LT3471B - New tetrahydonaphtalene derivatives - Google Patents

Abstract

This invention describes new tetrahydronaphtalene derivatives, which have a general formula (I),<IMAGE>whereR<1> is a hydrogen atom,R<2> is a hydrogen atom, C1-4 alkoxycarbonylalkyl or benzyl group, or R<1> and R<2> together is a group, and its formula is -(CH2)3-,R<3> is hydroxyl, C1-4 alkoxyl or benzyl group, or group, and its general formula (A),<IMAGE>whereR<5> is C1-4 alkyl group, and n is 0, 1, 2, 3, or 4 and pharmaceutically suitable saline, besides, its extraction method.These compounds are characterised by an anti-ulcer effect and have influence on both mammal and human cell protection.

Description

The present invention relates to novel tetrahydronaphthalene derivatives of general formula (I),

in which e

R ¹ is a hydrogen atom,

R ² is hydrogen atom, C ₃ _ ₄ - alkoxycarbonylalkyl or benzyl group, or

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

R ³ is hydroxyl, C _r . _An alkoxy or benzyloxy group 4 or a group of formula (A),

N-C00R5 (A), wherein e

R ⁵ is C _L. Alkyl group ₄ and

N is 0, 1, 2, 3 or 4, and pharmaceutically acceptable salts thereof, and a process for their preparation.

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

alkyl or alkoxyl groups may be linear or branched saturated hydrocarbon groups, i.e., methyl, ethyl, n- or isopropyl, in addition to n-, di- or t-butyl groups.

The novel compounds of the general formula (I) are biologically active and have a prophysical effect, i.e., an effect on cell protection.

The present invention further provides pharmaceutical compositions containing novel tetrahydronaphthalene derivatives of the basic formula (I) wherein R, R, R and n have the same meanings as defined above, and pharmaceutically acceptable salts thereof, moreover, the manner in which they are obtained.

Hydrogenation of unsaturated organic compounds using hydrogenated earth oxide hydride catalysts is known (see French Patent Nos. 8616279 and European Patent Specification 02273575).

The novel tetrahydronaphthalene derivatives of the invention have a narrow scope, and no closer technical analogues have been found in this field.

The therapeutic effect of the compounds of the basic formula (I) was investigated by the following tests

Protection of gastric cells in case of ulcer induced by acidified alcohol (A. Robert: Gastroenterology, 77, 761-767, 1979)

The test was performed on female mice weighing 120-150 g and hungry for 24 hours.

The test mixture was delivered through a probe in the form of a suspension in Tween 80. After 30 minutes, doses of 0.5 ml / 100 g of acidified alcohol were also delivered through the probe. After one hour, the animals are decapitated, their stomachs prepped and cut lengthwise. The reddish-brown spots (bleeding wounds) were then measured and their average size per stomach was calculated. The protective effect of the test mixture was determined by comparison with the control group.

Exposure of the mixture according to Example 1: ED ₅₀ = 0.1 mg / kg

Protection of gastric cells in chronic ulcer caused by acetic acid (Tagaki et al., Japanese Journal of Pharmacology 19, 418-426, 1969)

The test was performed on female mice hungry for 24 hours. After anesthesia, the peritoneum is cut and injected with 25 μΐ of 20% acetic acid solution into the serous layer of the gastric fold. Then the warbler was engaged and the animals received food and water ad libitum. Treatment is started on day 5 of the test and continued with a single daily suspension for 10 days. On day 15 the animals were decapitated and their stomachs were prepared. During the inspection, the diameter of the necrotic zones was measured and their surface area was calculated. The therapeutic effect of the test mixture was calculated using the following formula:

.2E £ S J3 ^ vjj ^ j-aus_plot ____ .Pjoyjjšius area _ (control) (test)

Surface area of the ulcer (control)

The therapeutic effect of the compound isolated according to Example 1 was 39% at a dose of 10 mg / kg.

Pharmacological studies have confirmed that the compounds of the present invention, as well as their salts, are potential anti-opiate agents.

The invention also provides a process for the preparation of tetrahydronaphthalene derivatives of the general formula (I) wherein R ¹ , R ² , R ³ and n have the meanings given above, which comprises the interaction of activated 4-oxy-4- (5,6,7 , 8-tetrahydro-2-naphthyl) -2 (E) -butenoic acid derivatives of formula (II),

with amino acid derivatives of the general formula (III),

NH-HH- (CH ₂ ) _n -C-R 4 R 12 '

4 wherein - R and R are as previously defined and R is a Ο _{3 to 4} alkoxy or benzyloxy group or a group of the general formula A - wherein R ⁵ is an alkyl group and where appropriate the compounds of the basic formula ( I), - wherein R ¹ and R ² are as previously defined and R ³ is a t-butyloxy group, acidolysis and / or, where appropriate, carried out on compounds of the basic formula (I), - wherein R ¹ and R ² are as defined above and R ³ represents a hydroxyl group, - interaction of the activated derivatives with a piperizine derivative of the formula A, - wherein R ⁵ is more acrid, - or a salt conversion using an inorganic or organic base.

The starting compounds of formula (III) are commercial products.

4-Oxo-4- (5,6,7,8-tetrahydro-2-naphthyl-2- (E) -butenoic acid of general formula (II) may be isolated from 1,2,3,4-tetrahydronaphthalene and maleic anhydride in the Friedel-Crafts reaction as described

D. Papa et al., J. Am. Chem. Soc .: 70, 3356, 1948.

According to the present invention, the formation of amides between the compounds of the basic formulas (II) and (III) is best accomplished when in situ activation is carried out primarily with 4-oxy-4- (5,6,7,8-tetrahydro-2-naphthyl). -2 (E) -butenoic acid of the basic formula (II) and its reaction in an inert organic solvent medium with an amino component of the formula (III). The carboxyl group of the compound of formula (II) may be activated with at least a stoichiometric amount of a carbodiimide-type reagent, i.e., dicyclohexylcarbodiimide, in an inert organic solvent, preferably a halogenated aliphatic hydrocarbon, preferably dichloromethane, and at a temperature ranging from 0 ° C to 20 ° C. Another good method of activation is the mixed anhydride method using a chloroformic acid ester, preferably ethyl chloroformate. The reaction is carried out in an inert organic solvent, i.e. a cyclic ether, preferably tetrahydrofuran, in the presence of stoichiometric amounts of a t-amino base, preferably triethylamine, at a temperature ranging from -20 ° C to 0 ° C. In the case where the compound of the general formula (I) - in which R ¹ and R have the former meaning and R ³ is a hydroxyl group - is reacted with a piperazine derivative, the acid is activated by any of the above methods, i.e., mixed anhydrides, or by the carbodiimide method.

If necessary, the compounds of the general formula (I) - in which R and R have the meanings given above and R is a hydroxyl group - may be converted to an alkali metal, alkaline earth metal or zinc salt with an organic or inorganic base.

The compounds of the general formula (I) in which R, R and R ³ have the same meaning as described above can be isolated by conventional methods, i.e., by filtration and purification by recrystallization.

The compounds of the present invention may be formulated into pharmaceutical compositions suitable for external and internal use by admixing with non-toxic, inert, solid or liquid carriers and / or additives. Such carriers may include water, gelatin, lactose, starch, pectin, magnesium stearin, stearic acid, talc, vegetable oils such as peanut oil, olive oil and the like. The active ingredient may be administered, as is customary in pharmaceutical compositions, in solid form, i.e., oval or quadrangular tablets, film-coated tablets, gelatin capsules, pills or suppositories.

If necessary, adjuvants such as antiseptics, stabilizers, wetting agents, emulsifying agents, and the like may be incorporated into the compositions. This may be accomplished by conventional techniques, for example, in the case of solid compositions, by sieving, mixing, granulating, or bulk pressing. Conventional technological processes, i.e. sterilization, can be employed in the preparation of such compositions.

The following examples illustrate in part the embodiment of the present invention.

example

Ethyl 4-oxo-4- (5,6,7,8-tetrahydro-2-naphthyl) -2 (E) -butenoyl-Lproline

4.6 g (0.02 mol) of 4-oxo-4- (5,6,7,8-tetrahydro-2-naphthyl) -2 (E) -butenoic acid are dissolved in 100 ml of anhydrous dichloromethane, followed by the addition of 5, 6 ml (0.04 mol) of triethylamine. The solution is cooled to -15 [deg.] C., followed by addition of 2.01 g (0.022 mol) of ethyl ester of L-proline in 10 ml of anhydrous dichloromethane. The reaction mixture is stirred initially at -15 ° C for 30 minutes, then at room temperature for one hour, and then extracted with solvents in the following sequence: 1N hydrochloric acid, water, 5% sodium carbonate, and saturated sodium chloride solution. The organic layer was dried over sodium sulfate and evaporated.

The residue is crystallized from a cyclohexane-petroleum ether mixture (1: 1).

Yield: 5.03 g (70%)

Melting point: 63-66 ° C [α] ρ25 _: -78.8 ° C (c = 0.5, chloroform)

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 t-butyl ester are stirred in 200 ml of 2, 4 N acetic acid in dioxane solution for 24 hours, after which the mixture was evaporated. The residue is dissolved in 200 ml of dichloromethane, and the solution is extracted with water and saturated sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated to an oil-like state.

Yield: 6.50 g (99%) of the sample

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

6.5 g of N- [4-oxo-4- (5,6,7,8-tetrahydro-2-naphthyl) -2 (E) butenoyl] -L-proline isolated according to Example 2 of the present invention are dissolved in a mixture. of 10 mL of water and 2.78 mL (0.02 mol) of triethylamine followed by addition of 1.36 g of zinc chloride. The precipitated compound is filtered off, washed with ice water, ethanol and diethyl ether. The product is a light yellow color.

Yield: 4.9 g (62%)

Melting point: 122-124 ° C ^- 82.4 ° C (c = 1, methanol)

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

4.6. g (0.02 mol) of 4-oxo-4- (5,6,7,8-tetrahydro-2-naphthyl) -2 (E) -butenoic acid are dissolved in 50 ml of anhydrous tetrahydrofuran, 5.6 ml of (04 moles) of triethylamine, and the solution is cooled to -10 ° C. To this solution is slowly added 2.01 ml (22 mmol) of ethyl chloroformate, diluted with 20 ml of anhydrous tetrahydrofuran. Thereafter, 4.5 g (0.02 mol) of diethyl ester of D-aspartic acid, diluted with 20 ml of anhydrous dichloromethane, are added while maintaining the reaction mixture at -10 ° C. The reaction mixture was stirred at -10 ° C for 30 minutes, then at room temperature for one hour and then poured into 200 mL of water. The mixture was extracted with dichloromethane. The organic layer was extracted with 5% sodium carbonate and saturated sodium chloride solutions. The organic layer was dried over anhydrous magnesium sulfate and the solvent evaporated. The residue is crystallized from petroleum ether to give light yellow crystals.

Yield: 5.6 g (70%)

Melting point: 95-97 ° C [α] ρ25 _: -0.33 ° C (c = 0.5 chloroform) Example 1- [N- / 4-oxo-4- (5,6,7,8-tetrahydro) -2-naphthyl) -2 (E) -butenoyl / -L-prolyl] -4-ethoxycarbonyl-piperizine

4.24 g (18.4 mmol) of 4-oxo-4- (5,6,7,7,8-tetrahydro-2-naphthyl) -2 (E) -butenoic acid are dissolved in 80 ml of anhydrous 3471B tetrahydrofuran, followed by the addition of 2.57 mL (18.4 mmol) of triethylamine, followed by 1.76 mL (18.4 mmol) of ethyl chloroformate, diluted with 10 mL of anhydrous tetrahydrofuran. To this mixture is added 4.7 g of 1-L-prolyl-4-ethoxycarbonylpiperazine prepared in accordance with the isolation of the starting materials described in b) and dissolved in 30 ml of anhydrous tetrahydrofuran. The reaction mixture was stirred at -15 ° C, then at -10 ° C for 30 minutes, then at room temperature for one hour. The mixture was then poured into 400 mL of water and extracted with dichloromethane. The organic layer is extracted first with 5% sodium carbonate followed by water, finally with a saturated sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and the solvent evaporated. The oily residue is recrystallized from a mixture of diethyl ether and isopropanol.

Yield: 4.87 g (57%)

Melting point: 110-112 ° C [<x] d25 _: + 9.4 ° c (c = 1, chloroform)

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 and 8.3 g (0.06 mol) of potassium carbonate are dissolved in a mixture of 100 ml of water and 100 ml of dichloromethane. The organic layer was dried and the solvent evaporated. The oily residue is 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 the resulting solution is cooled to -15 ° C. 8.4 ml (0.06 mol) of triethylamine are added followed by 6.1 ml (66 mmol) of ethyl chloroformate, diluted with 20 ml of anhydrous tetrahydrofuran. The prepared first step Lproline benzyl ester base dissolved in 20 ml of anhydrous tetrahydrofuran is then added. The reaction mixture is stirred at -15 ° C for 30 minutes, then at room temperature for one hour, after which it is poured into 400 ml of water and extracted with dichloromethane. The organic layer is washed first with 5% sodium carbonate solution, then with water and finally with saturated sodium chloride solution. The organic layer is dried over anhydrous magnesium sulfate and the solvent is evaporated. The oily residue is recrystallized from acetone-n-hexane.

Yield: 12.0 g (48%)

Melting point: 95-96 ° C [α] ρ25 _: -4i, l ° c (c = 1, chloroform)

Ethyl N- [4-oxo-4- (5,6,7,8-tetrahydro-2-naphthyl) -2 (E) -butenoyl] -β-alanine

2.3 g (0.01 mol) of 4-oxo-4- (5,6,6,7,8-tetrahydro-2-naphthyl) -2 (E) -butenoic acid and 1.53 g (0.01 mol) The ethyl ester of β-alanine hydrochloride is suspended in 50 ml of anhydrous dichloromethane and cooled to 0 ° C. Then, 1.01 g (0.01 mol) of N-methylmorpholine, diluted in 20 ml of anhydrous dichloromethane, are added to the suspension, followed by 2.06 g (0.01 mol) of dicyclohexylLT 3471 B carbodiimide. The reaction mixture was stirred for one hour at 0 ° C and then for one hour at room temperature.

The precipitate of dicyclohexylurea formed is filtered off and the filtrate is extracted with the solvents in the following order: 1N hydrochloric acid, water, saturated sodium carbonate solution and finally sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue is crystallized by addition of diethyl ether.

Yield: 1.3 g (41%)

Melting point: Example 112-114 ° C

Ethyl N- [4-oxo-4- (5,6,7,8-tetrahydro-2-naphthyl) -2 (E) -butenoyl] -6-aminohexanoic acid

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 (101 mol) of 6 The ethyl ester of -aminohexanoic acid is suspended in 60 ml of anhydrous dichloromethane and cooled to 0 ° C. To this mixture is first added 1.01 g (0.01 mol) of N-methylmorpholine in 20 ml of dry dichloromethane, followed by 2.06 g (0.01 mol) of dicyclohexylcarbodiimide. The reaction mixture was stirred at 0 ° C for one hour. The precipitate of dicyclohexylurea formed is filtered off and the filtrate is extracted with the solvents in the following order: IN 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 evaporated. The residue is crystallized from a mixture of diethyl ether and n-hexane.

Yield: 1.48 g (40%)

Melting point: 7 4-7 6 ° C Example

N- [4-Oxo-4- (5,6,6,7,8-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-oxy-4- (5,6,7,8-tetrahydro-2-naphthyl) -2 (E) -butenoic acid is suspended in 80 ml of anhydrous dichloromethane and cooled to 0 ° C. To this mixture was added 2.03 g (0.02 mol) of methylmorpholine dissolved in 30 ml of anhydrous dichloromethane followed by 4.12 g (0.02 mol) of dicyclohexylcarbodiimide. The reaction mixture was stirred for one hour at 0 ° C, then for one hour at room temperature. The resulting precipitate of dicyclohexylurea is filtered off and the filtrate is extracted with solvents in the following order: IN hydrochloric acid, water, saturated sodium carbonate solution and finally saturated sodium chloride solution.

The organic layer is dried over anhydrous magnesium sulfate and the solvent is evaporated. After evaporation, the residue is crystallized from a mixture of ethyl acetate and diethyl ether.

Yield: 3.7 g (47%)

Melting point: 145-147 ° C [α] ρ ²⁵ : -22.5 ° C (c = 1 methanol) Example - [N- / 4-oxo-4- (5,6,7,8-tetrahydro-2) -naphthyl) -2 (E) -butenoyl / -L-propyl] -4-ethoxycarbonylpiperazine

6.5 g of the oil state N- [4-oxo-4- (5,6,7,8-tetrahydro-2-naphthyl) -2 (E) -butenoyl] -L-proline, isolated according to the procedure described in Example 2, are dissolved in 150 ml of anhydrous dichloromethane are cooled to 0 [deg.] C., followed by addition of 3.16 g (0.02 mol) of 1-ethoxycarbonylpiperazine and 4-dimethylaminopyridine required for catalysis. To this mixture was added 4.54 g (22 mmol) of dicyclohexylcarbodiimide dissolved in 20 ml of anhydrous dichloromethane under constant stirring. The reaction mixture was stirred for 24 hours at room temperature. The precipitate of dicyclohexylurea formed is filtered off and washed with dichloromethane. The organic layer is extracted with solvents in the following sequence: IN hydrochloric acid, water, 10% sodium carbonate solution, water, and finally saturated sodium chloride solution. The organic layer was dried with sulfate, filtered, and the solvent was recrystallized from a mixture of diethyl ether and isopropanol.

anhydrous magnesium is evaporated. Yield: 5.1 g (55%)

Melting point: 110-112 ° C [α] ρ25. + 92 ° C (c = 1, chloroform)

Obtaining starting materials

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

5.23 g (0.02 mol) of L-proline t-butyl ester oxalate are suspended in 50 ml of dichloromethane and the mixture is extracted with 50 ml of water dissolved in 2.76 g (0.02 mol) of potassium carbonate until the solution is clear. . The organic layer was separated, dried over anhydrous sodium sulfate, and triturated.

Yield: 3.7 g of L-proline t-butyl ester.

4.6 g (0.02 mol) of 4-oxo-4- (5,6,7,8-tetrahydro-2-naphthyl) -2 (E) -butenoic acid are dissolved in 50 ml of anhydrous tetrahydrofuran and 2.8 ml are added. (0.02 mol) of triethylamine. The reaction mixture was cooled to -15 ° C, followed by the addition of 2.01 mL (22 mmol) of ethyl chloroformate, diluted with 20 mL of anhydrous tetrahydrofuran, followed by a pre-prepared solution of 3.7 g (22 mmol) of L- [ proline t-butyl ester and 20 ml anhydrous tetrahydrofuran. The reaction mixture was stirred at -15 ° C for 30 minutes, then poured into 200 mL of water and extracted with dichloromethane. The organic layer is extracted with solvents in the following sequence: 5% sodium carbonate solution, saturated sodium chloride solution and finally water. The organic layer was dried over anhydrous magnesium sulfate and the solvent evaporated. The residue is crystallized by addition of ethyl ether.

Yield: 3.89 g (51%)

Melting point: 95-98 ° C [gcId ^ S; -81.2 ° C (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 3471 B of 150 ml of anhydrous dichloromethane, cooled to + 5 ° C, 11.35 g (55 mmol) of dicyclohexylcarbodiimide dissolved in 50 ml of anhydrous dichloromethane are added, the mixture is stirred for 24 hours at room temperature, the precipitate of dicyclohexylurea is filtered off and the filtrate is extracted with solvents with 1 N hydrochloric acid, 10% aqueous sodium hydroxide, The organic layer is dried over anhydrous magnesium sulfate, the solvent is evaporated, and the product begins to crystallize upon freezing, and the white crystals formed are filtered off and washed with chilled diethyl ether.

Yield: 14.0 g (72%)

Melting point; 90.5-92 ° C [α] _D ²⁵ : -11.4 ° C (c = 1, methanol)

c) 1-L-prolyl-4-ethoxycarbonylpiperazine

7.4 g (19 mmol) of 1- (N-benzyloxycarbonyl-L-prolyl) -4-ethoxycarbonylpiperazine, isolated as described above, are dissolved in 150 ml of anhydrous methanol and the resulting solution is hydrogenated for 2 hours in the presence of PdO as a catalyst. After removal of the catalyst, the solution is evaporated.

Yield: 4.7 g (96.9%).

Claims (9)

DEFINITION OF INVENTION 1. New tetrahydronaphthalene derivatives of general formula (I) R is hydroxy, C ₃ _ ₄ alkoxy or PES, or a group of the general formula wherein R ¹ is a hydrogen atom, R ² is a hydrogen atom, C _r . _An alkoxycarbonylalkyl or benzyl group of 4 or 1 2 R and R together are a group of the formula - (CH ₂ ) ₃ -, benzyloxyl group (A), (A) Γ ~ \ - {ξ / N — COORS in which R ⁵ is C ₃ _ ₄ alkyl group on is 0, 1, 2, 3, or 4, their pharmaceutically acceptable salts. and 2. Compounds selected from the compounds of the general formula I as described in claim 1, which are: Ethyl 4-oxo-4- (5,6,7,8-tetrahydro-2-naphthyl) -2 (E) -butenoyl] -L-proline, N- [4-oxo-4- (5,6,7,8-tetrahydro-2-naphthyl) -2 (E) -butenoyl] -L-proline zinc salt tetrahydrate, 1- [N- / 4-Oxo-4- (5,6,7,8-tetrahydro-2-naphthyl) -2 (E) -butenoyl] -D-aspartic acid diethyl ester, 1- [N- / 4 -oxo-4- (5,6,7,8-tetrahydro-2-naphthyl) -2 (E) -butenoyl / -L-prolyl] -4-ethoxycarbonylpiperazine, Benzyl ester of N- [4-oxo-4- (5,6,7,8-tetrahydro-2-naphthyl) -2 (E) -butenoyl] -L-proline, Ethyl N- [4-oxo-4- (5,6,7,8-tetrahydro-2-naphthyl) -2 (E) -butenoyl] -β-alanine, N- [4-Oxo-4- (5,6,7,8-tetrahydro-2-naphthyl) -2 (E) -butenoyl] -6-aminohexanoic acid ethyl ester, N- [4-Oxo-4- (5,6,7,8-tetrahydro-2-naphthyl) -2 (E) -butenoyl] -L-phenylalanine methyl ester. 3. A pharmaceutical composition comprising the active ingredient and a pharmaceutically acceptable carrier and / or additive, characterized in that the active ingredient is a novel tetrahydronaphthalene derivative having the general formula (I) as defined in claim 1 or a pharmaceutically acceptable salt thereof. Novel tetrahydronaphthalene derivatives of the general formula (I) according to claim 1 and pharmaceutically acceptable salts thereof for the treatment and / or prophylaxis of mammalian (including human) inflammation of the trachea, stomach and duodenum. 5. New tetrahydronaphthalene derivatives of general formula (I) II (I) in which R ¹ is a hydrogen atom, R ² is a hydrogen atom, a C 1-4 alkoxycarbonylalkyl or benzyl group, or R ¹ and R ² together are a group of the formula - (CH ₂ ) -, R ^J is a hydroxyl, alkoxyl or benzyl group or a group of general formula (A), (A) wherein R ⁵ is C _x _ ₄ alkyl group on is 0, 1, 2, 3, or 4, and their pharmaceutically acceptable salts, besiski Riant in that a 4-oxo-interaction between 4- (5,6,7,8- tetrahydro-2-naphthyl) -2 (E) - butenoic acid of general formula (II) with amino acid derivatives of general formula (III) in which R ¹ and R ² have the meanings given above and R ⁴ is a C 1-4 alkoxyl group or a group of formula (A) wherein R ⁵ is a C x C ₄ alkyl group and optionally carries the compounds of general formula (I) wherein R and R are as defined above and R is a tert-butyloxy group. , acidolysis and / or, if necessary, interactions of the activated derivatives of the compounds of the general formula (I) in which R ¹ and R ² are the former and R ³ are a hydroxyl group with piperazine derivatives containing a group Formula A wherein R has the former meaning or is converted to a salt using an inorganic or organic base. 6. A process according to claim 5, wherein the carboxylic acid is activated in situ, preferably by a carbodiimide-type reagent or a mixed anhydride method. 7. The process of claim 5, wherein the 1-ethoxycarbonylpiperazine is used as a piperazine derivative. 8. A process according to claim 5, wherein the carboxylic acid is converted into an alkali metal, alkaline earth metal or zinc salt. 9. A process for the preparation of a pharmaceutical composition comprising the novel tetrahydronaphthalene derivatives of the general formula (I) wherein R ¹ is a hydrogen atom, R is a hydrogen atom, a C _{x 4} alkoxycarbonylalkyl or benzyl group, or R ¹ and R ² together represent a group of formula - (CH ₂ ) ₃ -, R ³ is hydroxy, C _x _ ₄ alkoxy or benzyloxy group or a group of the general formula (A) wherein R ⁵ is C _x , ₄ alkyl, on is 0, 1, 2, 3 or 4, or pharmaceutically acceptable salts thereof, with pharmaceutically acceptable carriers and / or additives.