CS214716B2 - Method of making the acids of 2-amino-3-alcylthiobenzoyl/+p/phenylacetic - Google Patents

Abstract

Compounds of the general formula <IMAGE> (wherein R represents a hydrogen atom or a lower alkyl group, R<1> represents hydrogen atom or a lower alkyl group or pharmaceutically acceptable metal cation, R<2> represents a hydrogen or halogen atom or a lower alkyl or lower alkoxy group, Am represents an amino, methylamino or dimethylamino group and the lower groups contain 1-6-carbon atoms) have anti-inflammatory and analgesic activity and inhibit blood platelet aggregation. They are prepared by the following route: <IMAGE>

Description

The present invention relates to a process for the preparation of certain novel 2-amino-3-benzoylphenylacetic acids substituted on the benzoyl moiety with alkylthio and their alkyl esters and metal salts.

Certain 2-amino-3- (5 and 6) -benzoylphenylacetic acids substituted on the benzoyl moiety with a lower alkyl group, a halogen atom, a nitro group or a trifluoromethyl group, and methods for their preparation and use are described in U.S. Patent No. 4,045,576. The invention cannot be prepared by the methods disclosed in said patent.

More particularly, the invention relates to a process for the preparation of 2-amino-3- (alkylthiobenzoyl) phenylacetic acids, their alkyl esters and their salts with pharmaceutically acceptable metals of the general formula I

in which

R represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms,

R1 represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or a cation of a pharmaceutically acceptable metal,

R ² is hydrogen, halogen, alkyl having 1-6 carbon atoms or alkoxy having 1 to 6 carbon atoms,

Am represents a primary amino, methylamino or dimethylamino group and

X represents an alkyl group having 1 to 6 carbon atoms.

The novel compounds of formula (I) have valuable pharmacological properties and can be used as an active ingredient in pharmaceutical compositions. The compounds exhibit anti-inflammatory and analgesic activity and inhibit platelet aggregation in warm-blooded animals.

Among the products for the preparation of compounds of formula I are 7-8- (alkyl of 1 to 6 carbon atoms) thiobenzoylindolin-2-ones of formula II

According to the invention, the compounds of formula (I) may be prepared by the method of (7-alkylthlobenzoyl) indol-2-one of formula II in which

R, R ² and X have the above meanings.

The anti-inflammatory activity of the compounds of the present invention has been demonstrated in experimental animals using the Sancilli test with Evans blue and inducing pleural exudation with carrageenin. F. Sancilio, J. Pharmacol. Exp. Ther. 168, 199-204 (1969).

The compounds of formula I showed an inhibitory effect on platelet aggregation in the platelet aggregation reduction assay described by Born in J. of Phys. 162, 67-68 (1962) and Evans with partners in J. Of Expt. Copper. 128: 877-894 (1968). The rats were orally administered test substances and after 2 hours the animals were bled and blood-platelet-rich plasma was scored. Collagen was added to plasma containing platelets to induce platelet aggregation and samples obtained from treated animals were compared to controls.

The compounds of formula I are also effective as analgesics as determined by the Dickerson test method for bradykinin analgesics. See Dickerson et al., Life. Sci. 4, 2063-2069 (1965), modified by Sancilia and Cheung / see. Fed. Why. 35, 774 (1976)].

It is therefore an object of the present invention to provide a process for the preparation of the novel compounds of formula I. Further, the invention aims to show the utility of these novel compounds in the treatment of animals, particularly mammals, mainly to alleviate inflammatory and painful conditions and to inhibit platelet aggregation with minimal undesirable side effects. effects.

The purpose and nature of the invention will become apparent from the following description.

In the above formulas I and II, the term "C 1 -C 0 alkyl" includes straight-chain or branched groups, preferably with a maximum of 4 carbon atoms, for example methyl, ethyl, propyl, isopropyl butyl, secondary butyl, tertiary butyl, amyl, isoamyl and hexyl groups.

The term "halogen atom" includes chlorine, fluorine, bromine and iodine atoms.

As the pharmaceutically acceptable salts of the compounds of the formula I, for example, sodium, potassium, calcium, magnesium, zinc and copper salts and their hydrates can be used.

in which

R, R2 and X are as defined above, hydrolyzed with an alkali metal hydroxide to give the alkali metal salt of 2'-amino- (3-alkylthiobenzoyl) phenylacetic acid of formula (Ia)

in which

R, R2, Arn and X are as defined above. In order to obtain the free acid of formula I (R11-H) from the alkali metal salt of formula Ia, acetic acid is carefully added to the aqueous solution of said salt, whereupon the free acid is precipitated. The precipitated acid is collected by filtration, washed with water and dried. The ester of formula I (R ¹ - C 1 -C 6 alkyl) can be obtained from an alkali metal salt of formula Ia by treatment with an alkyl iodide. having 1 to 6 carbon atoms in an environment of a suitable solvent, such as anhydrous dimethylformamide. After completion of the reaction, water is added to the reaction mixture, and the ester is taken up in a suitable solvent, for example diethyl ether, dried over sodium sulfate and the solvent is distilled off.

The compounds of formula (I) in which Am is a dimethylamino group are prepared by reacting a 2-amino-phenylacetic acid ester of formula (I) in which Am is an (NH2) group with formaldehyde and sodium cyanoborohydride in a suitable solvent, for example acetonitrile, in an acidic medium, for example in the presence of glacial acetic acid.

The starting 7- (alkylthiohenzoyl) indolin-2-enes of formula II can be prepared from fluoro-orbenzoylindolin-2-ones by one of the methods described in U.S. Patent No. 4,045,575. In one of these methods, 2-amino The -4'-halobenzoylbenzophenone is reacted with ethyl methylthioacetate and the target, butyl hypochlorite in the presence of triethylamine, and the obtained 7- (halobenzoyl) -3-methylthioindolin-2-one is reduced by Raney nickel to 7- (halobenzoyl) -3 -indolin-2-one.

In modifying this process, instead of Raney nickel, powdered tin is used in an alcoholic medium with concentrated hydrochloric acid. The following typical reaction scheme illustrates the preparation of 7- (fluorobenzoyl) indolin-2-ones used in the preparation of the compounds of formula (II) which are starting materials in the process of the invention.

c = o

The 7- (fluoro-benzoyl-indolin-2-ones) obtained in this way can be converted to the starting 7- (alkylthiobenzoyl) indolin-2-ones of formula II by reaction with alkali metal alkyl sulfides and subsequent acid hydrolysis as shown in the reaction below. scheme:

The reaction conditions used to prepare the starting fluorobenzoylindolin-2-ones are specifically elucidated in the following prepara- tional examples.

Preparation 1

7- (4-Fluorobenzoyl) -3-methylthioindolin-2-one

To a solution of 42.2 g (0.196 mol) of 2-amino-4'-fluorobenzophenone in 2 liters of methylene chloride was added 26.5 g (0.198 mol) of ethyl methylthioacetate while cooling to -65 ° C, and then A solution of 23.0 g (0.21 mol) of 95% t-butoxychloride in 50 ml of methylene chloride is added dropwise at a temperature below -65 ° C. The solution was concentrated to 700 ml, washed with water, the solvent was distilled off from the organic portion, and the residue was dissolved in a mixture of 40 ml of methanol and 30 ml of concentrated hydrochloric acid. The mixture was heated at reflux for one hour, then cooled

214,718 and let stand overnight. The precipitated crystalline material is filtered off, washed with methanol and dried; 31.4 g (53% yield) of a pale yellow solid are obtained with a melting point of 165-167.5 ° C.

Elementary analysis:

For C16H12NO2FS calculated:

C, 63.77; H, 4.01; N, 4.65. Found:

% C, 63.58;% H, 4.11;% N, 4.67.

Preparation 2

By the method described in Preparation 1 but using equimolar amounts of the following fluorobenzophenones instead of 2-amino-4‘-fluorobenzophenone:

2-amino-4‘-fluoro-4-methylbenzophenone,

2-amino-4‘-fluoro-5-methylbenzophenone,

^2-Amino-4 '-fluoro-6-methylbenzophenone,

2-amino-4--fluoro-4-chlorobenzophenone,

2-amino-4‘-fluoro-5-chlorobenzo-phenone,

2-Aimino ^{-fluoro-4'-6-chlorobenzophenone,}

2-Amino-4'-fluoro-5-methoxybenzophenone are obtained

7- (4-fluoro-benzoyl) -4-methyl-3-methylthioindolin-2-one;

7- (4-fluorobenzoyl) -5-methyl-3-methylthioindolin-2-one;

7- (4-fluorobenzoyl) -6-methyl-3-methylthioindolin-1-one,

7- (4-fluorobenzoyl) -4-chloro-3-methylthtoindolin-2-one;

7- (4-chlorobenzoyl) -5-chloro-3-methylthioindolin-2-one,

7- (4-fluorobenzoyl) -6-chloro-3-methylthioindolin-2-one,

7- (4-fluoro-benzoyl) -5-methoxy-3-methylthioindolin-2-one.

Preparation 3

7- (2-Fluorobenzoyl) -3-methylthioindolin-2-o-n

To a solution of 86 g (0.4 mol) of 2-amino-2'-fluorobenzophenone in 3 liters of methylene chloride was added 54 g (0.4 mol) of ethyl methylthioacetate while cooling to -65 ° C and then at a temperature below -65 ° C. 65 ° C, a solution of 46 g (0.42 mol) of 95% t-butoxychloride in 100 ml of methylene chloride is added dropwise. One hour after the addition, 41 g (0.4 mol) of triethylamine are added dropwise and the mixture is allowed to warm to room temperature. The solution was concentrated to about 1400 mL, washed with water, and the solvent was distilled off from the organic portion. The residue is dissolved in a mixture of 800 ml of methanol with 60 ml of concentrated hydrochloric acid, the mixture is refluxed for one hour and then cooled. The reaction mixture was allowed to stand overnight, the precipitated crystalline material was filtered off and recrystallized from 20% aqueous ethanol. 66 g (yield 55%) of the product are obtained in the form of pale yellow needle crystals, m.p. 147.0-148.5 ° C.

Elementary analysis:

For C16H1-2NO2FS calculated:

% C, 63.77;% H, 4.01;% N, 4.65.

% C, 63.97;% H, 4.19;% N, 4.66.

Preparation 4

As described in Preparation 3, but using an equimolar amount of 2-amino-3'-fluorobenzophenone instead of 2-amino-2 ^{<-fluorbenzofenohu} yielded 7- (3-fluorobenzoyl) -3-methylthiG ^{<indolyl-2-one.}

Preparation 5

7- (4-Fluoro-benzoyl) indolin-2-one

To a mixture of 40.0 g (0.133 mol) -7- (4-fluoro-4-fluorophenyl) -3-methoxypeptide-2-ol and 40.0 g (0.34 mol) of tin powder in one liter of 95% ethanol is added at boiling point. ml of concentrated hydrochloric acid. The reaction mixture is heated at reflux for 6 hours, then filtered while hot, the filtrate is cooled and the precipitate is filtered off. Recrystallization from isopropanol gave 24.5 g (72% yield of the product as almost colorless needle crystals having a melting point of 185-187.0 ° C).

Elementary analysis:

For C15H10NO2F

14 71 В calculated:

% C, 70.58;% H, 3.95;% N, 5.49.

% H, 4.12;% N, 5.51.

Preparation 6

By the method described in Preparation 5, but using equimolar amounts of the following indolinones instead of 7- (4-fluorobenzoyl) -3-methylthiimidolin-2-one:

7- (4-chlorobenzyl) -4-methyl-4-methylthioindolin-2-one,

7- (4-fluorobenzoyl) -5-methyl-3-methylthloindolin-2-one;

7- (4-fluorobenzoyl) -6-methyl-3-methylthio-indol-2-one,

7- [4-fluoro-benzoyl) -4-chloro-3-methyl-indol-2-one,

7- (4-fluorobenzoyl) -5-chloro-3-methylthioindolin-2-one;

7- (4-fluorobenzoyl) -6-chloro-3-methylthloindolin-4-one,

7- (4-fluorobenzoyl) -5-methoxy-3-methylthiolindol-4-one are obtained.

7- (4-fluorobenzoyl) -4-methylindolin-2-one;

7- (4-fluorobenzoyl) -5-methylindolin-2-ene,

7- (4-fluorobenzoyl) -6-methylidolin-2-one;

7- (4-fluorobenzoyl)

-2-on,

7- (4-fluorobenzoyl) -5-chloroindolin-2-one,

7- (4-fluorobenzoyl) -6-chloroindolin-2-one a

7- (4-fluorobenzoyl) -5-methoxyindolin-2-one.

Preparation 7

7- (2-Fluorobenzoyl) indolin-2-one

To a mixture of 60 g (0.2 mol) of 7- (2-fluorobenzoyl) -3-methylhaloindol-2-one and 60 g (0.5 mol) of tin powder in one liter of 95% ethanol is boiled 150 ml of concentrated hydrochloric acid are added. The reaction mixture is heated at reflux for 18 hours, then cooled, the precipitate of the precipitated product is decanted from the remaining tin and the precipitate is filtered off. The crude product was recrystallized twice from absolute ethanol to give 31 g (60% yield) of the title compound as colorless needles, mp 209-210 ° C.

Elementary analysis:

For C18H10NCl3 calculated:

% H, 3.95;% N, 5.49.

found:

% H, 4.08;% N, 5.56.

Preparation 8

Using the method described in Preparation 7, but using an equimolar amount of 7- (3-fluorobenzoyl) -3-methylthioindolin-2-one instead of 7 (2-fluorobenzoyl) -3-methylthloindolin-2: one, 7- ( 3-Fluorobenzyl) indolin-2-one.

Preparation 9

Using the method described in Preparation 1, but using an equimolar amount of ethyl .alpha .- (methylthio) propionate instead of ethylmethylthioacetate, 7- (6-fluorobenzoyl) -3-methyl-3-methylthioindolinolin-2-yne is obtained.

Preparation 10 ·

Using the method described in Preparation 5, but using an equimolar amount of 7- (4-fluorobenzol) -3-methyl-3-methylthiindolin-2-yne instead of 7- (4-fluorobenzoyl) -3-methylthioindolin-4-one, 7- (4-fluorobenzoyl) -3-methylindolin-2-ene.

A process for manufacturing ^2-Ami no-3- (alkylthloУenzooltfenyloctových · formula I, their esters and salts and intermediates of formula II according to the invention is illustrated by the following examples.

He did

7- (4-Methylphenylbenzyl) indolin-4-one

To a solution of sodium methyl mercaptide prepared from 400 ml of 3 N sodium hydroxide and 24 g (0.5 mol) of methyl mercaptan was added 25.5 g (0.1 mol) of 7- (4-fluorobenzoyl Jindotin-2-yne). The mixture was heated under reflux for 1.5 hours, then cooled and acidified (caution: large quantities of methylmercaptan are rapidly released). The precipitate was filtered off and recrystallized twice from benzene to give 17.8 g (yield 70). m.p. 167.0-169.0 ° C) as a yellow crystalline solid.

Elementary analysis:

л 4 7 i 6

For C16H13NO2S calculated:

67.82% C, 4.63% H, 4.94% N. Found:

% C, 67.65;% H, 4.63;% N, 4.91.

Example 2

By the method of Example 1, but using the following substituted indolinones in equimolar amounts instead of 7- (4-fluorobenzoyl) indoliin-2-om:

7- (4-fluorobenzoyl) -4-methylindolin-2-one,

7- (4-fluorobenzoyl) -5-methyl-indolin-2-one,

7 (4-Fluorobenzoyl) -6-methylindol-2-one

7- (4-fluorobenzoyl) -4-chloroindolin-2-one,

7- (4-fluorobenzoyl) -5-chloroindolin-2-one,

7.- (4-Fluorobenzoyl) -6-chloroindolin-2-one;

7- (4-fluorobenzoyl) -5-mothoxyindolin-2-one,

7- (2-fluorobenzoyl) indolin-2-one,

Of 7- (3-fluorobenzoyl) indolin-2-one are obtained

7- (4-methylthiobenzoyl) -4-methylindolin-2-one;

7- (4-methylthiobenzoyl) -5-methylindolin-2-one;

7- (4-methylthiobenzoyl) -6-methylindolin-2-oh,

7- (4-methylthiobenzoyl) -4-chloroindolin-2-one;

7- (4-methylthiobenzoyl) -5-chloroindolin-2-one;

7- (4-methylthiobenzoyl) -6-chloroindolin-2-one;

- (4-Methylthiobenzoyl) -5-methoxyindolin-2-one,

7- (2-methylthiobenzoyl) indolin-2-one a

7- (3-methylthiobenzoyl) indolin-2-one.

Example 3

In the manner described in Example 1 but using equimolar amounts of mercaptides instead of methylmercaptide:

sodium ethyl mercaptide, sodium isopropyl mercaptide, sodium n-butyl mercaptide, are obtained

7- (4-ethylthiobenzoyl) indolin-2-one,

7- (4-isopropylthiobenzyl) indolin-2-one a

7- (4-n-butylthiobenzoyl) indolin-2-one.

Example 4

2-Amino-3- (4-methylthiobenzoyl) phenylacetic acid sodium salt

A mixture of 5.2 g (0.0.18 mol) of 7- (4-ethylthiobenzoyl) indolin-2-one and 75 ml of 3 N sodium hydroxide solution is heated to reflux for 20 hours. The yellow precipitate was collected by filtration, washed with a small amount of cold water and triturated with tetrahydrofuran, filtered, dried and recrystallized from 95% ethanol to give 4.9 g (yield 83%) of pale yellow colored needles, m.p. 244-247. Deň: 32 ° C.

Elementary analysis:

For C 11 H 10 NOiSNa calculated:

56.30% C, 4.72% II, 4.10% N, found:

% H, 4.62;% N, 4.17.

Example 5

Using the method described in Example 4, but using equimolar amounts of the following substituted indolinohols instead

- (4-Methylthiobenzoyl) indolin-2-one:

7- (4-methylthiobenzoyl) -4-methylindolin-2-one;

7- (4-methylthiobenzoyl) -5-methylindolin-2-one,

14 7 J 6

7- (4-methylthiobenzoyl) -6-methylindol-2-one,

7- (4-methylthiobenzoyl) -4-chloroindolin-2-one;

7- (4-methylthiobenzoyl) -5-chloromethyl-2-ene,

7- (4-methylthiobenzoyl) -5-chloroindolin-2-one,

7- (4-methylthio) -benzoyl] -5-methoxyindolin-2-one,

7- (2-methylthio-benzoyl) indolin-2-one,

7- ^{(3-meÍhylth:} onenzoyl] indolin-2-CNU

7- (4-ethylthiobenzoyl) indolin-2-one;

Ί (4 - op o i i ob e ob]]]]]]]]]]]]]]]]]]]]

7- (4-n-butylthiobenzoyl) indolin-2-one yields sodium 2-amino-3- (4-methylthiobenzoyl) -6-methylphenylacetic acid, sodium 2-amino-3- (4- methylthiobenzoyl] 5-methylphenylacetic acid, sodium salt of 2-amino-3- (4-methylthlobenzoyl) -4-methylphenylacetic acid, sodium salt of 2-amino-3- (4-methylthiobenzoyl) -6-chlorophenylacetic acid, sodium salt 2-amino-3- (4-methylthiobenzoyl) -5-chlorophenylacetic acid, sodium 2-amino-3- (4-methylthiobenzoyl) -4-chlorophenylacetic acid, sodium 2-amino-3- (4-methylthiobenzoyl) -5-methoxyphenylacetic acid, sodium salt of 2-amino-3- (2-methylthiobenzoyl) phenyl acetic acid, sodium salt of 2-amino-3- (3-methylthiobenzoyl) phenylacetic acid, sodium salt of 2- amino-3- (4-ethylthiobenzoyl) phenyl acetic acid, sodium 2-amino-3- (4-isopropylthiobenzoyl) phenyl acetic acid and sodium 2-amino-3- (4-n-butylthiobenzoyl) phenylacetic acid .

Example 0

7- (4-Methylthiobenzoyl) -3-methylphenol-2-one

Using the procedure described in Example 1 but substituting an equimolar amount of 7- (4-fluorobenzoyl-3-methyl) indolin-2-one instead of 7- (4-fluorobenzoyl) indol-2-one gave the title compound.

Example 7

2-Amino-3- (4-methylthiobenzoyl) -α-methyl If enylacetic acid sodium salt

A suspension of 7- (4-methylthiobenzoyl) -3-methylindolin-2-one in 3 N sodium hydroxide solution was heated to reflux under a nitrogen atmosphere. Water is then distilled off under reduced pressure and the product is triturated with an organic solvent.

Example 8

2-Amino-3- (4-methylthiobenzoyl) -phenylacetic acid ethyl ester

To a solution of 17 g (0.05 mol) of 2-amino-3- (4-methylthiobenzoyl) phenylootonic acid sodium monohydrate in about 150 ml of dimethylformamide was added 33 g of ethyl iodide and the mixture was stirred at room temperature for 2.5 hours. The combined organic extracts were washed with dilute base and water, dried over anhydrous sodium sulfate, and the solvent was distilled off to give the title compound.

The invention also encompasses novel therapeutic compositions containing the compounds of formula I as active ingredients and methods of administering them to patients. Generally, animals can be administered effective amounts of any of the above pharmacologically active agents by various conventional means, for example orally in the form of capsules or tablets, parenterally in the form of sterile solutions or suspensions, and in some cases intravenously in the form of sterile solutions. When formulating new therapeutic agents, the active compound of formula I is admixed with a pharmaceutically acceptable carrier, for example, starch, gelatin, glucose, carbonate.

2147 16 magnesium, lactose, malt and the like. Ethyl alcohol, propylene glycol, glycerine, glucose syrup and the like can be used as suitable pharmaceutical carriers in the manufacture of liquid therapeutic preparations.

The pharmacologically active compounds of formula I may be administered, preferably in unit doses ranging from 0.1 to 150 mg. Said dose may be administered once daily or in multiple or divided daily doses. The daily dose is usually in the range of - 0.3 - 450 mg; five doses of 25 mg each appear as the optimal daily dose.

It is only necessary that the active ingredient be administered in an effective amount, i.e., that an effective dosage is obtained with the dosage form used. Of course, the exact individual dosage, as well as the amount of the daily dosage, should be determined according to standard medical principles and under the guidance of a physician or veterinarian.

The active compounds of the formula I can also be combined with other pharmacologically active substances or with buffers, antacids and the like, and the ratio of the active compound in the therapeutic preparation can vary within wide limits.

The method of formulation of therapeutic compositions is illustrated in greater detail in the following examples.

1. Capsules

Capsules are prepared containing 5, 25 and 50 milligrams of active compound of Formula I per capsule; the higher active ingredient content of the capsule is compensated by the amount of lactose.

Typical capsule formulation

The active compound lactose starch magnesium stearate

Quantity per capsule (mg)

5.0

296.7

129.0 ____ 4.3 total - - 435.0 mg

Another composition for the preparation of capsules, preferably with a higher content of active compound, has the following composition:

Folders

Quantity c. . per 1 capsule '(in mg)

In each case, the active ingredient of choice is uniformly mixed with lactose, starch and magnesium stearate and the homogeneous mixture is filled into capsules.

2. Tablets

A typical formulation for the preparation of tablets containing 5.0 mg of active compound per tablet has the following composition. The same mixtures can also be used to prepare tablets with a different content of active ingredient, the total weight of the tablet being compensated by dicalcium phosphate.

Folders

Quantity per tablet (mg)

1) active compound 5.0

2) maize starch13,6

3) corn starch paste3,4

4) lactose79,2

5) calcium hydrogen phosphate58.0

6) calcium stearate 0.9 total 170.1 mg

The components 1, 2, 4 and 5 are mixed uniformly. From component 3 a 10% paste in water is prepared. The former is granulated with starch paste and the wet material is sieved through a 3.15 mesh sieve (6 mesh). The wet granulate is dried and passed through a 12 mesh sieve. The dry granulate is mixed with calcium stearate and tableted.

3. Injection - 2% sterile solution

Folders

Amounts per ml of active compound preservative (eg chlorobutanol) water- for injection mg

0.5% (limiting / volume) and 1 ml

The components are dissolved in water for injection, filtered, filled into ampoules, sealed and autoclaved.

It will be apparent to those skilled in the art that various modifications of the method of the invention may be made without departing from the spirit and scope thereof, and it is therefore understood that the scope of the invention is not limited to the following definition of the subject matter.

active compound25.0 lactose306.5 starch99.2 magnesium stearate 4.3 total435.0

21471B

Claims (1)

Object of the invention A process for the preparation of 2-amino-3- (alkylthiobenzoyl) phenylacetic acids, their alkyl esters and salts with pharmaceutically acceptable metals, R represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, R1 represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or a cation of a pharmaceutically acceptable metal, R ² is hydrogen, halogen, alkyl of · 1-6 carbon atoms or alkoxy having 1 to 6 carbon atoms, Am represents a primary amino group, a methylamino- or dimethylamino group, and X is a (C1-C6) alkyl group, characterized in that 7- (alkylthiobenzoyl) indol-2-one of the formula (II): R, R2 and X are as defined above, hydrolyzed with an alkali metal hydroxide and the obtained alkali metal salt of formula Ia in which: R, R ² , Am and X are as hereinbefore defined, optionally acidified with an acid to form a free acid of formula I wherein R 1 is hydrogen, R, R 2, Am and X are as defined above; Ia esterifies to an ester of formula I wherein R1 is C1 -C6 alkyl, R, R2, Am and X are as defined above, or a compound of formula I wherein Am is a primary amino group, R, R ¹ , R 2 and X are as defined in formula (I), reacted with formaldehyde and sodium cyanoborohydride in acetonitrile in an acidic medium to form a compound of formula (I) wherein Am · denotes dimethylamino, R, R ¹ , R 2 and X are as defined for formula (I). Severography, n. P., Plant 7, Most