Use of novel 2-pyridylalkylsulphinylbenzimidazoles for the manufacture of pharmaceutical products which influence gastric acid secretion

(42) Start of patent term: 15. 8.1989 (45) Date of issue: 26. 2.1990 (51) Int.Cl.⁵ j AS1K 31/44 // A61K 31/415 (62) Elimination from application No: 2732/79

<td>(30) Priority:</td><td>(73) Patent owner:</td>

<td>14. 4.1978 SE 7804231 claims.</td><td>SHARE CAMP KÄSSLE</td>

<td>(56) Documents:</td><td>S-431 20 MÜLMML (SE).</td>

<td>0E-0S2548340 US-PS4045563</td><td>(72) Inventor: SZMUELSECN-JUSGREN VIOLA XNGA-LILL «LENA tSlLNLYCKE (ES). LUOöTr ^ M ΝΕίΙΞΤΗ SVZNESUS (SE). Säjstlwnd SVEN-ERIK KATRINEHOLM (SE).</td>

(54) USE OF PHARMACEUTICAL PREPARATIONS AFFECTING HEALEN 2-PYRIDYL ALKYL-SULFINYLCEHZIMIDAZOLENE FOR THE MANUFACTURE OF MAGNETIC ACID ERECTRECTION (57) Use of novel 2-pyridylalkylsulphinyl-cenziylimidazoles of general formula (I) wherein R and R are the same or different and each is hydrogen, Halogen, alkyl, carbooethoxy, carbethoxy, alkoxy or alkanoy1 in any position, R ⁶ Is hydrogen, methyl or ethyl and R ⁵, R ⁴ such as

R ⁵ are the same or different and each represents hydrogen, methyl, methoxy, ethoxy, Methoxyöthaxy or Äthoxyäthoxy, the Moßgobe old, that R ⁵, R ⁴ and

R ⁵ are not hydrogen at the same time and that one of the three substituents R, R and R has a meaning other than methyl when two of these substituents are hydrogen, as well as their hydrates, stereoisomers and therapeutically acceptable salts, for the preparation of secretase secretion-affecting pharmaceutical preparations for the treatment of gastric and duodenal ulcers.

<img file="AT389995B_D0001.tif" />

H

WRarasa

No. 389995

The invention relates to the use of novel 2-PyridylalkylsuIfinyl-benzimidazoles of the general formula

<img file="AT389995B_D0002.tif" />

H in which R and R are the same or different and each represents hydrogen, halogen, alkyl, carbomethoxy, carbethoxy, alkoxy or alkanoyl in any position, R⁵ Is hydrogen, methyl or ethyl and R³, R⁴ as well as R⁵ are the same or different and each represents hydrogen, methyl, methoxy, ethoxy, methoxyethoxy or ethoxyethoxy, with the proviso that R³, R⁴ and R⁵ not simultaneously hydrogen and that one of the three substituents R³, R⁴ and R⁵ has a meaning other than methyl, when two of these substituents are hydrogen, as well as their hydrates, stereoisomers and therapeutically acceptable salts, for the production of gastric acid secretion affecting pharmaceutical preparations for the treatment of gastric and duodenal ulcers.

The new compounds inhibit exogenous or endogenously stimulated gastric acid secretion.

It was previously known that compounds of the general formulas

<img file="AT389995B_D0003.tif" />

, 3.

No. 389995 wherein rI and R ^ are each hydrogen. Alkyl, halogen, cyano, carboxy, carboxyalkyl, carboalkoxy, carboalkoxyalkyl, carbamoyl, carbamoyloxy, hydroxy, alkoxy, hydroxyalkyl, trifluoromethyl or acyl in any position, R 1 is hydrogen, alkyl, acyl, carboalkoxy, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, alkylcarbonylmethyl, Alkoxycarbonylmethyl or alkylsulfinyl and R⁴ represents a straight or branched alkylene group having 1 to 4 carbon atoms, wherein at most one methylene group is present between S and the pyridyl group and wherein the pyridyl group may be further substituted by alkyl or halogen, have an inhibitory effect on Magsnsüracsekreticn.

From DE-OS 25 48 340 and US Patent 4,045,563 compounds are known, dis have a backbone such as the compounds of the general formula (IV) and are additionally substituted on the pyridine ring.

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

If R * and in formula (I) are alkyl, then they are expediently alkyl groups having up to 7 carbon atoms, preferably up to 4 carbon atoms. Thus, R¹ or R ^, when it is alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl.

If R ^ and R ^ are halogen, they are chlorine, bromine, fluorine or iodine.

When R 1 and R 2 are alkoxy, they are expediently alkoxy groups having up to 5 carbon atoms, preferably up to 3 carbon atoms, such as methoxy, ethoxy, n-propoxy or isopropoxy.

R¹ and for alkanoyl preferably have up to 4 carbon atoms and are e.g. As formyl, acyl or propionyl, preferably Äcetyl.

A preferred group of novel compounds of general formula (I) is that wherein R 1 and R 3 are the same or different and each is hydrogen, alkyl, carbomethoxy, alkoxy or alkanoyl wherein R 1 and R 1 are not both hydrogen Hydrogen stands, R ^, R⁴ and 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 R 1 are the same or different and each is hydrogen, alkyl, halogen, carbomethoxy, carbethoxy, alkoxy or alkanoyl, hydrogen, methyl or ethyl, R 1 is methyl, R 2⁴ Methoxy and R $ represents methyl.

A third preferred group of compounds of general formula (I) is that in which r 'and R? are the same or different and each is hydrogen, alkyl, halogen, carbomethoxy, carbethoxy, alkoxy or alkanoyl, R $ is hydrogen, methyl or ethyl, and R ^ is hydrogen, R⁴ Methoxy and R ^ methyl, or R ^ methyl, R⁴ Methoxy and R ^ is hydrogen.

A fourth preferred group of compounds of general formula (I) is that in which R 1 and the same or different and each represents hydrogen, alkyl, halogen, carbomethoxy, carbethoxy, alkoxy or

Alkanoyl, R ^ is hydrogen, methyl or ethyl, R 'and R ^ are hydrogen and R⁴ Methoxy is.

1

A fifth preferred group of compounds of the general formula (I) is that in which R¹ and R are the same or different and each is hydrogen, alkyl, halo, carbomethoxy, carbethoxy, alkoxy or alkanoyl, R ^ is hydrogen, methyl or ethyl, R ^ and R ^ are methyl and R⁴ Is hydrogen

A sixth preferred group of compounds of general formula (I) are those in which R * and the same or different and each is hydrogen, alkyl, halogen, carbomethoxy, carbethoxy, alkoxy or alkanoyl, R® is hydrogen, methyl or ethyl, R ^ and R $ hydrogen and R⁴ Represent ethoxy, methoxyethoxy or ethoxyethoxy.

A seventh preferred group of compounds of general formula (I) is that wherein R * and R 'are the same or different and each is hydrogen, alkyl, halo, carbomethoxy, alkoxy or alkanoyl, is hydrogen, methyl or ethyl, and r \ R⁴ and R $ are all methyl.

The compounds used in the invention can be prepared by adding a compound of the general formula

<img file="AT389995B_D0004.tif" />

<img file="AT389995B_D0005.tif" />

POOR

QUALITY

-3Nr. 385395

<img file="AT389995B_D0006.tif" />

Compound of the general formula (I) in a Stoeciditronsrelz überfokrt or rz3 a Selz foegecstzt wbd and / or a Stcreomerenmischung obtained, if desired aufgcKnatscht in en pure enantiomers or Diesteromerca.

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

<img file="AT389995B_D0007.tif" />

H in which and have the above meaning and represents SH or a reactive esterified hydroxy group, with a compound of the general formula

R '

<img file="AT389995B_D0008.tif" />

<img file="AT389995B_D0009.tif" />

wherein R®, R³, and R⁵ have the above meaning and iF represents a reactive esterified hydroxy group or SH, or by reacting a compound of the general formula

R * 1 2 wherein R * and R have the above meaning, with a compound of general formula

-4Nr. 389995. (X)

<img file="AT389995B_D0010.tif" />

wherein r6, r3, R⁴ and R⁵ above meaning are produced.

In the above reactions, and may be a reactive, esterified hydroxy group, meaning 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 , z. B. benzenesulfonic acid, 4-bromobenzenesulfonic acid or 4-toluenesulfonic acid, was esterified.

The oxidation of the sulfur atom to sulfmyl (S -> O) may preferably be carried out with an oxidizing agent from the group nitric acid, hydrogen peroxide, peracids Percster, Ozone, dinitrogen tetroxide, iodosobenzene, N-Halogensuccimmid, 1-chlorobenzotriazole, teru butyl hypochlorite, Diazabicyclo [2,2,2] octane-bromine complex, sodium metaperiodate selenium dioxide, manganese dioxide, Chromic acid, Ammonium cerium (IV), 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.

Particular preference is given according to the invention 2- (2- (3,5-dimethyl-4-methoxy) -pyridylmethylsulfinyI] -5methoxy-bcnzimidazol of the formula

OCH.

<img file="AT389995B_D0011.tif" />

da), which can be prepared by oxidation of 2- [2- (3,5-dimethyl-4-methoxy) -pyridylmethylthio] -5-methoxybenzimidazol, 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 are within the scope of the invention. Thus, basic, neutral or mixed salts can be obtained as well as hemi-, mono-, sesqui- or polyhydrates. 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 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 hydrochloric, 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, malic, hydroxymalein, pyruvic, phenylacetic , Benzoic, p-aminobenzoic. Anthranil, p-hydroxybenzoic, salicylic or p-aminosalicylic, embonic, methanesulfonic, ethanesulfonic, hydroxyethylsulfonic, ethylenesulfonic, halobenzenesulfonic, toluenesulfonic, naphthylsulfonic or sulfamic acid; Methionine, tryptophan, lysine or argin in.

-5Nr. 389995

These or other salts of the new compounds, such as. As picrates, ice cleaning agents can serve for the resulting free bases. Salts of the brooms can be formed, separated from the solution, and then the free base recovered from a new saline solution in a purer state. Because of the relationship between the new free-effervescent compounds and their salts, it is understood that the use of the corresponding salts falls within the scope of the invention

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

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

The resulting racemates can be separated by known methods, for. B. Recrystallization from an optically active solvent, use of microorganisms, reactions with optically active acids which form salts which can be separated, separation due to different solubilities of the diastereomers. Suitable optically active acids are the L and D forms of tartaric acid, di-o-tolyl-cinnamic 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 processes known per se.

For the synthesis of compounds of the general formula (Π) starting materials were prepared, for example, according to the following general instructions:

1. A 1,2-diamino compound, such as o-phenylenediamine, was reacted with potassium ethylxanthate (according to Org. Synth. Vol. 30, p. 56) to form 2-mercapto-benzimidazole (compound of general formula (VII));

Second the compound 2-chloromethylpyridine (compound of 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-Chlormelhylbcnzimidazol was by condensation of o-phenylenediamine with

Chloroacetic acid produced

The preparation of some novel compounds of the general formula (I) which can be used according to the invention is described concretely in the following working instructions. (The temperature is given in degrees Celsius):

Working instruction 1:

22.0 g of 2-mercapto (5-acyl-6-methyl) benzimidazole and 19.5 g of 2-chloromethyl (4,5-dimethyl) pyridinium hydrochloride were dissolved in 200 ml of 95% ethanol. 8th Sodium hydroxide in 20 ml of water was added and the solution was refluxed for two hours. The resulting sodium chloride was filtered off and the solution was evaporated in vacuo. The residue, 2- [2- (4,5-dimethyl) pyridylmethylthio] - (5-acetyl-6-methyl) -benzimidazole, was recrystallized from 70% aqueous ethanol. Yield : 10.6 g.

28.9 g of 2- (2- (4,5-dimethyl) -pyridylmethyllhio] - (5-acetyl-6-methyl) -bcnzimidazole were dissolved in 160 ml of CHCl 2. 24.4 g of m-chloropreparenzoic acid were added with stirring and cooling 5 ° C. in portions, after 10 min the rich m-chlorobenzoic acid was filtered off, the filtrate was extracted with CH₂C1₂ diluted, with Na₂CO₃Solution, washed over Na₂SO₄ dried and evaporated in vacuo. The residue crystallized on dilution with CH₃CN, and 2- (2- (4,5-DimcthyI) -pyridylmethylsulphinyl] - (5-acyl-6-methyl) -benzimidazole was recrystallized from CH 2 CO 3, yield: 22.3 g, m.p .: 158 ° C.

Working Regulations 2 to 30:

The preparation of compounds of the general formula (I) which are denoted by 2 to 26, carried out according to procedure 1. All Hcrgesiellten compounds are listed in Table 1, in which the substituents of these compounds and their melting points are collected together.

Protocol 31: 0.1 mol of 4,6-dimethyl-2-mcrcaptobenzimidazole was dissolved in 20 ml of water and 200 ml of ethanol containing 0.2 mol of sodium hydroxide. 0.1 mol of 2-chloromethyl- (3,5-dimcthyl) pyridinium hydrochloride was added and the mixture was refluxed for two 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-dimegyl) -pyridylmethylthio] - (4,6-dimcthyl) benzimidazole. Yield: 0.05 mol.

This compound was then oxidized according to procedure I to the corresponding sulfinyl compound, m.p .: 50-55 ° C

-6POOR, ttUAUTV

No. 389995

23, 4β 2- (3,4,5-trimethyl) -pyridylmethyltiotiamic acid and 16.6 β-o- (5-acetyl-6-tn-2-yl) phenylenedimine were incubated for 40 min in IGO ml of 4 N HCl The microtun was neutralized with ammonia cbgskSih mid. The neutral solution was then extracted with ethyltestet. The crystalline phase was treated with charcoal and evaporated in vacuo. The residue was dissolved in acetone, to which was added one equivalent of concentrated HCl. The hydrogen chloride hydrochloride was filtered off after cooling and the salt was recrystallised from absolute ethanol and a little ether. Yield of 2- (2- (3,4,5-trimethylpyridyl) methylthio] - (5-acetyl-6-methyl) -szmitimidzzz 6.5 g.

This compound was then oxidized according to procedure 1 to the corresponding SuUinylderivat mp: 190 ° C laÄi

<img file="AT389995B_D0012.tif" />

<td>Ex.</td><td>R¹</td><td>R²</td><td>R⁶</td><td>R³</td><td>R⁴</td><td>R⁵</td><td>Mp.</td>

<td>1</td><td>5-COCH3</td><td>6-CH3</td><td>H</td><td>H</td><td>ch₃</td><td>ch₃</td><td>158</td>

<td>2</td><td>5-COOCH3</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-COOCH3</td><td>H</td><td>H</td><td>H</td><td>ch₃</td><td>ch₃</td><td>141</td>

<td>4</td><td>5-COOCH3</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-COOCH3</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-CH3</td><td>H</td><td>ch₃</td><td>Η</td><td>ch₃</td><td>171</td>

<td>8th</td><td>5-COCH3</td><td>6-CH3</td><td>H</td><td>ch₃</td><td>ch₃</td><td>ch₃</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-CH3</td><td>H</td><td>ch₃</td><td>och₃</td><td>ch₃</td><td>156</td>

<td>12</td><td>5-CCXDCH3</td><td>6-CH3</td><td>H</td><td>ch₃</td><td>H</td><td>ch₃</td><td>144</td>

<td>13</td><td>5-COOCH3</td><td>6-CH3</td><td>H</td><td>ch₃</td><td>ch₃</td><td>ch₃</td><td>185</td>

<td>14</td><td>5COOCH3</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-COOCH3</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-COOCH3</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-COOCH3</td><td>6-CH3</td><td>H</td><td>ch₃</td><td>och₃</td><td>ch₃</td><td>155</td>

<td>18</td><td>5-COOCH3</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-COOCH3</td><td>H</td><td>H</td><td>ch₃</td><td>H</td><td>ch₃</td><td>141</td>

<td>20</td><td>5-COOCH₃</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-OCH 3</td><td>H</td><td>H</td><td>H</td><td>och₃</td><td>ch₃</td><td>178</td>

<td>23</td><td>5-OCH 3</td><td>H</td><td>H</td><td>ch₃</td><td>och₃</td><td>ch₃</td><td>156</td>

<td>24</td><td>5-CH3</td><td>H</td><td>H</td><td>ch₃</td><td>och₃</td><td>ch₃</td><td>181</td>

<td>25</td><td>H</td><td>H</td><td>H</td><td>ch₃</td><td>och₃</td><td>ch₃</td><td>165</td>

<td>26</td><td>5-C1</td><td>H</td><td>H</td><td>ch₃</td><td>och₃</td><td>ch₃</td><td>185</td>

<td>27</td><td>5-CH₃</td><td>H</td><td>H</td><td>H</td><td>oc, h_äoch₃</td><td>H</td><td>119</td>

<td>28</td><td>S-COOCtHs</td><td>H</td><td>H</td><td>ch₃</td><td>och₃</td><td>ch₃</td><td>150-5</td>

<td>29</td><td>5-COOCH3</td><td>H</td><td>CH3</td><td>ch₃</td><td>H</td><td>ch₃</td><td>130</td>

<td>30</td><td>23</td><td>H</td><td>ch₃</td><td>ch₃</td><td>H</td><td>ch₃</td><td>152</td>

nllAIITV

POOR

-7Nr. 389995

In the context of the use according to the invention for the production of pharmaceutical preparations for the treatment of gastric and duodenal ulcers by influencing the gastric secretion, the novel compounds for the preparation of preparations for oral, rectal or injection-based administration, which is an active component either as a free base or as a pharmaceutically acceptable salt, namely a non-toxic acid addition salt, like hydrochloride, lactate, Acetate, sulfamate, in combination with a pharmaceutically acceptable carrier.

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

In the use of the novel compounds according to the invention for the preparation of pharmaceutical preparations, the carrier in the preparations may be a solid, semi-solid, liquid diluent or a capsule. Usually, the amount of active compound of the general formula (I) is between 0.1 to 95% by mass of the preparation, between 0.5 and 20% by mass in preparations for injection and between 2 and 50% by mass in preparations for oral administration.

In the preparation of pharmaceutical preparations containing a novel compound in unit dosage form for oral administration, the chosen compound is combined with a solid, powdered carrier such as lactose, sucrose, sorbitol, mannitol starch, amylopectin, cellulose derivatives or gelatin, and with a lubricant, such as magnesium stearate, calcium stearate and polyethylene glycol waxes.

The mixture is then compressed into tablets. If coated tablets are desired, the core prepared as 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 may be prepared containing a mixture of the active compound useful in 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 prepared 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 glacial 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, e.g. B. Solutions containing from 02% to 20% by weight of active ingredient and the remainder being sugar and a mixture of ethanol, water, glycerol and propylene glycol. Optionally, such liquid preparations may contain coloring agents, flavoring agents, saccharin and Carbcxymethylccllulosc as Khrdickungsmiltel.

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 at a concentration of 0.5 to 10% by mass. These solutions may also contain stabilizers and / or buffering agents and may be prepared in ampoules at various dosage units.

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 adjuvants are mixed together with the binding agent solution. The resulting mixture is applied to form a uniform suspension of wet snow consistency. Moistening causes the particles to agglomerate easily and the resulting mass is passed 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 ten hours to achieve the desired particle size and consistency / to obtain. The granules of the dried mixture are screened to remove any powder. 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 obtain 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 made at a rate of 20,000 to 200,000 per hour. The tablets, especially the tart and bitter, 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 beakers, boxes, tubes and packages for special cans.

The invention is explained in more detail by the following examples

-8Nr. 389995

Example 1:

A syrup containing 2% (v / v) active substance was prepared from the following ingredients: 2- [2- (4-dimethylimidyl) pyridylmethylsulfinyl] (5-2CC-tyl-6-methyl) -benzimidazol · 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. After cooling, glycerol and a solution of flavors dissolved in ethanol were added. 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.

Rsispisü

2- (2- (3,4-Dimethyl) -pyridylmethylsulfinyl] - (5-acetyl-6-methyl) -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-mcsh 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 containing 25 mg of active substances. Tablets can be made with any amount of active ingredient.

RcispigLli

Granules were prepared from 2- [2- (3,5-dimethyl) -pyridylmethylsulfinyl] - (5-acetyl-6-methyl) benzimidazole p-hydroxybenzoal (250 g), lactose (175.9 g) and an alcoholic solution of Polyvinyl pyrrolidone (25 g). After drying, the granules were mixed with talc (25 g), potato starch (40 g) and magnesium stearate (2.30 g) and compressed to 10,000 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 icing sugar were used to the cup 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.

RgispiclÄ

2- (2- (3,5-Dimclethyl) -pyridylmethylsulfinyll- (5-acetyl-6-methyl) -benzimidazole hydrochloride (1g), sodium chloride (0.6g) and ascorbic acid (0.1g) were added in a sufficient amount Amount of distilled water was dissolved to give 100 ml of solution This solution containing 10 mg of active substance per ml was used to fill ampoules which had been sterilized by heating at 120 ° C for 20 minutes.

Examination of the bialosic kKima

The compounds used in the invention have valuable therapeutic properties as gastric acid secretion inhibitors, as evidenced by the following tests. To determine the gastric acid secretion-inhibitory properties, experiments were carried out on conscious dogs having gastric fistulae of conventional and duodenal fiskels, the latter being used for the direct intraduodenal decomposition of the tesivates. After 18 hours of starvation without water cryptography, the dogs were given a subcutaneous infusion of pcntagastrin (1-4 nmol / kg x 5 ») lasting 6-7 hours. The gastric juice was collected in successive samples every 30 min. An aliquot of each sample was titrated with 0.1 N NaOH to pH 7.0 to determine the titratable acid-carbonate fraction using an automatic titrator and pH meter (Radiometer, Copenhagen, Denmark). The acid output was expressed in mmol H® / 60 min. Percent inhibition compared to control experiments was calculated for each compound and the maximum inhibitory potency is given in Table 1. The test compounds suspended in 0.5% Mcthoccl® (Mcthylccllulosc) were administered intraduodenally at doses of 4-20 μΜοΙ / kg when the decrementing action on Pcntagastrin reached a uniform level.

In the test, already known compounds were compared with the compounds used according to the invention, as can be seen from Table 2.

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

-9Nr. 389995

MLC2

<img file="AT389995B_D0013.tif" />

<td>Verb. R¹to Ex.</td><td>R²</td><td>R⁶</td><td>R³</td><td>R⁴</td><td>R⁵</td><td>dose μΜοΙ / kg</td><td>Effect% inhibition</td>

<td>1 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 5-COCH3</td><td>6-CH₃</td><td>H</td><td>ch₃</td><td>ch₃</td><td>H</td><td>1</td><td>60</td>

<td>7 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 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 5-COCH₃</td><td>6CH₃</td><td>H</td><td>H</td><td>och₃</td><td>H</td><td>2</td><td>95</td>

<td>11 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 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 5-COCH₃</td><td>6-CH,</td><td>H</td><td>H</td><td>H</td><td>ch₃</td><td>8th</td><td>80</td>

<td>2 5-COOCH₃</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 5-COOCH₃</td><td>6-CH₃</td><td>H</td><td>CH,</td><td>ch₃</td><td>H</td><td>2</td><td>90</td>

<td>12 5-COOCH₃</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 5-COOCH₃</td><td>6-CH₃</td><td>H</td><td>ch₃</td><td>ch₃</td><td>ch₃</td><td>4</td><td>60</td>

<td>14 5-COOCH₃</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 5-COOCH₃</td><td>6-CH₃</td><td>H</td><td>H</td><td>oc₂H₅</td><td>Η</td><td>4</td><td>75</td>

<td>16 5-COOCH₃</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 5-COOCH₃</td><td>6-CH₃</td><td>H</td><td>ch₃</td><td>och₃</td><td>CH,</td><td>0.5</td><td>90</td>

<td>18 5-COOCH₃</td><td>6-CH₃</td><td>H</td><td>H</td><td>och₃</td><td>ch₃</td><td></td><td></td>

<td>x 5 COOCH₃</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 5 COOCH₃</td><td>6-CH₃</td><td>H</td><td>br</td><td>H</td><td>H</td><td>4</td><td>0</td>

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

<td>x 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>

- ioNo. 389995

Iabdli2 (continued)

<td>Ver, R¹to Ex.</td><td>R²</td><td>R⁶</td><td>R³</td><td>R⁴</td><td>R⁵</td><td>dose gMoVkg</td><td>Effect% inhibition</td>

<td>3 5-COCK</td><td>H</td><td>H</td><td>H</td><td>ch₃</td><td>ch₃</td><td>4</td><td>100</td>

<td>19 5-COOCH₃</td><td>H</td><td>H</td><td>ch₃</td><td>H</td><td>ch₃</td><td>2</td><td>60</td>

<td>20 5-COOCH₃</td><td>H</td><td>H</td><td>ch₃</td><td>och₃</td><td>ch₃</td><td>03</td><td>65</td>

<td>x 5 COOCH₃</td><td>H</td><td>H</td><td>H</td><td>H</td><td>CH,</td><td>20</td><td>90</td>

<td>x 5 COOCH₃</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H</td><td>20</td><td>50</td>

<td>21 5-COCH₃</td><td>H</td><td>H</td><td>ch₃</td><td>och₃</td><td>ch₃</td><td>03</td><td>60</td>

<td>x 5 COOCH₃</td><td>H</td><td>H</td><td>H</td><td>H</td><td>^C2^H5</td><td>20</td><td>40</td>

<td>22 5-OCH₃</td><td>H</td><td>H</td><td>H</td><td>och₃</td><td>ch₃</td><td></td><td></td>

<td>23 5OCH₃</td><td>H</td><td>H</td><td>ch₃</td><td>OCH3</td><td>ch₃</td><td>03</td><td>65</td>

<td>x 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 5-CH₃</td><td>H</td><td>H</td><td>ch₃</td><td>och₃</td><td>ch₃</td><td>03</td><td>50</td>

<td>x 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 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 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 5-COOC₉H_s</td><td>H</td><td>H</td><td>ch₃</td><td>och₃</td><td>ch₃</td><td>03</td><td>50</td>

<td>26 5-C1</td><td>H</td><td>H</td><td>ch₃</td><td>och₃</td><td>ch₃</td><td>03</td><td>25</td>

<td>27 5-CH₃</td><td>H</td><td>H</td><td>H</td><td>oc₉H₄och,</td><td>H</td><td>0.5</td><td>30</td>

<td>29 5-COOCH₃</td><td>H</td><td>CH_?</td><td></td><td>H</td><td>ch₃</td><td>03</td><td>40</td>

x denotes already known compound (not usable according to the invention)