5-chloro-2 //([(3,4-dimethoxy-2-pyridinyl)methyl] /sulfinil/) - 1h-benzimidazole or its pharmaceutically acceptable salt synthesis method, pharmaceutical composition and 5-chloro-2 //([(3,4-dimethoxy-2-pyridinyl)methyl]thio) - 1h-benzimidazole

 

(57) Abstract:

The use of the invention as a substance that inhibits the secretion of gastric acid in mammals. The inventive product: 5-chloro-[[(3,4-dimethoxy-2 - pyridinyl)methyl]sulfinil]-IH-benzimidazole or its pharmaceutically acceptable salt. Reagent 1:5-chloro-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]thio]- IH-benzimidazole. Reagent 2: oxidizer. Reaction conditions: selection, if desired, in the form of a salt. table 1.

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 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 associated with the secretion of gastric acid in mammals, including humans, e.g. lodochnoy cancer. 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 also in 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. The 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 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 the invention relates to methods for this new connection, the new is the active ingredient in medicinal preparations for medical use according to the testimony, above.

The purpose of the invention obtaining compounds 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 NN 1500043, 1525958, USA 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.

The compounds disclosed in these patents are effective inhibitors of acid secretion, and thus their use as antiulcer agents.

To further improve the EF of the 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]-IH-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-chloro-2-[[(3,4-dimethoxy-2-pyridinyl)methyl] sulfinil]-IH-2-benzimidazole (compound I) and its physiologically acceptable salt.

The proposed connection contains an asymmetric center at the sulfur atom, i.e. exists as two optical isomers (enantiomers).

Receive.

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

Carry out the oxidation of 5-chloro-2-[[(3,4 - dimethoxy-2-pyridinyl)-methyl] thio] -IH-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, iodosobenzene, 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 using an oxidizing enzyme or microbiologically using a suitable microorganism.

Depending on the process conditions and source the present invention is included as a neutral compound, and salt it. 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 Li+, K+, Mg2+Ca2+and N+(R)4where R means1-4alkyl,

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 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, NaOR, NaNH2, NaNR2, KORKNH2or KNR2where R means1C4-alkyl, in an anhydrous environment.

b) Salts in which the cation is Mg2+or Sa2+produced by processing the proposed connection of Mg(OR)2, Ca(OR)2or San2where R means1C4alkyl in anhydrous solvent, OAD">

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 perse.

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 preparations for parenteral administration, from 0.2 to 50 wt. in preparations for oral administration.

In the preparation of pharmaceutical compositions based on the proposed connection in the form of single doses for p is chose, sucrose, 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. Granules and tablets can be coated intersolubility and membranes 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, shellac or anionic film-forming polymers, such as phthalate cellulose acetate, hydroxypropylmethyl cellulose 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 to distinguish between tablets and granules with different active ingredients or with different doses of available active the main compounds of the invention, vegetable oil, fat 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 aerosolising 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, Surbiton, 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 oil or other medium suitable for the production of gelatin capsules for rectal application. These medicinal p is 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 carboxymethylcellulose, 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 before use directly bred appropriate will dissolve the current 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.

Example 1. Getting 5-chloro-2-[[(3,4-dimethoxy-2-pyridinyl) methyl]-sulfinil]-IH-benzimidazole.

5-chloro-2-[[(3,4-dimethoxy-2-pyridinyl)methyl] thio] IH-benzimidazole (645 mg, 0,0019 mol) is dissolved in 25 ml of CH2Cl2and then mixed with NaHCO3(323 mg, 0,0038 mol), dissolved in 10 ml of water. The stirred mixture is cooled to 0oC and treated MDFMK (MSRV) (84% 389 mg, 0,0019 mol) dissolved in 6 ml of CH2Cl2. After 10 min the resulting layers separated, and the aqueous layer was extracted using 5 ml of CH2Cl2. The organic layers are combined and extracted with 20 ml of water containing NaOH (154 mg, 0,0038 mol). The last aqueous layer was collected (the remainder of CH2Cl2distilled the evaporation apparatus) and treated with two portions of SOON3)2 x 118 μl, 0,0038 mol).

The resulting solid product is collected, washed with a small volume of water, cooled with ice from the exit 253 mg (38%) of pure product as a white powder. The mother liquor is quickly extracted using 20 + 10 ml of CH2Cl2. The organic layers are combined to A crystallizes. The solid precipitate collected, washed with a small volume of ice CH3CN with getting 225 (34%) of the pure target compound. Data of NMR analysis are shown below.

Example 2. Getting 5-chloro-2-[[3,4-dimethoxy-2-pyridinyl) methyl]sulfinil] -IH-benzimidazole in the form of the sodium salt of 5-chloro-2-[[(3,4-dimethoxy-2-pyridinyl)methyl] sulfinil] -IH-benzimidazole (4.1 g, 11,65 mmol) dissolved in dichloromethane (100 ml), transferred into a separation funnel. The resulting mixture was intensively stirred until homogeneous, then layers of solvent separated. The aqueous phase is washed with dichloromethane (2 x 25 ml) and then dried by freezing. The residue is recrystallized from a mixture of ethyl acetate/diethyl ether.

Yield: 3.7 g (86%) of the named compound. Data of NMR analysis are shown below.

The solvent I CDCl3(500 MHz) NMR data h/million 3,84 (c, 3H), 3,88 (c, 3H), 4,70 (d, 1H), 4,84 (d, 1H), 6,80 (d, 1H) 7,26 (DD, 1H), 7,55 (D, 1H), 7,58 (d, 1H), 8,16 (d, 1H),

Solvent 2 D2O (D2O 4,82) (300 MHz). These NMR d h/min 3,68 (c, 3H), 3,91 (C, 3H), with 4.64 (d, 1H), 4,80 (d, 1H),? 7.04 baby mortality (d, 1H), 7,20 (m, 1H), 7,60 (d, 1H), to 7.67 (d, 1H), 8,11 (d, 1H)

Obtaining synthetic intermediate compounds

Example 1.1. Obtaining 3,4-dimethoxy-2-chloromethylpyridine.

3,4-dimethoxy-2-the amount SOCl2(0.27 g, 0,00227 mol) dissolved in CH2Cl2under stirring at room temperature. After 10 min the mixture is neutralized using NaHCO3(5 ml). The formed phases are separated, CH2Cl2the phase is washed with NaCl solution, dried over Na2SO4and after evaporation obtain the desired product (0,61 g, 88%).

Example 1.2. Getting 5-chloro-2-[[(3,4-dimethoxy-2-pyridinyl) methyl]thio] -IH2-benzimidazole.

2-chloromethyl-3,4-dimethoxypyridine hydrochloride (896 mg, 0,004 mol) is dissolved in 25 ml Meon and treated with NaOH (390 mg, 0,008 mol), dissolved in 1.5 ml of water. Then add 5-chloro-2 - mercapto-IH-benzimidazole (812 mg, 0,0044 mol) and the mixture was incubated for 2 h at room temperature. The solvent is distilled off and the residue is divided between 50 ml of 2.5% NaOH and 75 ml of CH2Cl2. The aqueous layer was separated and extracted with twice 25 ml of CH2Cl2. The organic layers are combined, washed with 25 ml water, dried over MgSO4, and evaporated the solvent.

The crude product proscout using approximately 5 ml Etoc saturated with NH3. The solid precipitate is collected and after re-processing of the mother liquor get 650 mg (48%) of the named compound in the form of the Ted with the specified example.

The solvent 1-2 CDCl2. These NMR analysis d h/m (5 MHz)

3,96 (c, 3H), 3,99 (c, 3H), 4,46 (c, 2H), of 6.96 (d, 1H), 7,18 (DD, 1H), of 7.48 (d, IH), 7,56 (d, 1H), 8,31 (d, 1H)

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 invention as an active start, is illustrated in the following recipes.

The syrup.

Syrup, containing 1% (mass to 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 D. 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.

Tablets with intersolubility shell.

Tablet containing 50 mg of active compound in intersolubility shell, obtained on the basis of the track is>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, tablet press machine with 7 mm punch.

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

Solution for intravenous infusion.

The composition for parenteral, intravenous infusion, containing 4 mg of the active component per 1 ml, is obtained on the basis of the following ingredients:

Connection example 2 to 4 grams

Sterile water to a final volume of 1000 ml

Active the same time 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 700

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 g:

Phthalate hydroxypropylamino methylcellulose 70

Cetyl alcohol 4

Acetone 200

Ethanol 600

Pellets covered with a final layer encapsulate in capsules.

Suppose what Each suppository contains 40 mg of active compound.

Connection example 1, 4 g

Witipsol H-15 180 grams

The compound used as an active start, mixed with Witepsol H-15 at a temperature of 41oTo obtain a homogeneous mixture. Pre-made suppozitornoj packaging is filled with molten mass to a net weight of 1.8 to 4, 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 (I. 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 u T. N. Tozer, Clinical Pharmacacocinetics, 2nd, ed. Zea J Febiher, London, 1989, S. 42). The table shows the data obtained both in rats and dogs.

Model coarse screening.

Because the model of bioavailability, which is described above, it is extremely time consuming and requires a large number of analyses of blood plasma, islote (see for example: A 60th, Medical Pharmacology, 7th C. V. Mosby Company, Saint Zouis, 1974, S. 19). Thus, the expected ratio (called "Bioavailability" in the table) between the ED50intravenous and ED50when intraduodenal introduction. These data are also given in the table.

Activity.

Activity inhibition of gastric secretion were detected in the rat, male and dogs as in intravenous and intraduodenal administration. 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 of animals listed in the table.

Biological tests.

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

For tests used rats-males line Spraque-Dawley. In their stomach (cavity) and upper part of the duodenum were performed fistula with a needle to collect the secretion of gastric acid and the introduction of the tested substances, sootvetstvenno is S="ptx2">

Prior to testing, on the secretion of gastric acid, animals were deprived of food but not water for 20 hours the Stomach repeatedly washed through a gastric catheter was subcutaneously injected 6 mg 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 mg/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 of 5 rats. The release of acid during the specified periods after Vvedenie 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 was calculated by the fractional responses caused by the test compound and a carrier. The values of the ED50obtained from the graphical Interpol is s, assuming the same slope for all the curves of dependence "dose-effect". Determination of the bioavailability obtained by calculating the ratio of the ED50century century/ED50I. D. the results are based on secretion of gastric acid during the second hour after administration of the medicinal product or the media.

Biological activity 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 u P. Popovic, G. Appl. Phissiol, 1960, 15, S. 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 was made repeatedly sampling blood samples (0.1 to 0.4 g) at intervals up to 4 h after taking the specified dose of the curve "concentration-time" (AUC) 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 is 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 media in intercalary 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 not excluding, however, 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 sa in the specified faction before introduction to the value of 1.0.

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 blood sampling. AUC /square 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 x (AUC I. D./AUC centuries).

Chemical stability.

Chemical stability of various compounds of the invention were observed in the kinetics at low concentrations at 37oC in aqueous buffer solutions with different pH values. The results given in the table represent the period of time after which half the amount of starting compound remains unchanged.

test data for the proposed connection and known structural analogue, referred to in the table in the link as 5-fluoro-2-[[(3,4-dimethoxy-pyridinyl)methyl] sulfinil]-IH-benzimidazole disclosed in Europatent N 208452. As you can see from the table the proposed connection has a high bioavailability (F 97% in rats), high activity (ED50centuries of 1.3 µmol/kg, ED50I. D. 2.6 µmol/kg in rats) and high chemical stability (half life 30 hours). Biological availability of the proposed connection has a much higher (97% vs. 47% ) compared with the index of the connection shown in the link, although opposed connection has a higher activity and stability (in connection to link the ED50intravenous prepared 0.85 µmol/kg, ED50when intraduodenal of 1.75 µmol/kg and the half life is 58 hours).

1. 5-Chloro-2-[[3,4-dimethoxy-2-pyridinyl)methyl] -sulfinil]- 1H-benzimidazole of the formula I

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or its pharmaceutically acceptable salt.

2. Connection on p. 1, characterized in that it is a sodium salt.

3. Connection on p. 1 with inhibiting the secretion of gastric acid activity.

4. The pharmaceutical composition exhibiting inhibace acceptable carrier, characterized in that, as an active ingredient it contains a compound of formula I under item 1 in an amount of 0.1 to 95 wt.

5. The way to obtain 5-chloro-2- [[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinil]-1H-benzimidazole of the formula

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or its pharmaceutically acceptable salts, characterized in that 5-chloro-2- [[(3,4-dimethoxy-2-pyridinyl)methyl]thio]-1H-benzimidazole is subjected to oxidation with the release if desired in the form of salt.

6. 5-Chloro-2-[[(3,4-dimethoxy-2-pyridinyl)methyl] thio] -1H-benzimidazole of the formula



 

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