WO1993012070A1

WO1993012070A1 - New tetrahydronaphthalene derivatives

Info

Publication number: WO1993012070A1
Application number: PCT/HU1992/000058
Authority: WO
Inventors: Ildikó BALLÓ; László Dobay; Elemér Ezer; János Fischer; György Hajós; Judit MATÚZ; Ede MÁRVÁNYOS; Katalin Sághy; László Szporny
Original assignee: Richter Gedeon Vegyszeti Gyár Rt.
Priority date: 1991-12-19
Filing date: 1992-12-18
Publication date: 1993-06-24
Also published as: NO942306D0; JPH07502039A; IL104196A0; CA2126198A1; TW223623B; FI942927A0; EP0618894A1; FI942927A; NZ245534A; HUT63147A; HU914021D0; ZA929913B; CN1074213A; NO942306L; HU209487B

Abstract

The invention relates to new tetrahydronaphthalene derivatives of general formula (I) wherein R1 represents a hydrogen atom, R2 represents a hydrogen atom, a C¿1-4? alkoxycarbonylalkyl or benzyl group, or R?1 and R2¿ together represent a group of formula -(CH¿2?)3-, R?3¿ represents a hydroxy, C¿1-4? alkoxy or benzyloxy group or a group of general formula (A), wherein R?5¿ represents a C¿1-4? alkyl group, and n represents 0, 1, 2, 3 or 4, and their pharmaceutically acceptable salts, furthermore to a process for preparing the same. The compounds exert valuable antiulcer and cytoprotective activity in mammals including men.

Description

NEW TETRAHYDRONAPHTHALENE DERIVATIVES

The invention relates to new tetrahydro- naphthalene derivatives of general formula ( I)

wherein

R¹ represents a hydrogen atom,

R² represents a hydrogen atom, a Cι_₄ alkoxycarbonylalkyl or benzyl group, or R¹ and R² together represent a group of formula - (CH₂)₃-,

R³ represents a hydroxy, C^_ alkoxy or benzyl- oxy group or a group of general formula (A) ,

wherein

R⁵ represents a C1-₄ alkyl group, and n represents 0, 1, 2, 3 or 4, and their pharmaceutically acceptable salts, further¬ more to a process for preparing the same. Compounds of general formula (I) may be in

SUBSTITUTE SHEET (E) configuration.

In the C₁« alkyl or C₁-4 alkoxy groups the alkyl groups can be linear or branched saturated hydrocarbon groups, i.e. methyl, ethyl, n- or isopro- pγl, furthermore n-, sec- or t-b tyl groups.

The new compounds of general formula (I) proved to be biologically active, they exerted significant antiulcer, i.e. cytoprotective effect.

The invention relates furthermore to pharma- ceutical compositions containing new tetrahydro- naphthalene derivatives of general formula (I) - wherein R¹, R², R³ and n have the same meaning as above - and their pharmaceutically acceptable salts, furthermore to a process for preparing the same. The therapeutic effect of the compounds of general formula (I) was studied in the following tests.

Cytoprotective effect in the acidic alcohol induced gastric ulcer model

(A. Robert: Gastroenterology, ^~π_, 761-767, 1979) The study was performed in female rats weighing 120 - 150 g and starved for 24 hours. The test compound was administered in a suspension prepared with Tween 80, by gavage..After 30 minutes acidic alcohol, in doses of 0.5 ml/100 g body weight, was added similarly, by gavage. After one hour the animals were killed, their stomach was removed and cut along the curve. The reddish-brown strips (hemorrhagic lesions) were measured and their mean length pro stomach was calculated. The protective effect of the test compound was determined compared to the control group. The effect of the compound described in Example 1: ED5o= 0.1 g/kg p.o.

SUBSTITUTE SHEET Cytoprotective effect in the acetic acid induced chronic gastric ulcer model

(Tagaki et al: Japanese Journal of Pharmacology 19. 418-426, 1969) The study was performed in female rats starved for 24 hours. The abdominal wall was opened under ether a nesthesis, and 25 μl of 20 % acetic acid solution was injected in the subserous layer of the glandular part of the stomach, near the pylorus. Then the abdominal wall was closed and the animals received food and water ad libitum: Treatment was started on the 5th postoperative day and continued with single daily doses for 10 days. The animals were killed on the 15th postoperative day and their stomach was removed. Evaluation was performed by measuring the diameter of the necrotic areas and calculating their surface. The therapeutic effect of the test compound was calculated according to the following formula

ulcer surface (control) - ulcer surface (test compound) ulcer surface (control)

The therapeutic effect of the compound of Example 1 amounted to 39 % at doses of 10 mg/kg p.o.

The pharmacological studies confirmed that the compounds of the present invention as well as their pharmaceutically acceptable salts are potent antiulcer agents.

The invention also relates to a process for preparing new tetrahydronaphthalene derivatives of general formula (I) - wherein R¹, R², R³ and n have the same meaning as above - w h i c h c o m p r i s e s - reacting an activated derivative of 4-όxo-4-

SUBSTITUTE SHEET (5,6,7,8-tetrahydro-2-napthyl)-2(E)- butenoic acid of general formula (II) ,

with an amino acid derivative of general formula (III) ,

wherein R¹ and R² have the same meaning as above, and R⁴ represents a ^-₄ alkoxy or benzyloxy group or a group of formula A - wherein R⁵ represents a C _4 alkyl group - , and if desired, submitting to acidolysis the compounds of general formula (I) - wherein R¹ and R² have the same meaning as above and R³ stands for a t- butyloxy group - and/or if desired, reacting an activated derivative of a compound of general formula (I) - wherein R¹ and

R² have the same meaning as above and R³ stands for a hydroxy group - with a piperazine derivative contain-

SUBSTΓΓUTE SHEET ing a group of formula A - wherein R⁵ has the same meaning as above - or are converted with an inorganic or organic base to a salt.

From the starting materials applied in the process the compounds of general formula (III) are commercial products.

The 4-OXO-4-(5,6,7,8-tetrahydro-2-naphthyl- 2(E)-butenoic acid of general formula (II) can be prepared from 1,2,3,4-tetrahydronaphthalene and maleic anhydride in a Friedel-Krafts reaction according to D. Papa et al: J. Am. Che . Soc. : 10_, 3356, 1948.

According to a preferred embodiment of the present invention the amide formation between the compounds of general formulas (II) and (III) is performed by activating in situ first 4-oxo-4-

(5,6,7,8-tetrahydro-2-naphthyl)-2(E)-butenoic acid of formula (II) , and reacting it in an inert organic solvent with the amine component of the formula (III) . The carboxy group of the compound of formula (II) can be activated by not less than stoichiometric amounts of a carbodiimide type reagent, i. e. dicyclohexyl- carbodiimide, in an inert organic solvent, preferably in a halogenated aliphatic hydrocarbon, advantageously in dichloromethane, at a preferred temperature range of 0°C to 20°C. An other preferred type of activation is the mixed anhydride method, wherein a chloroformic acid ester, preferably ethyl chloroformate is applied. The reaction is performed in an inert organic solvent, i. e. in a cyclic ether, preferably in tetrahydrofu- ran, in the presence of stoichiometric amounts of a t- amine base, preferably in triethylamine, at a preferred temperature range of -20°C to 0°C. In the case when a compound of general formula (I)- wherein R¹ and R² have the same meaning as above and R³ is a hydroxy group - is reacted with a piperazine

SUBSTITUTESHEET derivative, the acid is activated by either of the above methods, i. e. either by the mixed anhydride or the carbodiimide method.

If desired, the compounds of general formula (I) - wherein R¹ and R² have the same meaning as above and R³ stands for a hydroxy group - can be converted by known methods with an organic or inorganic base into an alkali metal, alkali earth metal or zinc salt. The compounds of general formula (I) - wherein R¹, R² and R³ have the same meaning as above - prepar¬ ed by the process of the invention, can be isolated by known methods, i. e. filtration, and purified by re- crystallization.

The compounds of the invention can be converted into pharmaceutical formulations suitable for parenteral or enteral administration by mixing them with non-toxic, inert solid or liquid carriers and/or additives. Water, gelatin, lactose, starch, pectin, magnesium stearate, stearic acid, talc, and plant oils, such as peanut oil, olive oil, etc., can be used as carriers. The active ingredient can be formulated as is usual in pharmaceutical compositions, in solid forms, i.e. round or rectangular tablets, coated tablets, capsules, i. e. gelatine capsules, pills, or suppositories.

The compositions can contain, if required, the usual auxiliary materials, such as preservatives, stabilizers, wetting agents, emulsifying agents, etc. They can be prepared by usual methods, so in the case of solid formulations, by sieving, mixing, granulating and pressing. The formulations can.be submitted to the usual pharmaceutical technological procedures, .i. e. sterilization.

The following examples are illustrating but not limiting the scope of the invention.

SUBSTITUTE SHEET Example 1

4-OXO-4-(5,6,7,8-tetrahydro-2-naphthyl)-2 (E) -butenoyl-

L-proline ethyl ester 4.6 g (0.02 mole) of 4-oxo-4-(5,6,7,8-tetra- hydro-2-naphthyl-2(E)-butenoic acid are dissolved in 100 ml of anhydrous dichloromethane, then 5.6 ml (0.04 mole) of triethylamine are added. The solution is cooled to -15°C, thereafter 2.01 ml (0.022 mole) of ethyl chloroformate, dissolved in 10 ml of anhydrous dichloromethane, then at -15°C 4.0 g (0.022 mole) of L-proline ethyl ester hydrochloride, dissolved in 10 ml of anhydrous dichloromethane are added. The reaction mixture is stirred first at -15°C for 30 minutes, then at room temperature for 2 hours, and the mixture is extracted with the following solutions in the order listed: 1 N hydrochloric acid, water-, 5 % sodium carbonate and saturated sodium chloride solu¬ tion. The organic layer is dried over sodium sulfate and evaporated. The evaporation residue is crystallized from a mixture of cyclohexane-petroleum ether (1:1) .

Yield: 5.03 g (70 %)

M.p.: 63-66°C [α]π^25: -78.8°C (c=0.5, chloroform)

Example 2

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

-butenoy1]-L-proline 7.66 g (0.02 mole) 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 hydro¬ chloric acid solution in dioxane for 24 hours, then the mixture is evaporated. The evaporation residue is dissolved in 200 ml of dichloromethane and the

SUBSTITUTE SHEET solution is extracted with water and saturated sodium chloride solution. The organic layer is dried over anhydrous magnesium sulfate and the solvent is evapo¬ rated, to give an oil. Yield: 6.50 g (99 %) .

Example 3

N-[4-0xo-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, prepared according to the process of Example 2, are dissolved in a mix¬ ture of 10 ml of water and 2.78 ml (0.02 mole) of tri- ethylamine, then 1.36 g of zinc chloride in 10 ml of water are added. The precipitated compound is filter¬ ed, washed with ice-water, ethanol and diethyl ether. The product has light yellow colour. Yield: 4.9 g (62 %) M.p.: 122-124°C _[α_]D25^: -82.4° (c=l, methanol) .

Example 4

N-[4-0xo-4-(5 , 6 ,7 , 8-tetrahydro-2-naphthyl) -2 (E) - butenoyl] -D-aspartic acid diethyl ester 4.6 g (0.02 mole) of 4-oxo-4-(5, 6, 7 , 8-

-tetrahydro-2-naphthyl-2(E)-butenoic acid are dis¬ solved in 50 ml of anhydrous tetrahydrofuran, 5.6 ml (0.04 mole) of triethylamine are added and the solution is cooled to -10°C. To this solution are added slowly 2.01 ml (22 mmole) of- ethyl chloroformate in 20 ml of anhydrous tetrahydrofuran. Thereafter, maintaining the temperature of the reaction mixture at -10°C, 4.5 g (0.02 mole) of D-aspartic acid diethyl esther are added in 20 ml of anhydrous dichloromethane solution. The reaction mixture is stirred for 30

SUBSTITUTESHEET minutes at -10°C, subsequently for one hour at room temperature, then it is poured on 200 ml of water. The mixture is extracted with dichloromethane. The organic layer is repeatedly extracted with 5 % sodium carbona- te and saturated sodium chloride solutions. The organic layer is dried over anhydrous magnesium sulfate and the solvent is evaporated. Light yellow crystals are formed from the evaporation residue after adding petroleum ether. Yield: 5.6 g (70 %) M.p.: 95-97°C [α]o²⁵: -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-ethoxycarbonyl-piperazine

4.24 g (18.4 mmole) of 4-OXO-4-(5,6,7,8- tetrahydro-2-naphthyl)-2(E)-butenoic acid are dissolved in 80 ml of anhydrous tetrahydrofuran, 2.57 ml (18.4 mmole) of triethylamine are added, then 1.76 ml (18.4 mmole) of ethyl chloroformate in 10 ml of anhydrous tetrahydrofuran. To this mixture are added 4.7 g of l-L-prolyl-4-ethoxycarbonylpiperazine - prepared according to paragraph b) of the production process of starting materials - in 30 ml of anhydrous tetrahydrofuran. The reaction mixture is stirred at - 15°C, then at -10°C for 30 minutes and at room temperature for one hour. Subsequently the mixture is poured on 400 ml of water and extracted with dichloro- methane. The organic layer is extracted first with

5 % sodium carbonate solution, then with water, finally with saturated sodium chloride solution. The organic layer is dried over anhydrous magnesium sulfate and the solvent is evaporated. The residual oil is recrystallized from a mixture of diethyl ether and

SUBSTITUTE SHEET isopropanol. Yield: 4.87 g (57 %) M.p.: 110-112°C

[α]_D ²⁵: +9.4° (c=l, 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 mole) of L-proline benzyl ester hydrochloride and 8.3 g (0.06 mole) of potassium carbonate are dissolved in a mixture of 100 ml of water and 100 ml of dichloromethane. The organic layer is dried and the solvent is evaporated. The residual oil is directly processed in the next step. 13.8 g (0.06 mole) 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 solution is cooled to -15°C. Then 8.4 ml (0.06 mole) of triethylamine and subsequently 6.1 ml (66 mmole) of ethyl chloroformate in 20 ml of anhydrous tetrahydrofuran are added. Thereafter the solution of L-proline benzyl ester base in 20 ml of anhydrous tetrahydrofuran, obtained in the previous step, is added. The reaction mixture is stirred for 30 minutes at -15°C, for a further hour at room temperature, then it is poured on 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 a saturated sodium chloride solution. The organic layer is dried over anhydrous magnesium sulfate and the solvent is evaporated. The residue is crystallized from petroleum ether and recrystallized from a mixture of acetone-n-hexan. Yield: 12.0 g (48 %) . M.p.: 95-96°C.

SUBSTITUTE SHEET [ <X ] D^{2 5} : -411 ° (c=l , 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 mole) of 4-oxo-4-(5,6,7,8- tetrahydro-2-naphthyl)-2(E)-butenoic acid and 1.53 g (0.01 mole) of β-alanine ethyl ester hydrochloride are suspended in 50 ml of anhydrous dichloromethane and cooled to 0°C. Then 1.01 g (0.01 mole) of N-methyl- morpholine in 20 ml of anhydrous dichloromethane and finally 2.06 g (0.01 mole) of dicyclohexylcarbodiimide are added to the suspension. The reaction mixture is stirred for one hour at 0°C and for one hour at room temperature.

The precipitated dicyclohexylurea is filtered, and the filtrate is extracted with the following solvents in the order listed: 1 N hydrochloric acid, water, saturated sodium carbonate solution and finally sodium chloride solution. The organic layer is dried over anhydrous magnesium sulfate and the solvent is evaporated. The residue crystallizes upon the addition of diethyl ether. Yield: 1.3 g (41 %) . M.p.: 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 mole) of 4-oxo-4-(5,6,7,8-

-tetrahydro-2-naphthyl)-2-(E)-butenoic acid and 1.95 g (1.01 mole) of 6-aminohexanoic acid ethyl ester are suspended in 60 ml of anhydrous dichloromethane and cooled to 0°C. To this mixture first a solution of 1.01 g (0.01 mole) of N-methylmorpholine in 20 ml of

SUBSTITUTESHEET anhydrous dichloromethane, then 2.06 g (0.01 mole) of dicyclohexylcarbodiimide are added. The reaction mixture is stirred for one hour at 0°C and for one hour at room temperature. The precipitated di- cyclohexylurea is filtered and the filtrate is extracted with the following solutions in the order listed: 1 N 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. The residue is crystallized from a mixture of diethyl ether and n-hexane. Yield: 1.48 g (40 %) . M.p.: 74-76°C.

Example 9

N-[4-0xo-4-(5,6,7,8-tetrahydro-2-naphthyl)-2(E)- butenoyl]-L-phenylalanine methyl ester

4.3 g (0.02 mole) of L-phenylalanine methyl ester hydrochloride and 4.6 g (0.02 mole) of 4-oxo-4- (5,6,7,8-tetrahydro-2-naphthyl)-2(E)-butenoic acid are suspended in 80 ml of anhydrous dichloromethane and cooled to 0°C. To this mixture a solution of 2.03 g (0.02 mole) of N-methylmorpholine in 30 ml of an- hydrous dichloromethane, then 4.12 g (0.02 mole) of dicyclo-hexylcarbodiimide are added. The reaction mixture is stirred for one hour at 0°C and for one hour at room temperature. The precipitated dicyclo- hexylurea is filtered and the filtrate is extracted with the following solutions in the order listed: 1 N 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. The

SUBSTITUTE SHEET evaporation residue is crystallized from diethyl ether, and recrystallized from a mixture of ethyl acetate and diethyl ether. Yield: 3.7 g (47 %) . M.p.: 145-147°C.

[α]p²⁵: -22.5° (c=l, methanol) .

Example 10

1-[N-/4-OXO-4-(5,6,7,8-tetrahydro-2-naphthyl)-2(E)- butenoyl/-L-prolyl]-4-ethoxycarbonylpiperazine

6.5 g of the oily N-[4-oxo-4-(5,6,7,8- tetrahydro-2-naphthyl)-2(E)-butenoyl]-L-proline - prepared according to the process described in Example 2 - are dissolved in 150 ml of anhydrous dichloro- methane, cooled to 0°C, then 3.16 g (0.02 mole) of l- ethoxycarbonylpiperazine and catalytic amounts of 4- dimethylaminopyridine are added. To this mixture a solution of 4.54 g (22 mmole) of dicyclohexylcarbo¬ diimide in 20 ml of anhydrous dichloromethane are added under constant stirring. The reaction mixture is stirred for 24 hours at room temperature. The precipi¬ tated dicyclohexylurea is filtered and washed with with dichloromethane. The organic layer is extracted with the following solutions in the order listed: 1 N hydrochloric acid, water, 10 % sodium carbonate solution, water, and finally saturated sodium chloride solution. The organic layer is dried over anhydrous magnesium sulfate, filtered and the solvent is evaporated. The resulting oil is recrystallized from a mixture of diethyl ether and isopropanol. Yield: 5.1 g (55 %) . M.p.: 110-112°C. [a] D²⁵ +9.2° (c=l, chloroform).

Preparation of starting materials

SUBSTITUTESHEET 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 mole) of L-proline t-butyl ester oxalate are suspended in 50 ml of dichlorome- thane, and the mixture is extracted with a solution of 2.76 g (0.02 mole) of potassium carbonate in 50 ml of water up to the point the solution gets clear. The organic layer is separated, dried over anhydrous sodium sulfate, and evaporated. Yield: 3.7 g of L-proline t-butyl ester.

4.6 g (0.02 mole) of 4-oxo-4-(5,6,7,8-tetra- hydro-2-naphthyl)-2(E)-butenoic acid are dissolved in 50 ml of anhydrous tetrahydrofuran and 2.8 ml (0.02 mole) of triethylamine are added. The reaction mixture is cooled to -15°C, then a solution of 2.01 ml (22 mmole) ethyl chloroformate in 20 ml of anhydrous tetrahydrofuran are added, and thereafter the above prepared solution of 3.7 g (22 mmole) of L-proline t- butyl ester in 20 ml of anhydrous tetrahydrofuran. The reaction mixture is stirred for 30 minutes at -15°C, for 30 minutes at room temperature, then it is poured on 200 ml of water and extracted with dichloromethane. The organic layer is extracted with the following solutions in the order listed: 5 % sodium carbonate solution, saturated sodium chloride solution and finally water. The organic layer is dried over anhydrous magnesium sulfate and the solvent is evaporated. The residue crystallizes upon the addition of petroleum ether.

Yield: 3.89 g (51 %) .

M.p.: 95-98°C.

C^α3D25^: -81.2° (c=0.5, chloroform).

b) l-(N-Benzyloxycarbonyl-L-prolyl)-4-ethoxycarbonyl-

SUBSTΓΓUTE SHEET piperazine

12.45 g (0.05 mole) of N-benzyloxycarbonyl- L-proline and 7.91 g (0.05 mole) of 1-ethoxycarbonyl- piperazine are dissolved in 150 ml of anhydrous dichloromethane, cooled to +5°C, then a solution of 11.35 g (55 mmole) of dicyclohexylcarbodiimide in 50 ml of anhydrous dichloromethane are added. The mixture is stirred for 24 hours at room temperature, the precipitated dicyclohexylurea is filtered and the filtrate is extracted with the following solutions in the order listed: 1 N hydrochloric acid, water, 10 % sodium carbonate solution, and finally water. The organic layer is dried over anhydrous magnesium sulfate, and the solvent is evaporated. The product starts to crystallize upon refrigerating. The white crystals are filtered and washed with cool diethyl ether.

Yield: 14.0 g (72 %) . M.p.: 90.5-92°C. t^α]D30^: -11.4° (c=l, methanol) .

c) l-L-Prolyl-4-ethoxycarbonylpiperazine

7.4 g (19 mmole) of l-(N-benzyloxycarbonyl- L-prolyl) -4-ethoxycarbonylpiperazine - prepared above - are dissolved in 150 ml of anhydrous methanol and the solution is submitted to hydrogenation for 2 hours in the presence of a Pd-C catalyst. The solution is evaporated after the removal of the catalyst. Yield: 4.7 g (96.9 %) .

SUBSTITUTE SHEET

Claims

What we claim is

1. New tetrahydronaphthalene derivatives of general formula (I) ,

wherein R¹ represents a hydrogen atom,

R² represents a hydrogen atom, a ^-₄ alkoxycarbonylalkyl or benzyl group, or. R¹ and R² together represent a group of formula

- (CH₂)₃-, R³ represents a hydroxy, C_!_₄ alkoxy or benzyl- oxy group or a group of general formula (A) ,

wherein

R⁵ represents a Cι_4 alkyl group, and n represents 0, 1, 2, 3 or 4, and their pharmaceutically acceptable salts.

2. Compounds selected from the compounds of general formula (I) as claimed in claim 1:

SUBSTITUTE SHEET 4-OXO-4-(5,6,7,8-tetrahydro-2-naphthyl)-2(E)-butenoyl- L-proline ethyl ester,

N-[4-0x0-4-(5,6,7,8-tetrahydro-2-naphthyl)-2(E)- butenoyl]-L-proline zinc salt tetrahydrate, N-[4-0xo-4-(5,6,7,8-tetrahydro-2-naphthyl)-2(E)- butenoylJ-D-aspartic acid diethyl ester, 1-[N-/4-OXO-4-(5,6,7,8-tetrahydro-2-naphthyl)-2(E)- butenoyl/-L-prolyl]-4-ethoxycarbonylpiperazine, N-[4-Oxo-4-(5,6,7,8-tetrahydro-2-naphthyl)-2(E)- butenoyl]-L-proline benzyl ester,

N-[4-OXO-4-(5,6,7,8-tetrahydro-2-naphthyl)-2(E)- butenoyl]-β-alanine ethyl ester, 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. Pharmaceutical composition w h i c h c o m p r i s e s as active ingredient a new tetrahydronaphthalene derivative of general formula (I), wherein

R¹ represents a hydrogen atom,

R² represents a hydrogen atom, a C^-₄ alkoxycarbonylalkyl or benzyl group, or R¹ and R² together represent a group of formula

R³ represents a hydroxy, Cι_₄ alkoxy or benzyl- oxy group or a group of general formula (A) , wherein R⁵ represents a C^_₄ alkyl group, and n represents 0, 1, 2, 3 or 4, and a pharmaceutically acceptable salt thereof as defined in claim 1, in admixture with pharmaceutically acceptable carriers and/or additives.

4. Method for treating mammals (including

SUBSTITUTE SHEET human beings) suffering from various in lammations and ulcers of the trachea, stomach and duodenum and/or for prophylactic purposes, w h i c h c o m p r i s e s administering a therapeutically effective dose or doses of a new tetrahydronaphthalene derivative of general formula (I) , wherein R¹ represents a hydrogen atom, R² represents a hydrogen atom, a C^-₄ alkoxycarbonylalkyl or benzyl group, or R¹ and R² together represent a group of formula

- (CH₂)₃-, R³ represents a hydroxy, C^_4 alkoxy or benzyl- oxy group or a group of the general formula (A) , wherein R⁵ represents a C^-₄ alkyl group, and n represents 0, 1, 2, 3 or 4, and their pharmaceutically acceptable salts as defined in claim 1, in the form of a pure substance or as a pharmaceutical composition containing it as active ingredient.

5. Process for preparing new tetrahydro¬ naphthalene derivatives of general formula (I) ,

-R3 ->

wherein represents a hydrogen atom, R² represents a hydrogen atom, a C _₄ alkoxycarbonylalkyl or benzyl group, or

SUBSTITUTE SHEET R¹ and R² together represent a group of formula

- (CH₂)₃-, R³ represents a hydroxy, Cχ_₄ alkoxy or benzyl- oxy group or a group of general formula (A) ,

wherein

R⁵ represents a C^_4 alkyl group, and n represents 0, 1, 2, 3 or , and their pharmaceutically acceptable salts, w h i c h c o m p r i s e s reacting an activated derivative of 4-oxo-4-(5,6,7,8- tetrahydro-2-naphthyl)-2(E)-butenoic acid of general formula (II) ,

with an amino acid derivative of general formula (III) ,

SUBSTITUTE SHEET wherein R¹ and R² have the same meaning as above, and R⁴ represents a C^_4 alkoxy or benzyloxy group or a group of formula A - wherein R⁵ represents a C _₄ alkyl group - , and if desired, submitting to acidolysis the compounds of general formula (I) - wherein R¹ and R² have the same meaning as above and R³ stands for a t- butyloxy group, and/or if desired, reacting an activated derivative of a compound of the general formula (I) - wherein R¹ and R² have the same meaning as above and R³ stands for a hydroxy group - with a piperazine derivative containing a group of formula A - wherein R⁵ has the same meaning as above - or are converted with an inorganic or organic base to a salt.

6. Process as claimed in claim 5, w h i c h c o m p r i s e s activating the carbonic acid in situ preferably by a carbodiimide type reagent or by the mixed anhydride method.

7. Process as claimed in claim 5, h i c h c o m p r i s e s applying 1-etoxycarbonylpiperazine as the piperazine derivative.

8. Process as claimed in claim 5, w h i c h c o m p r i s e s converting the carboxylic acid into an alkali metal, alkali earth metal or zinc salt.

9. Process for preparing pharmaceutical compositions, w h i c h c o m p r i s e s mixing a new tetrahydronaphthalene derivative of the general formula (I) , wherein

R¹ represents a hydrogen atom, R² represents a hydrogen atom, a C^-4 alkoxycarbonylalkyl or benzyl group, or R¹ and R² together represent a group of formula

SUBSTITUTESHEET - (CH₂)₃-, R³ represents a hydroxy, Cι_₄ alkoxy or benzyl¬ oxy group, or a group of the general formula (A) , wherein R⁵ represents a C_]^ alkyl group, and n represents 0, 1, 2, 3 or- 4, or its pharmaceutically acceptable salt with pharmaceutically acceptable carriers and/or additives and transforming it into a pharmaceutical composition.

SUBSTITUTE SHEET