SK73594A3 - Substituted benzimidazoles, process for their production as well as their use - Google Patents

Abstract

The novel compounds of formula (I), wherein R<1> and R<2>, which are different, are each methyl, -C(O)-CH3 or -C(O)-OCH3 and whereby one of R<1> or R<2> is always methyl; and M is a physiologically acceptable counter cation, as well as processes for the preparation of said compounds, pharmaceutical compositions containing said compounds as active ingredient, and the use of the compounds in medicine.

Description

Technical field

The present invention relates to novel compounds that inhibit exogenously or endogenously stimulated gastric acid secretion and thus can be used in the prevention and treatment of gastrointestinal ulcer.

The invention also relates to the use of the compounds of the invention for inhibiting gastric acid secretion in mammals, including humans. More generally, the compounds of the present invention can be used for the manufacture of medicaments for the prevention and treatment of gastrointestinal inflammatory and gastric acid related diseases in mammals including humans, such as gastritis, gastric ulcer, duodenal ulcer, reflux esophagitis and Zisoningovirus syndrome. . In addition, the compounds may be used for the treatment of other gastrointestinal diseases where gastric antisecretory effect is desirable, for example in patients suffering from gastrinoma and in patients with acute gastrointestinal ulcer bleeding. The compounds of the invention may also be used in patients whose condition requires intensive care and preoperative and postoperative to prevent acid inhalation and against stress ulceration. The compounds of the present invention may r

also for use in the treatment or prophylaxis of inflammatory conditions in mammals including humans, particularly those associated with lysozyme enzymes. Conditions which may be particularly mentioned are rheumatoid arthritis and gout. The invention also relates to pharmaceutical compositions comprising the compounds of the invention as active ingredient. In another aspect, the invention relates to a process for the production of such novel compounds and to the use of the active compounds for the manufacture of pharmaceutical compositions for the therapeutic uses outlined above.

In addition, the compounds of the invention do not block the accumulation (absorption) of iodine in the thyroid gland. It has previously been stated in several lectures organized by the company where the present inventors work that thyroid toxicity depends on whether the compounds are lipophilic or not. We have now unexpectedly found that lipophilicity is not a critical parameter. The claimed compounds, which include rather hydrophilic compounds, exhibit no thyroid toxic effect and at the same time have a high acid secretion inhibiting effect.

The compounds of this invention will also exhibit high solubility and high chemical stability in water.

BACKGROUND OF THE INVENTION

Similar substituted 2 - [[(3,4-dialkoxy-2-pyridyl) methyl] sulfinyl] -1,1-benzimidazol-1-yl derivatives are disclosed in PCT application SET / SE91 / 00415, which was not available as a publication in at the time of filing the basic application in Sweden, but was published shortly thereafter.

Benzimidazole derivatives intended to inhibit gastric acid secretion are described in a number of patents. Of these, British Patent Nos. 1,500,043 and 1,525,958; U.S. Pat. Nos. 4,182,766, 4,255,431 and 4,599,347, Belgian patent no. No. 898,880, European Patent Nos. 124 495, 208 452, 221 041, 279 149 and 176 308 and Derwent Abstract 87-294 449/42. Benzimidazole derivatives designed for use in the treatment or prevention of particular gastrointestinal inflammatory diseases are disclosed in U.S. Pat. 4,359,465.

SUMMARY OF THE INVENTION

The compounds of this invention are effective as inhibitors of gastric acid secretion in mammals including humans and, moreover, do not block the accumulation of iodine in the thyroid gland.

The compounds of the invention also exhibit high solubility and high chemical stability in water.

The compounds of the invention are therefore particularly suitable for parenteral, in particular intravenous and intramuscular administration. The high solubility and chemical stability also make the compounds of the invention suitable for other routes of administration, such as oral and rectal administration.

The compounds of the invention have the general formula I '

in which

R ¹ and R ² , which are different, are each methyl, -C- (O) n CH ₃ or -C- (O) -OCH ₃ and one of R ¹ or R ² is methyl and

M represents a physiologically acceptable counterion.

The structural isomers of the compounds of formula (I) may be used separately, in straight mixtures or in mixtures with unequal isomer content.

The compounds of the formula I according to the invention have an asymmetric center on the sulfur atom, i.e. they can exist as two optical isomers (enantiomers). Both pure enantiomers and racemic mixtures (50% of each enantiomer) and the

i: r

Γ mixtures with unequal contents of both enantiomers are within the scope of ľ of this invention.

It is believed that the compounds of formula (I) are metabolised before their action is exerted. Such metabolism occurs at the N-substituent, a phosphorus-containing group, at the 1-position in the benzimidazole nucleus.

Production of compounds

Compounds according to the above methods.

of the invention can be produced further

a) Compound of formula II

(II) in which

R ¹ and R ² are as defined in formula I and

Z represents a halogen atom such as a chlorine, bromine or iodine atom, or a functionally equivalent group, is reacted with a compound of formula III

ABOUT

II

HO - P - O Q

I

Q (III) t!

in which '(

Q represents a counterion such as Na ⁺ , K ⁺ , Ag ⁺ or a trialkylammonium group.

The salts obtained can be converted into a therapeutically suitable salt, such as sodium and potassium salts, by the addition of sodium or potassium hydroxide, optionally by treatment with an ion exchanger.

b) Compound of formula IV

(IV) in which

Ί 9,,,

R, R and M are as defined above, oxidized to the compound of formula I.

This oxidation can be carried out using an oxidizing agent such as nitric acid, hydrogen peroxide (optionally in the presence of vanadium compounds), peroxyacids, peresters, ozone, nitric oxide, iodosobenzene, N-halosuccinimide, 1-chlorobenzotriazole, tert-butylhypichycloid, diazababiclo chloride. [2,2,2] octane complex with bromine, sodium periodate, selenium dioxide, manganese dioxide, chromic acid, ammonium cerium nitrite, bromine, chlorine and sulfuryl chloride. The oxidation usually takes place in a solvent such as halogenated hydrocarbons, alcohols, ethers and ketones.

The oxidation may also be carried out enzymatically, using an oxidizing enzyme, or microbiically, using a suitable microorganism.

The obtained structural isomers may be separated by crystallization or chromatography.

The racemates obtained can be separated by known methods, for example by recrystallization from an optically active solvent.

For clinical use, the compounds of this invention are formulated into pharmaceutical compositions for oral, rectal or other modes of administration. It is particularly advantageous to formulate the compounds of the invention into pharmaceutical compositions for parenteral administration. The pharmaceutical composition comprises a compound of the invention usually in combination with a carrier (carrier) that is acceptable from a pharmaceutical standpoint. The carrier may be in the form of a solid, semi-solid, or it may be a liquid diluent or capsule. These pharmaceutical compositions are a further object of the invention. The usual amount of active compound is from 0.1 to 95% by weight of the composition, and the amount is from 0.2 to 20% by weight of the compositions for parenteral use from 1 to 50% by weight of the compositions for oral administration.

In the manufacture of pharmaceutical compositions containing a compound of this invention in dosage unit form for oral administration, the selected compound may be admixed with a solid, powdered carrier such as lactose, sucrose, sorbitol, mannitol, starch, amylopectin, cellulose derivatives, gelatin or other suitable and

the carrier, as well as lubricants such as magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethylene glycol waxes. The mixture is then processed into granules or compressed into tablets. The sulfoxide-containing granules and tablets may be coated with an enteric coating which protects the active ingredient from acid-catalyzed degradation as long as the dosage form remains in the stomach. The enteric coatings are selected from pharmaceutically acceptable enteric coatings materials, for example beeswax, shellac or anionic film-forming polymers such as cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, partially methylesterified polymers of methacrylic acid and the like, preferably in combination with a suitable plasticizer. Various colorants may be added to the coatings to distinguish between tablets or granules with different active ingredients or different amounts of active ingredient present.

Soft gelatin capsules can be made as capsules containing a mixture of the active ingredient or ingredients of the present invention, vegetable oil, fat or other suitable soft gelatin capsule composition. Soft gelatin capsules may also be enteric coated as described above. The hard gelatin capsules may contain granules or enteric coated granules of the active ingredient. Hard gelatine capsules may also contain the active ingredient in combination with a solid powder carrier such as lactose, sucrose, sorbitol, mannitol, potato starch, amylopectin, cellulose derivatives or gelatin. Hard gelatine capsules may be enteric coated as described above.

Dosage units for rectal administration may be presented in the form of suppositories containing the active ingredient mixed with a neutral fat base or may be prepared in the form of gelatin rectal capsules containing the active ingredient in admixture with vegetable oil, paraffin oil or other suitable gelatin adjuvant. rectal capsules, or they can be made in the form of a ready-to-use microclysm, or they can be made in the form of a dry microclysm, which is reconstituted in a suitable solvent just prior to administration.

Liquid preparations for oral administration may be made in the form of syrups or suspensions, for example solutions or suspensions, containing from 0.2 to 20% by weight of the active ingredient, the remainder consisting of sugar, sugar alcohols and a mixture of ethanol, water, glycerol, propylene glycol and polyethylene glycol. If desired, such liquid compositions may contain coloring agents, flavoring agents, saccharin, carboxymethylcellulose, or other thickening agents. Liquid compositions for oral administration can also be made in the form of dry powders, which are reconstituted with a suitable solvent before use.

Solutions for parenteral administration may be prepared as a solution of a compound of the invention in a pharmaceutically acceptable solvent, preferably by weight. These, reagent solutions and / or buffers, and may be from 0.1 to 10%, may also contain a stabilizing agent to be manufactured as a filling of ampoules or vials with different unit doses. Solutions for parenteral administration can also be made as a dry preparation to be reconstituted with a suitable solvent just prior to use.

The usual daily dose of the active ingredient varies widely and will depend on various circumstances, such as the individual requirements of each patient, the route of administration and the disease. In general, oral and parenteral doses will range from 5 to 500 mg of active ingredient per day.

DETAILED DESCRIPTION OF THE INVENTION

The invention is illustrated by the examples below.

Example 1

A process for producing a disodium salt of [5-acetyl-6-methyl-2 - [[(3,4-dimethoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazol-1-yl] methyl ester or a disodium salt [6]. Acetyl-5-methyl-2 - [[(3,4-dimethoxy-2-pyridyl) methyl] sulfinyl] -4-benzimidazol-1-yl] phosphoric acid methyl ester

1.7 ml (7.0 mmol) of tributylamine are added with stirring to a solution of 0.24 ml (3.6 mmol) of a solution of 85% phosphoric acid in 2 ml of ethanol. The solvent is evaporated and the residue is taken up in 2.5 ml of methylene chloride. The organic phase was dried over sodium sulfate, filtered and evaporated. 0.12 g (0.28 mmol) of 5-acetyl-1-chloromethyl-6-methyl-2 - [[(3,4-dimethoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole or 6-acetyl- 1-Chloromethyl-5-methyl-2 - [[(3,4-dimethoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole and the tributylammonium phosphoric acid salt prepared above are dissolved in 6 ml of methylene chloride. The methylene chloride was distilled off and the residue was heated in a water bath at 60 ° C for 5 minutes. The residue is dissolved in 6 ml of methylene chloride and the methylene chloride is distilled off again and the oily product mixture is heated in a water bath at 60 ° C for 5 minutes. This procedure was repeated four times until the reaction was complete. The residue is dissolved in 4 ml of methylene chloride and washed with three portions of 4 ml of water each. A 0.2 molar sodium hydroxide solution was added to the organic phase with stirring while the pH of the aqueous layer was carefully monitored. When the pH of the aqueous phase reaches 9 to 9.5, the mixture is centrifuged. The aqueous layer was washed with three 4 mL portions of methylene chloride and then freeze-dried. 40 mg of the title compound is obtained corresponding to a yield of 27% of theory.

NMR spectral values are given below.

Example 2

Process for preparing disodium salt of [5-methoxycarbonyl-6-methyl-2 - [[(3,4-dimethoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazol-1-yl] methyl ester or disodium salt [6- Methoxycarbonyl-5-methyl-2 - [[(3,4-dimethoxy-2-pyridyl) methyl / sulfinyl] -1H-benzimidazol-1-yl] phosphoric acid methyl ester

1.8 ml (7.8 mmol) of tributylamine are added with stirring to 0.26 ml (3.9 mmol) of a solution of 85% phosphoric acid in 2.5 ml of ethanol.

The solvent was evaporated and the residue taken up in 3 ml of methylene chloride.

The organic phase was dried over sodium sulfate, filtered and evaporated. 0.14 g (0.32 mmol) of 5-methoxycarbonyl-1-chloromethyl-6-methyl-2 - [[(3,4-di10 methoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole or 6- Dissolve the methoxycarbonyl-1-chloromethyl-5-methyl-2 - [[(3,4-dimethoxy-2-pyridyl) methyl / sulfinyl] -1H-benzimidazole and the tributylammonium phosphate salt prepared in 6.5 ml of methylene chloride . The methylene chloride was distilled off and the residue was heated in a water bath at 60 ° C for 5 minutes. The residue is dissolved in 6.5 ml of methylene chloride, the methylene chloride is distilled off again, and the oily product mixture is reheated in a water bath at 60 ° C for 5 minutes. This procedure was repeated four times until the reaction was complete. The residue is dissolved in 4 ml of methylene chloride and washed with three portions of 4 ml of water each. A 0.2 molar sodium hydroxide solution is added to the organic phase with stirring, while the pH of the aqueous layer is carefully monitored. When the pH of the aqueous phase reaches 9 to 9.5, the mixture is centrifuged. The aqueous layer was washed with three 4 mL portions of methylene chloride and then freeze-dried. 11 mg of the title compound is obtained, corresponding to a yield of 6% of theory.

NMR spectral values are given below.

Table 1

Protons in water: 4.80.

Example Solvent NMR values .delta. Ppm

1 d ₂ ° 2.67 (with, 3H), 2.78 (with, 3H), 3.85 (with, 3H) (300 MHz) 3.98 (with, 3H), 4.98 (D, 1H), 5.08 (D, 1H) 5.98 (M, 2H), 7.15 (D, 1H), 7.78 (with, 1H) * 8.12 (D, 1H), 8.18 (with, 1H) 2 d ₂ ° 2.75 (with, 3H), 3.83 (with, 3H), 3.97 (with, 3H) (300 MHZ) 4.05 (with, 3H), 4.98 (D, 1H), 5.08 (D, 1H) 5.95 (M, 2H), 7.15 (D, 1H), 7.83 (with, 1H) 8.15 (D, 1H), 8.28 (with, 1H)

Process for preparing intermediates

Example I 1

5-Acetyl-1-hydroxymethyl-6-methyl-2 - [[(3,4-dimethoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole or 6-acetyl-1-hydroxymethyl-5-methyl- 2 - [/ (3,4-dimethoxy-2-pyridinyl) methyl / sulfinyl] benzimidazole

To a mixture of 5-acetyl-6-methyl-2 - [[(3,4-dimethoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole (2.00 g, 5.4 mmol) and methylene chloride (100 mL) was added 1.0 mL (25 mmol) of a 5 molar aqueous formaldehyde solution. Shake the mixture for 3 minutes. After separation, the organic solution was dried over sodium sulfate and evaporated under reduced pressure. 1.7 g of a red syrup are obtained. Yield: 78%. The product consists mainly of one of the structural isomers of the title compound as well as a small amount of the starting compound.

NMR spectral values are given below.

Example I 2

5-Acetyl-1-chloromethyl-6-methyl-2 - [[(3,4-dimethoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole or 6-acetyl-1-chloromethyl-5-methyl- 2 - [/ (3,4-dimethoxy-2-pyridinyl) methyl / sulfinyl] benzimidazole

A suspension of 1.7 g (4.2 mmol) of 5-acetyl-1-hydroxymethyl-6-methyl-2 - [[(3,4-dimethoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole and

6-Acetyl-1-hydroxymethyl-5-methyl-2 - [[(3,4-dimethoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole in 40 mL of acetonitrile was cooled to -15 ° C. 0.50 g (4.2 mmol) of thionyl chloride and 0.50 g (4.2 mmol) of triethylamine are added dropwise to the reaction mixture, respectively. The mixture was stirred at room temperature for 5 minutes and then evaporated under reduced pressure. The residue is chromatographed

It was eluted with 70 g of silica gel using ethyl acetate / methylene chloride as the eluent, increasing the amount of ethyl acetate during chromatography.

0.14 g of the product consists mainly of one of the structural isomers. Yield: 8%.

NMR spectral values are given below.

Example I 3

5-Methoxycarbonyl-1-hydroxymethyl-6-methyl-2 - [[(3,4-dimethoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole or 6-methoxycarbonyl-1-hydroxymethyl-5-methyl- 2 - [/ (3,4-dimethoxy-2-pyridinyl) methyl / sulfinyl] benzimidazole

To a solution of 0.34 g (0.87 mmol) of 5-methoxycarbonyl-6-methyl-2 - [[(3,4-dimethoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole in 25 mL of methylene chloride was added 1 7 ml (8.5 mmol) of a 5 molar aqueous solution of formaldehyde. The mixture was shaken for 3 minutes, after separation, the organic solution was dried over sodium sulfate and evaporated under reduced pressure to give 0.36 g of a red syrup. Yield 100%. The product consists mainly of one of the structural isomers of the title compound as well as a small amount of the starting compound.

NMR spectral values are given below.

Example I 4

5-Methoxycarbonyl-1-chloromethyl-6-methyl-2 - [[(3,4-dimethoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole or 6-methoxycarbonyl-1-chloromethyl-5-methyl- 2 - [/ (3,4-dimethoxy-2-pyridinyl) methyl / sulfinyl] benzimidazole

A solution of 0.36 g (0.87 mmol) of 5-methoxycarbonyl-1-hydroxymethyl-6-methyl-2 - [[(3,4-dimethoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole and 6-methoxycarbonyl -l-hydroxymethyl-5-methyl-2 - [/ (3,4-dimetoxy13

-2-pyridyl) methyl / sulfinyl] -ΙΗ-benzimidazole in 20 mL acetonitrile was quenched to -20 ° C. 0.066 ml (0.90 mmol) of thionyl chloride and 0.10 g (1.0 mmol) of triethylamine are added dropwise to the reaction mixture, respectively. The mixture was stirred at room temperature for 5 minutes and then evaporated under reduced pressure. The residue is chromatographed on 20 g of silica gel using a mixture of ethyl acetate and methylene chloride as eluent, and the ethyl acetate content is increased during chromatography. 0.16 g of the product consists mainly of one of the structural isomers. Yield: 43%.

NMR spectral values are given below.

table

Example

I 1

I 2

I 3

solvent NMR values δ ppm cdci ₃ 2.60 (s, 3H), 2.70 (s, 3H), 3.90 (s, 3H) 3.95 (s, 3H), 4.8-5.1 (m, 2H), 5.70 (d, 1 H), 6.10 (d, 1 H), 6.75 (d, 1 H) 7.40 (s, 1 H), 7.90 (d, 1 H), 8.10 (s, 1 H) cdci ₃ 2.66 (s, 3H), 2.72 (s, 3H), 3.90 (s, 3H) 3.91 (s, 3H), 4.91 (d, 1H), 5.02 (d, 1H) 6.23 (d, 1 H), 6.55 (d, 1 H), 6.80 (d, 1 H) 7.39 (s, 1 H), 8.15 (d, 1 H), 8.20 (s, 1 H) cdci ₃ 2.75 (s, 3H), 3.8-4.0 (m, 9H), 4.7-4 5.1 (m, 2H); 5.75 (d, 1H); 6.10 (d, 1H); 6.75 (d, 1 H), 7.40 (s, 1 H), 7.90 (d, 1 H) 8.30 (s, IH) cdci ₃ 2.79 (s, 3H), 3.89 (s, 3H), 3.91 (s, 3H) 3.93 (s, 3H), 4.90 (d, 1H), 5.02 (d, 1H) 6.23 (d, 1 H), 6.57 (d, 1 H), 6.80 (d, 1 H) 7.39 (s, 1 H), 8.15 (d, 1 H), 8.40 (s, 1 H)

Table 3

Examples of compounds encompassed by Formula I are shown in the following table.

Example R ¹ R ² M yield % identification cation data notes 1 ch ₃ C (o) ch ₃ or · Na ⁺ 27 NMR isolated c (o) ch ₃ ch ₃ isomer 2 ch ₃ C (o) and ₃ or Na ⁺ 6 NMR isolated c (o) and ₃ ch ₃ isomer 3 c (o) ch ₃ ch ₃ or Na ⁺ - - isolated ch ₃ c (o) ch ₃ isomer 4 c (o) and ₃ ch ₃ or Na ⁺ - - isolated c (o) and ₃ ch ₃ isomer 5 ch ₃ c (o) ch ₃ Na ⁺ - - isomer c (o) ch ₃ ch ₃ mixture 6 ch ₃ c (o) and ₃ Na ⁺ - - isomer c (o) and ₃ ch ₃ mixture

The best known embodiment of the present invention is to use the compound of Example 2.

Pharmaceutical compositions containing a compound of the invention as an active ingredient are illustrated by the following compositions.

syrup

A syrup containing 1% by weight of the active substance is prepared from the following ingredients:

the compound of Example 1 i, o g sugar, powdered 30,0 g saccharin 0.6 g glycerol 5.0 g seasoning 0.05 g ethanol, 96% 5.0 g distilled water as necessary to make up to 100 ml In 60 g of hot water take dissolves sugar and saccharin. After cooling to a sugar solution and glycerol, the active ingredient and then a flavoring solution dissolved in ethanol. The mixture was diluted with water to a final volume of 100 mL. Enteric coated tablets Enteric coated tablets are made from the following ingredients: containing 20 mg of the active substance, and I. a mixture of the compounds of Example 2 200 g lactose 700 g methylcellulose e g polyvinylpyrrolidone, crosslinked 50 g magnesium stearate 15 g

sodium carbonate distilled water

II.

cellulose acetate phthalate cetyl alcohol isopropanol methylene chloride g

as needed

200 g g

2000 g

2000 g

I. A powder mixture of the compounds of Example 2 is mixed with lactose and granulated with an aqueous solution of methylcellulose and sodium carbonate. The wet mass is passed through a sieve and the granulate is dried in an oven. After drying, the granulate is mixed with polyvinylpyrrolidone and magnesium stearate. The dry mixture is compressed into tablet cores (10,000 tablets), each containing 20 mg of active ingredient, in a tabletting machine using a punch having a diameter of 6 mm.

II. A solution of cellulose phthalate acetate and cetyl alcohol in isopropanol and methylene chloride is sprayed onto the tablets in a tablet coating machine (Accela Cota ^R , Manesty). 110 mg of final tablets are obtained.

Solution for intravenous administration

A parenteral preparation for intravenous use, containing 4 mg of active ingredient per milliliter, is prepared from the following ingredients:

Example 2 4 g sterile water to make up to a final volume of 1000 mL

The active substance is dissolved in water and made up to a final volume of 1000 ml. The solution is filtered through a 0.22 gm filter and immediately filled into sterile 10 ml ampoules. The ampoules are closed.

tablets

Tablets containing 30 mg of active ingredient are made from the following ingredients:

the compound of Example 3 in Table 3 300 g lactose 700 g methylcellulose 6 g polyvinylpyrrolidone, crosslinked (PVP-XL) 62 g disodium hydrogenphosphate 2 g magnesium stearate 30 g purified water as needed

The active ingredient is mixed with lactose and portions of cross-linked polyvinylpyrrolidone and granulated with a solution of methylcellulose and disodium hydrogen phosphate. The wet mass is passed through a sieve and dried in a fluid bed dryer. After the addition of magnesium stearate and the remainder of the cross-linked polyvinylpyrrolidone and mixing, the drug-containing mixture is compressed into tablets with an average weight of 110 mg. Each tablet contains 30 mg of active ingredient.

Enteric coated tablets

500 g of the tablets mentioned above are enteric coated. The solution of the mixture below is sprayed onto the tablets in a fluidized bed using a Wurster coating technique.

Coating solution Cellulose acetate phthalate Cetyl alcohol Isopropanol Dichloromethane g

400 g

400 g

The final coated tablets weighed 117 mg.

lace

The laces are made from the ingredients listed below using the welding process. Each lace contains 40 mg of active ingredient.

a mixture of the compounds of Example 4 in Table 3

Witepsol H-15 g

180 g

The active substance is mixed homogeneously with Witepsol H-15 at 41 C. The molten mass is filled to a given volume in pre-fabricated lace packs to a net weight of 1.84 g. After cooling, the packages are sealed with heat. Each lace contains 40 mg of active compound.

Immediately before use, the active ingredient dissolved in 10 ml of sterile water is transferred to 100 ml of normal saline for infusion to give a total volume of about 110 ml. The solution is administered as an intravenous infusion over approximately 30 minutes.

syrup

A syrup containing 1% of the active substance is prepared from the following ingredients:

the compound of Example 3 in Table 3 sugar, powdered saccharin flavor ethanol, 96% distilled water

1.0 g

30,0 g

0.6 g

0.05 g

5.0 g as necessary to make up to 100 ml

Dissolve sugar and saccharin in 60 g of hot water. After cooling, the active ingredient is added to the sugar solution, followed by a solution of the flavoring dissolved in ethanol. The mixture was diluted with water to a final volume of 100 mL.

Solution for intravenous or intramuscular injection Compound of Example 1 60 g water for injections to make up to 1000 ml

The active substance is dissolved in water to a final volume of 1000 ml. The solution is filtered through a sterile 0.22 gm filter and dispensed under aseptic conditions into 1 ml sterile ampoules. The amlule is sealed.

Formulation for Intravenous Infusion Sterile Compound of Example 2 60 mg sterile vials and mg caps of sterile active compound are dispensed into sterile 10 ml vials. The vials are closed with a rubber stopper. Filling operations are performed under aseptic conditions in a sterile production space at a vertical laminar flow.

Biological effects

Effects on the accumulation of iodine in the thyroid gland ₍

The effect of the compounds of formula I of the present invention, the accumulation of iodine in the thyroid gland is measured as the effect of the active compounds formed in the metabolism of compounds of the present invention to accumulate L ²⁵ in the thyroid gland.

Effect on accumulation of ¹²⁵ I in the thyroid gland

1-25j accumulation _{in the} thyroid gland was studied in male rats Sprague-Dawley strain, which was deprived of food for 24 hours before the test. The protocol of the experiment described by CE Searle et al. (Biochem. J. 47: 77-81 (1950)).

Test substances are suspended in 0.5% buffered methocel (pH 9) and administered orally via a gastric tube at a volume of 5 ml / kg body weight. After one hour, he will

OR ^{injects X1} I _with intraperitoneal infection _{with an} activity corresponding to 300 kBq / kg (3 ml / kg). Four hours after administration of ¹²⁵ i, the animals were sacrificed by asphyxiation with carbon dioxide and bled. The thyroid was removed together with a portion of the trachea and placed in a small test tube to determine the radioactivity in a gamma counter (LKB-Wallac model 1282 Compugamma). The percent inhibition is calculated according to the formula

T

100. (1 - ________),

P in which

T and P represent mean thyroid radioactivity, as determined in animals treated with test reagent and placebo (buffered metocel).

The statistical significance of the difference between the test reagent treated animals and the placebo treated animals was evaluated using the Mann-Whitney U test. P values < 0.05 are considered significant.

and

Results of biological tests.

Table> 4 lists the assay values available for compounds of the invention.

Table 4

Bioassay values

Test compound (number of animals)

Percent inhibition at

400 μιηοΐ / kg from accumulation of ¹²⁵ I in the thyroid gland active metabolite of example no.

1, 3 and 5-7 (n = 5) the active metabolite of Example 1;

2, 4 and 6 (n = 5) e

Claims (13)

PATENT A compound of formula I wherein: R ¹ and R ² , which are different, are each methyl, -C (O) -CH ₃ or -C (O) -OCH _3, and one of R ¹ or R ² is each methyl and M represents a physiologically acceptable counter-charged cation. A compound according to claim 1, wherein M represents Na, K, Ag or a trialkylammonium group. Compounds of formula I according to claim 1, which is a mixture of [5-acetyl-6-methyl-2 - [[(3,4-dimethoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole-1, disodium salt. -yl] methyl phosphate and disodium salt of [6-acetyl-5-methyl-2 - ([(3,4-dimethoxy-2-pyridyl) methyl / sulfinyl] -ΙΗ-benzoimidazol-1-yl) Methyl phosphoric acid. Compounds of formula I according to claim 1, which is a mixture of [5-methoxycarbonyl-6-methyl-2 - [[(3,4-dimethoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole disodium salt. 1-yl] methyl phosphate and disodium salt of [6-methoxycarbonyl-5-methyl-2 - [[(3,4-dimethoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazolyl] methyl ester phosphoric acid. 5. A compound according to claim 1 which is phosphoric acid disodium salt of [5-acetyl-6-methyl-2- [[(3,4-dimethoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazolyl]] methyl ester. . 6. A compound according to claim 1 which is [6-acetyl-5-methyl-2 - [[(3,4-dimethoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazol-1-yl] methyl ester disodium salt. phosphoric acid. The compound of claim 1 which is [5-methoxycarbonyl-6-methyl-2 - [[(3,4-dimethoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazol-1-yl] disodium salt) methyl phosphate. The compound according to claim 1, which is phosphoric acid disodium salt of [6-methoxycarbonyl-5-methyl-2 - [[(3,4-dimethoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazol-1-yl] methyl ester. . Pharmaceutical composition, characterized in that it contains a compound according to claim 1 as active substance. The compound of claim 1 for use in therapy. The compound of claim 1 for use in inhibiting gastric acid secretion in a mammal, including a human. The compound of claim 1 for use in the treatment of gastrointestinal inflammatory diseases in a mammal, including a human. ¹ 13. A method of inhibiting gastric acid secretion, comprising administering to a mammal, including a human, a compound of claim 1.