Carbamoylpyrrolidone derivatives, their use and preparation

Abstract: Compounds of the formula: (wherein R is phenoxy optionally substituted by a halogen, methoxy, or methyl group, one of A and B is and the other is R¹ is hydrogen or C₁-C₅ alkyl; Z¹ is phenyl, benzyl, or isoxazolyl each optionally substituted by a halogen, methoxy, or methyl group; Z² is hydrogen, C₁-C₅ alkyl, C₂-C₅ alkenyl, or phenyl optionally mono-, di-, or tri-substituted by a halogen, methoxy, or methyl group; or Z¹ and Z² taken together with the adjacent nitrogen atom may form 5-membered heterocyclic group; Z³ is C₁-C₅ hydroxyalkyl, di(C₁-C₅ alkyl)sulfamoyl, 6-membered hetero­ cyclic group, phenyl, benzyl, or phenylsulfonyl each phenyl moiety of the last three members being optionally substituted by a halogen, methoxy, or methyl group; Z⁴ 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; Z⁵ is thienyl or phenyl each optionally substituted by a halogen, methoxy, or methyl group; Z⁶ 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), and their acid addition salts may be useful as drugs for senile dementia, or as psychotropic, or antiamnesia agents.

Description: This invention relates to carbamoylpyrrolidone derivatives which are useful as drugs for senile dementia, or as psychotropic, and/or antiamnesia agents, to their preparation, to their use and to formulations containing the compounds. Pyrrolidone derivatives have heretofore been known as drugs for brain insufficiency disease for example, in EP-A-89900, in US-A-4369139, and in US-A-4118396. According to the present invention there is provided a compound of the formula (I) wherein R¹ is hydrogen or C₁-C₃ alkyl; n is an integer 2 or 3; Z₁ is phenyl or benzyl, each optionally mono-, di- or tri-substituted by methyl, methoxy or chlorine, or is methylisoxazolyl; and Z² is hydrogen, C₁-C₃ alkyl, phenyl or C₃-C₅ alkenyl; or Z¹ and Z₂ taken together with the adjacent Nitrogen atom may form one of A and B being and the other CH₂ ; Z⁵ being phenyl, chlorophenyl or thienyl; and Z⁶ being phenyl, chlorophenyl or thienyl when A is CH₂ or phenyl, chlorophenyl, methoxyphenyl or thienyl when B is CH₂. Salts of the above compounds (I) are included in the invention, e.g. pharmaceutically or veterinarily acceptable acid addition salts. The terms used in the above definition may be exemplified below. As C₁-C₃ alkyl, methyl, ethyl, and propyl, are exemplified. Processes for producing compounds (I) are shown in the following scheme. Possible specific means of carrying out the illustrated processes are described in what follows. Route A 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 - 150 °C, preferably at 115 - 125 °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. Route B The objective compound (Ia) is obtained by reacting Compound (III) with Compound (V). The reaction is carried out in an appropriate solvent at 10 - 120 °C, preferably at 50 - 100 °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 K₂CO₃, 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. Route D Compound (Ic) is obtained by subjecting Compound (Ia) to dehydration reaction, when 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 pentoxide, DCC, and Molecular Sieves are illustrated. Route E Compound (Id) is obtained by alkylating Compound (Ia) (when R¹ = H) with a suitable alkylating agent. Generally, this reaction is carried out in an appropriate solvent at room temperature (1 - 30 °C), preferably at 10 - 25 °C. As the solvent, THF and ethyl acetate are illustrated. As the alkylating agent, methyl iodide and ethyl iodide, 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. (n is an integer of 2 or 3)(See Reference Examples 1-3). The compounds (I) may also be manufactured by any conventional processes known in the chemical literature for the manufacture of analogous compounds. The compounds (I) can be converted into their pharmaceutically or veterinarily acceptable acid addition salts. 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 compounds (I) of this invention can be administered to humans or animals orally or parenterally. For instance, compounds (I) can be administered orally in the forms of tablets, granules, powder, capsules, solution, or given parenterally in the forms of injection or suppositories. These preparations may be manufactured by known processes 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 0.01 to 20 mg/kg may be orally or parenterally administered once or in several divisions. Thus, the invention includes a pharmaceutical or veterinary formulation comprising a compound of the invention or a salt of the invention formulated for pharmaceutical or veterinary use, respectively, optionally in unit dosage form, and/or optionally together with an acceptable diluent, carrier or excipient, and the preparation of such formulations. The invention also generally includes the use of a compound of the invention or a salt of the invention in the preparation of a medicament. In another aspect, the invention provides a compound of the invention or a salt of the invention for use in the treatment of senile dementia or for use as a psychotropic and/or antiamnesia agent. Embodiments of this invention are illustrated below in various Examples, together with Reference Examples, and a Preparation. The abbreviations used in the Examples, Reference Examples and Tables have the following meanings as mentioned below: DMF : N,N-Dimethylformamide m-CPBA : m-Chloroperbenzoic acid THF : Tetrahydrofuran EtI : Ethyl iodide Et₂O : Ether Me : Methyl Et : Ethyl MeO : Methoxy EtOH : Ethanol i-PrOH : Isopropanol MeOH : Methanol DMA : N,N-Dimethylacetamide hr. : hour d. : day Example 1 1-[[2-(4-Methoxyphenyl)aminoethyl]carbamoyl]-2-oxopyrrolidine (Ia-1) 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 K₂CO₃ and 0.30 g (2.00 mmol) of NaI, end the solution was heated with stirring at 80-85 °C for 40.5 hr. The reaction solution was mixed with ethyl acetate, washed with water, dried, and concentrated. The reside 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-hexene and collected by filtration. m.p. : 83.5 - 84.5 °C Anal. Calcd. (%) for C₁₄H₁₉N₃O₃ C, 60.63; H, 6.91; N, 15.15 Found (%) C, 60.65; H, 7.05; N, 15.30 IR (CHCl₃) : 3295, 2975, 1710, 1675 cm⁻¹ NMR (CDCl₃) : 2.00 (quint, J=7Hz, 2H), 2.57 (t, J=7Hz, 2H), 3.27 (t, J=6Hz, 2H), 3.53 (q, J=6Hz, 2H), 3.73 (s, 3H), 3.84 (t, J=7Hz, 2H), 6.59, 6.77 (A₂B₂, J=9Hz, 4H), 8.62(br., 1H) Examples 2 - 21 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. Example 22 1-[[2-(4-Methoxyphenyl)aminoethyl]carbamoyl]-2-oxopyrrolidine (Ia-1) 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 - 120 °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 - 84.5 °C were obtained by recrystallizing from ethanol. Examples 23 and 24 The reactions were carried out in the same method as in Example 22 described above. The reaction conditions and their properties of each objective compounds are shown in Tables 3 and 5, respectively. Example 25 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 compound are shown in Table 5. Example 26 1-[N-Methyl-[2-(4-methoxyphenyl)aminoethyl]carbamoyl]-2-oxo pyrrolidine (Ia-25) 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 - 120 °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-25) 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. Example 27 1-[N-Ethyl-[2-(4-methoxyphenyl)(n-propyl)amino]ethyl]carbamoyl]-2-oxopyrrolidine (Ia-26) 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 oily compound (Ia-26) 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. Example 28 1-[2-[(4-Methoxyphenyl)allylamino]ethyl]carbamoyl]-2-oxopyrrolidine (Ia-27) To a solution of 2.20 g (7.93 mmol) of 1-[2-[(4-methoxyphenylamino)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 - 85 °C. To the mixture were 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 NaHCO₃, water, and saturated brine in order. After drying, the solvent was removed by evaporation. The residue was refined by silica gel 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-27) melting at 53.0-54.0 °C was obtained as crystals. Yield : 76.4 % Anal. Calcd. (%) for C₁₇H₂₃N₃O₃ C, 64.33; H, 7.30; N, 13.24 Found (%) C, 64.13; H, 7.35; N, 13.35 IR (CHCl₃) : 3310, 1705, 1675, 1540, 1505 cm⁻¹ NMR (CDCl₃) : 1.83 - 2.17 (m, 2H), 2.57 (t, J=7Hz, 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) Examples 29 to 35 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 Table 6. Example 36 1-[[3-(4-Phenyl-1,2,3,6-tetrahydropyridin-1-yl)propyl]carbamoyl]-2-oxopyrrolidine maleate (Ic-1) A solution of 1.67 g (4.83 mmol) of 1-[[3-(4-hydroxy-4-phenyl-1-piperidino)propyl]carbamoyl]-2-oxopyrrolidine (Ia-30) in 25 ml of 10 % hydrochloric acid was refluxed for 2 hr. The reaction solution was made alkaline with aqueous NaHCO₃, 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 145.0 - 148 °C were obtained. The properties of the objective compound (Ic-1) are shown in Table 7. Example 37 1-[[3-[4-(4-Chlorophenyl)-1,2,3,6-tetrahydropyridin-1-yl]propyl]carbamoyl]-2-oxopyrrolidine (Ic-2) A solution of 1.6 g (4.21 mmol) of 1-[[3-[4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl]propyl]carbamoyl]-2-oxopyrrolidine (Ia-29) 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 CH₂Cl₂ / MeOH (20/1 v/v). Yield : 98.4 % By recrystallizing from ether - isopropyl alcohol, crystals melting at 88.0 - 88.5 °C were obtained. The properties of the objective compound (Ic-2) are shown in Table 7. Example 38 1-[[2-[4-(4-Chlorophenyl)-1,2,3,6-tetrahydropyridin-1-yl]ethyl]carbamoyl]-2-oxopyrrolidine (Ia-17) A solution of 1.68 g (4.59 mmol) of 1-[[2-[4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl]ethyl]carbamoyl]-2-oxopyrrolidine (Ia-14) and 1.05 g (5.5 mmol) of p-toluenesulfonlc 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 37, 1.57 g of the objective compound (Ia-17) was obtained. Yield : 98.3 % Example 39-42 In the same method as in Example 38, the reactions were carried out under the conditions shown in Tables 8 and 9, whereby the objective compounds (Ic) were obtained. The properties are shown in Table 10. Reference Example 1 2-Oxo-1-phenoxycarbonylpyrrolidine 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 H₂ 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 °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 CH₂Cl₂ - ether, 37.8 g of the objective compound (II) melting at 120.0 - 121.5 °C was obtained as crystals. Yield : 84.0 % The properties of the objective compound are shown in Table 11. Reference Example 2 1-(2-Chloroethylcarbamoyl)-2-oxopyrrolidine (III-1) A mixture of 65.1 g (765 mmol) of 2-oxopyrrolidine and 67.3 g (638 ml) of chloroethyl isocyenate was heated with stirring at 95 - 105 °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 CH₂Cl₂ - ether - n-hexane, whereby 107.7 g of the objective compound 1-(2-chloroethylcarbamoyl)-2-oxopyrrolidine (III-1) melting at 66.5 - 67.5 °C was obtained as crystals. Yield : 88.5 % The properties of the objective compound are shown in Table 11. Reference Example 3 1-(3-Chloropropylcarbamoyl)-2-oxopyrrolidine (III-2) 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 - 105 °C overnight. After cooling, the reaction solution was refined by silica gel chromatography. The resulting product obtained from the eluate with toluene - ethyl acetate (20/1 - 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 - 58.0 °C was obtained as crystals. Yield : 81.0 % The properties of the objective compound are shown in Table 11. Preparation 1-[[2-(4-Methoxyphenyl)aminoethyl)carbamoyl]-2-oxopyrrolidine 10 mg Wheat starch 48 mg Magnesium stearate 2 mg The above ingredients are mixed with each other to prepare a capsule. Effect of the Invention Carbamoylpyrrolidone derivatives (I) of the present invention showed good activity against amnesia introduced by electro convulsive shock. In the following experiment using the compounds of this invention, the numbers of the test compounds correspond to those used in Examples and/or Tables. Experiment Prevention against the ECS-Induced Amnesia in Mice The test apparatus was a black acrylic resin box (30 × 30 × 30 cm) with an electrifiable grid floor in which a white wooden platform (10 × 10 × 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 shook (3 mA, 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 shook, a single electroconvulsive shock (30 mA, 100 Hz (rectangular wave), for 0.2 sec.) was administered transcorneally and then 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 12, 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 Ia - 1 302 219 Ia - 5 166 108 Ia - 14 222 205 Ia - 29 181 122

Claims: Claims for the following Contracting States : AT, BE, CH, DE, FR, GB, IT, LI, LU, NL, SE A compound of the formula (I) wherein R¹ is hydrogen or C₁-C₃ alkyl; n is an integer 2 or 3; Z₁ is phenyl or benzyl, each optionally mono-, di- or tri-substituted by methyl, methoxy or chlorine, or is methylisoxazolyl; and Z² is hydrogen, C₁-C₃ alkyl, phenyl or C₃-C₅ alkenyl; or Z¹ and Z₂ taken together with the adjacent Nitrogen atom may form one of A and B being and the other CH₂ ; Z⁵ being phenyl, chlorophenyl or thienyl; and Z⁶ being phenyl, chlorophenyl or thienyl when A is CH₂ or phenyl, chlorophenyl, methoxyphenyl or thienyl when B is CH₂ . A compound as defined in claim 1 which is 1-[[2-(4-methoxyphenyl)aminoethyl]carbomyl]-2-oxopyrrolidine, 1-[[2-(4-chlorophenyl)-aminoethyl]carbomyl]-2-oxopyrrolidine, 1-[[2-(4-methoxyphenyl)allylaminoethyl)carbomyl]-2-oxopyrrolidine, 1-[N-methyl-[2-(4-methoxyphenyl]aminoethylcarbamoyl]-2-oxopyrrolidine, 1-[[3-(4-methoxyphenyl)-aminopropyl]carbamoyl]-2-oxopyrrolidine, 1-[[2-[4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridin-1-yl]ethyl]carbamoyl]-2-oxopyrrolidine, 1-[[3-[4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridin-1-yl]propyl]carbamoyl]-2-oxopyrrolidine, 1-[[3-[3](4-chlorophenyl)-1,2,3,6-tetrahydropyridin-1-yl]propyl]carbamoyl]-2-oxopyrrolidine, 1-[2-[4-(4-chlorophenyl)-4-hydroxypiperidino]ethylcarbamoyl]-2-oxopyrrolidine, 1-[3-[4-(4-chlorophenyl)-4-hydroxypiperidino]propylcarbamoyl]-2-oxopyrrolidine, 1-[3-[3-(4-chlorophenyl)-3-hydroxypiperidino]propylcarbamoyl]-2-oxopyrrolidine. A salt of a compound as claimed in claim 1 or claim 2, preferably a pharmaceutically or veterinarily acceptable acid addition salt. A process for preparing a compound as defined in claim 1, which process comprises either: (a) reacting a compound of formula (II) with a compound of formula (IV) or (b) reacting a compound of formula (III) with a compound of formula (V) in which M is hydrogen or an alkali metal; either (a) or (b) optionally being followed by treating the resulting compound of formula (Ia) in accordance with any of the following: (c) dehydration (when to produce a compound of the formula (Ic) or (d) alkylation (when R¹ is hydrogen) to produce a compound of formula (Ia) as aforesaid but in which R¹ is C₁-C₃ alkyl. A process as claimed in claim 4 in which the starting compound of formula (II) or formula (III) as aforesaid is produced by reacting 2-oxopyrrolidine with phenyl chloroformate or with chloroethyl or chloropropyl isocyanate, respectively. A pharmaceutical or veterinary formulation comprising a compound as claimed in claim 1 or claim 2 or a salt as claimed in claim 3 formulated for pharmaceutical or veterinary use, respectively, optionally in unit dosage form, and/or optionally together with an acceptable diluent, carrier or excipient. A process for preparing a pharmaceutical or veterinary formulation comprising the step of formulating a compound as claimed in claim 1 or claim 2 or a salt as claimed in claim 3 for pharmaceutical or veterinary use, respectively, together with an acceptable diluent, carrier or excipient, and optionally in unit dosage form. The use of a compound as claimed in claim 1 or claim 2 or a salt as claimed in claim 3 in the preparation of a medicament. The use claimed in claim 8 wherein the medicament is for the treatment of senile dementia. A compound as claimed in claim 1 or claim 2 or a salt as claimed in claim 3 for use in the treatment of senile dementia or for use as a psychotropic and/or antiamnesia agent. Claims for the following Contracting States : ES, GR A process for preparing a pharmaceutical or veterinary preperation for use in the treatment of senile dementia or as a psychtropic and/or anti-amnesia agent, which process comprises formulating a pharmacologically effective amount of a compound of the formula: wherein R¹ is hydrogen or C₁-C₃ alkyl; n is an integer 2 or 3; Z₁ is phenyl or benzyl, each optionally mono-, di- or tri-substituted by methyl, methoxy or chlorine, or is methylisoxazolyl; and Z² is hydrogen, C₁-C₃ alkyl, phenyl or C₃-C₅ alkenyl; or Z¹ and Z₂ taken together with the adjacent Nitrogen atom may form one of A and B being and the other CH₂ ; Z⁵ being phenyl, chlorophenyl or thienyl; and Z⁶ being phenyl, chlorophenyl or thienyl when A is CH₂ or phenyl, chlorophenyl, methoxyphenyl or thienyl when B is CH₂ or a salt thereof with a pharmaceutically or veterinarily acceptable carrier, excipient, or diluent; said preparation optionally being in unit dosage form. A process as claimed in claim 1 wherein the compound is 1-[[2-(4-methoxyphenyl)aminoethyl]carbomyl]-2-oxopyrrolidine, 1-[[2-(4-chlorophenyl)-aminoethyl]carbomyl]-2-oxopyrrolidine, 1-[[2-(4-methoxyphenyl)allylaminoethyl]carbomyl]-2-oxopyrrolidine, 1-[N-methyl-[2-(4-methoxyphenyl]aminoethylcarbamoyl]-2-oxopyrrolidine, 1-[[3-(4-methoxyphenyl)-aminopropyl]carbamoyl]-2-oxopyrrolidine, 1-[[2-[4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridin-1-yl]ethyl]carbamoyl]-2-oxopyrrolidine, 1-[[3-[4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridin-1-yl]propyl]carbamoyl]-2-oxopyrrolidine, 1-[[3-[3](4-chlorophenyl)-1,2,3,6-tetrahydropyridin-1-yl]propyl]carbamoyl]-2-oxopyrrolidine, 1-[2-[4-(4-chlorophenyl)-4-hydroxypiperidino]ethylcarbamoyl]-2-oxopyrrolidine, 1-[3-[4-(4-chlorophenyl)-4-hydroxypiperidino]propylcarbamoyl]-2-oxopyrrolidine, 1-[3-[3-(4-chlorophenyl)-3-hydroxypiperidino]propylcarbamoyl]-2-oxopyrrolidine. A process for preparing a compound as defined in claim 1, which process comprises either: (a) reacting a compound of formula (II) with a compound of formula (IV) or (b) reacting a compound of formula (III) with a compound of formula (V) in which M is hydrogen or an alkali metal; either (a) or (b) optionally being followed by treating the resulting compound of formula (Ia) in accordance with any of the following: (c) dehydration (when R is to produce a compound of the formula (Ic) or (d) alkylation (when R¹ is hydrogen) to produce a compound of formula (Ia) as aforesaid but in which R¹ is C₁-C₃ alkyl. A process as claimed in claim 3 in which the starting compound of formula (II) or formula (III) as aforesaid is produced by reacting 2-oxopyrrolidine with phenyl chloroformate or with chloroethyl or chloropropyl isocyanate, respectively. The use of a compound as defined in claim 1 or a salt thereof in the preparation of a medicament for use in the treatment of senile dementia.

Inventors: EIGYO MASAMI, MATSUMURA HIROMU, MATSUSHITA AKIRA, YANO TOSHISADA, EIGYO, MASAMI, MATSUMURA, HIROMU, MATSUSHITA, AKIRA, YANO, TOSHISADA
Applicants: SHIONOGI & CO, SHIONOGI SEIYAKU KABUSHIKI KAISHA TRADING UNDER THE NAME OF  SHIONOGI & CO. LTD.
Application year: 1988
Main classification: C07D207
IPC codes: C07D409, C07D207, C07D401, C07D417, C07D471, C07D403, C07D413