WO1993012079A1

WO1993012079A1 - Novel phenylsulfonylacrylate ester derivatives

Info

Publication number: WO1993012079A1
Application number: PCT/HU1992/000054
Authority: WO
Inventors: János Fischer; Ildikó BALLÓ; Tamás FODOR; Katalin SZO^'KE; E^´va PETE^´NYI GALLÓ; Ede MÁRVÁNYOS; Szilvia Wallerstein; Elemér Ezer; Judit MATÚZ; Katalin Sághy; László Szporny; György Hajós
Original assignee: Richter Gedeon Vegye^´Szeti Gyár Rt.
Priority date: 1991-12-12
Filing date: 1992-12-11
Publication date: 1993-06-24
Also published as: HU913908D0; IL103938A0; HU211020B; HUT63381A; LV10088A; CN1073938A

Abstract

The invention relates to novel phenylsulfonylacrylate ester derivatives of formula (I), wherein R stands for a C1-4alkyl group; a phenyl group optionally substituted by a C1-4alkoxy or a C1-4alkylcarbonyloxy group; an aralkyl group optionally substituted by a C1-4alkoxy group on the aromatic ring; a phenylsulfonylvinyl or phenylcarbonylvinyl group optionally substituted by a halogen on their phenyl moiety; methylsulfonylvinyl group; 4-oxo-4H-1-benzopyran-2-yl or 4-oxo-4H-1-benzothiopyran-2-yl group; R1 means hydrogen or a halogen; and n is 2 or 3. The invention further relates to pharmaceutical compositions containing these compounds as well as a process for the preparation of the compounds of formula (I). The compounds of the invention possess gastric acid secreto-inhibitory and gastrocytoprotective effects. Thus, they are useful for the prevention and/or healing of inflammatory and ulcerative diseases of esophagus, stomach or duodenum.

Description

NOVEL PHENYLSULFONYLACRYLATE ESTER DERIVATIVES

The invention relates to novel phenylsulfonyl- aerylate ester derivatives, to processes for their preparation, to pharmaceutical compostions containing them and to their medical use.

Ulcerative diseases of the digestive system affect a continuously increasing quote of population. In its active phase, the ulcer causes a strong pain and a bleeding may also occur. According to the traditional method of drug treatment, the primary target is to alleviate the pain and then to promote the restoration of the tissue part injured. The above target was tried to be achieved

through the diminution of gastric acid content or inhibition of the gastric acid secretion by using drugs (Pirenzepine, Cimetidine, Omeprazole and the like) considered to be traditional. In general, the ulcer heals within 4 to 6 weeks when an appropriate treatment and diet are employed; however, the ulcer frequently relapses and the drug treatment should again be started.

In the recent years, the so-called gastrocytoprotective compounds have more and more frequently appeared in the centre of interest. Due to their capability to increase the protective ability of stomach wall, the probability of relapse can significantly be diminished or the development of an ulcer in a patient having high risk of ulceration can be prevented by using such

compounds.

Most recently, an important role in the aetiology of gastritis or gastric and duodenal ulcer is attributed to the pathogenic bacterial strain Helicobacter pylori. Compounds possessing a gastric acid secret-inhibitory and antibacterial effect against Helicobacter pylori, in addition to their gastrocytoprotective activity, are of course extremely valuable.

The invention relates to novel, therapeutically active phenylsulfonylacrylate ester derivatives of the formula

wherein

R stands for a C_1-4alkyl group; a phenyl group optionally substituted by a C_1-4alkoxy or a (C_1-4alkylcarbonyl- oxy group; an aralkyl group optionally substituted by a C_1-4alkoxy group on the aromatic ring; a phenylsulfonylvinyl or phenylcarbonylvinyl group optionally substituted by a halogen on their phenyl moiety;

methylsulfonylvinyl group; 4-oxo-4H-1-benzopyran-2-yl or 4-oxo-4H-1-benzothiopyran-2-yl group;

R¹ means hydrogen or a halogen; and

n is 2 or 3.

Alkyl groups alone or as moieties of other groups herein mean saturated, straight or branched chain hydrocarbyl groups within the above-defined range of carbon atoms such as e.g. methyl, ethyl, n- or isopropyl, n-, sec- or tert-butyl groups.

The compounds of formula (I) according to the invention are new and possess valuable gastric acid secretion inhibiting, gastrocytoprotective and antibacterial

effects.

Accordingly, the present invention also relates

to a pharmaceutical composition for preventing and/or healing various inflammatory and ulcerative diseases of esophagus, stomach or duodenum comprising an amount of a compound of formula (I) effective in treating such conditions and a pharmaceutically acceptable carrier.

Furthermore, the invention relates to a method of treatment, which comprises administering a therapeutically effective amount of a compound of formula (I) to a mammal (including man) to be treated for preverting and/or healing various inflammatory and ulcerative diseases of esophagus, stomach or duodenum.

The invention also relates to a process for the preparation of the above compounds of formula (I)

and pharmaceutical compositions containing them.

Surprisingly, it has been found that the compounds of formula (I) show valuable pharmacological such as gastric acid secreto-inhibitory, gastrocytoprotective and antibacterial effects. Thus, they are useful to prevent and/or heal the various inflammatory and ulcerative diseases of the esophagus, stomach and duodenum; they are especially effective in cases, where the aetiology of disease is an infection caused by the pathogenic bacterial strain Heli- cobacter pylori.

The biological activity of the compounds according to the invention has been shown by the tests described here- inafter.

1. Investigation of the gastric acid secreto- inhibitory effect by using the pylorus ligation test

[Shay et al.: Gastroenterology 5 , 43-61 (1945)] Hannover-Wistar rats weighing 120-150 g each were used. After starving for 24 hours, the animals were subjected to pylorus ligation. The active agents of formula (I) were orally administered to the animals 30 minutes prior to the ligation. 4 hours following ligation the animals were killed and the acid content of their gastric juice was determined.

The gastric acid secreto-inhibitory effect of the compounds tested was determined and calculated as the ratio of their gastric acid content to the acid content measured in the gastric juice of the untreated control animals.

When determined in the above -test, the oral ED₅₀ value of compound prepared according to Example 1 was found to be 7.2 mg/kg of body weight.

When determined under the same conditions as described above, the ED₅₀ value of Cimetidine, a known drug was found to be 50 mg/kg of body weight.

2. Assay of the gastric laesion induced by acid- containing ethanol

[A. Robert: Gastroenterology 2 , 761-767 (1979)]- Female rats weighing 120-150 g each were used after starving for 24 hours. A mixture containing 1 ml of concentrated hydrochloric acid in 50 ml abs. ethanol was employed as necrotizing agent in an amount of 0.5 mg/100 g of body weight.

The compounds of formula (I) were introduced to the stomach of animals 30 minutes prior to administration of the acidic ethanol. One hour following the aministration of the acidic ethanol, the animals were killed and the average total length of longitudinal bleedings induced in the grandular part of the stomach by the acidic ethanol treatment were determined and calculated for one stomach.

The cytoprotective effect was characterized by the percentage of the average total length of bleedings in relation to the average total length measured in the control group (treated with acidic ethanol alone).

When determined in the above test, the oral ED₅₀ value of the compound of Example 1 was found to be 1.4 mg/kg of body weight.

When determined in the above test, the oral ED₅₀ value of Sucralfate, a known active cytoprotective agent, was found to be 150 mg/kg of body weight.

The therapeutical importance of compounds according to the invention is further pronounced .by the fact that they exert a bactericidal effect against bacterium Helicobacter pylori, the presence of which in the digestive system negatively affects the healing of ulcerative diseases of the digestive system or, the probability of development of ulcer, respectively is much higher in the presence of this bacterium [Internist 29 , 745-754 (1988)].

3. Investigation of the activity against Helico- bacter pylori bacterium

The activity of the compounds of formula (I)

according to the invention was evaluated in agar

diffusion and agar dilution tests. The experiments were carried out with Helicobacter pylori cultures isolated from 5 various human patients suffering from ulcer.

The MIC value (i.e. the minimum inhibitory concentration) of the compound of Example 1 against the Helicobacter pylori culture proved to be 10 μg/ml.

Thus, the compounds of formula (I) according to the invention significantly surpass the activity of the reference drugs in tests showing the gastric acid secre- to-inhibitory, gastrocytoprotective actions and possess a strong antibacterial effect against the Helicobacter pylori culture. The therapeutical dose for adults may be between 25 mg and 100 mg per day.

The active agents of formula (I) can be formulated in pharmaceutical compositions by mixing them with non-toxic, inert, solid or liquid carriers and/or auxiliaries commonly used in the therapy for parenteral or enteral administration. Useful carriers are e.g. water, gelatine, lactose, starch, pectin, magnesium stearate, talc, vege- table oils such as peanut oil, olive oil and the like. The active agent can be formulated in any usual pharmaceutical composition, particularly solid composition, e.g. rounded or edged tablet, dragee or capsule such as gelatine capsule, pill, suppository and the like. The amount of the solid active ingredient may be varied within a broad range in a dosage unit of the composition (tablet, capsule, one unit of the formulated solution and the like), preferably it is between about 25 mg and 1 g. Optionally, these compositions may also contain other commonly used pharmaceutical auxiliaries, e.g. stabilizers, preservatives, wetting agents, emulsifying agents and the like.

The compositions can be prepared in a known manner, e.g. by sieving, mixing, granulating and compressing the components in the case of solid compositions. The compositions may be subjected to other usual operations of the pharmaceutical technology, e.g. sterilization.

The dose to be used may be varied between wide limits depending on the body-weight and responsiveness of the person or animal to be treated, as well as on the severity of the state to be influenced, frequency and route of administration; however, the suitable dose can easily be determined by a physician skilled in the art.

The compounds of formula (I) contain two carboxylic acid ester moieties which are diesters of 1,2-ethylene glycol or 1,3-propylene glycol, respectively.

The presence of these two ester groups provides the possibility to prepare the compounds of formula (I)

through any of the ester moieties depending on the starting substances. Symmetric diesters of formula (I) can be prepared also by introducing both ester groups in a

single step. In this case, 1,2-ethylene glycol or 1,3- propylene glycol, respectively is reacted with 2 molar equivalents of a carboxylic acid of formula

wherein R means phenylsulfonylvinyl group optionally substituted by halogen on its phenyl moiety.

According to the invention, the novel compounds of formula (I) can be prepared by

a) reacting a carboxylic acid of formula (III), wherein R is as defined above, or an activated derivative thereof with a hydroxyalkyl phenylsulfonylacrylate of formula

wherein R¹ and n are as defined above, or

b) reacting a carboxylic acid of formula (III), wherein R stands for a phenylsulfonylvinyl group optionally substituted by halogen on its phenyl moiety, or an activated derivative thereof with a hydroxyalkyl ester derivative of formula

V

wherein R and n are as defined above, or

c) reacting at least two molar equivalents of a carboxylic acid of formula (III) wherein R represents phenylsulfonylvinyl group optionally substituted by halogen on its phenyl moiety, with one molar equivalent of a glycol of formula

X-(CH₂)_n-OH (V)

wherein X means hydroxy group and n is as defined

above,

by carrying out the reaction in the presence of an

activating agent in the above processes a) or b) when a carboxylic acid of formula (III) is used as starting substance.

The reaction resulting in the compounds of formula (I) is preferably carried out in a solvent being inert to the reaction conditions, advantageously in methylene chloride, tetrahydrofuran or dioxane, in the presence of stoichiometric amount of a base, suitably triethylamine.

The esterifying reactions are accomplished in such a way that the carboxy group of the compounds of formula (III) is firstly activated and the activated derivative obtained is brought into reaction without isolation with a hydroxyalkyl ester of formula (II).

Preferred activated derivatives of carboxylic acids of formula (III) are the carboxylic acid halides which may be prepared e.g. by heating the acid with an excess of

thionyl chloride. The acyl halide formed may be used without isolation for esterification. This reaction is carried out at a temperature between 0 °C and 20 °C.

The carboxy group of compounds of the formula (III) may be activated also in the form of acid anhydride. Thus, compounds of the formula (II) can be acetylated or propionylated by using acetic or propionic anhydride, respectively. This esterification reaction may be promoted by using catalytic amounts of pyridine bases, preferable 4-dimethylaminopyridine.

Furthermore, the carboxy group of compounds of

formula (III) may be activated also by using a coupling reagent in the reaction mixture itself. Suitable coupling reagents are the carbodiimides, e.g. dicyclohexylcarbodiimide. In this case a stoichiometric amount of the

compound of formula (II) is mixed with the carboxylic acid of formula (III) in an inert organic solvent, preferably dry methylene chloride, then the activation and coupling are carried out by using a stoichiometric amount of dicyclohexylcarbodiimide, preferably at a temperature between 0 °C and 25 °C. This reaction may be catalyzed by using a pyridine derivative, suitably 4-dimethylaminopyridine resulting in an improvement of the yield, too.

The compounds of formula (I) may be prepared also by reacting a hydroxyalkyl ester of formula (IV) with a carboxylic acid of formula (III) wherein R means phenylsulfonylvinyl group optionally substituted by halogen on its phenyl moiety, or with an activated derivative

thereof.

In this case the methods discussed above such as the acyl halide, preferably acyl chloride or acid anhydride formation may be used for the activation, though the esterification may be accomplished also by using a carbodiimide-type coupling reagent. These reactions are

carried out as described above.

The compounds of formula (IV) can be prepared by the direct esterification of the carboxylic acids of formula (III) with an excess of the compounds of formula (V), wherein X means hydroxy group and n is 2 or 3. In this reaction proton catalysis is used and the reaction is preferably carried out in the presence of a small amount of a mineral acid at a temperature range of 60 to 120 °C.

Otherwise, the compounds of formula (IV) may be prepared by reacting "the carboxylic acids of formula (III) with a 2-haloethanol or 3-halopropanol, wherein "halo" means halogen, preferably bromine. This reaction is accomplished in an inert organic solvent, suitably a dipolar aprotic solvent, e.g. dimethylformamide in the presence of a stoichiometric amount of a base, preferably triethylamine.

Finally, when it is desired to prepare compounds of the formula (I) with symmetric structure, i.e. in the case when in the formula (I) R stands for an optionally substituted phenylsulfonylvinyl group, a glycol of the formula (V), wherein X stands for hydroxy group and n is 2 or 3, can be reacted with two molar equivalents of the

carboxylic acid of formula (III) wherein R means phenylsulfonylvinyl group optionally substituted by halogen on its phenyl moiety, by boiling the reactants in an inert organic solvent, suitably methylene chloride while

continuously separating the water formed in the reaction. The reaction may be catalyzed by a strong acid, preferably hydrochloric or p-toluenesulfonic acid.

In addition to starting substances being commercially available, other starting commpounds are also required for the preparation of compounds of the formula (I). The preparation of the starting substances is partly described in the following Examples, whereas an other part of the starting substances can be prepared according to literature references.

The preparation of methylsulfonylacrylic acid is described in the Japanese patent specification No. 47-17836, that of phenylsulfonylacrylic acid in the Hungarian patent specification No. 203,839, that of 4-oxo-4H-1-benzopyran- 2-carboxylic acid by J. Schmutz et al. [Helv. Chim. Acta 34 767-779 (1951)], and that of 2-hydroxyethyl benzoate by L. H. Cretcher and W. H. Pittinger [J. Am. Soc. 47, 2561 (1925)].

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

Example 1

Preparation of 2-acetoxyethyl 3-phenylsulfonyl-2 (E)- propenoate

After dissolving 11.52 g (0.045 mol) of 2-hydroxyethyl 3-phenylsulfonyl-2 (E) -propenoate in 100 ml of dry methy- lene chloride, 0.1 g of 4-dimethylaminopyridine and then 10.5 g (0.1 mol) of acetic anhydride are portionwise added at room temperature. The reaction mixture is stirred at room temperature for 3 hours, then at 50 °C for 1 hour. Subsequently, the reaction mixture is cooled to room temperature and successively extracted with water, 5% sodium carbonate solution, saturated sodium chloride solution, 1 N hydrochloric acid and finally again with water. After drying the organic phase over anhydrous sodium sulfate and evaporation, hexane is added to the residue to give a white crystalline product, which is filtered and washed with petroleum ether to obtain the title compound in a yield of 11.1 g (83%), m.p. : 61-62 °C.

Preparation of the starting compound:

A solution of 16.8 g (80 mmol) of 3-phenylsulfonyl- 2 (E)-propenoic acid in 80 ml of ethylene glycol containing 1 ml of 6 N hydrogen chloride solution in dioxane is stirred at 120 °C for 5 hours, then cooled down to room temperature and poured into 300 ml of ice water. The crystalline precipitate is filtered and recrystallized from benzene to give 11.4 g (56.5%) of 2-hydroxyethyl 3-phenyl- sulfonyl-2(E)-propenoate, m.p.: 68-69 °C.

Example 2

Preparation of 2-propanoyloxyethyl 3-phenylsulfonyl- 2(E)-propenoate

A suspension containing 3.8 g (15 mmol) of 2-hydroxy ethyl 3-phenylsulfonyl-2 (E) -propenoate in 10 ml of propionic anhydride is stirred at 80 °C for 3 hours.

During this time the reaction mixture becomes gradually homogeneous. Thereafter, the excess of propionic anhydride is evaporated under reduced pressure, the residue is taken up in 50 ml of ethyl acetate, extracted with water, then with saturated sodium hydrogen carbonate solution and again with water. The organic phase is dried over

anhydrous magnesium sulfate and evaporated to give 4.2 g (89%) of crude product which is then purified on a silica gel column by using an 1:2 mixture of ethyl acetate/n- hexane as eluent. The fractions showing an R_f value of 0.35 are combined and the solvent is evaporated to obtain 3.2 g (68%) of the title compound.

Analysis for C₁₄H₁₆O₆S (molecular weight: 312.34)

calculated: C 53.84; H 5.16; S 10.26%;

found: C 54.63; H 5.52; S 10.91%.

Example 3

Preparation of 2-benzoyloxyethyl 3-phenylsulfonyl- 2(E)-propenoate

After dissolving 5.12 g (20 mmol) of 2-hydroxyethyl 3- phenylsulfonyl-2(E) -propenoate in 50 ml of dry methylene chloride, 4.0 g (36 mmol) of benzoic acid and 0.1 g of 4-dimethylaminopyridine are added. The solution is

cooled down to 0 °C and a solution containing 6.6 g

(36 mmol) of dicyclohexylcarbodiimide in 20 ml of

dry methylene chloride is dropwise added. After stirring the reaction mixture at 0 °C for 3 hours, the dicyclohexylurea precipitated is filtered and the filtrate

is successively extracted with 1 N hydrochloric acid, water, 5% sodium hydrogen carbonate solution and finally with saturated sodium chloride solution. The organic phase is dried over anhydrous magnesium sulfate and evaporated. After adding 20 ml of ethyl acetate to the residue, the dicyclohexylurea precipitated further is filtered and the filtrate is evaporated. The residue is purified by chromatography on a silica gel column by using a 3 : 1 mixture of petroleum ether/acetone as eluent. The combined fractions are evaporated and the residue is crystallized from cyclohexane to obtain the title compound in a yield of 2.4 g (33%), m.p.: 70-72 °C.

Example 4

Preparation of 1,2-bis[(3-phenylsulfonyl-2(E)- propenoyl)oxy]ethane

A solution containing 6.4 g (30 mmol) of 3-phenyl- sulfonyl-2(E)-propenoic acid in 50 ml of thionyl chloride is boiled for 1 hour. After evaporating the excess of thionyl chloride under reduced pressure, the residue is dissolved in 50 ml of dry dioxane and dropwise added to a solution of 7.7 g (30 mmol) of 2-hydroxyethyl

3-phenylsulfonyl-2(E)-propenoate and 4.2 ml (30 mmol) of triethylamine in 50 ml of dry dioxane at 0 °C. Thereafter, the reaction mixture is allowed to warm to room temperature and stirred for additional 10 hours. After filtering off the precipitated salt, the filtrate is evaporated. The residue is dissolved in 100 ml of methylene chloride and extracted with water and then

with 10% sodium carbonate solution. After drying the organic phase over anhydrous magnesium sulfate and

evaporating the solvent, the residue is recrystallized from ethyl acetate to give the title compound in a yield of 4.5 g (33%), m.p.: 146-148 °C.

Example 5

Preparation of 2-(3-methylsulfonyl-2(E)-propenoyl- oxy)ethyl 3-phenylsulfonyl-2(E)-propenoate

To a solution containing 4.0 g (16 mmol) of 2-hydroxy- ethyl 3-phenylsulfonyl-2(E)-propenoate in 50 ml of dry methylene chloride, 3.64 ml (26 mmol) of triethylamine and then 4.5 g (26 mmol) of methylsulfonyl-(E)propenoyl chloride are added. The reaction mixture is stirred at 0 °C for 1 hour and then at room temperature for 10 hours. Subsequently, the reaction mixture is successively extracted with water, 5% sodium carbonate solution, water,

1 N hydrochloric acid and finally with water. After drying the organic phase over anhydrous magnesium sulfate and evaporating the solvent, a brown oily product is obtained which is purified by chromatography on silica gel column. By using a 14:3 mixture of benzene/methanol as eluent, the title compound is obtained in a yield of 1.3 g (21%), m.p.: 125-128 °C.

Example 6

Preparation of 2-(4-oxo-4H-1-benzopyran-2-oyloxy)- ethyl 3-phenylsulfonyl-2(E)-propenoate

After dissolving 5.12 g (20 mmol) of 2-hydroxyethyl 3- phenylsulfonyl-2 (E) -propenoate in 50 ml of dry tetrahydrofuran and adding 3.2 g (20 mmol) of triethylamine, 5.2 g (25 mmol) of 4-oxo-4H-1-benzopyran-2- carboxylic acid chloride dissolved in 20 ml of dry tetrahydrofuran are portionwise added at a temperature of

0 °C. After mixing at room temperature for 10 hours, the reaction mixture is poured into 400 ml of water and

extracted with methylene chloride. The organic phase is successively extracted with 5% sodium carbonate solution, water, 1 N hydrochloric acid and finally with saturated sodium chloride solution. After drying the organic phase over anhydrous magnesium sulfate and evaporating, the residue is crystallized from acetone to obtain the title compound in a yield of 2.0 g (20%), m.p.: 124-125 °C.

Example 7

Preparation of 1-[3-phenylsulfonyl-2(E)-propenoyloxy]- 2-[2-(acetoxy)benzoyloxy]ethane

A solution containing 5.12 g (20 mmol) of 2-hydroxy- ethyl 3-phenylsulfony1-2(E)-propenoate and 3.6 g (20 mmol) of 2-acetoxybenzoic acid in 50 ml of dry methylene

chloride is cooled to 0 °C and a solution of 4.12 g (20 mmol) of dicyclohexylcarbodiimide in 20 ml of

methylene chloride is added. The reaction mixture is stirred at 0 °C for 2 hours and then at 20 °C for 10 hours. After filtering off the dicyclohexylurea precipitated, the filtrate is extracted with a 8% sodium hydrogen carbonate solution, then with water. The organic phase is dried over anhydrous magnesium sulfate and after evaporating the solvent, the oily evaporation residue is crystallized by using diethyl ether to obtain the title compound in a yield of 4.26 g (51%), m.p.: 89-92 °C.

Example 8

Preparation of 1-[3-phenylsulfonyl-2(E)-propenoyloxy]- 2-[2(S)-(6-methoxynaphthalen-2-yl)propionyloxy]ethane To a solution containing 4.6 g (20 mmol) of 2(S)-(6- methoxynaphthalen-2-yl)propionic acid and 5.12 g (20 mmol) of 2-hydroxyethyl 3-phenylsulfonyl-2(E)-propenoate in 50 ml of anhydrous methylene chloride 4.12 g (20 mmol) of dicyclohexylcarbodiimide dissolved in 20 ml of methylene chloride are portionwise added at 0 °C. The reaction mixture is stirred at 0 °C for 2 hours, and then at 20 °C for 5 hours. The dicyclohexylurea precipitated is filtered off and the filtrate is successively extracted with water, 5% sodium hydrogen carbonate solution and finally with water again. After drying the organic phase over anhydrous magnesium sulfate and evaporating the solvent, the oily residue is crystallized from a 3:1 mixture of methanol/ diethyl ether to result in the title compound in a yield of 6.3 g (67%), m.p.: 87-89 °C, [α]²⁵ _D +13.3° (c = 1, methylene chloride).

Example 9

Preparation of 2-(4-oxo-4-phenyl-2(E)-butenoyl) oxy- ethyl 3-phenylsulfonyl-2(E)-propenoate

After dissolving 3.84 g (0.015 mol) of 2-hydroxyethyl 3-phenylsulfonyl-2(E)-propenoate in 50 ml of dry

methylene chloride and adding 2.72 g (0.016 mol) of 4-oxo- 4-phenyl-2(E)-butenoic acid, a solution containing 3.3 g (0.016 mol) of dicyclohexylcarbodiimide in 20 ml of dry methylene chloride are dropwise added at 0 °C.

The reaction mixture is stirred at 0 °C for 3 hours and then at room temperature for 2 hours. The dicyclohexylure precipitated is filtered off and the filtrate is

successively washed with 20 ml of 1 N hydrochloric acid, twice with 20 ml of a 5% sodium hydrogen carbonate solution each and finally once with 20 ml of saturated sodiu chloride solution. After drying over anhydrous magnesium sulfate and filtering and evaporating the organic phase, ethyl acetate is added to the residue. The slightly yello crystals precipitated from the solution under cooling are filtered and recrystallized from ethanol to obtain the title compound in a yield of 3.4 g (55%), m.p.: 57-59 °C.

Example 10

Preparation of 1,2-bis[(3-phenylsulfony1-2(E)- propenoyl)oxy]ethane

After suspending 4.24 g (0.02 mol) of 3-phenyl- sulfonyl-2(E)-propenoic acid in 50 ml of toluene, 0.62 g (0.01 mol) of ethylene glycol and 2 ml of hydrogen

chloride/dioxane solution are added, then the reaction mixture is boiled under reflux at 110 °C for 9 hours.

Thereafter, the mixture is poured into ice-water. After filtering and washing with cold water, the precipitate is rescrystallized from ethyl acetate to yield 2.54 g (28%) of the title compound, m.p.: 145-147 °C.

Example 11

Preparation of 2-benzoγloxyethyl 3-phenylsulfonyl- 2(E)-propenoate

A solution of 6.4 g (0.03 mol) of 3-phenylsulfonyl- 2(E)-propenoic acid in 50 ml of thionyl chloride is boiled for 1 hour. Then, the excess of thionyl chloride is evaporated under reduced pressure and the residue is

dissolved in 50 ml of dry dioxane. This solution is dropwise added to a solution of 4.99 g (0.03 mol) of 2- hydroxyethyl benzoate and 4.2 ml (0.03 mol) of triethylamine in dry dioxane at 0 °C. The reaction mixture is allowed to warm to room temperature and stirred for additional 10 hours. The precipitated salt is filtered and the filtrate is evaporated. After dissolving the residue in 100 ml of methylene chloride, extracting with water and subsequently with 10% sodium carbonate solution, the organic phase is dried over anhydrous magnesium sulfate and after evaporation, the oily residue is re- crystallized from cyclohexane to obtain the title compoun in a yield of 7.5 g (69%), m.p.: 70-71 °C.

Example 12

Preparation of pharmaceutical compositions

Tablets

a) Tablets weighing 150 mg, containing 5 mg of active ingredient each

Ingredients g

Active ingredient 5

Gelatine 3

Magnesium stearate 2

Talc 5

Potato starch 40

Lactose 95

b) Tablets weighing 300 mg, containing 50 mg of active ingredient each

Ingredients g

Active ingredient 50

Polyvidone 6

Magnesium stearate 3

Talc 9

Potato starch 84

Lactose 148 After wet-granulating, the powder mixtures defined above under a) or b), respectively are compressed in the usual manner to give tablets weighing 150 or 300 mg each, respectively. Each tablet contains 5 or 50 mg, respectively of the active compound.

Claims

C L A I M S

1. Novel phenylsulfonylacrylate ester derivatives of the formula

wherein

R stands for a C_1-4alkyl group; a phenyl group optionally substituted by a C_{1- 4}alkoxy or a (C_1-4alkylcarbonyl- oxy group; an aralkyl group optionally substituted by a C_1-4alkoxy group on the aromatic ring; a phenylsulfonylvinyl or phenylcarbonylvinyl group optionally substituted by a halogen on their phenyl moiety;

R¹ means hydrogen or a halogen; and

n is 2 or 3.

2. 2-Acetoxyethyl 3-phenylsulfonyl-2(E)-propenoate.

3. A pharmaceutical composition for preventing

and/or healing various inflammatory and ulcerative

diseases of esophagus, stomach or duodenum, w h i c h c o m p r i s e s as active ingredient a therapeutically effective amount of a phenylsulfonylacrylate ester derivative of formula

wherein

R¹ means hydrogen or a halogen; and

n is 2 or 3,

in admixture with carriers and/or additives commonly used in the pharmaceutical industry.

4. A process for the preparation of the novel phenylsulfonylacrylate ester derivatives of the formula

wherein

R stands for a C_1-4alkyl group; a phenyl group optionally substituted by a C_1-4alkoxy or a (C_1-4alkylcarbonyloxy group; an aralkyl group optionally substituted by a C_1-4alkoxy group on the aromatic ring; a phenylsulfonylvinyl or phenylcarbonylvinyl group optionally substituted by a halogen on their phenyl moiety;

R¹ means hydrogen or a halogen; and

n is 2 or 3,

w h i c h c o m p r i s e s

a) reacting a carboxylic acid of formula R-COOH (III), wherein R is as defined above, or an activated derivative thereof with a hydroxyalkyl phenylsulfonylacrylate of formula

wherein R¹ and n are as defined above, or

O

||

R-C-O-(CH₂)_n-OH (lV)

wherein R and n are as defined above, or

X-(CH₂)_n-OH (V)

wherein X means hydroxy group and n is as defined

above, by carrying out the reaction in the presence of an activating agent in the above processes a) or b) when a carboxylic acid of formula (III) is used as starting substance.

5. A process as claimed in process a) or b) of claim 4, w h i ch c o mp r i s e s activating the carboxylic acid of formula (III), wherein R and n are as defined in claim 4, by an acyl chloride, preferably thionyl chloride or by dicyclohexylcarbodiimide.

6. A process as claimed in process c) of claim 4, wh i c h c o mp r i s e s carrying out the reaction in the presence of an acid catalyst.

7. A process as claimed in any of the claims 4 to 6, wh i c h c o mp r i s e s carrying out the reaction in a solvent being inert to the reaction conditions.

8. A process as claimed in any of the claims 4 to 7, wh i ch c o mp r i s e s carrying out the

reaction in the presence of an inert organic base, preferably triethylamine or 4-dimethylaminopyridine.

9. A process for the preparation of a pharmaceutical composition, w h i c h c o mp r i s e s mixing as active ingredient a therapeutically effective amount of a novel phenylsulfonylacrylate ester derivative of formula (I), wherein R, R¹ and n are as defined in claim 1, with carriers and/or additives commonly used in the pharmaceutical industry and formulating the mixture in a pharmaceutical composition.

10. A method of treatment for the prevention

and/or healing of various inflammatory and ulcerative diseases of esophagus, stomach and duodenum,

w h i c h c o mp r i s e s administaring to a

mammal including man to be treated a therapeutically effective amount of a phenylsulfonylacrylate ester

derivative of formula (I), wherein R, R¹ and n are as defined in claim 1, alone or in the form of a pharma ceutical composition.

11. The use of a phenylsulfonylacrylate ester

derivative of formula (I), wherein R, R¹ and n are as defined in claim 1, in the prepration of a pharmaceutical composition for the prevention and/or healing of

inflammatory and ulcerative diseases of esophagus, stomach or duodenum in mammals including man.