Process for preparing 2-pyridylmethylsulphinylbenzimidazoles

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)

<img file="CS261874B2_D0001.tif" />

<img file="CS261874B2_D0002.tif" />

where

R¹ and R² denotes a group selected from hydrogen, alkyl, halogen, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, carbamoyl, carbamoyloxy, hydroxy, alkoxy, hydroxyalkyl, trifluoromethyl and acyl at any position,

R³ represents a group selected from hydrogen, alkyl, acyl, alkoxycarbonyl, carbamoyl, alkoxycarbonylmethyl, alkylcarbamoyl, dialkylcarbamoyl, alkylcarbonylmethyl and alkylsulfonyl; and

R⁴ denotes a group selected from the group consisting of straight and branched alkylene groups having 1 to 4 carbon atoms,

211874 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

<img file="CS261874B2_D0003.tif" />

where

R¹ and R²which are the same or different are selected from hydrogen, halogen, alkyl of 1 to 7 carbon atoms, methoxycarbonyl, ethoxycarbonyl, alkoxy of 1 to 5 carbon atoms and alkanoyl of 1 to 4 carbon atoms in any position,

R⁶ represents a group selected from the group consisting of hydrogen, methyl and ethyl,

R³, R⁴ and R⁵which are identical or different are selected from the group consisting of hydrogen, methyl, inethoxy, ethoxy, methoxyethoxy and ethoxyethoxy, wherein R is³, R⁴ and R⁵ does not simultaneously represent a hydrogen atom and when it represents two of the substituents R³, R⁴and R⁵ a hydrogen atom, the third of these R substituents³, R⁴ and R⁵ is other than methyl.

Alkyl R¹ and R² in formula III, it is suitably alkyl of up to 7 carbon atoms, preferably up to 4 carbon atoms. Such an alkyl R 1¹ or R² is, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl.

Halogenem R¹ and R² is chlorine, bromine, fluorine or iodine.

Alkoxy R¹ and R² 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 R¹ and R² suitably have up to 4 carbon atoms and are, for example, formyl, acetyl or propionyl, preferably acetyl.

A preferred group of compounds of formula (III) are those wherein R @ 1¹ and R² are the same or different and are selected from the group consisting of hydrogen, alkyl, methoxycarbonyl, alkoxy and alkanoyl, wherein R is¹ and R² they do not simultaneously denote hydrogen,⁶ is hydrogen and R is³, R⁴ and R⁵ are the same or different and are selected from the group consisting of hydrogen, methyl, methoxy and ethoxy, wherein R is³, R⁴ and R⁵ they do not always denote a hydrogen atom and when they represent two substituents R³, R⁴ and R⁵ hydrogen the third of these substituents R @ 1³, R⁴ and R⁵ not methyl.

Another preferred group of compounds of formula (III) are those wherein R is¹ and R²are the same or different and each is selected from the group consisting of hydrogen, alkyl, halogen, methoxycarbonyl, ethoxycarbonyl, alkoxy, and alkanoyl;⁶ is selected from the group consisting of hydrogen, methyl and ethyl;³ denotes methyl, R⁴ is methoxy and R is⁵ denotes methyl.

A third preferred group of compounds of formula (III) are those wherein R 1 is R 2¹ and R²are the same or different and are selected from the group consisting of hydrogen, alkyl, halogen, methoxycarbonyl, ethoxycarbonyl, alkoxy, and alkanoyl;⁶ is selected from the group consisting of hydrogen, methyl and ethyl;³ R is hydrogen;⁴ is methoxy and R is⁵ is methyl or R 1³ denotes methyl, R⁴denotes inethoxy and R⁵ represents hydrogen.

A fourth preferred group of compounds of formula (III) are those wherein R is¹and R^of are the same or different and are selected from the group consisting of hydrogen, alkyl, halogen, methoxycarbonyl, ethoxycarbonyl, alkoxy and alkanoyl;⁶ represents hydrogen, methyl or ethyl;³ and R⁵ represents a hydrogen atom and R⁴ represents an inethoxy group.

A fifth preferred group of compounds of formula (III) are those wherein R 1¹ and R²are the same or different and are selected from the group consisting of hydrogen, alkyl, halogen, methoxycarbonyl, ethoxycarbonyl, alkoxy and alkanoyl;^E is selected from the group consisting of hydrogen, methyl and ethyl and R 1³ and R⁵ denotes methyl groups and R @ 1⁴ is hydrogen.

A sixth preferred group of compounds of formula (III) are those wherein R is¹and R² are the same or different and are selected from the group consisting of hydrogen, alkyl, halogen, methoxycarbonyl, ethoxycarbonyl, alkoxy and alkanoyl;^E is selected from the group consisting of hydrogen, methyl and ethyl;³and R⁵ represents a hydrogen atom and R⁴ represents ethoxy, methoxyethoxy or ethoxyethoxy.

A seventh preferred group of compounds of formula (III) are those wherein R 1¹and R² are the same or different and are selected from the group consisting of hydrogen, alkyl, halogen, methoxycarbonyl, alkoxy and alkanoyl;⁶ is selected from the group consisting of hydrogen, methyl and ethyl and R 1³, R⁴ and R⁵is methyl.

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

<img file="CS261874B2_D0004.tif" />

where

R¹ and R² and as defined above, reacted with a compound of formula X

<img file="CS261874B2_D0005.tif" />

where

R⁶, R³, R⁴ and R⁵ are as defined above to form an intermediate of formula (IV)

<img file="CS261874B2_D0006.tif" />

where

R¹, R², R^b, R³, R⁴ and R⁵ are as defined above, which is then oxidized to a compound of formula III which, if present as a base, may be converted to an acid addition salt, or, if present as a salt, may be converted to its base.

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-halenesuccinimide, 1-chlorobenzotriazole, tertiary. -butyl hypochlorite, 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 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 manner known per se 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-aminosalicylic, embonic acid, methanesulfonic 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 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 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 (diastereomerically) 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, sulfonic acid, quinic acid. Preferably, the more active portion is isolated from both antipodes.

The 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, sulphate, 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 5Ό 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, 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 particular particle size and also 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 slurry 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 solubility in water. 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 coarse and bitter, they can be covered with a layer of sugar or other tasty 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 limiting it. Temperatures are given in degrees Celsius.

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

1)

The 1,2-amino compound, such as o-phenylenediamine, is reacted with potassium ethylxanthate, according to Org. Synth., Vol. 38, p. 56, to give 2-mercaptobenzimidazole.

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) pyridylmethylthio] - (5-acetyil-6-methyl) benzimidazoil are dissolved in 160 ml of chloroform and added portionwise with stirring and cooling to 5 degrees Celsius. 4 g of m-chloroperbenzoic acid After 10 minutes, the precipitated m-chlorobenzoic acid is filtered off, the filtrate is diluted with methylene chloride, washed with sodium carbonate solution, dried with sodium sulfate and evaporated under reduced pressure, and the residue is crystallized after dilution with acetonitrile. 2- (2- (4,5-dimethyl) pyridylmethylsulfinyl) - (5-acetyl-6-methyl) benzimidazole was recrystallized from acetonitrile to yield 22.3 g, m.p. 158 ° C.

Example 1a

23.4 g of 2- [2- (3,4,5-trimethyl) pyridylmethylthio] formic acid and 16.6 g of o- (5-acetyl-6-methyl) phenylenediamine are boiled in 100 ml of 4N hydrochloric acid for 40 minutes. The mixture was cooled and neutralized with ammonia. The neutral solution is then extracted with ethyl acetate. The organic phase was treated with charcoal and evaporated under reduced pressure. The residue was dissolved in acetone and then an equivalent amount of concentrated hydrochloric acid was added. After cooling, the precipitated hydrochloride is filtered off and the salt is recrystallized from absolute ethanol containing a small amount of ether. The yield of 2- [2- (3,4,5-trimethylpyridyl) methylthio] - (5-acetyl-6-methyl) benzimidazole is 6.5 g.

This compound is oxidized by sweat as in Example 1 to give the corresponding sulfinyl derivative. The melting point is 190 degrees Celsius.

Examples 2 to 30

The process for preparing the other compounds of formula III is carried out as in the examples above. The prepared compounds are summarized in Table J, where the substituents in these compounds are also indicated.

<img file="CS261874B2_D0007.tif" />

<td>Example</td><td>R¹</td><td>R^of</td><td>R^G</td><td>R³</td><td>R⁴</td><td>R⁵</td><td>Temperature thaw Deň: 32 ° C</td>

<td> 1</td><td>5-COCH3</td><td>6-CH3</td><td>H</td><td>H</td><td>CH3</td><td>C.H3</td><td> 158</td>

<td> 2</td><td>5-COOCH 3</td><td>6-CH3</td><td>H</td><td>H</td><td>CH3</td><td>CH3</td><td> 163</td>

<td> 3</td><td>5-COOCHs</td><td>H</td><td>H</td><td>H</td><td>CH3</td><td>CH3</td><td> 141</td>

<td> 4</td><td>5-COCH3</td><td>6-CH3</td><td>H</td><td>CH3</td><td>CH3</td><td>H</td><td> 160</td>

<td> 5</td><td>5-COOCH 3</td><td>6-CH3</td><td>H</td><td>CH3</td><td>CH3</td><td>H</td><td> 163</td>

<td> 6</td><td>4-CH3</td><td>6-CH3</td><td>H</td><td>CH3</td><td>H</td><td>CH3</td><td> 50 — 55</td>

<td> 7</td><td>5-COCH3</td><td>6-Cl-13</td><td>H</td><td>CH3</td><td>H</td><td>CH3</td><td> 171</td>

<td> 8</td><td>5-COCH3</td><td>6-CH3</td><td>H</td><td>CH3</td><td>CH3</td><td>CHs</td><td> 190</td>

<td> 9</td><td>5-COCH3</td><td>6-CH3</td><td>H</td><td>H</td><td>OCH3</td><td>H</td><td> 165</td>

<td> 10</td><td>4-CH3</td><td>6-CH3</td><td>H</td><td>H</td><td>OCH3</td><td>H</td><td> 122</td>

<td> 11</td><td>5-COCH3</td><td>6-CH 2</td><td>H</td><td>CH3</td><td>OCH3</td><td>CHs</td><td> 156</td>

<td> 12</td><td>5-COOCH 3</td><td>6-CH 2</td><td>H</td><td>CH3</td><td>H</td><td>CH3</td><td> 144</td>

<td> 13</td><td>5-COOCH 3</td><td>6-CH3</td><td>H</td><td>CHS</td><td>CHs</td><td>CHs</td><td> 185</td>

<td> 14</td><td>5-COOCH 3</td><td>6-CH3</td><td>H</td><td>H</td><td>OCH3</td><td>H</td><td> 169</td>

<td> 15</td><td>5-COOCH 3</td><td>6-CH3</td><td>H</td><td>H</td><td>OC2H5</td><td>H</td><td> 148</td>

<td> 16</td><td>5-COOCHs</td><td>6-CH3</td><td>H</td><td>CH3</td><td>OCH3</td><td>H</td><td> 175</td>

<td> 17</td><td>5-COOCH 3</td><td>6-CH3</td><td>H</td><td>CHS</td><td>OCH3</td><td>CH3</td><td> 155</td>

<td> 18</td><td>5-COOCH 3</td><td>6-CH3</td><td>H</td><td>H</td><td>OCH3</td><td>CH3</td><td> 158</td>

<td> 19</td><td>5-COOCH 3</td><td>H</td><td>H</td><td>CH3</td><td>H</td><td>CHs</td><td> 141</td>

<td> 20</td><td>5-COOCH 3</td><td>H</td><td>H</td><td>CH3</td><td>OCH3</td><td>, CH3</td><td> 142</td>

<td> 21</td><td>5-COCH3</td><td>H</td><td>H</td><td>CH3</td><td>OCH3</td><td>CH3</td><td> 162</td>

<td> 22</td><td>5-OCH3</td><td>H</td><td>H</td><td>H</td><td>OCHs</td><td>CH3</td><td> 178</td>

Example R¹ R² R⁶

281874

<td> 23</td><td>5-OCH3</td><td>H</td><td>H</td>

<td> 24</td><td>5-CH3</td><td>H</td><td>H</td>

<td> 25</td><td>H</td><td>H</td><td>H</td>

<td> 26</td><td>5-C1</td><td>H</td><td>H</td>

<td> 27</td><td>5-CH3</td><td>H</td><td>H</td>

<td> 28</td><td>5-COOC2U5 &lt;</td><td>&gt; H</td><td>H</td>

<td> 29</td><td>5-COOCH 3</td><td>H</td><td>CHj</td>

<td> 30</td><td>5-CH 2</td><td>H</td><td>CH3</td>

<td colspan="2">Biological effect</td><td></td><td></td>

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 a gastric fist of the usual type and with a duodenal fistula, which is used for direct intraduodenal administration of test compounds. 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. The allquot of each sample was titrated with 0.1N sodium hydroxide to pH 7.0 to determine the titratable acid concentration.

<td>R³</td><td>R⁴</td><td>R⁵</td><td>Temperature thaw Deň: 32 ° C</td>

<td>CA3</td><td>OCHs</td><td>CH3</td><td> 156</td>

<td>iCH3</td><td>OCH3</td><td>CH3</td><td> 181</td>

<td>, CH3</td><td>OCH3</td><td>CA3</td><td> 165</td>

<td>CH3</td><td>OCH3</td><td>CH3</td><td> 185</td>

<td>H</td><td>OC2H4OCH3</td><td>H</td><td> 119</td>

<td>CH3</td><td>OCH3</td><td>CH3</td><td> 150 — 155</td>

<td>CH3</td><td>H</td><td>CH3</td><td> 130</td>

<td>CH3</td><td>H</td><td>CH3</td><td> 152</td>

The 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 µM / kg when the secretory response to pentagastrin reached a steady state level.

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

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

Example R¹

Table 2

<img file="CS261874B2_D0008.tif" />

Dose Effect μΐηοΐ / kg% inhibition

<td> 1</td><td>5-COCH3</td><td>6-CH3</td><td>H</td><td>H</td><td>CH3</td><td>CH3</td><td> 2</td><td> 90</td>

<td> 4</td><td>5-COCH3</td><td>6-CH3</td><td>H</td><td>CHs</td><td>CH3</td><td>H</td><td> 1</td><td> 60</td>

<td> 7</td><td>5-COCH3</td><td>6-CH3</td><td>H</td><td>CH3</td><td>H</td><td>CH3</td><td> 2</td><td> 100</td>

<td> 8</td><td>5-COCH3</td><td>6-CH3</td><td>H</td><td>CH3</td><td>CH3</td><td>CH3</td><td> 4</td><td> 100</td>

<td> 9</td><td>5-COCH3</td><td>6-CH3</td><td>H</td><td>H</td><td>OCH3</td><td>H</td><td> 2</td><td> 95</td>

<td> 11</td><td>5-COCH3</td><td>6-CH3</td><td>H</td><td>CH3</td><td>OCH3</td><td>CH3</td><td> 0,5</td><td> 70</td>

<td>X</td><td>5-COCH3</td><td>6-CH3</td><td>H</td><td>H</td><td>CH3</td><td>H</td><td> 20</td><td> 30</td>

<td>X</td><td>5-COCH3</td><td>6-CH3</td><td>H</td><td>H</td><td>H</td><td>CH3</td><td> 8</td><td> 80</td>

<td> 2</td><td>5-COOCH 3</td><td>6-CH3</td><td>H</td><td>H</td><td>CH3</td><td>CH3</td><td> 2</td><td> 60</td>

<td> 5</td><td>5-COOCH 3</td><td>6-CH3</td><td>H</td><td>CH3</td><td>CH3</td><td>H</td><td> 2</td><td> 90</td>

<td> 12</td><td>5-COOCH 3</td><td>6-CH3</td><td>H</td><td>CH3</td><td>H</td><td>CH3</td><td> 2</td><td> 70</td>

<td> 13</td><td>5-COOCH 3</td><td>6-CH3</td><td>H</td><td>CH3</td><td>CH3</td><td>CH3</td><td> 4</td><td> 80</td>

<td> 14</td><td>5-COOCH 3</td><td>6-CH3</td><td>H</td><td>H</td><td>OCH3</td><td>H</td><td> 2</td><td> 100</td>

<td> 15</td><td>5-COOCH 3</td><td>6-CH3</td><td>H</td><td>H</td><td>OC2H5</td><td>H</td><td> 4</td><td> 75</td>

<td> 16</td><td>5-COOCH 3</td><td>6-CH3</td><td>H</td><td>CH3</td><td>OCH3</td><td>H</td><td> 0,5</td><td> 65</td>

<td> 17</td><td>5-COOCH 3</td><td>6-CH3</td><td>H</td><td>CH3</td><td>OCH3</td><td>CH3</td><td> 0,5</td><td> 90</td>

<td> 18</td><td>5-COOCH 3</td><td>6-CH3</td><td>H</td><td>H</td><td>OCH3</td><td>GH3</td><td></td><td></td>

<td>X</td><td>5-COOCH 3</td><td>6-CH3</td><td>H</td><td>H</td><td>H</td><td>CH3</td><td> .4</td><td> 50</td>

<td>X</td><td>5-COOCH 3</td><td>6-CH3</td><td>H</td><td>Br</td><td>H</td><td>H</td><td> 4</td><td> 0</td>

Example R¹ r2 _R6 _R3

R⁴

R⁵ Dose Effect of jumol / kg% inhibition

<td> 6</td><td>4-CH3</td><td>6-CH3</td><td>H</td><td>CH3</td><td>H</td><td>CH3</td><td> 4</td><td> 40</td>

<td> 10</td><td>4-CH3</td><td>6-CH3</td><td>H</td><td>H</td><td>OCH3</td><td>H</td><td> 2</td><td> 40</td>

<td>x</td><td>4-CH3</td><td>6-CH3</td><td>H</td><td>H</td><td>H</td><td>H</td><td> 4</td><td> 30</td>

<td>X</td><td>4-CH3</td><td>6-CH3</td><td>H</td><td>H</td><td>H</td><td>CH3</td><td> 12</td><td> 50</td>

<td> 3</td><td>5-COOCH 3</td><td>H</td><td>H</td><td>H</td><td>CH3</td><td>CH3</td><td> 4</td><td> 100</td>

<td> 19</td><td>5-COOCH 3</td><td>H</td><td>H</td><td>CH3</td><td>H</td><td>CH3</td><td> 2</td><td> 60</td>

<td> 20</td><td>5-COOCH 3</td><td>H</td><td>H</td><td>CH3</td><td>OCH3</td><td>CH3</td><td> 0,5</td><td> 65</td>

<td>X</td><td>5-COOCH 3</td><td>H</td><td>H</td><td>H</td><td>H</td><td>CH3</td><td> 20</td><td> 90</td>

<td>X</td><td>5-COOCH 3</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H</td><td> 20</td><td> 50</td>

<td> 21</td><td>5-COCH3</td><td>H</td><td>H</td><td>CH3</td><td>OCH3</td><td>CH3</td><td> 0,5</td><td> 60</td>

<td>X</td><td>5-COCH3</td><td>H</td><td>H</td><td>H</td><td>H</td><td>C2H5</td><td> 20</td><td> 40</td>

<td> 22</td><td>5-OCH3</td><td>H</td><td>H</td><td>H</td><td>0CH3</td><td>CH3</td><td></td><td></td>

<td> 23</td><td>5-OCH3</td><td>H</td><td>H</td><td>CH3</td><td>OCHs</td><td>CH3</td><td> 0,5</td><td> 65</td>

<td>X</td><td>5-OCH3</td><td>H</td><td>H</td><td>H</td><td>CH3</td><td>H</td><td> 20</td><td> 10</td>

<td> 24</td><td>5-CH3</td><td>H</td><td>H</td><td>CH3</td><td>OCH3</td><td>CH3</td><td> 0.5</td><td> 50</td>

<td>X</td><td>5-CH3</td><td>H</td><td>H</td><td>H</td><td>H</td><td>CH3</td><td> 4</td><td> 50</td>

<td> 25</td><td>H</td><td>H</td><td>H</td><td>CH3</td><td>OCH3</td><td>CH3</td><td> 0,5</td><td> 60</td>

<td>X</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H</td><td> 4</td><td> 50</td>

<td> 28</td><td>5-COOC2H5</td><td>H</td><td>H</td><td>CH3</td><td>OCH3</td><td>CH3</td><td> 0,5</td><td> 50</td>

<td> 26</td><td>5-C1</td><td>H</td><td>H</td><td>CH3</td><td>CH3</td><td>CH3</td><td> 0,5</td><td> 25</td>

<td> 27</td><td>5-CH3</td><td>H</td><td>H</td><td>H</td><td>DC2H4OCH3</td><td>H</td><td> 0,5</td><td> 30</td>

<td> 29</td><td>5-COOCH 3</td><td>H</td><td>CH3</td><td>CH3</td><td>H</td><td>CH3</td><td> 0,5</td><td> 40</td>

x - designation for a previously known compound

Example 31

Syrup containing 2 wt. bulking agents are prepared from the following components:

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

2.0 g 0.6 g 30.0 g 5.0 g 0.1 g 10.0 g

100 ALIGN! ml

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 hydride is mixed with 175.8 g of lactose, 169.7 g of potato starch and 32 g of colloidal silicic acid. After being dried, 160 g of potato starch, 50 g of talc and 5 g of magnesium stearate are added and the mixture thus obtained is compressed into a total of 10 000 tablets, each tablet containing 25 mg of the active substance. Tablets can be prepared which contain any desired amount of active ingredient.

Example 33

The granules are prepared from 250 g of 2- [2- (3,5-dimethyl] pyridylmethylsulfinyl] - (5-acetyl-6-methyl) benzimidazole-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 to 10,000 tablets, which are first coated with a 10% alcoholic shellac solution followed by an aqueous solution containing 45 percent sucrose, 5% arabic gum and 4% gelatin with 0.2% dye. 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 g of 2- (2- (3,5-dimethyl) pyridylmethylsulfinyl] - (5-acetyl-6-methyl) benzimidazole hydrochloride, 0.5 g of sodium chloride and 0.1 g of ascorbic acid are dissolved in such an amount of distilled water, This solution, containing 10 mg / ml of active ingredient, is used to fill ampoules which are sterilized by heating to 120 ° C for 20 minutes.