WO1994014788A1

WO1994014788A1 - Novel derivatives of a five-membered ring fused benzene, pharmaceutical compositions containing them and process for preparing same

Info

Publication number: WO1994014788A1
Application number: PCT/HU1993/000078
Authority: WO
Inventors: György HOFFMAN; László Dobay; János Fischer; Éva PERÉNYI; Elemér Ezer; Judit MATÚZ; Katalin Sághy; László Szporny; György Hajós
Original assignee: Richter Gedeon Vegyészeti Gyár Rt.
Priority date: 1992-12-23
Filing date: 1993-12-17
Publication date: 1994-07-07
Also published as: HU9204112D0; HU211212B; AU5821694A; CN1096295A

Abstract

The invention relates to novel, therapeutically active acid, salt, ester and amide derivatives of a 5-membered ring fused benzene of formula (I), wherein R is selected from hydroxy, (C1-4)alkoxycarbonylmethoxy, (C1-4)alkylamino, cyclohexylamino; phenylamino optionally substituted by halogen; (C1-4)alkoxycarbonylmethylamino, 1-(C1-4)alkoxycarbonyl-2-phenylethylamino, pyrrolidino and N-(C1-4)alkoxycarbonylpiperazino; and X stands for oxygen or methylene, with the proviso that X means oxygen when R stands for hydroxy; and their salts formed with H2 receptor antagonists, when X means oxygen and R stands for hydroxy, as well as pharmaceutical compositions containing the above compounds. The invention relates also to a process for the preparation of the above compounds and compositions. The compounds of formula (I) show significant gastrocytoprotective and gastric acid secretion inhibitory activities. In addition, they possess an antibacterial activity against the pathogenic bacterial strain Helicobacter pylori. Thus, they are useful for the prevention and/or healing of various ulcerative diseases of the digestive system (oesophagus, stomach and duodenum).

Description

NOVEL DERIVATIVES OF A FIVE-MEMBERED RING FUSED BENZENE, PHARMACEUTICAL COMPOSITIONS CONTAINING THEM AND PROCESS FOR PREPARING SAME

The invention relates to novel, therapeutically active acid, salt, ester and amide derivatives of a 5-membered ring fused benzene of the formula

wherein R is selected from hydroxy, (C₁_₄)alkoxycarbonyl- methoxy, (C₁_4)alkylamino, cyclohexylamino; phenylamino optionally substituted by halogen; (C^_4)alkoxycarbonylmethylamino , 1-(C1..4)alkoxy- carbonyl-2-phenylethylamino, pyrrolidino and N-(C₁_4>alkoxycarbonylpiperazino; and X stands for oxygen or methylene, with the proviso that X means oxygen when R stands for hydroxy; and their salts formed with H2 receptor antagonists, preferably Famotidine, when X means oxygen and R stands for hydroxy; as well as pharmaceutical compositions containing the above com¬ pounds. Furthermore, the invention relates to a process for the preparation of the above compounds and compositions. The invention relates also to a method for the pre¬ vention and/or healing of various ulcerative diseases of oesophagus, stomach and duodenum in a mammal, including human, which comprises administering to said mammal a therapeutically effective amount of a compound of the formula (I) . ,

Alkyl groups alone or as parts of other groups may have a saturated straight or branched carbon chain, in which the number of carbon atoms varies within the limits defined above, such as e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or tertiary butyl groups. The halogen substituent may be chlorine, bromine, fluorine or iodine, perferably bromine.

A steadily increasing part of the population is involved in the ulceration of the digestive tract. Ulcers induce a very strong pain in their active stage and bleeding can also occur. According to traditional medication, the primary object is to reduce the pain, then to promote the healing of the injured tissues. Traditional medicaments (e.g. Pyrenzepine, Cimetidine, O eprazole, etc.) have been intended to achieve the above effects by the reduction of the gastric acid level and inhibition of the secretion of gastric acid, respectively. In the case of proper medication and diet, an ulcer is generally healed after 4 to 6 weeks. However, it happens frequently that the ulcer relapses and the medication should be recommenced.

Recent investigations are focussed increasingly to the so-called cytoprotective compounds. These com¬ pounds increase the protective ability of the stomach thereby upon the administration of such compounds the probability of a relapse of an ulcer is significantly reduced or the emergence of an ulcer can be prevented in a subject susceptible to an ulcer. Most recently an important role is attributed to the pathogenic bacterial strain Helicobacter pylori in the aetiology of gastritis as well as gastric and duodenal ulcers. Compounds exerting inhibitory activity on gastric acid secretion in addition to their cytoprotective activity are, of course, of particular interest.

It has surprisingly been found that compounds of the formula (I) show valuable pharmacological ac¬ tivities such as gastric acid secretion inhibitory, gastrocytoprotective and antibacterial activities. Thus, they are useful for the prevention and/or heal¬ ing of various inflammatory and ulcerative diseases of oesophagus, stomach and duodenum. The compounds of the formula (I) are particularly active in cases, when the aetiology of the disease is an infection induced by the pathogenic bacterial strain Helico¬ bacter pylori. The biological activity of compounds according to the present invention is illustrated by the tests des¬ cribed hereinafter.

1) Gastric acid secretion inhibitory activity in the pylorus ligature test The method of Shay et al. [Gastroenterology 5 , pages 43 to 61 (1945)] was used.

Female Hannover-Wistar 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 the animals were killed and the acid content of gastric juice was determined.

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

The ED₅₀ value of the compound of Example l was found to be 31 mg/kg of body weight in the above test after oral administration.

The ED₅₀ value of Cimetidine, a known drug was found to be 50 mg/kg of body weight in a test carried out under the same conditions as described above.

2) Effect on the gastric lesion induced by acid- containing alcohol

The method of A. Robert [Gastroenterology 7J_, pages 761 to 767 (1979) ] was followed.

Female rats weighing 120 to 150 g each fasted for 24 hours were used. A mixture containing 1 ml of con- centrated hydrochloric acid and 50 ml of abs. ethanol administered in a dose of 0.5 ml/100 g of body weight was employed as necrotizing agent.

The compounds of the formula (I) were administered 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 meas¬ ured and the average total length per stomach calculated. The gastrocytoprotective effect was expressed by the percentage of the average total length of longit¬ udinal bleedings in relation of the average total length measured in the control group treated with acidic alcohol alone. The ED5₀ value of the compound of Example 1 was found to be 0.8 mg/kg of body-weight in the above test after oral administration.

The ED5₀ value of Sucralfate, a known drug was found to be 150 mg/kg of body weight in the above test used for measuring the cytoprotective effect. The therapeutical importance of the compounds of the formula (I) according to the invention is further increased by the fact that they have bactericidal activity against Helicobacter pylori, the presence of which is a risk factor in the emergence of ulcers, or the healing of an ulcer of the digestive tract is in¬ fluenced negatively by the presence of this bacterium [Internist. 29., pages 745 to 754 (1988)].

3) Assay of the activity against Helicobacter pylori

The activity of compounds of the formula (I) accord¬ ing to the invention was tested by using the agar dif¬ fusion and agar dilution methods. The experiments were carried out on Helicobacter pylori cultures isolated from five various human ulcer patients.

The MIC (minimum inhibitory concentration) value of the compound of Example 1 was found to be 62.5 μg/ml on all the 5 bacterial cultures tested, whereas the MIC value of e.g. Metronidazole (chemically 2-methyl-5-nit- rolH-imidazole-1-ethanol) is 320 to 400 μg/ml [J. R.

Lambert: Drug Investigation 2. (Suppl. 1) pages 52 to 55 (1990) ] .

The compounds of the formula (I) significantly exceed the activity of the reference drugs both in the tests showing gastric acid secretion inhibitory and gastrocytoprotective activities as well as in their activity against Helicobacter pylori. The therapeutic dose for adult human patients may be varied between 10 mg and 100 mg per day. The active agents of the formula (I) can be transformed to pharmaceutical compositions by mixing them with non-toxic, inert, solid or liquid carriers and/or other auxiliaries commonly used in pharma¬ ceutical formulations for parenteral or enteral administration. Useful carriers are e.g. water, gelatine, lactose, starch, pectin, magnesium stearate, stearic acid, talc, vegetable oils such as peanut oil, olive oil and the like. The active agent can be for¬ mulated to usual pharmaceutical compositions, par- ticularly solid compositions, e.g. rounded or edged tablets, dragees or capsules such as gelatine capsules, pills, suppositories and the like. The amount of the solid active agent may be varied within broad limits, preferably it is between about 25 mg and 1 g per unit dose (i.e. tablet, capsule, one unit of solution, etc.). Optionally, these compositions may also contain other conventional pharmaceutical auxiliaries, e.g. stabilizers, preservatives, wetting agents, emul¬ sifying agents and the like. The compositions can be prepared in a known manner, e.g. by sieving, mixing, granulating and compressing the ingredients in the case of solid compositions. The compositions may be subjected to other usual operations of the pharmaceutical tech¬ nology, e.g. sterilization. The dose level to be used can be varied within broad limits depending on the body weight and the individual response of the patient or animal being treated, sever¬ ity of the condition to be influenced as well as the frequency and the particular route of administration. The amount of the suitable dose can easily be determined by a physician skilled in the art.

The invention relates also to a method for the pre¬ vention and/or healing of various ulcerative diseases of oesophagus, stomach and duodenum. This method com- prises administering a therapeutically effective amount of an active agent of the formula (I) to the patient.

The compounds of the formula (I) are novel 2,3-di- hydrobenzofuran derivatives when the X substituent means oxygen; whereas the compounds of the formula (I) are new indane derivatives when the X substituent is a methylene group.

The compounds of the formula (I) have (Z) confi¬ guration when X means oxygen; and they have (E) configu¬ ration when X is a methylene group. The compounds of the formula (I) can be divided to two main groups, i.e. to esters and amides if the especial case is disregarded when X stands for oxygen and R means a hydroxy group. In this latter case the invention relates also to the salts formed with H2 re- ceptor antagonists, preferably to the salt formed with Famotidine. (The chemical name of Famotidine is 3-{[[2- [ (aminoiminomethy1)amino]thiazoly1]methyl]tio}-N-(amino- sulfony1)propanimide amid.)

The Famotidine salt can be formed by reacting stoichiometric amounts of the components in an alcohol, preferably ethanol.

According to the invention the novel acid, salt, ester and amide derivatives of a 5-membered ring fused benzene of the formula (I) are prepared by a) reacting a benzofuran derivative of the formula

wherein X means oxygen, with glyoxylic acid in the presence of an acid catalyst to obtain a compound of the formula (I) , wherein R means hydroxy and X stands for oxygen; or b) reacting a salt of a carboxylic acid of the formula

wherein X is oxygen or methylene, with an ester of a halogenoacetic acid to obtain an ester derivative of the formula (I) ; or reacting a carboxylic acid of the formula (II) , wherein X is oxygen or methylene, with a primary or secondary amine of the formula

wherein R¹ stands for hydrogen and R² is selected from a Cι_4alkyl, cyclohexyl; a phenyl group op¬ tionally substituted by halogen; a (C_j^)alkoxy- carbonylmethyl; and a l-(Cι_4)alkoxycarbonyl-2- phenylethyl; or R¹ and R² together with nitrogen to which they are attached form a pyrrolidino or an N-(Cι_4)alkoxycarbonylpiperazino group, in the presence of an activating agent to obtain an amide derivative of the formula (I) ; and if desired, converting the compound of the formula (I) wherein X means oxygen and R stands for hydroxy obtained in process a) , with a H2 receptor-anta¬ gonist to a salt thereof. The reaction resulting in compounds of the formula (I) are preferably carried out in an inert solvent, suitably in methylene chloride, ethyl acetate or benzene.

Esters of the formula (I) are preferably prepar- ed by reacting a salt, suitably triethylamine salt of a carboxylic acid of the formula (II) with a halogeno- acetic acid ester, preferably with an alkyl bromoacetate in an inert organic solvent, preferably ethyl acetate under heating for several hours. Amides of the formula (I) are preferably pre¬ pared in such a way that the carboxy1 group of the carboxylic acids of the formula (II) are firstly activated and then coupled with a primary or secondary amine. An acyl halide derivative, preferably acyl chloride formed from the carboxylic acid may preferably be used as a reactive derivative. The acyl chloride may be pre¬ pared by reacting the carboxylic acid with thionyl chloride in an inert organic solvent, e.g. benzene. For activation of the carboxylic acid, methods commonly used in the peptide chemistry may also be employed (see e.g. in the monography of M. Bodanszky entitled: "Principles of Peptide Synthesis", Springer- Verlag, Berlin, Heidelberg, New-York, Tokyo, 1984) . The mixed anhydride method may preferably used for the activation of the carboxyl group. According to this method, the mixed anhydride is formed with a stoichio¬ metric amount of a chloroformate ester in the presence of a stoichiometric amount of a base, preferably tri- ethylamine under cooling, preferably at a temperature of -15 °C. An inert organic solvent, suitably methylene chloride is employed as solvent.

Subsequently, the activated derivative is reacted with the stoichiometric amount of a primary or sec- ondary amine under cooling, then the reaction mixture is gradually warmed to room temperature.

The compound of the formula (II) , wherein X stands for oxygen, may be prepared by condensing 3-oxo-2,3- dihydrobenzofuran with glyoxylic acid monohydrate in glacial acetic acid. In this way (Z)-2-carboxymethylene- 3-oxo-2,3-dihydrobenzofuran is obtained.

The compound of the formula (II) , wherein X is a methylene group, i.e. (E)-2-carboxymethylene-l-indanone may be prepared from 1-indanone e.g. by using the process described in the published PCT Application No. WO 91/17,983. In this process 1-indanone is condensed under basic conditions with glyoxylic acid prepared in situ.

Among the starting substances of the formula (III), 3-oxo-2,3-dihydrobenzofuran may be prepared by using a process known from the literature [Chem. Ber. 43. page 212 (1910)]. l-Indanone is a commercially available product.

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

Preparation of (Z)-2-carboxymethylene-3-oxo-2,3- dihydrobenzofuran

A suspension containing 13.4 g (0.1 mol) of 3-oxo- 2,3-dihydrobenzofuran and 13.8 g (0.15 mol) of glyoxylic acid monohydrate in 150 ml of glacial acetic acid is boiled under reflux for 5 hours. On evaporation of half of the solvent in vacuo and cooling, the title product precipitates in crystalline form to give a yield of 7.6 g (40%), m.p.: 180-181 °C, R_f = 0.5 (developing system: ethyl acetate/acetic acid 19:1). Example 2

Preparation of (Z)-2-carboxymβthylene-3-oxo-2,3- dihydrobenzofuran Famotidine salt A suspension containing 0.95 g (5 mmol) of the compound prepared in Example 1 and 1.68 g (5 mmol) of Famotidine base in 50 ml of ethanol is stirred for 6 hours. The title salt precipitated is filtered off and washed with 10 ml of ethanol to obtain a yield of 2.5 g (95%), m.p.: 175 °C (with decomposition). Example 3

Preparation of (E)-2-(ethoxycarbonyl-methoxycar- bonylmethylenβ)-3-oxo-1-indanone

A mixture containing 2.8 g (15 mmol) of 2-carboxy- methylene-3-oxo-l-indanone, 1.5 g (15 mmol) of triethyl¬ amine and 2.75 g (16 mmol) of ethyl bromoacetate is reacted in 70 ml of ethyl acetate. After heating at 80 °C for 5 hours, the reaction mixture is poured into water. The ethyl acetate phase is successively ex- tracted with 1 N hydrochloric acid, water, saturated sodium carbonate solution and again with water. After drying and evaporating the solvent, the residue is crystallized from diethyl ether to give 1.8 g (44%) of the title compound, m.p.: 114-116 °C, R = 0.75 (benzene/methanol 14:3). Example 4

Preparation of (Z)-2-(phenylamino-carbonyl- ethylene)-3-oxo-2,3-dihydrobenzofuran To a suspension of 1.9 g (0.01 mol) of the co - pound prepared in Example 1 in 150 ml of methylene chloride, 1.4 ml (0.01 mol) of triethylamine are added, then the solution is cooled to -15 °C. To this solution 0.96 ml (0.01 mol) of ethyl chloroformate is added at the same temperature, then the reaction mixture is stirred for 30 minutes. After adding 0.91 ml (0.01 mol) of aniline the reaction mixture is stirred at -15 °C for

1 hour, at 0 °C for 1 hour and finally at 20 °C for 2 hours. Subsequently, the reaction mixture is successive¬ ly extracted with water, 10% sodium bicarbonate solu- tion, 5% hydrochloric acid and again with water. After drying the organic phase over anhydrous magnesium sulfate and evaporation, the residue is crystallized by using 50 ml of diethyl ether to obtain the title com¬ pound in a yield of 2.1 g (79%), m.p.: 212-214 °C, Rf = 0.66 (ethyl acetate). Example 5

Preparation of (Z)-2-f(4-bromophenyl)-amino- carbonylmethylenβ]-3-0x0-2,3-dihydrobenzofuran To a suspension of 1.9 g (0.01 mol) of the compound prepared in Example 1 in 150 ml of methylene chloride, 1.4 ml (0.01 mol) of triethylamine are added, then the solution is cooled to -15 ^βC. At the same temperature 0.96 ml (0.01 mol) of ethyl chloroformate is added and the mixture is stirred for 30 minutes. Subsequently, after adding 1.72 g (0.01 mol) of 4-bromoaniline the reaction mixture is maintained at the same temperature for 1 hour, then at 0 °C for 1 hour and then stirred for

2 hours at room temperature. Then, the reaction mixture is successively extracted with water, 10% sodium bi- carbonate solution, 5% hydrochloric acid and again with water. After drying the organic solution over an¬ hydrous magnesium sulfate and evaporation, the residue is crystallized by using 50 ml of diethyl ether to give 2.3 g (67%) of the title compound, m.p.: 252-254 °C, Rf = 0.7 (ethyl acetate). Example 6

Preparation of (Z)-2-(l-pyrrolidinylcarbonyl- methylene)-3-oxo-2,3-dihydrobenzofuran To a suspension of 1.9 g (0.01 mol) of the compound of Example 1 in 150 ml of anhydrous methylene chloride. 1.4 ml (0.01 mol) of triethylamine and subsequently, 0.96 ml (0.01 mol) of ethyl chloroformate are added at a temperature of -15 °C, then the mixture is stirred for 30 minutes. Thereafter, 0.85 ml (0.01 mol) of pyrroli- dine is added at the same temperature and the reaction mixture is stirred at the same temperature for 1 hour, at 0 °C for 1 hour, finally at 20 °C for 2 hours. The reaction mixture is successively extracted with water, 10% sodium bicarbonate solution, 5% hydrochloric acid and again with water. After drying the organic phase over anhydrous magnesium sulfate and evaporation, the residue is crystallized by using 50 ml of diethyl ether to obtain 2.1 g (86%) of title product, m.p.: 116-118 °C, Rf - 0.34 (ethyl acetate). Example 7

Preparation of (Z)-2-[(4-ethoxycarbonyl-l-pipera- zinyl)carbonylmethylene]-3-oxo-2 ,3-dihydrobenzofuran To a suspension of 1.9 g (0.01 mol) of the compound of Example 1 in 150 ml of anhydrous methylene chloride, 1.4 ml (0.01 mol) of triethylamine and subsequently,

0.96 ml (0.01 mol) of ethyl chloroformate are added at a temperature of -15 °C and the mixture is stirred for 30 minutes. Then, 1.5 ml (0.01 mol) of 4-(ethoxycar- bonyl)piperazine are added and the reaction mixture is stirred at the same temperature for 1 hour, at 0 °C for 1 hour and at room temperature for 2 hours. Thereafter, the reaction mixture is successively extracted with water, 10% sodium bicarbonate solution, 5% hydrochloric acid and again with water. After drying the organic phase over anhydrous magnesium sulfate and evaporation, the residue is crystallized by adding 50 ml of diethyl ether to give 2.2 g (66%) of the title compound, m.p.: 106-108 °C, Rf = 0.6 (ethyl acetate/acetic acid 19:1). Example 8

Preparation of (Z)-2-[ (l-methoxycarbonyl-2(8)- phenylethyl)amino-carbonylmethylene]-3-0x0-2,3-di- hydrobenzofuran To a suspension of 1.9 g (0.01 mol) of the compound of Example 1 in 150 ml of anhydrous methylene chloride, 1.4 ml (0.01 mol) of triethylamine are added, then the mixture is cooled to a temperature of -15 °C, 0.96 ml (0.01 mol) of ethyl chloroformate is added and the mixture is stirred for 30 minutes. Subsequently, at the same temperature 2.15 g (0.01 mol) of methyl L-phenyl- alaninate hydrochloride arid 1.4 ml (0.01 mol) of tri¬ ethylamine are added, the mixture is stirred at the same temperature for 1 hour, at 0 °C for 1 hour and at room temperature for 2 hours. Thereafter, the reaction mixture is successively extracted with water, 10% so¬ dium bicarbonate solution, 5% hydrochloric acid and again with water. After drying the organic phase over anhydrous magnesium sulfate and evaporation, the residue is crystallized by using 50 ml of diethyl ether to ob¬ tain 2.1 g (60%) of the title compound, m.p.: 107-109 °C, Rf = 0.65 (ethyl acetate), [α] = +27.43° (c = 0.5, chloroform). Example 9 Preparation of (Z)-2-[(methoxycarbonyl-methyl)- amino-carbonylmethylene]-3-0x0-2 ,3-dihydrobenzofuran To the suspension of 1.9 g (0.01 mol) of the com¬ pound of Example 1 in 150 ml of anhydrous methylene chloride, 1.4 ml (0.01 mol) of triethylamine are added, then the reaction mixture is cooled to a temperature of -15 °C and, after adding 0.96 ml (0.01 mol) of ethyl chloroformate, the reaction mixture is stirred for 30 minutes at the same temperature. Subsequently, after adding 1.25 g (0.01 mol) of methyl glycinate hydro- chloride and 1.4 ml (0.01 mol) of triethylamine, the reaction mixture is stirred under cooling for 1 hour, at 0 °C for 1 hour and at room temperature for 2 hours. Then, the reaction mixture is successively extracted with water, 10% sodium bicarbonate solution, 5% hydro- chloric acid and again with water. After drying the organic phase over anhydrous magnesium sulfate and evaporation, the residue is crystallized by using 50 ml of diethyl ether to give the title compound in a yield of 1.5 g (57%), m.p.: 168-170 °C, R_f = 0.5 (ethyl acetate) .

Example 10

Preparation of (E)-2-(n-butylamino-carbonyl- methylene)-1-indanonβ

To solution containing 2.8 g (15 mmol) of (E)-2- carboxymethylene-1-indanone in 20 ml of benzene, 10 ml of thionyl chloride are added, the solution is stirred at 60 °C for 90 minutes, then the solvent is evaporated. The residue is dissolved in 40 ml of methylene chloride and added to 2.2 g (0.03 mol) of n-butylamine dissolved in 20 ml of methylene chloride at a temperature of

0 °C. Subsequently, the reaction mixture is stirred at room temperature for 90 minutes, then poured into water and the organic phase is successively extracted with saturated sodium carbonate solution, water, 1 N hydro- chloric acid and again with water. After drying the organic phase, the residue is crystallized by using di¬ ethyl ether to obtain 1.8 g (50%) of the title compound, m.p.: 152-154 °C, Rf = 0.65 (benzene/methanol 14:3). Example 11 Preparation of (E)-2-(cyclohexylamino-carbonyl- methylene)-l-indanone

To a solution containing 2.8 g (15 mmol) of 2- carboxymethylene-l-indanone in 20 ml of anhydrous benzene, 10 ml thionyl chloride are added, the solution is stirred at a temperature of 60 °C for 90 minutes, then the solvent is evaporated. After dissolving the residue in 40 ml of methylene chloride, 3.0 g (0.03 mol) of cyclohexyla ine dissolved in 20 ml of methylene chloride are added at 0 °C, the reaction mixture is stirred at room temperature for 12 hours and then poured into water. The organic phase is extracted with satur¬ ated sodium carbonate solution, dried over anhydrous magnesium sulfate and the solvent is evaporated. The residue is crystallized by adding diethyl ether to obtain the title compound in a yield of 2.6 g (68%), m.p.: 202-205 °C, Rf = 0.73 (benzene/methanol 14:3). Example 12

Preparation of (E)-2-(l-pyrrolidinylcarbonyl- methylene)-1-indanone To a suspension containing 2.88 g (15 mmol) of 2- carboxymethylene-1-indanone in 100 ml of benzene, 5 ml (0.07 mol) of thionyl chloride are added, the reaction mixture is heated at 60 °C for l hour, then evaporated. The residue is dissolved in 100 ml of ethyl acetate and the solution is added to the solution of 3.0 ml (35 mmol) of pyrrolidine in 100 ml of methylene chloride. After reacting the components for 1 hour, the solution is evaporated, the residue is dissolved in ethyl acetate and extracted with water. After drying, the organic phase is evaporated. The residue is crystal¬ lized by using diethyl ether to give the title compound in a yield of 1.8 g (50%), m.p.: 164-166 °C, R_f = 0.36 (ethyl acetate) . Example 13 Preparation of (E)-2-(phenylaminocarbonyl- methylene)-1-indanone

To a suspension containing 2.88 g (15 mmol) of 2- carboxymethylene-l-indanone in 100 ml of benzene, 5 ml (0.07 mol) of thionyl chloride are added and the re- action mixture is heated at 60 °C for 1 hour. After evaporating the solution, the residue is dissolved in 100 ml of anhydrous ethyl acetate and the solution is added to the solution of 3.1 ml (35 mmol) of aniline in 100 ml of methylene chloride. After stirring for 1 hour, the reaction mixture is extracted with

0.01 M hydrochloric acid solution and the precipitate is filtered to obtain 3.1 g (78%) of the title compound, m.p.: 241-243 °C, Rf = 0.7 (ethyl acetate). Example 14 Preparation of (E)-2-[(l-ethoxγcarbonyl-4-pipera- zinyl)carbonyl ethylene]-l-indanone After suspending 1.88 g (0.01 mol) of 2-carboxy- methylene-1-indanone in 60 ml of ethyl acetate and then cooling the suspension to a temperature of -10 °C, 1.01 g (0.01 mol) of triethylamine and 2.6 g (11 mmol) of diphenylphosphinyl chloride are portionwise added, the reaction mixture is stirred at the same temperature for 1 hour and subsequently, 1.01 g (0.01 mol) of tri¬ ethylamine and 1.6 g (0.01 mol) of N-(ethoxycarbony1)- piperazine are portionwise added. The reaction mixture is stirred at -10 °C for 1 hour, then at room tempera¬ ture for 1 hour. The precipitate is filtered off and the filtrate is successively extracted with water, 1 N hyd¬ rochloric acid, water, saturated sodium carbonate solu- tion and again with water. After drying the organic phase over anhydrous magnesium sulfate and evaporation, the residue is crystallized by using diethyl ether to obtain 1.06 (31%) of the title compound, m.p.: 172-174 °C, Rf = 0.63 (ethyl acetate/pyridine/glacial acetic acid/water 90:5:2:3). Example 15

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 148

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

Claims

C l a i m s

1) Novel acid, salt, ester and amide derivatives of a 5-membered ring fused benzene of the formula

wherein

R is selected from hydroxy, (Cι_4)alkoxycarbonyl- methoxy, (Cι_4)alkylamino, cyclohexylamino; phenylamino optionally substituted by halogen; (Cι_4)alkoxycarbonylmethylamino, l-(Cι_4)alkoxy- carbonyl-2-phenylethylamino, pyrrolidino and N-(Cι_4)alkoxycarbonylpiperazino; and X stands for oxygen or methylene, with the proviso that X means oxygen when R stands for hydroxy; and their salts formed with H2 receptor antagonists, when X means oxygen and R stands for hydroxy.

2) (Z)-2-Carboxymethylene-3-oxo-2, 3-dihydrobenzo- furan.

3) A pharmaceutical composition which c o m p r i s e s as active ingredient one or more novel acid, salt, ester or amide derivative(s) of a 5-membered ring fused benzene of the formula

wherein

R is selected from hydroxy, (Cι_4)alkoxycarbonyl- methoxy, (Cι_ )alkylamino, cyclohexylamino; phenylamino optionally substituted by halogen; (^c _l-4)alkoxycarbonylmethylamino , 1-(Cj^)alkoxy- carbonyl-2-phenylethylamino, pyrrolidino and N-(Cι_4)alkoxycarbonylpiperazino; and X stands for oxygen or methylene, with the proviso that X means oxygen when R stands for hydroxy; and their salts formed with H2 receptor antagonists, when X means oxygen and R stands for hydroxy, in admixture with nontoxic, inert, solid or liquid carriers and/or additives commonly used in pharma¬ ceuticals for enteral or parenteral administration. 4) A process for the preparation of novel acid, salt, ester and amide derivatives of a 5-membered ring fused benzene of the formula

wherein

R is selected from hydroxy, (C₁_₄)alkoxycarbonyl- methoxy, (Cι_4)alkylamino, cyclohexylamino; phenylamino optionally substituted by halogen; (Cι_4)alkoxycarbonylmethylamino, l-(Cι_4)alkoxy- carbonyl-2-phenylethylamino, pyrrolidino and N-(Cι_4)alkoxycarbonylpiperazino; and X stands for oxygen or methylene, with the proviso that X means oxygen when R stands for hydroxy; and their salts formed with H2 receptor antagonists, when X means oxygen and R stands for hydroxy, which c o m p r i s e s eacting a benzofuran derivative of the formula

wherein X is oxygen or methylene; with an ester of a halogenoacetic acid to obtain an ester derivative of the formula (I) ; or c) reacting a carboxylic acid of the formula (II) , wherein X is oxygen or methylene groups, with a prim- ary or secondary amine of the formula

wherein R¹ stands for hydrogen and R² is selected from a Cι_₄alkyl, a cyclohexyl; a phenyl optionally substituted by halogen; a (C₁_4)alkoxycarbonylmethyl and a l-(Cι_₄)alkoxycarbonyl-2-phenylethyl; or R¹ and R² together with nitrogen to which they are attached form a pyrrolidino or an N-(C₁_4)alkoxy- carbonylpiperazino; in the presence of an activating agent to obtain an amide derivative of the formula (I) ; and if desired, converting the compound of the formula (I) wherein X means oxygen and R stands for hydroxy obtained in process a) , with a H2 receptor-antagonist to a salt thereof.

5) A process according to process a) of claim 4, which c o m p r i s e s preparing the Famotidine salt of the compound obtained.

6) A process according to process a) of claim 4, which c o m p r i s e s carrying out the reaction in glacial acetic acid. 7) A process according to process b) of claim 4, which c o m p r i s e s using the triethylamine salt of the carboxylic acid of the formula (II) , wherein X is oxygen or methylene as starting ma¬ terial. 8) A process according to process c) of claim 4, which c o m p r i s e s activating the carboxylic acid of the formula (II) , wherein X is oxygen or methylene, by using an acyl chloride, preferably thionyl chloride or an ester of chlorofor ic acid. 9) A process according to claim 8, which c o m p r i s e s carrying out the reaction in the presence of an inert organic base, preferably triethyl¬ amine.

10) A process according to any of claims 4 to 8, which c o m p r i s e s carrying out the reaction in a solvent being inert under the reaction condi¬ tions.

11) A process for the preparation of a pharmaceutical composition, which c o m p r i s e s admixing one or more acid, salt, ester or amide derivative(s) of a 5-membered ring fused benzene of the formula

wherein

R is selected from hydroxy, (C₁_₄)alkoxycarbonyl- methoxy, (Cι_4)alkylamino, cyclohexylamino; phenylamino optionally substituted by halogen; (C₁__4)alkoxycarbonylmethylamino, l-(C₁_4)alkoxy- carbonyl-2-phenylethylamino, pyrrolidino and N-(Cι_₄)alkoxycarbonylpiperazino; and X stands for oxygen or methylene, with the proviso that X means oxygen when R stands for hydroxy; and their salts formed with H2 receptor antagonists, when X means oxygen and R stands for hydroxy, with non-toxic, inert, solid or liquid carriers and/or additives commonly used in pharmaceuticals for enteral or parenteral administration, and transforming the mixture to a pharmaceutical dosage form.

12) Method for the prevention and/or healing of various ulcerative disease of oesophagus, stomach or duodenum in a mammal including human, which c o m p r i s e s administering to said mammal a therapeutically effective amount of one or more novel acid, salt, ester or amide derivative(s) of a 5-mem¬ bered ring fused benzene of the formula

wherein

R is selected from hydroxy, (Cι_4)alkoxycarbonyl- methoxy, (C₁_4)alkylamino, cyclohexylamino; phenylamino optionally substituted by halogen; (Cι__4)alkoxycarbonylmethylamino, l-(Cι_4)alkoxy- carbonyl-2-phenylethylamino, pyrrolidino and N-(Cι_4)alkoxycarbonylpiperazino; and X stands for oxygen or methylene, with the proviso that X means oxygen when R stands for hydroxy; and their salts formed with H2 receptor antagonists, when X means oxygen and R stands for hydroxy, alone or in the form of a pharmaceutical composition.