Substituted pyridylsulfinylbenzimidazoles having gastric acid secretion properties, pharmaceutical preparations containing same, and intermediates for their preparation.

© Start of patent period: 1983 09 15 Longest possible duration:

© Published: 1984 04 25 © inventor: JUNGGREN ULF KRISTER

MÖLNLYCKE »SWEDEN 5J9STRAND SVEN ERIK KUNGSBACKA, SWEDEN © Dependency:

AT 374 471 © References contemplated by the prior art:

OE-CS 2548340 AT-PS 343659

- 2 No. 374471

The invention relates to a process for the preparation of novel 2-pyridylalkyl-sulfinyl-benzimidazoles of the general formula

<img file="AT374471B_D0001.tif" />

H where R¹ and R² are the same or different and each represents hydrogen, halogen, alkyl, carbomethoxy, carbethoxy, alkoxy or alkanoyl in any position, R⁶ Is hydrogen, methyl or ethyl and R³'R'¹ as well as R⁵ are the same or different and each represents hydrogen, methyl, methoxy, ethoxy, methoxy ethoxy or ethoxy ethoxy, with the proviso that R³, R * and R^s not simultaneously hydrogen and that one of the three substituents R³, R and R^s also has a meaning other than methyl, if two of these substituents are hydrogen, as well as their hydrates, stereoisomers and therapeutically acceptable salts.

The aim of the invention is the preparation of novel compounds which act on gastric acid secretion and inhibit exogenous or endogenously stimulated gastric acid secretion. The new compounds can be used in the treatment of gastric ulcers.

It was previously known that compounds of the general formulas and

<img file="AT374471B_D0002.tif" />

R³ (III) (IV) wherein R¹ and R² each represents hydrogen, alkyl, halogen, cyano, carboxy, carboxyalkyl, carboalkoxy, carboalkoxyalkyl, carbamoyl, carbamoyloxy, hydroxy, alkoxy, hydroxyalkyl, trifluoromethyl or acyl in any position, R³ Is hydrogen, alkyl, acyl, carboalkoxy, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, alkylcarbonylmethyl, alkoxycarbonylmethyl or alkylsulfonyl and R is a straight or branched alkylene group having 1 to 4 carbon atoms, with at most one methylene group between S and the pyridyl group being present and wherein the Pyridyl group with alkyl or halogen may be further substituted, have an inhibitory effect on gastric acid secretion.

However, it has now surprisingly been found that the new compounds of formula (I) have an even greater inhibitory effect than those mentioned above.

Stand R¹ and R^a in formula (I) for alkyl, they are useful alkyl atoms with up to 7 carbon atoms, preferably up to 4 carbon atoms. Thus, R¹ or R²when it is alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl.

Nr.374471

Stand R 'and R² for halogen, they are chlorine, bromine, fluorine or iodine.

Stand R¹ and R² for alkoxy, they are suitably alkoxy groups having up to 5 carbon atoms, preferably up to 3 carbon atoms, such as methoxy, ethoxy, n-propoxy or isopropoxy.

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

A preferred group of new compounds of general formula (I) which can be prepared is that in which R¹ and R² are the same or different and each is hydrogen, alkyl, carbomethoxy, alkoxy or alkanoyl, wherein R¹ and R² not both are hydrogen, R⁶ is hydrogen, R³, R and R⁵ are the same or different and each represents hydrogen, methyl, methoxy or ethoxy, with the proviso given above.

A second preferred group of novel compounds of general formula (I) is that in which R¹ and R² are the same or different and each is hydrogen, alkyl, halogen, carbomethoxy, carbethoxy, alkoxy or alkanoyl, R⁶ Is hydrogen, methyl or ethyl, R³ Methyl, R¹* Methoxy and R⁵ Represents methyl.

A third preferred group of compounds of general formula (I) is that in which R¹ and R² are the same or different and each is hydrogen, alkyl, halogen, carbomethoxy, carbethoxy, alkoxy or alkanoyl, R⁶ Represents hydrogen, methyl or ethyl, and R³ Hydrogen, R '* methoxy and R^s Methyl, or R³ Methyl, R * methoxy and R^s Is hydrogen.

A fourth preferred group of compounds of general formula (I) is that in which R¹ and R² are the same or different and each is hydrogen, alkyl, halogen, carbomethoxy, carbethoxy, alkoxy or alkanoyl, R⁶ Is hydrogen, methyl or ethyl, R³ and R⁵ Are hydrogen and R is methoxy.

A fifth preferred group of compounds of the general formula (I) is that in which R¹ and R² are the same or different and each is hydrogen, alkyl, halogen, carbomethoxy, carbethoxy, alkoxy or alkanoyl, R⁶ Represents hydrogen, methyl or ethyl, R³ and R⁵ Are methyl and R * is hydrogen.

A sixth preferred group of compounds of general formula (I) is that in which R¹ and R² are the same or different and each is hydrogen, alkyl, halogen, carbomethoxy, carbethoxy, alkoxy or alkanoyl, R⁶ Is hydrogen, methyl or ethyl, R³ and R⁵ Represent hydrogen and R * ethoxy, methoxy ethoxy or ethoxy ethoxy.

A seventh preferred group of compounds of general formula (I) is that in which R^l and R² are the same or different and each is hydrogen, alkyl, halogen, carbomethoxy, alkoxy or alkanoyl, R⁶ Is hydrogen, methyl or ethyl, and R³, R¹* and R⁵ all represent methyl.

The inventive method is characterized in that a compound of general formula

R

<img file="AT374471B_D0003.tif" />

H where R¹ , R², R⁶, R³, R¹* and R⁵ If desired, a compound of the general formula (I) obtained is converted into an acid addition salt or liberated from a salt and / or a stereo mixture obtained is, if desired, separated into the pure enantiomers or diastereomers.

A compound of the general formula (II) can be obtained, for example, by reacting a compound of the general formula

- 4 No. 374471 wherein R¹ and R² have the above meaning and Z¹ SH or a reactive esterified hydroxy group, with a compound of general formula

R²

<img file="AT374471B_D0004.tif" />

H

<img file="AT374471B_D0005.tif" />

(VIII) wherein R⁶ , R³, R¹· And R⁵ have the above meaning and Z² is a reactive esterified or SH, or by reacting a compound of the general formula

hydroxy

<img file="AT374471B_D0006.tif" />

(IX) wherein R^l and R² have the above meaning, with a compound of the general formula

R⁵ (X)

HOOC-S-CH /

IN where R⁶, R³, R¹* and R⁵ above meaning are produced.

In the above reactions, Z * and Z² a reactive, esterified hydroxy group, which means a hydroxy group containing a strong inorganic or organic acid, preferably hydrohalic acid, such as hydrochloric, hydrobromic or hydroiodic acid, also sulfuric acid or a strong organic sulfonic acid, such as a strong aromatic acid, eg benzenesulfonic acid, 4 Bromobenzenesulfonic acid or 4-toluenesulfonic acid, was esterified.

The oxidation of the sulfur atom to sulfinyl (S + O) is preferably carried out with an oxidizing agent selected from nitric acid, hydrogen peroxide, peracids, peresters, ozone, dinitrogen tetroxide, iodosobenzene, N-halosuccinimide, 1-chlorobenzotriazole, tert-butyl hypochlorite, diazabicyclo [2, 2,2] octane-bromine complex, sodium metaperiodate, selenium dioxide, manganese dioxide, chromic acid, ceric ammonium nitrate, bromine, Chlorine and sulfuryl chloride in the presence of a reaction-inert solvent. The oxidizing agent is expediently present in a certain excess with respect to the product to be oxidized.

Particularly preferred is 2- [2- (3,5-dimethyl-4-methoxy) -pyridylmethylsulfinyl] -5-methoxy-benz 25 imidazole of the formula

- 5 No. 374471

0CH₃

H₃C

H_aCO

<img file="AT374471B_D0007.tif" />

N

H ch₃ (Ia) by oxidation of 2- [2- (3,5-dimethyl-4-methoxy) pyridylmethylthio] -5-methoxy-benzimidazole prepared, being used as the oxidizing agent in particular m-chloroperbenzoic acid.

Depending on process conditions and starting materials, the final product is obtained either as a free base or as an acid addition salt, both of which fall 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 to the free base in a manner known per se, either by using basic agents such as alkali, or by ion exchange. On the other hand, the resulting free bases 10 can form salts with organic or inorganic acids. In the preparation of acid addition salts, it is preferred to use those acids which form suitable therapeutically acceptable salts. Such acids include the hydrogen halide, sulfonic, phosphoric, nitric and perchloric acids; aliphatic, alicyclic, aromatic, heterocyclic carboxylic or sulphonic acids, such as formic acid, acetic acid, propionic, succinic, glycolic, lactic, malic, tartaric, citric, ascorbic, maleic, hydroxymalein, pyruvic, Phenylacetic, benzoic, p-aminobenzoic, anthranilic, p-hydroxybenzoic, salicylic or p-aminosalicylic, embonic, methanesulfonic, ethanesulfonic, hydroxyethylsulfonic, ethylenesulfonic, halobenzenesulfonic, toluenesulfonic, naphthylsulfonic or sulphanilic acid ; Methionine, tryptophan, lysine or arginine.

These or other salts of the new compounds, such as picrates, can serve as cleaning agents for the resulting free bases. Salts of the bases can be formed, separated from the solution, and then the free base can be recovered from a new salt solution in a purer state. Because of the relationship between the novel free base compounds and their salts, it will be understood that the preparation of the corresponding salts falls within the scope of the invention.

Depending on the choice of starting materials and the process, some of the new compounds may be present as optical isomers or racemates or, if they contain at least two asymmetric carbon atoms, as an isomeric mixture (racemic mixture).

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

The resulting racemates can be separated by known methods, for example, recrystallization from an optically active solvent, use of microorganisms, reactions with optically active acids which form salts which can be separated, separation based on different solubilities of the diastereomers. Suitable optically active acids are the L35 and D forms of tartaric acid, di-o-tolyl tartaric acid, malic acid, mandelic acid, camphorsulfonic acid or quinic acid. Preferably, the more active part of the two antipodes is isolated.

The starting materials are known or, if they are new, can be obtained by methods known per se.

In clinical use, the compounds obtained according to the invention are administered orally, rectally or by injection in the form of a pharmaceutical preparation containing an active component either as a free base or as a pharmaceutically acceptable salt, namely a non-toxic acid addition salt such as hydrochloride, lactate, acetate, Sulfamate, in combination with a pharmaceutically acceptable carrier. The carrier can be a solid, semi-solid, liquid diluent or capsule. Usually, the amount of active compound is between 0.1 to 95% by weight of the preparation, between 0.5 and 20% by weight of preparations

- 6 No. 374471 for injection and between 2 and 50% mass in preparations for oral administration.

In the preparation of pharmaceutical preparations containing a compound obtained according to the invention in unit dosage form for oral administration, the chosen compound with a solid, powdery carrier such as lactose, sucrose, sorbitol, mannitol, starch, amylopectin, cellulose derivatives or gelatin, and with a Lubricating agents such as magnesium stearate, calcium stearate and polyethylene glycol waxes are mixed. The mixture is then compressed into tablets. If coated tablets are desired, the core as set forth above may be coated with a concentrated sugar solution which may contain gum arabic, gelatin, talc or titanium dioxide, or with a varnish dissolved in a volatile organic solvent or mixture of solvents. Various dyes may be added to this coating in order to distinguish between tablets with different active compounds or to differentiate with different amounts of active compounds contained.

Soft gelatin capsules can be prepared which contain a mixture of the active compound which can be prepared according to the invention and vegetable oil. 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 made in the form of suppositories containing the active substance in admixture with a neutral fat base, or they may be produced in the form of gelatin rectal capsules containing the active substance in admixture with a vegetable or paraffin oil.

Liquid preparations for oral administration may be prepared in the form of syrups or suspensions, for example solutions containing from 0.2 to 20% by weight of active ingredient, the remainder being sugar and a mixture of ethanol, water, glycerol and propylene glycol consists. Optionally, such liquid preparations may contain coloring agents, flavorings, saccharin and carboxymethylcellulose as thickening agents.

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

Pharmaceutical tablets for oral use are prepared in the following manner: The solid substances 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 the excipients are mixed together with the binder solution. The resulting mixture is moistened to form a uniform suspension with the consistency of wet snow. Moistening causes the particles to clump together, and the resulting mass is forced through a stainless steel sieve having a mesh size of about 1 mm. The layers of the mixture are dried in carefully controlled drying rooms for about 10 hours to obtain the desired particle size and consistency. The granules of the dried mixture are sieved to remove any powder particles. Disintegrating agents, lubricants and antiadhesives are added to this mixture. Finally, the mixture is compressed into tablets using a machine with the appropriate punches and punches to achieve the desired tablet size. The applied pressure affects the size of the tablet, its strength and water solubility. The applied compression pressure should be between 0.5 and 5 t. Tablets are produced at a rate of 20,000 to 200,000 / h. The tablets, especially the savory and bitter ones, may be coated with a layer of sugar or some other edible substance. They are then packed in machines with electronic counting devices. The various types of packaging include glass or plastic containers, boxes, tubes and packages for special cans.

The typical daily dose of the active substance varies according to individual needs and administration. In general, oral doses range from 100 to 400 mg / day of active substance and intravenous doses between 5 and 20 mg / day.

Nr.374471

In the following formulation instructions, the preparation of some pharmaceutical preparations is described concretely.

Formulation Procedure A syrup containing 2% (v / v) of active substance was prepared from the following ingredients:

2- [2- (4,5-Dimethyl) -pyridylmethylsulfinyl] - (5-acetyl-6-methyl) -benzimidazole · HCl 2.0 g

Saccharin 0.6 g

Sugar 30.0 g

Glycerol 5.0 g

Flavor 0.1 g

Ethanol 96% 10.0 ml

Distilled water (sufficient to give a final volume of 100 ml)

Sugar, saccharin and the acid addition salt were dissolved in 60 g of warm water. To

Cooling was added to glycerol and a solution of flavoring dissolved in ethanol. To the mixture was added water to obtain a final volume of 100 ml.

The above-mentioned active substance may be replaced by other pharmaceutically acceptable acid addition salts.

Formulation Procedure 2: 2- [2- (3,4-Dimethyl) -pyridylmethylsulfinyl] - (5-acetyl-6-methyl) 20-benzimidazole · HCl (250 g) was treated with lactose (175.8 g), potato starch (169 , 7 g) and colloidal silica (32 g). The mixture was moistened with 10% gelatin solution and ground through a 12-mesh sieve. After drying, potato starch (160 g), talc (50 g) and magnesium stearate (5 g) were added and the resulting mixture was compressed into tablets (10,000), each tablet containing 25 mg of active substance. Tablets can be made with any amount of active ingredient.

Formulation Procedure 3: Granules were prepared from 2- [2- (3,5-dimethyl) -pyridylmethylsulfinyl] - (5-acetyl-6-methyl) -benzimidazole p-hydroxy-benzoate (250 g), lactose (175.9 g). and an alcohol solution of polyvinylpyrrolidone (25 g). After drying, the granules were mixed with talc (25 g), potato starch (40 g) and magnesium stearate (2.50 g) and pressed into 10000 30 tablets. These tablets are first coated with a 10% shellac alcohol solution followed by an aqueous solution containing sucrose (45%) gum arabic (5%), gelatin (4%) and dye (0.2%). Talc and powdered sugar were used to powder after the first five servings. The wrapper was then covered with a 66% sugar syrup and polished with a solution of 10% carnauba wax in carbon tetrachloride.

Formulation procedure 4: 2- [2- (3,5-dimethyl) -pyridylmethylsulfinyl] ~ (5-acetyl-6-methyl) -benzimidazole hydrochloride (1 g), sodium chloride (0.6 g) and ascorbic acid (0.1 g) were dissolved in a sufficient amount of distilled water to give 100 ml of solution. This solution, containing 10 mg of active substance / ml, was used to fill ampoules which had been sterilized by heating at 120 ° C for 20 minutes.

Investigation of the biological activity: The compounds according to the invention have valuable therapeutic properties as gastric acid secretion inhibitors, as proved by the following tests. To determine the gastric acid secretion inhibitory properties, experiments were performed on conscious dogs with conventional gastric fistulas and duodenal fistulas, the latter being used for direct intraduodenal administration of the Test45 compounds. After starvation for 18 h without water administration, the dogs were given a subcutaneous infusion of pentagastrin (1 to 4 nmol / kg.h) lasting 6 to 7 hours.

The gastric juice was collected in successive samples every 30 min. An aliquot of each sample was mixed with 0.1 N NaOH to a pH of 7.0 to determine the titratable acid concentration using an automatic titrator and p-meter (Radiometer, Copenhagen, Germany). titrated. The acid output was expressed in mm H / 60 min. Percent inhibition compared to control experiments was calculated for each compound and the (R) maximal inhibitory effect is given in Table 1. The test compounds suspended in 0.5% Methocel ^ (methyl cellulose) were administered intraduodenally at doses of 4 to 20 pmol / kg when the secretory reaction to pentagastrin had reached a uniform level.

In the test, already known compounds were compared with the compounds prepared according to the invention, as can be seen from Table 1.

The following gastric acid inhibitory activity data were obtained for a number of compounds tested by the method described.

Table 1

<img file="AT374471B_D0008.tif" />

H

<td>Connection according to example</td><td>R¹</td><td>R^a</td><td>R⁶</td><td>R³</td><td>R</td><td>R^s</td><td>dose pmol / kg</td><td>effect % Inhibition</td>

<td>1</td><td>5-Cocha</td><td>6-CHs</td><td>H</td><td>H</td><td>CH,</td><td>CHa</td><td>2</td><td>90</td>

<td>4</td><td>5-Cocha</td><td>6-CHa</td><td>H</td><td>CHa</td><td>CH_S</td><td>H</td><td>1</td><td>60</td>

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

<td>8th</td><td>5-Cocha</td><td>6-CHa</td><td>H</td><td>CHa</td><td>CH_a</td><td>CH_a</td><td>4</td><td>100</td>

<td>9</td><td>5-Cocha</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-Cocha</td><td>6-CHa</td><td>H</td><td>CHa</td><td>OCHA</td><td>CH₃</td><td>0.5</td><td>70</td>

<td>X</td><td>5-Cocha</td><td>6-CHa</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-CHa</td><td>H</td><td>H</td><td>H</td><td>CHa</td><td>8th</td><td>80</td>

<td>2</td><td>5-COOCHa</td><td>6-CHa</td><td>H</td><td>H</td><td>CHa</td><td>CHa</td><td>2</td><td>60</td>

<td>5</td><td>5-COOCHa</td><td>6-CHa</td><td>H</td><td>CHa</td><td>CHa</td><td>H</td><td>2</td><td>90</td>

<td>12</td><td>5-COOCHa</td><td>6-CH3</td><td>H</td><td>CHa</td><td>H</td><td>CHa</td><td>2</td><td>70</td>

<td>13</td><td>5-COOCHa</td><td>6-CHa</td><td>H</td><td>CHa</td><td>CHa</td><td>CH₃</td><td>4</td><td>80</td>

<td>14</td><td>5-COOCHa</td><td>6-CHa</td><td>H</td><td>H</td><td>OCHA</td><td>H</td><td>2</td><td>100</td>

<td>15</td><td>5-COOCHa</td><td>6-CHa</td><td>H</td><td>H</td><td>OC₂H₅</td><td>H</td><td>4</td><td>75</td>

<td>16</td><td>5-COOCHa</td><td>6-CHa</td><td>H</td><td>CHa</td><td>OCH_a</td><td>H</td><td>0.5</td><td>65</td>

<td>17</td><td>5-COOCHa</td><td>6-CHa</td><td>H</td><td>CH_a</td><td>OCHA</td><td>CH_S</td><td>0.5</td><td>90</td>

<td>18</td><td>5-COOCHa</td><td>6-CH3</td><td>H</td><td>H</td><td>OCHA</td><td>CHa</td><td></td><td></td>

<td>X</td><td>5-COOCH_a</td><td>6-CHa</td><td>H</td><td>H</td><td>H</td><td>CH_S</td><td>4</td><td>50</td>

<td>X</td><td>5-COOCHa</td><td>6-CHa</td><td>H</td><td>br</td><td>H</td><td>H</td><td>4</td><td>0</td>

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

<td>10</td><td>4-CHa</td><td>6-CHa</td><td>H</td><td>H</td><td>OCHA</td><td>H</td><td>2</td><td>40</td>

- 9 No. 374471

Table 1 (continued)

<td>Connection according to example</td><td>R¹</td><td>R²</td><td>R⁶</td><td>R³</td><td>R-</td><td>R⁵</td><td>dose pmol / kg</td><td>effect % Inhibition</td>

<td>X</td><td>4-CH₃</td><td>6-CHa</td><td>H</td><td>H</td><td>H</td><td>H</td><td>4</td><td>30</td>

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

<td>3</td><td>5-COOCH₃</td><td>H</td><td>H</td><td>H</td><td>CH₃</td><td>CHa</td><td>4</td><td>100</td>

<td>19</td><td>5-COOCH₃</td><td>H</td><td>H</td><td>CH_S</td><td>H</td><td>CHa</td><td>2</td><td>60</td>

<td>20</td><td>5-COOCH₃</td><td>H</td><td>H</td><td>CHa</td><td>OCHA</td><td>CH_a</td><td>0.5</td><td>65</td>

<td>X</td><td>5-COOCH₃</td><td>H</td><td>H</td><td>H</td><td>H</td><td>CHa</td><td>20</td><td>90</td>

<td>X</td><td>5-COOCHa</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-Cocha</td><td>H</td><td>H</td><td>CH₃</td><td>OCHA</td><td>CHa</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-OCHA</td><td>H</td><td>H</td><td>H</td><td>OCH3</td><td>CH₃</td><td></td><td></td>

<td>23</td><td>5-OCH 3</td><td>H</td><td>H</td><td>CHa</td><td>OCH ₃</td><td>CH₃</td><td>0.5</td><td>65</td>

<td>X</td><td>5-OCH 3</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>OCH ₃</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>OCH ₃</td><td>CHa</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>OCH "</td><td>CHa</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>0CH₃</td><td>CHa</td><td>0.5</td><td>25</td>

<td>27</td><td>5-CH's</td><td>H</td><td>H</td><td>H</td><td>OCjHaOCH</td><td>a H</td><td>0.5</td><td>30</td>

<td>29</td><td>5-COOCH3</td><td>H</td><td>CH₃</td><td>CHa</td><td>H</td><td>CHa</td><td>0.5</td><td>40</td>

means already known connection

The starting materials for the synthesis of compounds of general formula (II) were prepared according to the following general instructions:

1. A 1,2-diamino compound, such as o-phenylenediamine, was treated with potassium ethylxanthate (according to 5 Org. Synth. Vol. 30, p. 56) to give 2-mercaptobenzimidazole (compound of the general

Formula (VII)) implemented;

Second the compound 2-chloromethylpyridine (compound of the general formula (VIII)) was prepared by reacting 2-hydroxymethylpyridine with thionyl chloride (according to Arch. Pharm. Vol. 26, pp. 448-451 (1956);

Third the compound 2-chloromethylbenzimidazole was prepared by condensation of o-phenylenediamine with chloroacetic acid.

The invention is further illustrated by the following examples, without the invention being limited thereto. The temperature is given in degrees Celsius.

Example 1: 22.0 g of 2-mercapto (5-acetyl-6-methyl) benzimidazole and 19.5 g of 2-chloromethyl15- (4,5-dimethyl) -pyridinium hydrochloride were dissolved in 200 ml of 95% ethanol. 8 g of sodium hydroxide in 20 ml of water were added, whereupon the solution was refluxed for 2 hours

Boiling was heated. The sodium chloride formed was filtered off and the solution was evaporated in vacuo. The residue, 2- [2- (4,5-dimethyl) -pyridylmethylthio] - (5-acetyl-6-methyl) -benzimidazole,

No.374471 was recrystallized from 70% aqueous ethanol. Yield: 10.6 g.

28.9 g of 2- [2- (4,5-dimethyl) -pyridylmethylthio] - (5-acetyl-6-methyl) -benzimidazole were dissolved in 160 ml of CHCl₃ dissolved, 24.4 g of m-chloroperbenzoic acid were added with stirring and cooling to 5 ° C in portions. After 10 minutes, the precipitated m-chlorobenzoic acid was filtered off. The filtrate was washed with CH_aCl_a diluted, with Na_a CO₃ Solution, washed over Na₂SO_H dried and evaporated in vacuo. The residue crystallized on dilution with CH₃CN, and 2- [2- (4,5-dimethyl) -pyridylmethylsulfinyl] - (5-acetyl-6-methyl) -benzimidazole was prepared from CH_aCN recrystallized. Yield: 22.3 g; Mp 158 ° C.

Examples 2 to 30: The preparation of compounds of the general formula (I) which are denoted by 2 to 26, carried out according to Example 1. The compounds provided are listed in Table 2, in which the substituents of these compounds and their melting points are compiled ,

Example 31: 0.1 mol of 4,6-dimethyl-2-mercaptobenzimidazole was dissolved in 20 ml of water and 200 ml of ethanol containing 0.2 mol of sodium hydroxide. 0.1 mole of 2-chloromethyl- (3,5-dimethyl) -pyridinium hydrochloride was added and the mixture was refluxed for 2 hours. The sodium chloride formed was filtered off and the solution was evaporated in vacuo. The residue was dissolved in acetone and treated with charcoal. An equivalent amount of concentrated hydrochloric acid was added, whereupon the monohydrochloride was isolated from 2- [2- (3,5-dimethyl) -pyridylmethylthio] - (4,6-dimethyl) -benzimidazole. Yield: 0.05 mol.

This compound was then oxidized according to Example 1 to the corresponding sulfinyl compound, mp. 50-55 ° C.

Example 32: 23.4 g of 2- (3,4,5-trimethyl) -pyridylmethylthio-formic acid and 16.6 g of o- (5-acetyl-6-methyl) phenylenediamine were added in 100 ml of 4N HCl for 40 min heated to boiling. The mixture was cooled and neutralized with ammonia. The neutral solution was then extracted with ethyl acetate. The organic phase was treated with charcoal and evaporated in vacuo. The residue was dissolved in acetone, whereupon one equivalent of concentrated HCl was added. The precipitated hydrochloride was filtered off after cooling and the salt was recrystallized from absolute ethanol and a little ether. Yield of 2- [2- (3,4,5-trimethylpyridyl) methylthio] - (5-acetyl-6-methyl) benzimidazole: 6.5 g.

This compound was then oxidized according to Example 1 to the corresponding sulfinyl derivative. Mp: 190 ° C.

Table 2

<img file="AT374471B_D0009.tif" />

H

<td>example</td><td>R¹</td><td>R^a</td><td>R⁶</td><td>R³</td><td>R °</td><td>fl⁵</td><td>Mp, ° C</td>

<td>1</td><td>5 COCH₃</td><td>6-CH_a</td><td>H</td><td>H</td><td>CHa</td><td>CHa</td><td>158</td>

<td>2</td><td>5-COOCH₃</td><td>6-CH3</td><td>H</td><td>H</td><td>CHa</td><td>CHa</td><td>163</td>

<td>3</td><td>5-COOCHa</td><td>H</td><td>H</td><td>H</td><td>CHa</td><td>CHa</td><td>141</td>

<td>4</td><td>5-Cocha</td><td>6-CH₃</td><td>H</td><td>CH_a</td><td>CHa</td><td>H</td><td>160</td>

<td>5</td><td>B-COOCHs</td><td>6-CH3</td><td>H</td><td>CHa</td><td>CHa</td><td>H</td><td>163</td>

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

<td>7</td><td>5-Cocha</td><td>6-CH₃</td><td>H</td><td>CHa</td><td>H</td><td>CHa</td><td>171</td>

<td>8th</td><td>5-Cocha</td><td>6-CH3</td><td>H</td><td>CHa</td><td>CHa</td><td>CH₃</td><td>190</td>

- 11 No. 374471

Table 2 (continued)

<td>example</td><td>R '</td><td>R²</td><td>R⁶</td><td>R³</td><td>R</td><td>R^s</td><td>Mp, ° C</td>

<td>9</td><td>5-COCH,</td><td>6-CH3</td><td>H</td><td>H</td><td>OCH,</td><td>H</td><td>165</td>

<td>10</td><td>4-CH,</td><td>6-CH,</td><td>H</td><td>H</td><td>OCH,</td><td>H</td><td>122</td>

<td>11</td><td>5 COCH₃</td><td>6-CH3</td><td>H</td><td>CH,</td><td>OCH,</td><td>CH,</td><td>156</td>

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

<td>13</td><td>5-COOCH3</td><td>6-CH,</td><td>H</td><td>CH₃</td><td>CH_a</td><td>CH 3</td><td>185</td>

<td>14</td><td>5-COOCH 3</td><td>6-CH,</td><td>H</td><td>H</td><td>OCH 3</td><td>H</td><td>169</td>

<td>15</td><td>5-COOCHa</td><td>6-CH,</td><td>H</td><td>H</td><td>0C₂H₅</td><td>H</td><td>148</td>

<td>16</td><td>5-COOCH3</td><td>6-CH3</td><td>H</td><td>CH₃</td><td>0CH₃</td><td>H</td><td>175</td>

<td>17</td><td>5-COOCH 3</td><td>6-CH3</td><td>H</td><td>CH,</td><td>OCH 3</td><td>CH,</td><td>155</td>

<td>18</td><td>5-COOCH,</td><td>6-CH3</td><td>H</td><td>H</td><td>OCH,</td><td>CH,</td><td>158</td>

<td>19</td><td>5-COOCH3</td><td>H</td><td>H</td><td>CH,</td><td>H</td><td>CH 3</td><td>141</td>

<td>20</td><td>5-COOCH3</td><td>H</td><td>H</td><td>CH,</td><td>OCH,</td><td>CH,</td><td>142</td>

<td>21</td><td>5-COCH3</td><td>H</td><td>H</td><td>CH,</td><td>OCH 3</td><td>CH,</td><td>162</td>

<td>22</td><td>5-OCH 3</td><td>H</td><td>H</td><td>H</td><td>OCH,</td><td>CH,</td><td>178</td>

<td>23</td><td>5-OCHA</td><td>H</td><td>H</td><td>CH,</td><td>OCH,</td><td>CH,</td><td>156</td>

<td>24</td><td>5-CHa</td><td>H</td><td>H</td><td>CH₃</td><td>OCH,</td><td>CH,</td><td>181</td>

<td>25</td><td>H</td><td>H</td><td>H</td><td>CH₃</td><td>OCH,</td><td>CH,</td><td>165</td>

<td>26</td><td>5-C1</td><td>H</td><td>H</td><td>CH,</td><td>OCH,</td><td>CH,</td><td>185</td>

<td>27</td><td>5-CH3</td><td>H</td><td>H</td><td>H</td><td colspan="2">OC₂HIGH₃ H</td><td>119</td>

<td>28</td><td>5-COOC₂H_s</td><td>H</td><td>H</td><td>CH,</td><td>OCH,</td><td>CH,</td><td>150-155</td>

<td>29</td><td>5-COOCH3</td><td>H</td><td>ch₃</td><td>CH 3</td><td>H</td><td>CH,</td><td>130</td>

<td>30</td><td>5-CH3</td><td>H</td><td>^CH.</td><td>CH,</td><td>H</td><td>CH,</td><td>152</td>