NZ245534A - Tetrahydronaphthalene derivatives and pharmaceutical compositions thereof - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number £45534 24 5 5 3 4 {•riom/ Coiupiale Specification Filed: I Class: !"??, 3.2> .Ity. .'.8$ . .. .3*> .^s.w?X Publication Date: ..?.?. .4Vi.!??? P.O. Journal. No: ....... I NO DRAMS Patents Form No. 5 ? A r , v o- O NEW ZEALAND PATENTS ACT 1953 COMPLETE SPECIFICATION NEW TETRAHYDRONAPHTHALENE DERIVATIVES » V -,-A r> tC\ ' ,f r H WE, RICHTER GEDEON VEGYESZETI GYAR RT., a body corporate under the laws of Hungary, of 1475 Budapest, Gyomroi ut 19-21, HUNGARY hereby declare the invention, for which We pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement: (followed by page la) / p" r* L v.' V: - to - NEW TETRAHYDRONAPHTHALENE DERIVATIVES The invention relates to new tetrahydro-naphthalene derivatives of general formula (I). 7 / ^ a 0 0 0 II II II c—ch=ch-c~n—ch-(ch,) - c- r3 I I 2n r> r2 ( I) wherein RA represents a hydrogen atom, R= represents a hydrogen atom, a Ci-4 a 1koxycarbony1 a 1ky1 or benzyl group, or R1 and R= together represent a group of formula 20 - (CH=)--, R-s represents a hydroxy, Ci-, alkoxy or benryl- oxy group or a group of general formula (A), (followed by page 2) 24 5 5 3 r~\ ^N-C00R5 (a ) wherein R* represents a Cx-« alkyl group, and n represents 0, 1, 2, 3 or 4, and their pharmaceutically acceptable salts, furthermore to a process for preparing the same.

Compounds of general formula (I) may be in (E) con f igura tion.

In the alkyl or Cx_.» alkoxy groups the alkyl groups can be linear or branched saturated hydrocarbon groups, i.e. methyl, ethyl, n- or isopropyl , furthermore n-, sec- or t-butyl groups.

The new compounds of general formula (1) 20 proved to be biologically active, they exerted significant antiulcer, i.e. cytoprotective effect.

The invention relates furthermore to pharmaceutical compositions containing new tetrahydro-naphthalene derivatives of general formula (I) -25 wherein Rj., Ra, R? 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, 77, 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: ED-»c.- 0.1 mg/kg p.o.

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 anesthesia, and 25 ul of 20 V. 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 formu1 a 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 pharmaceutical 1y acceptable salts are potent antiulcer agents.

The invention also relates to a process for preparing new tetrahydronaphthalene derivatives of general formula (I) - wherein R1, R3, Rs and n P 4 K ^ A have the same meaning as above -which comprises - reacting an activated derivative of 4-oxo-4-(5,6,7,8-tetrahydro-2-napthyl)-2(E)--butenoic acid of general formula (II), 0 II C- CH=CH—COOH (II ) with an amino acid derivative of general formula (III) nh-ch-(ch,l- |l e r1 r2 0 11 / c-r* (iii) wherein R1 and R= have the same meaning as above, and R* represents a Ci-* alkoxy or benzyloxy group or a group of formula A - wherein R® represents a Ci-« alkyl group - , and if desired, submitting to acidolysis the compounds of general formula (1) - wherein Rx and R2 have the same meaning as above and R7 stands for a 5 t-butyloxy group, and/or if desired, reacting an activated derivative of a compound of general formula (1) - wherein R1 and R= have the same meaning as above and R* stands for a hydroxy group - with a piperazine derivative 10 containing a group of formula A - wherein Rs 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 15 commercial products.

The 4-oxo-4-(5,6,7,8-tetrahydro-2-naphthy 1 --2(E)-butenoic acid of general formula (II) can be prepared from 1,2,3,4-tetrahydronaphtha1ene and maleic anhydride in a Friedel-Krafts reaction according to 20 D. Papa et al: J. Am. Chem. Soc.: 70, 3356, 1940.

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-(5,6,7,8-25 -tetrahydro-2-naphthy1)-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. dicyc1ohexy1carbo-diimide, 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 tetrahydrofuran, in the presence of stoichiometric amounts of a t-amine base, preferably in triethy1 amine, at a preferred temperature range of -20*C to 0*C. In the case when a compound of general formula (I)- wherein R1 and R3 have the same meaning as above and Rr is a hydroxy group - is reacted with a piperazine 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 R= have the same meaning as above and R31 stands for a hydroxy group - can be converted by known methods with an organic or inorganic base into an all<ali metal, alkali earth metal or rinc sa 11.

The compounds of general formula (I) -wherein R* , R= and R"5 have the same meaning as ® O / p-» •. ' K above - prepared by the process of the invention, can be isolated by known methods, i. e. filtration, and purified by recrystalliration.

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. steri1i zation.

The following examples are illustrating but not limiting the scope of the invention. 91, R J> 7 t- ' 'J K.

Example 1 4-0xo-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-naphthy1-2(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 m] 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 solution. The organic layer is dried over sodium sulfate and evaporated. The evaporation residue is crystallized from a mixture of eyelohexane-petroleum ether (1:1).

Yield: 5.03 g (70 7.) M.p.: 63—66*C [a]D=®: -78.8*C (c=0.5, chloroform) " 10 ~ O L r r '■1 ^ 4 ' v..' V Example 2 N—[4-0xo-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-tetra-hydro-2-naphthy1)-2(E)-butenoy1-L-proline t-butyl ester are stirred in 200 ml of 2.4 N hydrochlorid acid solution in dioxane for 24 hours, then the mixture is 10 evaporated. The evaporation residue is dissolved in 200 ml of dichloromethane and the solution is extracted with water and saturated sodium chloride solution. The organic layer is dried over anhydrous magnesium sulfate and the solvent is evaporated to give an oil. 15 Yield : 6.50 g (99 */.) .

Example 3 N-[4-0xo-4-(5,6,7,8-tetrahydro-2-naphthy1)-2(E)-20 -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 25 a mixture of 10 ml of water and 2.78 ml (0.02 mole) of triethylamine, then 1.36 g of zinc chloride in 10 ml of water are added. The precipitated compound is filtered, mg h <l. A ,. . V_.' r_/ \J '"■? washed with ice-water, ethanol and diethyl ether. The product has light yellow colour.

Yii?ld: 4.9 g (62 7.) M.p.: 122-124 * C 5 [ale,-' : -82.4* (c = 1, methanol).

Example 4 N-[ 4-0xo-4- (5,6,7,8-tetrahydro-2-naphthy 1)-2(E)-10 -butenoy1]-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 dissolved in 50 ml of anhydrous tetrahydrofuran, 5.6 ml 15 (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 20 (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 minutes at -10*C, subsequently for one hour at room temperature, then it is poured on 200 ml of water. The mixture is extracted 25 with dichloromethane. The organic layer is repeatedly extracted with 5 '/. sodium carbonate and saturated sodium chloride solutions. The organic layer is dried over KJ 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 -0.33* (c=0.5, chloroform).

Example 5 1-[N—/4-0xa-4-(5,6,7,B-tetrahydro-2-naphthy1)-2(E)--butenoy1/-L-proly1]-4-ethoxycarbonyl-piperazine 4.24 g (18.4 mmole) of 4-oxo-4-(5,6,7,8-tetra-hydro-2-naphthy1)-2(E)-butenoic acid are dissolved in 15 SO ml of anhydrous tetrahydrofuran, 2.57 ml (18.4 mmole) of triethy1 amine 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 1-L-proly1-4-ethoxycarbony1 piperazine -20 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 25 poured on 400 ml of water and extracted with dichloromethane. The organic layer is extracted first with 5 V. sodium carbonate solution, then with water, finally F r« r-n n , - f ; : 'a with saturated sodium chloride solution. The organic layer is dried over anhydrous magnesium sulfate and the solvent is evaporated. The residual oil is recrysta11ized from a mixture of diethyl ether and 5 isopropanol.

Yield: 4.87 g (57 7.) M.p.: 110-112'C [a]D = s': +9.4* (c = l, chloroform).

Example 6 N-[4-0x0-4-(5,6,7,B-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 20 directly processed in the next step. 13.8 g (0.06 mole) of 4-oxo-4-(5,6,7,8-tetra-hydro-2-naphthy1)-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 triethyl-25 amine 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 - ia - c A r- - ~, c. v y y ■ 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 5 400 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 10 is evaporated. The residue is crystallized from petroleum ether and recrysta)1ired from a mixture of acetone-n-hexan.

Yield: 12.0 g (48 */.) M.p.: 95-96 *C 15 [cod"*: -41.1* (c = i, chloroform) Example 7 N-[4-0xo-4-(5,6,7,B-tetrahydro-2-naphthy1)—2(E)-20 -butenoy1]-p-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 f3-alanine ethyl ester hydrochloride are 25 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 p. ,? p» p. /,,, . 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 dicyc1ohexy1 urea 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 1ayer is dried 10 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-t4-0xo-4-(5,6,7,8-tetrahydro-2-naphthy1)-2(E)--butenoyl]-6-aminohexanoic acid ethyl ester 2.3 g (0.01 mole) of 4-oxo-4-(5,6,7,8--tetrahydro-2-naphthy1)-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 25 cooled to 0*C. To this mixture first a solution of 1.01 g (0.01 mole) of N-methy1morpholine in 20 ml of anhydrous dichloromethane, then 2.06 g (0.01 mole) of - 16 - o f r* r~ "• * dicyc1ohexy1carbodiimide are added. The reaction mixture is stirred for one hour at 0*C and for one hour at room temperature. The precipitated dicyc1ohexylurea is filtered and the filtrate is extracted with the 5 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 10 crystallized from a mixture of diethyl ether and n-hexane.

Yield: 1 .48 g (40 7.) M.p.: 74-76*C Example 9 N-[4-Dxo-4-(5,6,7,8-tetrahydro-2-naphthy 1)-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-naphthy1) -2(E)-bu tenoic acid are suspended in 80 ml of anhydrous dichloromethane and cooled to 0*C. To this mixture a solution of 2.03 g 25 (0.02 mole) of N-methylmorpholine in 30 ml of anhydrous dichloromethane, then 4.12 g (0.02 mole) o"f dicyclo-hexy1carbodiimide are added. 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 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 evaporation residue is crystallized from diethyl ether, and recrystal1ized from a mixture of ethyl acetate and diethyl ether.

Yield: 3.7 g (47 V.) M.p.: 145-147'C Co»]d=c*: -22.5* (c = l, methanol) Example 10 1-tN-/4-0xo-4-(5,6,7,8-tetrahydro-2-naphthy1)-2(E)--butenoy1/-L-prolyl]-4-ethoxyearbonylpiperazine 6.5 g of the oily N-[4-oxo-4~(5,6,7,8--tetrahydro-2-naphthyl)-2(E)-butenoy1]-L-proline -prepared according to the process described in Example 2 - are dissolved in 150 ml of anhydrous dichloromethane, cooled to 0*C, then 3.16 g (0.02 mole) of 1-ethoxycarbony1piperazine and catalytic amounts of 4-dimethy1aminopyridine are added. To this mixture a solution of 4.54 g (22 mmole) of dicyc1ohexyl-carbo diimide in 20 ml of anhydrous dichloromethane are added under constant stirring. The reaction mixture is stirred for 24 hours at room temperature. The 5 precipitated dicyclohexy1 urea is filtered and washed 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 10 solution. The organic layer is dried over anhydrous magnesium sulfate, filtered and the solvent is evaporated. The resulting oil is recrysta11ized from a mixture of diethyl ether and isopropanol.

Yield: 5.1 g (55 "/.) M.p.: 110-112'C [ a J : +9.2* (c = l, chloroform) Preparation of starting materials a.) N-[ 4-0xo-4-(5,6,7,B-tetrahydro-2-naphthyl )-2(E)--butenoyl]-L-proline t-butyl ester .23 g (0.02 mole) of L-proline t-butyl ester oxalate are suspended in 50 ml of dichloromethane, and 25 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 £*** *f r-v *—*• L. • ' 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-naphthy1)-2(E)-butenoic acid are dissolved in 50 ml of anhydrous tetrahydrofuran and 2.8 ml (0.02 mole) of triethyl amine 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 [cOd2*: -81.2* (c=0.5, chloroform) b.) 1-(N-Benzyloxycarbonyl-L-prolyl)-4-ethoxycarbonyl-piperazine 12.45 g (0.05 mole) of N-benzyl oxycarbony1-L-5 -proline and 7.91 g (0.05 mole) of 1-ethoxycarbony1-piperazine are dissolved in 150 ml of anhydrous dichloromethane, cooled to + 5'C, then a solution of 11.35 g (55 mmole) of dicyc1ohexy1 carbodiimide in 50 ml of anhydrous dichloromethane are added. The mixture is 10 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 15 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 Cc*3*•"'t -11.4" (c = l, methanol) Cm) l-L-Prolyl-4-ethoxycarbonylpiperazine 7.4 g (19 mmole) of 1-(N-benzy1oxycarbony1-L- -prolyl)-4-ethoxycarbony 1piperazine - prepared above -are dissolved in 150 ml of anhydrous methanol and the

Claims (13)

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 7.) . - 22 - 245534 What we claim is

1. Tetrahydronaphthalene derivatives of general formula (I), 10 0 0 0 II II II c-ch=ch-c-n-ch-(ch,) — c-r3 II 2n r1 r2 (I) wherein 15 R1 represents a hydrogen atom, and R= represents a hydrogen atom, a Ci_« alkoxycarbony 1 a 1ky 1 or benzyl group, or R1 and R3 together represent a group of formula - (CHa)s-, 3 20 R represents a hydroxy, Ci-4 alkoxy or benzyl oxy group or a group of general formula (A), - 23 - 245534 r~\ n-coors — n w (a ) 5 wherein R 5 represents a Ci_^» alkyl group, and n represents 0, 1, 2, 3 or A, and their pharmaceutical 1y acceptable salts.

2. Compounds of general formula (I) as claimed in claim 1 selected from: 4-0xo-4-(5,6,7,8-tetrahydro-2-naphthyl)-2(E)-butenoyl -L-proline ethyl ester, N-[4-0xo-4-(5,6,7,8-tetrahydro-2-naphthyl)-2(E)--butenoy1]-L-proline zinc salt tetrahydrate, N-[4-0xo-4-(5,6,7,8-tetrahydro-2-naphthyl)-2(E)--butenoyl]-D-aspartic acid diethyl ester, l-[N-[4-0xo-4-(5,6,7,8-tetrahydro-2-naphthy 1)-2(E)--bu tenoy1].—L-proly1]-4-ethoxycarbony1 pi perazine, 245534 N-[4-0xo-4-(5,6,7,8-tet rahydro-2-naphthy1)—2(E) — —butenoyl3—L—proline benzyl ester, N-[4-0xo-4-(5,6,7,8-tetrahydro-2-naphthyl)-2(E)-5 -butenoy 1 ]-|3-a 1 anine ethyl ester, N-[4-0xo-4-(5,6,7,8-tetrahydro-2-naphthy1)-2(E)--butenoy1]-6-aminohexanoic acid ethyl ester, and 10 N-[4-0xo-4-(5,6,7,8-tetrahydro-2-naphthy1)-2(E)--butenoy1]-L-pheny1 a 1 anine methyl ester.

3. Pharmaceutical composition, which comprises as active ingredient a 15 tetrahydronaphthal ene derivative of general formula (I) as defined in claim 1, wherein RA represents a hydrogen atom, and Ra represents a hydrogen atom, a Ci-« 20 a 1koxycarbony1 a Iky 1 or benzyl group, or RA and R= together represent a group of formula - (CH=)3-f represents a hydroxy, Ci_.» alkoxy or benzyloxy group or a group of general formula (A) as 2455 or a pharmaceutica11y acceptable salt thereof, in admixture with one or more pharmaceutical]^ acceptable carriers and/or additives.

4. Process for preparing tetrahydro- naphthalene derivatives of general formula (I), 0 0 II II c—ch=ch-c—n—ch—(ch->l- r1 r2 0 II c- (I) wherein RA represents a hydrogen atom, and R= represents a hydrogen atom, a Cj.-* a 1koxycarbony1 a 1ky1 or benzyl group, or RA and R= together represent a group of formula - (CH=)3-, 3 R represents a hydroxy, C1-4 alkoxy or benzyl oxy group or a group of general formula (A) 26 - 245534 / \ n-coors ( a ) wherein 5 R represents a Cx-4 alkyl group, and n represents 0, 1, 2, 3 or 4, and their pharmaceutica11y acceptable salts, lO vMch comprises reacting an activated derivative of 4-oxo-4-(5,6,7,8-tetrahydro- -2-naphthyl)-2(E)-butenoic acid of general formula (II), 15 0 II c-ch=ch-cooh (II ) 20 with an amino acid derivative of general formula (III), 245534 0 11 ! nh-ch-(ch2l-c-r'> I I r' r2 (iii) wherein RA and R2 have the same meaning as above, and R* represents a cx_a alkoxy or benzyloxy group or a group of formula A - wherein Rp represents a 10 Ci-* 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 Rr stands for a t-butyloxy group-; and/or 15 if desired, reacting an activated derivative of a compound of general formula (I) - wherein R1 and R- have the same meaning as above and R3 stands for a hydroxy group - with a piperazine derivative containing a group of formula A - wherein R* has the 20 same meaning as above - or is converted to a salt with a pharmaceutically acceptable base. 25

5. Process as claimed in claim 4, which comprises activating the carboxy group of the compound of formula (II) as defined in claim 4 in situ by a carbodiimide type reagent " 6iv the mixed anhydride method. . — 28 — 245534

6. Process as claimed in claim 4, wherein the piperazine derivative is 1-ethoxycarbonylpiperazine.

7. Process as claimed in claim 4, which comprises converting the compounds of formula (I) of claim 1, wherein R1 and R2 are as defined in claim 1 and R3 is a hydroxy group, into an alkali metal, alkali earth metal or zinc salt.

8. Process for preparing pharmaceutica 1 lO compositions, which comprises mixing a tetrahydronaphthalene derivative of the general formula (1) as defined in claim 1, wherein RA represents a hydrogen atom, and 15 R3 represents a hydrogen atom, a Ci-* alkoxycarbony1alky 1 or benzyl group, or R* and R= together represent a group of formula — (CHa)3—, 3 R represents a hydroxy, Ci_4 alkoxy or benzyl- 20 oxy group, or a group of general formula (A) as defined in claim 1, wherein 5 R represents a C1-4 alkyl group, and n represents 0, 1, 2, 3 or 4, 25 or a pharmaceutically acceptable salt thereof with one or more pharmaceutically and/or additives. 245 S3 4 - 29 -

9. A compound according to claim 1 or claim 2, substantially as herein described.

10. A compound according to claim 1, substantially as described with reference to any one of the Examples.

11. A pharmaceutical composition according to claim 3, substantially as herein described.

12. A process according to any one of claims 4-8, substantially as herein described.

13. A process according to claim 4, substantially as described with reference to any one of the Examples. RICHTER* [GEDEON VEGYESZETI GYAR RT. .J fllfck if Attorneys BALDWIN, SON & CAREY