CS189491A3 - Substituted benzimidazoles, process of their preparation and their pharmaceutical application - Google Patents

Description

The way they are made and their - 1 -

Substituted benzimidazoles, pharmaceutical use

Technical field

SUMMARY OF THE INVENTION The present invention relates to novel compounds which prevent 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 the manufacture of a medicament for inhibiting gastric acid secretion in mammals including humans. More generally, the compounds of the present invention may be used in the manufacture of a medicament for the prevention and treatment of gastrointestinal inflammatory and gastric related diseases in mammals including humans, such as gastritis, gastric ulcer , duodenal ulcer, reflux esophagitis, and Zollinger-Ellison syndrome. In addition, the compounds may be used to produce a medicament for the treatment of other gastrointestinal diseases where gastric anti-secretory activity is desirable, e.g. patients suffering from gastroinomia and patients with acute gastrointestinal haemorrhage ·

The compounds of the invention can be used in patients requiring intensive care and pre-operative and postoperative care to prevent the inhalation of acid and against ulceration due to stress. The compounds of this invention may also be used for the treatment or prophylaxis of inflammatory conditions in mammals, including humans, particularly those associated with lysozyme enzymes. Conditions that may be particularly mentioned are rheumatoid arthritis and gout. The compounds are also useful in the treatment of diseases related to bone metabolism diseases as well as the treatment of ophthalmic glaucoma. and;

V * V;

The invention also relates to pharmaceutical compositions comprising a compound of the invention as an active ingredient. In a further aspect, the invention relates to a process for producing such novel compounds. The use of active compounds for the manufacture of pharmaceutical compositions for therapeutic use is outlined above. A particular object of the present invention relates to compounds with high bioavailability. The compounds of the invention also exhibit good stability-related properties in neutral and acidic pH values and good efficacy with respect to inhibition of gastric acid secretion. The compounds of this invention do not block iodine absorption (accumulation) in the thyroid.

Benzimidazole Derivatives for Inhibition of Stomach Gastric Acids are described in the Order. patent records. Of these, British Patent Nos. 1,500,443 and 1,525,958, U.S. Pat. Nos. 4,182,766, 4,255,431, and 4,599,347, Belgian Patent No. 898,880, European Patents No. 124,495,. 221 04I, 279 149 and 176 308 and Derwenť abstrakt87-294 449/42. Benzimidazole derivatives designed for use in the treatment or prevention of particular gastrointestinal inflammatory diseases are disclosed in U.S. Pat. Previously, it has been recited in a few recited societies where the inventors believe 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 inhibitory effect, good bioavailability and stability. Invention of the Invention

The compounds of formula I are effective as

gastric acid secretion inhibitors in mammals, including humans, do not block iodine absorption in the thyroid gland. It has also been found that the compounds of the general formula (I) below have high bioavailability. In addition, the compounds of the invention exhibit high chemical stability in solutions having an acidic or neutral pH. High chemical stability also in the acidic pH range causes the compounds to be suitable for oral formulations that do not have an enteric coating.

The compounds of the present invention have the general formula I

wherein R 2 and R 2 are each hydrogen, C 1 -C 4 alkyl, or -C (O) -R 4, wherein R 1 and R 2 are each day. each represents a group of formula -C (O) -R 6, wherein R 16 is an alkyl group having 1 to 4 carbon atoms or an alkoxy group having 1 to 4 carbon atoms, 4 7 R 1 is a group of the formula -CH 2 OCOOR wherein R is alkyl a group having from 1 to 6 carbon atoms or a benzyl group, R 4 and R 5 are the same or different and are selected from a methyl group, an ethyl group or a group of formulas

R5 and R5 together with the adjacent oxygen atom attached to the pyridine ring and the carbon atom in the pyridine ring form a ring wherein the substituent of R @ 4 and R @ 5 is --CH2 CH3 CH3 -. , -CH 2 CH 2 - or -CH 2 -. "'

It will be appreciated that the terms "alkyl" and "alkoxy" include straight and branched chain structures.

The structural isomers of the invention described in Examples 1 to 6 may be used separately or in equivalent or non-equivalent mixtures.

The compounds of the formula I according to the invention have an asymmetric center, on the sulfur atom, that is to say as two optical isomers (enantiomers), or if they contain one or more asymmetric carbon atoms, the compounds may have two or more diastereomeric fo -rem, each of which exists in two enantiomeric forms.

Both the pure enantiomers and the racemic mixtures (50% of each enantiomer) and the non-equivalent mixtures of the two enantiomers fall within the scope of the present invention. It is also to be understood that all possible diastereomeric forms (pure enantidomers or racemic mixtures) are within the scope of this invention. Preferred groups of compounds of formula (I) are as follows: 1. Compounds wherein P represents a group of formula -CH 2 OOCH 2 CH 2 CH 2. 2. Compounds wherein R and R are selected from the group consisting of hydrogen, methyl or -C (O) R6, wherein R1 is C1 -C4 alkyl or alkoxy; C 1 -C 4 carbon atoms. . 3. Particularly preferred benzimidazole structures are those of Formula 0

0 - 6 -

Particularly preferred are compounds wherein R and R are methyl. 5. Particularly preferred particular compounds of the invention are the compounds summarized in the table below. R1 R2 R3 R4 R5 CH3 C (O) OCH3 CH2 CH3 CH3 CH3 CH3 C (O) OCH3 CH3 CbT20C00CH2CH3 CH3 CH3 CHC (O) CH3 CHPOCOOCH-CH ,, - -; . .... CH, ·· ...... CH3 c (o) ch3. CH 3 CH 2 OCOOCH 2 CH 3. CH, CH, It is believed that the compounds of formula (I) are semi-metabolized to the corresponding compounds wherein R3 is hydrogen atom before effecting them.

The compounds of the present invention may be prepared by the methods set forth below. and)

Compound of Formula II - 8 - OR5 '' wil · JWM1 · *

the meanings given under the general formula of cat and metal are omitted. .iako .ie Na +. K +. Li + or in which "R 1, R 2, R 4 and R 5 cem I and Z"

The Ag + or quaternary ammonium ion, such as the tetra-butylammonium ion, is reacted with chloromethyl carbonate or benzyl chloromethyl carbonate. b) A compound of formula II wherein R 1, R 4, 5

R and R ^ are as defined in formula (I) and Z is hydroxymethyl, reacted with a compound of formula (III) XC (O) -O-R7 in which R is as defined above and - 9 - X is a chlorine atom, an imidazole residue, a p-nitro-phenoxy group or a functionally equivalent group, in the presence of a suitable base such as triethylamine.

The reactions described under a) and b) are expediently carried out under a protective atmosphere in the absence of water. Suitable solvents are hydrocarbons such as toluene or benzene or halogenated hydrocarbons such as methylene chloride or chloroform or acetone, acetonitrile or dimethylformamide. The reactions can be carried out at a temperature that is between room temperature and the boiling point of the reaction mixture.

• ··.

l: i?: - '& wherein R @ 4, R @ 4 and R @ 4 are as defined in Formula I, are oxidized.

This oxidation can be carried out using an oxidizing agent such as nitric acid, hydrogen peroxide (if present in the presence of vanadium compounds), peroxyacid, and the like. & 1 r · 'V' / »; Ozone, ozone, nitrogen dioxide, iodosobenzene, N-halogeno-; cinimide, 1-chlorobenzotriazole, tert-butylhypochlorite, di-azabicyclo [2.2.2] octane complex with bromine, sodium periodate, selenium dioxide, manganese dioxide, chromic acid, nitric cerium ammonium, bromine, chlorine and sulfuryl chloride . The oxidation is usually carried out in a solvent such as halogenated hydrocarbons, alcohols, ethers and ketones.

The oxidation can also be carried out enzymatically, using an oxidizing enzyme or microbiotic, using a suitable microorganism. The obtained structural isomers 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. In the racemic diastereomeric mixture, the mixture can be resolved into pure diastereomeric enantiomers by chromatography or fractional crystallization. The starting materials used for processes a) to c) are in some cases non-pure compounds. However, these compounds described above can be obtained by methods known to the person skilled in the art.

Alkyl chloromethyl carbonate and benzyl chloromethyl carbonate can be obtained from the corresponding alcohol by treatment with chloromethyl chloroformate in the presence of pyridine.

Intermediates of general formula (II) in which Z represents a hydroxymethyl group are obtained by reacting a corresponding benzimidazole derivative having a hydrogen atom in the 1-position on the nitrogen atom with formaldehyde. The starting compounds of formula III can be obtained by known methods, for example, from an alcohol of the formula HOR7 wherein R7 is as defined above, treated with phosgene, 1,1'-carbonyldiimidazole or p-nitrophenyl chloroformate.

For clinical use, the compound of the present invention is formulated into pharmaceutical compositions for oral, rectal, or other modes of administration. it comprises a compound of the invention customarily in combination with a pharmaceutically acceptable carrier (s). The carrier may be in the form of a solid, semi-solid, or may be a liquid diluent or capsule. Pharmaceutical compositions are a further object of the present invention. Typically, the amount of active compound employed is from 0.1 to 95% by weight of the composition, and is from 1 to 50% by weight of the compositions for oral administration. In the manufacture of pharmaceutical compositions comprising a compound of this invention in unit dosage 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 carrier, such as are alkali compounds, for example carbonates, hydroxides and oxides of sodium, potassium, calcium, magnesium and the like, 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 granules and tablets are coated with an enteric coating which protects the active agent from acid catalyzed degradation when the dosage form remains in the stomach. Enteral coatings are selected from pharmaceutically acceptable enteric coating materials, for example, beeswax, shellac, or anionic film-forming polymers such as cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, partially methyl esterified methacrylic polymers, and the like, preferably in combination with with a suitable plasticizer. Various dyes can be added to the coatings to distinguish between tablets with different active ingredients or different amounts of active ingredient present in the tablet. Similarly, granules may be passed through. Soft gelatin capsules can be produced as capsules containing a mixture of the active ingredient of the present invention, vegetable oil, fat or other suitable soft gelatin capsule formulation. The soft gelatin capsules may also be enteric coated as described above. The hard gelatin capsules may contain granules or enterally coated granules of the active ingredient. The hard gelatin capsules may also contain the active ingredient in combination with a solid powdered carrier such as lactose, sucrose, sorbitol, mannitol, potato starch, amylopectin, cellulose derivatives or gelatin. The hard gelatin capsules can be enterally coated as described above. Dosage units for rectal administration may be presented in the form of suppositories containing the active ingredient with a neutral neutral fat base or in the form of gelatin rectal capsules containing the active ingredient in admixture with vegetable oil, paraffin oil or other suitable gelatin rectal adjuvant Capsules may be prepared in the form of a microcryme for immediate use, or may be prepared in the form of a dry microclimate which is reconstituted in a suitable solvent just prior to administration.

Liquid preparations for oral administration may be in the form of syrups or suspensions, for example, solutions or a suspension 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 / or polyethylene glycol. If desired, the liquid compositions may contain coloring agents, flavoring agents, saccharin, carboxymethyl cellulose, or other thickening agents. Liquid formulations for oral administration can also be prepared in the form of dry powders which are reconstituted with a suitable solvent prior to use.

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

A, A, 55, ... 4 Examples of the Invention

The invention is illustrated by the following examples. Example 1;

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Process for the preparation of 5-carbomethoxy-6-methyl-2- [(3,4-dimethoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazol-1-ylmethyl ethyl carbonate and 6-carbomethoxy -5-methyl-2-t (3 ', 4 "dimethoxy-2-pyridyl) methyl] sulfinyl] -1 H -benzoimidazol-1-ylmethyl ethyl carbonate as an isomeric mixture to a suspension of 0.45 g ( 1.1 mmol) 5-carbomethoxy-6-methyl-2- [(3, 4-dimethoxy-2-pyridyl) methylsulfinyl] -1H-benzimidazole. and 0.25 g (1.8 mmol) of anhydrous potassium carbonate in 45 ml of anhydrous acetonitrile is added 0.21 g (1.5 mmol) of chloromethyl ethyl carbonate dissolved in 5 ml of acetone-14-tril. The solvent was then evaporated under reduced pressure and the residue was diluted with methylene chloride and water. The organic layer was dried over anhydrous sodium sulfate. Evaporation of the solvent under reduced pressure gave a crude material which was chromatographed on silica gel using ethyl acetate as eluent. 0.94 g of a yellow oil is obtained which slowly crystallizes. Recrystallization from ethanol gave 0.25 g of the title compounds as an isomeric mixture. Yield: 44 theory.

NMR spectra for the compounds produced are shown below. Example 2 - 6-Carbmethoxy-5-methyl-2 - [(3,4-dimethoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazol-1-ylmethyl-ethyl carbonate

The title compound is obtained by crystallization of the isomeric mixture obtained in Example 1 from ethanol.

NMS spectrum values are shown below. Example 3

Method for the preparation of 5-acetyl-6-methyl-2 - [(3,4-dimethoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazol-1-ylmethyl ethyl carbonate and 6-acetyl-5-methyl- 2 - [(3,4-dimethoxy-2-pyridyl) methyl] sulfonyl} -1H-benzimidazol-1-ylmethyl ethyl carbonate as an isomeric mixture To a magnetically stirred slurry of 0.48 g (3, 47 mmol) of anhydrous potassium carbonate in 80 ml of dried acetone.RTM. Are added dropwise to 0.80 g (2.14 mmol) of 5-acetyl-6-methyl-2- 15- [3,4-dimethoxy- 2-pyridyl) methylsulfinyl] -1H-benzimidazole and 0.39 g (2.8 mmol) of chloromethyl ethyl carbonate dissolved in 10 ml. Stirring was continued at room temperature for 20 hours. The solvent was evaporated under reduced pressure and the residue was dissolved in methylene chloride. The methylene chloride solution was washed with water and dried over anhydrous sodium sulfate. Evaporation of the solvent under reduced pressure left the crude which was chromatographed on silica gel eluting with ethyl acetate. 0.63 g of almost white crystalline solid is obtained. This was recrystallized from ethyl acetate to give 0.50 g of the title compounds to form an isomeric mixture. Yield: 49%.

t,; · ·

The NMR spectra of the compounds produced are given below. -. Knows • A1 Example 4 · .- · '·' /

Process for the preparation of 5-acetyl-6-methyl-2 - [(3,4-dimethoxy-2-pyridyl) - "methylsulfinyl] -1H-benzimidazol-1-ylmethyl ethyl carbonate

The title compound was isolated from an isomeric mixture of Example 3 by column chromatography on silica gel using methylene chloride / acetonitrile (6: 4) as eluent. The title compound is crystallized from ethanol.

The HMR spectra are shown below. i / '3 Example 5

Process for the preparation of 6-acetyl-5-methyl-2 - [(3,4-dimethoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazolylmethyl ethyl carbonate

Title Compound. iso- ΐ § 5 í £ '; The mixture obtained in Example 3 was chromatographed on a silica gel column using methylene chloride / acetonitrile (6: 4) as eluent. The title compound is crystallized from ethanol.

NMR spectra are shown below. Example 6

Process for the preparation of 5-carbethoxy-2 - [(3,4-dimethoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazol-1-ylmethyl ethyl carbonate and 6-carbethoxy-2 - [/ (3 4-dimethoxy-2-pyridylmethylmethylsulfinyl] -1H-benzimidazol-1-ylmethyl ethyl carbonate as an isomeric mixture - To a suspension of 0.28 g (0.72 mmol) 5-carbethoxy- 0.16 g (1.2%) of 2 - [(3,4-dimethoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole and 0.16 g (1.2 mmol) of anhydrous potassium carbonate in 20 ml of dried acetonitrile are added. mmol) of chloromethyl ethyl carbonate dissolved in 2 ml of dry acetonitrile. The resulting mixture was stirred at room temperature overnight. The solvent was evaporated and the crude material was chromatographed on silica gel column using ethyl acetate as eluent. The crystallization of ethanol is accomplished by the title compound as an isomeric mixture of 0.13 g.

NMR spectra of the compounds produced are given below. - 17 -

Table 1 Example 1

Solvent NMR Spectrum <RTI ID = 0.0> GDC13 </RTI> 1.20-1.30 (m, 3H), 2.70 (s, 1.8 (300 MHz) H), 2.75 (s, 1.2H), 3, 85-3.95 (broad s, 9H), 4.15-4.25 (r, 2H), 4.85-5.05 (m, 2H), 6.40-6.55 (m, 2H) , 6.75 (d, 1H), 7.45 (s, Ο, β-β), 7.65 (s, 0.4H), 8.10 (d, 1H), 8.20 (s, s), 8.20 (s,. 0.4 HI), 8.40 (s, 0.6H) CDCl3 1.30 (t, 3H), 2.70 (s, 3H), 3.90 (300 MHz) (s, 3H), 3 , 95 (s, 3H), 4.2! 3 (q, 2H), 4.95 ' Cd, 1H), 5.05 (d, 1H), 6.50 (m, 2H), 6.75 (a, 1K), 7.65 ( 8.20 (s, 1H) .delta. 1.30 (t, 3H), 2.60-2.70 1 (ra, 6H), (300 MHz) .delta. 3.85-3.90) (m, 6H), 4.25 (q, 2H), 4.85-5.05 (m, 2H), 6.75 (d, 1H), 7.45 ( s, 0.7H), 7.60 (s, 3H), 8.05 (s, 0.3K), 8.10 (a, 1H), 8, (s, Q, 7H) onci3 1.30 (t, 3H); 2.60 (s, 3H), 2.70 (300 MHz) (s, 3H), 3.90 (s, 3H), 3.90 (s, 3H), 4.20 (q, 2H), 4.90 '(a, 1H), 5.05 (a, 1H), 6.50 (m, 2H), 6.80 (d, 1H), 7.50. (s, 1H), 8.15 (d, 1H), 8.20) (s, 1H) .delta. 1.30 (t, 3H), 2.60 (s, 3H), 2.70 (300 MHz) (s, 3H), 3.90 (s, 3H), 3.90 (s, -18-).

Solvent NMR spectrum cf ppm 6 CPCl 3 (300 MHz) 3 H), 4.25 µg, 2H), 4.9C (a, 1H), 5.05 (a, 1H), 6.55 ( m, 2H), 6.80 (a, 1H), 7.60 (s, 1H), 8.05 (s, 1H), 8.15 (a, 1H), 1.30 (r, 3H), 1 45 (m, 3H), 3.90 (s, 3H), 3.90 (s, 3H), 4.25 (m, 2H), 4.45 (m, 2H), 5.0C (m). (2H), 6.55 (m, 2H), 6.80 (a, 1H), 7.70 (d, 0.55H), 7.80 (d, 0.45H), 8.10. (2H), 8.35 (s, 0.45H), 8.50 (d, 0.55H). * '-rfMh - *' f '· "- 19 -

Process for the production of intermediates

Example II

Method for the preparation of 5-carbomethoxy-6-methyl-2- [(3,4-dimethoxy-2-pyridyl) methyl] thio] -ΙΗ-benzimidazole 0.67 g (0.003 mol) 5-carbmethoxy-6-methyl Of 2-mercapto-1H-benzimidazole and 0.12 g (0.003 mol) of sodium hydroxide in 0.6 ml of water are dissolved in 15 ml of methanol. Approximately 0.0036 mol of 3,4-dimethoxy-2-chloromethylpyridine hydrochloride is added to the solution as a crude material in 10 ml of methanol and 0.144 g (0.0036 mol) of sodium hydroxide in 0.72 ml of water. The mixture is heated to reflux and refluxed for 1 hour. After evaporation of the solvent and purification on a silica gel column using methylene chloride / methanol 98: 2 as eluent, the mixture is refluxed for 1 hour. agent. 1.03 g of pure title compound is obtained. The yield is §2. $ theory. ..... - .......

NMR spectra are shown below. Example 12

Process for the preparation of 5-carbomethoxy-6-methyl-2 - [(3,4-dimethoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole 1.03 g (0.00276 mol) 5-carbomethoxy-6- methyl 2 - (((3,4-dimethoxy-2-pyridyl) methyl) thio] -1H-benzimidazole dissolved in 30 ml of methylene chloride, and 0.46 g (0.0055 mol) of sodium bicarbonate dissolved in 10 ml of water was added to the solution. the mixture is cooled to +2 DEG C. 0.62 g (0.0025 mol) of m-chloroperbenzoic acid (69.5 $) dissolved in 5 ml of methylene chloride are added dropwise to the cooled mixture while stirring. +2 ° C is continued for 15 minutes, after which the organic layer is extracted three times with 15 ml (0.009 mol) of 0.2 molar sodium hydroxide solution. The aqueous solutions are combined and meutralized with 0.56 ml (0.009 ml). mol) of methyl formate in the presence of 25 ml of methylene chloride.

After separation of the organic layer, this layer was dried over sodium sulfate and evaporated under reduced pressure. The residue was crystallized from 10 ml of acetonitrile. 0.68 g of the title compound is obtained. Yield: 70%.

NMR spectra are shown below. Example 13

Process for the preparation of 5-acetyl-6-methyl-2- [(3,4-dimethoxy-2-pyridyl) methyl] thio] -1H-benzimidazole. 4.2 g (20 mmol) of 1-5-acetyl-6-methyl-2-mercapto-1H-* -benzimidazole and 0.8 g (20 mmol) of sodium hydroxide per ml When dissolved in 60 ml of ethanol, 3,4-dimethoxy-2-chloromethylpyridine hydrochloride (approximately 17 mmol) was added to the solution as a crude product, and the mixture was heated to boiling. Sodium hydroxide (g, 17 mmol) in water (1 mL) was continued at reflux for 6 hours, the solvent was evaporated and the residue was diluted with methylene chloride and water. The organic phase was dried over sodium sulfate and the solvent was evaporated under reduced pressure. The title compound of 3.75 g., 62% of theory, was crystallized from acetonitrile.

NMR spectra are shown below. Example 14

Process for the preparation of 5-acetyl-6-methyl-2 - [(3,4-dimethoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole-21- 1.75 g (10 mmol) of 5-acetyl- 6-methyl-2- [(3,4-dimethoxy-2-pyridyl) methyl] thio] -1H-benzimidazole was dissolved in 70 mL of methylene chloride. Sodium bicarbonate (1.76 g, 21 mmol) in water (25 mL) was added and the mixture was cooled to about +3 ° C. To the reaction mixture, 2.43 g (9.8 mmol) of m-chloroperbenzoic acid (69.5 $) dissolved was added dropwise with stirring. in 20 ml of methylene chloride. Stirring is continued for 10 minutes. The pads were separated and the organic phase was dried over sodium sulfate and evaporated under reduced pressure. The residue was crystallized from acetonitrile. 2.25 g of the title compound is obtained. Yield: 60 $ theory. NMR spectra are shown below. ·· ··

Example '15 '.....'

Process for the preparation of 5-carbethoxy-2 - [(3,5,4-dimethoxy-2-pyridyl) methyl] thio] -1H-benzimidazole 2.0 g (9 mmol) 5-carbethoxy-2-mercapto-1H-benzoic acid of imidazole and 0.36 g (9 mmol) of sodium hydroxide in 1 ml of water are dissolved in 30 ml of ethanol. 3,4-Dimethoxy-2-chloromethyl-pyridine hydrochloride (approximately 6.6 mmol) was added to the solution as a crude material, and the mixture was heated to boiling. Sodium hydroxide (0.26 g, 6.6 mmol) in water (1 ml) was then added and the mixture was refluxed for 6 hours. The solvent was evaporated and the residue was diluted with methylene chloride and water. The organic phase was dried over sodium sulfate and the solvent was evaporated under reduced pressure. The residue was crystallized from acetonitrile. The title compound is obtained (1.75 g, yield = 7.1%). .teorie ... ..................... ..................... ...

NMR spectra are shown below. Example 16 k · '; ·. - 22 -

Process for the preparation of 5-carbethoxy-2-t (3,4-dimethoxy-2-pyridyl) methylsulphinyl] -1H-benzimidazole 1.4 g (0.0036 mol) 5-carbethoxy-2 - [/ (3 4-dimethoxy-2-pyridyl) methyl thio] -1H-benzimidazole (95%, 2% pure) was dissolved in 3 mL of methylene chloride. Sodium bicarbonate (0.6g, 0.0072 mol) in water (10 mL) was added to the solution and cooled to +2 ° C. 0.87 g (0.0035 mol) of m-chloroperbenzoic acid (69.5 g) dissolved in 5 ml of methylene chloride was added dropwise to the cooled reaction mixture with stirring. Stirring at +2 ° C was continued for 10 minutes. The phases were separated and the organic phase was dried over sodium sulfate and evaporated under reduced pressure. The residue was crystallized from 7 ml acetonitrile (15 ml). 0.76 g of the title compound is obtained. The yield was 54%.

NMR spectra are shown below. - 23 -

Example 2 Solvent NMR spectrum of PPm. 11 CDCl 3 2.70 (s, 3H), 3.90 (s, 3H), 3.95 (300 MHz) (s, 3H), 4.00 (s, 3H), 4.40 (s, 2H). ), 6.90 (d, 1H), 7.35 (s, 1H), 8.20 (s, 1H), 8.25 (d, 1H), 12-CDCl3, 2.70 (s, 3H), 3.85 (s, 3H), 3.90 (500 MHz) (s, 3H), 3.95 (s, 3H), 4.70 (d, 1H), 4.90 (d, 1H), 6.8 (d, 1H); 7.3 (broad signal, 1H); 8.20 (d, 1H), 8.35 (broad signal, " 1H) - > < 65 (s, 3H), 3.90 (300 MHz) (s, 3H), 3.90 (s, 3H), 4.35 (s, 2H-2H), 6.85 (d, 3H); 1Ή), -7.25 (-S-, Q6H), 7.40 (s, 0.4H), 7.85 (s, 0.4H), 8.05 (s, 0.6H), 8.30 (m, 1H) .14 CDCl3 2.60 (s, 6H), 3.85 (s, 3H), 3.85 (300 MHz) (s, 3H), 4.70 (d). (1H), 4.90 (d, 1H), 6.80 (d, 1H), 7.30 (broad signal, 1H), 8.15 (d, 1H), 8.20 (broad signal, 1K) 15 CDCl 3 1.40 (m, 3H), 3.90 (s, 2H), 3.90 (300 MHz) (s, 3H), 4.40 (m, 4K), 6.90 / s (dd, 1H), 7.45 (d, Q4H), 7.60 (d, Q6H), 7.90 (m, 1H), 8.20 (s, 0.6H), 8.25 (ra (1H), 8.25 (s, D, 4H) - 24 -

Table 2 - continued Example Solvent NMR spectrum ppm_ -16 GDC13 1.45 (t, 3H), 3.85 (s, 3H), 3.90 (300 MHz) (s, 3H), 4.40 (q, 2H) , 4.65 (d, 1H), 4.40 (d, 1H), 6.80 (d, 1H), 7.50-7.80 (broad signal, 1H), 8.05 (d, 1H) 8.20, 8.55 (broad signal, 1H), hb. ·. * - · "·· *" ....

The best known embodiment of the invention currently consists in using the mixture of Example 3 and the compound of Example 4. In Table 3, examples of compounds that are included under Formula I are given.

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Syrup

A syrup containing 1% (w / v) of the active ingredient is prepared from the following components: Example 4 sugar saccharin powder glycerol

Tween Flavor ethanol 96 $ distilled water 1.0 g 30.0 g 0.6 g5.0 g1.0 g0.05 g5.0 g as needed to make up to 100 ml 'Prepared' melt compound ice 4 in ethanol and Tween. Sugar saccharin dissolves in 60 g of hot water. After cooling, a solution of the active ingredient is added to the sugar solution and glycerol, followed by a solution of the flavoring agent dissolved in ethanol. The mixture was diluted with water to a final volume of 100 mL.

Tablets

Tablets containing mg of the active ingredient are prepared from the following components: I. a mixture of the compounds of Example 3 lactose 500 g 700 g methylcellulose 6 g crosslinked polyvinylpyrrolidone 50 g magnesium stearate 15 g sodium carbonate 6 g distilled water as needed - 27 II. Hydroxypropylmethylcellulose 36 g Polyethylene glycol 19 g Titanium dioxide dye 4 S Purified water 313 g I. A mixture of the compounds of Example 3 in powder form is mixed with lactose and granulated with an aqueous solution of methylcellulose and sodium carbonate. The wet mass is passed through a sieve of the agranulate and dried in an oven. After drying, the granulate is mixed with vinylpyrrolidone and magnesium stearate. The dry mixture is compressed into tablet cores (-10,000 tablets) each containing 50 mg of active ingredient in a tabletting machine using a 7 mm die. II. A solution of hydroxypropylmethylcellulose and polyethylene glycol in purified water is prepared. After dispersing the oxide titanium, the solution is sprayed onto the tablets obtained from the coating of tablets (Accela Cota, Manesty) to give final tablets of 125 mg.

Capsule

Capsules containing 30 mg of active compound are prepared from these components; Example 4 300 g lactose 700 g microcrystalline cellulose 40 g low substituted hydroxypropyl cellulose 62 g purified water as needed The active compound is mixed with the dry ingredients and granulated with a solution of dibasic sodium phosphate. The wet mass is then extruded, spheronized and dried in a fluid bed dryer. 500 g of pellets produced as described above are first coated with a solution of 30 g of hydroxypropyl methylcellulose in 600 g of water using a fluid bed pellet coating machine. After drying, the pellets are coated with a second coating as follows.

Hydroxypropylmethylcellulose phthalate solution 70 gcetyl alcohol 4 gaceton 600 gethanol 200 g

The final coated pellets are filled into capsules. Suppository suppositories are prepared from the ingredients listed below using a welding process. Each suppository contains 40 mg of the active ingredient. Example 4 4 g

Witepsol H-15 180 g The active substance is homogeneously mixed with Witepsol H-15 at a temperature of 41 ° C. The molten mass is filled to a given volume of preformed suppository packs, to a net weight of 1.84 g.

After cooling, the packages were sealed by heat. Each suppository contains 40 µg of active compound. - 29 -

Biological effects

Bioavailability

Bioavailability is determined by calculating the ratio of the area under the (ABC) concentration curve of the compound of formula (I) in which R 1 is a hydrogen atom (hereinafter defined as Compound A) in plasma after 1) intraduodenic (i, d.) or oral (pp) administration of the corresponding compound of the invention and 2) intravenous (iv) administration of Compound A, obtained in rat and dog. Low, therapeutically significant doses are used. Results are shown in Table 4. Acid secretion inhibition efficacy Acid secretion inhibition efficacy was measured after oral administration of compounds to female, rat, and dog, both intra-duodenal and oral administration to the dog. Efficacy results are shown in Table 4. Effect on iodine uptake in the thyroid gland The effect of the compound of formula (I) on iodine uptake in the thyroid gland is determined as the effect of thyroid accumulation I induced by the corresponding compound of formula (I). wherein P represents a hydrogen atom, i.e., a metabolized compound of Formula I. . ..Biological, Tests ---------- -......- ..r -

Inhibition of gastric acid secretion in a vigilant female rat

Female Sprague-Dawley rats are used for the assay. They have a cannulated fistula in the stomach (lumen) for capturing gastric secretion. Before starting testing, the surgical procedure will allow for a fourteen-day period to improve health. Before the secretion test, the animals are freed for 20 hours of food but not water. The stomach is repeatedly washed with a gastric cannula and 6 ml of Ringer-glucose is introduced subcutaneously. The acid secretion is stimulated by infusion of 1.2 ml / h of subcutaneously introduced pentagastrin and 20 and 110 nmol / kg.h of carbachol after 2.5 hours. during this time, the gastric secretions of the fractions collected after 30 minutes were collected. Test substances and vehicle are administered orally 120 minutes prior to initiation of stimulation in a volume of 5 ml / kg. Gastric juice samples are titrated to pH 7.0 with sodium hydroxide (0.1 mol / liter) and acid production is calculated as the product of the titer and concentration. Further calculations are based on an average response from 4 to 7 rats. Percent inhibition is calculated from absolute acid production size. Values are obtained from graphical interpolation on dose-response logarithms or estimates of single dose experiments assuming a similar slope for all dose-response curves. The results are based on gastric acid secretion within the third hour after drug or vehicle administration.

Bioavailability in Male Rat Adult male Sprague-Dawley rats are used in the assay. One day before the experiments, all rats are prepared by cannulating the left carotid artery under anesthetic conditions. Rats used for intravenous experiments are also digested into the jugular vein, see V. Popovic and P. Popovic, J.

Appl. Physiol. 15, 727-728 (1960). The rats used for intra-duodenal experiments are also cannulated at the upper part of the twelve-thirty-six. The cannulas are brought out in the neck of the neck. After surgery, the rats are placed individually and heated food, but not non-tubers, prior to administration of the test substances. The same doses (4 µlol / kg) are administered intravenously and intraduodenally as Jacobol for about one minute (2 ml / kg).

Blood samples weighing 0.1-0.4 g are repeatedly removed from the carotid artery up to 4 hours after dosing. Samples are stored frozen until analysis for the test compound.

Area under the blood concentration-dependence curve. on time, the AUC for the compound, A, is determined by linear means. Trapezoidal rule and extrapolates to the infinite division of the last determined blood concentration while eliminating the rate constant at the final stage. The systemic bioavailability (P%) of Compound A after intraduodenal administration of a compound of Formula I of this invention is calculated as AUC (Compounds A) ^ &amp; (compounds of the invention). P: - 100. • AUC (Compounds A) iv. (A)

Inhibition of gastric acid secretion and bioavailability of a dormant dog Both dogs of the same sex are used in the test, which are provided with duodenal fistulae; for the administration of test compounds. or vehicle-α-cannula-gastric-fissure or Heidenhain bag to capture gastric secret. Before secretory tests, the animals are deprived of food for about 18 hours, but are allowed to access the water freely. Gastric acid seizures are stimulated with a 4-hour infusion of 12 ml / h histamine dihydrochloride at a dose producing about 80 $ individual maximum secretion response and gastric juice collected in successive 30 minute fractions. The test substance or vehicle is administered orally, intraduodenally or intravenously 1 hour after the start of histamine infusion in a volume of 0.5 ml per kilogram body weight. In the case of oral administration, it should be emphasized that the test compound is administered to acid secretion into the dog's stomach from a Heiden-hain bag.

The acidity of gastric samples is determined by titration to pH 7.0 and calculation of acid production. Acid production during the capture period after administration of the test compound or vehicle is expressed as a fractional response, whereas the production of the acid in the fraction prior to administration is 1.0. Percent inhibition is calculated from fractional response determined for test compound and vehicle. The ED 50 values are obtained by graphically interpolating the log-dose-response curves or by estimating the single-dose dose, assuming a similar slope of the dose-response curve for all tested compounds. All results are based on acid production 2 hours after dosing.

Blood samples for plasma concentration of test compound are sampled at intervals of up to 3 hours dosing. The plasma is separated and freeze-dried within 30 minutes and analyzed later. The AUC (area under the plasma concentration-time curve) from 0 to 3 hours for compound A is calculated according to the linear trapezoidal rule. Systemic bioavailability (β 1) of compound A after oral or intraduodenal administration of the compounds of this invention is calculated as is described above in the rat model. 125 Effect on I Thyroid Accumulation I - 33 - 125- /

Thyroid accumulation I is studied in male Spargue-Lawley rats that are not given food for 24 hours prior to the test. The experimental record described by C.E. Searle et al. (Biochem. J. 47, 77-81 / 1550).

The test substances are suspended in buffered methocel (pH 9) and administered orally via a stomach probe at a volume of 5 ml / kg body weight. After one hour, an intraperitoneal injection of 300 kBq / kg (3 ml / kg) was introduced. Four hours after administration, the animals are sacrificed by carbon dioxide asphyxiation and bled. Thyroid gland together, with part of the trachea. was collected and placed in a small radioactivity assay tube in a gamma counter of the model 1282 Compugamma. The percent inhibition is calculated using the formula T '100. (1--) ...... P ........ '. wherein T and P represent the mean radioactivity determined in animals treated with test agent and placebo (buffered with methocel).

The statistical significance of the difference between the test reagent-treated animals and the lipid-treated animals is assessed using the Mann-Whitney U test. The value of <0.05 is considered significant.

Chemical stability The chemical stability of the compounds of this invention follows kinetically at low concentration at 37 ° C in an aqueous buffer solution with different pH values. The results in Table 5 show the half-life (t 1/2) at pK7, indicating the time period after which half of the parent compound remains unchanged and t 10 at pH 2, indicating the time period over which 10 original compounds are distributed. Results of biological tests and stability test

Tables 4 and 5 summarize the test values achieved with the compounds of this invention. .J- jKF · ·

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Claims (16)

»/ / Ø - wherein each of R 2 and R 2 is hydrogen, alkyl of 1 to 4 carbon atoms, or -C (OJ-R 6, wherein R 1 and R 2 are each is a group of the formula -G (O) -R 1, wherein R 1 is an alkyl group having 1 to 4 carbon atoms or an alkoxy group containing 1 to 4 carbon atoms; * Wherein R is alkyl with from 1 to 6 carbon atoms or a benzyl group; ................. .. h. R 5 and R 5 are the same or different and are selected from the group consisting of a group, an ethyl group or a group of formulas and -DiC1iOCH-j or R * and R together form a ring with the adjacent oxygen atom attached to the pyridine ring and the carbon atom in the pyridine ring, where the moiety R 1 and R 6 is -CH 2 CH 2 CH 2 -, -CH 2 CH 2 - or -CH 2 -. Compounds of formula (I) according to claim 1, wherein the mixture of 5-carbomethoxy-6-methyl-2 - [[(3,4-dimethoxy-4'-2-pyridyl) methyl] sulfinyl] -1H- benzimidazol-1-ylmethyl-ethyl-carbonate and 6-carbmethoxy-5-methyl-2- (3,4-dimethoxy-2-pyridyl) methyl sulfonyl-7-H-benzimidazol-1-ylmethyl-ethyl carbonate. Compounds of general formula I according to claim 1, which is a mixture of 5-acetyl-6-methyl-2 - [[(3,4-dimethoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazol-1-ylmethyl-ethyl carbonate and 6-acetyl-5-methyl-2- [3- (3,4-dimethoxy-2-pyridyl] -methyl] sulfinyl) -1H-benzimidazol-1-ylmethyl ethyl carbonate. 5-Carbomethoxy-6-methyl-2- [(3,4-dimethoxy-2-pyridyl) methyl] sulfinyl} -1H-benzimidazol-1-ylmethyl-ethyl; -Kart) oná 6-Carbethoxy-5-methyl-2 - [[(3,4-dimethoxy-2-pyridyl) methyl] sulfinyl} -1H-benzimidazol-1-ylmethyl-ethyl; -carbonate · The compound of claim 1 which is 5-acetyl-6-methyl-2- [7- (3,4-dimethoxy-2-pyridyl) methyl] sulfinyl] -3- (1H-benziraidazol-1-ylmethyl) -ethyl carbonate. A compound according to claim 1 which is 6-acetyl-5-methyl-2 - [[(3,4-dimethoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazol-1-ylmethyl-ethyl- carbonate · 8. A compound according to claim 1 wherein R is CH 2 OCOOCH 2 CH 2 • 2 9. A compound according to claim 1, wherein R and R are each hydrogen, methyl or-C (O) r6, wherein R5 is C1-4 alkyl or alkoxy containing 1-4. carbon atoms, 10. A pharmaceutical composition comprising as active ingredient a compound according to claim 1. A compound according to claim 1 for use in therapy. ..... ’, ............... The compound of claim 1 for use in inhibiting gastric acid secretion in mammals including humans. The compound of claim 1 for use in the treatment of gastrointestinal inflammatory diseases in mammals including humans. Use of a compound according to claim 1 for the manufacture of a medicament for inhibiting gastric acid secretion in mammals including humans. Use of a compound according to claim 1 for the manufacture of a medicament for the treatment of gastrointestinal inflammatory diseases in mammals, including humans. - 40 Ι- Ο A process for the preparation of a compound of formula I according to claim 1, wherein a) a compound of formula II wherein R 2, R 4 and R 6 are as defined in formula I and Z is either a metal cation, Na +, K +, Li + or a quaternary araonium ion such as a tetrabutylamine ion is reacted with an alkyl chloromethyl carbonate or benzyl b) a compound of formula (II) wherein R 2, R 2, and R 4 are as defined in formula (I) and is a hydroxymethyl group, is reacted with a compound of formula (III) XC (O) -O-R 7 (III) wherein X is chlorine, imldazole or p-nitrophenoxy or functionally equivalent, in the presence of a suitable base such as triethylamine or tc) a compound of formula IV is oxidized (IV) wherein r, R2, P, R4 and R6 are as defined in formula (1).