SI9200402A - Substituted benzimidazoles, process for their preparation and 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

Dos. 5135/22466

Aktiebolaget ASTRA Sodertalje / Sweden

Inventor: Bjorn Holstein

Gunnel Sunden

H 1129 1992'11'02 ML / EE / AW / EL

SUBSTITUTED BENZIMIDAZOLES, PROCEDURE FOR THEIR PREPARATION

AND THEIR APPLICATION 1

SUBSTITUTED BENZIMIDAZOLES, PROCEDURE FOR THEIR PREPARATION

AND THEIR USE

DESCRIPTION

FIELD OF THE INVENTION

It is an object of the present invention to provide novel compounds which will prevent exogenous or endogenously stimulated gastric acid secretion and will thus be used for the prevention and treatment of peptic ulcers.

The present invention also relates to the use of the compounds of the invention for preventing gastric acid secretion in mammals and humans. In a more general sense, the compounds of the invention can be used to prevent and treat gastrointestinal inflammation and gastric acid-related diseases in mammals including humans, such as gastritis, gastric ulcer, duodenal ulcer, reflux esophagitis, and Zollinger-Ellison syndrome. Furthermore, the compounds can be used to treat other gastrointestinal disorders where an anti-excretory effect in the stomach is desired, e.g. in patients suffering from gastrinomas or acute upper gastrointestinal bleeding. They can also be used in intensive care patients, pre- and postoperatively to prevent acid aspiration and stress ulceration. The compounds of the invention may also be used in the treatment or prevention of inflammatory conditions in mammals, including humans, in particular those comprising lysozyme enzymes. Conditions that can be specifically mentioned are rheumatoid arthritis and gout. The invention also relates to pharmaceutical compositions containing the compounds of the invention as active ingredient. In a further aspect, the invention relates to processes for the preparation of such novel compounds and to the use of active compounds for the manufacture of pharmaceutical compositions for use in medicine, as indicated above.

The compounds of the invention will not interfere with the uptake of iodine into the thyroid gland. Previously, it was revealed in several lectures given by the company where the inventors work that thyroid toxicity depends on whether the compounds are lipophilic or not. The inventors have now unexpectedly found that lipophilia is not the one parameter that would be critical. The required compounds, comprising fairly hydrophilic compounds, do not give any thyroid-toxic effects and at the same time have a high degree of inhibitory effect on acid secretion.

The compounds of the invention will also be highly soluble and very chemically stable in water. &Quot;

Background of the invention

Similarly disubstituted 2 - [[(3,4-dialkoxy-2-pyridinyl) -methylisulfinyl-1H-benzimidazol-1-yl compounds are described in PCT / SE91 / 00415, which was not publicly available at the time the invention was officially registered. in Sweden, but was published shortly afterwards.

Previous techniques

Benzimidazole derivatives intended to inhibit gastric acid secretion are disclosed in a number of patent documents. These include GB 1 500 043, GB 1 525 958, US 4 182 766, US 4 255 431, US 4 599 347, BE 898 880, EP 124 495, EP 208 452, EP 221 041, EP 279 149, EP 176 308 and Derwent's summary 87-294449 / 42. Benzimidazole derivatives presented for use in the treatment or prevention of specific diseases of gastrointestinal inflammation are explained in US 4,359,465.

An invention

The compounds of the invention are effective as inhibitors of gastric acid secretion in mammals and humans and do not further interfere with the uptake of iodine into the thyroid gland.

Furthermore, the compounds of the invention show high solubility and are very chemically stable in water.

The compounds of the invention are therefore particularly suitable for parenteral, in particular intravenous and intramuscular use. High solubility and chemical stability also allow the compounds of the invention to be acceptable for other routes of administration, such as oral or rectal administration.

The compounds of the invention are characterized by the following formula I:

I in which: R1 and R2, which are different, each of them methyl, -C (O) -CH3 or -C (O) -OCH3 and wherein one of R1 or R2 is always methyl and M is physiologically acceptable the opposite cation. 4

The structural isomers of the compounds of formula I may be used separately or in the same or unequal mixtures.

The compounds of the invention of formula I have an asymmetric center in the sulfur atom, i. exist as two optical isomers (enentio-measure). Both pure enantiomers, racemic mixtures (5% of each enantiomer), and unequal mixtures of both are encompassed in the present invention.

It is believed that the compounds of formula I are metabolized before they show an effect. Such metabolism occurs in the N substituent, in the phosphorus-containing group, and in position 1 in the benzimidazole nucleus.

Preparation

The compounds of the invention may be prepared by the following methods: a) By reacting a compound of formula II

wherein R 1 and R 2 are as defined in formula I, Z is halogen as Cl, Br or I or a functionally equivalent group, with a compound of formula III

5 Ο I

ΗΟ-Ρ-Ο Q

III ι Ο Ο where Q is the opposite ion, such as Na +, K +, Ag + or trialkylamo-m J.

The salts obtained can be converted into a therapeutically suitable salt such as sodium and potassium salts, by adding NaOH or KOH or by ion exchange.

b) By oxidizing a compound of formula IV

IV wherein R 1, R 2 and M have the same meaning as in the case of a compound of formula I.

This oxidation can be carried out using oxidizing agents such as nitric acid, hydrogen peroxide (optional in the presence of vanadium compounds), peracids, perestry, ozone, nitric oxide, iodozobenzene, N-halosuccinimide, 1- chlorobenzotriazole, t-butyl hypochlorite, bromine and diazabicyclo- (2,2,2) -octane complex, sodium metaperiodate, selenium dioxide, manganese dioxide, chromic acid, cericammonium nitrate, bromine, chlorine, and sulfur (IV) 6 chloride. Oxidation usually occurs in solvents such as halogenated hydrocarbons, alcohols, ethers, ketones.

The oxidation can also be carried out enzymatically using an enzyme that catalyzes the oxidation reaction or microbiotically using a suitable microorganism.

The structural isomers obtained can 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 the invention have been prepared in pharmaceutical forms for oral, rectal, parenteral or other routes of administration. It is especially preferred that the compounds of the invention in pharmaceutical forms be prepared for parenteral administration. The pharmaceutical composition comprises a compound of the invention in combination with a pharmaceutically acceptable carrier. The carrier may be in the form of a solid, semi-solid or liquid diluent or capsule. These pharmaceutical compositions are a further object of the invention. The amount of active compounds is usually between 0.1-95% by weight of the preparation, between 0.2 and 20% by weight in preparations for parental use and between 1 and 50% by weight in preparations for oral administration. In the preparation of pharmaceutical compositions containing a compound of the present invention in dosage unit form for oral administration, the selected compound may be mixed with a solid, powdered carrier such as lactose, sucrose, sorbitol, mannitol, starch, amylopectin, cellulose derivatives, gelatin or other suitable carrier, as well as with 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. 7

Granules and tablets containing sulfoxides can be coated with an enteric coating that protects the active compound from acid-catalyzed degradation for as long as the dose remains in the stomach. The enteric coating is selected from pharmaceutically acceptable enteric coating substances, for example beeswax, shellac or anionic membrane polymers such as cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, methyl acrylic acid methacrylic polymers and partially methyl esterified polymers. if desired in combination with a suitable plasticizer. Different colors can be added to the coating to differentiate between tablets or granules with different amounts of the active compound they contain.

Soft gelatin capsules can be prepared with capsules containing a mixture of the active compound or compounds of the invention, vegetable oils, ointment, or other suitable carriers for soft gelatin capsules. Soft gelatin capsules can also be coated as described above. Hard gelatin capsules may contain granules or enteric coated granules with the active compound. Hard gelatin capsules may also contain the active compound in combination with a solid powder carrier such as lactose, sucrose, sorbitol, mannitol, potato starch, amylopectin, cellulose derivatives or gelatin. Hard gelatin capsules can be enterically coated as described above.

Dosage units for rectal administration may be prepared in the form of a suppository containing the active substance mixed with a neutral fatty liner, or they may be prepared in the form of a gelatin rectal capsule containing the active substance in a mixture with vegetable oil, paraffin oil or other carrier suitable. for gelatin rectal capsules, or they can be prepared as a ready-made micro enema, or they can be prepared in the form of a dry preparation for micro 8 enemas, which will be reconstituted in a suitable solvent immediately before use.

Liquid preparations for oral use can be prepared in the form of syrups or suspensions, e.g. solutions or suspensions containing from 0.2% to 20% by weight of the active ingredient and a residue consisting of sugar or sugar alcohols and a mixture of ethanol, water, glycerol, propylene glycol and polyethylene glycol. If desired, such liquid preparations may contain coloring agents, flavoring agents, saccharin and carboxymethylcellulose, or other thickening agents. Liquid preparations for oral use 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 in a concentration of 0.1% to 10% by weight. These solutions may also contain stabilizing agents and / or buffering agents and may be manufactured in various ampoules or single dose bottles. Solutions for parenteral administration can be prepared as dry preparations, reconstituted with a suitable solvent improvised before use.

The typical daily dose of the active substance varies widely and will depend on various factors such as the individual needs of the individual patient, the route of administration and the disease. In general, oral and parenteral dosages will be in the range of 5 to 500 mg of active substance per day.

The invention is illustrated by the following examples. 9

Example 1. Preparation of [5-acetyl-6-methyl-2 - [[(3,4-dimethoxy-2-pyridinyl) methylisulfinyl] -1H-benzimidazol-1-yl] methyl phosphoric acid ester, disodium salt or [6-acetyl-5 -methyl-2- [1H (3,4-dimethoxy-2-pyridinyl) methyl sulfinyl] -1H-benzimidazol-1-yl] phosphoric acid methyl ester, disodium salt.

Tributylamine (1.7 mL, 7.0 mmol) was added with a solution of phosphoric acid, 85% (0.24 mL, 3.6 mmol) in ethanol (2 mL) with stirring. The solvent was evaporated and the precipitate was taken up in methylene chloride (2.5 ml). The organic phase was dried over sodium sulfate, filtered and evaporated. 5-acetyl-1-chloromethyl-6-methyl-2-C 1,4 (3,4-dimethoxy-2-pyridinyl) methyl] -sulfinyl] -1H-benzimidazole or 6-acetyl-1-chloromethyl-5-methyl-2- [[(3,4-dimethoxy-2-pyridinyl) methyl] sulfinium-1H-benzimidazole (0.12 g, 0.28 mmol) and the tributylammonium salt of phosphoric acid, previously prepared, were dissolved in methylene chloride (6 ml ). Methylene chloride was removed by distillation and the precipitate was heated on a water bath for 5 minutes at 60 ° C. The precipitate was dissolved in methylene chloride (6 ml); methylene chloride was removed again by distillation and the oily mixture of the product was heated on a water bath at 60 ° C for 5 minutes. The procedure was repeated four times until the reaction was complete. The precipitate was dissolved in methylene chloride (4 mL) and washed with three (4 mL) portions of water. Sodium hydroxide solution was added to the organic phase with stirring, while the pH of the aqueous layer was carefully controlled. When the pH in the aqueous phase reached 9-9.5, the mixture was centrifuged. The aqueous layer was washed with three portions (4 mL) of methylene chloride and then freeze-dried to give 40 mg, 27% of the title compound. NMR data are given below.

Example 2. Preparation of N-5-carbomethoxy-6-methyl-2 - [[(3,4-dimethoxy-2-pyridinyl) methyl] sulfinyl-1E-benzimidazol-1-yl] phosphoric acid methyl ester, disodium salt or [6-carbomethoxy-5-methyl-2 - [[(3,4-dimethoxy-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazol-1-yl] phosphoric acid methyl ester, disodium salt.

Tributylamine (1.8 mL, 7.8 mmol) was added to a solution of phosphoric acid, 85% (0.26, 3.9 mmol) in ethanol (2.5 mL) with stirring. The solvent was evaporated and the precipitate was taken up in methylene chloride (3 ml). The organic phase was dried over sodium sulfate, filtered and evaporated. 5-Carbomethoxy-1-chloromethyl-6-methyl-2 - [[(3,4-dimethoxy-2-pyridinyl) methyl-1H-sulfinyl] -1H-benzimidazole or 6-carbomethoxy-1-chloromethyl- 5-Methyl-2 - Γ] (3,4-dimethoxy-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazole (0.14 g, 0.32 mmol) and the tributylammonium salt of phosphoric acid, previously prepared, were dissolved in methylene chloride (6.5 ml). Methylene chloride was removed by distillation and the precipitate was heated on a water bath for 5 minutes at 60: C. The residue was dissolved in methylene chloride (6.5 ml) and the methylene chloride was removed again by distillation and the oily mixture of the product was heated on a water bath at 60 ° C for 5 minutes. This procedure was repeated four times until the reaction was complete. The residue was dissolved in methylene chloride (4 mL) and washed with three (4 mL) portions of water. Sodium hydroxide solution (0.2 M) was added to the organic phase with stirring, while the pH of the aqueous layer was carefully controlled. When the pH of the aqueous layer reached 9 - 9.5, the mixture was centrifuged. The aqueous layer was washed with three portions (4 mL) of methylene chloride and then freeze dried to give 11 mg, 6% of the title compound. NMR data are given below. 11

Table 1

Water protons continued at 4.80. Primpr Solvent_NMR Data_ΡΡΙΏ D2 ° 2.67 (s, 3H), 2.78 (s, 3H), 3 1.85 (s, 3H), (300 MHz) 3.98 (S, 3H), 4.98 (d, 1H), 5.08 (d, 1H) ), 5.98 (m, 2H), 7.15 (d, 1H), 7.78 (s, 1H), 8.12 (d, 1H), 8.18 (s, 1H). ° 2 ° 2.75 (s, 3H), 3.83 (s, 3H), 3.97 (s, 3H), (300 MHz) 4.05 (s, 3H), 4.98 (d, 1H), 5.08 (d, 1H) , 5.95 (m, 2H), 7.15 (d, 1H), 7.83 (s, 1H), 8.15 (d, 1H), 8.28 (s, 1H).

Preparation of intermediates

Example I 1

Preparation of 5-acetyl-1-hydroxymethyl-6-methyl-2- [E (3,4-dimethoxy-2-pyridinyl) methyl] sulfinyl] -Ιϋ-benzimidazole or 6-acetyl-1-hydroxymethyl-5-methyl -2- [E (3,4-dimethoxy-2-pyridinyl) methyl] sulfinyl] -Ιϋ-benzimidazole

Mixtures of 5-acetyl-6-methyl-2 - [(3,4-dimethoxy-2-pyridinyl) methyl) sulfinyl] -Ιϋ-benzimidazole (200 g, 5.4 mmol) and methylene chloride (100 ml) was added 5 M formaldehyde in water (5.0 ml, 25 mmol). The mixture was shaken for 3 minutes. After separation, the organic solution was dried over Na2SO4 and evaporated under reduced pressure to give a red syrup (1.7 g, 78%). The product formed mainly one of the isomers of the title compound as well as small amounts of the starting material. NMR data are given below.

Example I 2

Preparation of 5-acetyl-1-chloromethyl-6-methyl-2-CC (3,4-dimethoxy-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazole or 6-acet-yl-1-chloromethyl-5-methyl- 2 - [[(3,4-dimethoxy-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazole

Suspension of 5-acetyl-1-hydroxymethyl-6-methyl-2-Γ [(3,4-dimethoxy-2-pyridinyl) methyl] sulfinyl-1H-benzimidazole and 6-acetyl-1-hydroxymethyl-5-methyl- 2- [X (3,4-Dimethoxy-2-pyridinyl) methylsulfinyl] -1H-benzimidazole (1.7 g, 4.2 mmol) in acetonitrile (40 mL) was cooled to -15 ° C. Thionyl chloride (0.50 g, 4.2 mmol) and triethylamine (0.50 g, 4.2 mmol) were added dropwise to the suspension. The mixture was stirred for five minutes at room temperature and then evaporated under reduced pressure. The residue was chromatographed on silica gel (70 g) using a mixture of ethyl acetate and methylene chloride as eluent. The amount of ethyl acetate was increased during chromatography. The 0.14 g (18%) product mainly contained one structural isomer. NMR data are given below.

Example I 3

Preparation of 5-carbomethoxy-1-hydroxymethyl-6-methyl-2-yl] (3,4-13 dimethoxy-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazole or 6-carbomethoxy-1-hydroxymethyl-5- methyl 2-e [[(3,4-dimethoxy-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazole

A solution of 5-carbomethoxy-6-methyl-2-Q [(3,4-dimethoxy-2-pyridinyl) methyl] sulfinyl-1H-benzimidazole (0.34 g, 0.87 mmol) in methylene chloride (25 mL) ) 5 M aqueous formaldehyde solution was added. The mixture was shaken for three minutes. After separation, the organic solution was dried over Na2SO4 and evaporated under reduced pressure to give a red syrup (0.36 g, 100%). The product contained mainly one of the structural isomers of the title compound as well as a small amount of starting material. NMR data are given below.

Example I 4

Preparation of 5-carbomethoxy-1-chloromethyl-6-methyl-2 - [[(3,4-di-methoxy-2-pyridinyl) methyl] sulfinyl] -1] benzimidazole or 6-carbomethoxy-1-chloromethyl-5 -methyl-2 - [[(3,4-dimethoxy-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazole

Solution of 5-carbomethoxy-1-hydroxymethyl-6-methyl-2 - [[(3,4-dimethoxy-2-pyridinyl) methyl] sulfinyl] -ΙΗ-benzimidazole and 6-carbomethoxy-1-hydroxymethyl-5-methyl-2 - [[(3,4-dimethoxy-2-pyridinyl) methyl]. sulfinyl-1H-benzimidazole (0.36 g, 0.87 mmol) in acetonitrile (20 mL) was cooled to -20 ° C. Thionyl chloride (0.066 mL, 0.090 mmol) and triethylamine (0.10 g 1.0 mmol) were added dropwise to the suspension. The mixture was stirred for five minutes at room temperature and then evaporated under reduced pressure. The residue was chromatographed on silica gel (20 g) using a mixture of ethyl acetate and methylene chloride as eluent. The amount of ethyl acetate was increased during the chromatography. The product of 0.16 g (43%) contained mainly one of the structural isomers. NMR data are given below.

Table 2

Example Solvent_NMR data ppm I 1 CDCl 3 I 2 CDCl 3 I 3 CDCl 3 I 4 CDCl 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, 1H), 6.10 (d, 1H), 6.75 (d, 1H), 7.40 (s, 1H), 7.90 (d, 1H), 8.10 (s, 1H). 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, 1H), 6.55 (d, 1H), 6.80 (d, 1H), 7.39 (s, 1H), 8.15 (d, 1H), 8.20 (s, 1H). 2.75 (s, 3H), 3.8-4.0 (m, 9H), 4.7-5.1 (m 2H), 5.75 (d, 1H), 6.10 (d, 1H), 6.75 (d, 1H), 7.40 (s, 1H) ), 7.90 (d, 1H), 8.30 (s, 1H). 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, 1H), 6.57 (d, 1H), 6.80 (d, 1H), 7.39 (s, 1H), 8.15 (d, 1H), 8.40 (s, 1H).

Table 3

Examples of compounds included in formula I are given in the following table.

Profit Ident. Note-

Example R1 R2 M% data. be 1 ch3 C (0) CH3 or Na + 27 NMR Isolated C (0) CH3 ch3 isomer 2 ch3 or C (0) 0CH3 Na + 6 NMR Isolated isomer C (0) 0CH3 ch3 3 C (0) CH3 CH3 or Na + - - Isolated isomer ch3 C (0) CH3 4 c (o) och3 or ch3 Na + Isolated isomer C (0) 0CH3 CH3 5 ch3 C (0) CH3 Na + - - Isomeric c (o) ch3 CH3 mixture 6 ch3 C (0) 0CH3 Na + Isomeric C (O) 0CH3 CH3 mixture 16

The best embodiment of the invention now known is the use of the composition of Example 2.

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

Syrup

Syrup containing 1% (w / v) of active substance was prepared with the following ingredients:

Compound of Example 1 1.0 g Sugar, powder 30.0 g Saccharin 0.6 g Glycerin 5.0 g Flavor Corrector 0.05 g Ethanol 96% 5.0 g Distilled water q.s. to a final volume of 100 ml

The sugar and saccharin were dissolved in 60 g of warm water. After the sugar solution had cooled, the active compound and glycerol and a solution of flavor corrosives dissolved in ethanol were added. The mixture was diluted with water to a final volume of 100 ml.

Enteric coated tablets

An enteric coated tablet containing 20 mg of active compound was prepared with the following ingredients:

I

A mixture of the compounds of Example 2 200 g 17 17 700 g 6 g 50 g 15 g 6 g q · s. 200 g 15 g 2000 g 2000 g

Lactose

Methyl cellulose

Polyvinylpyrrolidone Cross-linked Magnesium stearate Sodium carbonate Distilled water II Cellulose acetate phthalate Cetyl alcohol Isopropanol Methylene chloride I The compound of Example 1, powder, was mixed with lactose and granulated with an aqueous solution of methyl cellulose and sodium carbonate. The wet material was pushed through a sieve and the granulate was dried in an oven. After drying, the granules were mixed with polyvinylpyrrolidone and magnesium stearate. The dry mixture was compressed into tablet cores (10,000 tablets), each containing 20 mg of active substance, in a tablet making machine using 6 mm diameter holes. II A solution of cellulose acetate phthalate and cetyl alcohol in isorpoanol / methylene chloride was sprayed on the tablets in an Accela CotaR Manestry coating machine. Tablets with a final weight of 110 mg were obtained.

Solution for intravenous administration

A parenteral form for intravenous use containing 4 mg of active compound per ml was obtained from the following ingredients:

The compound of Example 2 4 g

Sterile water up to a final volume of 1000 ml 18

The active compound was dissolved in water to a final volume of 1000 ml. The solution was filtered through a 0.22 μm filter and immediately divided into sterile 10 ml ampoules. We sealed the ampoules.

Pills

Tablets containing 30 mg of active compound were prepared from the following ingredients: 300 g 700 g 6 g 62 g 2 g 30 g q. s.

The compound of Example 3 in Table 3 Lactose

Methyl cellulose

Polyvinyl pyrrolidone cross-linked (PVP-XL) Disodium hydrogen phosphate Magnesium stearate Purified water

The active compound was mixed with lactose and a portion of PVP-XL and granulated with a solution of methyl cellulose and disodium hydrogen phosphate. The wet material was pushed through a sieve and dried in a fluidized bed dryer. After adding magnesium stearate and residue PVP-XL and mixing, the drug mixture was compressed into tablets with an average weight of 110 mg, each tablet containing 30 mg of active compound.

Enteric-coated tablets 50 g of the tablets described above were enteric-coated. The solution of the composition described below was sprayed onto the tablets in a fluidized bed apparatus using the Wurster technique. 19

Coating solution: 40 g 2 g 400 g 400 g

Cellulose acetate phthalate Cetyl alcohol Isopropanol Dichloromethane

The final coated tablet weighed 117 mg.

Candles

The candles were prepared from the following ingredients using a melting process. Each candle contained 40 mg of active compound.

The mixture of the compound according to example 4 in table 3 4 g

Witepsol H-151 180 g

The active compound mixture was homogeneously mixed with Vfitepsol H-15 at 41 ° C. The fused substance was poured into previously made candle wrappers to a net weight of 1.84 g. After cooling, the casings were melted in the hot. Each candle contained 40 mg of active compound.

Immediately before use, the active compound dissolved in 10 ml of sterile water is transferred to 100 ml of normal saline for infusion so that the total amount is 110 ml. The solution is given as an intravenous infusion over a period of about 30 minutes. 1

A mixture of glycerides derived from coconut oil (mainly glycerides from lauric acid, myristic acid, palmitic acid and stearic acid). It contains a specific amount of partial glycerides (as emulsifiers); tal. 33.5-35.5 ° C. 20

Syrup

Syrup containing 1% of active substance was prepared with the following ingredients: 1.0 g 30.0 g 0.6 g 0.05 g 5.0 g to 100 ml

The compound of Example 3 in Table 3

Sugar, powder

Saccharin

Flavors

Ethanol 96%

Purified water q.s.

The sugar and saccharin were dissolved in 60 g of warm water. After cooling, the active compound and a flavoring solution dissolved in ethanol were added to the sugar solution. The mixture was diluted with water to a final volume of 100 ml.

Solution for intravenous or intramuscular injection

The compound of Example 1 60 g

Water for preparation of injection 1000 ml

The active compound was dissolved in water to a final volume of 1000 ml. The solution was filtered through a sterile 0.22 well filter and aseptically divided into 1 ml ampoule. We sealed the ampoules.

Form for intravenous infusion

Sterile compound according to Example 2 60 mg

Sterile injection bottles and stoppers

The sterile active compound, 60 mg, was divided into 10 ml sterile injection bottles. The bottles were capped with sterile rubber stoppers. Filling was performed under aseptic conditions in a sterile area for fabrication under vertical laminar flow. 21

Biological effects Effects on absorption Walking into the thyroid gland

The effect of a compound of the invention of formula (I) on the uptake of iodine into the thyroid gland is measured as the effect of the active compound resulting from the metabolism of the compounds of the invention on the accumulation of 125I in the thyroid gland. Effect on 125I accumulation in the thyroid gland

The accumulation of 125I in the thyroid gland was studied in male Sprague-Dawley rats from which food was withdrawn 24 hours before the experiment. We followed the experimental protocol of Searle C.E. et al. (Biochem J. 1950; 47: 77-81).

The test substances suspended in 0.5% buffered (pH 9) methocel were administered orally in a volume of 5 ml / kg body weight. After 1 hour, 125 I (300 kBq / kg, 3 ml / kg) was given by intraperitoneal injection. Four hours after 125I administration, the animals were killed by suffocation with CO2 and bled. The thyroid gland was excised together with part of the trachea and placed in a small test tube for radioactivity testing in a gamma counter (LKB-Wallac model 1282 Compugamma). Percent inhibition was calculated according to formula 100 (1-T / P), where T and P are the mean radioactivity of thyroid glands from animals treated with the test agent and placebo (buffered methocel). Statistical significance for the difference between animals treated with the test agent and placebo was assessed by the Mann-Whitney U-test (two-track). We accepted P &lt; 0.05 as important. 22

Results of biological experiments

Table 4 provides available experimental data for the compounds of the invention.

Table 4, Biological data

Compound to be tested (number of animals)

Percentage inhibition 400 μπιοΐ / kg on 125I uptake into the thyroid gland

Active metabolite of cases no. 1.3 and 5 (n = 5) -7

Active metabolite of cases no. 2.4 and 6 (n = 5) 0

For

Aktiebolaget ASTRA: M. · ':

Claims (17)

23 CLAIMS 1. Compounds of formula I wherein: R 1 and R 2 are different, each methyl, -C (O) -CH 3 or -C (O) -OCH 3 and one of R 1 or R 2 is always methyl and M is a physiologically acceptable opposite cation. Compound according to Claim 1, characterized in that M is Na, K, Ag or trialkylammonium. Compounds of formula I of claim 1, characterized in that they are a mixture of [5-acetyl-6-methyl-2 - [[(3,4-dimethoxy-2-pyridinyl) -methylsulfinyl] -1E-benzimidazol-1-yl] Phosphoric acid methyl ester, disodium salt and [6-acetyl-5-methyl-2 - [[(3,4-dimethoxy-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazol-1-yl] phosphoric acid ester, disodium salt. 24 Compounds of formula I of claim 1, characterized in that the mixture of [5-carbomethoxy-6-methyl-2 - [[(3,4-dimethoxy-2-pyridinyl) methyl] sulfinyl-1H-benzimidazole is 1-yl] phosphoric acid methyl ester, disodium salt and [_ 6-carbomethoxy-5-methyl-2 - [[(3,4-dimethoxy-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazol-1-yl] methyl phosphoric acid ester, disodium salt. Compound according to Claim 1, characterized in that [5-acetyl-6-methyl-2 - [[(3,4-dimethoxy-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazol-1-yl ] phosphoric acid methyl ester, disodium salt. Compound according to Claim 1, characterized in that L6-acetyl-5-methyl-2- [C (3,4-dimethoxy-2-pyridinyl) methylsulfinyl] -ΐΗ-benzimidazol-1-yl] methyl ester phosphoric acid, disodium salt. Compound according to Claim 1, characterized in that L5-carbomethoxy-6-methyl-2- [C (3,4-dimethoxy-2-pyridinyl) methyl sulfinyl] -1H-benzimidazol-1-yl] methyl phosphoric acid ester, disodium salt. Compound according to Claim 1, characterized in that {] 6-carbomethoxy-5-methyl-2-L (3,4-dimethoxy-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazole-1- phosphoric acid methyl ester, disodium salt. Pharmaceutical composition, characterized in that it contains as active ingredient a compound according to Claim 1. A compound as defined in claim 1 for use in therapy. A compound as defined in claim 1 for use in inhibiting gastric acid secretion in mammals, including humans. A compound as defined in claim 1 for use in the treatment of gastrointestinal inflammation in mammals, including humans. Use of a compound according to claim 1 in the manufacture of a medicament for inhibiting gastric acid secretion in a mammal, including a human. Use of a compound according to claim 1 in the manufacture of a medicament for the treatment of gastrointestinal inflammation in a mammal, including a human. Process for the preparation of a compound of formula I according to Claim 1, characterized in that a) the compound of formula II is reacted 26 wherein R 1 and R 2 are as defined in the case of formula I and Z is halogen such as Cl, Br or I or a functionally equivalent group, with a compound of formula III 0 II HO-PO Q IH I 0 Q wherein Q is the opposite an ion such as Na +, K +, Ag + or trialkylammonium, or b) oxidizing a compound of formula IV wherein R 1, R 2 and M are given to give a compound of formula I. 16. A compound of formula II 27 wherein R 1 and R 2 are as defined in the case of formula I and Z is halogen, such as Cl, Br or I or a functionally equivalent group. A compound according to claim 16, wherein R 1 and R 2 are as defined above and Z is Cl or OH. For Aktiebolaget Astra: Patent Office Ljubljana 28 Abstract SUBSTITUTED BENZIMIDAZOLES, PROCESS FOR THEIR PREPARATION AND THEIR USE New compounds of formula I och3 OM 1 in which: R 1 and R 2, which are different, each of them methyl, -C (O) -CH 3 or -C (O) -OCH 3 and one of R 1 or R 2 is always methyl, M is physiologically acceptable the opposite cation, as well as processes for the preparation of these compounds, pharmaceutical compositions containing these compounds as active ingredients, and the use of the compounds in medicine.