JPH0442383B2 - - Google Patents

Description

[Detailed description of the invention]

INDUSTRIAL APPLICATION FIELD The present invention relates to novel oxindole derivatives. Disclosure of the Invention The oxindole derivative of the present invention is a novel compound that has not been described in any literature, and is represented by the following general formula (1). [In the formula, R is a hydrogen atom, a lower alkoxycarbonyl group, a phenyl lower alkyl group, or a benzoyl which may have 1 to 3 groups selected from the group consisting of a lower alkoxy group and a lower alkyl group as substituents on the phenyl ring. Indicates the group. ] The compound of the present invention represented by the above general formula (1) is
It has an effect of increasing myocardial contraction (positive inotropic effect) and an effect of increasing coronary blood flow, and is useful as a cardiotonic agent for the treatment of heart diseases such as congestive heart failure. In particular, the compounds of the present invention are characterized in that they do not increase heart rate or increase it only to a small extent. More specifically, each group shown in the above general formula (1) is as follows. Lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, tert-butyl,
Examples include straight chain or branched alkyl groups having 1 to 6 carbon atoms such as pentyl and hexyl groups. Examples of phenyl lower alkyl groups include benzyl,
2-phenylethyl, 1-phenylethyl, 3-
Phenylpropyl, 4-phenylbutyl, 1,1
-dimethyl-2-phenylethyl, 5-phenylpentyl, 6-phenylhexyl, 2-methyl-
Examples include phenylalkyl groups in which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms, such as 3-phenylpropyl group. Lower alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy,
Examples include straight chain or branched alkoxy groups having 1 to 6 carbon atoms such as tert-butoxy, pentyloxy, and hexyloxy groups. Examples of lower alkoxycarbonyl groups include straight-chain or branched carbon atoms having 1 to 6 carbon atoms, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, and hexyloxycarbonyl groups. Examples include alkoxycarbonyl groups. 1 group selected from the group consisting of lower alkyl group and lower alkoxy as a substituent on the phenyl ring
As a benzoyl group that may have ~3,
Benzoyl, 2-,3- or 4-methylbenzoyl, 2-,3- or 4-ethylbenzoyl, 3-isopropylbenzoyl, 4-hexylbenzoyl, 3,4-dimethylbenzoyl, 2,
5-dimethylbenzoyl, 3,4,5-trimethylbenzoyl, 2-,3- or 4-methoxybenzoyl, 2-,3- or 4-ethoxybenzoyl, 4-isopropoxybenzoyl, 4-
hexyloxybenzoyl, 3,4-dimethoxybenzoyl, 3,4-diethoxybenzoyl,
3,4,5-trimethoxybenzoyl, 2,5-
A phenyl ring such as a dimethoxybenzoyl group may have a straight chain or branched alkoxy group having 1 to 6 carbon atoms and/or a straight chain or branched alkyl group having 1 to 6 carbon atoms as a substituent. An example is a benzoyl group. The compound of the present invention can be produced by various methods, but one preferred example thereof is the method shown in Reaction Scheme-1 below. [In the formula, R is the same as above. X represents a halogen atom, a lower alkanesulfonyloxy group, an arylsulfonyloxy group, an aralkylsulfonyloxy group, or a hydroxyl group. ] In the general formula (3), specific examples of the halogen atom represented by Examples include isopropanesulfonyloxy, propanesulfonyloxy, butanesulfonyloxy, tert-butanesulfonyloxy, pentanesulfonyloxy, hexanesulfonyloxy groups, and specific examples of arylsulfonyloxy groups include phenylsulfonyloxy, 4- Methylphenylsulfonyloxy, 2-
Examples include substituted or unsubstituted arylsulfonyloxy groups such as methylphenylsulfonyloxy, 4-nitrophenylsulfonyloxy, 4-methoxyphenylsulfonyloxy, 3-chlorophenylsulfonyloxy, and α-naphthylsulfonyloxy groups. , and specific examples of the aralkylsulfonyloxy group include benzylsulfonyloxy, 2
-Phenylethylsulfonyloxy, 4-phenylbutylsulfonyloxy, 4-methylbenzylsulfonyloxy, 2-methylbenzylsulfonyloxy, 4-nitrobenzylsulfonyloxy, 4-methoxybenzylsulfonyloxy, 3
Examples include substituted or unsubstituted aralkylsulfonyloxy groups such as -chlorobenzylsulfonyloxy and α-naphthylmethylsulfonyloxy groups. As a starting material, in the compound of general formula (3), X is a halogen atom, a lower alkanesulfonyloxy group,
When using a compound exhibiting an arylsulfonyloxy group or an aralkylsulfonyloxy group,
The reaction between the known compound of general formula (2) and the compound of general formula (3) is generally carried out in a suitable inert solvent in the presence or absence of a basic condensing agent. Examples of inert solvents used include benzene, toluene,
Examples include aromatic hydrocarbons such as xylene, lower alcohols such as methanol, ethanol, isopropanol, and butanol, acetic acid, ethyl acetate, dimethyl sulfoxide, dimethylformamide, hexamethylphosphoric triamide, and the like. Examples of basic condensing agents include sodium carbonate,
Carbonates such as potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, metal hydroxides such as sodium hydroxide and potassium hydroxide, metal alcoholates such as sodium methylate and sodium ethylate, tertiary amines such as pyridine and triethylamine. etc. can be mentioned. The ratio of the compound of general formula (2) and the compound of general formula (3) to be used is not particularly limited and may be appropriately selected within a wide range, but the latter is usually at least equimolar to the former, preferably is preferably used in an equimolar to 5-fold molar amount. The reaction is usually carried out at about 40 to 120°C, preferably 50 to 100°C.
The reaction is generally completed in about 5 to 30 hours. When using a compound of general formula (3) in which X represents a hydroxyl group as a starting material, the reaction between the compound of general formula (2) and the compound of general formula (3) is carried out in the presence of a dehydration condensation agent. It is carried out without a solvent or in a suitable solvent. Examples of the dehydration condensation agent used include condensed phosphoric acids such as polyphosphoric acid, orthophosphoric acid, pyrophosphoric acid,
Phosphoric acids such as metaphosphoric acid, phosphorous acids such as northophosphorous acid, phosphoric anhydrides such as phosphorus pentoxide, acids such as hydrochloric acid, sulfuric acid, boric acid, sodium phosphate, boron phosphate, ferric phosphate, Examples include metal phosphates such as aluminum phosphate, activated alumina, sodium bisulfate, and Raney nickel. Examples of the solvent used include high boiling point solvents such as dimethylformamide and tetralin. The ratio of the compound of general formula (2) and the compound of general formula (3) to be used is not particularly limited and can be appropriately selected within a wide range, but usually the latter is used in an equimolar amount or more to the former, It is preferable to use equimolar to twice the molar amount. The amount of the dehydration condensing agent to be used is not particularly limited and can be appropriately selected from a wide range, but it is usually used in a catalytic amount or more, preferably in an amount of about 0.5 to 5 times the molar amount of the compound of general formula (2). In the above reaction, in order to prevent advantageous oxidation reactions, it is desirable to carry out the reaction in an inert gas stream, such as a carbon dioxide or nitrogen stream. Although the above reaction can be carried out either under normal pressure or under increased pressure, it is preferable to carry out the reaction under normal pressure. The above reaction is usually carried out at a temperature of about 100 to 350°C, preferably at a temperature of about 125 to 350°C.
The reaction proceeds suitably at 255°C and is generally completed in about 3 to 10 hours. In addition, in the above reaction, the general formula
The compound (3) may be used in the form of a salt. [In the formula, R' represents a benzoyl group which may have 1 to 3 groups selected from the group consisting of lower alkoxy groups and lower alkyl groups as substituents on the phenyl ring. X ¹ represents a hydroxyl group. ] The method shown by Reaction Scheme-2 is a method in which an oxindole derivative represented by general formula (1a) and a carboxylic acid represented by general formula (4) are reacted in a conventional amide bond forming reaction. The amide bond formation reaction can be carried out using various known methods, such as (a) mixed acid anhydride method, for example, a method in which carboxylic acid (4) is reacted with an alkylhalocarboxylic acid to form a mixed acid anhydride, and this is reacted with amine (1a). (b) Active ester method, for example, carboxylic acid (4) is converted into an active ester such as p-nitrophenyl ester, N-hydroxysuccinimide ester, 1-hydroxybenzotriazole ester, etc., and the amine (1a) is reacted with this. (c) Carbodiimide method, that is, a method in which amine (1a) is condensed with carboxylic acid (4) in the presence of an activator such as dicyclohexylcarbodiimide or carbonyldiimidazole; (d) Other methods, such as carboxylic acid A method in which (4) is converted into a carboxylic acid anhydride using a dehydrating agent such as acetic anhydride, and then reacted with an amine (1a).A method in which an ester of a carboxylic acid (4) and a lower alcohol is made into an amine (1a) under high pressure and high temperature. A method of reacting an acid halide of a carboxylic acid (4), that is, a carboxylic acid halide with an amine (1a)
This can be carried out by a method of reacting, etc. In the mixed acid anhydride method, the mixed acid anhydride used is obtained by a conventional Schotten-Baumann reaction, and is usually converted to amine (1a) without isolation.
A compound of general formula (1b) is produced by reacting with. The Schotten-Baumann reaction is usually carried out using basic compounds commonly used in the Schotten-Baumann reaction, such as triethylamine, trimethylamine, pyridine, dimethylaniline, N-methylmorpholine, 4-dimethylaminopyridine, 1,5
-diazabicyclo[4,3,0]nonene-5
(DBN), 1,8-diazabicyclo[5,4,0]
In the presence of organic bases such as undecene-7 (DBU), 1,4-diazabicyclo[2,2,2]octane (DABCO) and inorganic bases such as potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, etc. It is carried out at -20 to 100°C, preferably 0 to 50°C, for about 5 minutes to 10 hours, preferably 5 minutes to 2 hours. The reaction between the obtained mixed acid anhydride and amine (1a) takes about 5 minutes to 10 hours, preferably about 5 minutes to 5 hours at about -20 to 150°C, preferably 10 to 50°C. It is done. The above mixed acid anhydride is generally a solvent commonly used in this type of mixed acid anhydride method, specifically halogenated hydrocarbons such as methylene chloride, chloroform, and dichloroethane, and aromatic hydrocarbons such as benzene, toluene, and xylene. , ethers such as diethyl ether, tetrahydrofuran, and dimethoxyethane, esters such as methyl acetate and ethyl acetate, and aprotic polar solvents such as N,N-dimethylformamide, dimethyl sulfoxide, and hexamethylphosphoric triamide. carried out in the presence or absence of
Examples of the alkylhalocarboxylic acids used in the production of the mixed acid anhydride include methyl chloroformate, methyl bromoformate, ethyl chloroformate, ethyl bromoformate, isobutyl chloroformate, etc., which are usually amines (1a). It is used in at least an equimolar amount, preferably about 1 to 1.5 times the molar amount. The amount of carboxylic acid (4) to be used is usually at least equimolar, preferably about 1 to 1.5 times the molar amount of amine (1a). When employing the method of reacting carboxylic acid halide with amine (1a) shown in (d) above, the reaction is carried out in a suitable solvent in the presence of a dehydrohalogenating agent. As this dehydrohalogenation agent, a normal basic compound is used, and a wide range of known basic compounds can be used.For example, in addition to the basic compounds used in the Schotten-Baumann reaction, sodium hydroxide, hydroxide Potassium, sodium hydride, potassium hydride, etc. can be mentioned. Examples of the solvent include, in addition to the solvents used in the Schotten-Baumann reaction, alcohols such as methanol, ethanol, propanol, butanol, 3-methoxy-1-butanol, ethyl cellosolve, and methyl cellosolve, pyridine, and acetone. can. The ratio of the amine (1a) and the carboxylic acid halide to be used is not particularly limited and is appropriately selected within a wide range, but usually the latter is used in an amount of at least equimolar to the former, preferably equimolar to 5 times the molar amount. Good. The reaction is usually -
The reaction is carried out at about 20 to 180°C, preferably about 0 to 150°C, and the reaction is generally completed in 5 minutes to 30 hours. [In the formula, R″ represents a phenyl lower alkyl group. X ² represents a halogen atom.] Compound represented by general formula (1a) and general formula (5)
The reaction with the compound represented by formula (1a) is carried out under the same conditions as the reaction between the compound of general formula (1a) and carboxylic acid halide. The oxindole derivative represented by general formula (1) of the present invention can easily form an acid addition salt by acting with a pharmaceutically acceptable acid. Examples of the acid include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, and hydrobromic acid, oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid,
Organic acids such as benzoic acid may be mentioned. Further, among the oxindole derivatives represented by the general formula (1) of the present invention, a compound having an acidic group can be easily formed into a salt by reacting with a pharmaceutically acceptable basic compound. Examples of the basic compound include sodium hydroxide,
Potassium hydroxide, calcium hydroxide, sodium carbonate, potassium hydrogen carbonate, etc. can be mentioned. The target compounds obtained in each step can be easily isolated and purified by conventional separation means. Examples of the separation means include solvent extraction, dilution, recrystallization, column chromatography, preparatape thin layer chromatography, and the like. Incidentally, the present invention naturally also includes optical isomers. The compound of general formula (1) is usually used in the form of a common pharmaceutical preparation. The formulation is prepared using commonly used diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, surfactants, and lubricants. Various forms of this pharmaceutical preparation can be selected depending on the therapeutic purpose, and representative examples include tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, suppositories, and injections ( solutions, suspensions, etc.). When forming tablets, a wide variety of carriers conventionally known in this field can be used, such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, etc. Excipients, water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, binders such as polyvinylpyrrolidone, dry starch, sodium alginate, agar powder, laminaran powder , sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch,
Disintegrants such as lactose, disintegration inhibitors such as sucrose, stearin, cocoa butter, hydrogenated oil, etc., absorption enhancers such as quaternary ammonium bases and sodium lauryl sulfate, humectants such as glycerin and starch, starch, lactose, kaolin Examples include adsorbents such as bentonite and colloidal silicic acid, purified talc, stearate, boric acid powder, and lubricants such as polyethylene glycol. Furthermore, the tablets may be coated with a conventional coating, if necessary, such as sugar-coated tablets, gelatin-encapsulated tablets, enteric-coated tablets, film-coated tablets, double tablets, or multilayer tablets. When forming into a pill form, a wide variety of carriers conventionally known in this field can be used, such as excipients such as glucose, lactose, starch, cacao butter, hydrogenated vegetable oil, kaolin, and talc, powdered gum arabic, Binders such as tragacanth powder, gelatin, and ethanol,
Examples include disintegrants such as laminaran agar.
When forming into a suppository, a wide variety of conventionally known carriers can be used, such as polyethylene glycol, cacao butter, higher alcohols, esters of higher alcohols, gelatin, semi-synthetic glycerides, and the like. When prepared as injections, solutions and suspensions are preferably sterilized and isotonic with blood, and when forming these solutions, emulsions, and suspensions, this agent is used as a diluent. All those commonly used in the field can be used, including water, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters, and the like. In this case, the cardiotonic agent may contain a sufficient amount of salt, glucose, or glycerin to prepare an isotonic solution, and the usual solubilizing agents, buffers, soothing agents, etc. may be added. It's okay. Furthermore, coloring agents, preservatives, perfumes, flavoring agents, sweeteners, etc., and other pharmaceuticals may be included in the pharmaceutical preparation, if necessary. The amount of the compound of general formula (1) to be contained in the cardiotonic agent of the present invention is not particularly limited and can be appropriately selected within a wide range, but is usually 1 to 70% by weight, preferably 1 to 30% by weight based on the total composition. %. There are no particular restrictions on the method of administering the cardiotonic agent of the present invention,
Various formulation forms, patient age, gender and other conditions,
It is administered according to the patient's severity. For example, tablets, pills, solutions, suspensions, emulsions, granules, and capsules are administered orally. In the case of an injection, it is administered intravenously alone or mixed with a normal replacement fluid such as glucose or amino acids, and furthermore, if necessary, it is administered alone intramuscularly, intradermally, subcutaneously, or intraperitoneally. Suppositories are administered rectally. The dosage of the cardiotonic agent of the present invention depends on the usage, the age of the patient,
The amount of the compound of general formula (1), which is an active ingredient, is usually about 0.1 to 10 mg per kg of body weight per day, although it is selected as appropriate depending on gender and other conditions, the degree of disease, etc. It is also possible to contain two or more active ingredients in a dosage unit form.
It is best to contain ~200mg. Examples Examples are given below. Example 1 14 g of 5-aminooxindole, bis(β-
A mixture of 29 g of hydrobromide (bromoethylamine) and 250 ml of ethanol was stirred and refluxed for 8 hours. After standing at room temperature overnight, 10.1g of sodium carbonate
was added, and the mixture was further stirred and refluxed for 8 hours. After cooling to room temperature, the precipitated crystals were collected and recrystallized from water-ethanol to obtain 16 g of 5-(1-piperazinyl)oxindole hydrobromide. Pale yellow powder crystal NMR (20MHz, DMSO- _d6 ) δ; 3.30 (8H, s), 3.47 (2H, s), 6.78 (1H, d, J = 8.5Hz), 6.90 (1H, dd, J = 8.5Hz, 2Hz), 7.04 (1H, d, J = 2Hz), 8.88 (2H, brs), 10.27 (1H, s) Mass.M ⁺ : 217 Using appropriate starting materials, in the same manner as in Example 1. The compounds listed in Table 1 are obtained.

[Table] Example 8 5-(1-piperazinyl)oxindole
2.0 g of the hydrobromide salt was suspended in 30 ml of dimethylformamide (DMF), followed by triethylamine.
After adding 2.3 ml, cool the internal temperature to 0-5°C.
At the same temperature, while stirring, a solution of 1.5 g of 3,4-dimethoxybenzoyl chloride in 5 ml of DMF was gradually added dropwise. After dropping, stir at room temperature for 1 hour. The reaction solution was poured into a large amount of water and extracted with chloroform.
After washing with water, dry with sodium sulfate, and chloroform is distilled off. The residue was subjected to silica gel column chromatography (eluent: chloroform:methanol =
100:1) and recrystallized from methanol to obtain 1.5 g of 5-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]oxindole. Yellow powdery crystals mp. 197-199°C Example 9 The compounds of Examples 3-6 are obtained in the same manner as in Example 8 using appropriate starting materials. Example 10 5-(1-piperazinyl)oxindole
A mixture of 1.0 g of hydrobromide, 1.2 g of benzyl chloride, 1.1 g of triethylamine and 20 ml of acetonitrile is stirred at room temperature for 6 hours. The reaction solution was poured into a large amount of water and extracted with chloroform. After washing with water and drying with sodium sulfate, chloroform is distilled off. The residue is recrystallized from isopropanol to obtain 0.7 g of 5-(4-benzyl-1-piperazinyl)oxindole. Pale yellow-green granular crystals mp.202-203℃ Example 11 5-aminooxindole hydrobromide
3.8g, N,N-(di-2-hydroxyethyl)-
3,4-dimethoxybenzamide 5.9g and 85%
8.6 g of phosphoric acid was reacted with stirring at 165-175°C for 4.5 hours. After cooling, about 50 ml of water is added dropwise to dissolve, neutralized with 48% aqueous sodium hydroxide solution, and extracted with chloroform. After dehydration with potassium carbonate, chloroform was distilled off and recrystallized with methanol to obtain 4.1 g of 5-[4
-(3,4-dimethoxybenzoyl)-1-piperazinyl]oxindole was obtained. Yellow powder crystals mp. 197-199°C Example 12 The compounds of Example 1 and Examples 3-7 are obtained in the same manner as in Example 11 using appropriate starting materials. Example 13 2.6 g of 3,4-dimethoxybenzoic acid and 1,8-diazabicyclo[5,
4,0] Undecene-7 1.65 g was added to 100 ml of dimethylformamide, and 1.5 ml of isobutyl chloroformate was added dropwise under external ice cooling and stirring. After the dropwise addition, the mixture was stirred for 30 minutes, and a solution of 2.16 g of 5-(1-piperazinyl)oxindole dissolved in 40 ml of dimethylformamide was added thereto, followed by stirring at room temperature for 5 hours. After the reaction, the solvent was distilled off and the residue was dissolved in chloroform.
Extract with 300 ml and wash with dilute _NaHCO3 water, water, dilute hydrochloric acid, and water. After chloroform was distilled off, the residue was recrystallized from methanol and the 5-
1.6 g of [4-(3,4-dimethoxybenzoyl)-1-piperazinyl]oxindole is obtained. Yellow powder crystal Example 14 The compounds of Examples 3 to 6 are obtained in the same manner as in Example 13 using appropriate starting materials. <Pharmacological test> Pentobarbital sodium salt is administered intravenously at a rate of 30 mg/Kg to an adult male and female mixed breed dog weighing 8 to 13 kg and anesthetized. heparin sodium salt
After intravenous administration at a rate of 1000U/Kg, death was caused by exsanguination.
Remove the heart. The specimen consisted mainly of papillary muscles and the ventricular septum, and the donor dog weighed 18 to 27 kg and received blood from an intravenous injection of 30 mg/kg of pentobarbital sodium salt through a cannula inserted into the anterior septal artery. Perfused at a constant pressure of 100 mmHg. Give blood to a donor dog, anesthetize it, and administer heparin/sodium salt 1000U/
Kg is administered intravenously. Using bipolar electrodes, the papillary muscles are stimulated with a square wave at a voltage 1.5 times the threshold (0.5 to 3 V), a stimulation width of 5 msec, and a stimulation frequency of 120 times per minute.
The resting tension of the papillary muscles is 1.5 g, and the generated tension of the papillary muscles is measured via a force displacement exchanger. The blood flow in the anterior septal artery is measured using an electromagnetic flowmeter. Records of generated tension and blood flow are recorded on an ink recorder. The details of this method have already been reported by Endo and Hashimoto (Am.J.Physiol. 218 , 1459-
1463 pages, 1970). The test compound is administered intra-arterially in a volume of 10-30 μ over 4 seconds. The altering effect of the test compound is expressed as a percent change in the tension generated before drug administration. The effect on coronary blood flow is expressed as the change in absolute value (ml/min) from before administration. The results are shown in Table 2 below. Test compound No. 1 5-[4-(3,4-dimethoxybenzoyl)
-1-piperazinyl]oxindole 2 5-[4-(4-ethoxybenzoyl)-1-
Piperazinyl]oxindole 3 5-(4-ethoxycarbonyl-1-piperazinyl)oxindole 4 5-[4-(4-methylbenzoyl)-1-piperazinyl]oxindole 5 5-(4-benzyl-1-piperazinyl) oxindole

[Table] Formulation example 1 5-[4-(3,4-dimethoxybenzoyl)-1
-Piperazinyl]oxindole 5 mg Starch 132 mg Magnesium stearate 18 mg Lactose 45 mg Total 200 mg Tablets of the above composition were prepared in one tablet by a conventional method. Formulation Example 2 5-[4-(4-ethoxybenzoyl)-1-piperazinyl]oxindole 10 mg Starch 127 mg Magnesium stearate 18 mg Lactose 45 mg Total 200 mg Tablets of the above composition were prepared in one tablet by a conventional method. Formulation example 3 5-[4-(4-methylbenzoyl)-1-piperazinyl]oxindole 500 mg Polyethylene glycol (molecular weight: 4000) 0.3 g Sodium chloride 0.9 g Polyoxyethylene sorbitan 0.4 g Sodium metabisulfite monooleate 0.1 g Methyl - Parapen 0.18g Propyl-parapen 0.02g Distilled water for injection 100ml Dissolve the above parapenes, sodium metabisulfite and sodium chloride in the above distilled water at 80°C with stirring. The resulting solution was cooled to 40°C,
The compound of the invention, then polyethylene glycol and oxyethylene sorbitan monooleate were dissolved into the solution. Next, distilled water for injection is added to the solution to adjust the final volume, sterilized by sterilization using a suitable filter paper, and the solution is dispensed into 1 ml ampoules to prepare an injection. Formulation example 4 5-[4-(3,4,5-trimethoxybenzoyl)-1-piperazinyl]oxindole 5 mg Starch 132 mg Magnesium stearate 18 mg Lactose 45 mg Total 200 mg Tablets of the above composition in one tablet by a conventional method was manufactured.

Claims (1)

[Claims] 1. General formula [In the formula, R is a hydrogen atom, a lower alkoxycarbonyl group, a phenyl lower alkyl group, or a benzoyl which may have 1 to 3 groups selected from the group consisting of a lower alkoxy group and a lower alkyl group as substituents on the phenyl ring. Indicates the group. ] An oxindole derivative or a salt thereof represented by: