The invention relates to a novel, therapeutically active salicylic acid derivative of the formula

wherein

R means hydrogen or a Cι_4alkyl group; R ¹ stands for hydroxy group; a Cι_ ₄ alkoxy group; or a group of the formula

wherein R ² means hydrogen or benzyl group; and R ³ stands for a C _] __4alkyl group; or a group of the formula

wherein

R ⁴ means a C ₁ _ ₄ alkyl group, as well as ^' a salt thereof formed with a H2 receptor antagonist, preferably with Cimetidine or Famotidine; and a pharmaceutical compositions containing said compound.

Furthermore, the invention relates to a process for the preparation of said compounds and compositions. More particularly, the invention relates to a gastric acid secretion inhibitory and gastrocyto¬ protective pharmaceutical composition containing as active ingredient - a compound of the formula (I) , wherein R and R ¹ are as defined above; or - a compound of the formula

(II)

wherein R ¹ is as defined above; or - a compound of the formula

( III)

wherein R ¹ is as defined above.

The compounds of formulae (II) and (III) are salts formed from the salicylic acid derivatives of the for¬ mula (I) with Cimetidine and Famotidine, respectively.

Alkyl substituents in themselves or as structural moieties of other groups in the formulae are straight or branched chain, saturated hydrocarbyl groups containing a number of carbon atoms within the range defined above, such as e.g. the methyl, ethyl, n-propyl, isopropyl, n- butyl, sec-butyl or tert.-butyl groups.

The novel salicylic acid derivatives of the formula (I) as well as their Cimetidine salts of the formula (II) and Famotidine salts of the formula (III) , respectively possess valuable pharmacological activities; namely, they show gastric acid secretion inhibitory, gastrocyto¬ protective effects and antibacterial effect against the bacterial strain Helicobacter pylori. Thus, they are useful for the prevention and/or healing of various ulcerous diseases of the oesophagus, stomach and duo¬ denum.

Accordingly, the invention relates also to a method for the prevention and/or healing of various ulcerous diseases of the oesophagus, stomach and duodenum in a mammal, including man by administering one or more therapeutically effective dose(s) of a novel salicylic

acid derivative of the formula (I) according to the invention or a salt thereof formed with a H2 antagonist, preferably with Cimetidine or Famotidine, to said mammal. Cimetidine of the formula

(chemically 2-cyano-l-methyl-3- [2- [ [ (5-methylimidazol-4- yl)methyl]tio]ethyl]guanidine) and Famotidine of the formula

⁽ " ^l a ⁾

(chemically 3-[[[2-[ (aminoiminomethyl)amino]thiazol- yl]methyl]thio]-N-(aminosulfonyl)propaneimide amide) are known H2 receptor-antagonistic gastric acid secretion inhibitory drugs. sed in the therapy, however, their gastrocytoprotective effect is weak. Therefore, they are useful only for the treatment of gastric ulcer and gastritis but cannot prevent these diseases. A number of Cimetidine salts have been described in

the literature but no more effective derivative than the base itself has been found. In the European patent spe¬ cification No. 277,900 the salts of Cimetidine and Famotidine, respectively formed with aspartic acid and glutamic acid as well as the double salts thereof formed with ascorbic acid are disclosed. These salts are sup¬ posed to neutralize the toxic side effects of the drugs.

A number of simple salts (e.g. acetate, sulfate, hydrochloride, fumarate, aleate and the like) of Cimetidine ^" are described in the European patent spe¬ cification No. 255,376 since the polymorph Cimetidine B can be prepared by treating these salts with ammonia.

Up to the present no salts of Famotidine have been known in the literature which significantly influenced the pharmaceutical spectrum of effects of Famotidine. The Famotidine salts (e.g. Famotidine hydrochloride) described till now are known as the intermediates of the preparation of Famotidine (see e.g. the Spanish patent specification No. 2,012,735). The Cimetidine salts of the formula (II) and Famo¬ tidine salts of formula (III) are new compounds possess¬ ing significant gastrocytoprotective and antibacterial effects in addition to their expected gastric acid secretion inhibitory activity. Thus, they are useful not only for the treatment but also for the prevention of the disease.

The biological activity of the compounds according to our invention is illustrated by the tests described hereinafter. 1) Gastric acid secretion inhibitory effect in the pylorus ligature The method of Shay et al. [Gastroenterology 5 , pages 43 to 61 (1945)] was used.

Female Hannover- istar rats weighing 120 to 150 g each were starved for 24 hours, then pylorus ligature

was carried out in the animals. Active agents of the formula (I) were orally (p.o.) administered to the animals 30 minutes before the pylorus ligation. Four hours after the surgery, intervention the animals were killed and the acid content of the gastric juice was determined.

The gastric acid secretion inhibitory effect of the compounds tested was expressed in relation to the acid content measured in the gastric juice of untreated control animals.

2) Effect on the σastric lesion induced by acid- containinσ alcohol

The method of A. Robert [Gastroenterology 7_7, pages 761 to 767 (1979)] was followed. Female rats weighing 120 to 150 g each were used after starvation for 24 hours. A mixture containing 1 ml of concentrated hydrochloric acid and 50 ml of absolute ethanol administered in a dose of 0.5 ml/100 g of body weight was employed as necrotizing agent. The compounds of formula (I) were introduced to the stomach 30 minutes before administration of the acidic alcohol. One hour following the administration of the acidic alcohol, the animals were killed. The length of longitudinal bleedings induced by the acidic alcohol treatment on the glandular part of the stomach was measured, and the average total length per stomach cal¬ culated.

The gastrocytoprotective effect was expressed by the percentage of the average total length of longitud- inal bleedings in relation to the average total length measured in the control group treated with acidic alcohol alone.

3) Inhibition of the Indomethacin-induced σastric ulcer After starvation for 24 hours female RG- istar rats

were orally treated with the compounds to be tested and subsequently, after 30 minutes with 20 mg/kg of Indo- methacin. The evaluation was carried out in relation to the control group and the ED5 ₀ values were determined. 4) Inhibition of the gastric ulcer induced by Aspirin and stress The method of K. D. Rainsford [Agents, Actions 5 , pages 553 to 558 (1975)] was followed.

Female RG- istar rats weighing 120 to 150 g each were used ^" after starvation for 24 hours. The animals were treated with the compounds to be tested and sub¬ sequently, after 60 minutes they were given an oral dose of 50 mg/kg of body weight of Aspirin. The pre- treatment with Aspirin sensitized the animals and the subsequent stress (fastening, dipping in water at a temperature of 22 °C for 1 hour) induced a strong ulceration on the glandular part of stomach.

The number of the point-like ulcers appearing in the stomach was evaluated by the so-called ulcer index scoring from 0 to 5 in such a way that the values of control animals untreated with the active compound were taken as score 5 whereas the value of stomach showing the lowest number of ulcers was taken as score O.

5) Test on the acetic acid-induced chronic ulcer model

The method of Tagaki et al. [Japan Journal of Pharmacology .19., pages 418 to 426 (1969) ] was used.

The abdominal wall of the female rat starved previously for 24 hours was opened under etheral ana- esthesia. Near the pylorus 25 μl of 20% acetic acid solution were injected to the glandular part of the stomach, into the subserosal layer. Subsequently, the abdominal wall was closed and the animal received food and drink ad libitum. The treatment was started on the 5th day following surgery and was continued with one

daily dose for 10 days. On the 15th day following surgery the rats were killed and their stomach was re¬ moved. The ulcer was evaluated by measuring the diame¬ ters and calculating the areas of necrotic regions. The healing effect of the compound tested was calculated by using the following formula: ulcerous area(control. - ulcerous areafcompound tested^ x 100 ulcerous area(control)

6) Investigation of the activity against Helico- bacter pylori The activity of compounds of the formula (I) accord¬ ing to the invention was tested by using the agar diffusion and agar dilution methods. The experiments were carried out on Helicobacter pylori cultures isolated from five various human ulcer patients and the minimum inhibitory concentrations (MIC values) were determined.

The results obtained in the above tests are summarized in Tables I and II.

Table I Pharmacological activities of: Cimetidine; active compound of Example 3 of the invention; and Cimitidine salt of the same active compound of Example 8

Notes and abbreviations used in the Table:

ED ₅₀ oral dose (mg/kg) causing 50% inhibition * inhibition

** enhancement xx in vitro bactericidal effect measured on Helicobacter pylori

MIC minimum inhibitory concentration

Table I illustrates that the compounds of the for¬ mula (I) according to the invention in themselves are effective anti-ulcer and gastrocytoprotective substances possessing an additional favourable antibacterial effect, too. Cimetidine salts of compounds of the formula (I) possess an excellent gastrocytoprotective action while maintaining the favourable ulcer-inhibiting effect of Cimetidine.

Table II

Pharmacological activities of: Famotidine; active compounds of Examples 1, 3 and 7 of the invention; and Famotidine salts of Examples 11 and 13

Abbreviations:

ED ₅₀ : oral dose (mg/kg) causing 50% inhibition

* : inhibition

Table II illustrates that: on the one hand, the com¬ pounds of the formula (I) of the invention in themselves

are effective anti-ulcer and gastrocytoprotective sub¬ stances; and on the other hand, the Famotidine salts of the compounds being inactive in themselves in the above tests, retain the favourable ulcer-inhibiting effect of Famotidine and exert an excellent gastrocyto¬ protective action.

In tests showing the gastric acid secretion inhib¬ itory and gastrocytoprotective effect, the activity of the compounds of the formula (I) according to the inven- tion significantly exceed the activity of the reference drugs and, in addition, they possess a strong antibac¬ terial activity against Helicobacter pylori cultures.

In addition to the expected gastric acid secretion inhibitory effect, the novel Cimitidine and Famotidine salts of the formulae (II) and (III), respectively possess a significant gastrocytoprotective effect, too and therefore, they can be used not only for the treat¬ ment but also the prevention of the disease.

These two effects appear not only as a simple sum of the effects of both components forming the salt; but a significant synergism can also be observed.

For adult human patients the daily therapeutic dose of the active compounds of the invention may be varied between 25 and 500 mg. The active compounds of formula (I) can be trans¬ formed to pharmaceutical compositions by mixing them with non-toxic, inert, solid or liquid carriers and/or other auxiliaries commonly used in pharmaceuticals for parenteral or enteral administration. Useful carriers are e.g. water, gelatine, lactose, starch, pectin, magnesium stearate, talc, vegetable oils such as peanut oil, olive oil and the like. The active agent can be formulated to usual pharmaceutical compositions, par¬ ticularly solid compositions, e.g. rounded or edged tablet, dragee or capsule such as gelatine capsule,

pill, suppository and the like. The amount of the solid active agent in one unit of the pharmaceutical composi¬ tion (tablet, capsule, one unit of formulated solution and the like) may be varied in a broad range, preferably it is between about 25 mg and 1 g. Optionally these compositions may also contain other commonly used pharmaceutical auxiliaries, e.g. stabilizers, preserva¬ tives, 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 in¬ gredients in the case of solid compositions. The com¬ positions may be subjected to other usual operations of the pharmaceutical technology, e.g. sterilization. The dose level to be used can be varied within broad limits depending on the body weight and the indi¬ vidual response of the patient or animal being treated, severity of the condition to be influenced as well as the frequency and the particular route of administra¬ tion. The amount of the suitable dose can easily be determined by a physician skilled in the art.

According to the invention the novel salicylic acid derivatives of the formula (I) are prepared by: a) reacting 5-acetyl-2-hydroxybenzoic acid of the formula

with glyoxylic acid monohydrate in the presence of an acid catalyst, to obtain a compound of the formula (I) , wherein R means hydrogen and R ¹ stands for a

hydroxy group; or b) reacting the compound of the formula

with the stoichiometric amount of an alkyl halide or dialkyl sulfate containing an alkyl moiety corres-. ponding to the meaning of R ¹ , to obtain a compound of the formula (I) , wherein R means hydrogen and R ¹ stands for a C^-4alkoxy group; or c) reacting the compound of the formula (la) with at least twofold of the stoichiometric amount of an alkyl halide a dialkyl sulfate containing an alkyl moiety (moieties) corresponding to the meaning of R and/or R ¹ , respectively to obtain compounds of the formula (I) , wherein R means a Cι_4alkyl group and R ¹ stands for a C- - ₄ alkoxy group; or d) reacting the compound of the formula (la) with an amino acid ester of the formula

(IC)

wherein R ² and R ³ are as defined above, or with a piperazine compound of the formula

wherein R ⁴ is as defined above, in the presence of an activating agent, to obtain compounds of the formula (I) , wherein R means hydrogen and R ¹ stands for a group of the formula (A) or formula (B) , wherein R ² , R ³ and R ⁴ are as defined above and, if desired, converting a compound of the formula (I) , wherein R means hydrogen and R ¹ is as defined above, obtained by using any of the processes a) , b) or d) , with a H2 receptor antagonist to a salt thereof. The preparation of salicylic acid derivatives of the formula (I) will hereinafter be discussed in more detail.

The 4-(3-carboxy-4-hydroxyphenyl)-4-oxo-(2E)- butenoic acid of the formula (la) falling within the scope of the salicylic acid derivatives of the formula (I) of the invention has an own biological activity and simultaneously represents the starting substance for the preparation of a compound of the formula (I) , wherein the meaning of R or R ¹ is different from hydrogen.

The compound of the formula (la) can be prepared by the condensation reaction of 5-acetyl-2-hydroxybenzoic acid of the formula (lb) with glyoxylic acid mono- hydrate. This condensation reaction is preferably car- ried out in an inert organic solvent under mild heating

in the presence of an acid catalyst. No catalyst is needed when acetic acid is used as solvent. This con¬ densation may be carried out by heating the components in concentrated phosphoric acid, preferably in a phos- phoric acid of 85% by weight. In this latter case the reaction carried out at 80 °C for 8 hours results in 65% yield of the compound of the formula (la) .

The starting substance of formula (lb), i.e. 5- acetyl-2-hydroxybenzoic acid can be prepared according to the literature [J. Indian Chem. Soc. 2 β_, pages 235 to 238 (1949)]. Glyoxylic acid monohydrate is commercially available.

Compounds of the formula (I) , wherein R means hydrogen and R ¹ stands for a group [i.e. the monoesters of the compound of formula (la)], can be obtained by the esterification of the compound of formula (la) . It has been found that the esterifica¬ tion can be carried out with the corresponding alkyl halides or dialkyl sulfates most suitably in a dipolar aprotic solvent, preferably dimethylformamide, in the presence of a stoichiometric amount of a base, preferably triethylamine under mild heating, preferably at a temperature range of 50 °C to 80 °C.

Compounds of the formula (I) , wherein R and R ¹ mean the same Cι_ ₄ alkyl group, are diesters of the compound of formula (la) . These diesters may similarly be prepared as the monoesters, except that the triethylamine base is used in the twofold of the stoichiometric amount and the alkylating component is taken in an excess of at least the twofold of the stoichiometric amount. For esterification, the suitable alkyl halides, preferably an alkyl iodide or the corres¬ ponding dialkyl sulfate may be used in this case, too. Compounds of the formula (I) , wherein R means hydrogen and R ¹ stands for a group of the formula (A) or

(B) , wherein R ² , R ³ and R ⁴ are as defined above, can be prepared by acylating an amino acid ester of the formula (Ic) , wherein R ² and R ³ are as defined above, or a piperazine derivative of the formula (Id) , wherein R ⁴ is as defined above, with the compound of formula (la) in the presence of an activating agent.

According to a preferred embodiment of the acyla- tion, the compound of formula (la) is transformed to a mixed anhydride with a chloroformate ester, preferably ethyl chloroformate in an inert organic solvent, prefer¬ ably anhydrous methylene chloride, in the presence of a stoichiometric amount of a base, preferably triethyl¬ amine, then a compound of formula (Ic) or (Id) , respectively is reacted with this mixed anhydride. The mixed anhydride as well as the acylation are preferably carried out at a temperature of about -15 °C in such a way that during the progress of the acylating reaction the temperature of the reaction mixture is slowly raised to room temperature. The compounds of the formula (I) described above have (E) configuration; however, if desired, products of (Z) configuration can also be obtained by isomeriza- tion.

The isomerization can be achieved by subjecting the compounds of the formula (I) having (E) configuration to a photocatalytic isomerization. This isomerization is preferably performed by irradiating a compound of the formula (I) having (E) configuration with a high- pressure mercury vapour lamp at a wave-length of 366 nm at room temperature in an inert organic solvent, prefer¬ ably acetone.

The product of (Z) configuration can alternatively be prepared by isomerizing the starting compound of the formula (la) and then preparing the compound of the for- mula (I) from the resulting (Z) isomer.

The salts of the formulae (II) or (III) , respective¬ ly are formed from a starting compound of the formula (I) , wherein R and R ¹ are as defined above, with

Cimetidine or Famotidine base, respectively. The salts are formed by reacting stochiometric amounts of both components in an inert organic solvent at room temperature for a few hours. Methanol or ethanol are preferable solvents for this purpose.

Cimetidine base may be prepared e.g. according to the British patent specification No. 2,103,206.

The preparation of Famotidine base is disclosed in the Belgian patent specification No. 905,409.

The novel pharmaceutical compositions according to the invention can be prepared by admixing as active ingredient a compound of the formula (I) , wherein R and

R ¹ are as defined above; or a compound of the formula

(II) , wherein R ¹ is as defined above; or a compound of the formula (III) , wherein R ¹ is as defined above, with a non-toxic, inert, solid or liquid carrier and/or auxiliary commonly used in pharmaceuticals for parenteral or enteral administration and transforming the mixture to a pharmaceutical composition.

The following compounds according to the invention can be considered as active ingredients: 4-(3-carboxy-4-hydroxyphenyl)-4-oxo-(2E)-butenoic acid, methyl 4-(3-methoxycarbonyl-4-hydroxyphenyl)-4-oxo-(2E)- butenoate, methyl 4- ( 3-carboxy-4-hydroxyphenyl) -4-oxo- (2E) - butenoate, ethyl N- [4- ( 3-carboxy-4-hydroxyphenyl) -4-oxo- (2E) - butenoyl ] glycinate , methyl N- [ 4- (3-carboxy-4-hydroxyphenyl) -4-oxo- (2E) - butenoyl]-L-phenylalaninate, l-[4-(3-carboxy-4-hydroxyphenyl)-4-oxo-(2E)-butenoyl]-4- (ethoxycarbonyl)piperazine,

Cimetidine salt or Famotidine salt of methyl 4- ( 3- carboxy-4-hydroxyphenyl) -4-oxo- ( 2E) -butenoate and Cimitidine salt or Famotidine salt of l- [ 4- ( 3-carboxy- 4-hydroxyphenyl) -4-oxo- (2E) -butenoyl] -4- (ethoxycar- bonyl) piperazine .

Particularly preferred active agents among the compounds according to the invention are the following substances : 4- ( 3-carboxy-4-hydroxyphenyl) -4-oxo- (2E) -butenoic acid , methyl 4- ( 3-carboxy-4-hydroxyphenyl) -4-oxo- (2E) - butenoate ,

Cimetidine salt of methyl 4- (3-carboxy-4-hydroxyphenyl) - 4-oxo- ( 2E) -butenoate, Famotidine salt of methyl 4- (3-carboxy-4-hydroxyphenyl) - 4 -oxo- ( 2E) -butenoate and

Famotidine salt of l- [ 4- ( 3-carboxy-4-hydroxyphenyl) -4- oxo- (2E) -butenoyl ] -4- (ethoxycarbonyl) piperazin .

The invention is illustrated in detail by the following non-limiting Examples . Example 1

Preparation of 4-(3-carboxy-4-hydroxyphenyl)-4-oxo- (2E)-butenoic acid

To a suspension containing 62.5 g (0.35 mol) of 5- acetyl-2-hydroxybenzoic acid in 625 ml of 85% phosphoric acid, 62.5 g (0.68 mol) of glyoxylic acid monohydrate are added. The reaction mixture is maintained at 80 °C for 8 hours, then cooled down to room temperature and poured into the mixture of 200 g of ice and 1200 ml of water. After stirring for 30 minutes the precipitate is filtered and washed with water. The product is dissolved in 300 ml of methanol and water is added until the crystallization begins. Subsequently, the solution is cooled to 10 °C and the precipitate is filtered to obtain 53 g (65%) of the title compound in the form of yellow crystals, Rf = 0.35 (ethyl acetate/acetic acid

9:1) .

Example 2

Preparation of methyl 4-(3-methoxycarbonyl-4- hydroxyphenyl)-4-oxo-(2E)-butenoate A solution containing 2.36 g (0.01 mol) of 4-(3- carboxy-4-hydroxyphenyl)-4-oxo-(2E)-butenoic acid in 30 ml of dry dimethylformamide is heated to 80 °C and 2.8 ml (0.02 mol) of triethylamine and 1.2 ml (0.02 mol) of methyl iodide are added. After 2 hours the same amounts of triethylamine and methyl iodide are again added. After heating at 80 °C for additional 2 hours, the reaction mixture is cooled to room temperature and evaporated. The residue is dissolved in 100 ml of ethyl acetate and twice washed with 50 ml of water each and twice with 520 ml of 10% sodium bicarbonate solution each. After clarification with charcoal, the organic phase is evaporated and the residue is recrystallized from 25 ml of ethyl acetate to give 1.8 g (70%) of the yellow crystalline title compound, m.p. : 128-130 °C. Example 3

Preparation of methyl 4-(3-carboxy-4-hydroxyphenyl)- 4-oxo-(2E)-butenoate

After dissolving 23.6 g (0.1 mol) of 4-(3-carboxy-4- hydroxyphenyl)-4-oxo-(2E)-butenoic acid in 300 ml of dry dimethylformamide, 12.0 ml (0,2 mol) of methyl iodide are added and the solution is heated at 70 °C, then 14 ml (0.1 mol) of triethylamine are dropwise added thereto. The reaction mixture is heated at a temperature of 70 °C for additional 2 hours, then the solvent is evaporated. To the residue 150 ml of water and 30 ml of 10% hydrochloric acid solution are added and the mixture is extracted 3 times with 100 ml of ethyl acetate each. After clarifying with charcoal, the organic phase is evaporated until crystals begin to pre- cipitate. On cooling, the title product precipitates in

crystalline form to give 12.0 g (53%) of the lemon- yellow crystalline title compound, m.p. : 168-170 °C. Example 4

Preparation of methyl 4-(3-carboxy-4-hydroxyphenyl)- 4-oxo-(2Z)-butenoate

A solution containing 3.5 g (14 mmol) of methyl 4- (3-carboxy-4-hydroxyphenyl)-4-oxo-(2E)-butenoate in 400 ml of acetone is irradiated by UV light of 366 nm wave-length for 4 hours. Then, the mixture is evaporated to dryness, the residue is suspended in 50 ml of diethyl ether, stirred for 30 minutes and filtered to give 2.3 g (65%) of the white crystalline title product, m.p.: 129-131 °C. Example 5 Preparation of ethyl N-[4-(3-carboxy-4-hydroxy- phenyl)-4-oxo-(2E)-butenoyl]glycinate To a suspension of 9.44 g (0.04 mol) of 4-(3- carboxy-4-hydroxyphenyl)-4-oxo-(2E)-butenoic acid in 300 ml of dry methylene chloride 11.2 ml (0.08 mol) of triethylamine are added. The solution is cooled to -15 °C, 4 ml (0.04 mol) of ethyl chloroformate are dropwise added and the reaction mixture is maintained at the same temperature for 30 minutes. Subsequently, 5.6 g (0.04 mol) of ethyl glycinate hydrochloride and 5.6 ml (0.04 mol) of triethylamine are added and the reaction mixture is left at -15 °C for 30 minutes, at 0 °C for 1 hour and finally at 25 °C for 3 hours. The organic solution is twice extracted with 50 ml of water each, then 50 ml of 10% hydrochloric acid solution, clarified with charcoal and evaporated. After recrystallization of the residue from methanol, 8.25 g (64%) of the title compound are obtained, m.p.: 210-212 °C.

Example 6

Preparation of methyl N-[4-(3-carboxγ-4- hydroxyphenyl)-4-oxo-(2E)-butenoyl]-L-phenyl- alaninate To a suspension containing 4.72 g (0.02 mol) of 4- (3-carboxy-4-hydroxyphenyl)-4-oxo-(2E)-butenoic acid in 150 ml of dry methylene chloride, 5.6 ml (0.04 mol) of triethylamine are added. After cooling down the solu¬ tion to -15 °C, 2 ml (0.02 mol) of ethyl chloroformate are dropwise added and the mixture is reacted at -15 °C for 90 minutes. Then, 4.32 g (0.02 mol) of methyl L-phenylalaninate hydrochloride and 2.8 ml (0.02 mol) of triethylamine are added and the reaction mixture is stirred at -15 °C for 30 minutes, at 0 °C for 1 hour and at room temperature for 3 ^' hours ^' . The organic phase is washed twice with 30 ml of water each, 30 ml of 10% hydrochloric acid solution, then clarified with charcoal and evaporated. After suspending in diethyl ether, the residue is stirred for 1 hour and the yellow crystalline product is isolated. In this way the title product is obtained in a yield of 3.6 g (45%), m.p.: 168 °C (with decomposition); [α]D ²⁵ = +102.0° (c = 1, pyridine). Example 7 Preparation of l-[4-(3-carboxy-4-hydroxyphenyl)-4- oxo-(2E)-butenoyl]-4-(ethoxycarbonyl)piperazine

After suspending 7.08 g (0.03 mol) 4-(3-carboxy-4- hydroxyphenyl)-4-oxo-(2E)-butenoic acid in 300 ml of dry methylene chloride and adding 8.4 ml (0.06 mol) of triethylamine, a solution is obtained which is cooled down to -15 °C, 3 ml (0.03 mol) of ethyl chloroformate are dropwise added and the mixture is left at the same temperature for 30 minutes. Thereafter, 4.5 ml (0.03 mol) of N-(ethoxycarbonyl)piperazine are added and the reaction mixture is stirred at -15 °C for 30 minutes, at 0 °C for 1 hour and at room temperature for 3 hours.

The organic phase is twice washed with 50 ml of water each, then 50 ml of 10% hydrochloric acid solution. The organic solution is clarified with charcoal, then evap¬ orated. After suspending in diethyl ether the residue is stirred with the ether for 1 hour and then filtered to give 7.78 g (69%) of the yellow crystalline title product, m.p. : 211-213 °C. Example 8

Preparation of the Cimetidine salt of methyl 4-(3- carboxy-4-hydroxyphenyl)-4-oxo-(2E)-butenoate

. A solution of 1.88 g (7,5 mmol) of methyl 4-(3- carboxy-4-hydroxyphenyl)-4-oxo-(2E)-butenoate in 50 ml of methanol is added to a solution containing 1.89 g . (7.5 mmol) of Cimetidine base in 50 ml of methanol. The mixture is stirred at 25 °C for 1 hour, then the solvent is distilled off at 30 °C under reduced pressure to obtain 3.7 g (98%) of the yellow amorphous title com¬ pound.

Example 9 Preparation of the Cimetidine salt of ethyl N-[4- (3-carboxy-4-hydroxypheny1)-4-oxo-(2E)-butenoyl]- glycinate

A suspension containing 1.61 g (5 mmol) of ethyl N- [4-(3-carboxy-4-hydroxyphenyl)-4-oxo-(2E)-butenoyl]- glycinate in 50 ml of methanol is added to 1.26 g (5 mmol) of Cimetidine base dissolved in 50 ml of methanol. After stirring the solution for 1 hour, the solvent is evaporated at 30 °C under reduced pressure to give 2.8 g (98%) of the amorphous yellow title compound. Example 10

Preparation of the Cimetidine salt of l-[4-(3- carboxy-4-hydroxyphenyl)-4-oxo-(2E)-butenoyl]-4- (ethoxycarbonyl) iperazine

A suspension containing 1.88 g (5 mmol) of l-[4-(3-

carboxy-4-hydroxypheny1)-4-oxo-(2E)-butenoyl]-4-(ethoxy- carbonyl)piperazine in 50 ml of methanol is added to 1.26 g (5 mmol) of Cimetidine base dissolved in 50 ml of methanol. The solution is stirred for 1 hour, then evaporated at 30 °C under reduced pressure to obtain the title porduct as an amorphous yellow substance in a yield of 3.1 g (98%) .

Example 11

Preparation of the Famotidine salt of methyl 4-(3- carboxy-4-hydroxyphenyl)-4-oxo-(2E)-butenoate

A solution of 1.88 g (7.5 mmol) of methyl 4-(3- carboxy-4-hydroxyphenyl)-4-oxo-(2E)-butenoate in 50 ml of ethanol is added to a suspension of 2.53 g (7.5 mmol) of Famotidine base in 50 ml of ethanol. After stirring for 6 hours, the product is filtered and washed with 30 ml of ethanol to yield 4.3 g (98%) of the yellow title product, m.p. : 165-166 °C.

Example 12

Preparation of the Famotidine salt of ethyl N-[4- (3-carboxy-4-hydroxypheny1)-4-oxo-(2E)-butenoyl]- glycinate

A suspension containing 1.6 g (5 mmol) of ethyl N- [4-(3-carboxy-4-hydroxypheny1)-4-oxo-(2E)-butenoyl]- glycinate in 50 ml of methanol is added to a suspension of 1.68 g (5 mmol) of Famotidine base in 50 ml of me¬ thanol under vigorous stirring. After stirring for 6 hours, the product is filtered, washed with methanol to give 3.2 g (98%) of the white title product, m.p.: 199-200 °C. Example 13

Preparation of the Famotidine salt of l-[4-(3- carboxy-4-hydroxypheny1)-4-oxo-(2E)-butenoyl]-4-

(ethoxycarbonyl) iperazine

A suspension containing 1.88 g (5 mmol) of l-[4-(3- carboxy-4-hydroxypheny1)-4-oxo-(2E)-butenoyl]-4-(ethoxy-

carbonyl)piperazine in 50 ml of methanol is added to a suspension of 1.68 g (5 mmol) of Famotidine base in 50 ml of methanol. The mixture is stirred for 5 hours, then the product is filtered and washed with 30 ml of methanol to give the white title product in a yield of 3.4 g (95%), m.p.: 125-127 °C. Example 14 Preparation of 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 140

Tablets weighing 150 or 300 mg, respectively each are compressed from the powder mixture with the composition defined under a) or under b) , respectively in the usual manner by wet granulation and compression. Each tablet contains 5 or 50 mg, respectively of active ingredient.