# Patent

## Title
Piperidinyl and piperazinyl derivatives

## Abstract

this application is a divisional of copending application Ser. No. 07/571,402, filed on Aug. 23, 1990, now U.S. Pat. No. 5,120,733 which is a divisional application of Ser. No. 07/233,142, filed on Aug. 17, 1988 (now U.S. Pat. No. 4,977,167). The entire contents of which are hereby incorporated by reference.

## Background
This invention relates to carbamoylpyrrolidone derivatives. More particularly, this invention is directed to carbamoylpyrrolidone derivatives which have been found to be particularly available as a drug for senile dementia, psychotropic, and/or antiamnesia agent, to their preparation, to their use and to pharmaceutical formulations containing the compounds.

Pyrrolidone derivatives have heretofore been known as the drugs for brain insufficiency disease and so on, for example, in EP Pat. Publn. No. 89900-B, in U.S. Pat. No. 4,369,139, and in U.S. Pat. No. 4,118,396.

The inventors of the present invention have been studying on antiamnesia agents of the pyrrolidone family including such compounds. Thus, the present invention has been established. The compounds of the present invention can be applicable for treating some kinds of senile dementia.

According to the present invention, there is provided a carbamoylpyrrolidone derivative of the formula: ##STR2## (wherein R is phenoxy optionally substituted by a halogen, methoxy, or methyl group. ##STR3## R.sup.1 is hydrogen or C.sub.1 -C.sub.5 alkyl; Z.sup.1 is phenyl, benzyl, or isoxazolyl each optionally substituted by a halogen, methoxy, or methyl group; Z.sup.2 is hydrogen, C.sub.1 -C.sub.5 alkyl, C.sub.2 -C.sub.5 alkenyl, or phenyl optionally mono-, di-, or tri-substituted by a halogen, methoxy, or methyl group; or Z.sup.1 and Z.sup.2 taken together with the adjacent nitrogen atom may form 5-membered hetrocyclic group; Z.sup.3 is C.sub.1 -C.sub.5 hydroxyalkyl, di(C.sub.1 -C.sub.6 alkyl)sulfamoyl, 6-membered heterocyclic group, phenyl, benzyl, or phenylsulfonyl each phenyl moiety of the last three members being optionally substituted by a halogen, methoxy, or methyl group; Z.sup.4 is phenyl optionally substituted by a halogen, methoxy, or methyl group or 5- or 6-membered heterocyclic group which is optionally substituted by a halogen, methoxy, or methyl group and which can be optionally condensed with a benzene ring; Z.sup.5 is thienyl or phenyl each optionally substituted by a halogen, methoxy, or methyl group; Z.sup.6 is thienyl or phenyl each optionally substituted by a halogen, methoxy, or methyl group; m is an integer from 0 to 2; n is an integer from 2 to 3)

or its pharmaceutical acceptable acid addition salt.

The terms used in the above definition are explained below.

As the alkyl, methyl, ethyl, propyl, isopropyl, butyl, and pentyl are exemplified. As the alkoxy, methoxy, ethoxy, propoxy, isopropoxy, butoxy, and pentyloxy are exemplified. As the hydroxyalkyl, hydroxymethyl, hydroxyethyl, and hydroxybutyl are exemplified. As the dialkylsulfamoyl, dimethylsulfamoyl, diethylsulfamoyl, and dibutylsulfamoyl are exemplified. As the halogen, fluorine, chlorine, bromine, and iodine are indicated. As the 5- or 6-membered heterocyclic group, isothiazolyl, pyrazolyl, pyrimidinyl, triazolyl, thiadiazolyl, imidazolyl, isoxazolyl, and pyridyl are illustrated.

The processes of producing Compound (I) are shown in the following scheme. ##STR4##

Compound (Ia) is obtained by reacting Compound (II) with a reagent (IV). In this reaction, no solvent is used and the reaction is carried out at comparatively high temperature of 100.degree.-150.degree. C., preferably at 115.degree.-125.degree. C. As the reagent (IV), 2-(4-methoxyphenylamino)ethylamine, 2-(4-methylphenylamino)ethylamine, 2-(4-chlorophenylamino)ethylamine, 1-aminoethylpyrazole, 2-(4-methoxyphenylamino)-N-methylethylamine, 2-(4-methoxyphenyloxy)-N-methylethylamine, 2-(4-methoxyphenyloxy)ethylamine, and 2-(5-methylisoxazol-3-ylamino)ethylamine are exemplified.

The objective compound (Ia) is obtained by reacting Compound (III) with Compound (V). The reaction is carried out in an appropriate solvent at 10.degree.-120.degree. C., preferably at 50.degree.-100.degree. C. As the solvent, benzene, dimethyl sulfoxide, DMF, chloroform, ethyl acetate, and THF are illustrated. If necessary, organic bases such as pyridine, triethylamine, and dimethylaniline; or inorganic bases such as K.sub.2 CO.sub.3, NaH, and NaOH may be added as dehydrohalogenating agents. Also an alkali metal iodide such as NaI and KI may be used to accelerate the reaction.

Compound (Ib) can be obtained by oxidizing Compound (Ia) (when R=SZ.sup.4) with a suitable peracid. Generally, this reaction is carried out in an appropriate solvent at room temperature (1.degree.-30.degree. C.), preferably at 10.degree.-25.degree. C. As the solvent, there are chloroform, CH.sub.2 Cl.sub.2, carbon tetrachloride, ethyl acetate, and 1,2-dichloroethane, or a mixture of some of these solvents. As the peracid, peracetic acid, perbenzoic acid, and m-chloroperbenzoic acid (m-CPBA) are used.

Compound (Ic) is obtained by subjecting Compound (Ia) to dehydration reaction, when R is ##STR5##

This reaction is carried out in an appropriate solvent in the presence of dehydrating agents at the refluxing temperature of the solvent. As the solvent, toluene, dioxane, hexamethylphosphoramide, and ethyl acetate are exemplified. As the dehydrating agent, phosphorus pentaoxide, DCC, and Molecular Sieves are illustrated.

Compound (Id) is obtained by alkylating Compound (Ia) (when R.sup.1 =H) with a suitable alkylating agent. Generally, this reaction is carried out in an appropriate solvent at room temperature (1.degree.-30.degree. C.), preferably at 10.degree.-25.degree. C. As the solvent, THF and ethyl acetate are illustrated. As the alkylating agent, methyl iodide, ethyl iodide, butyl chloride, and allyl bromide are exemplified. In order to accelerate the reaction, a suitable base may be used. As the base, alkali metal hydroxide such as sodium hydroxide and potassium hydroxide; potassium hydrogencarbonate, pyridine, triethylamine are exemplified.

The production of the starting materials (II) and (III) are shown in the following scheme. ##STR6## (n is an integer of 2 or 3) (See Referential Examples 1-3)

The compounds (I) may be manufactured by any of the conventional processes known in the chemical literature for the manufacture of analogous compounds.

The compound (I) can be converted into its pharmaceutically acceptable acid addition salt. Such acids illustratively include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, hydrobromic acid, and hydrogen iodide and organic acids such as acetic acid, maleic acid, malic acid, citric acid, lactic acid, succinic acid, and methanesulfonic acid.

The objective compound (I) of this invention can be administered to humans or animals orally or parenterally. For instance, Compound (I) can be administered orally in the forms of tablets, granules, powder, capsules, solution, etc., or it is given parenterally in the forms of injection or suppositories. These preparations are manufactured in a known process by using additives such as diluents, binders, disintegrators, lubricants, stabilizers, corrigents, suspenders, dispersants, solubilizers, and antiseptics.

As the diluents, lactose, sucrose, starch, cellulose, and sorbit; as the binders, gum arabic, gelatin, and polyvinylpyrrolidone; and as the lubricants, magnesium stearate, talc, and silica gel are exemplified, respectively. When the objective compound (I) of this invention is used for the treatment of senile dementia, a daily dose of about 0.01 to 20 mg/kg may be orally or parenterally administered once or in several divisions.

Embodiments of this invention are illustrated below by indicating Examples, Referential Examples, and Preparations.

The abbreviations used in the Examples, Referential Examples and Tables have the following meanings as mentioned below: ##STR7##

To a solution of 1.0 g (5.24 mmol) of 1-[(2-chloroethyl)carbamoyl]-2-oxopyrrolidine and 0.646 g (5.24 mmol) of p-anisidine in 15 ml of DMF were added 1.09 g (7.86 mmol) of K.sub.2 CO.sub.3 and 0.03 g (2.00 mmol) of NaI, and the solution was heated with stirring at 80.degree.-85.degree. C. for 40.5 hr. The reaction solution was mixed with ethyl acetate, washed with water, dried, and concentrated. The residue was refined by silica gel chromatography, and 0.37 g (Yield 25.4%) of the objective compound (Ia-1) was obtained from the eluate with benzene - ethyl acetate (3/1 v/v). The product obtained was washed with ether -n-hexane and collected by filtration.

m.p. : 83.5.degree.-84.5.degree. C.

Anal. Calcd. (%) for C.sub.14 H.sub.19 N.sub.3 O.sub.3 : C, 60.63; H, 6.91; N, 15.15. Found (%) : C, 60.65; H, 7.05; N, 15.30.

IR (CHCl.sub.3) : 3295, 2975, 1710, 1675 cm.sup.-1

NMR (CDCl.sub.3) : 2.00 (quint, J=7 Hz, 2H), 2.57 (t, J=7 Hz, 2H), 3.27 (t, J=6 Hz, 2H), 3.53 (q, J=6 Hz, 2H), 3.73 (s, 3H), 3.84 (t, J=7 Hz, 2H), 6.59, 6.77 (A.sub.2 B.sub.2, J=9 Hz, 4H), 8.62(br., 1H)

The reactions were carried out in the same method as in Example 1 mentioned above, whereby the compounds (Ia) were obtained. The reaction conditions and their properties are shown in Tables 1 and 2, respectively. __________________________________________________________________________ ##STR8## Reaction Ia III-1 Compound (V)            K.sub.2 CO.sub.3 NaI     Conditions      Com- Ex. g                       g   g   g   DMF     Temp. Yield Yield pd. No. (mmol) Z.sup.1      Z.sup.2 (mmol) (mmol) (mmol) (ml) Time (.degree.C.) (g) (%) No. __________________________________________________________________________ 2  2.0 (10.5) ##STR9##    Me     1.73 (12.6) 3.63 (26.2) 2.36 (15.8) 25  5 d. 100- 105 2.00 65.4 I a-2 3  2.86 (15.0) ##STR10##   Et     2.50 (16.5) 5.18 (37.5) 3.37 (22.5) 30  6 d. 100- 105 2.10 45.8 I a-3 4  3.15 (16.5) ##STR11##   n-Pr   3.00 (18.2) 5.70 (41.3) 3.71 (24.8) 35  7 d. 100- 105 2.23 42.2 I a-4 5  2.0 (10.5) ##STR12##   H      1.60 (10.5) 2.16 (15.7) 1.0 (6.67) 30  8 d. 95-100 0.64 20.0 I a-5 6  3.0 (15.7) ##STR13##   H      2.88 (15.7) 3.24 (23.6) 3.54 (23.6) 35  5 d. 95-100 2.59 49.0 I a-6 7  3.0 (15.7) ##STR14##   H      2.52  (23.5) 3.22 (23.5) 3.52 (23.5) 35  4 d. 85  1.15 28.0 I a-7 8  1.6 (8.39) ##STR15##   Me     1.037 (8.56) 1.96 (14.3) 0.3 (2.0) 20  4.6 d. 80-90 1.26 54.5 I a-8 9  2.86 (15.0) ##STR16## ##STR17## 3.02 (16.5) 5.18 (37.5) 3.37 (22.5) 30  12 d. 100- 105 0.60 11.9 I a-9 10 1.50 (7.87) ##STR18##   H      1.08 (7.87) 1.63 (11.8) 1.60 (10.7) 20  2.9 d. 20 hr. 55-60  95-100 0.89 20.2 I a-10 11 3.60 (18.9) ##STR19##   H      2.40 (19.8) 6.53 (47.3) 4.25 (28.4) 35  4.5 d. 85-90 1.62 31.1 I a-11 12 1.50 (7.87) ##STR20##   H      1.11  (7.87) 1.63 (11.8) 1.6 (10.7) 20  2.8 d. 17 hr. 55-60 100 1.36 25.2 I a-12 13 2.0 (10.5) ##STR21##   H      2.14 (10.5) 5.10 (36.8) 0.79 (5.25) 30  7.5 d. 80-90 0.98 14.5 I a-13 14 3.0 (15.7) ##STR22##          2.90 (16.5) 3.24 (23.6) 3.54 (23.6) 30  2.2 d. 90-95 2.87 55.2 I a-14 15 3.0 (15.7) ##STR23##          2.67 (16.5) 3.24 (23.6) 3.54 (23.6) 30  3.2 d. 95-100 3.50 70.3 I a-15 16 3.0 (15.7) ##STR24##          3.54 (23.6) 3.24 (23.6) 3.54 (23.6) 30  3.8 d. 90-95 4.58 84.0 I a-16 17 1.91 (10.02) ##STR25##          2.30 (10.06) 2.25 (15.0) 2.86 (15.0) 20  2.9 d. 90-95 1.68 48.4 I a-17 18 1.91 (10.02) ##STR26##          2.37 (10.0) 4.1 (30.0) 2.25 (15.0) 30  5 d. 90-95 1.18 37.0 I a-18 19 5.0 (26.2) ##STR27##          3.76 (28.9) 7.24 (52.4) 5.89 (39.3) 50  5 d. 90  4.38 58.8 I a-19 20 1.50 (7.89) ##STR28##          2.16 (8.28) 2.18 (1.58) 1.77 (1.18) 20  4 d. 100- 105 1.66 50.8 I a-20 21 1.64 (8.60) ##STR29##          2.21 (9.03) 2.38 (17.2) 1.93 (12.9) 25  3.8 d. 100- 105 1.10 32.1 I a-21 22 1.64 (8.60) ##STR30##          2.36 (9.21) 2.38 (17.2) 1.93 (12.9) 25  4 d. 100- 105 0.65 50.8 I a-22 23 2.42 (12.7) ##STR31##          2.80 (14.5) 3.51 (25.4) 2.86 (19.1) 30  5 d. 100 2.02 45.8 I a-23 24 2.30 (12.1) ##STR32##          2.93 (12.7) 3.32 (24.2) 2.72 (18.2) 25  3.2 d. 100 3.29 65.5 I a-24 25 0.89  (4.67) ##STR33##          0.99 (4.68) 0.97 (7.02) 1.05 (7.01) 10  2.9 d. 90-95 1.48 86.6 I a-25 26 3.00 (15.7) ##STR34##          2.82 (17.3) 5.38 (39.2) 3.53 (23.5) 55  5 d. 115 3.1 62.0 I a-26 27 2.56 (13.4) ##STR35##          2.50 (14.1) 4.63 (33.5) 3.0 (20.1) 30  3 d. 100- 105 3.07 69.0 I a-27 28 1.15 (6.03) ##STR36##          1.25 (6.03) 2.08 (15.1) 1.36 (9.04) 20  3 d. 100- 105 1.65 75.7 I a-28 29 0.96 (5.06) ##STR37##          1.0 (5.16) 1.75 (12.6) 1.14 (7.59) 20  3.75 d. 100- 105 0.34 19.4 I a-29 30 2.81 (14.7) ##STR38##          2.70 (14.7) 6.10 (44.1) 3.30 (22.0) 30  4 d. 100- 105 3.89 78.2 I a-30 31 2.08 (10.9) ##STR39##          2.00 (10.9) 4.52 (32.7) 2.45 (16.4) 30  4 d. 100- 105 1.91 51.9 I a-31 32 2.79 (14.6) ##STR40##          3.10 (14.6) 6.05 (43.8) 3.28 (21.9) 35  5 d. 100- 105 4.25 79.4 I a-32 33 1.80 (9.46) ##STR41##          1.72 (8.53) (.HCl salt) 3.92 (2.84) 2.13 (1.42) 30  4 d. 100- 105 2.38 87.4 I __________________________________________________________________________ a-33 __________________________________________________________________________ Com- m.p. (.degree.C.) pound (Recrystallizing Elementary Analysis IR (cm.sup.-1) No. solvent) Found (Calcd.) (%) (CHCl.sub.3) NMR (CDCl.sub.3) .delta. __________________________________________________________________________ Ia-2 84.5-85.5 C.sub.15 H.sub.21 N.sub.3 O.sub.3 3300, 1705, 1680 1.75-2.15(m, 2H), 2.55(t, J=7Hz, 2H), (Et.sub.2 O) C, 61.73 (61.84) 1540, 1510 2.90(s, 3H), 3.40(s, 4H), 3.74(s, H, 7.26 (7.27)        3H), 3.80(t, J=7Hz, 2H), 6.80(s, 4H), N, 14.39 (14.42)      8.50(br., 1H) Ia-3 87.0-88.5 C.sub.16 H.sub.23 N.sub.3 O.sub.3 3300, 1705, 1670 1.10(t, J=7Hz, 3H), 1.80-2.16(m, 2H), (Et.sub.2 O) C, 62.93 (62.93) 1530 (sh), 1505 2.57(t, J=7Hz, 2H), 3.28(q, J=7Hz, H, 7.64 (7.59)        2H), 3.36(s, 3H), 3.83(t, J=7Hz, 2H), N, 13.73 (13.76)      6.80(s, 4H), 8.54(br., 1H) Ia-4 70.0-71.0 C.sub.17 H.sub.25 N.sub.3 O.sub.3 3280, 1700, 1670 0.90(t, J=7Hz, 3H), 1.55(quint, J=7Hz, (Et.sub.2 O) C, 64.09 (63.92) 1530 (sh), 1500 2H), 2.00(quint, J=7Hz, 2H), 2.56(t, H, 7.90 (7.89)        J= 7Hz, 2H), 3.16(t, J=7Hz, 2H), 3.33 N, 13.18 (13.16)      (s, 4H), 3.73(s, 3H), 3.83(t, J=7Hz, 2H), 6.80(s, 4H), 8.54(br., 1H) Ia-5 --       C.sub.15 H.sub.21 N.sub.3 O.sub.4 3300, 1710, 1680 2.00(quint, J=7Hz, 2H), 2.57(t, J=7Hz, C, 58.53 (58.62) 1615, 1600 2H), 3.20-3.60(m, 4H), 3.73(s, 3H), H, 6.84 (6.89) 1540 (sh), 1520 3.78(s, 3H), 3.85(t, J=7Hz, 2H), 4.50 N, 13.46 (13.67)      (br., 1H), 6.13(dd, J.sub.1 =9Hz, J.sub.2 =2Hz, 1H) 6.23(d, J=2Hz, 1H), 6.64(d, J=9Hz, 1H), 8.60(br., 1H) Ia-6 124.0-125.5 C.sub.16 H.sub.23 N.sub.3 O.sub.5 3290, 1700, 1665 2.00(quint, J=7Hz, 2H), 2.57(t, J=7Hz, (EtOH)   C, 56.96 (56.96) 1600, 1535, 1500 2H), 3.29(q, J=6Hz, 2H), 3.51(q, J=6Hz, H, 6.85 (6.87)        2H), 3.71(s, 3H), 3.80(s, 6H), 3.84(t, N, 12.32 (12.46)      J=7Hz, 2H) 5.85(s, 2H), 8.60(br., 1H) Ia-7 maleate  C.sub.14 H.sub.19 N.sub.3 O.sub.2.C.sub.4 H.sub.4 O.sub.4 (free base) (free base) 143.0-144.0 C, 57.17 (57.28) 3290, 1700, 1670 1.80-2.13(m, 2H), 2.56(t, J=7H, 2H), 2.79 (i-PrOH) H, 6.32 (6.14) 1535    (t, J=6Hz, 2H), 3.40(q, J=6Hz, 2H), 3.80 N, 11.12 (11.14)      (s, 2H), 3.80(t, J=7Hz, 2H), 7.30(s, 5H), 8.60(br., 1H) Ia-8 maleate  C.sub.15 H.sub.21 N.sub.3 O.sub.2.C.sub.4 H.sub.4 O.sub.4 (free base) (free base) 130.0-130.5 C, 58.24 (58.30) 3300, 1705, 1675 2.00(quint, J=7Hz, 2H), 2.48-2.70(m, 4H), (i-PrOH) H, 6.46 (6.44) 1530    2.87(s, 3H), 3.43(q, J=6Hz, 2H), 3.54(s, N, 10.70 (10.74)      2H), 3.83(t, J=7Hz, 2H), 7.20-7.40(m, 5H), 8.67(br., 1H) Ia-9 97.0-98.0 C.sub.20 H.sub.23 N.sub.3 O.sub.2 3290, 1705, 1675 1.98(quint, J=7Hz, 2H), 2.56(t, J=7Hz, 2H) (Et.sub.2 O) C, 71.19 (71.19) 1590, 1530, 1500 3.58(s, 4H), 3.81(t, J=7Hz, 2H), 4.59(s, H, 6.91 (6.87)        2H), 6.60-7.30(m, 10H), 8.53(br., 1H) N, 12.49 (12.45) Ia-10 maleate  C.sub.15 H.sub.21 N.sub.3 O.sub.3.C.sub.4 H.sub.4 O.sub.4 (free base) (free base) 142.5-143.5 C, 55.98 (56.01) 3300, 1710, 1680 1.80-2.15(m, 2H), 2.57(t, J=7Hz, 2H), 2.77 (i-PrOH) H, 6.25 (6.19) 1610, 1580, 1540 (t, J=6Hz, 2H), 3.40(q, J=6Hz, 2H), 3.76 N, 10.27 (10.31) 1505    (s, 3H), 3.80(t, J=7Hz, 2H), 6.85, 7.23 (A.sub.2 B.sub.2, J=9Hz, 4H), 8.60(br., 1H) Ia-11 maleate  C.sub.15 H.sub.21 N.sub.3 O.sub.2.C.sub.4 H.sub.4 O.sub.4 (free base) (free base) 155.0-156.0 C, 58.11 (58.30) 3290, 1700, 1670 1.98(quint, J=7Hz, 2H), 2.30(s, 3H), 2.55 (i-PrOH) H, 6.43 (6.44) 1535    (t, J=7Hz, 2H), 2.77(t, J=6Hz, 2H), 3.39 N, 10.68 (10.74)      (q, J=6Hz, 2H), 3.75(s, 2H), 3.80(t, J=7Hz 2H), 7.10, 7.20(A.sub.2 B.sub.2, J=9Hz, 4H), 8.58 (br., 1H) Ia-12 maleate  C.sub.14 H.sub.18 N.sub.3 O.sub.2 Cl.C.sub.4 H.sub.4 (free base) (free base) 161.5-162.0 C, 52.47 (52.50) 3300, 1705, 1675 1.99(quint, J=7Hz, 2H), 2.57(t, J=7Hz, 2H) (i-PrOH) H, 5.31 (5.38) 1540    2.75(t, J=6Hz, 2H), 3.39(q, J=6Hz, 2H), N, 10.26 (10.20)      3.75(s, 2H), 3.80(t, J=7Hz, 2H), 7.28(s, Cl, 8.69 (8.61)       4H), 8.60(br., 1H) Ia-13 --       C.sub.16 H.sub.23 N.sub.3 O.sub.4.1/5CH.sub.2 Cl.sub.2 3300, 1705, 1670 1.97(quint, J=7Hz, 2H), 2.54(t, J=7Hz, 2H) C, 57.59 (57.51) 1610, 1580, 1545 2.80(t, J=6Hz, 2H), 3.47(q, J=6Hz, 2H), H, 7.06 (6.97) 1500    3.74(s, 2H), 3.78(t, J=7Hz, 2H), 3.80(s, N, 12.66 (12.42)      6H), 6.43(br., 2H), 7.20(d, J=9Hz, 1H), 8.60(br., 1H) Ia-14 80.5-81.5 C.sub.18 H.sub.26 N.sub.4 O.sub.2 3300, 1705, 1670 2.00(quint, J=7Hz, 2H), 2.45-2.70(m, 12H), (Et.sub.2 O- C, 65.52 (65.43) 1540, 1520 (sh) 3.40(q, J=6Hz, 2H), 3.50(s, 2H), 3.84(t, n-Hexane = H, 7.97 (7.93)        J=7Hz, 2H), 7.30(s, 5H), 8.63(br., 1H) 2:1v/v)  N, 16.94 (16.96) Ia-15 133.0-134.0 C.sub.17 H.sub.24 N.sub.4 O.sub.2 3280, 1700, 1670 2.00(quint, J=7Hz, 2H), 2.50-2.70(m, 8H), (Et.sub.2 O- C, 64.52 (64.53) 1590, 1520, 1485 3.13-3.27(m, 4H), 3.45(q, J=6Hz, 2H), 3.84 n-Hexane = H, 7.60 (7.65)        (t, J=7Hz, 2H), 6.73-7.00(m, 3H), 7.13-7.30 1:1v/v)  N, 17.62 (17.71)      (m, 2H), 8.65(br., 1H) Ia-16 maleate  C.sub.18 H.sub.26 N.sub.4 O.sub.3.C.sub.4 H.sub.4 O.sub.4 (free base) (free base) 180.0-183.0(d) C, 57.03 (57.13) 3300, 1700, 1665 1.97(quint, J=7Hz, 2H), 2.45-2.70(m, 6H), (i-PrOH--MeOH) H, 6.72 (6.54) 1580, 1520, 1490 3.04-3.20(m, 4H), 3.45(q, J=6Hz, 2H), 3.82 N, 12.14 (12.12)      (t, J=7Hz, 2H), 3.84(s, 3H), 6.92(s, 4H), 8.65(br., 1H) Ia-17 124.5-125.5 C.sub.18 H.sub.26 N.sub.4 O.sub.3 3300, 1705, 1670 2.00(quint, J=7Hz, 2H), 2.50-2.70(m, 8H), (Et.sub.2 O--CH.sub.2 Cl.sub.2) C, 62.43 (62.41) 1540 (sh), 1505 3.05-3.17(m, 4H), 3.47(q, J=6Hz, 2H), 3.75 H, 7.48 (7.56)        (s, 3H), 3.85(t, J=7Hz, 2H), 6.87(A.sub.2 B.sub.2, J= N, 16.31 (16.17)      9Hz, 4H), 8.67(br., 1H) Ia-18 80.5-81.5 C.sub.16 H.sub.22 N.sub.6 O.sub.2 3300, 1705, 1670 2.01(quint, J=7Hz, 2H), 2.47-2.70(m, 8H), (Et.sub.2 O) C, 56.62 (56.59) 1580, 1540, 1500 3.45(q, J=6Hz, 2H), 3.75-3.93(m, 6H), 6.45 H, 6.94 (6.96) 1485 (sh) (t, J=5Hz, 1H), 8.27(d, J=5Hz, 2H), 8.68 N, 26.28 (26.40)      (br., 1H) Ia-19 109.0-111.0 C.sub.13 H.sub.24 N.sub.4 O.sub.3 3300, 1705, 1675 2.02(quint, J=7Hz, 2H), 2.47-2.70(m, 14H), (Et.sub.2 O) C, 54.68 (54.91) 1520    3.04(s, 1H), 3.40(q, 6Hz, 2H), 3.62(t, J= H, 8.40 (8.51)        6Hz, 2H), 3.87(t, J=7Hz, 2H), 8.64(br., N, 19.56 (19.71)      1H) Ia-20 149.0-150.0 C.sub.17 H.sub.23 N.sub.4 O.sub.4 SCl 3290, 1700, 1670 2.00(quint, J=7Hz, 2H), 2.45-2.65(m, 8H), (EtOH)   C, 49.09 (49.21) 1580, 1530 3.00-3.13(m, 4H), 3.37(q, J=6Hz, 2H), 3.82 H, 5.49 (5.59)        (t, J=7Hz, 2H), 7.53-7.74(A.sub.2 B.sub.2, J=9Hz, 4H) N, 13.35 (13.50)      8.52(br., 1H) S, 7.71 (7.73) Cl, 8.40 (8.54) Ia-21 110.5-111.5 C.sub.17 H.sub.23 N.sub.4 O.sub.4 SF 3300, 1705, 1675 1.85-2.16(m, 2H), 2.46-2.60(m, 8H), (EtOH)   C, 51.05 (51.24) 1590, 1525, 1490 3.00-3.12(m, 4H), 3.36(q, J=6Hz, 2H), 3.81 H, 5.59 (5.82)        (t, J=7Hz, 2H), 7.22(t, J=9Hz, 2H), 7.78 N, 13.87 (14.06)      (d-d, J.sub.1 =9Hz, J.sub.2 =6Hz, 2H), 8.52(br., 1H) S, 8.26 (8.05) F, 5.03 (4.77) Ia-22 186.5-187.5 C.sub.18 H.sub.26 N.sub.4 O.sub.5 S 3310, 1705, 1675 1.80-2.15(m, 2H), 2.40-2.65(m, 8H), 2.96- (EtOH)   C, 52.54 (52.67) 1595, 1575, 1530 3.08(m, 4H), 3.35(q, J=6Hz, 2H), 3.80(t, H, 6.39 (6.38) 1490    J=7Hz, 2H), 8.85(s, 3H), 7.00, 7.65(A.sub.2 B.sub.2, N, 13.53 (13.65)      J=9Hz, 4H), 8.47(br., 1H) S, 7.84 (7.81) Ia-23 97.0-97.5 C.sub.13 H.sub.25 N.sub.5 O.sub.4 S 3290, 1700, 1670 1.83-2.17(m, 2H), 2.40-2.67(m, 8H), 2.80 (EtOH)   C, 44.87 (44.97) 1520    (s, 6H), 3.20-3.50(m, 6H), 3.83(t, J=7Hz, H, 7.15 (7.25)        2H), 8.62(br., 1H) N, 20.13 (20.16) S, 9.13 (9.23) Ia-24 195.0-200.0 C.sub.20 H.sub.27 N.sub.5 O.sub.3.C.sub.2 H.sub.5 OH 3425, 3270, 1710 1.64-2.20(m, 4H), 2.53-2.85(m, 10H), 3.44 (EtOH)   C, 61.18 (61.23) 1675, 1600, 1515 (q, J=6Hz, 2H), 3.86(t, J=7Hz, 2H), 4.73 H, 7.49 (7.71) 1495    (s, 2H) 6.70-7.40(m, 5H), 7.64(br. s, 1H), N, 16.84 (16.23)      8.88(br., 1H) Ia-25 152.5-153.5 C.sub.18 H.sub.24 N.sub.3 O.sub.3 Cl 3580, 3300, 1705 1.62-2.30(m, 6H), 2.40-2.85(m, 8H), 3.42 (Et.sub.2 O--CH.sub.2 Cl.sub.2) C, 58.87 (59.09) 1670, 1525 (q, J=6Hz, 2H), 3.80(t, J= 7Hz, 2H), 7.29, H, 6.54 (6.61)        7.43(A.sub.2 B.sub.2, J=9Hz, 4H), 8.65(br., 1H) N, 11.28 (11.49) Cl, 9.52 (9.69) Ia-26 dimaleate C.sub.16 H.sub.23 N.sub.6 O.sub.2.2C.sub.4 H.sub.4 O.sub.4 (Nujol) (free base) 149.0-150.0 C, 52.5 (52.45) dimaleate 1.85-2.17(m, 2H), 2.50-2.63(m, 6H), 3.35- (MeOH-i-PrOH) H, 5.75 (5.69) 3310, 1715, 1680 3.60(m, 6H), 3.84(t, J=7Hz, 2H), 6.50-6.73 N, 12.69 (12.75) 1630, 1610 (m, 2H), 7.28-7.55(m, 1H), 8.17(d-d, J.sub.1 = 9Hz, J.sub.2 =2Hz, 1H), 8.69(br., 1H) Ia-27 113.0-114.0 C.sub.18 H.sub.25 N.sub.3 O.sub.3 3260, 2910, 1705 1.70-2.90(m, 16H), 3.45(q, J=6Hz, 2H), (EtOH)   C, 65.29 (65.23) 1670, 1520 3.85(t, J=7Hz, 2H), 7.36, 5.51(A.sub.2 B.sub.2, H, 7.61 (7.60)        J=9Hz, 4H), 8.66(br., 1H) N, 12.67 (12.68) Ia-28 105.5-106.5 C.sub.19 H.sub.27 N.sub.3 O.sub.4 3290, 2930, 1705 1.68-2.85(m, 15H), 3.43(q, J=6Hz, 2H), (i-PrOH--Et.sub.2 O) C, 63.02 (63.14) 1675, 1610, 1505 3.79(s, 3H), 3.82(t, J=7Hz, 2H), 6.86, H, 7.58 (7.53)        7.43(A.sub. 2 B.sub.2, J=9Hz, 4H), 8.64(br., 1H) N, 11.47 (11.63) Ia-29 141.5-142.5 C.sub.18 H.sub.22 N.sub.3 O.sub.2 Cl 3290, 2895, 1700 2.03(quint, J=7Hz, 2H), 2.50-2.80(m, 8H), (i-PrOH) C, 62.24 (62.15) 1670, 1530 3.21(q, J=3Hz, 2H), 3.51(q, J=6Hz, 2H), H, 6.36 (6.37)        3.87(q, J=7Hz, 2H), 6.06(br., 1H), 7.20- N, 12.05 (12.08)      7.37(m, 4H), 8.60(br., 1H) Cl, 10.23 (10.19) Ia-30 126.0-126.5 C.sub.16 H.sub.23 N.sub.3 O.sub.3 S 3560, 3350, 1705 1.90-2.30(m, 7H), 2.50-2.80(m, 8H), (CH.sub.2 Cl.sub.2 --Et.sub.2 O) C, 56.89 (56.95) 1670, 1530 3.443(q, J=5.4Hz, 2H), 3.857(t, J=7.2Hz, H, 6.84 (6.87)        2H), 6.90-7.30(m, 3H), 8.650(br., 1H) N, 12.41 (12.45) S, 9.41 (9.50) Ia-31 tartrate C.sub.16 H.sub.23 N.sub.3 O.sub.3 S.C.sub.4 H.sub.6 O.sub.6 1/2H.sub.2 O  (Nujol) (free base) powder   C, 48.62 (48.38) L-tartrate 1.65-1.90(m, 2H), 1.95-2.15(m, 5H), H, 6.18 (6.09) 3380, 3280, 1700 2.417, 2.881(ABq, J=11Hz, 2H), 2.55-2.65 N, 8.12 (8.46) 1670, 1600, 1535 (m, 4H), 2.934(d, J=10Hz, 1H), 3.30-3.50 S, 6.33 (6.46)        (m, 2H), 3.855(t, J=7Hz, 2H), 4.219 (s, 1H), 6.954-6.973(m, 2H), 7.182-7.222 (m, 1H), 8.918(br. s, 1H) Ia-32 119.5-120.5 C.sub.18 H.sub.24 N.sub.3 O.sub.3 Cl 3500, 3280, 1705 1.65-2.15(m, 7H), 2.404(a part of ABq, (Et.sub.2 O-toluene) C, 59.11 (59.09) 1675, 1545, 1525 J=11Hz, 1H), 2.55-2.75(m, 5H), 2.975(d, H, 6.45 (6.61) 1485    J=10Hz, 1H), 3.418(m, 2H), 3.867(t, J=7Hz, N, 11.49 (11.49)      2H), 4.162(s, 1H), 7.272-7.501(m, 3H), Cl, 9.96 (9.96)       8.929(br., 1H) Ia-33 tartrate C.sub.16 H.sub.21 N.sub.3 O.sub.2 S.C.sub.4 H.sub.6 O.sub.6 1/2H.sub.2 O  (Nujol) (free base) powder   C, 49.78 (50.20) L-tartrate 2.020(quint, J=7Hz, 2H), 2.355(s, 2H) H, 5.82 (5.90) 3260, 1700, 1670 2.590(t, J=7Hz, 2H), 2.63-2.75(m, 6H), N, 8.33 (8.78) (sh), 1650 (sh), 3.37-3.40(m, 2H), 3.518(q, J=6Hz, 2H), S, 6.37 (6.70) 1590, 1525 3.858(t, J=7Hz, 2H), 6.16-6.20(m, 1H), 6.88-7.19(m, 3H) __________________________________________________________________________ ##STR42##

To a solution of 1.9 g (27.5 mmol) of 1,2,4-triazole in 15 ml of DMF was added 1.1 g (27.5 mmol) of 60% NaH, and the mixture was heated at 90.degree. C. for about 2 hr. Then, 13 ml of DMF containing 3.50 g (18.4 mmol) of 1-[(2-chloroethyl)carbamoyl]-2-oxopyrrolidine (III-1) was added to the mixture, which was heated at 90.degree. C. for 4.5 hr. The reaction solution was poured into CH.sub.2 Cl.sub.2, and the insoluble material was removed by filtration. After evaporating the solvent, the CH.sub.2 Cl.sub.2 layer was refined by silica gel column chromatography, whereby 2.28 g (55.6%) of the objective compound (Ia-34) was obtained from the eluate with CH.sub.2 Cl.sub.2 - methanol (20/1 v/v). The crystals melting at 106.0.degree.-107.0.degree. C. were obtained by recrystallizing from ethanol.

Anal. Calcd. (%) for C.sub.9 H.sub.13 N.sub.5 O.sub.2 : C, 48.42; H, 5.87; N, 31.38. Found (%) : C, 48.47; H, 5.77; N, 31.19.

IR (CHCl.sub.3) : 3300, 1710, 1685, 1530, 1505 (sh), 1485, 1455, 1430 cm.sup.-1

NMR (CDCl.sub.3) : 1.85-2.20 (m, 2H), 2.58 (t, J=7 Hz, 2H), 3.65-3.90 (m, 4H), 4.37 (t, J=7 Hz, 2H), 7.97 (s, 1H), 8.08 (s, 1H), 8.55 (br., 1H) ##STR43##

In the same method as in Example 34 described above, 3.0 g (15.7 mmol) of 1-[(2-chloroethyl)carbamoyl]-2-oxopyrrolidine (III-1) was reacted with a solution of 1.29 g (18.9 mmol) of 1H-imidazole in 24 ml of DMF at 110.degree. C. for 6.5 hr. in the presence of 0.75 g. (18.9 mmol) of 60% NaH, whereby the compound (Ia-35) was obtained.

Yield : 1.22 g; 34.9%

m.p. : 130.5.degree.-131.5.degree. C. (Et.sub.2 O)

Anal. Calcd. (%) for C.sub.10 H.sub.14 N.sub.4 O.sub.2 : C, 54.04; H, 6.35; N, 25.21. Found (%) : C, 53.89; H, 6.29; N, 25.00.

IR (CHCl.sub.3) : 3300, 1710, 1680 (sh), 1540, 1510 (sh) cm.sup.-1

NMR (CDCl.sub.3) : 1.86-2.20 (m, 2H), 2.60 (t, J=7 Hz, 2H), 3.60 (q, J=6 Hz, 2H), 3.83 (t, J=7 Hz, 2H), 4.12 (t, J=6 Hz, 2H), 6.95 (s, 1H), 7.07 (s, 1H), 7.48 (s, 1H), 8.55 (br., 1H) ##STR44##

A mixture of 4.0 g (19.5 mmol) of 1-phenoxycarbonyl-2-oxopyrrolidine and 3.4 g (20.4 mmol) of 2-(4-methoxyphenylamino)ethylamine was heated at 115.degree.-120.degree. C. for 4 hr. The reaction solution was refined by silica gel column chromatography, whereby 4.94 g (87.0%) of the objective product (Ia-1) was obtained from the eluate with toluene - ethyl acetate (3/1 v/v). The needles melting at 83.5.degree.-84.5.degree. C. were obtained by recrystallizing from ethanol.

The reactions were carried out in the same method as in Example 36 described above. The reaction conditions and their properties of each objective compounds are shown in Tables 3 and 5, respectively. __________________________________________________________________________ ##STR45## Reaction Compound                Conditions Compound (Ia) Com- Ex. (II)  Compound (IV)     Temp. (.degree.C.) Yield   pound No. g (mmol) R            g (mmol) Time   (g) (%) No. __________________________________________________________________________ 37 2.86 (13.9) ##STR46##   2.2 (14.6) 115-120 5.5 hr. 3.21 88.1 I a-36 38 2.18 (10.6) ##STR47##   2.0 (11.7) 120-125 4 hr. 2.88 96.0 I a-37 __________________________________________________________________________

To a solution of 3.58 g (14.8 mmol) of 2-phthalimidoethylpyrazole in 45 ml of methanol was added 1.11 g (22.2 mmol) of hydrazine hydrate, and the mixture was refluxed for 7 hr. The solvent was evaporated under reduced pressure, and the residue was washed with CH.sub.2 Cl.sub.2 and ethyl acetate, and filtered. The filtrate was evaporated under reduced pressure, and then 2.73 g (13.3 mmol) of 2-oxo-1-phenoxycarbonylopyrrolidine (II) was added to the residue, and the mixture was heated at 115.degree.-120.degree. C. for 3 hr. After cooling, the reaction mixture was refined by silica gel column chromatography, and the resulting crystalline product obtained from the eluate with tolunene/ethyl acetate (3/1-1/1 v/v) was recrystallized from ether, whereby 1.91 g (64.7%) of the objective compound (Ia-38) melting at 62.5.degree.-63.5.degree. C. was obtained.

The reaction was carried out in the same method as mentioned above. The reaction conditions are shown in Table 4 and properties of the objective compounds are shown in Table 5. __________________________________________________________________________ ##STR48## Reaction Compound              Conditions Compound (Ia) Com- Ex. (II)  Compound (IV)   Temp. (.degree.C.) Yield   pound No. g (mmol) R          g (mmol) Time   (g) (%) No. __________________________________________________________________________ 40 4.8 (23.4) ##STR49## 5.3* (19.5) 115-120 3 hr. 3.51 62.8 I a-39 __________________________________________________________________________ *phthalimidate (Ia-40) ##STR50##

A mixture of 5.31 g (25.9 mmol) of 2-oxo-1-phenoxycarbonylpyrrolidine (II) and 4.67 g (25.9 mmol) of Compound (IV) was heated with stirring at 110.degree.-120.degree. C. for 4 hr. in a bath. After cooling, the reaction solution was refined by silica gel column chromatography, whereby 5.57 g of the oily objective compound (Ia-40) was obtained from the eluate with toluene/ethyl acetate (1/1 v/v) and ethyl acetate, respectively. Yield:74.0%

The properties of the objective compound are shown in Table 5. ##STR51##

A mixture of 1.87 g (9.13 mmol) of 2-oxo-1-phenoxycarbonylpyrrolidine (II), 2.39 g (9.13 mmol) of 2-(4-methoxyphenyloxy)ethyl-N-methylamine hydrobromide and 2.30 g (22.8 mmol) of triethylamine in 0.5 ml of DMA was heated at 115.degree.-125.degree. C. for 6.5 hr. and ethyl acetate was added to the reaction solution. The mixture was washed with aqueous NaHCO.sub.3 and water, and dried, then the solvent was distilled off. The residue was refined by silica gel column chromatography, whereby 2.37 g of an oily compound (Ia-41) was obtained from the eluate with toluene/ethyl acetate (5/1-3/1 v/v). Yield:88.8%

The properties of the objective compound are shown in Table 5. ##STR52##

A mixture of 1.16 g (5.64 mmol) of 2-oxo-1-phenoxycarbonylpyrrolidine (II) were added 2.0 g (8.06 mmol) of 2-(4-methoxyphenyloxy)ethylamine hydrobromide and 1.63 g (16.1 mmol) of triethylamine was heated at 110.degree. C. for 3 hr. After evaporation of the solvent, the residue was refined by silica gel column chromatography, whereby 1.86 g of the objective compound (Ia-42) was obtained as crystals from the eluate with toluene/ethyl acetate (5/1-3/1 v/v). Yield:83.0%

The objective compound melting at 62.5.degree.-64.5.degree. C. was obtained by recrystallizing from ethanol - ether. The properties of the objective compound (Ia-42) are shown in Table 5. dine (Ia-43) ##STR53##

To a mixture of 1.01 g (3.16 mmol) of 1-[2-[(4-methoxyphenyl)-(n-propyl)amino]ethyl]carbamoyl]-2 -oxopyrrolidine (Ia-4) in 15 ml of THF was added 126 mg (3.16 mmol) of NaH (60% at room temperature, and the mixture was stirred for 50 min. Then, the mixture was added to 0.265 ml (3.32 mmol) of EtI and stirred for 3 days at room temperature. The reaction solution was mixed with ethyl acetate and dried, and the solvent was removed by evaporation. The oily residue obtained was refined by silica gel column chromatography, whereby 330 mg of an oil compound (Ia-43) was obtained from the eluate with toluene/ethyl acetate (3/1-1/1 v/v).

Yield:30%

The properties of the objective compound are shown in Table 5. __________________________________________________________________________ m.p. (.degree.C.) Compd. (Recrystallizing Elementary Analysis IR (cm.sup.-1) No.  Solvent) Found (Calcd.) (%) (CHCl.sub.3) NMR (CDCl.sub.3) .delta. __________________________________________________________________________ Ia-36 102.0-103.0 C.sub.14 H.sub.19 N.sub.3 O.sub.2 3280, 1705, 1670 2.00(quint, J=7Hz, 2H), 2.21(s, 3H), 2.57 (EtOH)  C, 64.41 (64.32) 1610, 1535, 1510 (t, J=7Hz, 2H), 3.20-3.60(m, 4H), 3.83(t, N H, 7.33 (7.33)     J=7Hz, 2H), 6.53, 6.96(A.sub.2 B.sub.2, J=9Hz, 4H), N, 16.05 (16.08)   8.57(br., 1H) Ia-37 141.0-142.0 C.sub.13 H.sub.16 N.sub.3 O.sub.2 Cl 3280, 1705, 1670 (CDCl.sub.3 /CD.sub.3 OD=3/1) (EtOH)  C, 55.35 (55.42) 1595, 1530, 1495 2.04(quint, J=7Hz, 2H), 2.61(t, J=7Hz, 2H) H, 5.62 (5.72)     3.21-3.65(m, 4H), 3.86(t, J=7Hz, 2H), 6.57 N, 14.95 (14.91)   7.13(A.sub.2 B.sub.2, J=9Hz, 4H), 8.70(br., 1H) Cl, 12.47 (12.58) Ia-38 98.5-99.5 C.sub.11 H.sub.16 N.sub.4 O.sub.3 3300, 1710, 1680 2.02(quint, J=7Hz, 2H), 2.27(s, 3H), 2.59 (EtOH)  C, 52.34 (52.37) 1630, 1540 (t, J=7Hz, 2H), 3.30-3.55(m, 4H), 3.83(t, H, 6.38 (6.39)     J=7Hz, 2H), 5.47(s, 1H), 8.60(br., 1H) N, 22.24 (22.21) Ia-39 62.5-63.5 C.sub.10 H.sub.14 N.sub.4 O.sub.2 3280, 1700, 1.83-2.17(m, 2H), 2.57(t, J=7Hz, 2H), 3.75 (Et.sub.2 O) C, 54.21 (54.04) 1670 (sh), 1530 (q, J=5Hz, 2H), 3.83(t, J=7Hz, 2H), 4.28 H, 6.38 (6.35)     (t, J=5Hz, 2H), 6.23(d, J=2H, 1H), 7.37(d, N, 25.26 (25.21)   J=2Hz, 1H), 7.53(d, J=2Hz, 1H), 8.53(br., 1H) Ia-40 --      C.sub.15 H.sub.21 N.sub.3 O.sub.3 1710, 1660, 1500 1.92(quint, J=7Hz, 2H), 2.40(t, J=7Hz, 2H) C, 61.61 (61.84) 1470 (sh), 1455 2.99(s, 3H), 3.26(t, J=6Hz, 2H), 3.50-3.80 H, 7.22 (7.27)     (m, 4H), 3.72(s, 3H), 6.57, 6.76(A.sub.2 B.sub.2, J= N, 14.09 (14.42)   9Hz, 4H) Ia-41 --      C.sub.15 H.sub.20 N.sub.2 O.sub.4 1710, 1660, 1495 2.00(quint, J=7Hz, 2H), 2.42(t, J=7Hz, 2H) C, 61.60 (61.63) 1470 (sh), 1455 3.10(s, 3H), 3.75(s, 3H), 3.60-3.80(m, H, 6.97 (6.90) 1440 (sh), 1420 4H), 4.10(t, J=6Hz, 2H), 6.83(s, 4H) N, 9.50 (9.58) (sh) Ia-42 62.5-64.5 C.sub.14 H.sub.18 N.sub.2 O.sub.4 3280, 1705, 1.98(quint, J=7Hz, 2H), 2.55(t, J=7Hz, 2H) (EtOH--Et.sub.2 O) C, 60.45 (60.42) 1670 (sh), 1530, 3.75(s, 3H), 3.52-4.06(m, 6H) H, 6.55 (6.52) 1505, 1460 N, 10.01 (10.07) Ia-43 --      C.sub.19 H.sub.29 N.sub.3 O.sub.3 1705, 1650, 1500 0.88(t, J=7Hz, 3H), 1.18(t, J=7Hz, 3H), C, 65.46 (65.68) 1450, 1415 1.33-2.00(m, 4H), 2.30(t, J=7Hz, 2H), H, 8.49 (8.41)     3.00-3.55(m, 10H), 3.74(s, 3H), 6.65, N, 11.95 (12.10)   6.79(A.sub.2 B.sub.2, J=9Hz, __________________________________________________________________________ 4H) ##STR54##

To a solution of 2.20 g (7.93 mmol) of 1-[2-[(4methoxyphenylamino)ethyl]carbamoyl]-2-oxopyrrolidine (Ia-1) in 10 ml of DMA were added 1.01 ml (11.9 mmol) of allyl bromide and 1.92 ml (23.8 mmol) of pyridine, and the mixture was stirred for 20 min. at 80.degree.-85.degree. C. To the mixture was added 1.5 ml of pyridine and 0.8 ml of allyl bromide, and the mixture was further stirred for 10 min. and 1 hr. at the same temperature. The reaction solution was poured into ethyl acetate and washed with aqueous NaHCO.sub.3, water, and saturated brine in order. After drying, the solvent was removed by evaporation. The residue was refined by silica gas column chromatography, and the resulting crystalline compound from the eluate with toluene/ethyl acetate (8/1-3/1 v/v) was recrystallized from ether - n-hexane, whereby 1.92 g of the objective compound (Ia-44) melting at 53.0.degree.-54.0.degree. C. was obtained as crystals. Yield:76.4%

Anal. Calcd. (%) for C.sub.17 H.sub.23 N.sub.3 O.sub.3 : C, 64.33; H, 7.30; N, 13.24. Found (%) : C, 64.13; H, 7.35; N, 13.35.

IR (CHCl.sub.3) : 3310, 1705, 1675, 1540, 1505 cm.sup.-1

NMR (CDCl.sub.3) : 1.83-2.17 (m, 2H), 2.57 (t, J=7 Hz, 2H) 3.40 (s, 4H), 3.73 (s, 3H), 3.80-3.90 (m, 4H), 5.05-5.25 (m, 2H), 5.60-6.05 (m, 1H), 6.80 (s, 4H), 8.52 (br., 1H) ##STR55##

To a solution of 2.10 g (11.0 mmol) of 1-[2-chloroethylcarbamoyl]-2-oxopyrrolidine and 1.40 g (10 mmol) of 4-methoxybenzenethiol in 25 ml of DMF were added 2.47 g (16.5 mmol) of NaI and 3.02 g (22 mmol) of K.sub.2 CO.sub.3, and the mixture was heated at 100.degree. C. for 4.5 hr. The reaction solution was poured into ethyl acetate, washed with water, diluted hydrochloric acid, water, and saturated brine in order. After drying, the solvent was removed by evaporation. The residue was refined by silica gel column chromatography, whereby 2.78 g (94.6%) of the crystalline objective compound (Ia-45) was obtained from the eluate with benzene/ethyl acetate (8/1-5/1 v/v). The needles melting at 64.0.degree.-65.0.degree. C. are obtained by recrystallizing from ether - n-hexane. The properties of the objective compound (Ia-45) are shown in Table 7.

The reactions were carried out in the same method as in Example 46. The reaction conditions are shown in Table 6 and the properties are in Table 7. __________________________________________________________________________ ##STR56## Compound                        Reaction (III-1) HSR           K.sub.2 CO.sub.3 NaI     Conditions Compound (Ia) Ex g               g   g   g   DMF Temp. (.degree.C.) Yield No (mmol) R         (mmol) (mmol) (mmol) (ml) Time   (g) (%) No. __________________________________________________________________________ 47 3.50 (18.4) ##STR57## 2.15 (19.3) 5.05 (36.8) 4.14 (27.6) 40  110 21 hr. 2.83 58.0 Ia-46 48 2.50 (13.1) ##STR58## 1.54 (13.8) 3.6 (26.2) 2.94 (19.6) 25  100-105 89 hr. 2.60 74.4 Ia-47 49 2.50 (13.1) ##STR59## 1.40 (13.8) 3.6 (26.2) 2.94 (19.6) 25  105 89.5 hr. 0.85 25.4 Ia-48 50 1.09 (5.25) ##STR60## 0.73 (5.51) 1.44 (10.5) 1.18 (7.88) 20  110 3 hr. 0.57 45.9 Ia-49 51 3.50 (18.4) ##STR61## 2.30 (19.3) 5.05 (36.8) 4.14 (27.6) 40  110 14 hr. 2.37 47.2 Ia-50 52 3.50 (18.4) ##STR62## 3.70 (22.1) 5.05 (36.8) 4.14 (27.6) 40  110 14 hr. 5.02 85.0 Ia-51 __________________________________________________________________________ __________________________________________________________________________ m.p. (.degree.C.) Compd. (Recrystalliz- Elementary Analysis IR No.  ing solvent) Found (Calcd.) (%) (CHCl.sub.3) NMR (CDCl.sub.3) .delta. __________________________________________________________________________ I a-45 64.0-65.0 C.sub.14 H.sub.18 N.sub.2 O.sub.3 S 3290, 1700, 1670 1.80-2.16(m, 2H), 2.57(t, J=Hz, 2H), (Et.sub.2 O- C, 57.12 (57.12) 1585, 1530, 1485 2.97(t, J=7Hz, 2H), 3.45(q, 7Hz, 2H), n-hexane) H,  6.03  (6.16) 1450, 1430 3.80(s, 3H), 3.82(t, J=7Hz, 2H), 6.85 N,  9.53  (9.52)   7.40(A.sub.2 B.sub.2, J=9Hz, 4H), 8.67(br., 1H) S, 10.90 (10.89) I a-46 62.5-63.5 C.sub.12 H.sub.15 H.sub.3 O.sub.2 S 3300, 1700, 1675 1.83-2.18(m, 2H), 2.57(t, J=7Hz, 2H), (Et.sub.2 O) C, 54.39 (54.32) 1575, 1530, 1485 3.25-3.66(m, 4H), 3.83(t, J=7Hz, 2H), H,  5.70  (5.70) 1450, 1405 6.85-7.60(m, 3H), 8.45(dd, J.sub.1 =6Hz, J.sub.2 = N, 15.83 (15.84)   2Hz), 8.67(br., 1H) S, 11.96 (12.08) I a-47 96.0-97.0 C.sub. 11 H.sub.14 H.sub.4 O.sub.2 S 3300, 1700, 1670 1.83-2.20(m, 2H), 2.58(t, J=7Hz, 2H), (EtOH) C, 49.60 (49.61) 1550 (sh), 1540 3.33(t, J=7Hz, 2H), 3.62(q, J=7Hz, 2H), H,  5.33  (5.30)   3.84(t, J=7Hz, 2H), 6.97(t, J=5Hz, 1H), N, 20.97 (21.04)   8.55 (d, J=5Hz, 2H), 8.70(br., 1H) S, 11.94 (12.04) I a-48 123.0-124.0 C.sub.9 H.sub.13 N.sub.5 O.sub.2 S 3375, 3270, 1710 (CDCl.sub.3.CDOD=3/1) (EtOH) C, 42.32 (42.24) 1675    1.86-2.20(m, 2H), 2.62(t, J=7H, 2H), H,  5.13  (5.13)   3.27(t, J=7Hz, 2H), 3.60(q, J=7Hz, 2H), N, 27.27 (27.43)   3.83(t, J=7Hz, 2H), 8.13(s, 1H), 8.77 S, 12.46 (12.56)   (br. s, 1H) I a-49 112.0-113.0 C.sub.10 H.sub.14 N.sub.4 O.sub.2 S.sub.2 3300, 1705, 1675 1.87-2.20(m, 2H), 2.59(t, J=7Hz, 2H), 2.71 (EtOH) C, 41.98 (41.94) 1530, 1480, 1450 (s, 3H), 3.40-3.95(m, 6H), 8.70(br., 1H) H,  4.96  (4.93) 1425, 1375 N, 19.62 (19.56) S, 22.36 (22.39) I a-50 71.0-72.0 C.sub.10 H.sub.15 N.sub.3 O.sub.2 S.sub.2 3300, 1705, 1680 1.85-2.20(m, 2H), 2.60(t, J=7Hz, 2H), (EtOH) C, 44.05 (43.94) 1560 (sh), 1530 3.19-3.47(m, 4H), 3.57(t, J=7Hz, 2H), 3.83 H,  5.51  (5.53) 1480, 1455, 1430 (t, J=7Hz, 2H), 4.20(t, J=7Hz, 2H), 8.63 N, 15.40 (15.37)   (br., 1H) S, 23.40 (23.46) I a-51 114.5-115.5 C.sub.14 H.sub.16 N.sub.3 O.sub.2 S.sub.2 3300, 1700, 1680 1.77-2.10(m, 2H), 2.48(t, J=7Hz, 2H), (EtOH) C, 52.27 (52.32) 1530, 1480, 1455 3.45-3.78(m, 4H), 3.80(t, J=7Hz, 2H), H,  4.52  (4.70) 1420    7.15-7.50(m, 2H), 7.67-7.90(m, 2H), 8.70 N, 12.88 (13.07)   (br., 1H) S, 20.10 (19.95) __________________________________________________________________________ ##STR63##

To a solution of 0.70 g (2.38 mmol) of 1-[[2-(4-methoxyphenylthio)ethyl]carbamoyl]-2-oxopyrrolidine in 30 ml of CH.sub.2 Cl.sub.2 was added 0.96 g (4.76 mmol) of m-CPBA (content 85%), and the mixture was stirred for 1.5 hr. at room temperature. The reaction solution was poured into ethyl acetate, washed with aqueous NaHCO.sub.3 and water. After drying, the solvent was removed by evaporation. The residue was refined by silica gel column chromatography, then the crystalline objective compound was obtained from the eluate with benzene/ethyl acetate (1/1 v/v). The product was recrystallized from ether to give 0.0684 g of crystals (Ib-1) melting at 124.0.degree.-125.0.degree. C.

Yield:88.0%

The properties of the objective compound are shown in Table 10.

The reaction was carried out in the same method as in Example 53. The reaction conditions are shown in Table 8 and the properties are in Table 10. __________________________________________________________________________ ##STR64## Reaction Compound (Ia) m-CPBA Conditions Compound (Ib) Ex.       mg  CH.sub.2 Cl.sub.2 g    Temp. (.degree.C.) Yield   Compound No. R      (mmol) (ml) (mmol) Time   (g) (%) No. __________________________________________________________________________ 54 ##STR65## 1.66 (6.23) 55   2.70* (12.5) Room Temp. 3 hr. 1.10 59.1 Ib-2 __________________________________________________________________________ *: Content 80%

To a solution of 2.0 g (7.54 mmol) of 2-oxo-1-[[2-pyridin-2-ylthio)ethyl]carbamoyl]pyrrolidine in 35 ml of CH.sub.2 Cl.sub.2 was added 1.63 g (7.54 mmol) of m-CPBA (content 80%) under ice-cooling. Then the mixture was stirred for 1.5 hr. at room temperature. The reaction solution was washed with aqueous NaHCO.sub.3 and water. After drying, the solvent was removed by evaporation. The residue was refined by silica gel column chromatography, then the crystalline objective compound was obtained from the eluate with benzene/ethyl acetate (3/1-1/1 v/v). The compound was washed with Et.sub.2 O and collected by filtration, whereby 0.93 g of the crystalline compound (Ib-3) melting at 119.5.degree.-120.5.degree. C. was obtained. Yield:43.9%

The properties of the objective compounds are shown in Table 8.

In the same method as in Example 55, the reactions were carried out as shown in Table 9. The properties are shown in Table 10. __________________________________________________________________________ ##STR66## Reaction Compound (Ia)      m-CPBA Conditions Compound (Ib) Ex.          mg  CH.sub.2 Cl.sub.2 g    Temp. (.degree.C.) Yield   Compound No. R         (mmol) (ml) (mmol) Time   (g) (%) No. __________________________________________________________________________ 56 ##STR67## 1.62 (6.08) 45   1.23* (6.08) Room Temp. 2.25 hr. 1.08 62.9 Ib-4 57 ##STR68## 2.13 (6.62) 30   1.43** (6.62) Room Temp. 2.5 hr. 1.86 83.2 Ib-5 __________________________________________________________________________ *Content 85%; **Content 80% __________________________________________________________________________ m.p. (.degree.C.) Compd. (Recrystalliz- Elementary Analysis IR (cm.sup.-1) No.  ing solvent) Found (Calcd.) (%) (CHCl.sub.3) NMR (CDCl.sub.3) .delta. __________________________________________________________________________ I b-1 124.0-125.0 C.sub.14 H.sub.18 N.sub.2 O.sub.6 S 3300, 1710, 1685 1.80-2.15(m, 2H), 2.56(t, J=7Hz, 2H), 3.37 (EtOH) C, 51.48 (51.52) 1595, 1580, 1535 (t, J=6Hz, 2H), 3.62(q, J=6Hz, 2H), 3.74 H,  5.52  (5.56) 1500    (t, J=7Hz, 2H), 3.88(s, 3H), 7.02, 7.84 N,  8.64  (8.58)   (A.sub.2 B.sub.2, J=9Hz, 4H), 8.64(br. s, 1H) S,  9.87  (9.82) I b-2 104.5-105.5 C.sub.11 H.sub.14 N.sub.4 O.sub.4 S 3300, 1710, 1685 1.85-2.18(m, 2H), 2.57(t, J=7Hz, 2H), (EtOH) C, 44.25 (44.29) 1560, 1535, 1485 3.73-3.90(m, 6H), 7.58(t, J=5Hz, 1H), H,  4.70  (4.73) 1460, 1430 8.98(d, J=5Hz, 2H), 8.74(br., 1H) N, 18.74 (18.78) 2, 10.63 (10.75) I b-3 119.5-120.5 C.sub.12 H.sub.15 N.sub. 3 O.sub.3 S 3290, 1710, 1680 1.80-2.16(m, 2H), 2.56(t, J=7Hz, 2H), (Et.sub.2 O) C, 51.18 (51.23) 1575, 1530 3.02-3.41 (m, 2H), 3.55-3.87(m, 4H), H,  5.26  (5.37)   7.27-7.45(m, 1H), 7.80-8.07(m, 2H), N, 14.87 (14.94)   8.50-8.75(m, 2H) S, 11.47 (11.40) I b-4 123.0-124.0 C.sub.11 H.sub.14 N.sub.4 O.sub.3 S 3290, 1710, 1685 1.84-2.19(m, 2H), 2.57(t, J=7Hz, 2H), (EtOH) C, 46.83 (46.80) 1560, 1530 3.23-3.50(m, 2H), 3.66-3.88(m, 4H), 7.43 H,  5.06  (5.00)   (t, J=6Hz, 1H), 8.57(br., 1H), 8.90(d, N, 19.71 (19.85)   J=6Hz, 2H) S, 11.08 (11.36) I b-5 144.0-145.0 C.sub.14 H.sub.16 N.sub.3 O.sub.3 S.sub.2 3280, 1710, 1685 1.70-2.00(m, 2H), 2.27-2.50(m, 2H), 3.50- (EtOH) C, 49.86 (49.84) 1525    3.95(m, 6H), 7.37-7.66(m, 2H), 7.95-8.14 H,  4.35  (4.48)   (m, 2H), 8.53(br., 1H) N, 12.39 (12.45) S, 18.87 (19.00) __________________________________________________________________________

The reactions were carried out in the same method as in the aforementioned Example 1, whereby the compounds (Ia) were obtained. The reaction conditions and the properties of the objective compounds are shown in Tables 11 and 12, respectively. __________________________________________________________________________ ##STR69## Compound              Reaction (III-2) (V) K.sub.2 CO.sub.3 NaI     Condition Compound (Ia) Ex. g     g   g   g   DMF Temp. (.degree.C.)  Yield Compd. No. (mmol) (mmol) (mmol) (mmol) (ml) Time   Z.sup.1,   Z.sup.2 (g) (%) No. __________________________________________________________________________ 58 3.17 (15.5) 2.10 (17.0) 5.36  (38.8) 3.48 (23.2) 35  105-110 29 hr. ##STR70## H 1.90 42.1 Ia-52 59 3.00 (14.7) 3.41 (16.1) 5.08 (36.8) 3.30 (22.1) 35  100-105 6 d. ##STR71##   4.24 76.0 Ia-53 60 3.00 (14.7) 2.84 (16.1) 5.08 (36.8) 3.30 (22.1) 35  100-105 6 d. ##STR72##   4.29 85.0 Ia-54 61 2.74 (13.4) 2.50 (14.1) 4.63 (33.5) 3.0 (20.1) 30  100-105 3 d. ##STR73##   3.95 85.4 Ia-55 62 1.23 (6.0) 1.27 (6.12) 2.07 (15.0) 1.35 (9.0) 20  95-100 4 d. ##STR74##   1.49 66.0 Ia-56 63 3.73 (18.2) 3.34 (18.2) 7.55 (54.6) 4.06 (27.3) 35  100-105 4 d. ##STR75##   5.76 89.9 Ia-57 64 2.08 (10.9) 2.41 (11.6) 4.52 (32.7) 2.45 (16.4) 30  100-105 4 d. ##STR76##   3.12 81.5 Ia-58 65 2.99 (14.6) 3.10 (14.6) 6.05 (43.8) 3.28 (21.9) 35  100-105 5 d. ##STR77##   4.96 89.3 Ia-59 __________________________________________________________________________ __________________________________________________________________________ m.p. (.degree.C.) Compound (Recystalliz- Elementary Analysis No.   ing solvent Found (Calcd.) (%) IR (cm.sup.-1) NMR (CDCl.sub.3) .delta. __________________________________________________________________________ I a-52 114.5-115.5 C.sub.15 H.sub.21 N.sub.3 O.sub.3 (CHCl.sub.3) 1.83(t, J=6Hz, 2H), 2.01(quint, J=7Hz, 2H) (EtOH) C, 61.78 (61.84) 3280, 1700, 1670 2.60(t, J=7Hz, 2H), 3.16(t, J=6Hz, 2H), H,  7.13  (2.26) 1540, 1500, 1480 3.45(q, J=6Hz, 2H), 3.75(s, 3H), 3.86(t, N, 14.36 (14.42) 1455    J=7Hz, 2H), 6.60, 6.80 (A.sub.2 B.sub.2, J=9Hz, 4H), 8.50(br., 1H) I a-53 138.0-139.0 C.sub.19 H.sub.26 N.sub.3 O.sub.3 Cl (CHCl.sub.3) 1.60-3.40(m, 16H), 3.36(q, J=6Hz, 2H), (EtOH-Et.sub.2 O) C, 59.73 (60.07) 3290, 1700, 1670 3.77(t, J=7Hz, 2H), 7.30, 7.47(A.sub.2 B.sub.2, J=9Hz H,  6.92  (6.90) 1535, 1480 4H), 8.58(br., 1H) N, 10.93 (11.06) Cl, 9.55  (9.33) I a-54 dimaleate C.sub.19 H.sub.23 N.sub.4 O.sub.2. (Nujol) (CD.sub.3 OD: D.sub.2 O=6:1) 200.0-201.0 2C.sub.4 H.sub.4 O.sub.4 dimaleate dimaleate (d)          C, 56.02 (56.24) 3250, 1700 1.78-2.03(m, 4H), 2.54(t, J=7Hz, 2H), (MeOH-       H,  6.28  (6.29) 1680 (sh), 1610 3.03-3.93(m, 12H), 3.68(t, J=7Hz, 2H), i-PrOH)      N,  9.75  (9.72) 1560    4.19(s, 2H), 6.21(s, 4H), 7.42(s, 5H) I a-55 94.5-95.5 C.sub.19 H.sub.27 N.sub.3 O.sub.3 (CHCl.sub.3) 1.70-2.88(m, 17H), 3.37(q, J=6Hz, 2H) (i-PrOH-     C, 66.13 (66.06) 3295, 2920, 2800 3.85(t, J=7Hz, 2H), 7.20-7.60(m, 5H), 8.57 Et.sub.2 O)  H,  7.84  (7.88) 1705, 1670, 1535 (br., 1H) N, 12.14 (12.17) I a-56 98.5-99.0 C.sub.20 H.sub.29 N.sub.3 O.sub.4 (CHCl.sub.3) 1.60-2.90(m, 17H), 3.36(q, J=6Hz, 2H) (i-PrOH-     C, 63.69 (63.97) 3275, 2920, 1705 3.79(s, 3H), 3.83(t, J= 7Hz, 2H), 6.86, Et.sub.2 O)  H,  7.83  (7.79) 1603, 1535, 1505 7.44 (A.sub.2 B.sub.2, J=9Hz, 4H), 8.55(br., 1H) N, 11.20 (11.19) I a-57 1/2(COOH).sub.2 C.sub.17 H.sub.25 N.sub.3 S.CHO.sub.2 (Nujol) (free base) 224.0-226.0  C, 54.42 (54.81) 1/2(COOH).sub.2 1.744(quint, J=7.2Hz, 17H), 1.85-2.25(m, (d)          H,  6.51  (6.64) 3290, 3110, 1700 6H), 2.40-2.80(m, 8H), 3.346(q, J=6Hz, (MeOH-       N, 10.56 (10.65) 1678, 1630 2H), 3.83(t, 7=7Hz, 2H), 6.97-6.98(m, 2H), i-PrOH)      S,  7.93  (8.13)   7.17-7.21(m, 1H), 8.516(br., 1H) I a-58 (COOH).sub.2 C.sub.17 H.sub.25 N.sub.3 O.sub.3 S. (Nujol) (free base) 144.0-145.0 C.sub.2 H.sub.2 O.sub.4 1/2H.sub.2 O (COOH).sub.2 1.65-1.85(m, 4H), 1.90-2.10(m, 5H), 2.240, (i-PrOH)     C, 50.86 (50.66) 3450, 3310, 3230 2.879(ABq, J=11Hz, 2H), 2.469(t, J=7Hz, H,  6.08  (6.26) 1700, 1665, 1640 2H), 2.613(t, J=8Hz, 2H), 2.937(br., N,  9.26  (9.33) 1620 (sh) J=12Hz, 1H), 3.900(m, 2H), 3.865(t, J=7Hz, S,  7.12  (7.12)   2H, 4.230(br. s, 1H), 6.956-6.974(m, 2H), 7.187-7.273(m, 1H), 8.607(br. s, 1H) I a-59 74.5-76.0 C.sub.19 H.sub.26 N.sub.3 O.sub.3 Cl (CHCl.sub.3) 1.65-1.82(m, 5H), 1.90-2.10(m, 4H), 2.198 (Et.sub.2 O) C, 60.16 (60.07) 3470, 3300, 1705 (a part of ABq, J=11Hz, 1H), 2.467(t, H,  6.72  (6.90) 1670, 1540, 1485 J=5Hz, 2H), 4.16(s, 1H), 7.26-7.50(m, 4H), N, 11.12 (11.06)   8.594(br. s, 1H) S,  9.40  (9.33) __________________________________________________________________________ lidine maleate (Ic-1) ##STR78##

A solution of 1.67 g (4.83 mmol) of 1-[[3-(4-hydroxy-4-phenyl-1-piperidino)propyl]carbamoyl ]-2-oxopyrrolidine (Ia-55) in 25 ml of 10% hydrochloric acid was refluxed for 2 hr. The reaction solution was made alkaline with aqueous NaHCO.sub.3, extracted with ethyl acetate, and washed with saturated brine. After drying, the solvent was removed by evaporation. The residue was refined by silica gel column chromatography, whereby 0.65 g of the objective product (Ic-1) was obtained from the eluate with ethyl acetate. Yield:41%

The objective product (Ic-1) (maleate) was recrystallized from isopropyl alcohol - ether, whereby crystals melting at 1.45.0.degree.-148.degree. C. were obtained.

The properties of the objective compound (Ic-1) are shown in Table 13. -2-oxopyrrolidine (Ic-2) ##STR79##

A solution of 1.6 g (4.21 mmol) of 1-[[3-[4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl]propyl]carbamoyl]-2-oxop yrrolidine (Ia-53) and 0.96 g (5.05 mmol) of p-toluenesulfonic acid monohydrate in 75 ml of toluene was refluxed for 29 hr. The water was removed azeotropically using a Dean-Stark trap containing 10 g of Molecular Sieves-4A. the solution, after being made alkaline with aqueous NaOH, was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine in order. After drying, the solvent was removed by evaporation. The residue was refined by silica gel column chromatography, whereby 1.50 g of the objective crystalline compound (Ic-2) was obtained from the eluate with ethyl acetate and then CH.sub.2 Cl.sub.2 /MeOH (20/1 v/v).

Yield:98.4%

By recrystallizing from ether - isopropyl alcohol, crystals melting at 88.0.degree.-88.5.degree. C. were obtained. The properties of the objective compound (Ic-2) are shown in Table 13. __________________________________________________________________________ m.p. (.degree.C.) Compd. (Recrystalliz- Elementary Analysis No.  ing solvent) Found (Calcd.) (%) IR (cm.sup.-1) NMR .delta. __________________________________________________________________________ I c-1 maleate C.sub.19 H.sub.25 N.sub.3 O.sub.2. (Nujol) (CD.sub.3 OD) 145.0-148.0 C.sub.4 H.sub.4 O.sub.4 maleate maleate (i-PrOH-    C, 62.35 (62.29) 3300, 2910, 2840 1.95-2.15(m, 4H), 2.61(t, J=8Hz, 2H), Et.sub.2 O) H,  6.62  (6.59) 1705, 1675, 1620 2.90(br., 2H), 3.25-3.35(m, 2H), 3.43 N,  9.46  (9.48) 1580, 1510 (t, J=6Hz, 2H), 3.58(br., 2H), 3.81(t, t=7Hz, 2H), 3.96(br., 2H), 6.15(br., 1H), 6.25(s, 2H), 7.30-7.55(m, 5H) I c-2 88.0-88.5 C.sub.19 H.sub.24 N.sub.3 O.sub.2 Cl (CHCl.sub.3) (CDCl.sub.3) (i-PrOH-    C, 63.16 (63.06) 3275, 2850, 1705 1.75-1.90(m, 2H), 2.02(quint, J=7Hz, 2H), Et.sub.2 O) H,  6.74  (6.68) 1530    2.47-2.75(m, 8H), 3.16(q, J= 3Hz, 2H), N, 11.61 (11.61)   3.38(q, J=6Hz, 2H), 3.86(t, J=7Hz, 2H), Cl, 10.02  (9.80)   6.05(br., 1H), 7.27, 7.30(A.sub.2 B.sub.2, J=7Hz, 4H) 8.48(br., 1H) __________________________________________________________________________ -oxopyrrolidine (Ia-29) ##STR80##

A solution of 1.68 g (4.59 mmol) of 1-[[2-[4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl]ethyl]carbamoyl]-2-oxopy rrolidine (Ia-25) and 1.05 g (5.5 mmol) of p-toluenesulfonic acid monohydrate in 75 ml of toluene was refluxed for 25 hr. using a Dean-Stark trap containing 10 g of Molecular Sieves-4A. By proceeding as in Example 67, 1.57 g of the objective compound (Ia-29) was obtained.

Yield:98.3%

In the same method as in Example 68, the reactions were carried out under the conditions shown in Tables 14 and 15, whereby the objective compounds (Ic) were obtained. The properties are shown in Table 16. __________________________________________________________________________ ##STR81## Compd. (Ia) p-TsOH.H.sub.2 O Refluxing Compound (Ic) Ex.      g     g        Toluene Time   Yield No.  n   (mmol) (mmol)   (ml)   (hr.)  (g)  (%)  No. __________________________________________________________________________ 69   3   4.23  2.75     250    26     3.94 98.2 Ic-3 (12.0) (14.4) 70   2   2.00  1.46     150    25     1.75 92.4 1 c-4 (5.93) (7.70) __________________________________________________________________________ __________________________________________________________________________ ##STR82## Compd. (Ia) p-TsOH.H.sub.2 O Refluxing Compound (Ic) Ex.       g     g        Toluene Time    Yield No.   n   (mmol) (mmol)   (ml)    (hr.)   (g)  (%)  No. __________________________________________________________________________ 71    3   4.40  2.97     250     48      3.57 85.0 Ic-5 (11.6) (15.6) 72    2   1.60  1.12     120     48      1.52 92.1 Ic-6 (4.37) (5.90) __________________________________________________________________________ __________________________________________________________________________ m.p. (.degree.C.) Compd. (Recrystalliz- Elementary Analysis IR (cm.sup.-1) No.  ing solvent) Found (Calcd.) (%) (CHCl.sub.3) NMR (CDCl.sub.3) .delta. __________________________________________________________________________ I c-3 maleate C.sub.17 H.sub.23 N.sub.3 O.sub.2 S. (Nujol) (free base) 152.0-153.5 C.sub.4 H.sub.4 O.sub.4 maleate 1.804(quint, J=7Hz, 2H), 2.015(quint, (MeOH-      C, 56.06 (56.11) 3320, 1715, 1690 J=7Hz, 2H)2.50-2.75(m, 8H), 3.131(quint, i-PrOH)     H,  5.95  (6.05) 1620, 1595, 1530 J=3Hz, 2H), 3.380(q, J=6Hz, 2H), 3.855 N,  9.41  (9.35)   (t, J=7Hz, 2H), 6.075(m, 1H), 6.90-7.30 S,  7.04  (7.13)   (m, 3H), 8.499(br., 1H) I c-4 98.5-100 C.sub.16 H.sub.21 N.sub.3 O.sub.2 S 3300, 1730, 1675 2.022(quint, J=7.2Hz, 2H), 2.55-2.80(m, (i-PrOH-    C, 60.26 (60.16) 1540    8H), 3.194(q, J=3Hz, 2H), 3.489(q, J=6Hz, Et.sub.2 O) H,  6.62  (6.63)   2H), 3.858(t, J= 7Hz, 2H), 6.071(m, 1H), N, 13.09 (13.16)   6.90-7.15(m, 3H), 8.613(br., 1H) S,  9.88 (10.04) I c-5 maleate C.sub.19 H.sub.24 N.sub.3 O.sub.2 Cl. (Nujol) (free base) 134.5-135.5 C.sub.4 H.sub.4 O.sub.4 1/5H.sub.2 O maleate 1.845(quint, J=7Hz, 2H), 2.014(quint, (i-PrOH)    C, 57.46 (57.37) 3290, 1695, 1610 J=7Hz, 2H), 2.30-2.40(m, 2H), 2.55-2.65 H,  5.82  (5.94) 1570 (sh), 1525 m, 6H), 3.27-3.30(m, 2H), 3.392(q, J=6Hz, N,  8.56  (8.73) 1450    2H), 3.854(t, J=7Hz, 2H), 6.09-6.12(m, Cl, 7.29  (7.36)   1H, 7.264(s, 4H), 8.499(br. s, 1H) I c-6 102.5-104.0 C.sub.18 H.sub.22 N.sub.3 O.sub.2 Cl 3290, 1705, 1670 2.026(quint, J=7Hz, 2H), 2.343-2.380 (MeOH-      C, 62.10 (62.15) 1540, 1520 (sh), (m, 2H), 2.558-2.757(m, 6H), 3.357(s, 2H), Et.sub.2 O) H, 6.35  (6.37) 1485    3.527(q, J=5.6Hz, 2H), 3.864(t, J=7Hz, N, 11.91 (12.08)    2H), 6.10-6.15(m, 1H), 7.265(s, 4H), Cl, 9.99 (10.19)    8.624(br. s, 1H) __________________________________________________________________________ ##STR83##

To a solution of 7.36 g (184 mmol) of NaH (60%) in 200 ml of THF was added 15.68 g (184 mmol) of 2-oxopyrrolidine with stirring under ice-cooling, and further the mixture was stirred at room temperature for 1 hr. until H.sub.2 gas ceased to evolve. The reaction solution was added to a solution of 29.7 g (190 mmol) of phenyl chloroformate in 100 ml of THF cooled at -60.degree. C. and then stirred at room temperature for 4 hr. The reaction solution was poured into ice water, and then extracted with ethyl acetate. After drying, the solvent was removed by evaporation. When the crystalline residue was recrystallized from CH.sub.2 CL.sub.2 - ether, 37.8 g of the objective compound (II) melting at 120.0.degree.-121.5.degree. C. was obtained as crystals. Yield:84.0%

The properties of the objective compound are shown in Table 17. ##STR84##

A mixture of 65.1 g (765 mmol) of 2-oxopyrrolidine and 67.3 g (638 mmol of chloroethyl isocyanate was heated with stirring at 95.degree.-105.degree. C. overnight. After cooling, the reaction solution was refined by silica gel chromatography. The resulting compound obtained from the eluate with toluene - ethyl acetate (20/1-10/1 v/v) was recrystallized from CH.sub.2 Cl.sub.2 -ether - n-hexane, whereby 107.7 g of the objective compound 1-(2-chloroethylcarbamoyl)-2-oxopyrrolidine (III-1) melting at 66.5.degree.-67.5.degree. C. was obtained as crystals.

Yield:88.5%

The properties of the objective compound are shown in Table 17. ##STR85##

A mixture of 17.1 g (201 mmol) of 2-oxopyrrolidine and 20 g (167 mmol) of chloropropyl isocyanate was heated with stirring at 95.degree.-105.degree. C. overnight. After cooling, the reaction solution was refined by silica gel chromatography. The resulting product obtained from the eluate with toluene - ethyl acetate (20/-10/1 v/v) was washed with ether - n-hexane and then collected by filtration, whereby 27.87 g of the objective compound 1-(3-chloropropylcarbamoyl)-2-oxopyrrolidine (III-2) melting at 57.0.degree.-58.0.degree. C. was obtained as crystals. Yield:81.0%

The properties of the objective compound are shown in Table 17. __________________________________________________________________________ Ref. m.p. (.degree.C.) Ex. (Recrystalliz- Elementary Analysis IR (cm.sup.-1) No. ing solvent) Found (Calcd.) (%) (CHCl.sub.3) NMR (CDCl.sub.3) .delta. __________________________________________________________________________ 1  120.0-121.5 C.sub.11 H.sub.11 NO.sub.3 1795, 1750 (sh), 2.09(quint, J=7Hz, 2H), 2.60(t, J=7Hz, 2H) (CH.sub.2 Cl.sub.2 - C, 64.43 (64.38) 1730, 1590, 1485 3.93(t, J=7Hz, 2H), 7.10-7.50(m, 5H) Et.sub.2 O) H,  5.33  (5.40) N,  6.87  (6.83) 2  66.5-67.5 C.sub.7 H.sub.11 N.sub.2 O.sub.2 Cl 3300, 1705, 1680 2.04(quint, J=7Hz, 2H), 2.63(t, J=7Hz, 2H) (Ch.sub.2 Cl.sub.2 - C, 43.83 (44.10) 1540    3.63 (s, 2H), 3.66(s, 2H), 3.87(t, J=7Hz, Et.sub.2 O- H,  5.80  (5.82)   2H), 8.77(br. s, 1H) n-hexane) N, 14.88(14.70) Cl, 18.80 (18.60) 3  57.0-58.0 C.sub.8 H.sub.13 N.sub.2 O.sub.2 Cl 3275, 1700, 1.80-2.20(m, 4H), 2.60(t, J=7Hz, 2H), 3.45 (Et.sub.2 O- C, 46.96 (46.95) 1670 (sh), 1530, (q, J=6Hz, 2H), 3.84(t, J=6Hz, 2H), 8.46 n-hexane) H,  6.37  (6.40)   (br. s, 1H) N, 13.78 (13.69) Cl, 17.48 (17.32) __________________________________________________________________________ 1-[[2-(4-Methoxyphenyl)aminoethyl]- 10 mg carbamoyl]-2-oxopyrrolidine Wheat starch           48 mg Magnesium stearate      2 mg ______________________________________

The above ingredients are admixed each other to prepare a capsule.

Carbamoylpyrrolidone derivatives (I) of the present invention showed good activity against amnesia introduced by electro convulsive shock.

In the following experiment of the compounds of this invention, the numbers of the test compounds correspond to them in Examples and/or Tables.

The test apparatus was a black acrylic resin box (30.times.30.times.30 cm) with an electrifiable grid floor in which a white wooden platform (10.times.10.times.1 cm) was placed in one corner. The step-down passive avoidance test was conducted on 3 groups of 10 SD mice each (male, 4 to 5 weeks age). A solvent was orally administered to the animals of the first group as a control group and the test compounds at doses of 5 and 50 mg/kg were orally given to other 2 groups 60 min. before the acquisition trial. In the acquisition trail, mice were individually placed on the platform and a scrambled foot shock (3mA, for 5 sec.) was delivered through the grid floor as soon as the mouse moved off the platform. Five to ten min. after the foot shock, a single electroconvulsive shock (30 mA, 100 Hz (rectangular wave), for 0.2 sec.) was administered transcorneally and ten each animal was placed in the home cage. After 24 hr. later, each mouse was again placed on the platform and the latency for descending on the grid floor was measured. A long latency in the retention test indicates good acquisition. The step-down latencies were evaluated using the Mann-Whitney U-test.

In Table 5, the results were shown as percent change in latencies over control defined as 100. ______________________________________ Effects of Compounds against Amnesia Induced by Electro Convulsive Shock Compound No.     5 mg/kg     50 mg/kg ______________________________________ I a - 1          302***      219* I a - 5          166**       108 I a - 18         223*        249** I a - 25         222***      205*** I a - 45         144         181*** I a - 53         181**       122 ______________________________________ *p < 0.05 **p < 0.025 ***p < 0.01

## Claims

1. A compound of the formula: ##STR86## wherein R.sup.1 is hydrogen, or C.sub.1 -C.sub.6 alkyl; n is an integer of from 2 to 3; Z.sup.1 is phenyl, benzyl, or isoxazolyl and each is optionally substituted by a halogen, a methoxy, or a methyl group; Z.sup.2 is hydrogen, C.sub.1 -C.sub.5 alkyl, allyl, unsubstituted phenyl, or phenyl substituted by halogen, methyl, or methoxy; or a pharmaceutically acceptable acid addition salt thereof.

2. The compound as claimed in claim 1 which is 1-[[2-(4-methoxyphenyl)aminoethyl]carbamoyl]-2-oxopyrrolidine.

3. The compound as claimed in claim 1 which is 1-[[2-(2,5-dimethoxyphenyl)aminoethyl]carbamoyl]-2-oxopyrrolidine.

4. A pharmaceutical composition comprising a pharmaceutically effective amount of a compound as recited in claim 1, together with a carrier, diluent or excipient.

5. A pharmaceutical composition comprising a pharmaceutically effective amount of a compound as recited in claim 2, together with a carrier, diluent or excipient.

6. A pharmaceutical composition comprising a pharmaceutically effective amount of a compound as recited in claim 3, together with a carrier, diluent or excipient.

7. A compound of the formula ##STR87## wherein R.sup.1 is hydrogen or C.sub.1 -C.sub.6 alkyl, n is an integer of from 2 to 3; Z.sub.1 and Z.sub.2 are taken together with the adjacent nitrogen atom to form triazolyl, imidazolyl or pyrazolyl; or a pharmaceutically acceptable acid addition salt thereof.

8. A pharmaceutical composition comprising a pharmaceutically effective amount of a compound as recited in claim 7, together with a carrier, diluent or excipient.