HU209487B - Process for producing tetrahydro-naphtaline derivatives and pharmaceutical compositions containing them as active agents - Google Patents

Description

The present invention relates to novel tetrahydronaphthalene derivatives of the formula I wherein R ¹ is hydrogen,

R ² is hydrogen or C 1-4 alkoxycarbonyl-C 1-4 alkyl or benzyl, or

R ¹ and R ² together are - (CH ₂ ) ₃ -

R ³ is hydroxy or C 1-4 alkoxy or benzyloxy or a group of formula A wherein R ⁵ is C 1-4 alkyl n is 0, 1, 2,3 or 4 and pharmaceutically acceptable bases and its salts by reacting a compound of formula (II)

An activated derivative of 4-oxo-4- (5,6,7,8-tetrahydro-2-naphthyl) -2 (E) -butenoic acid with an amino acid derivative of formula (III) wherein R ¹ and R ² are above, R ⁴ is 1-4 carbon atoms.

fi fi fi

C-CH = CH-C-N-CH- (CH, L-ΟΙ. ^{1 2n} R ¹ R ²⁾

R3

II

C-CH = CH-C00H

NH-CH- (CH 1) _n -C-R 4

II

R ¹ R ² (I) (II) (III)

HU 209 487

Scope of the description: 8 pages (including 1 page figure)

Alkoxy or benzyloxy or a group of Formula A wherein R ^s is C 1 -C 4 alkyl, and if desired, the resulting compounds of Formula I wherein R ^{1 is} and R ² is as defined above, R ³ is tert-butyloxy - subject to acidolysis and / or, if desired, the resulting compound of formula I wherein R ¹ and R ² are as defined above, R ³ is an activated derivative of a hydroxyl group is reacted with a piperazine derivative of the formula A wherein R ⁵ is as defined above or converted to a salt with an inorganic or organic base.

The present invention also relates to a process for the preparation of an anti-ulcer pharmaceutical composition containing the compounds of formula (I) as an active ingredient.

The present invention relates to novel tetrahydronaphthalene derivatives of the formula I wherein R ¹ is hydrogen,

R ² is hydrogen or C 1-4 alkoxycarbonyl-C 1-4 alkyl or benzyl, or

R ¹ and R ² together are - (CH ₂ ) 3 -

R ³ is hydroxy or C 1-4 alkoxy or benzyloxy or a group of formula A wherein R ⁵ is C 1-4 alkyl, n is 0, 1, 2, 3 or 4 and pharmaceutically acceptable salts thereof.

The compounds of formula (I) may have the configuration (E).

In C 1 -C 4 alkyl and alkoxy groups, alkyl groups are linear or branched saturated hydrocarbon groups such as methyl, ethyl, n- or 1-propyl; η, chair or tert-butyl groups.

In our studies with the new compounds of the formula I, they have been found to be biologically active and have a significant anti-ulcer effect, such as cytoprotective.

The present invention also relates to pharmaceutical compositions containing novel tetrahydronaphthalene derivatives of the formula I and their pharmaceutically acceptable base salts. In this formula the value of R ^1, R ^2, R ³ and n are as defined above.

The therapeutic activity of the compounds of formula I was investigated by the following methods:

Examination of acidic alcohol-induced gastric damage (A. Róbert, Gastroenterology, 1979, 77; 761-767)

Female rats 120-150 g fasted for 24 hours were used for the study. The test substance was administered by gavage in a suspension of Tween 80 in rats. Half an hour later, 0.5 ml / 100 g of acidic alcohol was injected into the animals' stomach by gavage. One hour later, the animals were sacrificed, the stomach was removed, and cut at high curvature. The red-brown bands (hemorrhagic lesions) were weighed and the average total length per stomach was calculated. The efficacy of the test compound was compared to a control group. The compound of Example 1 of the present invention has an effect of ED ₅₀ = 0.1 mg / kg po. dosing.

Acetic acid chronic ulcer model assay [Tagaki et al .; Japanese Journal of Pharmacology 19, 418-426 (1969)].

Carry out the test as follows:

The fasted abdominal wall of female rats is exposed to ether for an hour. Near the pylorus, 25 μΐ of 20% acetic acid solution was injected into the subserotic layer into the glandular part of the stomach. Then the abdominal wall is closed and the animal is given food and drink according to the animal's needs. On the 5th day after surgery, start treatment for 10 days with a single daily dose. So on the 15th day after the operation, the rats are sacrificed and their stomachs are removed. The ulcer is evaluated by measuring the diameter of the necrotic areas and calculating their area. The curative effect of the test compound is calculated according to the following formula:

ulcer area (control) - ulcer area (test substance) ulcer area (control)

The compound of Example 1 tested was 10 mg / kg po. a cure rate of 39% was achieved.

As can be seen from the pharmacological results, the compounds of the invention, their pharmacologically acceptable salts, have excellent anti-ulcer properties.

According to the invention, the novel tetrahydronaphthalene derivatives of formula (I), wherein R ¹ , R ² , R ³ and n are as defined above, may be prepared by reacting a 4-oxo-4- ( An activated derivative of 5,6,7,8-tetrahydro-2-naphthyl) -2 (E) -butenoic acid with an amino acid derivative of formula (III) wherein R ¹ and R ² are as defined above, R ⁴ is C 1 -C 4 alkoxy or benzyloxy; or a group of formula A wherein R ⁵ is C 1 -C 4 alkyl; and, if desired, the resulting compounds of formula wherein R ¹ and R ² are as defined above, R ³ is t-butyloxy group - preparation of the hydroxyl-containing R ³ of formula (I) compounds was subjected to acidolysis and / or desired site for R ³ of formula (I) containing a group of formula to prepare the compounds of formula (I) wherein R ¹ and R ² are as defined above, the activated derivative of R ³ is hydroxy, is reacted with a piperazine derivative of formula A wherein R ⁵ is as defined above, or with an organic base.

Among the starting compounds used in the process, the compounds of formula (ΠΙ) are commercially available.

HU 209 487 B

The 4-oxo-4- (5,6,7,8-tetrahydro-2-naphthyl) 2 (E) -butenoic acid of formula (II) is prepared by D. Papa et al., I. Am. Chem. Soc. , 70, 3358 (1948), may be prepared from 1,2,3,4-tetrahydronaphthalene and maleic anhydride by Friedel-Crafts reaction.

Advantageously, the process of the present invention can be carried out, for example, by reacting the 4-oxo-4- (5,6,7,8) amide formation reaction of the compounds of formula (II) and (III). -tetrahydro-2-naphthyl) -2 (E) -butenoic acid is first activated in situ and then reacted with the amine component (ΠΙ) in an inert organic solvent. Activation of the carboxyl group of the carboxylic acid of formula (Π) may be carried out with at least a stoichiometric amount of a carbodiimide type reagent such as dicyclohexylcarbodiimide in the presence of an inert organic solvent, optionally halogenated aliphatic hydrocarbon, preferably dichloromethane. The reaction temperature is conveniently maintained at 0 ° C to 20 ° C. Another preferred mode of activation is the formation of mixed anhydride, using, for example, an ethyl chloroformate as an ester of chloroformate. The reaction is carried out in the presence of a stoichiometric amount of a tertiary amine base, preferably triethylamine, in an inert organic solvent such as a cyclic ether, preferably tetrahydrofuran, preferably at -20 ° C to 0 ° C. When a compound of formula (I) wherein R ¹ and R ² are as defined above and R ³ is hydroxy is reacted with a piperazine derivative, activation of the acid as described above, e.g. carbodiimide reagent.

Compounds of formula (I) wherein R ¹ and R ² are as defined above and R ³ is hydroxy may, if desired, be converted to an alkali metal, alkaline earth metal or zinc salt by an organic or inorganic base.

The compounds of formula (I) according to the invention, wherein R ¹ , R ² and R ³ are as defined above, may be isolated from the reaction mixture by known methods, for example by filtration and purified by recrystallization.

The compounds of the invention may be formulated into pharmaceutical compositions by admixing with non-toxic inert solid or liquid carriers and / or excipients suitable for parenteral or enteral administration in the pharmaceutical field. Suitable carriers include, for example, water, gelatin, lactose, starch, pectin, magnesium stearate, stearic acid, talc, vegetable oils such as peanut oil, olive oil and the like. It can be used. The active ingredient may be in the form of conventional pharmaceutical compositions, in particular solid forms, for example, round or square tablets, dragees, capsules such as gelatin capsules, pills, suppositories and the like. in the form of.

The compositions may optionally contain conventional pharmaceutical excipients such as preservatives, stabilizers, wetting agents, emulsifying agents, and the like. also contain. They may be prepared by conventional techniques such as sieving, mixing, granulating and pressing the components in the case of solid compositions. The compositions may also be subjected to other conventional pharmaceutical techniques such as sterilization.

The invention is illustrated by the following non-limiting examples.

Example 1

N- [4-Oxo-4- (5,6,7,7a-tetrahydro-2-naphthyl) -2 (E) -butenoyl] -L-proline, ethyl ester

4.6 g (0.02 mol) of 4-oxo-4- [5,6,7,8-tetrahydro-2-naphthyl) -2 (E) -butenoic acid were dissolved in 100 ml of anhydrous dichloromethane and triethylamine (0.04 mol) was added. The solution is cooled to -15 ° C and 2.01 ml (0.022 mol) of ethyl chloroformate in 10 ml of anhydrous dichloromethane are added. Then 4.0 g (0.022 mol) of L-proline ethyl ester hydrochloride in 10 ml of anhydrous dichloromethane are added to the reaction mixture. The reaction mixture was stirred for half an hour at -15 ° C and for two hours at room temperature and then extracted with 1 N hydrochloric acid, water, 5% sodium carbonate solution, and saturated sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and evaporated. The residue was crystallized from cyclohexane / petroleum ether 1: 1. Weight of the title product: 5.03 g. Yield: 70%.

M.p. 63-66 ° C.

Optical rotation values: [a] _D = -78.8 ° (c = 0.5, chloroform).

Example 2

N- [4-Oxo-4- (5,6,7,8-tetrahydro-2-naphthyl) -2 (E) -butenoyl] -L-proline

7.66 g (0.02 mol) of 4-oxo-4- (5,6,7,8-tetrahydro-2-naphthyl) -2 (E) -butenoyl-L-proline tert-butyl ester in 200 ml

After stirring overnight at room temperature in 2.4N HCl in dioxane, it is evaporated. The residue was dissolved in dichloromethane (200 mL). The solution was extracted with water and then with saturated sodium chloride solution. The organic phase is dried over anhydrous magnesium sulfate and the solvent is evaporated. The title compound was obtained as an oil, 6.50 g.

Yield: 99%.

Example 3

N- [4-Oxo-4- (5,6,7,8-tetrahydro-2-naphthyl) -2 (E) -butenoyl] -L-proline zinc salt tetrahydrate. N- [4-oxo-4- (5,6,7,8-tetrahydro-2-naphthyl) -2 (E) -butenoyl] -L-proline in 10 ml water and 2.78 ml (0.02 mol) triethyl 1.36 g of zinc chloride in 10 ml of an aqueous solution are added. The precipitate is filtered off, washed with ice water and then washed with ethanol and diethyl ether. A pale yellow product is formed. Weight of the title product: 4.9 g.

Yield: 62%

HU 209 487 B

Melting point 122-124 ° C.

Optical rotation: [α] D = -82.4 ° (c = 1, methanol).

Example 4

N- [4-Oxo-4- (5,6,7,8-tetrahydro-2-naphthyl) -2 (E) butenoyl] -D-aspartic acid diethyl ester

4-Oxo-4- (5,6,7,8-tetrahydro-2-naphthyl) -2 (E) -butenoic acid (4.6 g, 0.02 mol) was dissolved in 50 ml of anhydrous tetrahydrofuran. To the solution was added triethylamine (5.6 mL, 0.04 mol) and cooled to -10 ° C. Then, 2.01 ml (22 mmol) of ethyl chloroformate was slowly added in 20 ml of anhydrous tetrahydrofuran solution. Then, while maintaining the temperature of the reaction mixture at -10 ° C, 4.5 g (0.02 mol) of D-aspartic acid diethyl ester hydrochloride in 20 ml of anhydrous dichloromethane are added. The reaction mixture was stirred for half an hour at -10 'C and then for one hour at room temperature. The reaction mixture was poured into water (200 mL) and extracted with dichloromethane which was repeatedly extracted with 5% sodium carbonate solution, saturated sodium chloride solution. The organic phase is dried over anhydrous magnesium sulfate and the solvent is evaporated. The residue on evaporation gives petroleum ether as a pale yellow crystalline product.

Weight: 5.6 g.

Yield: 70%.

Melting point: 95-97 ° C.

Optical rotation: [α] D = -0, 33 ° (c = 0.5, chloroform).

Example 5 1- {N- [4-Oxo-4- (5,6,7,8-tetrahydro-2-naphthyl) -2 (E) butenoyl] -L-prolyl} -4-ethoxycarbonylpiperazine 4, 4-Oxo-4- (5,6,7,8-tetrahydro-2-naphthyl) -2 (E) -butenoic acid (24 g, 18.4 mmol) was dissolved in dry tetrahydrofuran (80 mL). To the solution was added triethylamine (2.57 mL, 18.4 mmol) and ethyl chloroformate (1.76 mL, 18.4 mmol) in anhydrous tetrahydrofuran (10 mL). To the mixture was added a solution of 4.7 g of l-L-prolyl-4-ethoxycarbonylpiperazine (4.7 g) obtained in (b) in the preparation of the starting compounds, in 30 ml of anhydrous tetrahydrofuran. The reaction mixture was stirred at -15 ° C for half an hour at -10 ° C for one hour at room temperature. The reaction mixture was poured into water (400 mL) and extracted with dichloromethane. The organic layer was extracted with 5% sodium carbonate solution, water, then saturated sodium chloride solution. The organic phase is dried over anhydrous magnesium sulfate and the solvent is evaporated. The residual oil was crystallized from a mixture of diethyl ether and isopropanol. Weight of the title product: 4.87 g. Yield: 57%.

Melting point: 110-112 ° C.

Optical rotation: [α] D = + 9.4 ° (c = 1, chloroform).

Example 6

N- [4-Oxo-4- (5,6,7,8-tetrahydro-2-naphthyl) -2 (E) -butenoyl] -L-proline benzyl ester

14.5 g (0.06 mol) of L-proline benzyl ester hydrochloride, 8.3 g (0.06 mol) of potassium carbonate are dissolved in 100 ml of water and 100 ml of dichloromethane. The organic phase is dried and the solvent is evaporated. The residual oil was used directly in the next step.

13.8 g (0.06 mol) of 4-oxo-4- (5,6,7,8-tetrahydro-2-naphthyl) -2 (E) -butenoic acid are dissolved in 150 ml of anhydrous tetrahydrofuran and cooled to -15 ° C. To the solution

Triethylamine (8.4 mL, 0.06 mol) was added followed by ethyl chloroformate (6.1 mL, 66 mmol) in anhydrous tetrahydrofuran (20 mL). To the mixture was added a solution of the L-proline benzyl ester base obtained in the previous step in 20 ml of anhydrous tetrahydrofuran. The reaction mixture was stirred at -15 ° C for half an hour, then for another hour at room temperature and then poured into water (400 ml) and extracted with dichloromethane. The organic layer was extracted with 5% sodium carbonate solution, then with water and finally with saturated sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and then the solvent was evaporated. The residue was crystallized from petroleum ether and recrystallized from acetone / n-hexane.

Weight of the title product: 12.0 g.

Yield: 48%.

Melting point: 95-96 ° C.

Optical rotation: [α] D = -41.1 ° (c = 1, chloroform).

Example 7

N- [4-Oxo-4- (5,6,7,8-tetrahydro-2-naphthyl) -2 (E) butenoyl] -β-alanine ethyl ester

2.3 g (0.01 mol) of 4-oxo-4- (5,6,7,8-tetrahydro-2-naphthyl) -2 (E) -butenoic acid and 1.53 g (0.01 mol) of? -alanyl ethyl ester hydrochloride was suspended in 50 ml of anhydrous dichloromethane and cooled to 0 ° C. To the mixture was added N-methylmorpholine (1.01 g, 0.01 mol) in anhydrous dichloromethane (20 ml) followed by dicyclohexylcarbodiimide (2.06 g, 0.01 mol). The reaction mixture was stirred for 1 hour at 0 ° C and then for 1 hour at room temperature.

The precipitated dicyclohexylurea is filtered off and the filtrate is extracted with 1 N hydrochloric acid, water, saturated sodium carbonate solution, and finally saturated sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue crystallizes upon addition of diethyl ether.

Weight: 1.3 g.

Yield: 41%.

Melting point: 112-114 ° C.

Example 8

N- [4-Oxo-4- (5,6,7,8-tetrahydro-2-naphthyl) -2 (E) butenoyl] -6-aminohexanoic acid ethyl ester

2.3 g (0.01 mol) of 4-oxo-4- (5,6,7,8-tetrahydro-2-naphthyl) -2 (E) -butenoic acid and 1.95 g (1.01 mol) of The ethyl amino hexanoic acid was suspended in 60 ml of anhydrous dichloromethane and cooled to 0 ° C. To the mixture was added N-methylmorpholine (1.01 g, 0.01 mol) in anhydrous dichloromethane (20 ml) followed by dicyclohexylcarbodiimide (2.06 g, 0.01 mol). The reaction mixture was stirred at 0 ° C for 1 hour and at room temperature for 1 hour

Stir. The precipitated dicyclohexylurea was filtered and the filtrate was extracted with 1 N hydrochloric acid, water, saturated sodium carbonate solution, and finally saturated sodium chloride solution. The organic phase is dried over anhydrous magnesium sulfate and the solvent is evaporated. The residue was crystallized from a mixture of diethyl ether and n-hexane.

Weight of the title product: 1.48 g.

Yield: 40%.

74-76 ° C.

Example 9

N- [4-Oxo-4- (5,6,7,8-tetrahydro-2-naphthyl) -2 (E) -butenoyl] -L-phenylalanine methyl ester

4.3 g (0.02 mol) of L-phenylalanine methyl ester hydrochloride and 4.6 g (0.02 mol) of 4-oxo-4- (5,6,7,8-tetrahydro-2-naphthyl) -2 (E) -butenoic acid was suspended in 80 ml of anhydrous dichloromethane and cooled to 0 ° C. To the mixture was added N-methylmorpholine (2.03 g, 0.02 mol) in dichloromethane (30 ml) followed by dicyclohexylcarbodiimide (4.12 g, 0.02 mol). The reaction mixture was stirred for 1 hour at 0 ° C and then for 1 hour at room temperature. The precipitated dicyclohexylurea was filtered and the filtrate was extracted with 1 N hydrochloric acid, water, saturated sodium carbonate solution, and then saturated sodium chloride solution.

The organic phase is dried over anhydrous magnesium sulfate and the solvent is evaporated. The residue was crystallized from diethyl ether and then recrystallized from ethyl acetate / diethyl ether.

Yield: 3.7 g.

Yield: 47%.

145-147 ° C.

Optical rotation: [.alpha.] D @ 20 = -22.5 DEG (c = 1, methanol).

Example 10 1- {N- [4-Oxo-4- (5,6,7,8-tetrahydro-2-naphthyl) -2 (E) butenoyl] -L-prolyl} -4-ethoxycarbonylpiperazine A 2 6.5 g of the oil of N- [4-oxo-4- (5,6,7,8-tetrahydro-2-naphthyl) -2 (E) -butenoyl] -L-proline, prepared in Example 150, in 150 ml of anhydrous dissolved in methane, cooled to 0 ° C. To the mixture was added 3.16 g (0.02 mol) of 1-ethoxycarbonylpiperazine and a catalytic amount of 4-dimethylaminopyridine. A solution of 4.54 g (22 moles) of dicyclohexylcarbodiimide in 20 ml of anhydrous dichloromethane was added to the reaction mixture with constant stirring. The reaction mixture was stirred for 24 hours at room temperature. The precipitated dicyclohexylurea was removed by filtration and washed with dichloromethane (20 mL). The organic phase is extracted in the following order:

hydrochloric acid, water, 10% sodium carbonate solution, water, and finally saturated sodium chloride solution. The organic phase is dried over anhydrous magnesium sulfate, the desiccant is filtered off and the solvent is evaporated. The resulting oil was crystallized from diethyl ether / isopropanol.

Weight: 5.1 g.

Yield: 55%.

Melting point: 110-112'C.

Optical rotation: [α] D = + 9.2 ° (c = 1, chloroform).

Preparation of starting compounds:

a) N- [4-Oxo-4- (5,6,7,8-tetrahydro-2-naphthyl) -2 (E) -butenoyl] -L-proline tert-butyl ester

5.23 g (0.02 mol) of L-proline tert-butyl ester oxalate are suspended in 50 ml of dichloromethane and extracted with a solution of 2.76 g (0.02 mol) of potassium carbonate in 50 ml of water until a clear solution is obtained. produced. The organic layer was separated, dried over sodium sulfate and evaporated to give 3.7 g of L-proline tert-butyl ester.

4-Oxo-4- (5,6,7,8-tetrahydro-2-naphthyl) -2 (E) -butenoic acid (4.6 g, 0.02 mol) was dissolved in anhydrous tetrahydrofuran (50 mL) and treated with (2.8 mL). 0.02 mol) of triethylamine. The reaction mixture was cooled to -15 'C and a solution of 2.01 mL (22 mmol) of ethyl chloroformate in 20 mL of dry tetrahydrofuran was added. Then add the above prepared

A solution of L-proline tert-butyl ester (3.7 g, 22 mmol) in dry tetrahydrofuran (20 mL) was added. The reaction mixture was stirred for half an hour at -15 ° C and then for half an hour at room temperature. The reaction mixture was poured into 200 ml of water and extracted with dichloromethane. The organic phase is extracted with 5% sodium carbonate solution, saturated sodium chloride solution and water. The organic phase is dried over anhydrous magnesium sulfate and the solvent is evaporated. The residual product crystallizes on petroleum ether.

Weight of the title product: 3.89 g.

Yield: 51%.

Melting point: 95-98 ° C.

Optical rotation: [α] D = -81.2 ° (c = 0.5, chloroform).

b) 1- (N-Benzyloxycarbonyl-L-prolyl) -4-ethoxycarbonylpiperazine

12.45 g (0.05 mol) of N-benzyloxycarbonyl-L-proline and 7.91 g (0.05 mol) of 1-ethoxycarbonylpiperazine are dissolved in 150 ml of anhydrous dichloromethane and cooled to +5 ° C. Dicyclohexylcarbodiimide (11.35 g, 55 mmol) in anhydrous dichloromethane (50 mL) was added. After stirring for 24 hours at room temperature, the precipitated DCU was filtered and the filtrate was extracted with 1 N hydrochloric acid, water, 10% sodium carbonate solution, and water again. The organic phase is dried over anhydrous magnesium sulfate. The solvent was evaporated, and upon cooling, crystallization began. The white crystalline product is filtered off and washed with cold diethyl ether.

Weight of the title product: 14.0 g.

Yield: 72%.

Melting point: 90.5-92 ° C.

Optical rotation: [α] D -11.4 ° (c = 1, methanol).

c) 1-L-prolyl-4-ethoxycarbonylpiperazine

1- (N-Benzyloxycarbonyl-L-prolyl) -4-ethoxycarbonylpiperazine (7.4 g, 19 mmol) prepared above was dissolved in 150 ml of anhydrous methanol and hydrogenated for two hours in the presence of palladium on charcoal. After removal of the catalyst, the solution was evaporated. The resulting 1-L-prolyl-4-ethoxycarbonylpiperazine had a mass of 4.7 g.

Yield: 96.9%.

HU 209 487 Β

Claims (5)

PATENT CLAIMS A process for the preparation of tetrahydronaphthalene derivatives of the formula I wherein R ¹ is hydrogen, R ² is hydrogen or C 1-4 alkoxycarbonyl-C 1-4 alkyl or benzyl, or R ¹ and R ² together are - (CH ₂ ) ₃ - R ³ is hydroxy or C 1 -C 4 alkoxy or benzyloxy or a group of formula A wherein R ⁵ is C 1 -C 4 alkyl, n is 0, 1, 2, 3 or 4 and pharmaceutically for use in the preparation of salts thereof with bases, characterized in that an activated derivative of a 4-oxo-4- (5,6,7,8-tetrahydro-2-naphthyl) -2 (E) -butenoic acid of the formula (Π) is ) wherein R ¹ and R ² are as defined above, R ⁴ is C 1 -C 4 alkoxy or benzyloxy, or a group of Formula A wherein R ⁵ is C 1 -C 4 alkyl reacting, and if desired, obtaining the compounds of formula (I) wherein R ¹ and R ² are as defined above and R ³ is tert-butoxy, to produce compounds of formula (I) wherein R ³ is hydroxy. acido lysed and / or preparation of a compound of formula (I) R ³ represents the radical of the general formula (I), a compound of formula - wherein R ¹ and R ² are as defined above, R ³ is a hydroxy group with an activated derivative or a salt thereof with an inorganic or organic base, containing a group of the general Formula A, wherein R ⁵ is as defined above. Process according to claim 1, characterized in that the process for activating the carboxylic acid in situ is preferably carried out using a carbodiimide type reagent or a mixed anhydride method. The process according to claim 1, wherein the piperazine derivative is 1-ethoxycarbonylpiperazine. The process of claim 1, wherein the carboxylic acid is converted to an alkali metal, alkaline earth metal or zinc salt. 5. A process for the preparation of a pharmaceutical composition comprising a tetrahydronaphthalene derivative of the general formula (I) obtained by the process according to claim 1 R ¹ is hydrogen, R ² is hydrogen or C 1-4 alkoxycarbonyl-C 1-4 alkyl or benzyl, or R ¹ and R ² together are - (CH ₂ ) ₃ - R ³ is C 1 -C 4 alkoxy or benzyloxy or hydroxy, or a group of Formula A wherein R ⁵ is C 1 -C 4 alkyl or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable carrier and / or excipient. mixed. (I) HU 209 487 B Int CL ⁵ : C 07 C 235/78