JPH0472828B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides novel oxindole derivatives, more particularly those having the general formula [In the formula, R ¹ is a hydrogen atom or a lower alkyl group,
R ² is a lower alkyl group, R ³ is a hydrogen atom or a lower alkyl group, and R ⁴ is a hydrogen atom or a benzoyl group that may have one halogen atom on the phenyl ring. However, R ³ and R ⁴ are not hydrogen atoms at the same time.] The present invention relates to oxindole derivatives and salts thereof.

The compound of the present invention has an anti-ulcer effect and is useful as a therapeutic agent for gastrointestinal ulcers such as gastric ulcer and duodenal ulcer. The compounds of the present invention are particularly characterized in that they have remarkable preventive and therapeutic effects on chronic ulcer conditions such as experimental acetic acid ulcers and burnt ulcers, have low toxicity and side effects, and are effective against chronic ulcers. It's a drug. The compounds of the present invention also have the effect of increasing the amount of endogenous prostaglandin E ₂ and are useful as medicinal effects derived from prostaglandin E ₂ , such as prophylactic and therapeutic agents for ulcers.

In this specification, lower alkyl includes straight chain or branched alkyl having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, and the like.

Examples of the benzoyl group that may have one halogen atom on the phenyl ring include benzoyl group, 2
-, 3- or 4-chlorobenzoyl, 2-, 3
- or 4-fluorobenzoyl, 2-, 3- or 4-bromobenzoyl, 2-, 3- or 4
-iodobenzoyl and the like. Halogen atoms include fluorine, chlorine, bromine and iodine.

The compound of the present invention has optically active forms or stereoisomers, and these are also included in the present invention.

The compound of the present invention can be produced by various methods, for example, by the method shown in the reaction formula below.

[In the formula, R ¹ and R ² are the same as above, R ³ ′ is a lower alkyl group, and R ⁴ ′ is a benzoyl group that may have one halogen atom on the phenyl ring] Compound (2) or ( The reaction between 1b) and compound (3) is achieved by subjecting it to a conventional amide bond forming reaction. In this case, the compound (3) may be an activated compound.

The conditions for the amide bond forming reaction can be applied to the amide bond forming reaction. For example, (a) mixed acid anhydride method, that is, a method of reacting compound (3) with an alkylhalocarboxylic acid to form a mixed acid anhydride, and reacting this with compound (2) or (1b), (b) active ester method or activated amide method, i.e. compound
(3) is an active ester such as p-nitrophenyl ester, N-hydroxysuccinimide ester, 1-hydroxybenzotriazole ester, or an active amide with benzoxazoline-2-thione, and compound (2) is added to this. or (1b)
(c) Carbodiimide method, that is, a method of dehydrating compound (2) or (1b) to compound (3) in the presence of a dehydrating agent such as dicyclohexylcarbodiimide or carbonyldiimidazole; (d) carbodiimide method; Acid halide method, that is, a method in which compound (3) is induced into a halide form and reacted with compound (2) or (1b); (e) Other methods include compound (3) using a dehydrating agent such as acetic anhydride. A method of reacting compound (2) or (1b) with a carboxylic acid anhydride, or reacting compound (2) or (1b) with an ester of compound (3) and, for example, a lower alcohol under high pressure and high temperature. Examples include methods. Alternatively, a method may be adopted in which compound (3) is activated with a phosphorus compound such as triphenylphosphine or diethylchlorophosphate, and the activated compound is reacted with compound (2) or (1b). Examples of the alkyl carboxylic acids used in the mixed acid anhydride method include methyl chloroformate, methyl bromoformate, ethyl chloroformate, ethyl bromoformate,
Examples include isobutyl chloroformate. The mixed acid anhydride is obtained by the usual Schotten-Baumann reaction, and the compound (1a) or (1c) of the present invention is produced by reacting it with the compound (2) or (1b) without isolation. . The Schotten-Baumann reaction is usually carried out in the presence of a basic compound. As the basic compound used, compounds commonly used in the Schotten-Baumann reaction are used, such as triethylamine, trimethylamine, pyridine, dimethylaniline, N-methylmorpholine, 4-dimethylaminopyridine, 1,5
-diazabicyclo[4.3.0]nonene-5 (DBN),
1,5-diazabicyclo[5.4.0]undecene-
(DBU), 1,4-diazabicyclo[2.2.2]octane (DABCO), and other organic bases; and inorganic bases such as potassium carbonate, sodium carbonate, potassium hydrogen carbonate, and sodium hydrogen carbonate. The reaction is carried out at about -20 to 100°C, preferably 0 to 50°C, and the reaction time is about 5 minutes to 10 hours, preferably 5 minutes to 2 hours. The reaction between the obtained mixed acid anhydride and compound (2) or (1b) is −20 to
It is carried out at about 150°C, preferably 10 to 50°C, for about 5 minutes to 10 hours, preferably about 5 minutes to 5 hours. Although the mixed acid anhydride method does not require the use of a solvent, it is generally carried out in a solvent. Any solvent commonly used in the mixed acid anhydride method can be used, specifically halogenated carbons such as methylene chloride, chloroform, and dichloroethane, and aromatic hydrocarbons such as benzene, toluene, and xylene. , diethyl ether, tetrahydrofuran,
Examples include ethers such as dimethoxyethane, esters such as methyl acetate and ethyl acetate, and aprotic polar solvents such as dimethylformamide, dimethyl sulfoxide, and hexamethylphosphoric triamide. Compound (3), alkylhalocarboxylic acid and compound (2) or (1b) in the method
Usually, at least the same mole of the alkylhalocarboxylic acid and the compound (2) or (1b) are used per mole of the compound (3).

In the above (b) active ester method or active amide method, for example, when N-hydroxysuccinimide ester is used, an appropriate solvent that does not affect the reaction, such as the mixed acid anhydride method described above, is used. Using 1-methyl-2-pyrrolidone or the like in addition to the same solvent as above, in the presence of an appropriate base, for example, the same base as used in the carboxylic acid halide method described below, the temperature is 0 to 150°C, preferably 10 to 100°C. 100℃
The reaction is carried out by reacting for 0.5 to 10 hours. In this case, compound (2) or (1b) and N-
The ratio of the hydroxysuccinimide ester used is usually at least equimolar of the latter to the former.
Preferably, the amount is equimolar to twice the molar amount.

In the carboxylic acid halide method (c) above, compound (3) is reacted with a halogenating agent to form a carboxylic acid halide, and this carboxylic acid halide is isolated and purified, or a compound is added to it without isolation and purification. It is carried out by reacting (2) or (1b).

The reaction between this carboxylic acid halide and compound (2) or (1b) is carried out in a suitable solvent in the presence of a dehydrohalogenating agent. Basic compounds are usually used as the dehydrohalogenating agent, and in addition to the basic compounds used in the Schotten-Baumann reaction described above, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, silver carbonate, sodium methylate, etc. , alkali metal alcoholates such as sodium ethylate, and the like. Incidentally, the reaction compound compound (2) or (1b) can also be used in excess as a dehydrohalogenating agent. In addition to the solvent used in the Schotten-Baumann reaction, examples of the solvent include water, methanol, ethanol, propanol, butanol,
Examples include alcohols such as 3-methoxy-1-butanol, ethyl cellosolve, and methyl cellosolve, pyridine, acetone, acetonitrile, and mixed solvents of two or more thereof. Compound
The ratio of (2) or (1b) and carboxylic acid halide to be used is not particularly limited and can be selected over a wide range, but usually the latter is used in at least an equimolar amount, preferably an equimolar to twice the molar amount of the former. The reaction temperature is usually about -30 to 180°C, preferably about 0 to 150°C,
Generally, the reaction is completed in 5 minutes to 30 hours.

The carboxylic acid halide used is produced by reacting the compound (3) with a halogenating agent without a solvent or in a solvent. Any solvent can be used as long as it does not adversely affect the reaction, such as aromatic hydrocarbons such as benzene, toluene, and xylene, halogenated hydrocarbons such as chloroform, methylene chloride, and carbon tetrachloride, dioxane, and tetrahydrofuran. , ethers such as diethyl ether, dimethylformamide, dimethyl sulfoxide, and the like. As the halogenating agent, a normal halogenating agent that converts the hydroxyl group of a carboxy group into a halogen can be used, such as thionyl chloride,
Phosphorus oxychloride, phosphorus oxybromide, phosphorus pentachloride,
Examples include phosphorus pentabromide.

The ratio of compound (3) and halogenating agent to be used is not particularly limited and is selected as appropriate, but when the reaction is carried out without a solvent, the latter is usually used in a large excess amount relative to the former, or in the solvent. When carrying out the reaction, the latter is usually used in at least an equimolar amount, preferably twice the molar amount of the former. The reaction temperature and reaction time are also not particularly limited, but are usually room temperature to
At about 100℃, preferably 50 to 80℃, for 30 minutes or more
It will take about 6 hours.

Further, the method of activating compound (3) with a phosphorus compound such as triphenylphosphine or diethylchlorophosphate and reacting it with compound (2) or (1b) is carried out in a suitable solvent. Any solvent can be used as long as it does not affect the reaction, and specifically, halogenated carbons such as methylene chloride, chloroform, and dichloroethane, aromatic hydrocarbons such as benzene, toluene, and xylene, Examples include ethers such as diethyl ether, tetrahydrofuran, and dimethoxyethane, esters such as methyl acetate and ethyl acetate, and aprotic polar solvents such as dimethyl formamide, dimethyl sulfoxide, and hexamethyl phosphoric acid triamide. In this reaction, compound (2) or (1) itself acts as a basic compound, so the reaction proceeds well by using it in excess of the theoretical amount, but if necessary, other basic compounds may be added. , for example, triethylamine, trimethylamine, pyridine, dimethylaniline, N-methylmorpholine, 4-dimethylaminopyridine, 1,5
-diazabicyclo[4.3.0]nonene-5 (DBN),
1,5-diazabicyclo[5.4.0]undecene-
Organic bases such as 5(DBU), 1,4-diazabicyclo[2.2.2]octane (DABCO), and inorganic bases such as potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, etc. can also be used. The reaction is carried out at a temperature of about 0-150°C, preferably about 0-100°C.
C. for about 1 to 30 hours. The ratio of the phosphorus compound and compound (3) to compound (2) or (1b) is usually at least about equimolar amounts, preferably 1 to 3 times the molar amount.

In the above reaction formula -, by esterifying compound (2) or (1a) with the alcohol of formula (4), the corresponding target compound (1b) is obtained.
Or it can lead to (1c).

This esterification reaction can be carried out under any of the usual reaction conditions for esterification reactions, such as (1) dehydration condensation in a solvent in the presence of a dehydrating agent, or (2) a suitable acidic or basic catalyst. React in a solvent. Examples of the solvent used in method (1) include halogenated carbons such as methylene chloride, chloroform, and dichloroethane, aromatic hydrocarbons such as benzene, toluene, and xylene, and ethers such as diethyl ether, tetrahydrofuran, and dimethoxyethane. Examples include aprotic polar solvents such as dimethylformamide, dimethylsulfoxide, and hexamethylphosphoric triamide. Examples of the dehydrating agent include dicyclohexylcarbodiimide and carbonyldiimidazole. The ratio of alcohol (4) to compound (2) or (1a) is at least equimolar, preferably equimolar - 1.5 times molar. The proportion of the dehydrating agent used is at least equimolar, preferably equimolar to 1.5 times the molar amount of compound (2) or (1a).
The reaction temperature is usually room temperature to 150℃, preferably 50 to 100℃
℃, the reaction is generally complete in 1 to 10 hours.

Examples of acidic catalysts used in method (2) include hydrochloric acid gas, concentrated sulfuric acid, phosphoric acid, polyphosphoric acid, boron trifluoride, inorganic acids such as perchloric acid, trifluoroacetic acid, trifluoromethanesulfonic acid, and naphthalenesulfone. Examples include organic acids such as P-tosylic acid, benzenesulfonic acid and ethanesulfonic acid, acid anhydrides such as trichloromethanesulfonic anhydride and trifluoromethanesulfonic anhydride, thionyl chloride, and acetone dimethyl acetal. Furthermore, acidic ion exchange resins can also be used as catalysts in the present invention. A wide range of known basic catalysts can be used, such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate,
Inorganic bases such as silver carbonate, sodium methylate,
Examples include alcoholates such as sodium ethylate. This reaction proceeds either without a solvent or in a solvent. As the solvent, those used in ordinary esterification reactions can be effectively used, and specifically, aromatic hydrocarbons such as benzene, toluene, and xylene, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, etc. Examples include ethers such as halogenated hydrocarbons, diethyl ether, tetrahydrofuran, dioxane, and ethylene glycol monomethyl ether. Further, the above reaction is advantageously carried out by using a desiccant such as anhydrous calcium chloride, anhydrous copper sulfate, anhydrous calcium sulfate, phosphorus pentoxide, or the like. The ratio of compound (2) or (1a) and alcohol (4) to be used in the reaction is not particularly limited and can be appropriately selected from a wide range, but in the case of no solvent, the latter is used in large excess to the former, and the solvent When using the latter, the former is used in an equimolar to 5 times molar amount, preferably an equimolar to
Use twice the molar amount. The reaction temperature is not particularly limited, but is usually about -20 to 200°C, preferably 0 to 150°C.
The reaction time is usually about 1 to 20 hours.

In addition, in the above reaction formula -, compound (1c)
can also be hydrolyzed to lead to compound (1a),
The hydrolysis can be carried out using suitable hydrolysis catalysts, such as hydrohalic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid,
In the presence of inorganic alkaline compounds such as inorganic acids such as phosphoric acid, alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, alkali metal carbonates or bicarbonates such as sodium carbonate, potassium carbonate, sodium bicarbonate, If treated without solvent or in a suitable solvent (for example, water or a mixed solvent of water and a lower alcohol such as methanol or ethanol) at room temperature to 150°C, preferably 50 to 100°C, for about 30 minutes to 24 hours. good.

The compound of the present invention has the following reaction formula - - Reaction formula -
Manufactured by the method shown in

[In the formula, R ¹ , R ² , R ³ and R ⁴ are the same as above,
X represents a halogen atom] Compound (5) in the above reaction formula contains some new substances, which are described in Japanese Patent Application No. 1988-88948. This reaction between compound (5) and compound (6) is carried out in a suitable solvent in the presence of a basic compound. The solvent used is methanol,
Alcohols such as ethanol and isopropanol, aromatic hydrocarbons such as benzene, toluene, and xylene, ethers such as dioxane, diethyl ether, tetrahydrofuran, and ethylene glycol dimethyl ether, dimethylformamide, dimethyl sulfoxide, hexamethylphosphoric triamide, acetone, Examples include polar solvents such as acetonitrile and mixed solvents thereof. Examples of basic compounds include inorganic bases such as potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, sodium hydride, sodium bicarbonate, and sodium amide; Examples include tertiary amines. The reaction is usually carried out at room temperature to 150°C, preferably at room temperature to 150°C.
It completes in about 1 to 10 hours at around 100℃.
The amount of compound (6) to be used is at least equimolar, preferably equimolar to 1.5 times the molar amount of compound (5).

[In the formula, R ² , R ³ and R ⁴ are the same as above, and R ¹ ' represents a lower alkyl group] The alkylation reaction of the above compound (1d) can be carried out using, for example, sodium hydride, potassium hydride, metallic potassium, The reaction is carried out in a suitable solvent in the presence of a basic compound such as metallic sodium, sodium amide, potassium amide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, or the like. Examples of solvents that can be used include ethers such as dioxane, tetrahydrofuran, diethyl ether, and diethylene glycol dimethyl ether, aromatic hydrocarbons such as benzene, toluene, xylene, and chlorobenzene, dimethylformamide, dimethyl sulfoxide, hexamethylphosphoric triamide, and aqueous ammonia. or a mixed solvent thereof. As an alkylating agent, the general formula
Examples include alkyl halides of R ¹ ′X (R ¹ ′ and Although the proportion used is not particularly limited, it is usually at least equimolar, preferably equimolar to twice the molar amount of compound (1d). The reaction is usually carried out at around 0 to 70°C, preferably around 0°C to room temperature, and generally for 30 minutes to 12
It will finish in about an hour.

In addition, in the above alkylation reaction, depending on the conditions, not only the 1st position of compound (1d) but also the 3rd position (when R ² is a hydrogen atom) and the side chain carboxylic acid (when R ³ is a hydrogen atom) However, by selecting the reaction conditions, products reacting only at the 1st position can be obtained in good yield, and products reacting at some and/or all of the other positions can be obtained in good yield. It can be separated and purified by conventional means, and those reacted with the carboxylic acid in the 3-position side chain can be easily hydrolyzed under the same conditions as the hydrolysis of compound (1c) in the above reaction formula. You can also.

Among the compounds represented by the general formula (1), those having an acidic group can form a salt with a pharmacologically acceptable basic compound. Such basic compounds include, for example, sodium hydroxide, potassium hydroxide,
metal hydroxides such as calcium hydroxide, potassium metal carbonates or bicarbonates such as sodium carbonate, sodium bicarbonate, sodium methylates,
Examples include alkali metal alcoholates such as potassium ethylate. Furthermore, among the compounds represented by the general formula (1), those having a basic group can easily form a salt with a common pharmacologically acceptable acid. Examples of such acids include inorganic acids such as sulfuric acid, nitric acid, hydrochloric acid, and hydrobromic acid, and organic acids such as acetic acid, P-toluenesulfonic acid, ethanesulfonic acid, oxalic acid, maleic acid, succinic acid, and benzoic acid. Can be mentioned.

The compound of the present invention produced by the above method can be easily isolated from the reaction system by conventional separation methods such as distillation, recrystallization, column chromatography, preparative thin layer chromatography, and solvent extraction. Can be separated and purified.

The compound of the present invention is useful as an anti-ulcer agent, and is usually used in the form of a general pharmaceutical agent. The formulation is prepared using commonly used diluents or excipients such as fillers, fillers, binders, wetting agents, disintegrants, surfactants, and lubricants. Various forms of this pharmaceutical preparation can be selected depending on the therapeutic purpose, and typical examples include tablets, pills, powders,
Examples include 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 , disintegrants such as sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose, disintegration inhibitors such as sucrose, stearin, cocoa butter, hydrogenated oil, etc. class ammonium base,
Absorption enhancers such as sodium lauryl sulfate, humectants such as glycerin and starch, adsorbents such as starch, lactose, kaolin, bentonite, and colloidal silicic acid, and lubricants such as purified talc, stearate, boric acid powder, and polyethylene glycol. Examples include brighteners. 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, cocoa butter, hydrogenated vegetable oil, kaolin, talc, gum arabic powder, etc. ,
Examples include binders such as tragacanth powder, gelatin, and ethanol, and disintegrants such as laminaran and 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,
Examples include semi-synthetic glycerides.
When prepared as injections, solutions and suspensions are preferably sterile and isotonic with blood, and when formed into solutions, emulsions, and suspensions, diluents are used. All those commonly used in this 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 anti-ulcer agent may contain a sufficient amount of salt, glucose, or glycerin to prepare an isotonic solution, and may also contain conventional solubilizing agents, buffers, and soothing agents. colorants, preservatives, etc. as necessary.
Flavoring agents, flavoring agents, sweetening agents, and other pharmaceutical agents may also be included in the therapeutic agent.

The amount of the compound of the present invention to be contained in the anti-ulcer agent of the present invention is not particularly limited and can be selected within a wide range, but is usually 1 to 70% by weight, preferably 5 to 50% by weight based on the total composition. .

There are no particular restrictions on the method of administering the anti-ulcer agent of the present invention, and it can be administered in a manner depending on various formulation forms, age, sex and other conditions of the patient, degree of disease, etc. For example, tablets, pills, solutions, suspensions, emulsions, granules and capsules are administered orally. In the case of injections, they are administered intravenously alone or mixed with normal replacement fluids such as glucose and amino acids, and if necessary, they can also be administered intramuscularly alone.
Administered intradermally, subcutaneously, or intraperitoneally. In the case of suppositories, they are administered directly into the abdomen.

The dosage of the anti-ulcer agent of the present invention is appropriately selected depending on the usage, age, sex and other conditions of the patient, degree of disease, etc., but the amount of the compound of the present invention is usually 0.6 to 50 mg per kg body weight per day. The dosage unit form preferably contains 10 to 1000 mg of the active ingredient.

EXAMPLES Next, the present invention will be explained in more detail with reference to Examples, but the present invention is not limited thereto.

Example 1 Methyl 2-(4-chlorobenzoylamino)-3
- 2.4 g of (oxindol-3-yl)propionel was dissolved in 30 ml of acetone and 10 ml of water,
Add 0.34 g of sodium carbonate and 1 g of methyl iodide to this, and reflux for 6 hours. Acetone is distilled off and extracted with chloroform. After washing the chloroform layer with water, it was dried over magnesium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography (chloroform:methanol = 100:1), and then recrystallized from hexane-ethyl acetate. 2-(4-chlorobenzoylamino)-
3-(3-methyloxindol-3-yl)
Obtain 0.5 g of propionate. Colorless needle crystals, melting point
201-202°C Example 2 The following compound is obtained in the same manner as in Example 1 above using appropriate starting materials.

2-(4-chlorobenzoylamino)-3-(3
-Methyloxindol-3-yl)propionic acid, white powder, melting point 190-195°C NMR ( _CDCl3 ) δ: 1.33 (3H, s), 2.2-2.6
(2H, m), 4.2−4.5 (1H, m), 7.10 (2H, d, J
= 9Hz), 7.47 (2H, d, J = 9Hz), 6.70−8.0
(4H, m), 8.27 (1H, brs.), 9.10 (1H, brs) Methyl 2-(4-chlorobenzoylamino)-3
-(1,3-dimethyloxindol-3-yl)propionate, colorless scaly crystals (hexane-
2-(4-chlorobenzoylamino)-3-(1,
3-dimethyloxindol-3-yl)propionic acid, white powder, melting point 110-120℃ NMR δ: 1.40 (3H, s) 2.50 (2H, d, J = 7
Hz), 2.80 (3H, s), 4.10−4.40 (1H, m), 7.27
(2H, d, J=9Hz), 7.67 (2H, d, J=9
Hz), 6.70-8.10 (5H, m) Example 3 Methyl 2-(4-chlorobezoylamino)-3-
Add 2.9 g of (3-methyloxindol-3-yl)propionate to 10 ml of 10% hydrochloric acid and reflux for 3 hours. After cooling, extract with chloroform. The extract is washed with water and dried over magnesium sulfate. The solvent was distilled off, the residue was dissolved in a saturated aqueous sodium bicarbonate solution, filtered through Celite, acidified with 10% hydrochloric acid, and the precipitated crystals were collected to give 2-(4-chlorobenzoylamino)-3-(3-methyloxy indole
230 mg of 3-yl)propionic acid are obtained. White powder, melting point 190-195℃ NMR δ: 1.33 (3H, s), 2.2-2.6 (2H, m),
4.2−4.5 (1H, m), 7.10 (2H, d, J = 9Hz),
7.47 (2H, d, J = 9Hz), 6.70−8.0 (4H, m),
8.27 (1H, brs), 9.10 (1H, brs) Example 4 In the same manner as in Example 3 above, using appropriate starting materials, the following compounds are obtained.

2-(4-chlorobenzoylamino)-3-(1,
3-dimethyloxindol-3-yl)propionic acid, white powder, melting point 110-120°C NMR (CDCl ₃ ) δ: 4.40 (3H, s), 2.50 (2H,
d, J=7Hz), 2.80 (3H, s), 4.10−4.40 (1H,
m), 7.27 (2H, d, J=9Hz), 7.67 (2H, d,
J = 9 Hz), 6.70-8.10 (5H, m) Example 5 13 g of 2-amino-3-(1,3-dimethyloxyisodol-3-yl)propionic acid was dissolved in 300 ml of methanol, and under ice cooling, Thionyl chloride 9.4g
was added dropwise and stirred at room temperature overnight. Methanol is distilled off, the residue is extracted with chloroform, the extract is dried over sodium sulfate, and then the chloroform is distilled off. The residue was subjected to silica gel column chromatography (eluent, chloroform:methanol = 40:
1) to obtain oily methyl 2-amino-3-
(1,3-dimethyloxindol-3-yl)
7.3 g of propionate are obtained. The structure was determined by NMR.

Claims (1)

[Claims] 1. General formula [In the formula, R ¹ is a hydrogen atom or a lower alkyl group,
R ² is a lower alkyl group, R ³ is a hydrogen atom or a lower alkyl group, and R ⁴ is a hydrogen atom or a benzoyl group that may have one halogen atom on the phenyl ring. However, R ³ and R ⁴ are not hydrogen atoms at the same time.] Oxindole derivatives and salts thereof.