CS261872B2 - Process for preparing 2-pyridylmethylsulphinylbenzimidazoles - Google Patents

Description

R ¹ and R ^z is a group selected from the group consisting of hydrogen, alkyl, halogen, cyano, carboxy, carboxyalkyl, alkoxykarbonylkarbamoyl, aílkoxykarbonylalkyl, kanbamoyloxyskupinu, hydroxy, alkoxy, hydroxyalkyl, trifluoromethyl and acyl in any position,

R ³ represents a group selected from the group consisting of 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,

281872 wherein at most 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 the group consisting of hydrogen, halogen, C 1 -C 7 alkyl, methoxycarbonyl, ethoxycarbonyl, C 1 -C 5 alkoxy and C 1 -C 4 alkanoyil 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 ⁴ , R ³ and R ^5, a hydrogen atom, the third of these substituents R ³ , R ⁴ and R ⁵ being other than methyl.

The alkyl R ¹ and R ² of formula III are suitably 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 and R ¹ and suitably comprises ^from alkoxy 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 proplonyl, 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 ^e is hydrogen and R ³ , R ⁴ and R ⁵ are the same or different and 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 denote R 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 alkanoyl; R ⁶ 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 alkanoyl; R ⁶ 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 identical or different and are selected from the group consisting of hydrogen, alkyl, halogen, methoxycarbonyl, ethoxycarbonyl, an alkoxy, and alkanoyl, ^R is hydrogen, methyl or ethyl, R 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 identical or different and are selected from the group consisting of hydrogen, alkyl, halogen, carbomethoxy, carbethoxy, alkoxy, and alkanoyl, ^R is selected from the group consisting of 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 alkenoyl; R ⁶ is selected from hydrogen, methyl and ethyl and R ³ , R ⁴ and R ^{5 are} each methyl.

The compounds of formula (III) according to the invention are prepared by producing a compound of formula (III)

where

R ^1, R ^2, and R ^fi are defined as above and M represents a metal selected from the group consisting of potassium, sodium, and lithium, with a compound of formula

where

R ^3, R ⁴ and R ⁵ have the abovementioned meanings and

Z is a reactive esterified hydroxy group to form a compound of formula III which, if present as a base, can be converted to an acid addition salt, or, if present as a salt, can be converted to its base.

The above-mentioned substituent Z is a reactive esterified hydroxy group, such as a hydroxy group esterified with saliva with an inorganic or organic acid, preferably a hydrohalic acid such as hydrochloric acid, hydrobromic acid or hydroiodic acid, sulfuric acid or a strong organic sulfonic acid such as a strong aromatic acid such as benzenesulfonic acid, 4-bromobenzenesulfonic acid or 4-toluenesulfonic acid.

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 as well as hemi-, mono-, sesqui, or polyhydrates can be obtained. The acid addition salts of the novel compounds can be converted into the free bases in a known manner using basic agents such as alkali 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 hydrohalic 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. , maleic, hydroxymalein, pyruvic, phenylacetic, benzoic, p-aminobenzoic, anthranilic, p-hydroxybenzoic, salicylic, or p -aminosailicylic, embonic, methanesulfonic, ethanesulfonic, hydroxyethanesulfonic, ethylenesulfonic, methanesulfenesulfonic, toluenesulfonic acid, toluenesulfonic acid, toluenesulfonic acid 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 solution of the new salt in a purer state. 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, depending on the choice of starting material and process, may be present as optical isomers or racemate, 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 (diastereomerically) pure racemates by chromatography or fractional crystallization.

The racemates obtained can be separated 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 separation 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. Usually, the amount of active ingredient is 0.1 to 95% by weight. 0.5 to 20 wt. for injectables and 2 to 50 wt. compositions for oral administration.

In preparing pharmaceutical compositions comprising a compound of this 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, mannitoil, starch, amylopectin, cellulose derivatives or gelatin. is magnesium stearate, calcium stearate and polyethylene 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 coloring agents 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, gilycerol 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 sieved 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 the practice of the invention without being limited thereto. Temperatures are given in degrees Celsius.

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

1]

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

2)

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

3) ’

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

Example 1

Dissolve 0.1 mol of 2- (Li-methylsulfinyl) - (5-acetyl-6-methyl) benzimidazole in 150 ml of benzene, then add 0.1 mol of 2-chloro- (3,5-dimethyl) pyridine and The resulting lithium chloride was filtered off and the solution was evaporated under reduced pressure, and the residue was crystallized from acetonitrile and recrystallized from the same solvent to yield 0.82 mol of 2- [2- (3,5-dimethyl) pyridylmethylsulfinyl] -i ( 171 DEG C. 5-acetyl-6-methylbenzimidazoil.

Examples 2 to 30

The process for preparing the other compounds of formula (III) is carried out as in the example above. The prepared compounds are summarized in Table 1, where they are also labeled with substituents in these compounds.

Table 1

Example number R ¹ R ² R ^s R ³ R ⁴ R ⁵ Temperature thaw Noc: 2 ° C 1 5-COCH3 6-CH3 H H CH3 CH3 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 CH3 CHs H 163 6 4-CH3 6-CH3 H CH3 H CH3 50-55 7 5-COCHs 6-CH3 H CH3 H CHS 171 8 5-COCH3 6-CH3 H CH3 CH3 CHs 190 9 5-COCH3 6-CH3 H H OCH3 H 65 10 4-CH3 6-CH3 H H OCH3 H 122 11 5-COCH3 6-CH3 H CH3 OCH3 CH3 156 12 5-COOCHs 6-CH3 H CH3 H CH3 144 13 5-COOCHs 6-CH3 H CH3 CH3 CH3 185 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-COOCHs 6-CH3 H CH3 OCH3 H 175 17 5-COOCH 3 6-CH3 H CH3 OCHs CH3 155 18 5-COOCH 3 6-CH3 H H OCH3 CHs 158 19 Dec 5-COOCH 3 H H CH3 H CHs 141 20 May 5-COOCH 3 H H CH3 OCH3 CHs 142 21 5-COCH3 H H CH3 OCH3 CH3 162 22nd 5-OCH3 H H H OCH3 CH3 178 23 5-OCH3 11 H CH3 OCH3 CH3 156 24 5-CH3 H H CH3 OCH3 CH3 181 25 I-I H H CH3 OCH3 CH3 165 26 5-C1 H H CH3 OCH3 CHs 185 27 Mar: 5-CH3 H H H OC2H4OCH3 H 119 28 5-COOC2H5 H H CH3 OCH3 CH3 150—155 29 5-COOCH 3 H CH3 CH3 H CH3 130 30 5-CH3 H CH3 CH3 H CHs 152 Biological effect čenin. After 18 hours of fasting, it was administered

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 were performed on dogs with gastric fistula of the usual type and duodenal fistula, which is used for direct intraduodenal administration of test conduits, given to dogs. 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 0.1 N sodium hydroxide to pH 7.0 to determine the titratable acid concentration. using an automated titrator and a pH meter (Radiometer, Copenhagen, Denmark) For 261872 the acidity 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 shown in Table 2. Test compounds suspended in 0.5% methylcellulose (Methocel ^R ) were administered intraduodenally at doses of 4 to 20 µmol / kg when the secretory response to pentagastrin reached a steady state level.

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

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

Example number R ¹ R ² R ⁶ R ³ R ⁴ R ⁵ Dose μΐηοΐ / kg Effect % inhibition 1 5-COCH3 6-CH3 H H CH3 CH3 2 90 4 5-COCHs 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 CHS CHs 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-OOCH3 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-COO.CH3 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 OCHs CH3 0.5 90 18 5-COOCH 3 6-CH3 H H OCII3 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-CH3 6-CH3 H CHs H CHs 4 40 10 4-CH3 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 CHs 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 CHs 0.5 60 X 5-COCH3 H H H H C2H5 20 May 40 22nd 5-OCH3 H H H OCH3 CHs 23 5-OCH3 H H CH3 OCH3 CH3 0.5 65 X 5-OCH3 H H H CH3 H 20 May 10 24 5-CH3 H H CH3 OCH3 CH3 0.5 50 X 5-CH3 H H H H CH3 4 50 25 H H H CHs OCH3 CH3 0.5 60 X H H H H H H 4 50 28 5-COOC2H5 H H CH3 OCH3 CH3 0.5 50 26 5-C1 H H CH3 OCH3 CH3 0.5 25 27 Mar: 5-CH3 H H H OC2H4OCH3 H 0.5 30 29 5-COOCH 3 H CHS CH3 H CHs 0.5 40

x - designation for a previously known compound

Example 31

Syrup containing 2 wt. by volume of the active substance are prepared from the following components:

2- [2- (4,5-dimethyl) pyridyllmethylsulfinyl] - (5-acetyl-6-methyl) benzimidazole hydrochloride saccharin sugar glycerin flavor ethanol, 96% distilled water

2.0 g 0.6 g

30.0 g 5.0 g 0.1 g

10.0 ml ad 100 mil

The sugar, saccharin and acid addition salt are dissolved in 60 g of warm water. After cooling, glycerin and a flavoring solution 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.

is compressed into a total of 10,000 tablets, each containing 25 mg of active ingredient. Tablets can be prepared which contain any desired amount of active ingredient.

Example 33

The granules are prepared from 250 g of 2- (3,5-trimethyl) pyridylmethylsulphinyl] - (5-acetyl-6-methyl) benzimidazoil-p-hydroxybenzoate, 175.9 g of lactose and an alcohol solution of 25 g of polyvinylpyrrolidone. For 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, which are first coated with a 10% alcoholic shellac solution followed by an aqueous solution containing 4'5% sucrose. % of gum arabic, 4% of gelatin and 0.2% of dye Talc and powdered sugar are used for dusting after the first five layers, then covered with 66% sugar syrup and polished with a solution of 10% carnauba wax in carbon tetrachloride.

Example 32

Example 34

250 g of 2- [2- (3,4-dimethyl) pyridylmethylsulfinyl] - (5-acetyil-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. After drying, 160 g of potato starch, 50 g of talc and 5 g of magnesium stearate are added, and the mixture thus obtained g of 2- [2- (3,5-dimethyl) pyridylmethylsulfinyl] - (5-acetyl-6-methyl) benzimidazole hydrochloride, 0.6 g of sodium chloride and 0.1 g of ascorbic acid are dissolved in an amount of distilled water to give 100 ml of a solution, containing 10 mg / ml of the active substance, to fill ampoules which are sterilized by heating to 120 ° C for 20 minutes.

Claims (6)

OBJECT OF THE INVENTION A process for the preparation of 2-pyridylmethylsulphinylenzimidazoles of formula III R ¹ and R ² , which may be the same or different, are selected from the group consisting of hydrogen, halogen, alkyl of 1 to 7 carbon atoms, methoxycarbonyl, ethoxycarbonyl, alkoxy of 1 to 5 carbon atoms and alkanoyil of 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 of the invention, methoxyethoxy and ethoxyethoxy, wherein R ³ , R ⁴ and R ^{5 do} not both represent hydrogen and two of R ³ , R ⁴ and R ^{5 are} hydrogen, the third of R ³ , R ⁴ and R ⁵ being other than methyl, and therapeutically acceptable salts thereof, characterized in that the compound of the formula wherein: R ¹ , R ² and R ^b are as defined above and M is a metal selected from the group consisting of potassium, sodium and lithium, reacted with a compound of the general formula R ’ Z N R where R ^3, R ⁴ and R ⁵ have the abovementioned meanings and Z is a reactive esterified hydroxy group, to form a compound of formula III which, if present as a base, can be converted to an acid addition salt, or, if present as a salt, can be converted to its base. 2. The method of item 1, for. preparing 2-pyridylmethylsuilfinylbenzoimidazoles of formula III wherein R ¹ represents a group selected from the group consisting of hydrogen, alkyl of 1-7 carbon atoms, methoxycarbonyl, alkoxy having 1-5 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, methoxycarbonyl, alkoxy having 1-5 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 and R ^{5 are} hydrogen, the third of R ³ R ⁴ and R ⁵ are other than methyl, as well as their therapeutically useful compounds, characterized in that the compound of formula (I) is a compound of formula (I) O S-CH-M1, where R ¹ , R ² and R ^B are as defined above and M is a metal selected from the group consisting of potassium, sodium and lithium, reacted with a compound of the formula wherein R ^3, R ⁴ and R ⁵ have the abovementioned meanings and Z is a reactive esterified hydroxy group, to form a compound of formula III which, if present as a base, can be converted to an acid addition salt, or, if present as a salt, can 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 (III) wherein: R ¹ represents hydrogen, chloro, methyl, ethyl, ethoxy, acetyl, ethoxycarbonyl or methoxycarbonyl, R ² represents hydrogen or methyl. R ^e represents hydrogen, methyl or ethyl, R ³ and R ⁵ denote 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 or methyl 'ethyl, R ⁶ is hydrogen, methyl or ethyl, R ⁴ represents methoxy, R ³ denotes hydrogen and R ⁵ is methyl or R ³ denotes methyl and R ⁵ represents hydrogen, or therapeutically acceptable salts thereof. 5. A process according to claim 1, wherein the corresponding starting materials are used to form 2- (2- (3,4-dimethylpyridylmethylsulfinyl) - (5-acetyl-6-methyl) benzimidazole, 2- [2- (3,5-dimethyl) pyridylmethylsulfinyl] - (4,6-dimethyl) benzimidazole, 2- (2- (4,5-dimethyl) pyridylmethylsulfinyl) - (5-methoxycarbonyl) benzimidazole, 2- (2- (4,5-dimethyl) pyridylmethylsulphinyl) - (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) pyridylmethyilsulfinyl) - (5-acetyl-6-methyl) benzimidazole, 2- [2- (4-methoxy) pyridylmethylsulfinyl] - (5-acetyl-6-methyl) benzimidazole, 2- [2- (4-methoxy) pyridylmethylsulfonyl] - (4,6-methyl) benzimidazole, 2- [2- (3,5-dimethyl-4-methoxy) pyridylmethylsulphinyl] -N- (5-acetyl-6-methyl) benzimidazole, 2- (2- (3,5-dimethyl) pyridylmethylsulphinyl) N- (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-methoxypyridylmethylsulfinyl) - (5-methoxycarbonyl) -bonyl -6-methyl) benzimidazole, 2- (2- (3,5-dimethyl-4-methoxy) pyridylmethylsulfinyl) - (5-methoxycarbonyl-6-methyl) benzimidazole, 2- [2- (4-methoxy-5-methylpyridylmethylsulfinyl) -, (5-methoxycarbonyl-6-methyl) 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} pyridylmethylsulphinyl) - (5-methyl) benzimidazole, 2- [2- (3,5-dimethyl-4-methoxy) pyridylmethylsulfinyl] 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) benzimidazoil.