WO1994014765A1

WO1994014765A1 - Cyclohexylsulfonyl-acrylic acid and its derivatives, pharmaceutical compositions containing them and process for preparing same

Info

Publication number: WO1994014765A1
Application number: PCT/HU1993/000069
Authority: WO
Inventors: Ede MÁRVÁNYOS; János Fischer; Éva PETÉNYI; Elemér Ezer; Judit Matuz; Katalin Sághy; László Szporny; György Hajós
Original assignee: Richter Gedeon Vegyészeti Gyár Rt.
Priority date: 1992-12-29
Filing date: 1993-12-10
Publication date: 1994-07-07
Also published as: AU5658694A; HUT67024A; HU9204141D0; HU210930B; CN1096028A

Abstract

The invention relates to the novel cyclohexylsulfonyl-acrylic acid and its derivatives of general formula (I), pharmaceutically acceptable salts thereof, pharmaceutical compositions containing them and a process for their preparation. In general formula (I), R means: a hydroxyl group; a phenyloxy group optionally substituted by a C1-4 alkoxy group or halogen; 4-(C1-4 alkoxy)carbonyl-1-piperazinyl group; 4-[(C1-4alkyl)carbonyl-phenyl]-1-piperazinyl group; 4-piperonyl-1-piperazinyl group; 2-[(C1-4 alkoxy)carbonyl]ethylamino group; 1-ethyl-2-pyrrolidinyl-aminomethyl group; or 2-benzyloxy-carbonyl-1-pyrrolidinyl group derived from L-proline. The compounds of general formula (I) possess excellent antiulcer properties and a significant effect against Helicobacter pylori bacteria. Thus, they are useful for the therapeutic and/or prophylactic treatment of various ulcers of the oesophagus, stomach and duodenum.

Description

CYCLOHEXYLSULFONYL-ACRYLIC ACID AND ITS DERIVATIVES, PHARMACEUTICAL COMPOSITIONS CONTAINING THEM AND PROCESS

FOR PREPARING SAME

The invention relates to the novel cyclohexyl- sulfonyl-acrylic acid and its derivatives of general formula (I) ,

wherein

R means: a hydroxyl group; a phenyloxy group optionally substituted by a C_T^ alkoxy group or halogen; ⁴~(^c _l-4 alkoxy)carbonyl-1-piperazinyl group; 4-[(C₁_₄ alkyl)carbonyl-phenyl]-1-piper- azinyl group; 4-piperonyl-l-piperazinyl group; 2- ~[(^cl-4 alkoxy)carbony1]ethylamino group; 1-ethyl- -2-pyrrolidinyl-aminomethyl group; or 2-benzyloxy- -carbonyl-1-pyrrolidinyl group derived from L- -proline, as well as pharmaceutically acceptable salts thereof and pharmaceutical compositions containing these compounds.

According to an other aspect of the invention, there is provided a process for the preparation of the new compounds of general formula (I) and pharmaceutically acceptable salts thereof.

The compounds of general formula (I) may exist both in E and Z configuration.

In this description the ~\-_L\ alkyl groups and the

Cι_4 alkyl moieties of Cι_4 alkoxy groups are saturated. straight or branched chain hydrocarbyl groups, e.g. methyl, ethyl, n- or isopropyl, n-, sec- or tert-butyl groups.

It has been found during investigations on the novel compounds of general formula (I) that they are bio¬ logically active: namely, they have a significant anti- ulcer, e.g. cytoprotective, effect and in addition, they possess a significant antibacterial action.

Thus, the invention relates also to a method of treatment, which comprises administering a therapeutically effective dose of a compound of the general formula (I) , wherein R is as defined above or a pharmaceutically acceptable salt thereof alone or in the form of a pharmaceutical composition into the organism of a mammal, including man, for the prophylaxis and/or therapy of various ulcerative diseases of the oesophagus, stomach and duodenum.

The pharmacological activity of the compounds of general formula (I) ) was studied by using the following methods.

Investigation of the ventricular lesion induced by acid-containing alcohol

The method of A. Robert [Gastroenterology 77. 761-767 (1979) ] was followed. Female rats weighing 120 to 150 g each were used for these experiments after starving for 24 hours. The compound to be tested was applied as a 80 % Tween suspension into the stomach of the animals through a gastric tube. Thirty minutes later, 0.5 ml/100 g of body-weight of acidic alcohol was administered into the stomach of the animals through a tube. After one hour the animals were killed, their stomach was removed and dissected along the great curvature. The reddish-brown streaks (haemorrhagic lesions) were measured and the average total length was calculated for one stomach. The activity of the tested compound was compared to that of the control group.

The compound described in Example 3 of the inven¬ tion showed an ED5₀ value of 0.6 mg/kg after oral administration. Activity against Helicobacter pylori bacteria

The activity of the compounds of general formula (I) according to the invention was investigated by using the agar diffusion and agar dilution methods on Helico¬ bacter pylori cultures isolated from various ulcers of human patients.

The minimum inhibitory concentration (MIC) value of the compounds of Example 3 was found to be 7.8 to 15.4 μg/ml.

It can clearly be seen from the pharmacological results that the compounds of general formula (I) and their pharmaceutically acceptable salts according to the invention possess significant cytoprotective properties and a significant effect against Helicobacter pylori bacteria. According to the invention, the novel compounds of general formula (I) , wherein R is as defined above, are prepared by oxidizing 3-cyclohexylthio-2(Z)-propenoic acid of the formula (II)

and, if desired, reacting the obtained compound of general formula (I) , wherein R stands for hydroxyl group, or a reactive derivative thereof with a) a 4-halophenol or b) a Cι_4alkanol or c) a piperazine derivative of the general formula (III),

wherein

R¹ means (Cι_₄ alkoxy)carbonyl group; ( ^- alkyl)-carbonyl-phenyl group; 3,4-methylene- dioxybenzoyl group, or d) an amine derivative of the general formula (IV) ,

H₂N-R² (IV)

wherein

R² stands for a (C^_₄ alkoxy)carbonyl-ethyl group or a l-(Cι_4 alkyl)-2-pyrrolidinyl-methyl group; or e) L-proline benzyl ester, or f) diazomethane and, if desired, transforming the compound of general formula (I) obtained, wherein R represents 4-(Cι_4 alkyl)- carbonyl-phenyl-1-piperazinyl, 2-(Cι_₄ alkoxy)carbonyl- -ethylamino or l-ethyl-2-pyrrolidinyl-aminomethyl group, to an acid-addition salt.

According to a preferable embodiment of the process of the invention, the compound of general formula (I) , wherein R stands for a hydroxyl group, is obtained by oxidizing 3-cyclohexylthio-2(Z)-propenoic acid of formula (II) preferably by heating it in a glacial acetic acid solution containing hydrogen peroxide. This reaction is carried out in glacial acetic acid containing 30 % hydrogen peroxide at 100 °C for 3 hours and a yield of about 80 % is achieved. The compound of formula (II) can be prepared in a known manner [see B. eibull: Arkiv Kemi 3., 225-248 (1951)] by the reaction of a stoichiometric amount of cyclohexyl mercaptane and propiolic acid in aqueous sodium hydroxide solution. Compounds of the general formula (I) , wherein R means Cι_₄ alkoxy group or phenoxy group optionally substituted by halogen, are prepared by acylation of the appropriate C - _\ alkanol or an optionally substituted phenol with a known reactive derivative of the compound of formula (I), wherein R stands for a hydroxyl group. An acyl halide, preferably acyl chloride, may be used as reactive derivative. The acyl chloride is preferably prepared from the appropriate acid and tionyl chloride by heating the reactants for a few hours. The acyl cloride obtained after evaporation of the excess thionyl chloride may directly be used for the acylating step without purification. The acylation with the compound of formula (I) , wherein R means hydroxyl group, is suitably carried out by using the acyl halide in an inert organic solvent, preferably anhydrous dichloromethane, in the presence of an at least stoichiometric amount of an inert base, preferably triethylamine, under cooling, suitably at a temperature of about 0 °C.

Reactive derivatives of the carboxylic group of the compound of general formula (I) , wherein R means hydroxyl group, can be prepared by using other methods known from the literature, e.g. as described in the monography of M. Bodanszky entitled "Principles of Peptide Synthesis", pages 9 to 52, Springer Verlag, Berlin, Heidelberg, New York, Tokyo (1984).

Compounds of general formula (I) of the present invention, wherein R means

4-(C^_4-alkoxy)carbony1-1-piperaziny1 group, 4-(Cι_₄alkyl)carbonyl-phenyl-l-piperazinyl group, 4-piperonyl-l-piperazinyl group. 2-(Cι_4alkoxy)carbonyl-ethylamino group, l-ethyl-2-pyrrolidinyl-aminomethyl group or 2-benzyloxycarbonyl-l-pyrrolidinyl group derived from L- -proline, can similarly be prepared from the compound of formula (I) , wherein R stands for hydroxyl group, by reacting an above-described derivative activated on the carboxyl group, preferably the acyl chloride thereof, with the appropriate base listed hereinafter in an inert organic solvent, preferably anhydrous dichloromethane in a stoichiometric ratio under cooling: ethoxycarbonyl-pipe- razine, 4-piperazino-acetophenone, l-piperonyl- -piperazine, β-alanine alkyl ester, L-proline benzyl ester or l-ethyl-2-methylamino-pyrrolidine. These reactions are suitably performed in the presence of an at least stoichiometric amount of an inert base, preferably triethylamine. Alternatively, the acyl chloride of the compound of formula (I) , wherein R is hydroxyl group, is reacted with the twofold stoichiometric amount of the base reagent.

Compounds of the general formula (I) , wherein R stands for C^_₄ alkoxy group, can be prepared also by reacting a compound of formula (I) , wherein R is hydroxyl group, with the appropriate C^_₄ diazoalkane without using any activating reagent.

The compounds according to the invention can be transformed to pharmaceutical compositions by mixing them with non-toxic inert, solid or liquid carriers and/or additives commonly used in the therapy for parenteral or enteral administration. Suitable carriers are e.g. water, gelatine, lactose, starch, pectin, magnesium stearate, stearic acid, talc, vegetable oils such as peanut oil or olive oil and the like. The active agent may be formulated to the usual pharmaceutical compositions, par- ticularly solid compositions, e.g. rounded or edged tablets, dragees, capsules, such as gelatine capsules, as well as pills, suppositories and the like.

The compositions optionally may contain also the usual pharmaceutical additives, e.g. preserving agents, stabilizers, wetting and emulsifying agents and the like. These compositions are prepared by using common methods, e.g. by sieving, mixing, granulating and compressing the ingredients, e.g. in case of preparing solid composi¬ tions. The compositions can furthermore be subjected also to other usual methods of pharmaceutical technology, e.g. sterilization.

The invention also relates to a method of treatment for the prevention and/or therapy of various ulcerative diseases of the oesophagus, stomach and duodenum. This method comprises administering a therapeutically effective amount of an active agent of formula (I) or a pharmaceutically acceptable salt thereof to a mammal, including man, in the need of such treatment.

The invention is illustrated in detail by the following non-limiting Examples. Example l

Preparation of 3-cyclohexylsulfonyl-2(Z)-propenoic acid

A mixture containing 5.55 g (29.9 mmol) of 3-cyclo- hexylthio-2-propenoic acid, 11.9 ml of 30 % hydrogen peroxide and 60 ml of glacial acetic acid is stirred at 100 °C for 3 hours. After evaporating the reaction mixture, te oily residue is crystallized by adding n- -hexane to obtain the aimed compound in a yield of 5.3 g (81 %) , m.p.: 55-57 °C; Rf value = 0.27 (developing system: pyridine/glacial acetic acid/water/ethyl acetate 16:5:9:70) .

Example 2

Preparation of 4-chlorophenγl-3-cyclohexylsulfonyl- -2(E)-propenoa e a) Preparation of 3-cyclohexylsulfonyl-2(E)- -propenoyl chloride

A solution of 4.37 g (0.02 mol) of 3-cyclohexyl- sulfonyl-2(Z)-propenoic acid in 30 ml of thionyl chloride is boiled under reflux for 3 hours. After evaporating the excess thionyl chloride the residue is dissolved in 20 ml of anhydrous dichloromethane and directly used for acylation. b) Preparation of 4-chlorophenyl-3-cyclohexyl- sulfonyl-2(E)-propenoate

To a solution containing 2.57 g (0.02 mol) of 4- -chlorophenol in 30 ml of anhydrous dichloromethane, 5.6 ml (0.02 mol) of triethyla ine are added, the solution is cooled to 0 °C, then the solution prepared as described under the preceding step a) is dropwise added. The reaction mixture is stirred at room temperature for one day, then poured into 300 ml of water and extracted with dichloromethane. The organic solution is successively washed with 1 N hydrochloric acid, water, finally with 5 % aqueous sodium carbonate solution. After drying the organic solution over anhydrous magnesium sulfate and evaporation, the oily residue is crystallized by adding ethyl acetate to obtain the aimed compound in a yield of 3.1 g (47 %) , m.p.: 126-128 °C; R_f value = 0.64 (benzene/methanol 14:3). Example 3

Preparation of l-[3-cyclohexylsulfonyl-2(E)- propenoyl]-4-ethoxycarbonyl-piperazine A solution containing 7.9 g (0.05 mol) of ethoxy- carbonyl-piperazine in 30 ml of anhydrous dichloromethane is cooled to 10 °C and the solution of acyl chloride prepared as described in Example 2a) is dropwise added during 15 minutes under stirring. After stirring the reaction mixture at room temperature for 24 hours and then pouring it into 300 ml of water, the organic phase is separated and then successively washed with 1 N hydro¬ chloric acid, water and finally with saturated sodium chloride solution. After drying the organic solution over anhydrous magnesium sulfate and evaporation, the oily residue is purified by column chromatography (by using Kieselgel 60 as sorbent with a particle size of 0.063 to 0.2 mm) by using ethyl acetate as eluent. The purified product becomes crystalline on adding n-hexane to yield 2.3 g (32 %) of the aimed compound, .p. :^' 92-94 °C; Rf value = 0.42 (benzene/methanol 14:3).

Example 4

Preparation of l-[3-cyclohexylsulfonyl-2 (E)-

-propenoyl]-4-(4-acetylphenyl)-piperazine

To a solution containing 4.08 g (0.02 mol) of 4- piperazinoacetophenone in 50 ml of anhydrous dichloro¬ methane, 2.8 ml (0.02 mol) of triethylamine are added, and after cooling the mixture to 0 °C the dichloromethane solution of the acyl chloride prepared as described in Example 2a) is dropwise added. The reaction mixture is stirred at room temperature for one day, then poured into 500 ml of water and after separation it is extracted twice with dichloromethane. The organic solution is washed with water and then with saturated sodium chloride solution. After drying the organic solution over anhydrous magnesium sulfate and evaporation, the oily residue is purified by column chromatography (Kieselgel of 0.063-0.2 mm particle size) by using a 5:1 mixture of ethyl acetate and n-hexane as eluent. The pure product is recrystallized from a mixture of methanol and n-hexane to give 5.8 g (71.8 %) of the aimed product, m.p.: 156- 157 °C; Rf value = 0.31 (ethyl acetate/n-hexane 5:1).

Example 5

Preparation of l-piperonyl-4-[3-cyclohexylsulfonyl-

-2(E)-propenoyl]piperazine After dissolving 4.41 g (0.02 mol) of 1-piperonyl- piperazine in 50 ml of anhydrous dioxane, 2.8 ml (0.02 mol) of triethylamine are added, then the solution is cooled to 10 °C and the dioxane solution of the acyl chloride prepared according to Example 2a) is drop- wise added. The reaction mixture is stirred at room temperature for one day, then poured into 500 ml of water and extracted with dichloromethane. The organic solution is washed with water and then with saturated sodium chloride solution. After drying and evaporating the organic phase, the oily residue is crystallized from a mixture of methanol and diethyl ether to obtain 4.2 g (49.9 %) of the aimed product, m.p.: 129-130 °C; Rf-value = 0.56 (benzene/methanol 14:3). Example 6 Preparation of ethyl N-[3-cyclohexylsulfonyl-2(E)- -propenoyl]-β-alaninate

5.6 ml (0.04 mol) of trietylamine are added to a solution containing 3.08 g (0.02 mol) of ethyl β- -alaninate hydrochloride in 50 ml of anhydrous dichloro- methane. After cooling the solution to o °C, the dichloromethane solution of the acyl chloride prepared according to Example 2a) is dropwise added, the reaction mixture is stirred at room temperature for one day, then poured into 500 ml of water and extracted with dichloro- methane. The organic solution is successively washed with water, 1 N hydrochloric acid, water and finally with saturated sodium chloride solution. After drying the organic solution over anhydrous magnesium sulfate and evaporation, the residue is purified by column chro ato- graphy (Kieselgel 60, particle size of 0.063-0.2 mm) by using a mixture of benzene/acetone/triethylamine 14:3:0.5 as eluent. The product purified in this way becomes crystalline on adding n-hexane to obtain 3.9 g (61 %) of the aimed product, m.p.: 100-102 °C; Rf value = 0.50 (benzene/acetone/triethylamine 14:3:0.5). Example 7

Preparation of benzyl l-[3-cyclohexylsulfonyl-2 (E)-

-propenoyl]-2 (S)-pyrrolidinecarboxylate

After suspending 4.7 g (0.02 mol) of L-proline benzyl ester hydrochloride in 50 ml of anhydrous dioxane and adding 5.6 ml (0.04 mol) of triethylamine, the suspension is cooled to 10 °C and a dioxane solution of the acyl chloride prepared according to Example 2a) is dropwise added. After stirring the reaction mixture at room temperature for one day and then pouring into 500 ml of water, it is extracted with dichloromethane. The organic solution is successively washed with 1 N hydro¬ chloric acid, water, and saturated sodium chloride solution. Subsequently, the obtained solution is dried and evaporated. The oily residue is purified by column chromatography (Kieselgel 60, particle size of 0.063-0.2 mm) by using a 3:1 mixture of ethyl acetate and n-hexane as eluent. The obtained oil becomes crystalline on adding petroleum ether to give 2.3 g (28.3 %) of the aimed product, m.p.: 114-116 °C, [α]²⁵ _D = -76.7° (c = 1, chloroform); Rf value = 0.54 (ethyl acetate/n-hexane 3:1) .

Example 8

Preparation of l-ethyl-2-{[3-cyclohexylsulfonyl- -2(E)-propenoyl]aminomethyl}pyrrolidine dihydro- chloride

2.56 g (0.02 mol) of l-ethyl-2-aminomethyl-pyrro- lidine hydrochloride are dissolved in 50 ml of dichloro¬ methane, then 5.6 ml (0.04 mol) of triethylamine are added. After cooling the mixture to 0 °C, the dichloro¬ methane solution of the acyl chloride prepared according to Example 2a) is dropwise added. The reaction mixture is stirred at room temperature for 2 days, then poured into 500 ml of water and extracted with dichloromethane. The organic extract is washed with saturated sodium chloride solution, dried and the solvent is evaporated. The oily residue is purified by chromatography (Kieselgel 60, particle size of 0.063-0.2 mm) by using a 9:1 mixture of acetone and triethylamine to give 3.8 g (52.0 %) of the aimed product, m.p.: 139-141 °C; Rf value = 0.60 (acetone/triethylamine 9:1). Example 9

Preparation of l-[3-cyclohexylsulfonyl-2(Z)- -propenoyl]-4-ethoxycarbony1-piperazine To the solution of 3.27 g (0.015 mol) of 3-cyclo- hexylsulfonyl-2(Z)-propenoic acid in 70 ml of abs. tetra- hydrofuran 2.1 ml (0.015 mol) of triethylamine are added, then the solution is cooled to -15 °C and 1.43 ml (0.0156 mol) of ethyl chloroformate and then 2.37 g (0.015 mol) of 1-ethoxycarbonyl-piperazine dissolved in 15 ml of abs. tetrahydrofuran are dropwise added at -15 °C under stirring. After stirring at -15 °C for one hour and then at room temperature for further one hour, the mixture is poured into 400 ml of water and extracted twice with 50 ml of dichloromethane each. The combined organic phases are washed first with 10 ml of water, then with 10 ml of 1 N hydrochloric acid, dried over anhydrous magnesium sulfate and evaporated. The oily residue is purified by column chromatography, using a 1:1 mixture of acetone and n-hexane as eluent. The purified oil is again evaporated. On adding petroleum ether to the obtained product. 1.2 g (22.3 %) of the aimed compound are obtained, m.p.: 108-110 °C. Example 10 Preparation of methyl 3-cyclohexylsulfonyl~2(Z)- -propenoate

A solution containing 33 mmol of diazomethane in dichloromethane is slowly dropped to a solution of 6.47 g (30 mmol) of 3-cyclohexylsulfonyl-2(Z)-propenoic acid in 50 ml of dichloromethane while stirring. After evapor- ating the solvent from the mixture under reduced press¬ ure, the residue is purified by column chromatography, using a 3:1 mixture of ethyl acetate and hexane as eluent to obtain 3.1 g (44.5 %) of the crystalline aimed product, m.p.: 69-70 °C. Example 11

Preparation of methyl 3-cyclohexylsulfonyl-2(Z)- -propenoate

To a solution containing 6.47 g (30 mmol) of 3- -cyclohexylsulfony1-2(Z)-propenoic acid in 50 ml of dichloromethane, 1.2 ml (30 mmol) of methanol, 6.2 g (30 mmol) of dicyclohexylcarbodiimide and a catalytic amount of 4-dimethylaminopyridine are added. The reaction mix¬ ture is stirred at 20 °C for 8 hours. The organic phase is successively washed with water, 5 % sodium hydrogen carbonate solution, again with water, then with 1 N hydrochloric acid and finally with water. The obtained solution is dried over anhydrous magnesium sulfate, then evaporated and crystallized to obtain the aimed product in a yield of 3.1 g (46 %) , m.p.: 69-70 °C.

Claims

1. Compounds of the general formula (I),

wherein

R means: a hydroxyl group; a phenyloxy group optionally substituted by a C;L_ alkoxy group or halogen; 4-(Cι_₄ alkoxy)carbonyl-1-piperazinyl group; 4-[(Cι_₄ alkyl)carbony1-phenyl]-1-piper- azinyl group; 4-piperonyl-l-piperazinyl group; 2- -[(C₁_4 alkoxy)carbonyl]ethylamino group; 1-ethyl- -2-pyrrolidinyl-aminomethyl group; or 2-benzyloxy- carbonyl-1-pyrrolidinyl group derived from L- -proline, and pharmaceutically acceptable salts of these compounds.

2. A compound selected from the group consisting of

3-cyclohexyIsulfony1-2( )-propenoic acid,

4-chlorophenyl-3-cyclohexylsulfonyl-2(E)-propenoate, l-[3-cyclohexylsulfonyl-2(E)-propenoyl]-4-ethoxycarbonyl-

-piperazine, l-[3-cyclohexylsulfonyl-2(E)-propenoyl]-4-(4-acety1- phenyl)-piperazine, l-piperonyl-4-[3-cyclohexylsulfonyl-2(E)-propenoyl]- piperazine, ethyl N-[3-cyclohexylsulfonyl-2(E)-propenoyl]-β-

-alaninate, benzyl l-[3-cyclohexylsulfonyl-2(E)-propenoyl]-2(S)-

-pyrrolidinecarboxylate, l-ethyl-2-{ [3-cyclohexylsulfonyl-2(E)-propenoyl]amino- methyl}pyrrolidine hydrochloride, l-[3-cyclohexylsulfonyl-2(Z)-propenoyl]-4-ethoxycarbonyl- -piperazine and methyl 3-cyclohexylsulfonyl-2(Z)-propenoate. 3. A pharmaceutical composition, which c o m p r i s e s as active ingredient a novel compound of general formula (I) , wherein R is as defined in claim 1, in admixture with carriers and/or additives commonly used in the pharmaceutical industry. 4. A process for the preparation of the novel compounds of general formula (I) ,

wherein R means: a hydroxyl group; a phenyloxy group optionally substituted by a Cι_4 alkoxy group or halogen; ⁴~(^c _l-₄ alkoxy)carbonyl-1-piperazinyl group; 4-[ (Cj^ alkyl)carbonyl-phenyl]-l-piper- azinyl group; 4-piperonyl-l-piperazinyl group; 2- ~[(^ci-4 alkoxy)carbonyl]ethylamino group; 1-ethyl- -2-pyrrolidinyl-aminomethyl group; or 2-benzyloxy- carbonyl-1-pyrrolidinyl group derived from L- -proline, and pharmaceutically acceptable salts of these compounds, which c o m p r i s e s oxidizing 3-cyclohexylthio-2(Z)- -propenoic acid of the formula (II)

(II) and, if desired, reacting the obtained compound of general formula (I) , wherein R stands for hydroxyl group, or a reactive derivative thereof with a) a 4-halophenol or b) a Cι_ alkanol or c) a piperazine derivative of the general formula (III),

wherein

R¹ means (C^_4 alkoxy)carbonyl group; (Cι_4 alkyl) carbonyl-phenyl group; 3,4-methylenedioxy- benzoyl group, or d) an amine derivative of the general formula (IV) ,

H₂N-R² (IV)

wherein

R² stands for a (Cι_₄ alkoxy)carbonyl-ethyl group or a 1-(C₁_4 alkyl)-2-pyrrolidinyl-methyl group; or e) L-proline benzyl ester, or f) diazomethane and, if desired, transforming the compound of general formula (I) obtained, wherein R represents 4-(Cι_4 alkyl)- carbonyl-phenyl-1-piperazinyl, 2-(C₁_₄ alkoxy)-carbonyl- -ethylamino or l-ethyl-2-pyrrolidinyl-aminomethyl group, to an acid-addition salt.

5. A process as claimed in claim 4, which c o m p r i s e s using the acyl halide as reactive derivative of the compound of general formula (I) , wherein R means hydroxyl group.

6. A process for the preparation of a pharma¬ ceutical composition, which c o m p r i s e s mixing as active ingredient a novel compound of the general formula (I) , wherein R is as defined in claim 1, or a pharma- ceutically acceptable salt thereof, prepared by using the process claimed in claim 4, with carriers and/or additives commonly used in the pharmaceutical industry and transforming them to a pharmaceutical composition.

7. Method of therapeutic and/or prophylactic treatment of mammals, including man, suffering from various ulcerative diseases of the oesophagus, stomach or duodenum, which c o m p r i s e s administering a prophylactically or therapeutically efective amount of a compound of general formula (I) , wherein R is as defined in claim 1, or a pharmaceutically acceptable salt thereof, to a subject in need of such treatment.