Since a compound represented by general formula (1), its pharmaceutically acceptable salt and a hydrate of the pharmaceutically acceptable salt have high antipsychotic activity, they may be used as an active ingredient for preparation of an antipsychotic. ##STR1## Also provided are an optical resolution method of the above compound and an intermediate for preparation of the compound.

EXAMPLES 
Examples of preparation, formulation and evaluation for the compounds of 
this invention will be described, but this invention is not limited to the 
specific embodiments. 
Preparation Example 1 
Preparation of 
1-(4-chlorophenyl)-3-(4-(2-methoxyethyl)piperazin-1-yl)methyl-2-pyrrolidin 
one(Table 1; Compound No. 146; racemic modification) 
(1)Preparation of 1-(4-chlorophenyl)-2-pyrrolidinone 
To a mixture of 372 g of p-chloroaniline and 251 g of .gamma.-butyrolactone 
was added 75 mL of hydrochloric acid. The mixture was slowly warmed to an 
inner temperature of 110 to 115.degree. C., and refluxed for 9 hours. 
Then, removing the refluxing liquid to slowly raise the inner temperature 
to 140.degree. C., the reaction was continued for 8 hours. Consequently, 
80 mL of the refluxing liquid was removed. After cooling to an inner 
temperature of 70.degree. C., the mixture was dissolved in 2000 mL of 
ethyl acetate and washed sequentially with water, aqueous sodium carbonate 
solution and water. The organic layer was dried over magnesium sulfate and 
concentrated to about 1000 mL, and the precipitated crystals were 
collected by filtration. The filtrate was further concentrated to about 
200 mL to collect the precipitated crystals. The combined crystals were 
washed with ethyl acetate and dried in vacuo to give 347 g of the title 
compound. 
.sup.1 H NMR(CDCl.sub.3, .delta. ppm): 2.17(2H, quintet), 2.61(2H, t), 
3.83(2H, t), 7.32(2H, d), 7.58 (2H, d) 
(2) Preparation of 1-(4-chlorophenyl)-3-ethoxycarbonyl-2-pyrrolidinone 
To a suspension of 25 g of sodium hydride (60% oil dispersion) in 100 mL of 
tetrahydrofuran was added 37 g of diethyl carbonate. Under reflux, to the 
mixture was added dropwise a solution of 52.0 g of 
1-(4-chlorophenyl)-2-pyrrolidinone in 150 mL of tetrahydrofuran over about 
1.5 hours. After refluxing for 4.5 hours, the reaction mixture was cooled, 
and carefully poured into ice-water. The mixture was made to weakly 
alkaline with diluted hydrochloric acid and extracted with 300 mL of ethyl 
acetate. The organic layer was washed sequentially with water, aqueous 
sodium bicarbonate solution and water, dried over anhydrous magnesium 
sulfate and concentrated to give an oil. To the residue was added 200 mL 
of n-hexane, and the precipitated crystals were collected by filtration. 
The crystals were washed with n-hexane and dried in vacuo to give 60 g of 
the title compound. 
.sup.1 H NMR (CDCl.sub.3, .delta. ppm): 1.32(3H, 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(2H, q), 
7.33(2H, d), 7.58(2H. d) 
(3) Preparation of 1-(4-chlorophenyl)-3-hydroxymethyl-2-pyrrolidinone 
Under ice-cooling, 3.9 g of sodium borohydride was added portionwise to a 
solution of 30.0 g of 1-(4-chlorophenyl)-3-ethoxycarbonyl-2-pyrrolidinone 
and 15 g of anhydrous calcium chloride in 150 mL of methanol. After 
completion of the reaction, the mixture was concentrated, and water and 
ethyl acetate were added. The mixture was acidified with diluted 
hydrochloric acid. After separation, the organic layer was washed with 
water, dried over anhydrous magnesium sulfate and concentrated. The 
residue was crystallized with n-hexane-ethyl ether. The crystals were 
collected by filtration, washed with a mixture of n-hexane and diethyl 
ether and dried in vacuo to give 23.3 g of the title compound. 
.sup.1 H NMR(CDCl.sub.3, .delta. ppm): 1.94-2.09(1H, m), 2.23-2.35(1H, m), 
2.83-2.94(1H, m), 2.99(1H, bs), 3.75-3.89(3H, m), 3.94-4.00(1H, m), 
7.33(2H, dd), 7.59(2H, dd) 
(4) Preparation of 1-(4-chlorophenyl)-3-mesyloxymethyl-2-pyrrolidinone 
Under ice-cooling, 14.0 g of methanesulfonyl chloride was added dropwise to 
a solution of 23.2 g of 1-(4-chlorophenyl)-3-hydroxymethyl-2-pyrrolidinone 
and 12.5 g of triethylamine in 200 mL of dichloromethane. After 2 hours, 
the reaction mixture was washed with water, dried over anhydrous magnesium 
sulfate and concentrated to give crystals. The crystals were sludged with 
diethyl ether and collected by filtration. The crystals were washed with 
diethyl ether and dried in vacuo to give 29.8 g of the title compound. 
.sup.1 H NMR(CDCl.sub.3, .delta. 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(2H, d) 
(5) Preparation of 1-formyl-4-(2-methoxyethyl)piperazine 
To a solution of 37.1 g of N-formylpiperazine and 37.1 g of anhydrous 
sodium carbonate in 50 mL of methanol was added dropwise 53.15 g of 
methoxyethyl bromide, and the mixture was refluxed for 3.5 hours. After 
cooling to room temperature, insolubles were filtered out and the filtrate 
was concentrated. To the residue was added water and chloroform. After 
separating the organic layer, the aqueous layer was extracted with 
chloroform. The combined organic layer was dried over anhydrous magnesium 
sulfate and concentrated to give 57.2 g of the title compound. 
.sup.1 H NMR(CDCl.sub.3, .delta. 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(1H, s) 
(6) Preparation of 1-(2-methoxyethyl)piperazine dihydrochloride 
To a solution of 57.2 g of 1-formyl-4-methoxyethylpiperazine in 100 mL of 
methanol was added dropwise 180 mL of 4N-hydrochloric acid/1,4-dioxane 
over 1.5 hours. The mixture was stirred at room temperature for 1 hour, 
and the resulting crystals were filtered, washed with isopropyl ether and 
dried in vacuo to give 68.8 g of the title compound. 
(7) Preparation of 1-(2-methoxyethyl)piperazine 
To an aqueous solution of 68.8 g of 1-(2-methoxyethyl)piperazine 
dihydrochloride (water; 50 mL) was added dropwise an aqueous solution of 
33.0 g of sodium hydroxide (water; 100 mL). The mixture was extracted with 
chloroform. The, organic layer was dried over anhydrous magnesium sulfate 
and evaporated to give 41.3 g of the title compound. 
.sup.1 H NMR(CDCl.sub.3, .delta. ppm): 1.80(1H, s), 2.47-2.60(6H, m), 
2.90-2.94(4H, m), 3.36(3H, s), 3.52(2H, t) 
(8) Preparation of 
1-(4-chlorophenyl)-3-(4-(2-methoxyethyl)piperazin-1-yl)methyl-2-pyrrolidin 
one 
Triethylamine (8.0 g) was added to a solution of 18.5 g of 
1-(4-chlorophenyl)-3-mesyloxymethyl-2-pyrrolidinone and 17.6 g of 
1-(2-methoxyethyl)piperazine in 50 mL of acetonitrile, and the mixture was 
heated under reflux for 4 hours. After concentrating, water was added to 
the reaction mixture to precipitate crystals, which were then collected by 
filtration and dried in vacuo to give 18.5 g of the title compound. 
Melting point: 103-105.degree. C.; .sup.1 H NMR(CDCl.sub.3, .delta. ppm): 
2.01-2.12 (1H, m), 2.29-2.62 (12H, m), 2.78-2.94(2H, m), 3.35(3H, s), 
3.51(2H, t), 3.74-3.80(2H, m), 7.32(2H, d), 7.59(2H, d) 
Preparation Example 2 
Preparation of 
1-(4-chlorophenyl)-3-(4-(2-methoxyethyl)piperazin-1-yl)methyl-2-pyrrolidin 
one dihydrochloride(Table 2; Compound No. 50; racemic modification) 
A solution of 1.41 g of 
1-(4-chlorophenyl)-3-(4-(2-methoxyethyl)piperazin-1-yl)methyl-2-pyrrolidin 
one in 10 mL of methanol was acidified by adding 4N hydrochloric 
acid/1,4-dioxane. The precipitated crystals were collected by filtration, 
washed with diethyl ether and dried in vacuo to give 1.62 g of the title 
compound. 
Melting point: 261-262.degree. C.; .sup.1 H NMR(DMSO, .delta. 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) 
Preparation Example 3 
Preparation of 
1-(4-chlorophenyl)-3-(4-(2-hydroxyethyl)piperazin-1-yl)methyl-2-pyrrolidin 
one(Table 1; Compound No. 145; racemic modification) 
The title compound was prepared from 
1-(4-chlorophenyl)-3-mesyloxymethyl-2-pyrrolidinone and 
1-hydroxyethylpiperazine, in the same manner as in Preparation Example 
1(8). 
Melting point: 130-131.degree. C.; .sup.1 H NMR(CDCl.sub.3, .delta. ppm): 
2.01-2.13(1H, m), 2.30-2.93(14H, m), 3.61(2H, t), 3.75-3.80(2H, m), 
7.29-7.35(2H, m), 7.56-7.62(2H, m) 
Preparation Example 4 
Preparation of 
1-(4-chlorophenyl)-3-(4-(2-hydroxyethyl)piperazin-1-yl)methyl-2-pyrrolidin 
one dihydrochloride(Table 2; Compound NO. 49; racemic modification) 
The title compound was prepared in the same manner as in Preparation 
Example 2. 
Melting point: 269.6-271.3.degree. C.; .sup.1 H NMR(D.sub.2 O, .delta. 
ppm): 2.03-2.15(1H, m), 2.50-2.60(1H, m), 3.37-3.59(4H, m), 3.69-4.04(13H, 
m), 7.48(4H, s) 
Preparation Example 5 
Preparation of 
1-(4-chlorophenyl)-3-(4-(3-hydroxypropyl)piperazin-1-yl)methyl-2-pyrrolidi 
none(Table 1; Compound No. 157; racemic modification) 
(1) Preparation of 1-(3-hydroxypropyl)piperazine 
The title compound was prepared from formylpiperazine and 
3-bromo-1-propanol in the same manner as in Preparation Example 1(5) to 
(7). 
.sup.1 H NMR(CDCl.sub.3, .delta. ppm): 1.67-1.84(2H, m), 2.32-2.52(2H, m), 
2.59-2.67(4H, m), 2.88-2.94(4H, m), 3.77-3.82(2H, 
(2) Preparation of 
1-(4-chlorophenyl)-3-(4-(3-hydroxypropyl)piperazin-1-yl)methyl-2-pyrrolidi 
none 
The title compound was prepared from 
1-(4-chlorophenyl)-3-mesyloxymethyl-2-pyrrolidinone and 
1-hydroxypropylpiperazine, in the same manner as in Preparation Example 
1(8). 
.sup.1 H NMR(CDCl.sub.3, .delta. ppm): 1.66-1.86(2H, m), 1.92-2.14(1H, m), 
2.29-2.41(1H, m), 2.43-2.66(11H, m), 2.76-2.96(2H,m), 3.75-3.82(4H, m), 
7.32(2H, d), 7.59(2H, d) 
Preparation Example 6 
Preparation of 
1-(4-chlorophenyl)-3-(4-(3-hydroxypropyl)piperazin-1-yl)methyl-2-pyrrolidi 
none dihydrochloride(Table 2; Compound No 61; racemic modification) 
The title compound was prepared in the same manner as in Preparation 
Example 2. 
Melting point: 263.8-264.2.degree. C.; .sup.1 H NMR(D.sub.2 O, .delta. 
ppm): 1.98-2.14(3H, m), 2.48-2.60(1H, m), 3.32-4.04(17H, m), 7.48(4H, s) 
Preparation Example 7 
Preparation of 
1-(4-chlorophenyl)-3-(4-(2-ethoxyethyl)piperazin-1-yl)methyl-2-pyrrolidino 
ne(Table 1; Compound No. 147; racemic modification) 
(1) Preparation of 1-(2-ethoxyethyl)piperazine 
The title compound was prepared from formylpiperazine and 2-bromoethyl 
ethyl ether in the same manner as in Preparation Example 1(5) to (7). 
.sup.1 H NMR(CDCl.sub.3, .delta. ppm): 1.19(3H, t), 2.46-2.49(2H, m), 
2.55-2.61(4H, m), 2.88-2.92(4H, m), 3.45-3.59(4H, m) 
(2) Preparation of 
1-(4-chlorophenyl)-3-(4-(2-ethoxyethyl)piperazin-1-yl)methyl-2-pyrrolidino 
ne 
The title compound was prepared from 
1-(4-chlorophenyl)-3-mesyloxymethyl-2-pyrrolidinone and 
1-ethoxyethylpiperazine, in the same manner as in Preparation Example 
1(8). 
.sup.1 H NMR(CDCl.sub.3, .delta. ppm): 1.20(3H, t), 1.98-2.16(1H, m), 
2.29-2.41(1H, m), 2.49-2.61(11H, m), 2.77-2.93(2H, m), 3.46-3.58(4H, m), 
3.74-3.80(2H, m), 7.32(2H, d), 7.59(2H, d) 
Preparation Example 8 
Preparation of 
1-(4-chlorophenyl)-3-(4-(2-ethoxyethyl)piperazin-1-yl)methyl-2-pyrrolidino 
ne dihydrochloride(Table 2; Compound No. 51; racemic modification) 
The title compound was prepared in the same manner as in Preparation 
Example 2. 
Melting point: 261.0-261.4.degree. C.; .sup.1 H NMR(D.sub.2 O, .delta. 
ppm): 1.21(3H, t), 1.99-2.15(1H, m), 2.50-2.61(1H, m), 3.34-3.46(1H, m), 
3.53-4.13(18H, m), 7.48(4H, s) 
Preparation Example 9 
Preparation of 
1-(4-chlorophenyl)-3-(4-(2-(2-propynyloxy)ethyl)piperazin-1-yl)methyl-2-Py 
rrolidinone(Table 1; Compound No. 156; racemic modification) 
(1) Preparation of 1-tert-butoxycarbonyl-4-(2-hydroxyethyl)piperazine 
To a solution of 10.00 g of 1-(2-hydroxyethyl)piperazine in 70 mL of 
dioxane at room temperature was added dropwise a solution of 16.43 g of 
di-tert-butyl dicarbonate in 30 mL of 1,4-dioxane with stirring. After 
completion of the reaction, the mixture was concentrated and n-hexane was 
added to the residue. The solid was collected by filtration and dried to 
give 14.11 g of the title compound. 
(2) Preparation of 1-tert-butoxycarbonyl-4-(2-(2-propynyl)ethyl)piperazine 
To a refluxing solution of 1.67 g of sodium hydride in 20 mL of 
tetrahydrofuran was added dropwise a solution of 9.00 g of 
1-tert-butoxycarbonyl-4-(2-hydroxyethyl)piperazine in 15 mL of 
tetrahydrofuran and then 5.63 g of propargyl bromide was added dropwise to 
the resultant mixture. After completion of the reaction, the mixture was 
concentrated, poured into ice-water, and the mixture was extracted with 
ethyl acetate. The organic layer was dried over anhydrous magnesium 
sulfate and evaporated to give 10.70 g of the title compound. 
(3) Preparation of 1-(2-(2-propynyloxy)ethyl)piperazine dihydrochloride 
To a solution of 10.70 g of 
1-tert-butoxycarbonyl-4-(2-(2-propynyl)ethyl)piperazine in 1,4-dioxane was 
added 4N hydrochloric acid/1,4-dioxane, and the mixture was stirred at 
60.degree. C. After completion of the reaction, the mixture was 
concentrated and diethyl ether was added. The solid was collected by 
filtration and dried to give 11.83 g of the title compound. 
(4) Preparation of 1-(2-(2-propynyloxy)ethyl)piperazine 
To an aqueous solution of 11.83 g of 1-(2-(2-propynyloxy)ethyl)piperazine 
dihydrochloride (water: 10 mL) was added aqueous sodium hydroxide 
solution, and the mixture was extracted with ethyl acetate. The organic 
layer was dried over anhydrous magnesium sulfate and evaporated to give 
3.09 g of the title compound. 
.sup.1 H NMR(CDCl.sub.3, .delta. ppm), 2.42(1H, t), 2.41-2.49(2H, m), 
2.60(4H, t), 2.91(4H, t), 3.67(2H, t), 4.18(2H, d) 
(5) Preparation of 
1-(4-chlorophenyl)-3-(4-(2-(2-propynyloxy)ethyl)piperazin-1-yl)methyl-2-py 
rrolidinone 
The title compound was prepared from 
1-(4-chlorophenyl)-3-mesyloxymethyl-2-pyrrolidinone and 
1-(2-(2-propynyloxy)ethyl)piperazine, in the same manner as in Preparation 
Example 1(8). 
.sup.1 H NMR(CDCl.sub.3, .delta. ppm): 1.94-2.12(1H, m), 2.29-2.39(1H, m), 
2.42(1H, t), 2.53-2.74(11H, m), 2.78-2.94(2H, m), 3.65-3.71(2H, m), 
3.74-3.80(2H, m), 4.18(2H, d), 7.32(2H, d), 7.59(2H, d) 
Preparation Example 10 
Preparation of 
1-(4-chlorophenyl)-3-(4-(2-(2-propynyloxy)ethyl)piperazin-1-yl)methyl-2-py 
rrolidinonedihydrochloride(Table 2; Compound No.60; racemic modification) 
The title compound was prepared in the same manner as in Preparation 
Example 2. 
Melting point: 246.2-247.0.degree. C.; .sup.1 H NMR(D.sub.2 O, .delta. 
ppm): 1.99-2.14(1H, m), 2.48-2.60(1H, m), 2.95(1H, t), 3.32-3.49(1H, m), 
3.51-4.23 (16H, m), 4.29(2H, d), 7.48(4H, s) 
Preparation Example 11 
Preparation of 1-(4-chlorophenyl)-3-(4-(3-methoxypropyl 
)piperazin-1-yl)methyl-2-pyrrolidinone(Table 1; Compound No. 158; racemic 
modification) 
(1) Preparation of 1-(3-methoxypropyl)piperazine 
The title compound was prepared from 1-piperazinepropanol in the same 
manner as in Preparation Example 9(1) to (4). 
.sup.1 H NMR(CDCl.sub.3, .delta. ppm): 1.72-1.82(2H, m), 2.37-2.43(6H, m), 
2.89(4H, t), 3.33(3H, s), 3.42(2H, t) 
(2) Preparation of 
1-(4-chlorophenyl)-3-(4-(3-methoxypropyl)piperazin-1-yl)methyl-2-pyrrolidi 
none 
The title compound was prepared from 
1-(4-chlorophenyl)-3-mesyloxymethyl-2-pyrrolidinone and 
1-(3-methoxypropyl)piperazine, in the same manner as in Preparation 
Example 1(8). 
.sup.1 H NMR(CDCl.sub.3, .delta. ppm): 1.71-1.82(2H, m), 2.01-2.12(1H, m), 
2.29-2.73(12H, m) 2.78-2.93(2H, m), 3.33(3H, s), 3.42(2H, t), 
3.74-3.82(2H, m), 7.32(2H, d), 7.59(2H, d) 
Preparation Example 12 
Preparation of 
1-(4-chlorophenyl)-3-(4-(3-methoxypropyl)piperazin-1-yl)methyl-2-pyrrolidi 
none dihydrochloride(Table 2; Compound No. 62; racemic modification) 
The title compound was prepared in the same manner as in Preparation 
Example 2. 
Melting point: 264.1-265.0.degree. C.; .sup.1 H NMR(D.sub.2 O, .delta. 
ppm): 2.02-2.14(3H, m), 2.49-2.60(1H, m), 3.37(3H, s), 3.32-4.04(17H, m), 
7.48(4H, s) 
Preparation Example 13 
Preparation of 
1-(3-chlorophenyl)-3-(4-(2-methoxyethyl)piperazin-1-yl)methyl-2-pyrrolidin 
one(Table 1; Compound No. 122; racemic modification) 
(1) Preparation of 1-(3-chlorophenyl)-3-mesyloxymethyl-2-pyrrolidinone 
The title compound was prepared from m-chloroaniline and 
.gamma.-butyrolactone in the same manner as in Preparation Example 1(1) to 
(4). 
.sup.1 H NMR(CDCl.sub.3, .delta. ppm): 2.17-2.32(1H, m), 2.36-2.48(1H, m), 
2.99-3.08(1H, m), 3.06(3H, s), 3.82-3.87(2H, m), 4.48-4.52(1H, m), 
4.58-4.63(1H, m), 7.10-7.13(1H, m), 7.20-7.34(1H, m), 7.50-7.54(1H, m), 
7.69-7.70(1H, m) 
(2) Preparation of 
1-(3-chlorophenyl)-3-(4-(2-methoxyethyl)piperazin-1-yl)methyl-2-pyrrolidin 
one 
The title compound was prepared from 
1-(3-chlorophenyl)-3-mesyloxymethyl-2-pyrrolidinone and 
1-(2-methoxyethyl)piperazine, in the same manner as in Preparation Example 
1(8). 
.sup.1 H NMR(CDCl.sub.3, .delta. ppm): 1.98-2.25(1H, m), 2.30-2.42(1H, m), 
2.53-2.65(11H, m), 2.78-2.94(2H, m), 3.35(3H, s), 3.49-3.54(2H, m), 
3.71-3.84(2H, m), 7.10-7.13(1H, m), 7.25-7.31(1H, m), 7.54-7.58(1H, m), 
7.67-7.69(1H, m) 
Preparation Example 14 
Preparation of 
1-(3-chlorophenyl)-3-(4-(2-methoxyethyl)piperazin-1-yl)methyl-2-pyrrolidin 
one dihydrochloride(Table 2; Compound No. 2; racemic modification) 
The title compound was prepared in the same manner as in Preparation 
Example 2. 
Melting point: 227.6-228.1.degree. C.; .sup.1 H NMR(D.sub.2 O, .delta. 
ppm): 2.02-2.14(1H, m), 2.49-2.60(1H, m), 3.33-3.46(1H, m), 3.42(3H, s), 
3.49-3.57(3H, m), 3.67-4.04(13H, m), 7.32-7.38(1H, m), 7.41-7.48(2H, m), 
7.61(1H, s) 
Preparation Example 15 
Preparation of 
1-(4-bromophenyl)-3-(4-(2-methoxyethyl)piperazin-1-yl)methyl-2-pyrrolidino 
ne(Table 1; Compound No. 218; racemic modification) 
(1) Preparation of 1-(4-bromophenyl)-3-mesyloxymethyl-2-pyrrolidinone 
The title compound was prepared from p-bromoaniline and 
.gamma.-butyrolactone in the same manner as in Preparation Example 1(1) to 
(4). 
Melting point: 120-123.degree. C. 
(2) Preparation of 
1-(4-bromophenyl)-3-(4-(2-methoxyethyl)piperazin-1-yl)methyl-2-pyrrolidino 
ne 
The title compound was prepared from 
1-(4-bromophenyl)-3-mesyloxymethyl-2-pyrrolidinone and 
1-(2-methoxyethyl)piperazine, in the same manner as in Preparation Example 
1(8). 
.sup.1 H NMR(CDCl.sub.3, .delta. ppm): 1.98-2.12(1H, m), 2.29-2.41(1H, m), 
2.53-2.63(11H, m), 2.78-2.94(2H, m), 3.35(3H, s), 3.51(2H, t), 
3.74-3.82(2H, m), 7.46(2H, d), 7.54(2H, d) 
Preparation Example 16 
Preparation of 
1-(4-bromophenyl)-3-(4-(2-methoxyethyl)piperazin-1-yl)methyl-2-pyrrolidino 
ne dihydrochloride(Table 2; Compound No. 146; racemic modification) 
The title compound was prepared in the same manner as in Preparation 
Example 2. 
Melting point: 272.1-272.6.degree. C.; .sup.1 H NMR(DMSO, .delta. ppm): 
1.99-2.07(1H, m), 3.05-3.84(18H, m), 3.31(3H, s), 7.58(2H, d), 7.66(2H, d) 
Preparation Example 17 
Preparation of 
1-(3-bromophenyl)-3-(4-(2-methoxyethyl)piperazin-1-yl)methyl-2-pyrrolidino 
ne(Table 1; Compound No. 194; racemic modification) 
(1) Preparation of 1-(3-bromophenyl)-3-mesyloxymethyl-2-pyrrolidinone 
The title compound was prepared from m-bromoaniline and 
.gamma.-butyrolactone in the same manner as in Preparation Example 1(1) to 
(4). 
.sup.1 H NMR(CDCl.sub.3, .delta. ppm): 2.21-2.39(1H, m), 2.41-2.48(1H, m), 
2.83-3.06(1H, m), 3.07(3H, s), 3.82-3.87(2H, m), 4.48-4.53(1H, m), 
4.58-4.64(1H, m), 7.22-7.33(2H, m), 7.57-7.61(1H, m), 7.82-7.84(1H, m) 
(2) Preparation of 
1-(3-bromophenyl)-3-(4-(2-methoxyethyl)piperazin-1-yl)methyl-2-pyrrolidino 
ne 
The title compound was prepared from 
1-(3-bromophenyl)-3-mesyloxymethyl-2-pyrrolidinone and 
1-(2-methoxyethyl)piperazine, in the same manner as in Preparation Example 
1(8). 
.sup.1 H NMR(CDCl.sub.3, .delta. ppm): 2.01-2.12(1H, m), 2.34-2.60(12H, m), 
2.78-2.94(2H, m), 3.35(3H, s), 3.48-3.53(2H, m), 3.74-3.80(2H, m), 
7.19-7.28(2H, m), 7.59-7.64(1H, m), 7.81(1H, d) 
Preparation Example 18 
Preparation of 
1-(3-bromophenyl)-3-(4-(2-methoxyethyl)piperazin-1-yl)methyl-2-pyrrolidino 
ne dihydrochloride(Table 2; Compound No. 98; racemic modification) 
The title compound was prepared in the same manner as in Preparation 
Example 2. 
Melting point: 237.8-238.8.degree. C.; .sup.1 H NMR(DMSO, .delta. ppm): 
2.04(1H, m), 3.31(3H, s), 3.31-3.86(18H, m), 7.36-7.37(2H, m), 
7.60-7.62(1H, m), 8.00(1H, s) 
Preparation Example 19 
Preparation of 
(R)-1-(4-chlorophenyl)-3-(4-(2-methoxyethyl)piperazin-1-yl)methyl-2-pyrrol 
idinone (R)-(-)-mandelate (Table 3; Compound No. 148; (R)-isomer) 
To a hot solution of 66.6 g of 
1-(4-chlorophenyl)-3-(4-(2-methoxyethyl)piperazin-1-yl)methyl-2-pyrrolidin 
one in 350 mL of ethyl acetate was added a hot solution of (R)-(-)-mandelic 
acid in 120 mL of ethyl acetate. After cooling, the precipitated crystals 
were filtered, washed with ethyl acetate and dried in vacuo to give 36.4 g 
of the title compound. 
Melting point: 137-138.degree. C.; 
Enantiomer excess: at least 99% ee(calculated from the HPLC area ratio) 
The enantiomer excess was calculated from the peak areas determined by 
liquid chromatography using a chiral column. The values hereinafter were 
determined in a similar manner. 
.sup.1 H NMR(DMSO, .delta. ppm): 1.83-1.97(1H, m), 2.19-2.97(14H, m), 
3.23(3H, s), 3.41-3.48(2H, 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) 
Preparation Example 20 
Preparation of 
(R)-1-(4-chlorophenyl)-3-(4-(2-methoxyethyl)piperazin-1-yl)methyl-2-pyrrol 
idinone (Table 1; Compound No. 146: (R)-isomer) 
(R)-1-(4-chlorophenyl)-3-(4-(2-methoxyethyl)piperazin-1-yl)methyl-2-pyrroli 
dinone (R)-(-)-mandelate (30.5 g) recrystallized from 100 mL of ethanol was 
dissolved in 300 mL of water, and the solution was desalted with sodium 
carbonate and extracted with ethyl acetate. The organic layer was dried 
over anhydrous magnesium sulfate and concentrated to give 19.5 g of the 
title compound. 
Melting point: 102-103.degree. C.; Optical rotation:+; Enantiomer excess: 
at least 99% ee; .sup.1 H NMR(CDCl.sub.3, .delta. ppm): 2.04(1H, m), 
2.35(1H, m), 2.4-2.7(11H, 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) 
The title compound could be also synthesized by the following procedure: 
A solution of L-tartaric acid (150 mg) in ethanol (1.5 ml) was added to 
1-(4-chlorophenyl)-3-(4-(2-methoxyethyl)piperazin-1-yl)methyl-2-pyrrolidin 
one (351 mg) in ethanol (6 ml). The solid material thus precipitated was 
collected and subjected to desalting in an aqueous solution of sodium 
carbonate to obtain the title compound. 
Enantiomer exess: 25% ee 
Preparation Example 21 
Preparation of 
(R)-1-(4-chlorophenyl)-3-(4-(2-methoxyethyl)piperazin-1-yl)methyl-2-pyrrol 
idinone dihydrochloride(Table 2; Compound No. 50; (R)-isomer) 
A solution of 18.7 g of 
(R)-1-(4-chlorophenyl)-3-(4-(2-methoxyethyl)piperazin-1-yl)methyl-2-pyrrol 
idinone in 130 mL of methanol was acidified with 4N hydrochloric 
acid/1,4-dioxane. The precipitated crystals were filtered, washed with 
diethyl ether and dried in vacuo to give 22.6 g of the title compound. 
Melting point: 252-253.degree. C. (decomposed); Optical rotation:-; 
Enantiomer excess: at least 99% ee; .sup.1 H NMR(D.sub.2 O, .delta. ppm): 
2.06(1H, m), 2.52(1H, m), 3.41(3H, s), 3.32-4.03(17H, m), 7.48(4H, s) 
Preparation Example 22 
Preparation of 
(S)-1-(4-chlorophenyl)-3-(4-(2-methoxyethyl)piperazin-1-yl)methyl-2-pyrrol 
idinone (S)-(+)-mandelate(Table 3; Compound No. 156; (S)-isomer) 
Under heating, 152 mg of (S)-(+)-mandelic acid was added to a solution of 
352 mg of 
1-(4-chlorophenyl)-3-(4-(2-methoxyethyl)piperazin-1-yl)methyl-2-pyrrolidin 
one in 3 mL of ethyl acetate. After cooling, the precipitated crystals were 
filtered and dried in vacuo to give 180 mg of the title compound. 
.sup.1 H NMR (DMSO, .delta. ppm): 1.83-1.97(1H, m), 2.19-2.97(14H, m), 
3.23(3H, s), 3.41-3.48(2H, 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) 
Preparation Example 23 
Preparation of 
(S)-1-(4-chlorophenyl)-3-(4-(2-methoxyethyl)piperazin-1-yl)methyl-2-pyrrol 
idinone (Table 1; Compound No. 146; (S)-isomer) 
Into 2 mL of water was dissolved 180 mg of 
(S)-1-(4-chlorophenyl)-3-(4-(2-methoxyethyl)piperazin-1-yl)methyl-2-pyrrol 
idinone (S)-(+)-mandelate, and the solution was desalted with sodium 
carbonate and extracted with ethyl acetate. The organic layer was dried 
over anhydrous magnesium sulfate and concentrated to give 120 mg of the 
title compound. 
Melting point: 105-106.degree. C.; Optical rotation:-; Enantiomer excess: 
at least 92% ee; .sup.1 H NMR(CDCl.sub.3, .delta. ppm): 2.01-2.12(1H, m), 
2.30-2.63(12H, m), 2;78-2.94(2H, m), 3.35(3H, s), 3.51(2H, t), 
3.74-3.80(2H, m), 7.30-7.35(2H, m), 7.56-7.62(2H, m) 
Preparation Example 24 
Preparation of 
(S)-1-(4-chlorophenyl)-3-(4-(2-methoxyethyl)piperazin-1-yl)methyl-2-pyrrol 
idinone dihydrochloride(Table 2; Compound No. 50; (S)-isomer) 
A solution of 1.0 g of 
(S)-1-(4-chlorophenyl)-3-(4-(2-methoxyethyl)piperazin-1-yl)methyl-2-pyrrol 
idinone in 50 mL of ethanol was acidified with 4N hydrochloric 
acid/1,4-dioxane. The precipitated crystals were filtered, washed with 
diethyl ether and dried in vacuo to give 1.18 g of the title compound. 
Melting point: 258.degree. C. (decomposed); Optical rotation:+; Enantiomer 
excess: at least 99% ee; .sup.1 H NMR(D.sub.2 O, .delta. ppm): 2.06(1H, 
m), 2.52(1H, m), 3.41(3H, s), 3.32-4.03(17H, m), 7.48(4H, s) 
Preparation Example 25 
Preparation of 
(R)-1-(4-chlorophenyl)-3-(4-(2-methoxyethyl)piperazin-1-yl)methyl-2-pyrrol 
idinone dihydrochloride dihydrate(Table 2; Compound No. 74; (R)-isomer) 
(R)-1-(4-chlorophenyl)-3-(4-(2-methoxyethyl)piperazin-1-yl)methyl-2-pyrroli 
dinone dihydrochloride (1.98 g) was placed in an incubator kept at 
25.degree. C. under a relative humidity of 75% for 24 hours to give 2.14 g 
of the title compound. 
Melting point: 264.6-265.1.degree. C. (decomposed) Optical rotation:-; 
Enantiomer excess: at least 99% ee; .sup.1 H NMR(D.sub.2 O, .delta. ppm): 
2.06(1H, m), 2.52(1H, m), 3.41(3H, s), 3.32-4.03(17H, m), 7.48(4H, s) 
Alternatively, the compound may be prepared as follows. 
Under reflux, water was added dropwise to a suspension of 100 mg of 
(R)-1-(4-chlorophenyl)-3-(4-(2-methoxyethyl)piperazin-1-yl)methyl-2-pyrrol 
idinone dihydrochloride in 3 mL of ethanol until the reaction system became 
homogeneous. After cooling to room temperature, the precipitated solid was 
filtered and dried to give 88.5 mg of the title compound. 
Preparation Example 26 
Preparation of 
(R)-1-(4-chlorophenyl)-3-(4-(2-methoxyethyl)piperazin-1-yl)methyl-2-pyrrol 
idinone dihydrobromide(Table 3; Compound No. 11; (R)-isomer) 
To a mixture of 379 mg of 47% hydrobromic acid aq. and 10 mL of ethanol was 
added a solution of 352 mg of 
(R)-1-(4-chlorophenyl)-3-(4-(2-methoxyethyl)piperazin-1-yl)methyl-2-pyrrol 
idinone in 10 mL of ethanol. The mixture was stirred at room temperature 
and then cooled. The precipitated solid was filtered and dried to give 488 
mg of the title compound. 
Melting point: 244.1-245.1.degree. C.; .sup.1 H NMR(DMSO, .delta. 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) 
Preparation Example 27 
Preparation of 
(R)-1-(4-chlorophenyl)-3-(4-(2-methoxyethyl)piperazin-1-yl)methyl-2-pyrrol 
idinone sulfate monohydrate(Table 3; Compound No. 32; (R)-isomer) 
A solution of 101 mg of conc. sulfuric acid in 5 mL of ethanol was added to 
a solution of 352 mg of 
(R)-1-(4-chlorophenyl)-3-(4-(2-methoxyethyl)piperazin-1-yl)methyl-2-pyrrol 
idinone in 10 mL of ethanol. The mixture was stirred at room temperature 
and then concentrated to 3 mL. To the mixture was added 5 mL of ethyl 
acetate. The precipitated solid was filtered and dried to give 389 mg of 
the title compound. 
Melting point: 166.4-166.7.degree. C.; .sup.1 H NMR (DMSO, .delta. ppm): 
1.84-1.99(1H, m), 2.15-4.35(21H, m), 7.44(2H, d), 7.71(2H, d) 
Preparation Example 28 
Preparation of 
(R)-1-(4-chlorophenyl)-3-(4-(2-methoxyethyl)piperazin-1-yl)methyl-2-pyrrol 
idinone benzenesulfonate monohydrate(Table 3; Compound No.132; (R)-isomer) 
To a solution of 176 mg of benzenesulfonic acid monohydrate in 10 mL of 
ethanol was added a solution of 352 mg of 
(R)-1-(4-chlorophenyl)-3-(4-(2-methoxyethyl)piperazin-1-yl)methyl-2-pyrrol 
idinone in 10 mL of ethanol. The mixture was concentrated. The residue was 
sludged with ethanol. The solid formed was filtered and dried to give 407 
mg of the title compound. 
Melting point: 82.2-85.9.degree. C.; .sup.1 H NMR (DMSO, .delta. ppm): 
1.88-1.99(1H, m), 2.31-3.81(21H, m), 7.31-7.36(3H, m), 7.43(2H, d), 
7.59-7.68(2H, m), 7.69-7.72(2H, m) 
Preparation Example 29 
Preparation of 
(R)-1-(4-chlorophenyl)-3-(4-(2-methoxyethyl)piperazin-1-yl)methyl-2-pyrrol 
idinone dibenzenesulfonate 3.5 hydrate(Table 3; Compound No. 139; 
(R)-isomer) 
To a solution of 352 mg of benzenesulfonic acid monohydrate in 10 mL of 
ethyl acetate was added a solution of 352 mg of 
(R)-1-(4-chlorophenyl)-3-(4-(2-methoxyethyl)piperazin-1-yl)methyl-2-pyrrol 
idinone in 10 mL of ethyl acetate. The mixture was stirred at room 
temperature and cooled. The precipitated solid was filtered and dried to 
give 585 mg of the title compound. 
Melting point: 162.5-163.4.degree. C.; .sup.1 H NMR(DMSO, .delta. ppm): 
1.78-1.97(1H, m), 2.18-3.84(21H, 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) 
Preparation Example 30 
Preparation of 
(R)-1-(4-chlorophenyl)-3-(4-(2-methoxyethyl)piperazin-1-yl)methyl-2-pyrrol 
idinone di-p-toluenesulfonate dihydrate(Table 2; Compound No. 129; 
(R)-isomer) 
To a solution of 380 mg of p-toluenesulfonic acid monohydrate in 10 mL of 
ethyl acetate was added a solution of 352 mg of 
(R)-1-(4-chlorophenyl)-3-(4-(2-methoxyethyl)piperazin-1-yl)methyl-2-pyrrol 
idinone in 10 mL of ethyl acetate. The mixture was stirred at room 
temperature and cooled. The precipitated solid was filtered and dried to 
give 712 mg of the title compound. 
Melting point: 209.8-210.3.degree. C.; .sup.1 H NMR(DMSO, .delta. 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) 
Preparation Example 31 
Preparation of 
(R)-1-(4-chlorophenyl)-3-(4-(2-methoxyethyl)piperazin-1-yl)methyl-2-pyrrol 
idinone methanesulfonate(Table 3; Compound No. 107; (R)-isomer) 
A solution of 240 mg of methanesulfonic acid in 5 mL of ethyl acetate was 
added to a solution of 880 mg of 
(R)-1-(4-chlorophenyl)-3-(4-(2-methoxyethyl)piperazin-1-yl)methyl-2-pyrrol 
idinone in 15 mL of ethyl acetate. The mixture was stirred at room 
temperature and cooled. The precipitated solid was filtered and dried to 
give 892 mg of the title compound. 
.sup.1 H NMR(D.sub.2 O, .delta. 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(2H, m), 
3.81-3.97(2H, m), 7.46(4H, s) 
Preparation Example 32 
Preparation of 
(R)-1-(4-chlorophenyl)-3-(4-(2-methoxyethyl)piperazin-1-yl)methyl-2-pyrrol 
idinone dimethanesulfonate(Table 3; Compound No. 111; (R)-isomer) 
A solution of 480 mg of methanesulfonic acid in 5 mL of ethyl acetate was 
added to a solution of 880 mg of 
(R)-1-(4-chlorophenyl)-3-(4-(2-methoxyethyl)piperazin-1-yl)methyl-2-pyrrol 
idinone in 15 mL of ethyl acetate. The mixture was stirred at room 
temperature and cooled. The precipitated solid was filtered and dried to 
give 1127 mg of the title compound. 
.sup.1 H NMR(D.sub.2 O, .delta. 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) 
Preparation Example 33 
Preparation of 
(R)-1-(4-chlorophenyl)-3-(4-(2-methoxyethyl)piperazin-1-yl)methyl-2-pyrrol 
idinone L-lactate(Table 3; Compound No. 140; (R)-isomer) 
A mixture of 106 mg of 85% L-lactic acid aq. and 10 mL of ethyl acetate was 
added to a solution of 352 mg of 
(R)-1-(4-chlorophenyl)-3-(4-(2-methoxyethyl)piperazin-1-yl)methyl-2-pyrrol 
idinone in 10 mL of ethyl acetate. The mixture was stirred at room 
temperature and then concentrated. The residue was sludged with diethyl 
ether and dried to give 180 mg of the title compound. 
.sup.1 H NMR(DMSO, .delta. ppm): 1.23(3H, d), 1.80-2.00(1H, m), 
2.15-4.10(23H, m), 7.43(2H, d), 7.70(2H, d) 
Preparation Example 34 
Preparation of 
(R)-1-(4-chlorophenyl)-3-(4-(2-methoxyethyl)piperazin-1-yl)methyl-2-pyrrol 
idinone L-tartrate(Table 3; Compound No. 180; (R)-isomer) 
To a solution of 150 mg of L-tartaric acid in 10 mL of ethanol was added a 
solution of 352 mg of 
(R)-1-(4-chlorophenyl)-3-(4-(2-methoxyethyl)piperazin-1-yl)methyl-2-pyrrol 
idinone in 10 mL of ethyl acetate. The mixture was stirred at room 
temperature and cooled. The precipitated solid was filtered and dried to 
give 488 mg of the title compound. 
Melting point: 183.2-184.9.degree. C.; .sup.1 H NMR(DMSO, .delta. ppm): 
1.82-1.94(1H, m), 2.21-3.79(21H, m), 4.17(2H, s), 7.40-7.46(2H, m), 
7.67-7.73(2H, m) 
Alternatively, the compound may be prepared as follows. 
Into 62 mL of 18% water-ethanol were suspended 5.00 g of 
(R)-1-(4-chlorophenyl)-3-(4-(2-methoxyethyl)piperazin-1-yl)methyl-2-pyrrol 
idinone and 2.13 g of L-tartaric acid. After making it homogeneous by 
heating under reflux, the solution was cooled. The precipitated solid was 
filtered and dried to give 6.39 g of the title compound. 
Preparation Example 35 
Preparation of 
(R)-1-(4-chlorophenyl)-3-(4-(2methoxyethyl)piperazin-1-yl)methyl-2-pyrroli 
dinone di-L-tartrate dihydrate(Table 3; Compound No. 186; (R)-isomer) 
To a solution of 300 mg of L-tartaric acid in 20 mL of ethanol was added a 
solution of 352 mg of 
(R)-1-(4-chlorophenyl)-3-(4-(2-methoxyethyl)piperazin-1-yl)methyl-2-pyrrol 
idinone in 10 mL of ethanol. The mixture was stirred at room temperature 
and cooled. The precipitated solid was filtered and dried to give 205 mg 
of the title compound. 
.sup.1 H NMR(DMSO, .delta. ppm): 1.87-1.98 (1H, m), 2.25-2.89 (14H, m), 
3.25(3H, s), 3.41-3.51(2H, m), 3.74-3.80(2H, m), 4.21(4H, s), 7.42(2H, 
dd), 7.70(2H, dd) 
Preparation Example 36 
Preparation of 
(R)-1-(4-chlorophenyl)-3-(4-(2-methoxyethyl)piperazin-1-yl)methyl-2-pyrrol 
idinone di-D-tartrate(Table 3; Compound No. 192; (R)-isomer) 
A solution of 75 mg of D-tartaric acid in 3 mL of ethanol was added to a 
solution of 176 mg of 
(R)-1-(4-chlorophenyl)-3-(4-(2-methoxyethyl)piperazin-1-yl)methyl-2-pyrrol 
idinone in 3 mL of ethanol. The mixture was stirred at room temperature and 
cooled. The precipitated solid was filtered and dried to give 110 mg of 
the title compound. 
.sup.1 H NMR(DMSO, .delta. ppm): 1.86-1.94(1H, m), 2.25-3.00(14H, m), 
3.25(3H, s), 3.47-3.51(2H, m), 3.74-3.80(2H, m), 4.22(2H, s), 7.43(2H, d), 
7.70(2H, d) 
The title compound could be also synthesized by the following procedure: 
A solution of D-tartaric acid (450 mg) in ethanol (6 ml) was added dropwise 
at an outer temperature between 50 and 60.degree. C. to a solution of 
1-(4-chlorophenyl)-3-(4-(2-methoxyethyl)piperazin-1-yl)methyl-2-pyrrolidin 
one (1056mg) in ethanol (6ml). The reaction mixture was allowed to stand 
for cooling and the solid material thus precipitated was collected by 
filtration. The solid material was further crystallized in 10 ml of 
ethanol to obtain 372 mg of the title compound. Enantiomer excess: 97% ee 
Preparation Example 37 
Preparation of 
(R)-1-(4-chlorophenyl)-3-(4-(2-methoxyethyl)piperazin-1-yl)methyl-2-pyrrol 
idinone disuccinate(Table 3; Compound No. 75; (R)-isomer) 
A solution of 591 mg of succinic acid in 20 mL of ethanol was added to a 
solution of 880 mg of 
(R)-1-(4-chlorophenyl)-3-(4-(2-methoxyethyl)piperazin-1-yl)methyl-2-pyrrol 
idinone in 20 mL of ethanol. The mixture was stirred at room temperature 
and cooled. The precipitated solid was filtered and dried to give 356 mg 
of the title compound. 
Melting point: 98.1-99.1.degree. C.; .sup.1 H NMR(DMSO, .delta. 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(2H, d) 
Preparation Example 38 
Preparation of 
(R)-1-(4-chlorophenyl)-3-(4-(2-methoxyethyl)piperazin-1-yl)methyl-2-pyrrol 
idinone difumarate(Table 3; Compound No. 59; (R)-isomer) 
Into 62 mL of 13% water-ethanol were suspended 5.00 g of 
(R)-1-(4-chlorophenyl)-3-(4-(2-methoxyethyl)piperazin-1-yl)methyl-2-pyrrol 
idinone and 3.30 g of fumaric acid. After making it homogeneous by heating 
under reflux, the solution was cooled. The precipitated solid was filtered 
and dried to give 7.45 g of the title compound. 
Melting point: 192-193.degree. C.; .sup.1 H NMR(DMSO, .delta. ppm): 
1.82-1.97(1H, m), 2.19-2.31(1H, m), 2.35-2.97(13H, m), 3.24(31H, s), 
3.44-3.48 (2H, m), 3.73-3.79(2H, m), 6.60(4H, s), 7.43(2H, d), 7.70(2H, d) 
Preparation Example 39 
Preparation of 
(R)-1-(4-chlorophenyl)-3-(4-(2-methoxyethyl)piperazin-1-yl)methyl-2-pyrrol 
idinone dimaleate(Table 3; Compound No. 67; (R)-isomer) 
Into 62 mL of 9% water-ethanol were suspended 5.00 g of 
(R)-1-(4-chlorophenyl)-3-(4-(2-methoxyethyl)piperazin-1-yl)methyl-2-pyrrol 
idinone and 3.30 g of maleic acid. After making it homogeneous by heating 
under reflux, the solution was cooled. The precipitated solid was filtered 
and dried to give 7.10 g of the title compound. 
Melting point: 178.5-179.1.degree. C.; 1H NMR(DMSO, .delta. 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), 7.44(2H, d), 7.71(2H, d) 
Formulation Example 1 
Tablets were prepared using the following components. 
(R)-1-(4-chlorophenyl)-3-[(4-(2-methoxyethyl)piperazin-1-yl)methyl]-2-pyrro 
lidinone hydrochloride (Table 2; Compound No. 50; (R)-isomer; produced in 
Preparation 
______________________________________ 
Example 21 120 g 
Citric acid 1 g 
Lactose 35 g 
Calcium phosphate, dibasic 72 g 
Pluronic F-68 30 g 
Sodium lauryl sulfate 20 g 
Polyvinylpyrrolidone 14 g 
Polyethylene glycol (Carbowax 1500) 5 g 
Polyethylene glycol (Carbowax 6000) 45 g 
Corn starch 33 g 
Dried sodium stearate 3 g 
Dried magnesium stearate 3 g 
Ethanol quantum sufficiat 
______________________________________ 
First, the above pyrrolidinone derivative hydrochloride, citric acid, 
lactose, dibasic calcium phosphate, Pluronic F-68 and sodium lauryl 
sulfate were blended. The mixture was sieved with a No.60 screen and 
wet-granulated with an alcoholic solution containing polyvinylpyrrolidone, 
Carbowax 1500 and Carbowax 6000, during which alcohol was, when necessary, 
added to make the powder a paste mass. Corn starch was added to the 
resulting granules, and the mixture was blended until homogeneous granules 
were formed. The mixture was passed through a No.10 screen, placed on a 
tray, dried in an oven at 100.degree. C. for 12 to 15 hours, and sieved 
with a No.16 screen. To the powder were added dried sodium lauryl sulfate, 
and the mixture was blended and compressed with a tablet machine to a 
desired form to give uncoated tablets. 
The uncoated tablets were treated with varnish after spraying talc for 
prevention of moisture absorption, the tablets were coated with a primer 
layer (varnish-coating layer). The primer layer was formed by a sufficient 
number of application of varnish for oral administration. For rounding and 
smoothing the tablets, a further primer layer and a smooth coating were 
applied with varnish. Furthermore, coloring coating was applied until a 
desired coating was formed. After drying the coated tablets were polished 
to give evenly bright tablets. 
Evaluation Example 1 (Radioreceptor assay for a .sigma..sub.1 receptor) 
Procedure 
Radioreceptor assay for a .sigma..sub.1 receptor was conducted according to 
a modified method of Vilner et al.(B. J. Vilner and W. D. Bowen, Multiple 
Sigma and PCP Receptor Ligands: Mechanisms for Neuromodulation and 
Neuroprotection?, NPP Books: pp.341(1992)). P.sub.2 fraction (20 mg/mL) 
prepared from a whole brain of a guinea pig without cerebellum and medulla 
was incubated with a test drug and a .sup.3 H-ligand (3 nM .sup.3 
H-(+)pentazocine(NEN)) at room temperature for 2 hours. 
The brain tissue was vacuum-filtrated on a glass-fiber filter 
paper(Whatman, GF/B) with Cell Harvester(Brandel, LL-12), and then washed 
with buffer (3 mL.times.2). The glass-fiber filter paper was placed in a 
vial. Into the vial was added 3.5 mL of scintillator (Amersham, ACSII), 
and after 10 hours the amount of the .sup.3 H-ligand binding to the 
receptor was determined with a liquid scintillation counter. Blank was 
determined using (+)-pentazocine (10 .mu.M). 
Binding rates of the .sup.3 H-ligand to the receptor for various 
concentration of the test drug were plotted in a graph where a rate 
without the test drug=100% and a rate with the blank compound=0%, and the 
concentration of the test drug showing a binding rate of 50% was 
determined as IC.sub.50. From the IC.sub.50, Ki value was calculated 
according to the following equation: 
EQU Ki=IC.sub.50 /{1+[.sup.3 H-ligand]/K.sub.D } 
wherein K.sub.D is a dissociation constant between the .sup.3 H-ligand and 
the receptor calculated by Scatchard plotting for binding of the .sup.3 
H-ligand to the receptor, changing the concentration of the .sup.3 
H-ligand. 
Rimcazole was also evaluated. 
Results 
The results are shown in Table 4, indicating that the compounds of this 
invention had high affinity for a .sigma..sub.1 receptor. 
Evaluation Example 2 (Radioreceptor assay for D.sub.2 receptor) 
Procedure 
.sup.3 H-spiperone (Amersham) and a test drug were incubated with a 
homogenate of rat cerebral striatal site as described in D. R. Burt et 
al., Proc.Natl.Acad.Sci.U.S.A. 72:4655 (1975), and Ki value was determined 
as described in the above r radioreceptor assay. 
Rimcazole was also evaluated. 
Results 
The results are also shown in Table 4, indicating that the compounds of 
this invention did not have affinity for a D.sub.2 receptor. 
TABLE 4 
______________________________________ 
Affinity for a receptor 
Ki (nM) 
Preparation Example No. 
.sigma..sub.1 
D.sub.2 
______________________________________ 
2 85 &gt;3300 
8 14 &gt;3300 
10 10 &gt;3300 
18 7.5 &gt;2800 
21 72 &gt;3900 
Rimcazole 1000 11600 
______________________________________ 
Evaluation Example 3 (Anti-SKF effect) 
Procedure 
Antipsychotic activity for a test drug was studied by means of head weaving 
behavior induced by a .sigma.-receptor agonist SKF-10047 for a mouse. For 
the experiment were used 10 male ddY mice aged 5 weeks (Nippon SLC) per a 
group. The mice were placed in a measuring cage and calmed 1 hour before 
the initiation of the test. To the mice was orally administered a test 
drug and after 60 min was subcutaneously administered SKF-10047 in a dose 
of 20 mg/kg. After 20 min, head weaving was counted for 10 min. Efficacy 
of the drug was evaluated by determining an inhibition (%) compared with 
the control group from the average of the 10 min scores of the test-drug 
groups, 20 min after administering SKF-10047, and then estimating a 
ED.sub.50 value. 
The compound represented by the following formula (IV) which is described 
in Japanese Patent Laid-Open (Kokai) No. 252219/95 (JP-A 7-252219) was 
also evaluated. 
##STR12## 
Results 
The results are shown in Table 5, indicating that the compounds of this 
invention had a higher antipsychotic activity than the compound of formula 
(IV). 
Evaluation Example 4 (Anti-PCP effect) 
Antipsychotic activity for a test drug was studied by means of head weaving 
behavior induced by phencyclidine (PCP) for a rat. For the experiment were 
used male Wistar(ST) rats aged 4weeks (Nippon SLC). The rats were placed 
in a measuring cage and calmed 1 hour before the initiation of the test. 
To the rats was orally administered a test drug and after 60 min was 
intraperitoneally administered PCP in a dose of 7.5 mg/kg. After 20 min, 
head weaving was counted for 10 min. Efficacy of the drug was evaluated by 
determining an inhibition (%) compared with the control group from the 
average of the scores of the test-drug groups, and then estimating a 
ED.sub.50 value. 
The compound of formula (IV) described in JP-A 7-252219 was also evaluated. 
Results 
The results are also shown in Table 5, indicating that the compounds of 
this invention had a higher antipsychotic activity than the compound of 
formula (IV). 
TABLE 5 
______________________________________ 
Antipsychotic activity 
ED.sub.50 (mg/kg) Oral 
treatment before 60 min 
Preparation Example No. 
Anti-SKF Anti-PCP 
______________________________________ 
2 2.1 1.3 
16 0.52 1.9 
21 0.77 0.75 
37 -- 1.15 
38 -- 1.48 
39 -- 1.08 
Compound of formula (IV) 14 11 
______________________________________ 
Evaluation Example 5 (Persistence of anti-SKF effect) Procedure 
Persistence of antipsychotic activity for a test drug was studied by means 
of head weaving behavior induced by a receptor agonist SKF-10047 for a 
mouse. For the experiment were used 10 male ddY mice aged 5 weeks (Nippon 
SLC) per a group. The mice were placed in a measuring cage and calmed 1 
hour before the initiation of the test. To the mice was orally 
administered a test drug and after 4 hours was subcutaneously administered 
SKF-10047 in a dose of 20 mg/kg. After 20 min, head weaving was counted 
for 10 min. Efficacy of the drug was evaluated by determining an 
inhibition (%) compared with the control group from the average of the 10 
min scores of the test-drug groups, 20 min after administering of 
SKF-10047, and then estimating a ED.sub.50 value. 
The compound of formula (IV) described in JP-A 7-252219 and the compound 
represented by the following formula (V) which is described in Japanese 
Patent Laid-Open (Kokai) No. 40667/97 (JP-A 9-40667) were also evaluated. 
##STR13## 
Results 
The results are shown in Table 6, indicating that the compound of this 
invention was effective for more than 4 hours and improved in its duration 
of effectiveness compared with the compounds of the above formulas (IV) 
and (V). 
TABLE 6 
______________________________________ 
Persistence of anti-SKF effect 
Preparation Example No. 
ED.sub.50 (mg/kg) (after 4 hours) 
______________________________________ 
21 3.19 
Compd. of formula (IV) &gt;100 
Compd. of formula (V) 23.2 
______________________________________ 
Evaluation Example 6 (Effect to reverse tolerance development due to 
repetitive administration of methamphetamine) 
Procedure 
For the experiment, male Std:Wistar(ST) rat (Nippon SLC) aged 5 weeks were 
used. A test drug, the compound of formula (IV) described in JP-A 7-252219 
or the compound of formula (V) described in JP-A 9-40667 was dissolved in 
purified water or 0.5% C.M.C./saline. Methamphetamine (mAMP) was dissolved 
in saline. Dosage volume was 1 mL/kg body weight. 
Test Procedure 
a) Repetitive Administration of a Test Drug and mAMP 
The drugs were repetitively administered for 10 days with a regimen that to 
a rat, a test drug was orally or intraperitoneally administered and after 
60 min mAMP was intraperitoneally administered in a dose of 2 mg/kg. To a 
normal group, solvent alone was administered in place of the combination 
of the test drug and mAMP. To a control group, solvent was orally or 
intraperitoneally administered, and then intraperitoneally mAMP was 
additionally administered. 
b) Effect of a Test Drug on a Process of Reverse Tolerance Development 
After the repetitive administration, there was provided a withdrawal period 
for 7 days during which the test drug or mAMP was not administered. After 
the withdrawal, the test drug was discontinued and mAMP was administered 
in a dose of 2 mg/kg, and then stereotyped behavior of the animal was 
observed. 
c) Rating of Stereotyped Behavior 
After administering mAMP, stereotyped behavior was rated in accordance with 
the following scale, for 1 min every 10 min until 60 min. 
Scale 
0: Calm 
1: Common behavior with exploratory activities 
2: Sniffing and head-movement with hyperkinesis 
3: Intermittent sniffing and head-movement with periodical hyperkinesis 
4: Almost continuous sniffing and head-movement with occasional 
transposition movement 
5: Continuous sniffing and head-movement without transposition movement 
The results are expressed as an inhibition (%) of reverse tolerance 
development calculated from the following equation, using a total score 
for six minutes: Inhibition of reverse tolerance development (%)=100-A 
wherein A represents a value calculated from the following equation: 
EQU A=[{(Score for the test drug group)-(Score for the normal group)}/{(Score 
for the control group)-(Score for the normal group)}].times.100 
Results 
The results are shown in Table 7, indicating that the compound of this 
invention dose-dependently inhibited reverse tolerance development to 
methamphetamine; specifically it almost completely inhibited reverse 
tolerance in a dose of 15 mg/kg (oral administration). In contrast, the 
cited compounds in an intraperitoneal dose of 30 mg/kg showed inhibition 
effect comparable to the compound of this invention, which indicates that 
the compound of this invention had significantly higher effect than the 
cited compounds. 
TABLE 7 
______________________________________ 
Effect on reverse tolerance development due to 
repetitive administration of methamphetamine 
Dose Route of Inhibition of reverse 
Preparation Example No. (mg/kg) administration tolerance (%) 
______________________________________ 
21 7.5 Oral 81.0 
21 15.0 Oral 93.9 
Compd. of formula IV 30.0 Intraperitoneal 92.9 
Compd. of formula V 10.0 Intraperitoneal 81.7 
Compd. of formula V 30.0 Intraperitoneal 87.8 
______________________________________ 
Evaluation Example 7 (Blood kinetics) 
Procedure 
For the experiment, male beagle dogs were employed. A test drug was 
intravenously or orally administered in a dose of 10 mg/kg. Blood samples 
were collected at 0.25, 0.5, 1, 2, 4, 6 and 24 hours after administering 
the test drug, and the samples were centrifuged to separate plasma, for 
which a plasma level of the test drug was determined by HPLC. Half-life of 
the test drug in blood was estimated from the results at the intravenous 
administration. An extent of bioavailability is expressed as a rate of AUC 
at the oral administration to AUC at the intravenous administration. 
The compound of formula (V) described in JP-A 9-40667 was also evaluated. 
Results 
The results are shown in Table 8, indicating that the compound of this 
invention had a longer half-life and was significantly improved in an 
extent of bioavailability, compared with the compound of formula (V). 
TABLE 8 
______________________________________ 
Blood kinetics parameters 
Half-life C.sub.MAX 
Extent of 
Preparation Example No. (hour) (.mu.g/mL) Bioavailability (%) 
______________________________________ 
21 3.5 1.52 83.1 
Compd. of formula (V) 1.5 0.46 64.3 
______________________________________ 
Evaluation Example 8 (Safety) 
Procedure 
For the experiment, male Std:ddY mice aged 5 weeks were used. The mice were 
weighed, and then calmed in an observation cage for more than 1 hour. To 
the mice, a test drug was orally administered in a dose of 300 mg/kg to 
observe them for general symptoms until 2 hours. 
The compounds of formulas (IV) and (V) described in JP-A 7-252219 and 
9-40667, respectively, were also evaluated. 
Results 
The results are shown in Table 9, indicating that the compounds of this 
invention exhibited no toxicity, i.e., a significant reduction in toxicity 
compared with the compound of formula (IV). 
TABLE 9 
______________________________________ 
Simple acute toxicity for a mouse 
Preparation Example No. 
Convulsion/Treatment 
Death/Treatment 
______________________________________ 
2 0/6 0/6 
8 0/3 0/3 
16 0/5 0/5 
21 0/4 0/4 
Compd. of formula (IV) 5/5 5/5 
Compd. of formula (V) 1/3 0/3 
______________________________________ 
It was demonstrated that the compounds of this invention had affinity for a 
a receptor and high antipsychotic activity, i.e., anti-SKF and anti-PCP 
effects. They were highly effective to a methamphetamine (mAMP)-induced 
reverse tolerance model, i.e., an exacerbation model of schizophrenia. 
Since they do not have affinity for a dopamine receptor and can inhibit 
reverse tolerance without extrapyramidal side effects, the compounds of 
this invention may be expected to be effective against recurrence or 
intractabilization of schizophrenia. 
Furthermore, the compounds of this invention are highly selective toward a 
.sigma..sub.1 receptor compared with a .sigma..sub.2 receptor, and 
inhibited not only head weaving but also rearing, for PCP-induced abnormal 
behavior. Furthermore, the compounds of this invention surprisingly 
inhibited a dopaminergic activity, apomorphine-induced climbing behavior, 
in spite of no affinity for a dopamine receptor, while exhibiting no 
effect on apomorphine-induced stereotyped behavior (side effects). 
Optically resolved compounds of this invention which were optically 
resolved from the racemic modifications exhibited more improved affinity 
for a .sigma. receptor, and more improved antipsychotic activity. 
The compounds of this invention showed significantly longer duration of 
drug efficacy and an improved extent of bioavailability than the cited 
compounds described in JP-A 7-252219 and JP-A 9-40667, respectively, and 
much higher effect in a metamphetamine (mAMP) reverse tolerance model than 
the cited compounds. Furthermore, the compounds of this invention were 
significantly improved in safety compared with the compound described in 
JP-A 7-252219.