipitated solid was collected by filtration and dried to obtain 488 mg of the desired product. Melting point: 244.1-244.1 ° C. ¹ H NMR (DMSO, δ ppm): 1.90-2.
60 (1H, m), 2.40-2.55 (1H, m),
2.78-4.00 (20H, m), 7.46 (2H,
d), 7.73 (2H, d)

Production Example 8 Production of (R) -1- (4-chlorophenyl) -3- (4- (2-methoxyethyl) piperazin-1-yl) methyl-2-pyrrolidinone sulfate monohydrate (Table) (R) -form of compound No. 32 of No. 3) (R) -1- (4-chlorophenyl) -3- (4- (2
-Methoxyethyl) piperazin-1-yl) methyl-2
-To a solution of 352 mg of pyrrolidinone in 10 ml of ethanol was added a solution of 101 mg of concentrated sulfuric acid in 5 ml of ethanol. After stirring at room temperature, the mixture was concentrated to 3 ml, ethyl acetate (5 ml) was added, and the precipitated solid was collected by filtration and dried to obtain 389 mg of the desired product. Melting point: 166.4-166.7 ° C ¹ H NMR (DMSO, δ ppm): 1.84-1.
99 (1H, m), 2.15-4.35 (21H,
m), 7.44 (2H, d), 7.71 (2H, d)

Production Example 9 (R) -1- (4-chlorophenyl) -3- (4- (2-methoxyethyl) piperazin-1-yl) methyl-2-pyrrolidinone benzenesulfonate monohydrate benzenesulfone To a solution of 176 mg of acid monohydrate in ethanol (10 ml) was added (R) -1- (4-chlorophenyl) -3- (4- (2-methoxyethyl) piperazine-
A solution of 352 mg of 1-yl) methyl-2-pyrrolidinone in ethanol (10 ml) was added. After sludge the concentrated residue with ethanol, the solid was collected by filtration and dried to obtain 407 m of the desired product.
g was obtained. Melting point: 82.2-85.9 ° C. ¹ H NMR (DMSO, δ ppm): 1.88-1.
99 (1H, m), 2.31-3.81 (21H,
m), 7.31-7.36 (3H, m), 7.43 (2
H, d), 7.59-7.68 (2H, m), 7.69.
-7.72 (2H, m)

Production Example 10 (R) -1- (4-chlorophenyl) -3- (4- (2-methoxyethyl) piperazin-1-yl) methyl-2-pyrrolidinone dibenzenesulfonate Pentahydrate To a solution of 352 mg of benzenesulfonic acid monohydrate in ethyl acetate (10 ml) was added (R) -1- (4-chlorophenyl) -3- (4- (2-methoxyethyl) piperazine-
A solution of 352 mg of 1-yl) methyl-2-pyrrolidinone in ethyl acetate (10 ml) was added. After stirring at room temperature and cooling, the precipitated solid was collected by filtration and dried to obtain 585 mg of the desired product. Melting point: 162.5-163.4 ° C. ¹ H NMR (DMSO, δ ppm): 1.78-1.
97 (1H, m), 2.18-3.84 (22H,
m), 7.23-7.36 (6H, m), 7.45-
7.49 (2H, m), 7.58-7.64 (4H,
m), 7.70-7.75 (2H, m)

Production Example 11 (R) -1- (4-chlorophenyl) -3- (4- (2-methoxyethyl) piperazin-1-yl) methyl-2-pyrrolidinone dip-toluenesulfonate dihydrate Compound (R) -1- (4-Chlorophenyl) -3- (4- (2-methoxyethyl) piperazin-1-yl) methyl was added to a solution of 380 mg of p-toluenesulfonic acid monohydrate in ethyl acetate (10 ml). A solution of 352 mg of 2-pyrrolidinone in ethyl acetate (10 ml) was added. After stirring at room temperature and cooling, the precipitated solid was collected by filtration and dried to obtain 712 mg of the desired product. Melting point: 209.8-210.3 ° C. ¹ H NMR (DMSO, δ ppm): 1.85-2.
10 (1H, m), 2.25-2.50 (1H, m),
2.29 (6H, s), 2.70-3.95 (20H,
m), 7.12 (4H, d), 7.30 (2H, d),
7.45-7.49 (6H, m)

Production Example 12 (R) -1- (4-chlorophenyl) -3- (4- (2-methoxyethyl) piperazin-1-yl) methyl-2-pyrrolidinone methanesulfonate (R) -1- (4-chlorophenyl) -3- (4- (2
-Methoxyethyl) piperazin-1-yl) methyl-2
-To a solution of 880 mg of pyrrolidinone in 15 ml of ethyl acetate was added 240 mg of methanesulfonic acid in ethyl acetate (5 m
l) The solution was added. After stirring at room temperature and cooling, the precipitated solid was collected by filtration and dried to obtain 892 mg of the desired product. ¹ H NMR (D ₂ O, δ ppm): 1.95-2.10.
(1H, s), 2.41-2.55 (1H, s), 2.
74-3.45 (13H, m), 2.80 (3H,
s), 3.39 (3H, s), 3.73-3.77 (2
H, m), 3.81-3.97 (2H, m), 7.46.
(4H, s)

Production Example 13 (R) -1- (4-chlorophenyl) -3- (4- (2-methoxyethyl) piperazin-1-yl) methyl-2-pyrrolidinone dimethanesulfonate (R) -1 -(4-chlorophenyl) -3- (4- (2
-Methoxyethyl) piperazin-1-yl) methyl-2
To a solution of 880 mg of pyrrolidinone in 15 ml of ethyl acetate was added 480 mg of methanesulfonic acid in ethyl acetate (5 m
l) The solution was added. After stirring at room temperature and cooling, the precipitated solid was collected by filtration and dried to give 1127 mg of the desired product. ¹ H NMR (D ₂ O, δ ppm): 1.98-2.13
(1H, m), 2.49-2.62 (1H, m), 2.
80 (6H, s), 3.31-4.19 (17H,
m), 3.41 (3H, s), 7.48 (4H, s)

Production Example 14 (R) -1- (4-chlorophenyl) -3- (4- (2-methoxyethyl) piperazin-1-yl) methyl-2-pyrrolidinone L-lactate (R) -1- (4-chlorophenyl) -3- (4- (2
-Methoxyethyl) piperazin-1-yl) methyl-2
-To a solution of 352 mg of pyrrolidinone in 10 ml of ethyl acetate was added a mixture of 106 mg of an aqueous 85% L-lactic acid solution and 10 ml of ethyl acetate. After stirring at room temperature, the concentrated residue was sludged with diethyl ether and dried to obtain the desired product 1
80 mg were obtained. Melting point: 64.9-86.0 ° C. ¹ H NMR (DMSO, δ ppm): 1.23 (3
H, d), 1.80-2.00 (1H, m), 2.15
-4.10 (23H, m), 7.43 (2H, d),
7.70 (2H, d)

Production Example 15 (R) -1- (4-chlorophenyl) -3- (4- (2-methoxyethyl) piperazin-1-yl) methyl-2-pyrrolidinone L-tartrate L-tartaric acid 150 mg of ethanol (R) -1- (4-chlorophenyl) -3- (4-
352 mg of (2-methoxyethyl) piperazin-1-yl) methyl-2-pyrrolidinone in ethyl acetate (10 m
l) The solution was added. After stirring at room temperature and cooling, the precipitated solid was collected by filtration and dried to obtain 488 mg of the desired product. Melting point: 183.2-184.9 ° C. ¹ H NMR (DMSO, δ ppm): 1.82-1.
94 (1H, m), 2.21-3.79 (22H,
m), 4.17 (2H, s), 7.40-7.46 (2
H, m), 7.67-7.73 (2H, m) The present compound can also be synthesized by the following method. (R) -1- (4-chlorophenyl) -3- (4- (2
-Methoxyethyl) piperazin-1-yl) methyl-2
-5.00 g of pyrrolidinone and 2.13 g of L-tartaric acid in 1
The suspension was suspended in 8% water-ethanol (62 ml). After heating to reflux to form a homogeneous solution, the mixture was cooled, and the precipitated solid was collected by filtration.
Drying yielded 6.39 g of the desired product.

Production Example 16 (R) -1- (4-chlorofu)
Enyl) -3- (4- (2-methoxyethyl) piperazine
N-1-yl) methyl-2-pyrrolidinone di-L-tartaric acid
Salt dihydrate L-tartaric acid 300mg ethanol (20ml) solution
In addition, (R) -1- (4-chlorophenyl) -3- (4-
(2-methoxyethyl) piperazin-1-yl) methyl
-2-pyrrolidinone 352 mg of ethanol (10 m
l) The solution was added. After stirring at room temperature, the solid precipitated
Was collected by filtration and dried to obtain 205 mg of the desired product. ¹ 1 H NMR (DMSO, δ ppm): 1.87-1.
98 (1H, m), 2.25-2.89 (14H,
m), 3.25 (3H, s), 3.41-3.51 (2
H, m), 3.74-3.80 (2H, m), 4.21
(4H, s), 7.42 (2H, dd), 7.70 (2
H, dd)

Production Example 17 (R) -1- (4-chlorophenyl) -3- (4- (2-methoxyethyl) piperazin-1-yl) methyl-2-pyrrolidinone di-D-tartrate (R) -1 -(4-chlorophenyl) -3- (4- (2
-Methoxyethyl) piperazin-1-yl) methyl-2
-To a solution of 176 mg of pyrrolidinone in ethanol (3 ml) was added a solution of 75 mg of D-tartaric acid in ethanol (3 ml). After stirring at room temperature and cooling, the precipitated solid was collected by filtration and dried to obtain 110 mg of the desired product. ¹ H NMR (DMSO, δ ppm): 1.86-1.
94 (1H, m), 2.25-3.00 (14H,
m), 3.25 (3H, s), 3.47-3.51 (2
H, m), 3.74-3.80 (2H, m), 4.22
(2H, s), 7.43 (2H, d), 7.70 (2
H, d)

Production Example 18 (R) -1- (4-chlorophenyl) -3- (4- (2-methoxyethyl) piperazin-1-yl) methyl-2-pyrrolidinone disuccinate (R) -1- (4-chlorophenyl) -3- (4- (2
-Methoxyethyl) piperazin-1-yl) methyl-2
-To a solution of 880 mg of pyrrolidinone in ethanol (20 ml) was added a solution of 591 mg of succinic acid in ethanol (20 ml). After stirring at room temperature and cooling, the precipitated solid was collected by filtration and dried to obtain 356 mg of the desired product. Melting point: 98.1-99.1 ° C. ¹ H NMR (DMSO, δ ppm): 1.82-1.
96 (1H, m), 2.18-2.97 (14H,
m), 2.41 (4H, s), 3.23 (3H, s),
3.41-3.45 (2H, m), 3.70-3.81
(2H, m), 7.43 (2H, d), 7.70 (2
H, d)

Production Example 19 (R) -1- (4-chlorophenyl) -3- (4- (2-methoxyethyl) piperazin-1-yl) methyl-2-pyrrolidinone difumarate (R) -1- (4-chlorophenyl) -3- (4- (2
-Methoxyethyl) piperazin-1-yl) methyl-2
5.00 g of pyrrolidinone and 3.30 g of fumaric acid in 13
% Water-ethanol (62 ml). After heating to reflux to form a homogeneous solution, the solution was cooled, and the precipitated solid was collected by filtration and dried to obtain 7.45 g of the desired product. Melting point: 192-193 ° C ¹ H NMR (DMSO, δ ppm): 1.82-1.
97 (1H, m), 2.19-2.31 (1H, m),
2.35-2.97 (13H, m), 3.24 (3H,
s), 3.44-3.48 (2H, m), 3.73-
3.79 (2H, m), 6.60 (4H, s), 7.4
3 (2H, d), 7.70 (2H, d)

Production Example 20 (R) -1- (4-chlorophenyl) -3- (4- (2-methoxyethyl) piperazin-1-yl) methyl-2-pyrrolidinone dimaleate (R) -1- (4-chlorophenyl) -3- (4- (2
-Methoxyethyl) piperazin-1-yl) methyl-2
-5.00 g of pyrrolidinone and 3.30 g of maleic acid in 9
% Water-ethanol (62 ml). After heating to reflux to form a homogeneous solution, the mixture was cooled, and the precipitated solid was collected by filtration and dried to obtain 7.10 g of the desired product. Melting point: 178.5-179.1 ° C ¹ H NMR (DMSO, δ ppm): 1.76-1.
98 (1H, m), 2.23-2.35 (1H, m),
2.66-3.30 (13H, m), 3.30 (3H,
s), 3.60-3.72 (2H, m), 3.76-
3.81 (2H, m), 6.14 (4H, s), 7.4
4 (2H, d), 7.71 (2H, d)

Formulation Example 1 (Tablets) The total amount of the active ingredient which is the compound of the present invention, crystalline cellulose and a part of corn starch were mixed and granulated to obtain corn starch pasta. The resulting grit was sieved, dried and mixed with the remaining corn starch and magnesium stearate. The coarse particles were then added at 1 mg, 2 mg, 25 mg, and 5 mg / tablet.
Compressed into tablets containing 0 mg of active ingredient.

Active ingredient 1.0 mg 2.0 mg 25.0 mg 50.0 mg Microcrystalline cellulose 49.25 mg 48.75 mg 37.25 mg 100.0 mg Maize starch 49.25 mg 48.75 mg 37.25 mg 4.25 mg Magnesium stearate 0.50 mg 0.50 mg 0.50 mg 0.75 mg

Formulation Example 2 (Injection) 600 mg of the active ingredient which is the compound of the present invention was taken, and 0.9 mg
Dissolved in 10 ml of 10% physiological saline and filtered to remove bacteria.
It was sealed in an ampoule to give an injection.

Evaluation Example 1 Effect Enhancing Effect The effect enhancing effect of the test compound on the apomorphine-induced climbing behavior inhibitory effect of haloperidol, a D2 receptor blocker, was evaluated. Using a 5-week-old ddy male mouse, haloperidol was added to 0. 10 minutes after oral administration of the test compound.
23 mg / kg (ED50) was orally administered. After 60 minutes, 3 mg / kg of apomorphine was subcutaneously administered, and after 20 minutes, the climbing action time was measured for 2 minutes. The results are shown in Table 1 (Table 1). As a result of the test, the compound of the present invention significantly enhanced the effect of haloperidol.

[0057]

Table 1 Table 1 Apomorphine climbing inhibitory effect 作用 Test drug dose ( mg / kg) Climbing time (seconds) Average ± SE, N = 10 ─────────────────────────────────生理 Saline − 98.9 ± 4.5 Test compound 3 83.0 ± 6.1 Halohelitol 0.23 60.6 ± 10.8 ** Halohelitol 0.23 + Test compound 0.3 52.0 ± 8.3 Halohelitol 0.23 + Test compound 1 44.1 ± 8.9 Halohelitol 0.23 + Test compound 3 20.3 ± 4.6 # ─────────────────────────────────── **: p <0.01 vs saline, #: p < 0.05 vs halo perimeter alone

Evaluation Example 2 Effect of Reducing Side Effects The inhibitory effect of the compound of the present invention on haloperidol-induced catalepsy, which is a D2 receptor blocker, was evaluated. 7 weeks old
Oral administration of test compound using Wistar male rats 6
0 minutes later, haloperidol was orally administered, and 1, 2, 3
At 6 hours, the catalepsy time was measured up to 210 seconds. Catalepsy time was scored according to Table-2 (Table 2). The evaluation results are shown in Table 3 (Table 3). The compounds of the present invention alleviated catalepsy, a side effect induced by haloperidol.

[0059]

[Table 2] Table 2 Catalepsy score ─────────────────────── Catalepsy time (seconds) Score ─────────── ──────────── 0 0 1 to 30 1 31 to 60 2 61 to 90 3 91 to 120 4 121 to 150 5 151 to 180 6 181 to 210 7 211 or more 8 ───── ──────────────────

[0060]

[Table 3] Haloperidol-induced catalepsy inhibitory activity-Test Drug dose Catalepsy score (mg / kg po) Mean ± SE, N = 6 ─────────────────────────────────ハ ロ Haloperitol 0.9 4.3 ± 0.4 Haloperitol 0.9 + Test compound 1 4.3 ± 0.4 Haloperitol 0.9 + Test compound 3 2.1 ± 0.3 Haloperitol 0.9 + Test compound 10 1.8 ± 0.6 ── ───────────────────

Evaluation Example 3 Effect of Reducing Side Effects The effect of the test compound on the cognitive impairment of haloperidol, a D2 receptor blocker, was evaluated. Using five-week-old male Wistar rats, condition avoidance behavior was examined using a shuttle box. Rats that performed 20 avoidance trainings a day for 10 days, followed by 10 trials a day for 5 days, and showed an avoidance rate of 80% or more for 3 consecutive days were used in the experiments. Haloperidol was orally administered 60 minutes after the oral administration of the test compound, and conditioned avoidance behavior was measured at 0.5, 1, 3, 6, and 24 hours after the administration. The results are shown in Table 4 (Table 4). The compound of the present invention significantly improved haloperidol cognitive impairment.

[0062]

Table 4 Table 4 Improvement effect of haloperidol on cognitive impairment 被 験 Test Medication Dose Conditional avoidance rate (%) (mg / kg po) Mean ± SE, N = 6 ──────────────────────────── ─────── Physiological saline − 85.0 ± 5.0 Test compound 1 88.3 ± 1.7 Test compound 10 88.3 ± 7.6 Halohelitol 0.5 23.3 ± 12.8 ** Halohelitol 0.5 + Test compound 1 41.7 ± 9.5 Halohelitol 0.5 + Test compound 3 80.0 ± 5.2 # ─────────────────────────────────── **: p <0.01 vs saline, #: p <0.05 vs haloperitol alone

[0063]

From the above evaluation examples, the compounds of the present invention enhance the effects of dopamine antagonists, reduce and improve the side effects of dopamine antagonists, and are therefore useful in diseases in which dopamine antagonists are used for treatment. It is clear that it is a drug.

 ──────────────────────────────────────────────────続 き Continuing on the front page (72) Inventor Hiroshi Nagase 1144 Togo, Mobara-shi, Chiba Mitsui Chemicals Co., Ltd. (72) Inventor Kazutoshi 1900-1, Togo, Togo, Mobara-shi, Chiba Mitsui Pharmaceutical Co., Ltd. (72) Inventor Shinji Takahashi 1900, Togo, Togo, Mobara-shi, Chiba Pref. (72) Inventor Kaoru 1,900-1, Togo, Togo, Mobara-shi, Chiba Pref.

Claims (8)

[Claims] 1- (4-chlorophenyl) -3- [4
-(2-methoxyethyl) piperazin-1-yl] methyl-2-pyrrolidinone or a pharmacologically acceptable salt thereof and a hydrate of the pharmacologically acceptable salt thereof as an active ingredient. Dopamine antagonist effect enhancer. 2. 1- (4-chlorophenyl) -3- [4
The effect enhancer of a dopamine antagonist according to claim 1, wherein the absolute configuration of-(2-methoxyethyl) piperazin-1-yl] methyl-2-pyrrolidinone is R. 3. The dopamine antagonist effect enhancer according to claim 2, wherein the dopamine antagonist is a D2 receptor blocker. 4. The effect enhancer of a dopamine antagonist is a tablet, granule, powder, suspension, emulsifier, capsule, or syrup for oral administration, injection, suppository or isotonic solution for infusion. The agent for enhancing the effect of a dopamine antagonist according to any one of claims 1 to 3. 5. 1- (4-chlorophenyl) -3- [4
-(2-methoxyethyl) piperazin-1-yl] methyl-2-pyrrolidinone or a pharmacologically acceptable salt thereof and a hydrate of the pharmacologically acceptable salt thereof as an active ingredient. A drug that reduces the side effects of a dopamine antagonist. 6. 1- (4-chlorophenyl) -3- [4
The agent for reducing a side effect of a dopamine antagonist according to claim 5, wherein the absolute configuration of-(2-methoxyethyl) piperazin-1-yl] methyl-2-pyrrolidinone is R. 7. The agent for reducing a side effect of a dopamine antagonist according to claim 6, wherein the dopamine antagonist is a D2 receptor blocker. 8. The agent for reducing side effects of a dopamine antagonist is a tablet, granule, powder, suspension, emulsifier, capsule, or syrup for oral administration, injection, suppository or isotonic solution for infusion. 8. The agent for reducing side effects of a dopamine antagonist according to claim 5.