MXPA99005558A - The use of 7-(2-oxa-5,8-diazabicyclo[4.3.0]non-8-yl)-quinolone carboxylic acid and naphthyridon carboxylic acid derivatives for the treatment of helicobacter pylori infections and associated gastroduodenal diseases - Google Patents

Abstract

The invention relates to the use of quinolone and naphthyridon carboxylic acid derivatives, which are substituted by a 2-oxa-5,8-diazabicyclo[4.3.0]-non-8-yl-radical in position seven, as well as to their pharmaceutically applicable hydrates and/or salts in the treatment of Helicobacter pylori infections and associated gastroduodenal diseases.

Description

Use of derivatives of 7- (2-oxa-5 r8-di? *? I ci? -lof .3.01 non-8-yl) -quinolonecarboxylic acid and - naphthyridonecarboxylic acids for the therapy of Helicobacter-pylori and the sastroduodenal diseases associated with them The invention relates to the use of quinolone and naphthyridonecarboxylic acid derivatives which are substituted in the 7-position with a 2-oxa-5,8-diazabicyclo [4.3.0] non-8-yl radical, as well as its salts, for the therapy of Helicobacter-pylori infections and the gastroduodenal diseases associated with them. With the rediscovery of Helicobacter pylori (H. pylori, formerly Campylobacter pylori) by Warren and Marshall in 1983, the pathophysiological concepts about the etiology of human gastroduodenal diseases have been developed in the following years. H. pylori is considered the cause of type B gastritis and seems to play a causal role in the perpetuation of peptic ulcer disease. Epidemiological and pathological investigations also indicate a relationship between the prolonged colonization of the gastric mucosa by the bacteria and the formation of certain forms of gastric carcinoma. Therefore H. pylori was classified in 1994 as a first class carcinogen (category more REF .: 30522 dangerous cause of cancer). A rare stomach cancer, MALT lymphoma (mucosa-associated lymphoid tissue, lymphoid tissue associated with mucosa), also seems to be frequently caused by the germ. In the first casuistry, after the eradication of H. pylori, not only the reactive infiltrates but also a part of the malignant MALT lymphomas disappeared. Relationships with gastritis of giant folds are also discussed. The role of H. pylori in gastric irritation (non-ulcer dyspepsia) is not yet clear. Several epidemiological studies conclude that about half of the world population is infected with the bacteria. The risk of colonization of the stomach by Helicobacter increases with age. The optimal adaptation of Helicobacter to living conditions in the unique habitat of the stomach of low competition seems to be the condition for the successful establishment of chronic infection and the widespread spread of this pathogenic species.

The germs are very mobile with their flagella not only in medium but also in the viscous mucus of the gastric mucosa, adhere to the cells of the gastric epithelium and reproduce optimally with an oxygen content of 5%, such as the one that reigns in the mucosa of the gastric wall. In addition bacteria form large amounts of the enzyme urease, which dissociates urea into ammonia and carbon dioxide. Maybe the "ammonia cloud" that is formed helps them neutralize the acid medium in the microenvironment and thus protect from the aggressive gastric acid. Peptic ulcer disease The introduction of histamine H2 receptor antagonists represented a milestone in the therapy of peptic ulcer disease in the 1970s. The frequency of surgical interventions for the treatment of ulcerative ailments consequently decreased worldwide drastically. This principle of acid blockade was further improved with the development of the still more effective proton pump inhibitors. However, only the symptoms of the ulcerative disease can be influenced by the acid inhibitor therapy, not the natural course of the disease, which is characterized by the appearance of recurrences, whose causal treatment would be for the eradication of the germs. Thus, practically all patients with duodenal ulcers and the vast majority of patients with gastric ulcers have H. pylori infection of the stomach and consequently suffer from infectious diseases. Only ulcerations caused by non-steroidal antiphlogistics are not associated with H. pylori infection. Accordingly, according to the recommendations of a consensus conference held in 1994 by the American National Institute of Health (NIH), all patients with peptic ulcer who are detected germs they are treated with an eradication therapy directed against H. pylori (NIH Consensus Statement 1; 1-23; 1994). The controlled studies of therapy, in which it has been shown that after an effective eradication of germs, ulcer recurrence rates are drastically reduced (0% -29% versus 61% -95%), provide arguments for this. Therapy against H. pylori The current eradication of H. pylori is problematic in practice. There is no simple therapy available and, nevertheless, guaranteed efficacy. The germ is well protected and is difficult to attack under the layer of mucus. H. pylori is sensitive in vitro to numerous antibiotics. These are nonetheless ineffective in vivo as monotherapy. For this, among others are penicillin, amoxicillin, tetracycline, erythromycin, ciprofloxacin, metronidazole and clarithromycin. They also have antibacterial activity in vitro but not in vivo bismuth salts and to a small extent even proton pump inhibitors (omeprazole, lansoprazole). Among all the therapy modalities used so far for the eradication of H. pylori, only the following are sufficiently effective at present: 1. Triple therapy of classical bismuth (bismuth salt plus two antibiotics) 2. Modified triple therapy (acid inhibitor) plus two antibiotics).

However, these regimens are annoying eradication procedures with poor acceptance that can be accompanied in up to 35% of cases of side effects (stomach aches, nausea, diarrhea, dry mouth, taste disorders, allergic skin reactions, etc.). ). Consequently, extensive use is difficult. An even greater drawback is the high number of medications to be taken daily (12-16 tablets / day). The more tolerable dual therapy (combination of amoxicillin with omeprazole) that spread in Germany is however only ineffective and does not even seem to work to a large extent in patients previously treated with omeprazole and in flimers. In triple therapy, amoxicillin, nitroimidazole compounds (metronidazole, tinidazole), tetracycline as well as recent macrolides (clarithromycin) [in 3-4 partial doses] are usually administered as an antibiotic component. In all cases, eradication rates of 70-90% are achieved. However, several factors can affect the achievement of this eradication: 1. First of all it is worth mentioning the resistance of the germ (developing countries up to 60%, Germany: up to 10%) against metronidazole, the most frequently used antibiotic in the triple therapy. Claritromycin treatment also has the disadvantage of a Development of resistance of up to 10%. 2. Another factor to mention is the aforementioned acceptance by the patient. Animal model As a suitable animal model, a model of mouse H. felis has been described [A. Lee et al., Gastroenterology 99 1315-1323 (1990)] and modified by the applicant so as to be well suited to the selection and comparative evaluation of the aforementioned compounds. The urease-forming H. ureis bacteria similar to a corkscrew is, despite great morphological differences, very closely related to H. pylori. H. felis is a habitual inhabitant of the gastric mucosa of dogs and cats. After oral inoculation, the germs also colonize the stomach of the mice analogously to H. pylori in the human stomach. The established chronic prolonged infection leads in cats to active gastritis and induces a corresponding immune response. The therapeutic effectiveness of test preparations determined in the mouse H. felis model is considered in the literature as predictive of the corresponding clinical activity. Despite the very good in-vitro activity of antibiotics (eg amoxicillin or erythromycin) against H. pylori, they do not show any significant clinical therapeutic activity in monotherapeutic clinical use. This fact it is also reproduced in the mouse H. felis model. Correspondingly, the known clinical activity of eradication of classical triple therapy has also been confirmed in the model of H. felis in mice. European patent application 550 903 (Bayer) has already disclosed derivatives with antibacterial activity of 7- (2-oxa-5,8-diazabicyclo [4.3.0] non-8-yl) -quinolone and naphyridonecarboxylic. The surprising activity of such compounds to combat Helicobacter species has remained unknown until now. In the Japanese patent application JP 8048629 (Dainippon) it has been described that compounds such as 8-chloro-l-cyclopropyl-7- ([S, S] -2,8-diazabicyclo [4.3.0] non-8- il) -6-fluoro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid (BAY and 3118) exhibit an antibacterial activity against H. pylori. It is also known that a series of highly active quinolones, such as ciprofloxacin, lomefloxacin or ofloxacin (Journal of Antimicrobial Chemotherapy 22, 631-636 [1988], Antimicrobial Agents and Chemotherapy, 33, 108-109 [1989]) exhibit activity in vitro against Helicobacter species. However, in the animal model (Helicobacter felis, mouse) it is demonstrated that these quinolones with antibacterial activity used clinically in doses of therapeutic use are not capable of leading to an eradication of the germ. Neither by means of a monotherapeutic treatment with high activity quinolones, not introduced until now in the market, as per example with the aforementioned BAY and 3118, an eradication of H. felis can be achieved in the mouse model. The use of trovafloxacin or its derivatives in combination with other antibiotics such as amoxicillin or tetracyclines or proton pump inhibitors such as omeprazole for H. pylori therapy is described in patent applications EP 676 199 and GB 2 289 674 (Pfizer). It has therefore been a fundamental objective of the invention to find well-tolerable active principles that are capable of eradicating this highly specialized bacterium by means of simple monotherapy. It has now been found that compounds of general formula (I) wherein R1 represents alkyl of 1 to 4 carbon atoms, which may be mono- or disubstituted with halogen, phenyl optionally substituted with 1 or 2 fluorine atoms or cyclopropyl, optionally substituted with 1 or 2 fluorine atoms, R2 represents hydrogen, alkyl of 1 to 4 carbon atoms, optionally substituted by hydroxy, methoxy, amino, methylamino or dimethylamino or (5-methyl-2-oxo-l, 3-dioxol-4-) il) -methyl, A represents N or C-R3, where R3 represents hydrogen, halogen, methyl, methoxy, difluoromethoxy or cyano or can also together with R1 form a bridge of structure - * 0-CH2-CH-CH3 or - * 0- CH2-N-CH3, in which the atom marked with * is bonded to the carbon atom of A, R4 represents hydrogen, benzyl, C ^ C ^ alkyl (5-methyl-2-oxo-1, 3 -dioxol-4-yl) -methyl, structural residues -CH = CH-COOR5, -CH2CH2COOR5, -CH2CH2CN, -CH2CH2COCH3, -CH2COCH3, in which R5 represents methyl or ethyl, R6 represents hydrogen, amino, hydroxy, methyl or halogen, in the form of racemates, mixtures of diastereomers or as pure enantiomers or pure diastereomers, their hydrates and pharmaceutically usable acid addition salts, as well as the alkaline, alkaline earth, silver and guanidinium salts of the original carboxylic acids, have a high antibacterial activity against Helicobacter species and can be used for the eradication of these germs. Preferred are compounds of formula (I) in which R 1 represents tere-butyl, optionally mono- or disubstituted with fluorine or cyclopropyl optionally substituted with 1 fluorine atom, R 2 represents hydrogen, alkyl of 1 to 4 carbon atoms or (5-methyl-2-oxo-l, 3-dioxol-4-yl) -methyl, A represents C-R3, wherein R3 represents hydrogen, fluorine, methoxy, difluoromethoxy or cyano or can also be formed together with R1 a bridge of structure - * 0-CH2-CH-CH3 or - * 0-CH2-N-CH3, in which the atom marked with * is attached to the carbon atom of A, R represents hydrogen, Cj-Cs alkyl, remains of structures -CH2-CH2-COOR5, -CH2CH2CN, -CH2COCH3, in which R5 represents methyl or ethyl, R (represents hydrogen, amino or methyl, and their hydrates and pharmaceutically usable acid addition salts, as well as the alkali, alkaline earth salts , silver and guanidinium of the original carboxylic acids.

Especially preferred are compounds of formula (I) in which R 1 represents tere-butyl optionally mono- or disubstituted with fluorine or cyclopropyl, R 2 represents hydrogen, methyl or ethyl, A represents C-R 3, in which R 3 represents hydrogen, methoxy , difluoromethoxy or cyano or can also form together with R1 a bridge of structure - * 0-CH2-CH-CH3 or - * 0-CH2-N-CH3, in which the atom marked with * is attached to the carbon atom of A, R4 represents hydrogen or methyl, R6 represents hydrogen, and its hydrates and pharmaceutically usable acid addition salts, as well as the alkaline, alkaline earth, silver and guanidinium salts of the original carboxylic acids. The compounds which are suitable for use according to the invention are partly already known from the European patent application 550 903 as well as from German patent application 4 329 600 or can be prepared according to the methods described therein. If for example 9, 10-difluoro-3,8-dimethyl-7-oxo-2,3-dihydro-7H-pyrido- [1, 2, 3 -d, e] [1, 3, 4 ] benzoxadiazine-6-carboxylic acid and 2-oxa-5,8-diazabicyclo [4.3.0] nonane the course of the reaction can be represented by the following scheme of formulas: The 7-halogeno-quinolonecarboxylic acid derivatives used for the preparation of the compounds of the formula (I) according to the invention are known or can be prepared by known methods. Thus, 7-chloro-8-cyano-l-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid or the ethyl ester of 7-chloro-8-cyano-l-cyclopropy1-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid is described in European patent application 276 700. The corresponding 7 -Fluoro derivatives can be synthesized for example through the following sequence of reactions: The amines used for the preparation of the compounds of formula (I) according to the invention are known from the European patent applications 550 903, 551 653 as well as from DE 4309964. Examples of the compounds according to the invention are mention in addition to the compounds set forth in the preparation examples the compounds set out in Table 1 below, which can be used both in racemic form and also as pure enantiomeric compounds or pure diastereomers.

Table 1 The compounds according to the invention have a strong antibiotic activity and show, with low toxicity, a broad antibacterial spectrum against gram-positive and gram-negative organisms, but above all also against Helicobacter species. These valuable properties enable their use as active chemotherapeutic agents for the therapy of Helicobacter pylori infections and gastroduodenal diseases associated with them, which can be prevented, improved or cured with the compounds according to the invention. The compounds according to the invention can be used in various pharmaceutical preparations. Preferred pharmaceutical preparations are tablets, dragees, capsules, pills, granules, solutions, suspensions and emulsions. Although the compounds according to the invention can be used as monotherapeutic agents they can, if necessary, also be used in combination with other therapeutic agents. By way of example, the following are to be mentioned as companions in the combination: nitroimidazole derivatives, for example metronidazole; inhibitors of proton pumps, for example omeprazole, pantoprazole or lansoprazole; H2 receptor antagonists, such as for example cimetidine, ranitidine, famotidine or nizatidine; bismuth compounds, such as bismuth salicylate or CBS (subcitrate) of colloidal bismuth); other antibiotics, such as amoxicillin, azlocillin or clarithromycin; antacids The minimal inhibitory concentrations (MIC), which are set forth in Table 2 for some of the compounds according to the invention by way of example as compared to ciprofloxacin, were determined in the agar-agar dilution assay on Columbia or on agar. base 2 (Oxoid) with 10% horse blood lysed at pH 7 or pH 5 with 1 g / 1 urea. The test substances were tested in duplicate plates containing concentrations of the active principle respectively decreasing by double dilution. For the inoculation, fresh cultures of liquid culture Helicobacter or suspension of agar plate germs were used. The inoculated agar plates were incubated at 37 ° C in an atmosphere with 5-10% C02 for 48-72 hours. The MIC value (mg / l) determined indicates the minimum concentration of active principle at which no growth can be seen at a glance. The following Helicobacter isolates were used: H. felis ATCC 49179, H. pylori NCTC 11637, clinical isolate of H. pylori 008.

Ta í? -? - MIC values (mg / l) of some compounds according to the invention (agar dilution test) For the investigations in the animal model Swiss female mice (8 to 12 weeks old, SPF breed) with commercial feed and water were kept. For colonization, a defined H. felis strain was used (ATCC 49179). The bacteria were applied as suspension (0.1 ml with 108-109 bacteria) 4 times in the course of 7 days by esophageal tube. As an alternative to this, stomach homogenates from previously infected mice were also used for infection. After 3-5 days of establishment of the infection, treatment with the test preparations was started. As The first result of the treatment was the reduction of germs as "clearance" (clearance) 24 hours after the last treatment (for example days 3, 7, 10, 14, 1-3 times daily). In some cases, the eradication of the germ was also determined 2-4 weeks after treatment. According to the "CLO" test used in the clinical diagnosis, a urease test based on microtiter was used. The color change was tested within 24 hours of defined samples of stomach biopsy. In Table 3, the result of the therapy after a 7-day treatment of mice infected with 8-cyano-1-cyclopropi 1-6- acid is shown as an example of the surprisingly high in vivo activity of the compounds according to the invention. fluoro- 7- ((SS, 6S) -2-oxa-5,8-diazabicyclo [4.3.0] non-8-yl) -1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (Example IA) so as with 9-fluoro-3-methyl-10- acid. { (SS, 6S) -2-oxa-5,8-diazabicyclo [4.3.0] non-8-yl) -7-oxo-2,3-dihydro-7H-pyrido- [1,2,3-d, e] [1,3,4] benzoxadiazine-6-carboxylic acid (Example 2) compared to treatment with ciprofloxacin: while with ciprofloxacin under these test conditions no clearance was achieved, it reached 100% with the compliant compounds to the invention. A 14-day treatment of the mice with 2 x 10 mg / kg of 8-cyano-l-cyclopropyl-6-fluoro-7- ((SS, 6S) -2-oxa-5,8-diazabicyclo [4.3. 0] non-8-yl) -1,4-dihydro-4-oxo-3-quinolinecarboxylic acid even led to total eradication of the germ.

Table 3: Result of therapy after 7 days of treatment of infected mice (5 animals per group) Preparation of the intermediates Example 2 1 8-Cyano-l-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester to. 3-Bromo-2,4,5-trifluoro-benzoic acid methyl ester To a mixture of 1460 ml of methanol and 340 g of triethylamine were added dropwise under ice-cooling 772 g of 3-bromo-2, 4 fluoride. , 5-trifluoro-benzoyl. It followed stirring for 1 hour at room temperature. The reaction mixture was concentratedThe residue was suspended in water and methylene chloride and the aqueous phase was extracted once more with methylene chloride. After drying the organic phase over sodium sulfate, it was concentrated and the residue was distilled off in vacuo. 752.4 g of 3-bromo-2,4,5-trifluoro-benzoic acid methyl ester of boiling point 122 ° C / 20 mbar were obtained. b. 3-Cyano-2,4,5-trifluoro-benzoic acid methyl ester: 269 g of 3-bromo-2,4,5-trifluoro-benzoic acid methyl ester and 108 g of cyanide were heated under reflux for 5 hours. of copper in 400 ml of dimethylformamide. Then all volatile components of the reaction mixture were removed in vacuo. The distillate was then fractionated in a column. 133 g of 3-cyano-2,4,4-trifluoro-benzoic acid methyl ester of boiling point 88-89 ° C / 0.01 mbar were obtained. c. 3-Cyano-2,4,5-trifluoro-benzoic acid: A solution of 156 g of 3-cyano-2,4,5-trifluoro-benzoic acid methyl ester in 960 ml of acid was refluxed for 8 hours. Glacial acetic acid, 140 ml of water and 69 ml of concentrated sulfuric acid. The acetic acid was then removed thoroughly by vacuum distillation and the residue was mixed with water. The precipitated solid was filtered with suction, washed with water and dried. 118.6 were obtained g of 3-cyano-2,4,5-trifluorobenzoic acid as a white solid of melting point 187-190 ° C. d. 3-Cyano-2,4,5-trifluoro-benzoic acid chloride: They were stirred for 5 hours at room temperature by adding a few drops of dimethylformamide 111 g of 3-cyano-2,4,5-trifluoro-benzoic acid and 84 g of oxalyl chloride in 930 ml of dry methylene chloride. The methylene chloride was then removed and the residue distilled in vacuo. 117.6 g of 3-cyano-2,4,5-trifluoro-benzoyl chloride were obtained as a yellow oil. and. 2- (3-Cyano-2,4,5-trifluoro-benzoyl) -3-dimethylamino-acrylic acid ethyl ester: To a solution of 36.5 g of 3-dimethylamino-acrylic acid ethyl ester and 26.5 g of triethylamine in 140 ml of toluene was added dropwise a solution of 55 3-cyano-2,4,5-trifluoro-benzoic acid chloride so that the temperature remained between 50 and 55 ° C. Then, stirring was continued for 2 hours at 50 ° C. The reaction mixture was concentrated in vacuo and used without further processing in the next step. F. 2- (3-Cyano-2,4,5-trifluorobenzoyl) -3-cyclopropylamino-acrylic acid ethyl ester: 30 g of glacial acetic acid were added dropwise at 20 ° C to the reaction product from step e. Then a solution of 15.75 g of cyclopropylamine in 30 ml of toluene was added dropwise. The mixture was stirred for 1 hour at 30 ° C.

Then 200 ml of water were added to this, stirred for 15 minutes, the organic phase was separated and this was again extracted with 100 ml of water. The organic phase was then dried over sodium sulfate and concentrated in vacuo. The crude product thus obtained was used without further processing in the next step. g. Ethyl ester of 8-cyano-l-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid: The reaction product from step f and 27.6 g of potassium carbonate were stirred at 80 ° C. ml of dimethylformamide for 16 hours at room temperature. The reaction mixture was then poured into 750 ml of ice water, the solid was filtered off with suction and washed with 80 ml of cold methanol. After drying it, 47 g of 8-cyano-l-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester of melting point 209-211 ° C were obtained. Preparation of the active ingredients Example 1 A) 8-Cyano-l-cyclopropyl-6-fluoro-7- ((S, 6S) -2-oxa-5, 8-di-az-abi-cyclo-4, 3, 01-non-8-yl) -1 acid 4-dihydro-4-oxo-3-quinolinecarboxylic acid The mixture was stirred for 25 hours under argon at 40-45 ° C. 1.00 g (3.26 mmol) of 7-chloro-8-cyano-l-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo acid. -3-quinolinecarboxylic acid with 501 mg (3.91 mmol) of (1S, 6S) -2-oxa-5,8-diazabicyclo [4.3.0] nonane and 0.9 ml of triethylamine in 30 ml of acetonitrile. All volatile components were removed in vacuo and the residue was crystallized from ethanol. Yield: 1.22 g (94%) Melting point: 294 ° C (decomposition) B) 8-Cyano-l-cyclopropyl-6-fluoro-7- ((1S.6S) -2-oxa hydrochloride -5.8-diazabicyclo T4.3.01non-8-yl) -1,4-dihydro-4-oxo-3-quinolinecarboxylic acid. They were stirred for 2 hours under argon at 40-45 ° C in 3 ml of acetonitrile 200 mg (0, 63 mmol) of 8-cyano-l-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester with 97 mg (0.75 mmol) of (IS, 6S) -2-oxa-5,8-diazabicyclo [4.3.0] nonane and 0.17 ml of triethylamine. All the volatile components were removed in vacuo, the residue was mixed with water, the insoluble part was removed by filtration and the filtrate was extracted with dichloromethane. The organic phase was dried over sodium sulfate and then concentrated in vacuo. The resulting residue was dissolved in 6 ml of tetrahydrofuran and 2 ml of water and mixed with 30 mg (0.72 mmol) of lithium hydroxide monohydrate. After stirring for 16 hours at room temperature, it was acidified at room temperature with dilute hydrochloric acid and the The resulting precipitate was filtered with suction and dried. Yield: 155 mg (57%) Melting point: > 300 ° C Example 2 9-f luoro-3-methyl-10- ((ÍS.6S) -2-oxa-5,8-diazabicyclo.4.3.01non-8-yl) -7-oxo-2,3-dihydro-7H- acid pyrido ri, 2, 3-d, Q.3, 41-benzoxadiazine-6-carboxylic acid were heated in 3 ml of DMSO for one hour under argon at 120 ° C 100_mg (0.354 mmol) of 9,10-difluoro-3- acid Methyl-7-oxo-2, 3-dihydro-7H-pyrido [1,2,3-d, e] [1,3,4] benzoxadiazine-6-carboxylic acid with 91 mg (0.71 mmol) of , 6S) -2-oxa-5,8-diazabicyclo [4.3.0] nonane. The mixture was concentrated under high vacuum, the residue was crystallized from ethanol and dried. Yield: 106 mg (77% of theory) Melting point: 205 ° C (with decomposition) Example 3 1- (l-Fluoromethyl-l-methyl-2-fluoroethyl) -6-fluoro-7-r (1S, 6R) -2-oxa-5,8-diazabicyclo [4.3.01 non-8-ill -1] , 4-dihydro-4-oxo-3-quinolinecarboxylic acid A solution of 1- (1-fluoromethyl-l-methyl-2-fluoroethyl) -6,7-difluoro-l, 4-dihydro-4-oxo-3- acid quinolinecarboxylic acid (400 mg, 1.26 mmol), (SS, 6R) -2-oxa-5,8-diazabicyclo [4.3.0] nonane (176 mg, 1.39 mmol) and 1,4-diazabicyclo [2.2. 2] Octane (141 mg, 1.26 mmol) in absolute acetonitrile (20 ml) was heated to reflux overnight. After cooling the reaction mixture to room temperature, the precipitated crystals were separated by filtration and washed with actonitrile. Yield: 392 mg (73% of theory) Melting point: 245 ° C Example 4 1- (l-Fluoromethyl-l-methyl-2-fluoroethyl) -6-fluoro-7-r (IR, 6S) -2-oxa-5,8-diazabicyclo .4.3.0non-8-ill-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid The title compound was prepared analogously to that described in Example 3 by reaction with (IR, 6S) -2-oxa-5,8-diazabicyclo [4.3.0] nonane. Performance: 58% of the theory. Melting point: > 250 ° C Example 5 1- (Cyclopropyl) -6-fluoro-8-methoxy-7-r (lS-6R) -2-oxa-5,8-diazabicyclo4.3.01non-8-yl-1-l-4-dihydro-4-hydrochloride -oxo-3-quinolinecarboxylic The title compound was prepared analogously to described in Example 3 by reaction with (ÍS, 6R) -2-oxa-5,8-diazabicyclo [4.3.0] nonane. The crude product was purified by column chromatography (CH2Cl2 / MeOH / AcOH, 10: 5: 0.5), yielding the product as an acetate salt. After adding methanol and 1 N HCl and concentrating the solution in vacuo, the crystalline hydrochloride was obtained. Performance: 67% of the theory. Melting point: > 250 ° C Example 6 1- (Cyclopropyl) -6-fluoro-8-methoxy-7-r (IR, 6S) -2-oxa-5,8-diazabicyclohydrochloride .4.3.01 non-8-ill -1, 4-dihydro -4-Oxo-3-quinolinecarboxylic acid The title compound was prepared analogously to that described in Example 5 by reaction with (IR, 6S) -2-oxa-5,8-diazabicyclo [4.3.0] nonane. Performance: 37% of the theory. Melting point: > 250 ° C Example 7 1- (cis-2-fluorocyclopropyl) -6,8-difluoro-l, 4-dihydro-7- (5S-2-oxa-5,8-diazabicyclo [4.3.01non-8-yl] -4 acid -oxo-3-quinolinecarboxylic acid A mixture of 3.6 g (12 mol) of l- (cis-2-fluorocyclopropyl) -6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid in 50 ml of acetonitrile and 25 ml of dimethylformamide with 3.36 g (30 mol) of 1,4-diazabicyclo [2.2.2] octane and 3.7 g (12.8 mmol) of IS, 6S-2-dibromide. -oxa-5,8-diazabicyclo [4.3.0] nonane was heated to reflux for 1 hour. The mixture was concentrated, the residue was mixed with a little water and treated for 30 minutes in an ultrasonic bath. The undissolved precipitate was filtered with suction, washed with water and dried under high vacuum at 80 ° C. Yield: 4.2 g (86% of theory) Melting point: 274-276 ° C (with decomposition).

Example 8 Acid l-cyclopropyl-8-difluoromethoxy-6-f luoro-1,4-dihydro-7- ((S6S) -2-oxa-5,8-diazabicyclo .4.3.01 non-8-yl) - 4-oxo-3-quinolinecarboxylic acid A mixture of 166 mg (0.5 mmol) of 1-cyclopropyl-8-difluoromethoxy-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid in 1 , 5 ml of acetonitrile and 0.75 ml of dimethylformamide with 73 mg (0.65 mmol) of 1,4-diazabicyclo [2.2.2] octane and 100 mg (0.78 mmol) of IS, 6S-2-oxa -5,8-diazabicyclo [4.3.0] nonane was heated to reflux for 1 hour. The mixture was concentrated, the residue was mixed with a little water and treated for 20 minutes in an ultrasonic bath. The undissolved precipitate was filtered with suction, washed with water and dried under high vacuum at 80 ° C. Yield: 164 mg (75% of theory) Melting point: 209-211 ° C (with decomposition). [] D25: -250 ° (c = 0.25, DMF).

Example 9 Analogously as in Example 8, 1-cyclopropyl-8-difluoromethoxy-6-f-luoro-1,4-dihydro-7- ((S, 6R) -2-oxa-5,8-diazabicyclo acid was obtained. 4.3.0] on-8-yl) -4-oxo-3-quinolinecarboxylic acid of Melting point: 181-182 ° C (with decomposition). [a] D25EQ: -23 ° (c = 0.25, DMF). Example 10 Analogously as in Example 8, 1-tert-butyl-6-fluoro-1,4-dihydro-7- ((SS, 6R) -2-oxa-5,8-diazabicyclo [4.3.0] was obtained. non-8-yl) -4-oxo-3-quinolinecarboxylic acid of Melting point: 224-226 ° C (with decomposition). [a] D25: + 70 ° (c = 0.25, DMF) Example 11 Analogously as in Example 8, 6-fluoro-1- (fluoro-tert-butyl) -1,4-dihydro-7- ((S, 6R) -2-oxa-5,8-diazabicyclo acid was obtained. [4.3.0] non-8-yl) -4-oxo-3-quinolinecarboxylic acid from Melting point: 243-244 ° C (with decomposition). [c.] D25: + 71 ° (c = 0.25, DMF) Example 12 Acid 8-cyano-l-cyclopropyl-6-fluoro-7- ((IR, 6R) -2-oxa-5,8-diaz bicichlor4.3.01 non-8-yl) -1, 4-dihydro-4-oxo -3-quinolinecarboxylic acid The title compound was prepared analogously to that described in Example 1. Melting point: 294 ° C [] D27: + 103.6 ° (c = 0.33, 1 N NaOH) Example 13 L-Cyclopropyl-6-fluoro-8-methoxy-7- ((SS, 6S) -2-oxa-5,8-diazabicyclo4.3.01non-8-yl) -1,4-dihydro-4-hydrochloride oxo-3-quinolinecarboxylic acid The title compound was prepared analogously to that described in Example 5 by reaction with (S, 6S) -2-oxa-5,8-diazabicyclo [4.3.0] nonane. The crude product was purified by column chromatography (CH2Cl2 / MeOH / AcOH, 10: 5: 0.5), yielding the product as an acetate salt. After adding methanol and 1 N HCl and concentrating the solution in vacuo, the crystalline hydrochloride was obtained. Melting point: > 250 ° C Example 14 Acid 6- luoro-l- ((1R, 2S) -2-f luorocyclopropyl) -7- ((ÍS, 6S) -2-oxa-5,8-diazabicyclo.4.3.01non-8-il) -1.4- dihydro-4- oxo-3-quinolinecarboxylic acid The title compound was prepared analogously to that described in Example 8 by the reaction of 6,7-difluoro-1- ((1R, 2S) -2-fluorocyclopropyl) -1,4-dihydrogen -4-oxo-3-quinolinecarboxylic acid with (SS, 6S) -2-oxa-5,8-diazabicyclo [4.3.0] -nonano. Melting point: > 250 ° C Examples 15-21 Analogously as in Example 8 using (IR, 6S) -2-oxa-5,8-diazabicyclo [.3.0] nonane, the following compounds were obtained, which were isolated in part as hydrochlorides by dissolution in semi-concentrated hydrochloric acid, evaporation and treatment with ethanol: Example 15 6-Fluoro-l- (cis-2-fluorocyclopropyl) -1,4-dihydro-7- ((IR, 6S) -2 -oxa-5,8-diazabicyclo [4.3.0] non-8- acid il) -4 -oxo-3-quinolinecarboxylic acid (A = CH), Melting point: 236-238 ° C (with decomposition); Example 16 6,8-difluoro-1- (cis-2-fluorocyclopropyl) -1,4-dihydro-7- ((IR, 6S) -2-oxa-5, 8- hydrochloride diazabicyclo [4.3.0] non-8-yl) -4-oxo-3-quinolinecarboxylic acid (A = CF; x HCl), Melting point: 275-280 ° C (dec.); Example 17 8-Chloro-6-fluoro-l- (cis-2-fluorocyclopropyl) -1,4-dihydro-7- ((IR, 6S) -2-oxa-5,8-diazabicyclohydrochloride [4.3. 0] non-8-yl) -4-oxo-3-quinolinecarboxylic acid (A = CCl; x HCl), Melting point: 210-215 ° C (with decomposition); Example 18 6-F luoro-1- (cis-2-fluorocyclopropyl) -1,4-dihydro-7- ((IR, 6S) -2-oxa-5,8-diazabicyclo [4.3.0] non-hydrochloride - 8-yl) -4-oxo-l, 8-naphthyridine-3-carboxylic acid (A = N; x HCl), Melting point: 281-284 ° C (with decomposition); Example 19 6-Fluoro-l- (trans-2-fluorocyclopropyl) -1,4-dihydro-7- ((IR, 6S) -2-oxa-5,8-diazabicyclo [4.3.0] non-8- acid il) -4-oxo-3-quinolinecarboxylic acid (A = CH), melting point: 270-274 ° C (with decomposition); Example 20 8-Chloro-6-fluoro-l- (trans-2-fluorocyclopropyl) -1,4-dihydro-7- ((IR, 6S) -2-oxa-5,8-diazabicyclo [4.3.0] acid non-8-yl) -4-oxo-3-quinolinecarboxylic acid (A = CCl), Melting point: 160-164 ° C (dec.); Example 21 6-Fluoro-l- (trans-2-fluorocyclopropyl) -1,4-dihydro-7- ((IR, 6S) -2-oxa-5,8-diazabicyclo [4.3.0] non-8-il) -4-oxo-l, 8-naphthyridine-3-carboxylic acid (A = N), Melting point: 310-314 ° C (with decomposition). It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is the conventional one for the manufacture of the objects or products to which it refers.

Claims (8)

CLAIMS Having described the invention as above, the content of the following claims is claimed as property:

1. Use of compounds of general formula (I) characterized in that: R1 represents alkyl of 1 to 4 C atoms, optionally mono- or disubstituted with halogen, phenyl optionally substituted with 1 or 2 fluorine atoms or cyclopropyl optionally substituted with 1 or 2 fluorine atoms, R2 represents hydrogen, optionally substituted alkyl of 1 to 4 carbon atoms with hydroxy, methoxy, amino, methylamino or dimethylamino or (5-methyl-2-oxo-l, 3-dioxol-4-yl) -methyl, A represents N or C-R3, in which R3 represents hydrogen, halogen, methyl, methoxy, difluoromethoxy or cyano or can also form together with R1 a bridge of structure - * 0-CH2-CH-CH3 or - * 0- CH2-N- CH3, in which the atom marked with * is attached to the carbon atom of A, R4 represents hydrogen, benzyl, Cj-Ca alkyl, (5-methyl-2-oxo-1,3-dioxol-4-yl) -methyl, remains of structures -CH = CH-C00R5 , -CH2CH2COOR5, -CH2CH2CN, -CH2CH2C0CH3, -CH2COCH3, wherein R5 represents methyl or ethyl, R6 represents hydrogen, amino, hydroxy, methyl or halogen, in the form of racemates, mixtures of diastereomers or as pure enantiomers or pure diastereomers , its hydrates and acid addition salts. pharmaceutically usable, as well as the alkaline, alkaline earth, silver and guanidinium salts of the original carboxylic acids, for the therapy of Helicobacter pylori infections and the gastroduodenal diseases associated with them.

2. Use of compounds of formula (I), characterized in that: R1 represents tere-butyl, optionally mono- or disubstituted with fluorine or cyclopropyl optionally substituted with 1 fluorine atom, R2 represents hydrogen, alkyl of 1 to 4 carbon atoms or (5-methyl-2-oxo-l, 3) -dioxol-4-yl) -methyl, A represents C-R3, in which R3 represents hydrogen, fluorine, methoxy, difluoromethoxy or cyano or can also form together with R1 a bridge of structure - * 0-CH2-CH-CH3 or - * 0-CH2-N-CH3, in which the atom marked with * is attached to carbon atom of A, R4 represents hydrogen, C, - ^ alkyl, structural residues -CH2-CH2-COOR5, -CH2CH2CN, -CH2COCH3, in which R5 represents methyl or ethyl, R6 represents hydrogen, amino or methyl, and their hydrates and pharmaceutically usable acid addition salts, as well as the alkaline, alkaline earth, silver and guanidinium salts of the original carboxylic acids, for the therapy of Helicobacter pylori infections and the gastroduodenal diseases associated therewith.

3. Use of compounds of formula (I), characterized in that: R 1 represents tere-butyl optionally mono- or disubstituted with fluorine or cyclopropyl, R 2 represents hydrogen, methyl or ethyl, A represents C-R 3, in which R 3 represents hydrogen, methoxy , difluoromethoxy or cyano or can also form together with R1 a bridge of structure - * 0-CH2-CH-CH3 or - * 0-CH2-N-CH3 / in which the atom marked with * is attached to the carbon atom of A, R4 represents hydrogen or methyl, R6 represents hydrogen, and their hydrates and pharmaceutically usable acid addition salts, as well as the alkaline, alkaline earth, silver and guanidinium salts of the original carboxylic acids, therapy of Helicobacter pylori infections and gastroduodenal diseases associated with them.

4. Use of pure diastereomeric compounds and enantiomers cr-n-rore pouches to r-dvjurt-ücrrp (t-5s 1 to 3 ca - to - t - = ------ zacb pa-that is for therapy of Helicobacter pylori infections and gastroduodenal diseases associated with them.

5. Use of 8-cyano-l-cyclopropyl-6-fluoro-7- ((SS, 6S) -2-oxa-5,8-diazabicyclo [4.3.0] non-8-yl) -1,4-dihydro acid -4-c «p-3-jp.t > 1 inreytrr.il ipr? saa-at -? --- r - za-b perqué is paca la 1. = *. ^ -..- de -infe ------ nes per Helicobacter pylori and gastroduodenal diseases associated with them.

6. Pure diastereomeric compounds and pure enantiomers carac -------------- cs pa-qe sa-ecocna of the groups that you caisiste in: 8-cyano-l-cyclopropyl-6-f luoro-7 acid - (2-oxa-5,8-diazabicyclo [4.3.0] non-8-yl) -1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, l-cyclopropyl-8-difluoromethoxy-6-f luoro -1,4-dihydro-7- (2-oxa-5,8-diazabicyclo [4.3.0] non-8-yl) -4-oxo-3-quinolinecarboxylic acid.

7. The acid 8-cyano-l-cyclopropyl-6-f luoro-7- ((SS, 6S) -2-oxa-5,8-diazabicyclo [4.3.0] non-8-yl) -1,4-dihydro -4-oxo-3-quinolinecarboxylic acid.

8. Use of 8-cyano-l-cyclopropyl-6-fluoro-7- ((SS, 6S) -2-oxa-5,8-diazabicyclo [4.3.0] non-8-yl) -1,4-dihydro acid -4-oxo-3-quinolinecarboxylic acid. 9 ^ Md-tt-anailX-ß, cacaterizabs because acpfcLa-en ar-idn 8-CT- = r? Ol-cyclopropyl-6-f luoro-7- ((ÍS, 6S) -2-oxa-5, 8 -diazabicyclo [4.3.0] non-8-yl) -1,4-dihydro-4-oxo-3-quinolinecarboxylic acid.