5-fluoro-2-*01([(4-cyclopropylmethoxy-2-pyridinyl)methyl] sulfinil*01)-1h-benzimidazole or its physiologically acceptable salt, farmcampsite on its basis and intermediate compounds

 

(57) Abstract:

Usage: as a therapeutic agent for the prevention and treatment of peptic ulcers. The inventive product-5-fluoro-2-{[(4-cyclopropylmethoxy-2-pyridinyl)methyl] sulfinil} -benzimidazole or a physiological acceptable salt, e.g. the sodium or magnesium salt, C17 W16 FN2 02 S, the yield of 69%. Reagent 1: 5-fluoro-2-{[(4-cyclopropylmethoxy-2-pyridinyl)methyl] thio} -1H-benzimidazole. Reaction conditions: in the presence of aqueous NaHCO3. 7C. and 2H. p. F.-ly, 1 table.

The aim of the invention is to obtain a new compound and its therapeutically acceptable salts, which are exogenous and endogenous inhibit excessive secretion of gastric acid and thus can be used for the prevention and treatment of peptic ulcers.

The present invention also relates to the use of the proposed connection, especially its therapeutically acceptable salts for inhibiting secretion of gastric acid in mammals, including man. In a more General sense, the proposed connection can be used for the prevention and treatment of inflammatory diseases of the gastrointestinal tract and diseases, swapdwordtointel ulcer, replacethat and ulcerogenic adenoma of the pancreas. Moreover, the proposed connection can be used to treat other gastrointestinal pathologies that require antisecretory effect on gastric acid, for example in patients suffering from ulcerogenic adenoma of the pancreas and patients with gastrointestinal bleeding. It can also be used for patients in cases of intensive therapy, and pre - and postoperative periods to prevent aspiration of acid and formation of ulcers. The proposed connection can also be used for the treatment and prevention of inflammatory processes in mammals, including humans, particularly processes related to lysosomally enzymes. K such diseases that can be specified include rheumatoid arthritis and gout. The proposed connection can also be used in the treatment of diseases associated with metabolic disorders in the bones, as well as the treatment of glaucoma.

The present invention also relates to medicinal preparations on the basis of the claimed compounds or pharmaceutically acceptable salts, used as an active ingredient. In another aspect of nasienia in the process of obtaining the proposed connection and use it as an active ingredient in medicinal preparations for medical use according to the testimony, above.

The main objective of the present invention receiving the connection with high biological availability. The proposed connection also has a high stability at neutral pH and relatively high activity of inhibiting secretion of gastric acid.

Bioavailability is defined as a fraction or percentage of injected dose of a compound that enters the bloodstream, not undergoing changes. Efficiency in this application is defined as the index ED50.

Derivatives of benzimidazole, intended for inhibiting the secretion of gastric acid, are disclosed in numerous patent documents, among which you can specify patents great Britain N 1500043, 1525958, USA N 4182766, 4255431, 4599347, 555518, 4727150, 4629098, Europatent N 208452 and abstracts journal Derwent 87 294449/42. Derivatives of benzimidazole, proposed for the treatment and prevention of inflammatory diseases of the gastrointestinal tract are disclosed in U.S. patent N 4539465.

Compounds disclosed in the above patents, are effective inhibitors of acid secretion, and thus their use as antiulcer agents.

For dapoli, and furthermore, these compounds should have high activity in the inhibition of the secretion of gastric acid, as well as high chemical stability at neutral pH.

During the tests found that 2-[(2-pyridinylmethyl)sulfinil]-1H-benzimidazole find a strong variation in bioavailability and activity and stability, and it is difficult to establish connections with all three of these properties. In the known technical solutions there are no data regarding the method of obtaining compounds with the above combination of properties.

The proposed connection, as it shows an extremely high bioavailability, and at the same time it is very effective as an inhibitor of the secretion of gastric acid and shows high chemical stability in solution at neutral pH. Thus, the proposed connection you can use if the above symptoms of diseases in mammals, including humans.

The proposed connection is a 5-fluoro-2-[[4-cyclopropylmethoxy-2-pyridinyl)methylsulfinyl] ) -1H-benzimidazole (compound I) and its physiologically acceptable salts. The proposed connection of owls). In the scope of the present invention includes both a pure enantiomer, racemate (containing 50% of each of these enantiomers) and non-equilibrium mixture of both. In the scope of the present invention also includes 4 synthetic intermediate compounds and the method of obtaining.

Getting

The proposed connection can be obtained in accordance with the following method.

Carry out the oxidation of 5-fluoro-2-[(4-cyclopropylmethoxy-2-pyridinyl)methyl] -thio-1H-benzimidazole (compound (II) to obtain the proposed connection. The oxidation can be performed using an oxidizing agent such as nitric acid, hydrogen peroxide (possibly in the presence of vanadium compounds), nagkalat, esters of nakilat, ozone, attaway anhydride, iodobenzoyl, N-galijasevic succinimide, 1-chlorobenzotriazole, tert-butyl hypochlorite, diazabicyclo[2,2,2] -octane bromine complex, metaperiodate sodium dioxide village dioxide magnesium, chromic acid, nitrate of cereomony, chloride, bromine, chlorine or Sulfuryl. The oxidation is usually carried out in a solvent, for example galijasevic hydrocarbons, alcohols, ethers, ketones.

The oxidation reaction can also be carried out by enzymatic method with use of the Sabbath.">

Depending on the process conditions and starting materials of the proposed connection are given either in the form of a neutral compound or as a salt. In the scope of the present invention is included as a neutral compound, and salt. Thus, you can get basic, neutral or mixed salts, and Hemi-, mono, Sesqui - or polyhydrate.

Alkali metal salts of the proposed connection presents its salts with Zi+, Na+, K+, Mg2+Ca2+and N+(R), where R is C1-4alkyl. Especially preferred salts with the cation Na+Ca2+and Mg2+. And the most preferred salt with the cation Na+and Mg2+. Such salts can be obtained by the interaction of the compounds of the present invention with the base, is able to give the desired cation. Examples of such bases and examples of the reaction conditions.

a) Salt in which the cation is Li+, Na+or K+produced by processing the proposed connection LiOH, NaOH or KOH in aqueous or anhydrous environment or using LiOR, LiNH2, LiNR2, NaNH, NaNR2, KOR, KNH2or NR2where R means1-C4-alkyl, in an anhydrous environment. b) R), Ca(OR)2or San, where R is C1-C4alkyl in an anhydrous solvent, for example, alcohol (only for alcoholate), for example, ROH, either a simple or an ether, such as tetrahydrofuran.

Resulting racemates can be divided into pure enantiomers. This operation can be performed with known methods, for example, from racemic diastereoisomeric salts by chromatography or fractional crystallization.

Source materials disclosed in the examples of the preparation of the intermediate compounds can be obtained by known methods reg se.

For use in clinical conditions of the proposed connection prepared as pharmaceutical compositions for oral, rectal, parenteral or other method. The drug include the proposed connection usually in combination with a pharmaceutically acceptable carrier. The specified media may be in the form of solid, semi-solid or liquid diluent or in the form of capsules. These drugs represent another object of the present invention. Usually the amount of active compound ranges from 0.1 to 95 wt. all of the preparation, from 0.2 to 20 wt. in drugs research Institute of pharmaceutical compounds based on the proposed connection in the form of single doses for oral administration selected compound can be mixed with solid, powdered carrier such as lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose derivatives, gelatin, or another suitable carrier, stabilizer, such as alkaline compounds, such as carbonate, hydroxide or oxide of sodium, potassium, calcium, magnesium and the like, as well as oiling agents, such as magnesium stearate, calcium stearate, sodium fumarate and polietilenglikolya waxes. The mixture is then processed into granules or pressed into tablets. Granules and tablets can be coated intersolubility shells that protect the active compound from the acid catalyzed decomposition up until the dosage form is retained in the stomach. Intersolubility floor choose among pharmaceutically suitable materials for use as intersolubility shell, such as bee wax, alkaline or anionic film-forming polymers, such as phthalate cellulose acetate, hydroxypropyl-methylcellulose phthalate, polymers based on partial methyl ester of methacrylic acid and the like, optionally in combination with a suitable plasticizer. In these coatings, you can enter different dyes for equal connection.

Soft gelatin capsules can be obtained with capsules with a mixture consisting of the active compounds of the present invention, vegetable oil, grease or other media suitable for soft gelatin capsules. These capsules can also cover intersolubility shell, as discussed above. Hard gelatin capsules may contain granules or coated intersolubility shell granules with the proposed connection as an active start. Hard gelatin capsules may also include the proposed active compound in combination with a powdered solid carrier, for example lactose, saccharose, sorbitol, mannitol, potato starch, amylopectin, cellulose derivatives or gelatin. Hard gelatin capsules can be coated with the above intersolubility shell.

Dosage forms for rectal injection can be prepared in the form of suppositories containing the proposed active compound in a mixture with a neutral base of the fatty series, or you can get them in the form of gelatin capsules, rectal insertion, containing the compound as an active start in a mixture with vegetable, paraffin is related drugs can also be prepared in a form ready for use microclysters, either in the form of a dry composition for micro, which before use diluted in an appropriate solvent.

Liquid preparations for oral administration can be prepared in the form of syrups, suspensions, for example solutions, suspensions, containing from 0.2 to 20 wt. the active component, and the rest is sugar or alcohols and a mixture of ethanol, water, glycerol, propylene glycol and/or polyethylene glycol. If desired, these liquid preparations may include colorants, flavouring agents, saccharine and carboxymethyl cellulose or other thickeners. Liquid preparations for oral administration can also be obtained in the form of a dry powder, which before use is diluted with a suitable solvent.

Solutions for parenteral administration can be obtained in the form of a solution containing the proposed connection in a pharmaceutically acceptable solvent, preferably at a concentration of from 0.1 to 10 wt. These solutions may also include stabilizers and/or buffers and can be released into ampoules or vials with different therapeutic single doses. Solutions for parenteral administration can also be prepared in the form of a dry preparation that before using diluting the various factors, for example, the individual characteristics of each patient, route of administration and the disease. Usually dosage for oral and parenteral administration is 5 to 500 mg of active ingredient per day.

The invention is illustrated in the following examples.

Getting 5-fluoro-2[[4-cyclopropylmethoxy-2-pyridinyl)methyl] sulfinil] -1H-benzimidazole.

5-fluoro-2[[4-cyclopropylmethoxy-2-pyridinyl)methyl] sulfinil]-1H-benzimidazole (1,25 g, 0,0036 mol) is dissolved in CH2Cl2(40 ml). To the resulting solution was added NaHCO3(0.6 g 0,0072 mol) dissolved in water (20 ml) and the resulting mixture is cooled to 2oC. With stirring was added m-chlormadinone acid, 84 (0.73 g, 0,0036 mol) dissolved in CH2Cl2(5 ml). Stirring is continued at room temperature for 15 minutes the Resulting two phases are separated and the organic layer was added NaOH (0.29 grams, 0,0072 mol) dissolved in N2O (25 ml). The resulting mixture is stirred, the resulting layers are separated and the aqueous phase is treated with noricum and then filtered. With stirring, added dropwise methyl ester of formic acid (0.45 ml, 0,0073 mol) dissolved in N2O (5 ml). After extraction of CH2

Example 2

Getting 5-fluoro-2[[4-cyclopropylmethoxy-2-pyridinyl)methyl] sulfinil] -1H-benzimidazole, sodium salt of 5-fluoro-2[[4-cyclopropylmethoxy-2-pyridinyl)methyl] sulfinil]-1H-benzimidazole (5 g, 14.5 mmol) dissolved in dichloromethane (100 ml), and sodium hydroxide (0.56 g, 14.5 mmol) dissolved in water (100 ml), placed in a separating funnel.

The resulting mixture was stirred by shaking until a homogeneous state, then the resulting phase solvents share. The aqueous solution was washed with dichloromethane (I ml) and then dried by freezing. The residue is recrystallized from a solvent mixture of dichloromethane /diethyl ether to obtain 3.7 g (71%) of the named compound. The following data shows the NMR analysis.

The intermediate compounds

Example 1.1

Getting 4-cyclopropylmethoxy-2-methylpyridine-1-oxide.

To sodium hydride (55 purity, 4.4 g, 0.1 mol), washed with petroleum ether, added cyclopropylmethanol (50 ml). Then for 1 h to the resulting solution was added 2-methyl-4-nitropyridine-N-oxide (6.5 g, 0,042 mol) in cyclopropylmethanol (30 ml). The obtained dark brown, the ethanol is distilled off under reduced pressure and then adding to the residue methylene chloride (100 ml). The resulting mixture is stirred for about 30 min, then filtered and evaporated to yield 9.5 g of the crude product.

The crude product is purified flash chromatography on silica using as eluent a mixture of methylene chloride/methanol (90/10). The result is 4.0 g (53%) of pure titled compound. The following data shows the NMR analysis.

Example 1.2.

Getting 2-acetoxymethyl-4-cyclopropylmethoxy.

4 Cyclopropylmethoxy-2-methylpyridine-1-oxide (3.8 g, 0,021 mol) is dissolved in acetic anhydride (10 ml) and then added dropwise to acetic anhydride (20 ml), heated to 90oS, after which the temperature of the mixture was raised to 110oWith, and then it is stirred at a temperature of 110oC for 1 h Then the solvent is distilled off and the resulting crude product is used without purification. The following data shows the NMR analysis.

Example 1.3.

Getting 4-cyclopropylmethoxy-2-hydroxymethylpropane.

To crude 2-acetoxymethyl-4-cyclopropylmethoxy added NaOH (100 ml, 2M) and the mixture is boiled to reflux for 2 hours Then the mixture is extracted with methylene chloride, and the image of the ü is distilled to yield 2.7 g of the crude titled compound. The following data shows the NMR analysis. The crude product is used without any additional purification.

Example 1.4.

Getting 4-cyclopropylmethoxy-2-chloromethylpyridine hydrochloride.

4 cyclopropylmethoxy-2-hydroxymethylamino pyridine (93% purity, 0.9 g, 0,0046 mol) is dissolved in methylene chloride (10 ml) and cooled to 0oC. To the resulting solution was added dropwise l2(0.5 ml, 0,0069 mol) in methylene chloride (5 ml) at a temperature of 0oC, and the reaction mixture stirred for 15 min at room temperature for 15 minutes Add isopropanol (0.5 ml) and after evaporation of the mixture get the desired product (0.68 g, 78). The following data shows the NMR analysis.

Example 1.5.

Getting 5-fluoro-2[[(4-cyclopropylmethoxy-2-pyridinyl)methyl]-thio] -1H-benzimidazole used as the starting material.

To 5-fluoro-2 - mercapto-1H-benzimidazole (0.88 g, 0,0051 mol) in methanol (25 ml) was added sequentially with NaOH (0.2 g, 0,0051 mol) dissolved in water (1 ml), and 4-cyclopropylmethoxy-2-chlormethiazole pyridine hydrochloride (0,91 g, 0,0046 mol) dissolved in methanol (10ml). The resulting mixture is heated to boiling, add NaOH (0.2 g, of 0.005 mol) dissolved in water (1 is>
(75 ml) and N2O (50 ml) to bring the pH to 10. The mixture is intensively stirred, the resulting phases are separated, the organic layer is dried over Na2SO4and after evaporation obtain the desired product (1.25 g, 72). The following data shows the NMR analysis.

Best mode for carrying out the invention known at present is to use the sodium salt of the proposed compounds described in example 2.

Pharmaceutical preparations containing the compound of the present invention as an active start, is illustrated in the following recipes.

The syrup.

Syrup, containing 1% (wt. volume) of the active substance, is obtained on the basis of the following ingredients:

The compound of example 1 1,0

Sugar, powder 30,0

Saccharin 0,6

Glycerin 5,0

Odorant 0,05

Ethanol 96% 5,0

Distilled water g.S. to a final volume of 100 ml

Sugar and saccharin dissolved in 60 g of warm water. After cooling, the active compound is added to the sugar solution, and then add to the resulting mixture of glycerol and the solution containing the aromatic additives in ethanol. The mixture was diluted with water to a final volume of 100 ml.

The table is strong shell, get on the basis of the following ingredients, g

1. The compound of example 1 in the form of a Mg salt 500

lactose 700

the methylcellulose 6

crosslinked polyvinylpyrrolidone 50

magnesium stearate 15

sodium carbonate 6

distilled water g.S

phthalate cellulose acetate 200

cetyl alcohol 15

isopropanol 2000

methylene chloride 2000

The compound of example 1, the powder is mixed with lactose and granularit using an aqueous solution of methylcellulose and sodium carbonate. The wet mass is passed through a sieve, and the resulting granulate is dried in an oven. After drying, the granulate is mixed with polyvinylpyrrolidone and magnesium stearate. The dry mixture is pressed into the matrix tablets (10,000 tablets), each tablet contains 50 mg of active substance in tablet press machine with 7 mm punch.

II. The solution containing phthalate cellulose acetate and cetyl alcohol in isopropanol/methylene chloride is sprayed onto the tablets in a device for producing coatings company ccela CotaR, Manesty. Get a tablet weight of 110 mg.

Solution for intravenous infusion.

The composition for parenteral, intravenous infusion, containing 4 mg of the active ingredient in 1 ml, get n ml

The active compound is dissolved in water to obtain a final volume of 1000 ml, the Solution is filtered through 0.22 μm filter and immediately poured into 10 ml ampoules. Vials hermetically sealed.

The capsule.

Capsules containing 30 mg of active compound, is obtained on the basis of the following ingredients:

Connection example 1 300

Lactose 700

Microcrystalline cellulose

40

Partially substituted hydroxypropylcellulose 62

Dinatriumfosfaatti 2

Distilled water g.S.

The active compound is mixed with the dry ingredients and granularit using a solution containing dinatriumfosfaatti. The wet mass is passed through an extruder to obtain pellets (granules), which are dried in the dryer fluidized bed.

500 g of the above granules were immersed in the solution containing 30 g hydroxypropylamino methylcellulose in 750 g of water to obtain a first coating layer using a machine for coating using a fluidized bed. After drying, the granules cover the second coating layer, the composition of which is given below:

Solution to obtain a coating

Phthalate hydroxypropylamino methylcellulose in capsules.

Suppositories.

Suppositories are derived from the following ingredients using the method of stitching. Each suppository contains 40 mg of active compound.

Connection example 1, 4 g

Witepsol H-15 180 grams

The compound used as an active start is mixed with Witepsol H-15 at a temperature of 41oTo obtain a homogeneous mixture. Pre-made suppozitornoj packaging is filled with molten mass to the net weight of 1.84, After cooling the above package is hermetically sealed. Each suppository contains 40 mg of active compound.

Biological effects.

Bioavailability.

Bioavailability is determined by calculating the ratio of the area of the curve of concentration changes in plasma after intraduodenal (C. D.) and intravenous (centuries) in rats or dogs. Use low, relevant therapeutic dose. The method is recognized from a scientific point of view as reliable in determining the bioavailability (see for example: M. Rowland and T. N. Tozer, Clinical Pharmacokinetics, 2 nd ed, Lea and Febiger, London, 1989, page 42). In table. 3 shows the data obtained as rats and dogs.

Rodamco and requires a large number of analyses of blood plasma, also used the model coarse screening, based on the relative ability of inhibition of acid secretion (see, for example: A. Goth, Medical Pharmacology, 7 th ed. C. V. Mosby Company, Saint Lous 1974, page 19). Thus, the expected ratio (called "Bioavailability" in table. 3) between the ED50intravenous and ED50when intraduodenal introduction. These data are also shown in table. 3.

Activity.

Activity inhibition of gastric secretion were detected in the rat, male and dogs as in intravenous and intraduodenal introduction. If to match test data on animals relative to the activity of this compound per person compared with the existing type of compounds, the activity on the person, will correspond to a level somewhere between the rate obtained in the rat, male and established the dog. Activity data obtained from these two species are given in table 3.

Biological tests

Inhibition of the secretion of gastric acid from in consciousness rat-male.

For tests used rats-males line Spocgue-Dawley, stomach (cavity) and the upper division of the duodenum kick is responsible. Before carrying out the tests provided a 14-day period of healing after surgery.

Prior to testing, on the secretion of gastric acid, the animals were deprived of food but not water for 20 hours the Stomach repeatedly washed through a gastric catheter was subcutaneously injected 6 ml Rangelovska glucose solution. The acid secretion stimulated by infusion within 3.5 h (1.2 ml/h subcutaneously) of pentagastrin and carbachol (20 and 100 nmol/kg/h), respectively, and during this time was collected fractions of gastric secretion with an interval of 30 minutes the Subjects of the substance or carrier injected intravenously or intraduodenally at 90 min after the start of stimulation in a dose of 1 ml/kg Samples of gastric juice were brought to pH 7.0 using NaOH, 0.1 mol/l, and the release of acids was calculated as the product of concentration and volume of the titrated solution. Further calculations were carried out on the basis of group-averaged responses from 4-5 rats. The release of acid during the specified periods after administration of the tested compounds or media were expressed as responses to the collection of fractions with the establishment acid release over a 30-minute interval before the introduction to the value of 1.0. The rate of inhibition percentage was calculated by some interpolation on a logarithmic curves "dose-effect" or calculated on the basis of trials of a single dose, assuming the same slope for all the curves of dependence "dose-effect". Determination of the bioavailability obtained by calculating the ratio of the ED50and so on, the results are based on secretion of gastric acid during the second hour after administration of the medicinal product media.

Bioavailability in rat-male.

Used adult rats-males. The day before the experiments, all rats were prepared by catheterization of the left carotid artery under anesthesia. Rats used for intravenous trials have also introduced a catheter in the jugular vein (see V. Popovic and P. Popovic, 1960, 15, pp. 727-728). Rats used for intraduodenal experiments, has introduced a catheter into the upper part of the duodenum. The catheter was led out to the back of the neck. Each rat after the above operations were placed separately and were deprived of food, except water, before the introduction of the tested substances. The same dose (4 µmol/kg) was injected intravenously and intraduodenal bolus over approximately 1 min (2 ml/kg). From the carotid artery produced a re-sampling of blood (0.1-0.4 g) at intervals up to 4 h after the adoption of this dose of the test substance. Samples prior to analysis the C was determined by linear trapezoid and extrapolated to infinity by dividing the concentration in the blood, installed last with the exception of the rate constants in the terminal phase. Systemic bioavailability (F%) after intraduodenal injection was calculated by the formula:

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Inhibition of the secretion of gastric acid and bioavailability of conscious dogs.

Used the hound dogs of both sexes. They put a fistula in the duodenum for the introduction of the test compounds or vehicle and ventricular fistula catheter for collection of gastric secretion.

Before conducting tests on the secretory function of the animals were deprived of food for about 18 hours, but did not rule out the water. The secretion of gastric acid stimulated by the injection of histamine dihydrochloride (12 ml/h) dose, generates about 80% of the individual maximal secretory response, and gastric juice was collected fractions at intervals of 30 minutes the Test compound or the media was injected intravenously or intraduodenally through 1 h after infusion of histamine in the amount of 0.5 ml/kg of body weight. The acidity of the samples of gastric juice was determined by titration with bringing the pH to 7 and the expected release of acid. The secretion of acid in the course of time collecting fractions after administration of the test soedinenii faction before introduction to the value of 1.0.

The percentage of inhibition was calculated based on responses fractions caused by the test compound and a carrier. The values of the ED50a graphical interpolation of the curves dose-response relationships or expected from experiments on the selection of a single dose on the basis of the same curvature curve "dose-effect" for all of the tested compounds. All results are based on the release of acid in 2 h after injection.

Produced a sample of blood for analysis of the concentration of the test compound in the plasma at intervals up to 3 h after dosing. Plasma was separated and frozen within 30 min after blood collection. AUC (the area on the curve "concentration-time"), extrapolated to infinity, calculated by the linear trapezoid rule. Systemic bioavailability (F) after intraduodenal injection was calculated by the formula 100(AUCI. D./AUCcentury).

Chemical stability.

Chemical stability of various compounds of the invention were observed in the kinetics at low concentrations at 37oWith in aqueous buffer solutions with different pH values. The results are shown in table. 3 shows the bottom half of the LM is moved without any changes.

The results of the tests of biological activity and stability.

In table. 3 summarizes the obtained test data for the proposed connection and known structural analogue, referred to in the table in the link as 5-fluoro-2-[[(4-isopropoxy-2-pyridinyl)methyl]sulfinil]-1H-benzimidazole disclosed in U.S. patent N 4727150. As can be seen from the table. 3, the proposed connection has a high bioavailability (F=82 in rats), high activity (ED50at intravenous introduction 1.2 µmol/kg, ED50when intraduodenal introduction 2.2 µm in rat) and high chemical stability (BP. 1/2 23 h). Moreover, when analyzing the biological availability of the specified connection has a much higher (82 vs. 31) compared with the index of the connection shown in the link, but also surpasses it in other characteristics (the ED50when administered intravenously is 1.8 µmol/kg, ED50when intraduodenal introduction is 4.0 µmol/kg and the half life is 14 hours at the opposed connection.

1. 5-fluoro-2-{ [(4-cyclopropylmethoxy-2-pyridinyl)methyl]sulfinil}-1H-benzimidazole of the formula

or its physiologically acceptable salt.

2. Connect viteska composition, possessing inhibiting the secretion of gastric acid by the action, containing the active ingredient and pharmaceutically acceptable carrier, wherein the active substance contains 5-fluoro-2{ [(4-cyclopropyl-methoxy-2-pyridinyl)methyl] sulfinil}-1H-benzimidazole or its physiologically acceptable salt PP. 1 3 in the following, wt.

5-fluoro-2-{ [(4-cyclopropyl-methoxy-2-pyridinyl)methyl] sulfinil}-1H-benzimidazole or its physiologically acceptable salt of 0.1 95,0

Pharmaceutically acceptable carrier Rest.

5. 4 Cyclopropylmethoxy-2-methylpyridin-12-oxide as an intermediate product for the synthesis of 5-fluoro-2-{[(4-cyclopropylmethoxy-2-pyridyl)methyl] sulfinil}-1H-benzimidazole.

6. 2-Acetoxymethyl-4-cyclopropylmethoxy as an intermediate product for the synthesis of 5-fluoro-2-{[(4-cyclopropylmethoxy-2-pyridyl)methyl]sulfinil}-1H-benzimidazole.

7. 4 Cyclopropylmethoxy-2-hydroxymethylpropane as an intermediate product for the synthesis of 5-fluoro-2-{[(4-cyclopropylmethoxy-2-pyridyl)methyl]sulfinil}-1H-benzimidazole.

8. 4 Cyclopropylmethoxy-2-chloromethylpyridine hydrochloride as an intermediate product for sin is openmutexa-2-pyridinyl)methyl]-thio}-1H-benzimidazole as an intermediate product for the synthesis of 5-fluoro-2-{[(4-cyclopropylmethoxy-2-pyridyl)methyl]sulfinil}-1H-Benzema - dazole.

 

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