EP0772614A1

EP0772614A1 - Halogenated imidazopyridines

Info

Publication number: EP0772614A1
Application number: EP95928467A
Authority: EP
Inventors: Richard Riedel; Stefan Postius; Gerhard Grundler; Jörg Senn-Bilfinger; Georg Rainer; Wolfgang-Alexander Simon
Original assignee: Byk Gulden Lomberg Chemische Fabrik GmbH
Current assignee: Takeda GmbH
Priority date: 1994-07-28
Filing date: 1995-07-26
Publication date: 1997-05-14
Also published as: AU3221795A; CA2196075A1; WO1996003402A1; JPH10505330A

Abstract

The invention concerns compounds of formula I, wherein the substituents and symbols have the meanings indicated in the description, and the use of these compounds in the treatment of gastro-intestinal diseases.

Description

Haloimidazopyridines

Field of application of the invention

The invention relates to new halogenimidazopyridines which are to be used in the pharmaceutical industry as active ingredients for the production of medicaments.

Known technical background

European patent application EP-A-0033094 describes imidazo [1,2-a] pyridines which bear an aryl substituent in the 8-position, which is preferably a phenyl, thienyl, pyridyl or chlorine, fluorine, methyl, tert-butyl, trifluoromethyl, methoxy or cyano substituted phenyl. Particularly interesting aryl radicals mentioned in EP-A-0033094 are the radicals phenyl, o- or p-fluorophenyl, p-chlorophenyl and 2,4,6-trimethylphenyl, of which the radicals phenyl, o- or p-fluorophenyl and 2, 4,6-trimethylphenyl are particularly preferred. - In the European patent applications EP-A-0204 285, EP-A-0228006, EP-A-0268989 and EP-A-0308917 imidazo [1,2-a] pyridines are described which have an unsaturated aliphatic radical in the 3-position , in particular carry a (substituted) alkynyl radical. - European patent application EP-A-0266890 describes imidazo [1,2-a] pyridines which are substituted in the 8-position by an alkenyl, alkyl or cycloalkylalkyl radical.

Description of the invention

It has now been found that the compounds described in more detail below, which differ from the compounds of the prior art in particular by the substitution in the 3- or in the 8-position, have surprising and particularly advantageous properties.

The invention relates to compounds of the formula I (see attached formula sheet), in which R0 halogen or thiocyanate,

R1 1-4C-alkyl,

R2 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, halogen or trifluoromethyl,

R3 1-4C-alkoxy,

R4 is hydrogen, 1 -4C-alkyl, 1 -4C-alkoxy, halogen or trifluoromethyl,

R5 is hydrogen, 1-4C-Al kyl, 1 -4C-Al koxy or Hal ogen and

A means 0 (oxygen) or NH,

and their salts.

Halogen in the sense of the invention is bromine, chlorine and fluorine.

1-4C-Alkyl stands for straight-chain or branched alkyl radicals with 1 to 4 carbon atoms. Examples include butyl, iso-butyl, sec-butyl, tert. -Butyl, propyl, isopropyl, ethyl and especially the methyl radical.

1-4C-alkoxy represents an oxygen atom to which one of the above-mentioned 1-4C-alkyl radicals is attached. The methoxy radical is preferred.

Suitable salts for compounds of the formula I are preferably all acid addition salts. Particular mention should be made of the pharmacologically acceptable salts of the inorganic and organic acids commonly used in galenics. Pharmacologically incompatible salts, which may initially be obtained as process products in the preparation of the compounds according to the invention on an industrial scale, are converted into pharmacologically acceptable salts by processes known to the person skilled in the art. Suitable as such are water-soluble and water-insoluble acid addition salts with acids such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, acetic acid, citric acid, D-gluconic acid, benzoic acid, 2- (4-hydroxybenzoyl) benzoic acid, butyric acid, sulfosalicylic acid, maleic acid , Malic acid, fumaric acid, succinic acid, oxalic acid, tartaric acid, embonic acid, stearic acid, toluenesulfonic acid, methanesulfonic acid or 3-hydroxy-2-naphthoic acid, the acids used in salt production - depending on whether it is a mono- or polybasic acid and depending on which salt is desired - be used in an equimolar or a different quantity ratio. Compounds of formula I to be emphasized are those in which

R0 bromine, chlorine or fluorine,

R1 1-4C-alkyl,

R2 1-4C-alkyl, chlorine or fluorine,

R3 1-4C-alkoxy,

R4 is hydrogen,

R5 hydrogen and

A means 0 (oxygen) or NH,

and their salts.

Particularly noteworthy compounds of formula I are those in which

R0 bromine or chlorine,

R1 1-4C-alkyl,

R2 1-4C-alkyl,

R3 1-4C-alkoxy,

R4 is hydrogen,

R5 hydrogen and

A means 0 (oxygen) or NH,

and their salts.

Exemplary compounds according to the invention are listed in Table 1 below:

Table 1

Compounds of formula I (see attached formula sheet) with R1 = CH ₃ , R4 = H, R5 = H and the following further substituent and symbol meanings:

Continuation of table 1:

0

and the salts of the compounds listed in the table.

The invention further relates to a process for the preparation of the compounds of the formula I and their salts. The process is characterized in that a) compounds of the formula II (see the enclosed formula sheet), in which R0, R1 and A have the meanings given above, with compounds of the formula III (see attached formula sheet), in which R2, R3, R4 and R5 have the meanings given above and X represents a suitable leaving group, or that b) for the preparation of compounds of the formula I in which R0 is bromine or thiocyanate, compounds of the formula IV (see attached formula sheet), in which R1, R2, R3, R4, R5 and A have the meanings given above, are reacted with bromine and, if desired, subsequently with alkali thiocyanate and that, if desired, the compounds I obtained according to a) or b) are subsequently converted into their salts, or if desired subsequently releases the compounds I from the salts of the compounds I obtained. The reaction of the compounds II with the compounds III is carried out in a manner known per se to the person skilled in the art, for example using methods analogous to those described in European patent applications EP-A-0 268989 or EP-A-0308917.

A suitable leaving group is, for example, a halogen atom (preferably chlorine or bromine) or a methanesulfonyloxy group. The reaction is advantageously carried out in the presence of a base (for example an inorganic hydroxide such as sodium hydroxide or an inorganic carbonate such as potassium carbonate or an organic nitrogen base such as triethylamine, pyridine, collidine or 4-dimethylaminopyridine), with the addition of catalysts such as alkali iodide or tetrabutylammonium bromide, the reaction can be favored.

The bromination of the compounds IV and, if desired, the subsequent reaction with alkali thiocyanate (alkali thiocyanate) is likewise carried out in a manner known per se to the person skilled in the art, as is customary for the preparation of such compounds, preferably by bromination of the compounds IV in glacial acetic acid and, if desired Reaction with sodium or potassium thiocyanate in situ in the same solvent.

The person skilled in the art is familiar with the reaction conditions which are required for carrying out the process in detail on the basis of his specialist knowledge.

The substances according to the invention are isolated and purified in a manner known per se, e.g. such that the solvent is distilled off in vacuo and the residue obtained is recrystallized from a suitable solvent or subjected to one of the customary purification methods, such as, for example, column chromatography on a suitable carrier material.

Acid addition salts are obtained by dissolving the free base in a suitable solvent, for example in water, in a chlorinated hydrocarbon, such as methylene chloride or chloroform, a lower aliphatic alcohol (ethanol, isopropanol), a ketone, such as acetone, or an ether, such as THF or Diisopropyl ether, which contains the desired acid, or to which the desired acid is then added. The salts are obtained by filtration, reprecipitation, precipitation with a non-solvent for the addition salt or by evaporation of the solvent. Salts obtained can be converted into the free bases by alkalization, for example with aqueous ammonia solution, which in turn can be converted into acid addition salts. In this way, pharmacologically unacceptable acid addition salts can be converted into pharmacologically unacceptable acid addition salts.

The starting compounds II can be prepared as described in the examples below, for example by halogenating those compounds II (with intermediate protection of the radical -AH) in which R0 denotes a hydrogen atom. Alternatively, the compounds II can also be prepared from suitable starting compounds using methods analogous to those described in EP-A-0268989 or in EP-A-0308917 (Process 1 or Process A). The starting compounds III can be prepared in a manner analogous to that described in European patent application EP-A-0308917.

The starting compounds IV can be obtained from known starting compounds and / or using analogous methods (see

EP-A-0033094, EP-A-0268989 and EP-A-0308917) can be prepared in a manner known per se.

The following examples serve to explain the preparation of the compounds according to the invention in more detail. In particular, the examples also serve to exemplify the reactions according to process variants a and b and the preparation of selected starting compounds. Likewise, further compounds of the formula I and further starting compounds, the preparation of which is not explicitly described, can be prepared in an analogous manner or in a manner familiar to the person skilled in the art using customary process techniques. The abbreviation RT stands for room temperature, h stands for hour (s), min for minute (s), mp for melting point, dec. for decomposition. At game e

End products

1. 3-chloro-8- (2-methoxycarbonylamino-6-methylbenzylamino) -2-methylimidazo [1,2-a] pyridine

A suspension of 8-amino-3-chloro-2-methylimidazo [1,2-a] pyridine (1.0 g, 5.5 mmol), 2-methoxycarbonylamino-6-methylbenzyl chloride (1.2 g , 5.5 mmol), sodium iodide (1.0 g, 6.6 mmol) and sodium carbonate (1.45 g, 13.75 mmol) in anhydrous acetone (100 ml) are stirred at RT for 16 h. The solvent is then distilled off on a rotary evaporator. The residue is taken up in water (200 ml) and extracted with ethyl acetate (4 x 150 ml). The organic extracts are washed with water (200 ml), dried over magnesium sulfate and concentrated. The remaining brown oil is chromatographed on silica gel (eluent: toluene / dioxane - 9: 1). The fractions with Rf = 0.3 are concentrated and crystallized from ethyl acetate. The title compound (1.0 g, 51%) is isolated as a colorless solid. Mp

165-166 ° C.

2. 3-bromo-8- (2-methoxycarbonylamino-6-methylbenzyloxyl-2-methylimidazo [1,2-a] pyridine

To a suspension of 8- (2-methoxycarbonylamino-6-methyl-benzyloxy) -2-methylimidazo [1,2-a] pyridine (0.5 g, 1.5 mmol) in glacial acetic acid (20 ml) Solution of bromine (0.1 ml, 1.7 mmol) in glacial acetic acid (5 ml) was added dropwise with vigorous stirring. The mixture is stirred at RT for a further 1 h and then the solvent is distilled off. The residue is taken up in water (100 ml) and extracted with ethyl acetate (4 x 70 ml). The organic extracts are washed with water (100 ml), dried over magnesium sulfate and concentrated. The residue is purified by chromatography on silica gel (eluent: toluene / dioxane - 20: 1). The fractions with Rf - 0.3 are concentrated and crystallized from methanol. The title compound (0.18 g, 30%) was isolated as a light yellow solid. Mp 205 ° C (dec.) 3. 8- (2-methoxycarbonylamino-6-methyl-benzyloxy) -2-methyl-3-thiocyanatoimidazo [1,2-a] pyridine

To a suspension of 8- (2-methoxycarbonylamino-6-methyl-benzyloxy) -2-methyl-imidazo [1,2-a] pyridine (1.0 g, 3 mmol) and potassium rhodanide (1.5 g, 15 mmol ) in glacial acetic acid (25 ml), a solution of bromine (0.15 ml, 3 mmol) in glacial acetic acid (5 ml) is added dropwise with vigorous stirring. The mixture is stirred at RT for a further 2 h and then the solvent is distilled off. The residue is taken up in aqueous sodium bicarbonate solution (150 ml) and extracted with ethyl acetate (4 x 100 ml). The organic extracts are made with water

(200 ml) washed, dried over magnesium sulfate and concentrated. The residue is purified by chromatography on silica gel (eluent: toluene / dioxane = 10: 1). The fractions with Rf = 0.2 are concentrated and crystallized from ethyl acetate. The title compound (0.27 g, 20%) is isolated as a light yellow solid. Mp 171-173 ° C.

4. 3-Chloro-8- (2-methoxycarbonylamino-6-methylbenzyloxy) -2-methylimi dazo [1,2-a] pyridine

A suspension of 8- (2-methoxycarbonylamino-6-methylbenzyloxy) -2-methylimidazo [1,2-a] pyridine (0.6 g, 1.8 mmol) in ethanol (10 ml) is washed with N -Chlorsuccinimid added and stirred at RT for 30 min. Then a 1% sodium chloride solution (30 ml) is added and extracted with ethyl acetate (3x30 ml). The organic extracts are washed with brine (30 ml), dried over magnesium sulfate and concentrated. After crystallization from ethyl acetate, the title compound is isolated as a colorless powder. Educ. 85%; Mp 197-199 ° C.

5. 3-bromo-8- (2-methoxycarbonyl ami no-6-methyl-benzyl ami no) -2-methyl -imi dazo [1, 2-a] pyridine

According to the procedure given for Example 1, starting from 8-amino-3-bromo-2-methylimidazo [1,2-a] pyridine and 2-methoxycarbonylamino-6-methylbenzyl chloride, the title compound is obtained after purification by chromatography on silica gel (eluent: toluene / dioxane = 9: 1) and crystallization from ethyl acetate as a beige powder. Educ. 47%; M.p. 178-179 ° C. 6. 3-fluoro-8- (2-methoxycarbonylamino-6-methylbenzyl) amino-2-methylimidazo [1,2-a] pyridine

0.37 g (2.2 mmol) of 8-amino-3-fluoro-2-methylimidazo [1,2-a] pyridine, 0.51 g (2.4 mmol) of 2-methoxy-carbonylamino-6- Methyl benzyl chloride and 0.56 g (5.6 mmol) sodium carbonate are suspended in 10 ml acetone and, after the addition of 0.09 g (0.6 mmol) sodium iodide, stirred vigorously for 16 hours at RT. The mixture is then mixed with 50 ml of water, extracted twice with methylene chloride, the organic phase dried over sodium sulfate and evaporated to dryness in vacuo. After purification on silica gel (methylene chloride / methanol = 100: 1) and seeding with diethyl ether, 0.27 g of the title compound of mp 84-88 ° C are obtained.

7. 3-Fluoro-8- (2-methoxycarbonylamino-6-methylbenzyl) oxy-2-methylimidazo [1,2-a] pyridine

A mixture of 0.3 g (1.8 mmol) of 3-fluoro-8-hydroxy-2-methylimidazo [1,2-a] pyridine, 0.42 g (2 mmol) of 2-methoxycarbonylamino-6- methylbenzyl chloride, 0.48 g (4.5 mmol) sodium carbonate, 0.07 g (0.5 mmol) sodium iodide and 10 ml acetone are stirred vigorously for 16 hours at RT. The reaction mixture is then mixed with 50 ml of water and extracted twice with methylene chloride, the organic phase is dried over sodium sulfate and, after concentration in vacuo, is purified on silica gel (methylene chloride / methanol = 100: 1). 0.3 g of the title compound of mp 169-172 ° C are obtained.

Output connections

A1. 3-chloro-2-methyl-8-pivaloylamino-imidazo [1,2-a] pyridine

5.0 g (18.6 mmol) of 2-methyl-8-pivaloylamino-imidazo [1,2-a] pyridine hydrochloride, prepared from 8-amino-2-methyl-imidazo [1,2-a], are dissolved. pyridine and pivaloyl chloride, m.p. 229-230 ° C, in glacial acetic acid (20 ml) and slowly introduces chlorine gas at 15 ° C until the reaction is complete after TLC control (approx. 20 min). Then the solvent is distilled off, the residue is taken up in ethyl acetate / water (in each case 30 ml), made basic with saturated sodium bicarbonate solution and extracted. Then again extracted with ethyl acetate (3 x 30 ml). The combined organic extracts are washed with water (50 ml), dried over magnesium sulfate and concentrated. The residue is purified by chromatography on silica gel (eluent: toluene / dioxane = 9: 1). After concentration of the fractions with Rf = 0.2, the title compound (4.1 g, 83%) is obtained as a colorless solid. Mp 117-118 ° C.

A2. 8-amino-3-chloro-2-methylimidazo [1,2-a] pyridine

A suspension of 3-chloro-2-methyl-8-pivaloylamino-imidazo [1,2-a] pyridine (4.0 g, 15 mmol) in 60% sulfuric acid (25 ml) is stirred at 100 ° C for 1 hour. After cooling to RT, water (100 ml) is added and the pH is adjusted to 10 using 10 N sodium hydroxide solution. Then it is extracted with ethyl acetate (3 x 50 ml). The combined organic extracts are washed with water (50 ml), dried over magnesium sulfate and concentrated. The residue is taken up in boiling toluene, clarified with silica gel and crystallized. The title compound is isolated as a beige solid. Educ. 1.9 g (70%), m.p. 126-127 ° C.

A3. 8- (2-methoxycarbonylamino-6-methylbenzyloxy) -2-methylimidazo [1,2-a] pyridine

8-Hydroxy-2-methylimidazo [1,2-a] pyridine (4.8 g, 32.4 mmol) is added in portions at RT with vigorous stirring to a suspension of sodium hydride (1.1 g, 80% in Paraffin) in tetrahydrofuran (200 ml). The mixture is stirred for a further 30 min, then a solution of 2-methoxycarbonylamino-6-methylbenzyl chloride (6.9 g, 32.4 mmol) in tetrahydrofuran (100 ml) is added dropwise and the mixture is stirred at RT for a further 3 h. The solvent is then distilled off on a rotary evaporator, the residue is taken up in water (200 ml) and extracted with ethyl acetate (4 × 150 ml). The organic extracts are washed with water (200 ml), dried over magnesium sulfate and concentrated. The remaining brown oil is chromatographed on silica gel (eluent: toluene / dioxane 9: 1 to 4: 1). After concentration of the fractions with Rf = 0.4, the title compound (3.0 g, 28%) is isolated as a beige solid. Mp 170-172 ° C. B1. 3-bromo-2-methyl-8-pivaloylamino-imidazo [1,2-a] pyridine

To a solution of 2-methyl-8-pivaloylamino-imidazo [1,2-a] pyridine hydrochloride (10 g, 37.3 mmol) in glacial acetic acid (100 ml) is added a solution of bromine (1, 91 ml, 37.3 mmol) in glacial acetic acid (10 ml) were added dropwise with vigorous stirring. The mixture is then stirred for a further 30 minutes at 4 ° C. and then the glacial acetic acid is distilled off. The remaining oil is taken up in a mixture of saturated sodium bicarbonate solution and ethyl acetate (100 ml each) and extracted with ethyl acetate (3x100 ml). The organic extracts are dried over magnesium sulfate and concentrated. The residue is purified by chromatography on silica gel (eluent: toluene / dioxane = 20: 1). After crystallization from di isopropyl ether, the title compound is obtained as a beige solid. Educ. 89%; Mp 144-146 ° C.

B2. 8-amino-3-bromo-2-methylimidazo [1,2-a] pyridine

According to the example A2. given procedure, starting from 3-bromo-2-methyl-8-pivaloylamino-imidazo [1,2-a] pyridine, the title compound is obtained as a beige solid after crystallization from toluene. Educ. 45%;

Mp 156-157 ° C.

C1. 8-benzyloxy-3-fluoro-2-methylimidazo [1,2-a] pyridine

A mixture of 9 g of 2-amino-3-benzyloxypyridine, 9.6 g of 1-bromo-1-fluoroacetone and 50 ml of ethanol is heated under reflux for 8 hours. After standing at RT for 16 hours, the mixture is evaporated to dryness in vacuo, Pour 100 ml of saturated sodium bicarbonate solution over it and extract twice with methylene chloride. The organic phase is dried, concentrated in vacuo and the residue is purified on silica gel (methylene chloride / methanol = 100: 3). After inoculation with diethyl ether, 2.8 g of the title compound of mp 128-130 ° C are obtained.

C2. 3-fluoro-8-hydroxy-2-methylimidazo [1,2-a] pyridine

A mixture of 0.5 g (1.95 mmol) of 8-benzyloxy-3-fluoro-2-methylimidazo- [1,2-a] pyridine, 0.4 ml (4 mmol) of cyclohexadiene-1,4 and 0.08 g of palladium / C-type 90 catalyst in 10 ml of tetrahydrofuran is refluxed for 4 h, filtered off from the catalyst, the filtrate concentrated in vacuo and the residue purified on silica gel (methylene chloride / methanol = 13: 1). 0.16 g of the title compound of mp 168-171 ° C are obtained.

C3. 3-fluoro-2-methyl-8-pivaloylamino-imidazo [1,2-a] pyridine

A mixture of 1.5 g (7.7 mmol) of 2-amino-3-pivaloylamino-pyridine and 1.3 g (8.4 mmol) of 1-bromo-1-fluoroacetone in 12 ml of tetrahydrofuran is 5 hours on Boiled under reflux, then filtered, the filtrate taken up in 50 ml of ethyl acetate and stirred with saturated sodium bicarbonate solution. After concentration of the filtrate and purification on silica gel (methylene chloride / methanol = 13: 1), 0.8 g of the title compound are obtained as a reddish, viscous oil.

C4. 8-amino-3-fluoro-2-methylimidazo [1,2-a] pyridine

0.7 g (2.8 mmol) of 3-fluoro-2-methyl-8-pivaloylamino-imidazo [1,2-a] pyridine are heated in 10 g of 60% sulfuric acid at 100 ° C for 45 min, the reaction mixture is cooled Poured 50 ml of ice water and adjusted to a pH of 8-9 with 6N sodium hydroxide solution and saturated sodium hydrogen carbonate solution. This mixture is extracted twice with methylene chloride, the organic phase is dried with sodium sulfate and concentrated in vacuo. 0.4 g of the title compound of mp 65-68 ° C are obtained.

Industrial applicability

The compounds of the formula I and their salts have valuable pharmacological properties which make them commercially useful. In particular, they have a pronounced inhibition of gastric acid secretion and an excellent gastric and intestinal protective effect in warm-blooded animals. The compounds according to the invention are distinguished here by a high selectivity of action, a comparatively long duration of action, good enteral activity, the absence of significant side effects and a wide therapeutic range.

In this context, "gastric and intestinal protection" means the prevention and treatment of gastrointestinal diseases, in particular gastrointestinal inflammatory diseases and lesions (such as, for example, ulcer ventriculi, duodenal ulcer, gastritis, hyperacid or drug-induced irritable stomach), which are caused, for example, by microorganisms (eg Helicobacter pylori), bacterial toxins, medications (e.g. certain anti-inflammatory drugs and anti-rheumatic drugs), chemicals (e.g. ethanol), stomach acid or stressful situations. The compounds of the invention also have an intrinsic activity against the Helicobacter pylori germ.

In their excellent properties, the compounds according to the invention surprisingly prove to be clearly superior to the compounds known from the prior art on various models in which the antiulcerogenic and the antisecretory properties are determined. On the basis of these properties, the compounds of the formula I and their pharmacologically acceptable salts are outstandingly suitable for use in human and veterinary medicine, and are used in particular for the treatment and / or prophylaxis of diseases of the stomach and / or intestine.

The invention therefore furthermore relates to the compounds according to the invention for use in the treatment and / or prophylaxis of the abovementioned diseases. The invention also includes the use of the compounds according to the invention for the production of medicaments which are used for the treatment and / or prophylaxis of the abovementioned diseases.

The invention further comprises the use of the compounds according to the invention for the treatment and / or prophylaxis of the abovementioned diseases.

The invention further relates to medicaments which contain one or more compounds of the formula I and / or their pharmacologically tolerable salts.

The pharmaceuticals are produced by methods known per se and familiar to the person skilled in the art. The pharmacologically active compounds (= active ingredients) according to the invention are used as pharmaceuticals either as such or preferably in combination with suitable pharmaceutical auxiliaries or carriers in the form of tablets, dragées, capsules, suppositories, plasters (for example as TTS), emulsions, suspensions or solutions used, the active substance content advantageously being between 0.1 and 95% and the galenic dosage form (for example a slow-release form or an enteric-resistant form) which is precisely adapted to the active substance and / or to the desired onset of action being achieved by the appropriate choice of auxiliaries and carriers can be.

The person skilled in the art is familiar with the auxiliaries or excipients suitable for the desired pharmaceutical formulations on the basis of his specialist knowledge. In addition to solvents, gel formers, suppository bases, tablet excipients and other active ingredients, for example antioxidants, dispersants, emulsifiers, defoamers, taste correctors, preservatives, solubilizers, dyes or in particular permeation promoters and complexing agents (e.g. cyclodextrins) can be used.

The active ingredients can be administered orally, parenterally or percutaneously. In general, it has proven advantageous in human medicine to give the active ingredient (s) when administered orally in a daily dose of about 0.01 to about 20, preferably 0.05 to 5, in particular 0.1 to 1.5 mg / kg of body weight , if necessary in the form of several, preferably 1 to 4 individual doses to achieve the desired result. In the case of parenteral treatment, similar or generally lower doses (in particular when the active compounds are administered intravenously) can be used. The determination of the respectively required optimal dosage and type of application of the active substances can easily be done by any expert on the basis of his specialist knowledge.

If the compounds and / or salts according to the invention are to be used for the treatment of the abovementioned diseases, the pharmaceutical preparations can also contain one or more pharmacologically active constituents of other groups of medicaments, such as antacids, for example aluminum hydroxide, magnesium aluminate; Tranquilizers, such as benzodiazepines, for example diazepam; Antispasmodics, e.g. Bietamiverin, Camylofin, Anticholinergica, e.g. Oxyphencyclimine, phencarbamide; Local anesthetics, e.g. Tetracaine, procaine; optionally also contain ferments, vitamins or amino acids.

In this context, the combination of the compounds according to the invention with pharmaceuticals which inhibit acid secretion, such as, for example, H blockers (for example cimetidine, ranitidine), H ⁺ / K ⁺ -ATPase inhibitors (for example omeprazole, pantoprazole), or furthermore with so-called peripheral agents, should be emphasized Antichol inergics (e.g. pirenzepin, telenzepin) as well as with gastrin antagonists with the aim of strengthening the main effect in an additive or superadditive sense and / or eliminating or reducing the side effects, or further the combination with antibacterially active substances (such as cephalosporins, Tetracyclines, nalidixic acid, penicillins or bismuth salts) to combat Helicobacter pylori. pharmacology

The excellent gastric protective effect and the gastric acid secretion-inhibiting effect of the compounds according to the invention can be demonstrated in studies on animal models. The compounds according to the invention investigated in the model listed below have been given numbers which correspond to the numbers of these compounds in the examples.

Testing the secretion-inhibiting effect on the perfused rat stomach

Table A below shows the influence of the compounds according to the invention after intravenous administration on the acid secretion of the perfused rat stomach stimulated by pentagastrin in vivo.

methodology

After tracheotomy, anesthetized rats (CD rat, female, 200-250 g; 1.5 g / kg in urethane) were opened using a median upper abdominal incision and a PVC catheter was transorally fixed in the esophagus and another via the pylorus in such a way that the tube ends just protruded into the stomach lumen. The catheter leading out of the pylorus led outwards through a lateral opening in the right abdominal wall. After thorough rinsing (approx. 50-100 ml), the stomach was continuously perfused with physiological NaCl solution at 37 ° C (0.5 ml / min, pH 6.8-6.9; Braun-Unita I). The pH value (pH meter 632, glass electrode EA 147; Φ = 5 mm, Metrohm) and the titration with a freshly prepared 0.01 N NaOH to pH 7 (Dosimat 665 Metrohm) were measured in the effluate collected every 15 minutes. the secreted HCl determined.

Gastric secretion was stimulated by continuous infusion of 1 pg / kg (= 1.65 ml / h) IV. Pentagastrin (V. fern, sin.) Approx. 30 min after the end of the operation (i.e. after determining 2 pre-fractions). The substances to be tested were administered intravenously in 1 ml / kg liquid volume 60 min after the start of the continuous pentagastrin infusion.

The body temperature of the animals was kept constant at 37.8-38 ° C by infrared radiation and heating pads (automatic, stepless regulation via rectal temperature sensor).

Claims

claims

1. Compounds of the formula I

wherein

R0 halogen or thiocyanate,

R1 1-4C-alkyl,

R2 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, halogen or trifluoromethyl,

R3 1-4C-alkoxy,

R4 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, halogen or trifluoromethyl,

R5 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy or halogen and

A means 0 (oxygen) or NH,

and their salts.

2. Compounds of formula I according to claim 1, in which

R0 bromine, chlorine or fluorine,

R1 1-4C-alkyl,

R2 1-4C-alkyl, chlorine or fluorine,

R3 1-4C-alkoxy,

R4 is hydrogen, R5 hydrogen and

A means 0 (oxygen) or NH,

and their salts.

3. Compounds of formula I according to claim 1, in which

R0 bromine or chlorine,

R1 1-4C-alkyl,

R2 1-4C-alkyl,

R3 1-4C-alkoxy,

R4 is hydrogen,

R5 hydrogen and

A means 0 (oxygen) or NH,

and their salts.

4. Compounds of formula I according to claim 1, wherein R0 is fluorine.

5. A process for the preparation of the compounds of the formula I according to claim 1 and their salts, characterized in that a) compounds of the formula II (see the enclosed formula sheet), in which R0, R1 and A have the meanings given according to claim 1, with Compounds of the formula III (see attached formula sheet), in which R2, R3, R4 and R5 have the meanings given according to Claim 1 and X represents a suitable leaving group, or in that b) for the preparation of compounds of the formula I in which RO Bromine or thiocyanate means compounds of the formula IV (see attached formula sheet), in which R1, R2, R3, R4, R5 and A have the meanings given according to Claim 1, with bromine and, if desired, subsequently with alkali thiocyanate and that if desired subsequently the compounds I obtained according to a) or b) are converted into their salts, or that, if desired, the compounds are subsequently obtained from the salts of the compounds I obtained gen I releases.

6. Medicament containing a compound according to claim 1 and / or a pharmacologically acceptable salt thereof together with conventional pharmaceutical auxiliaries and / or carriers.

7. Compounds according to claim 1 and their pharmacologically acceptable salts for use in the prevention and treatment of gastrointestinal diseases.

8. Use of compounds according to claim 1 and their pharmacologically acceptable salts for the manufacture of medicaments for the prevention and treatment of gastrointestinal diseases.