CS261873B2 - Process for preparing 2-pyridylmethylsulphinylbenzimidazoles - Google Patents

Description

(54) A method for producing 2-pyridylmethylsulfinylbenzimidazoles

The invention relates to a process for the production of novel compounds having valuable gastric acid secretion properties in mammals including humans. Effects on gastric acid secretion and pharmaceutical compositions containing these novel compounds are also discussed.

It is an object of the present invention to provide compounds which act on gastric acid secretion and which inhibit exogenously or endogenously stimulated gastric acid secretion. These compounds can be used in the treatment of gastric ulcer disease.

It is known that the compounds of formula (I)

where

R ¹ and R ^{2 are} selected from the group consisting of hydrogen, alkyl, halogen, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, carbamoyl, carbamoyloxy, hydroxy, alkoxy, hydroxyalkyl, trifluoromethyl and acyl at any position,

R ³ represents a group selected from hydrogen, alkyl, acyl, alkoxycarbonyl, carbamoyl, alkoxycarbonylmethyl, alkylcarbamoyl, dialkylcarbamoyl, alkylcarbonylmethyl and alkylsulfonyl; and

R ⁴ represents a group selected from the group consisting of straight and branched alkylene groups having 1 to 4 carbon atoms,

281873 wherein at least one methylene group is present between the sulfur atom and the pyridyl group and wherein the pyridyl group is optionally further substituted by an alkyl or halogen, they have an inhibitory effect on gastric acid secretion.

However, it has now surprisingly been found that the compounds described below have an even greater inhibitory effect than the compounds mentioned above.

The compounds of the invention have the general formula III

where

R ¹ and R ² , which may be the same or different, are selected from hydrogen, halogen, C 1 -C 7 alkyl, methoxycarbonyl, ethoxycarbonyl, C 1 -C 5 alkoxy, and C 1 -C 4 alkanoyl in any one location

R ^e represents a group selected from the group consisting of hydrogen, methyl and ethyl,

R ³ , R ⁴ and R ⁵ , which are the same or different, are selected from the group consisting of hydrogen, methyl, methoxy, ethoxy, methoxyethoxy and ethoxyethoxy, wherein R ³ , R ⁴ and R ^{5 do} not simultaneously denote a hydrogen atom and denote two of the substituents R ³ , R ⁴ and R ^5, a hydrogen atom, the third of the substituents R ³ , R ⁴ and R ⁵ being other than methyl.

The alkyl R ¹ and R ² in formula III is suitably an alkyl of up to 7 carbon atoms, preferably up to 4 carbon atoms. Such alkyl R ¹ or R ² is, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl.

Halogen R ¹ and R ² is chloro, bromo, fluoro or iodo.

Alkoxy groups R ¹ and R ² suitably form alkoxy groups with up to 5 carbon atoms, preferably up to 3 carbon atoms, such as methoxy, ethoxy, n-propoxy or isopropoxy.

Alkanoyl R ¹ and R ² are suitably up to 4 carbon atoms and is, for example, formyl, acetyl or propionyl, particularly preferably acetyl.

A preferred group of compounds of formula III are those wherein R ¹ and R ² are the same or different and are selected from hydrogen, alkyl, methoxycarbonyl, alkoxy, and alkanoyl, wherein R ¹ and R ² are not simultaneously hydrogen, R ⁶ is hydrogen and R ³ , R ⁴ and R ⁵ are the same or different and are selected from the group consisting of hydrogen, methyl, methoxy and ethoxy, wherein R ³ , R ⁴ and R ⁵ do not always denote a hydrogen atom and when two substituents R are ³ , R ⁴ and R ⁵ hydrogen, the third of these substituents R ³ , R ⁴ and R ⁵ is not methyl.

Another preferred group of compounds of formula III are those wherein R ¹ and R ² are the same or different and each is selected from hydrogen, alkyl, halogen, methoxycarbonyl, ethoxycarbonyl, alkoxy, and alkanoyil; R ^B is selected from the group consisting of: hydrogen, methyl and ethyl, R ³ denotes methyl, R ⁴ denotes methoxy and R ⁵ denotes methyl.

A third preferred group of compounds of formula III are those wherein R ¹ and R ² are the same or different and are selected from hydrogen, alkyl, halogen, methoxycarbonyl, ethoxycarbonyl, alkoxy and ailkanoyl; R ^B is selected from hydrogen, methyl and ethyl, R ³ is hydrogen, R ⁴ is methoxy and R ⁵ is methyl or R ³ is methyl, R ⁴ is methoxy and R ⁵ is hydrogen.

A fourth preferred group of compounds of formula III are those wherein R ¹ and R ² are the same or different and are selected from hydrogen, alkyl, halogen, methoxycarbonyl, ethoxycarbonyl, alkoxy, and alkanoyl; R ⁶ is hydrogen, methyl or ethyl; ³ and R ^{5 are} hydrogen and R ⁴ is methoxy.

A fifth preferred group of compounds of formula III are those wherein R ¹ and R ² are the same or different and are selected from hydrogen, alkyl, halogen, methoxycarbonyl, ethoxycarbonyl, alkoxy, and alkanoyl; R ⁶ is selected from hydrogen, methyl and ethyl and R ³ and R ⁵ denote methyl groups and R ⁴ is hydrogen.

A sixth preferred group of compounds of formula (III) are those wherein R ¹ and R ² are the same or different and are selected from hydrogen, alkyl, halogen, methoxycarbonyl, ethoxycarbonyl, alkoxy, and alkanoyl; R ^B is selected from hydrogen, methyl and ethyl, R ³ and R ^{5 are} hydrogen and R ⁴ is ethoxy, methoxyethoxy or ethoxyethoxy.

A seventh preferred group of compounds of formula III are those wherein R ¹ and R ² are the same or different and are selected from hydrogen, alkyl, halogen, methoxycarbonyl, alkoxy and alkanoyl, R ⁶ is selected from hydrogen, methyl and ethyl and R ³ , R ⁴ and R ^{5 are} each methyl.

According to the invention, the compounds of the formula III are prepared by the process of preparing a compound of the formula VII

where

R ¹ and R legends ^of the abovementioned meanings, is reacted with a compound of formula VIII

where

R ^6, R ^3, R ⁴ and R ⁵ have the meanings indicated above and one of Z ¹ and Z represents ^a .reaktivní esterified hydroxy and the other is a group SH,

where

R ^1, R ^2, R ^6, R ^4, R ³ and R ⁵ have the meanings indicated above, which is then oxidized to a compound of formula III, which, if present as a base can be converted to an acid addition salt or them if present as a salt, it can be converted to its base.

Of the above substituents ^of Z ¹ .a reactive esterified hydroxy, such as hydroxy esterified by a strong inorganic or organic acid, preferably a hydrohalic acid, such as hydrochloric acid or hromovodíkovou hydroiodic acid, sulfuric acid or a strong organic sulfonic acid as a strong aromatic acid such as benzenesulfonic acid, 4-bromobenzenesulfonic acid or 4-toluenesulfonic acid.

Oxidation of the sulfur atom in the above chains to sulfinyl (S-> O) occurs in the presence of an oxidizing agent selected from the group consisting of nitric acid, hydrogen peroxide, peroxyacids, peresters, ozone, nitrogen dioxide, iodosobenzene, N-halosuccinimide, 1-chlorobenzotriazole, tertiary. -butyl hypochloride, diazobicyclo [2.2.2] octane bromine complex, sodium metaperiodate, selenium dioxide, manganese dioxide, chromic acid, cerium ammonium nitrate, bromine, chlorine and sulfuryl chloride. The oxidation usually takes place in a solvent in which the oxidizing agent is present in some excess relative to the product to be oxidized.

Depending on the process conditions and starting materials, the end product is obtained either as the free base or as an acid addition salt, which are included within the scope of the invention. Thus, basic, neutral or mixed salts, such as gaming, mono-, sesqui- or polyhydrates, can be obtained. The acid addition salts of the novel compounds can be converted into the free bases in a manner known per se using basic media such as alkalis or ion exchangers. On the other hand, the free bases obtained can form salts with organic or inorganic acids. In the preparation of acid addition salts, preferably those acids which form therapeutically acceptable salts are used. These acids include hydrohalogenic acids, sulfuric, phosphoric, nitric and perchloric acids, aliphatic, alicyclic, aromatic, heterocyclic carboxylic acids or sulfonic acids such as formic, acetic, propionic, succinic, glycolic, lactic, malic, tartaric, citric, ascorbic acids. , roalein, hydroxymalein, pyruvic, phenyillacetic, benzoic, p-aminobenzoic, anthranilic, p-hydroxybenzoic, salicylic or p-aminosalicylic, embonic acid, methansuilphonic acid _; ethanesulfonic, hydroxyethanesulfonic, ethylenesulfonic, halobenzenesulfonic, toluenesulfonic, naphthylsulfonic or sulfanilic acids, methionine, tryptophan, lysine or arginine.

These or other salts of the novel compounds, such as picrates, can serve as cleaning agents of the free bases obtained. Base salts can be formed, separated from solution, and then the free base can be recovered from the pure salt solution of the new salt. Because of the relationship between the new free base compounds and their salts, it is to be understood that the corresponding salts are included within the scope of the invention.

Some of the novel compounds may be present as optical isomers or racemate, depending on the choice of starting material and process, or, if they contain at least 2 asymmetric carbon atoms, may be present as a mixture of isomers (racemic mixture).

The obtained isomeric mixtures (racemic mixtures) can be separated into two stereoisomerically (diastereometrically) pure racemates by chromatography or fractional crystallization.

The racemates obtained can be resolved by known methods, for example, by recrystallization from an optically active solvent using microorganisms, by reaction with optically active acid-forming salts which can be separated by resolution based on the different solubility of the diastereomers. Suitable optically active acids are the L- and D-forms of tartaric acid, di-o-tolyltartaric acid, malic acid, mandelic acid, camphorsulfonic acid, quinic acid. Preferably, the more active portion is isolated from both antipodes.

Starting materials are known or, if new, can be obtained in a manner known per se.

In clinical use, the compounds of the invention are administered orally, rectally or by injection in the form of a pharmaceutical composition containing the active ingredient either as a free base or as a pharmaceutically acceptable non-toxic acid addition salt such as hydrochloride, lactate, acetate, sulfamate, in combination with a pharmaceutically acceptable carrier. The carrier may be in solid form, semi-solid form, or in the form of a liquid solvent or as a capsule. The usual amount of active ingredient is 0.1 to 95% by weight. 0.5 to 20 wt. for injectables and 2 to 50 wt. in formulations for oral administration.

In preparing pharmaceutical compositions comprising a compound of the invention in the form of a dosage unit for oral administration, the selected compound may be admixed with a solid powder carrier such as lactose, sucrose, sorbitol, mannitol, starch, amylopectin, cellulose derivatives or gelatin, as well as a friction reducing agent. such as magnesium stearate, calcium stearate and poilyethylene glycol waxes. The mixture is then compressed into tablets. In preparing the coated tablets, the core thus prepared is coated with a concentrated sugar solution, which may contain gum arabic, gelatin, talc, titanium dioxide or varnish dissolved in a volatile organic solvent or solvent mixture. Various colorants may be added to this coating to distinguish tablets with different active compounds or different amounts of active compound present.

Soft gelatin capsules can be prepared which contain a mixture of the active compound or compounds of the invention and a vegetable oil. The hard gelatin capsules may contain granules of the active compound in combination with a solid powdered carrier such as lactose, sucrose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives or gelatin.

Dosage units for rectal administration may be presented in the form of suppositories containing the active ingredient in admixture with a neutral fat base or may be prepared in the form of gelatin rectal capsules containing the active ingredient in admixture with vegetable or paraffin oil.

Liquid compositions for oral administration may be prepared in the form of syrups or suspensions, for example as solutions containing 0.2 to 20% by weight of the composition. active ingredient, the remainder consisting of sugar and a mixture of ethanol, water, glycerol and propylene glycol. If desired, such liquid compositions may contain coloring agents, flavoring agents, saccharin, and carboxymethylcellulose as a thickening agent.

Solutions for parenteral administration by injection may be prepared as aqueous solutions of the pharmaceutically acceptable water-soluble salt of the active compound, preferably at a concentration of 0.5 to 10% by weight. These solutions may also contain stabilizing agents and / or buffers and may be prepared in ampoules with different dosage units.

Pharmaceutical tablets for oral use are prepared as follows:

The solids are ground or crosslinked to a certain particle size, and the binder is homogenized and suspended in a suitable solvent. The therapeutically active compounds and excipients are mixed with a binder solution. The resulting mixture is moistened to form a uniform suspension of wet snow consistency. Moistening causes the particles to clump a little and the resulting mass is passed through a stainless steel sieve with a mesh size of about 1 mm. The mixture layer is dried in carefully controlled drying chambers for approximately 10 hours to achieve the desired particle size and consistency. The granules of the dried mixture are sieved to remove any dust. Tablet disintegrating aids, reducing friction and preventing adhesion are added to this mixture. Finally, the mixture is compressed into tablets using a suitable punch and die machine to obtain a suitable tablet size. The pressure applied affects the size of the tablet, its strength and its water solubility. This pressure should be in the range of 49 to 490 MPa. Tablets are produced at a rate of 20,000 to 200,000 pieces per hour. Tablets, especially those that are coarse and bitter, may be coated with a layer of sugar or other palatable substance. The tablets are then packaged using machines with electronic counting equipment. The different types of packaging consist of glass or plastic cups, boxes, tubes and other containers for special dosing.

The usual daily dose of the active ingredient varies according to the individual need and the mode of administration. In general, oral dosages range from 100 to 400 mg per day of active ingredient and intravenous dosages range from 5 to 20 mg per day.

The following examples illustrate embodiments of the invention without departing from the invention

281873 limited. Temperatures are given in degrees Celsius.

In the following examples, starting materials are prepared by the following methods:

1)

A 1,2-diamino compound, such as o-phenylenediamine, is reacted with potassium ethylxanthate, according to Org. Synth., Vol. 30, p. 56 to give 2-mercaptobenzimidazoil.

2)

2-Chloromethylpyridine is prepared by reacting 2-hydroxymethylpyridine with thionyl chloride, according to Arch. Pharm., Vol. 26, pp. 448-451 (1956).

3)

2-Chloromethylbenzimidazole is prepared by condensing o-phenylenediamine with chloroacetic acid.

Example 1

28.9 g of 2- [2- (4,5-dimethyl] pyridylmethyl-thio] - (5-acetyl-6-methyl) -benzimidazoil are dissolved in 160 ml of chloroform and portion-wise to 5 ° C with stirring and cooling. After 24 minutes, the precipitated m-chlorobenzoic acid is filtered off, the filtrate is diluted with methylene chloride, washed with sodium carbonate solution, dried over sodium sulphate and evaporated under reduced pressure, and the residue is crystallized after dilution with acetonitrile. 2- (4,5-dimethyl) pyridylmethylsulfinyl] - (5-acetyl-6-methylbenzimidazoil) was recrystallized from acetonitrile to yield 22.3 g, m.p. 158 ° C.

Example 1a

Dissolve 0.1 mol of 4,6-dimethyl-2-mercaptobenzimidazole in 20 ml of water and 200 ml of ethanol containing 0,2 mod sodium hydroxide. 0.1 Mod of 2-chloromethyl- (3,5-dimethylpyridine hydrochloride) is added and the mixture is refluxed for 2 hours, the sodium chloride is filtered off and the solution is evaporated under reduced pressure, the residue is dissolved in acetone and treated with activated carbon. An equivalent amount of concentrated hydrochloric acid was then added and the product 2- [2- (3,5-dimethyl) -pyridylmethyl-thio] - [4,6-dimethyl] -benzimidazole monohydrochloride was isolated, yielding 0.05 mole of product.

This compound is then oxidized as in Example 1 to give the corresponding sulfinyl compound, m.p. 50-55 ° C.

Example 1b

22.0 g of 2-mercapto- (5-acetyl-6-methyl) benzimidazole and 19.5 g of chloromethyl- (4,5-dimethyl) pyridine hydrochloride are dissolved in 200 ml of 95% ethanol, and then 8 g of sodium hydroxide in 20 ml of water are added. The solution is refluxed for 2 hours, the sodium chloride is filtered off and the solution is evaporated under reduced pressure, and the residue of 2- [2- (4,5-dimethylpyridylmethylthio) - (5-acetyl-6-methyl) benzimidazole is recrystallized ^70!% ethanol. Yield 10.6 g.

This compound is then oxidized as in Example 1 to give the corresponding sulfinyl derivative. Melting point: 158 degrees Celsius.

Examples 2 to 30

The process for the preparation of the other compounds of the general formula (III) is carried out as in the examples mentioned above. The prepared compounds are summarized in Table 1, where the substituents in those compounds are also indicated.

Table 1

R ^((III)

Example R ¹ R ^z R ⁶ R ³ R ⁴ R ⁵ Temperature thaw Noc: 2 ° C 1 5-COCH3 6-CH3 H H CH3 C'H3 158 2 5-COOCH 3 6-CH3 H H CH3 CH3 163 3 5-COOCH 3 H H H CH3 CH3 141 4 5-COCH3 6-CH3 H CH3 CH3 H 160 5 5-COOCH 3 6-CH3 H ICH3 CH3 H 163 6 4-CH3 6-CH3 H CH3 H CHó 50-55 7 5-COCH3 6-CH3 H 1CH3 H CH3 171 8 5-COCH3 6-CH3 H CH3 CH3 CH3 190 9 5-COCHs 6-CH3 H H OCH3 H 165 10 4-CH3 6-CH3 H H OCH3 II 122 11 5-COCH3 6-CH3 H iCH3 OCH3 CD 156 12 5-COOCH 3 6-CH3 H CH3 H Target 144 13 5-COOCH 3 6-CH3 H CH3 CH.3 iCHj O X 14 5-COOCH 3 6-CH3 H H OCH3 H 169 15 Dec 5-COOCH 3 6-CH3 H H OC2H5 H 148 16 5-COOCH 3 6-CH3 H CH3 OCH3 H 175 17 5-COOCH 3 6-CH3 H CH3 OCH3 , CH3 155 18 5-COOCH 3 6-CH3 H H OCH3 CH3 158 19 Dec 5-COOCH 3 H H , CH3 H CH3 141 20 May 5-COOCH 3 H H CH3 OCH3 CH3 142 21 5-COCH3 H H CH3 OCH3 CH3 162 22nd 5-OCH3 H H H OCH3 ICH3 178 23 5-OCH3 H H CH3 OCH3 ICH3 156 24 5-CH3 H H CH3 OCH3 ICH3 181 25 H H H CH3 OGH3 CH3 165 26 5-C1 H H CH3 OCH3 CH3 185 27 Mar: 5-CH3 H H H OC2H4OCH3 H 119 28 5-COOC2H5 H H 1CH3 OCH3 , CH3 150—155 29 5-COOCH 3 H CH3 C'H3 H 'CH3 130 30 5-CH3 H CH3 CH3 H 'CH3 152 Biological effect use automatic titrator with pH-meter.

The compounds of the invention have valuable therapeutic properties as inhibitors of gastric acid secretion, as shown in the following tests. To determine the ability to inhibit gastric acid secretion, conscious experiments in dogs and gastric fistula of the conventional type and duodenal fistula, used for direct intraduodenal administration of test compounds, were performed. After 18 hours of fasting without water, dogs were given a subcutaneous infusion of pentagastrin (1-4 nmol / kg.h) lasting 6-7 hours. Gastric juice was collected in samples at 30 minute intervals. An aliquot of each sample was titrated with 0.1N sodium hydroxide to pH 7.0 to determine the titratable acid concentration, for (Radiometer, Copenhagen, Denmark.) Acid production was calculated as mmol H ⁺ / 60 minutes. The percent inhibition compared to the control was calculated for each compound and the highest inhibitory effect is given in Table 2. Test compounds suspended in 0.5% methylcellulose (Methocel ^R ) were administered intraduodenally at doses of 4 to 20 µmol / kg when secretory. the response to pentagastrin reached a constant level.

In the tests, the previously known compounds were compared with the compounds of the invention, as shown in Table 2.

The following gastric acid inhibition effect data were obtained for compounds tested by the method described.

Table 2

Example R ¹ R ² R ⁶ R ³ R ⁴ R ⁵ Dose mole / kg Effect % inhibition 1 5-COCH3 6-CH3 H H CH3 CH3 2 90 4 5-COCH3 6-CH3 H CH3 CH3 H 1 60 7 5-COCH3 6-CH3 H CH3 H CH3 2 100 ALIGN! 8 5-COCH3 6-CH3 H CH3 CH3 CH3 4 100 ALIGN! 9 5-COCH3 6-CH3 H H OCH3 H 2 95 11 5-COCH3 6-CH3 H CH3 OCH3 CH3 0.5 70 X 5-COCH3 6-CH3 H H CH3 H 20 May 30 X 5-COCH3 6-CH3 H H H CH3 8 80 2 5-COOCH 3 6-CH3 H H CH3 CH3 2 60 5 5-COOCH 3 6-CH3 H CH3 CH3 H 2 90 12 5-COOCH 3 6-CH3 H CH3 H CH3 2 70 13 5-COOCH 3 6-CH3 H CH3 CH3 CH3 4 80 14 5-COOCH 3 6-CH3 H H OCH3 H 2 100 ALIGN! 15 Dec 5-COOCH 3 6-CH3 H H OC2H5 H 4 75 16 5-COOCH 3 6-CH3 H CH3 OCH3 H 0.5 65 17 5-COOCH 3 6-CH3 H CH3 OCH3 CH3 0.5 90 18 5-COOCH 3 6-CH3 H H OCH3 CH3 X 5-COOCH 3 6-CH3 H H H CH3 4 50 X 5-COOCH 3 6-CH3 H Br H H 4 0 6 4-iOH 3 6-CH3 H CI-13 H CH3 4 40 10 4-ΠΗ3 6-CH3 H H OCH3 H 2 40 X 4-CH3 6-CH3 H H H H 4 30 X 4-CH3 6-CH3 H H H CH3 12 50 3 5-COOCH 3 H H H CH3 CH3 4 100 ALIGN! 19 Dec 5-COOCH 3 H H CH3 H CH3 2 60 20 May 5-COOCH 3 H H CH3 OCH3 CH3 0.5 65 X 5-COOCH 3 H H H H CH3 20 May 90 X 5-COOCH 3 H H H H H 20 May 50 21 5-COCH3 H H CH3 OCH3 CH3 0.5 60 X 5-COCH3 H H H H OC2H5 20 May 40 22nd 5-OCH3 H H H OCHs CH3 23 5-OCH3 H H CH3 OCH3 CH3 0.5 65 X 5-OCH.3 H H H CH3 H 20 May 10 24 5-CH3 H H CH3 OCH3 CH3 0 5 50 X 5-GHs H H H H CH3 4 50 25 H H H CH3 OCH3 CH3 0.5 60 X H H H H H H 4 50 28 5-COOC2H5 H H GH3 OCH3 CH3 0.5 50 26 5-C1 H H CH3i OCHs CH3 0.5 25 27 Mar: 5-CH3 H H H OC2H4 OCH3 14 0.5 30 29 5-COOCH 3 H CH3 CH3 H CH3 0.5 40

χ - designation for a previously known compound

Claims (6)

The sugar, saccharin and acid addition salt are dissolved in 60 g of warm water. After cooling, glycerin and a solution of flavors dissolved in ethanol are added. Water was added to the final volume of 100 ml. The above active ingredient may be replaced by another pharmaceutically acceptable acid addition salt. Example 32 250 g of 2- [2- (3,4-dimethyl) pyridylmethylsulfinyl] - (5-acetyl-6-methyl) benzimidazole hydrochloride are mixed with 175.8 g of lactose, 169.7 g of potato starch and 32 g of colloidal silicic acid. The mixture is moistened with a 10% gelatin solution and passed through a 1.41 mm sieve, 160 g of potato starch, 50 g of talc and 5 g of magnesium stearate are added after drying, and the mixture thus obtained is compressed into a total of 10,000 tablets. Each tablet contains 25 mg of active ingredient Tablets containing any desired amount of active ingredient may be prepared. Example 33 The granules are prepared from 250 g of [2- (3,5-dimethyl) pyridylmethylsulphinyl] - (5-acetyl-6-methyl) benzimidazole-p-hydroxybenzoate, 175.9 g of lactose and an alcohol solution of 25 g of polyvinyl pyrrolidone. After drying, the granules are mixed with 25 g of talc, 40 g of potato starch and 2.50 g of magnesium stearate and compressed into 10,000 tablets. These tablets were first coated with a 10% alcoholic shellac solution followed by an aqueous solution containing 45% sucrose, 5% gum arabic, 4% gelatin and 0.2% colorant. Talc and powdered sugar are used for dusting after the first five layers. The coating is then coated with 66% sugar syrup and polished with a solution of 10% carnauba wax in carbon tetrachloride. Example 34 Dissolve 1 g of 2- [2- (3,5-dimethyl) pyridylmethylsulphinyl] - (5-acetyl-6-methyl) benzimidazole hydrochloride, 0,6 g of sodium chloride and 0,1 g of ascorbic acid in such quantities of distilled water, This solution, containing 10 mg / ml of active ingredient, is used to fill ampoules which are sterilized by heating at 120 ° C for 20 minutes. Process for the preparation of 2-pyridylmethyilsulfinylbenzimidazoles of formula III (til) INVENTION hydrogen, methylmethoxy, ethoxy, methoxyethoxy and ethoxyethoxy, wherein R ³ , R ⁴ and R ^{5 do} not simultaneously denote hydrogen and when two of R ³ , R ⁴ and R ^{5 are} hydrogen, the third of R ³ , R ^{3 4} and R ⁵ are other than methyl, and therapeutically acceptable salts thereof, characterized in that the compound of formula (VII): R ¹ and R ² , which may be the same or different, are selected from hydrogen, halogen, C 1 -C 7 alkyl, methoxycarbonyl, ethoxycarbonyl, C 1 -C 5 alkoxy, and C 1 -C 4 alkanoyl in any one location R ⁶ is selected from the group consisting of hydrogen, methyl and ethyl, R ³ , R ⁴ and R ⁵ , which are identical or different, are selected from the group consisting of wherein R ¹ and R ² have the abovementioned meaning, 281873 is reacted with a compound of the formula wherein R ^B , R ³ , R ⁴ and R ⁵ are as defined above and one of Z ¹ and Z ² is a reactive esterified hydroxy group and the other a SH group to form an intermediate of formula IV wherein: R ¹ and R ² have the abovementioned meaning, R ^e represents a group selected from the group consisting of hydrogen, methyl and ethyl, R ³ , R ⁴ and R ⁵ , which are the same or different, are selected from the group consisting of hydrogen, methyl, methoxy, ethoxy, methoxyethoxy and ethoxyethoxy, wherein R ³ , R ⁴ and R ^{5 do} not simultaneously denote a hydrogen atom and denote two of the substituents R ³ , R ⁴ and R ^5, a hydrogen atom, the third of the substituents R ³ , R ⁴ and R ⁵ has a different meaning from methyl, which is then oxidized to a compound of formula III which, if present as a base, converted to an acid addition salt or, if present as a salt, may be converted to its base. 2. The process of item 1, for the preparation of 2-pyridylmethylsulfinylbenzimidazoles of formula III H where R ¹ represents a group selected from the group consisting of hydrogen, alkyl of 1-7 carbon atoms, a methoxycarbonyl group, an alkoxy having 1 to 5 carbon atoms and alkanoyl having 1-4 carbon atoms in any position, R ² represents a group selected from alkyl of 1-7 carbon atoms, a methoxycarbonyl group, an alkoxy having 1 to 5 carbon atoms and alkanoyl having 1-4 carbon atoms in any position, R ^B is hydrogen, R ³ , R ⁴ and R ⁵ are the same or different and are selected from the group consisting of hydrogen, methyl, methoxy and ethoxy, when two of R ³ , R ⁴ , R ^{5 are} hydrogen, the third of R ³ R ⁴ and R ⁵ are other than methyl, and therapeutically acceptable salts thereof, characterized in that the compound of formula (VII): R ¹ and R ² have the above meanings, is reacted with a compound of formula VIII wherein R ^B , R ³ , R ⁴ and R ⁵ have the meanings given above and one of Z ¹ and Z ² represents a reactive esterified hydroxy group and the other a group SH, to form an intermediate of formula (IV) above, Kae R ¹ and R ² , which may be the same or different, are selected from hydrogen, halogen, C 1 -C 7 alkyl, methoxycarbonyl, ethoxycarbonyl, C 1 -C 5 alkoxy and alkanoyl 1 to 4 carbon atoms in any position, R ^b is selected from the group consisting of hydrogen, methyl and ethyl, R ³ , R ⁴ and R ⁵ , which are the same or different, are selected from the group consisting of hydrogen, methyl, methoxy, ethoxy, methoxyethoxy and ethoxyethoxy, wherein R ³ , R ⁴ and R ^{5 do} not simultaneously denote a hydrogen atom and denote two R ³ , R ⁴ and R ⁵ represent a hydrogen atom, the third of R ³ , R ⁴ and R ⁵ having a different meaning from methyl which is then oxidized to a compound of formula III which, if present as a base, may may be converted to an acid addition salt or, if present as a salt, may be converted to its base. 3. A process according to claim 1, wherein the corresponding starting materials are used to form a compound of formula (1Π), wherein R ¹ represents hydrogen, chloro, methyl, ethyl, methoxy, acetyl, ethoxycarbonyl or methoxycarbonyl, R ² represents hydrogen or methyl, R ^Ti is hydrogen, methyl or ethyl, R ³ and R ⁵ are methyl and R ⁴ is methoxy, or therapeutically acceptable salts thereof. 4. A process according to claim 1, wherein the corresponding starting materials are used to form a compound of formula (III) wherein R ¹ represents hydrogen, chloro, methyl, ethyl, acetyl, methoxy, methoxycarbonyl or ethoxycarbonyl, R ² represents hydrogen, methyl or ethyl, R ^e represents hydrogen, methyl or ethyl, R ⁴ is methoxy, R ³ is hydrogen and R ⁵ is methyl or R ³ denotes methyl and R ⁵ denotes hydrogen or therapeutically acceptable salts thereof. 5. A process according to claim 1, wherein the corresponding starting materials are used 2- (2- (3,4-dimethylpyridylmethylsulfinyl) - (5-acetyl-6-methyl) benzimidazole, 2- (2- (3,5-dimethyl) pyridylmethylsulfinyl) -1H- (4,6-dimethyl) benzimidazole, 2- (2- (4,5-dimethylpyridylmethylsulfinyl) - (5-methoxycarbonyl) benzimidazole, 2- [2- (4,5-dimethylpyridylmethylsulfinyl) -N- (5-acetyl-6-methyl) benzimidazole, 2- (2- (4,5-dimethyl) pyridylmethylsulfinyl) - (5-methoxycarbonyl-6-methyl) benzimidazoil, 2- (2- (3,4-dimethyl) pyridylmethylsulfinyl) - (5-methoxycarbonyl-6-methyl) benzimidazole, 2- [2- (3,5-dimethyl) pyridylmethylsulfinyl] - (5-acetyl-6-methyl) benzimidazole, 2- (2- (3,4,5-trimethyl) pyridylmethylsulfinyl) - (5-acetyl-6-methylbenzimidazole), 2- (2- (4-methoxy) pyridylmethylsulfinyl) - (5-acetyl-6-methyl) benzimidazole, 2- [2- (4-methoxy) pyridylmethylsulfinyl] - (1,4-methyl) benzimidazole, 2- [2- (3,5-dimethyl-4-methoxy) pyridylmethylsulfinyl] - (5-acetyl-6-methyl) benzimidazole, 2- (2- (3,5-dimethyl) pyridylmethylsulfinyl) - (5-methoxycarbonyl-6-methyl) benzimidazole, 2- (2- (3,4,5-trimethyl) pyridylmethylsulfinyl) - (5-methoxycarbonyl-6-methyl) benzimidazole, 2- (2- (4-methoxy) pyridylmethylsulfinyl) - (5-methoxycarbonyl-6-methyl) benzimidazole, 2- (2- (4-ethoxy) pyridylmethylsulfinyl) - (5-methoxycarbonyl-6-methyl) benzimidazole, 2- (2- (3-methyl-4-methoxy) pyridylmethylsulfinyl) - (5-methoxycarbonyl-6-methyl) benzimidazole, 2- (2- (3,5-dimethyl-4-methoxy) pyridylmethylsulphinyl) - (5-methoxycarbonyl-6-methyl) benzimidazole, 2- (2- (4-methoxy-5-methyl) pyridylmethylsulfinyl) -, (5-methoxycarbonyl-6-acetyl) benzimidazole, 2- (2- (3,5-dimethyl-pyridylmethylsulfinyl) - (5-methoxycarbonyl) benzimidazole, 2- [2- (3,5-dimethyl-4-methoxy) pyridylmethylsulfinyl] - (5-methoxycarbonyl) benzimidazole, 2- (2- (3,5-dimethyl-4-methoxy) pyridylmethylsulfinyl) - (5-acetyl) benzimidazole, 2- (2- (4-methoxy-5-methyl) pyridylmethylsulfinyl) - (5-methoxy) benzimidazole, 2- (2- (3,5-dimethyl-4-methoxy) pyridylmethylsulfinyl) - (5-methoxy) benzimidazole, 2- [2- (3,5-Dimethyl-4-methoxy) pyridylmethylsulfinyl] - (5-methyl) benzimidazole, 2- [2- (3,5-dimethyl-4-methoxypyridylmethylsulfinyl] benzimidazole; or 2- (2- (3,5-dimethyl-4-methoxy) pyridylmethylsulfinyl) - (5-chloro) benzimidazole. 6. The process of claim 1, wherein the corresponding starting materials are used to give 2- (2- (3,5-dimethyl-4-methoxy) pyridylmethylsulfinyl) - (5-methoxy) benzimidazole.