Process for the production of granules, or tablets, or capsules for oral administration

The present invention relates to a method for the production of granules or tablets or capsules for oral administration under

1) Granulation of a substituted 2- [2-pyridylmethylsulfinylj-benzimidazole or of a hydrate, stereoisomer or therapeutically acceptable salt thereof with a solid, powdery carrier material, preferably selected from the group consisting of lactose, sucrose, sorbitol, mannitol, starch, amylopectin, cellulose derivatives and gelatin, optionally with moistening with a binder solution, preferably containing gelatin or Polyvinylpyrrolidone,

2) optionally grinding the material obtained in the moistening step,

3) drying and sieving of the granules obtained and

4) if applicable

a) Compression of the granulate, preferably with the addition of disintegration-promoting agents, lubricants and anti-adhesive agents, to form tablets, which are optionally coated, for example with a coating solution comprising a lacquer dissolved in a volatile organic solvent or a mixture of solvents, or with a coating solution comprising sugar and optionally also gum arabic, gelatin, talc or titanium dioxide, or

b) Filling the granulate obtained into hard gelatin capsules.

Substituted 2- [2-pyridylmethylsulfinyl] -benzimidazoles inhibit exogenously or endogenously stimulated gastric acid secretion.

It was previously known that compounds of the general formulas and

<img file="AT406119B_D0001.tif" />

, (III), (IV) wherein R¹ and R² each represent 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 R⁴ represents a straight or branched alkylene group with 1 to 4 carbon atoms, with at most one methylene group being present between S and the pyridyl group and with the pyridyl group being further substituted by alkyl or halogen, have an inhibitory effect on gastric acid secretion.

From DE 25 48 340 A1 and US Pat. No. 4,045,563 A, compounds are known which have a basic structure like the compounds of the general formula (IV) and are additionally substituted on the pyridine ring.

In addition, DE 25 48 340 A1 describes processes for producing tablets or granules containing the active ingredients disclosed there.

However, it has now been found, surprisingly, that the new compound of the formula (I) used according to the invention has an even greater inhibitory effect than those listed above.

According to the present invention, the 2- [2- (3,5-dimethyl-4-methoxy) pyridylmethylsulfinyl] -5-methoxy-benzimidazole becomes of the formula

AT 406 1 1 9 Β

<img file="AT406119B_D0002.tif" />

or its hydrates, stereoisomers or therapeutically acceptable salts are used in a process of the type specified at the outset.

To treat gastric and duodenal ulcers by influencing gastric secretion, the granules or tablets or capsules produced according to the invention are administered orally in the form of a pharmaceutical preparation which contains the 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 typical daily dose of the active substance varies depending on the individual needs and form of administration. In general, oral doses range from 100 to 400 mg / day of active substance.

In the method according to the invention for the production of pharmaceutical preparations, a solid, semi-solid, liquid diluent or a capsule can be used as a carrier in the preparations. The amount of active compound of the general formula (I) is usually between 2 and 50% by weight in the case of preparations for oral administration.

In the manufacture of pharmaceutical preparations containing a new compound in dosage unit form for oral administration, the selected compound with a solid, powdery 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 can be coated with a concentrated sugar solution, which may contain gum arabic, gelatin, talc or titanium dioxide, or with a lacquer dissolved in a volatile organic solvent or a mixture of solvents. Various dyes can be added to this coating in order to distinguish between tablets with different active compounds or with different amounts of contained active compounds to be able to differentiate.

Soft gelatin capsules can be produced which contain a mixture of the active compound useful in the invention and vegetable oil. Hard gelatin capsules can contain granules of the active compound in combination with a solid, powdery carrier such as lactose, sucrose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives or gelatin.

Tablets for oral use are produced in the following way; 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 adjuvants are mixed together with the binder solution. The resulting mixture is moistened to form a uniform suspension with the consistency of wet snow. The moistening causes the particles to clump together slightly and the resulting mass is forced through a stainless steel sieve with a mesh size of approximately 1 mm. The layers of mixture are dried in carefully controlled drying rooms for approximately ten hours to obtain the desired particle size and consistency. The granules of the dried mixture are sieved 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 achieve the desired tablet size. The pressure applied affects the size of the tablet, its strength and its solubility in water. The compression pressure used 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 pungent and bitter ones, can be coated with a layer of sugar or any other edible substance. They are then packed in machines with electronic counting devices. The different types of packaging include glass or plastic containers, boxes, tubes and packs for special cans.

AT 406 119 Β

Investigation of the biological effect: The compound used according to the invention has valuable therapeutic properties as a gastric acid secretion inhibitor, as is proven by the following tests. To determine the gastric acid secretion inhibitory properties, experiments were carried out on conscious dogs exhibiting gastric fistulas of the conventional type and duodenal fistulas, the latter being used for direct intraduodenal administration of the test compounds. After starving for 18 hours without water administration, the dogs were given a subcutaneous infusion of pentagastrin (1-4 nMoI / kg.hr) for 6 to 7 hours. The gastric juice was collected in consecutive samples every 30 minutes. An aliquot of each sample was titrated with 10 0.1 N NaOH to pH 7.0 for determination of the titratable acid concentration using an automatic titrator and pH meter (Radiometer, Copenhagen, Denmark). The acid release was expressed in mmol H760 min. The percent inhibition compared to control experiments was calculated for each compound and the maximum inhibitory effect is given in Table 1. The test compounds suspended in 0.5% Methocel® (methyl cellulose) were administered intraduodenally in doses of 4-20 μΜοΙ / kg when the secretion response to pentagastrin had reached a steady level.

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

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

Table 1

<img file="AT406119B_D0003.tif" />

<td colspan="2">Connection R¹duner</td><td>R.^s</td><td>R *</td><td>R.^J</td><td>R «</td><td>R.^s</td><td>dose umol / ko%</td><td>effect Inhibition</td>

<td>X</td><td>5-COCH,</td><td>6-CH,</td><td>H</td><td>H</td><td>ch₃</td><td>H</td><td> 20</td><td> 30</td>

<td>X</td><td>5-COCH,</td><td>6-CH,</td><td>H</td><td>H</td><td>H</td><td>ch₃</td><td> 8</td><td> 80</td>

<td>X</td><td>5-COOCH,</td><td>6-CH,</td><td>H</td><td>H</td><td>H</td><td>ας</td><td> 4</td><td> 50</td>

<td>X</td><td>5-COOCH,</td><td>NS₃</td><td>H</td><td>Br</td><td>H</td><td>H</td><td> 4</td><td>O</td>

<td>X</td><td>4-CH,</td><td>6-CH,</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,</td><td>6-CH,</td><td>H</td><td>H</td><td>H</td><td>CH,</td><td> 12</td><td> 50</td>

<td>X</td><td>5-COOCH,</td><td>H</td><td>H</td><td>H</td><td>H</td><td>CH,</td><td> 20</td><td> 90</td>

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

<td>X</td><td>5-COCH,</td><td>H</td><td>H</td><td>H</td><td>H</td><td>C, H_S.</td><td> 20</td><td> 40</td>

<td></td><td>5-OCH,</td><td>H</td><td>H</td><td>ch₃</td><td>oh₃</td><td>CH,</td><td> 0.5</td><td> 65</td>

<td>X</td><td>5-OCH,</td><td>H</td><td>H</td><td>H</td><td>ch₃</td><td>H</td><td> 20</td><td> 10</td>

<td>X</td><td>5-ch,</td><td>H</td><td>H</td><td>H</td><td>H</td><td>CH,</td><td> 4</td><td> 50</td>

<td>X</td><td>H</td><td>H</td><td></td><td>a</td><td>H</td><td>H</td><td> 4</td><td>-Stfi</td>

x means already known connection

The compound used in the present invention can be prepared, for example, by reacting a compound of the general formula

R.¹

Z¹ , (VII)

AT 406 119 Β wherein R¹ and R² have the corresponding meaning and Z¹ Represents SH or a reactive esterified hydroxy group, with a compound of the general formula

R.

<img file="AT406119B_D0004.tif" />

where R⁶, R³, R⁴ and R⁵ have the corresponding meaning and Z² represents a reactive esterified hydroxyl group or SH, or by reacting a compound of the general formula (IX), R is obtained¹ and R² have the corresponding meaning with a compound of the general formula

<img file="AT406119B_D0005.tif" />

R.

R where R⁶, R³, R⁴ and R⁵ have the corresponding meaning.

In the above reactions, Z¹ and Z² be a reactive esterified hydroxyl group, which means a hydroxyl group, which with a strong inorganic or organic acid, preferably hydrohalic acid, such as hydrochloric acid, hydrobromic acid or hydroiodic acid, also sulfuric acid or a strong organic sulfonic acid, such as a strong aromatic acid, e.g. benzenesulfonic acid, 4- Bromobenzenesulfonic acid or 4-toluenesulfonic acid, has been esterified.

The oxidation of the sulfur atom to sulfinyl (S-&gt; 0) can preferably be carried out with an oxidizing agent from the group consisting of nitric acid, hydrogen peroxide, peracids, peresters, ozone, nitrous tetroxide, iodosobenzene, N-halosuccinimide, 1-chlorobenzotriazole, tert-butyl hypochlorite, diazabicyclo [2,2, diazabicyclo 2] octane-bromine complex, sodium metaperiodate, selenium dioxide, manganese dioxide, chromic acid, cerium (IV) ammonium nitrate, bromine, Chlorine and sulfuryl chloride carried out in the presence of a solvent inert to the reaction. The oxidizing agent is expediently present in a certain excess with respect to the product to be oxidized.

The 2- (2- (3,5-dimethyl-4-methoxy) -pyridylmethylsulfinyl] -5-methoxy-benzimidazole of the formula used according to the invention

OCH (Ia) can be prepared by oxidation of 2- (2- (3,5-dimethyl-4-methoxypyridylmethylthio] -5-methox-benzimidazole, m-chloroperbenzoic acid in particular being used as the oxidizing agent.

Depending on the process conditions and starting materials, the end product is obtained either as a free base or as an acid addition salt, both of which fall within the scope of the invention. So basic, neutral or mixed salts as well as hemi-, mono-, sesqui- or polyhydrates can be obtained. The acid addition salts of the new compound can be converted into the free base in a manner known per se, either using basic agents, such as alkali, or by ion exchange. On the other hand, the free base obtained can form salts with organic or inorganic acids. In the preparation of acid addition salts, it is preferred to use acids which form suitable therapeutically acceptable salts. Such acids include the hydrohalic, sulfonic, phosphoric, nitric, and perchloric acids; aliphatic, alicyclic, aromatic, heterocyclic carbon or

AT 406 119 Β

Sulphonic acids, such as formic acid, acetic acid, propionic, succinic, glycolic, lactic, apple, tartaric, lemon, ascorbic, maleic, hydroxymaleic, pyruvic, phenylacetic, benzoin, p-aminobenzoic, anthranil -, p-Hydroxybenzoic, salicylic or p-aminosalicylic acid, Embon, methanesulphone, ethanesulphone, hydroxyethanesulphone, ethylene sulphone, halobenzenesulphone,

Toluenesulfonic, naphthylsulfonic or sulfanilic acid; Methionine, tryptophan, lysine or arginine.

These or other salts of the new compound, such as. B. picrates, can serve as cleaning agents for the free bases obtained. Salts of the base 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 new compound in free base form and its salts, it will be understood that the use of the corresponding salts falls within the scope of the invention.

Depending on the choice of starting materials and the process, the new compound can be present as optical isomers or racemates or as a mixture of isomers (racemic mixture).

The mixture of isomers (racemic mixture) that is obtained can be separated into two stereoisomeric (diastereomeric) pure racemates by means of chromatography or fractional crystallization.

The racemates obtained can be separated by known processes, for example recrystallization from an optically active solvent, use of microorganisms, reactions with optically active acids which form salts which can be separated off,

Separation on the basis of different solubilities of the diastereomers. Suitable optically active acids are the L- and D-forms of tartaric acid, di-o-tolyltartaric acid, malic acid, mandelic acid, camphor sulfonic acid or quininic acid. The more active part of the two antipodes is preferably isolated.

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

For the synthesis of the compound used according to the invention, starting materials were prepared, for example, according to the following general rules:

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-mercaptobenzimidazole (compound of the general formula (VII));

2. the compound 2-chloromethylpyridine (compound of the general formula (VIII)) was obtained by reacting 2-hydroxymethylpyridine with thionyl chloride (according to Arch. Pharm. Vol. 26,

Pp. 448 to 451 (1956);

3rd the compound 2-chloromethylbenzimidazole was prepared by condensation of o35 phenylenediamine with chloroacetic acid.

The compound used according to the invention can be prepared according to the following working instructions. (The temperature is given in degrees Celsius):

Working instruction 1:

22.0 g of 2-mercapto- (5-acetyl-6-methyl) -benzimidazole and 19.5 g of 2-chloromethyl- (4,5-dimethyl) 40 pyridinium hydrochloride were dissolved in 200 ml of 95% ethanol. 8 g of sodium hydroxide in 20 ml of water were added and the solution was refluxed for two hours. 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, 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 in portions with stirring and cooling to 5 ° C. After 10 minutes, the precipitated m-chlorobenzoic acid was filtered off. The filtrate was washed with CH₂CI₂ diluted with Na₂CO₃ Solution washed over Na₂SO₄ dried and evaporated in vacuo. The residue crystallized on dilution with CH₃CN, and 2- [2- (4,550 dimethyl-pyridylmethylsulfinyl] - (5-acetyl-6-methyl) -benzimidazole were removed from CH₃CN crystallizes around. Yield: 22.3 g; M.p. 158 ° C.

Working instruction 2:

The compound used according to the invention was prepared according to the working instructions

1.

AT 406 1 1 9 Β

<img file="AT406119B_D0006.tif" />

<td>7erbinduna R^x</td><td>R.^x</td><td>R *</td><td>R.³</td><td>R *</td><td>R.⁵</td><td>Fd. ° C</td>

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

Patent claims: