LT3977B - Dialkoxy-pyridinyl-benzimidazole derivatives, process for their preparation and their pharmaceutical use - Google Patents

Abstract

The novel compounds of formula (I), wherein R<1> and R<2>, which are different, is each H, alkyl containing 1-4 carbon atoms or -C(O)-R<6>; one of R<1> or R<2> is always selected from the group -C(O)-R<6>; wherein R<6> is alkyl containing 1-4 carbon atoms or alkoxy containing 1-4 carbon atoms, R<3> is the group -CH2OCOOR<7>, wherein R<7> is alkyl containing 1-6 carbon atoms or benzyl; R<4> and R<5> are the same or different and selected from -CH3, -C2H5, (a), (b) and -CH2CH2OCH3, or R<4> and R<5> form together with the adjacent oxygen atoms attached to the pyridine ring and the carbon atoms in the pyridine ring a ring, wherein the part constituted by R<4> and R<5> is -CH2CH2CH2-, -CH2CH2- or -CH2- as well as pharmaceutical compositions containing such compounds as active ingredient, and the use of the compounds in medicine.

Description

The present invention relates to novel compounds and therapeutically acceptable salts thereof which inhibit exogenously and endogenously stimulated gastric juice secretion and can therefore be used for the prevention and treatment of peptic ulcer.

The present invention also relates to the use of the invented compounds and their therapeutically acceptable salts for inhibiting gastric acid secretion in mammals, including man. More generally, the invented compounds can be used in the treatment and prophylaxis of gastrointestinal inflammatory disorders, as well as in mammals associated with gastric acidity and in human conditions such as gastritis, gastric ulcer, duodenal ulcer, reflux oesophagitis, and Zolinger-Ellison syndrome. The compounds may also be used to treat other gastrointestinal disorders where gastric secretion needs to be reduced, such as in patients with gastrinomas, and in patients with severe upper gastrointestinal bleeding. They can also be used in intensive care and before and after surgery to prevent acid aspiration and stress ulcers. The invented compounds can also be used in the treatment and prophylaxis of inflammations, particularly those involving lysozyme enzymes, in mammals and man. Such inflammations include rheumatoid arthritis and gout. The compounds can also be used to treat bone metabolism disorders and gleucoma. The invention also encompasses pharmaceutical compounds containing, as active ingredient, the invented compounds and pharmaceutically acceptable salts thereof. The present invention further relates to the preparation of these novel compounds, novel intermediates for use in the preparation of inventive compounds and the use of active compounds in pharmaceutical formulations for the treatment of the above-mentioned diseases.

The main object of the invention is to obtain compounds with a high bioavailability. The invented compounds exhibit good stability and good inhibition of gastric acid secretion at neutral pH. In addition, the invented compounds do not block the entry of iodine into the thyroid gland. Earlier, several lectures given by a company employing inventors revealed that the compounds' thyroid toxicity depends on whether the compounds are lipophilic or not. However, the inventors unexpectedly discovered that the decisive parameter is not lipophilicity at all. The selected compounds, which also contain hydrophilic compounds, are non-thyroid toxic and at the same time exhibit strong inhibition of acid secretion, good bioavailability and stability.

Benzimidazole derivatives for inhibiting gastric acid secretion have been described in a number of patent documents. These include GB No. 1,500,043, GB No. No. 1,525,958, U.S. Pat. 4,182,766, U.S. Pat. No. 4,255,431, U.S. Pat. 4,599,347; 124,495, BE no. EP 898 880 208,452 and Derwent Ref. 87-294449 / 42.

Benzimidazole derivatives for the treatment and prophylaxis of special gastrointestinal disorders are described in U.S. Pat. 4,359,465.

Description of the Invention

The compounds of formula I have been found to have high bioavailability. The compounds of formula I are also effective inhibitors of gastric acid secretion in mammals and man and do not block the entry of iodine into the thyroid gland. The invented compounds are also chemically stable in solutions with a neutral pH. The compounds of the formula I found are:

H and their physiologically acceptable salts, wherein R ¹ and R ² are different and each represents 1-4 carbon atoms or -C (O) -R ⁵ ; wherein one of R ¹ or R ^{2 is} always -C (O) -R ⁵ ; and wherein R ⁵ is alkyl of 1-4 carbon atoms or alkoxy of 1-4 carbon atoms;

R ³ and R ⁴ are the same or different and are composed of -CH ₃ , -C ₂ H ₅ , -CH ₂ '(I, -CH ₂ -V) ° and -CH ₂ CH ₂ OCH ₃ or R ³ and R ⁴ , taken together with adjacent oxygen atoms attached to the pyridine ring and carbon atoms of the pyridine ring, forms a ring wherein the portion consisting of R ³ and R ⁴ is -CH ₂ CH ₂ CH ₂ -, -CH ₂ CH ₂ -, or -CH ₂ . It is to be understood that the terms "alkyl" and "alkoxy" define straight and branched structures.

The inventive compounds of formula I have an asymmetric center in the sulfur atom, i.e. have two optical isomers (enantiomers) or, if they also contain one or more asymmetric carbon atoms, the compounds have two or more diastereomeric forms, each having two enantiomeric forms.

The present invention includes both pure enantiomers, racemic mixtures (50% each enantiomer) and unequal mixtures of these enantiomers. It is to be understood that the invention encompasses all possible diastereomeric forms (pure enantiomers or racemic mixtures).

The main groups of compounds of formula I are as follows:

Compounds wherein R ¹ and R ² are selected from H, methyl or -C (O) R ⁵ , wherein R ⁵ is alkyl having from 1 to 4 carbon atoms or alkoxy having 14 carbon atoms.

2. The benzimidazole of particular interest has the following structures:

H H

Compounds wherein R ³ and R ⁴ are CH ₃ .

Compounds wherein R ³ and R ⁴ , together with adjacent oxygen atoms attached to the pyridine ring and carbon atoms of the pyridine ring, form a ring wherein the portion consisting of R ³ and R ⁴ is -CH ₂ CH ₂ CH ₂ -, - CH ₂ CH ₂ - or CH ₂ -.

6. The following specific compounds of particular importance are listed in the table below:

R ¹ R ² R ³ R ⁴ C (O) OCH ₃ ch ₃ ch ₃ ch ₃ C (O) CH ₃ ch ₃ ch ₃ ch ₃ C (O) OCH ₃ ch ₃ -ch ₂ - C (O) CH ₃ ch ₃ -ch ₂ ch ₂ ch ₂ -

CH ₂ CH ₂ CH ₂ 5

Receipt

The invented compounds can be obtained by the following process: Oxidation of a compound of formula II

H wherein R ¹ , R ² , R ³ and R ⁴ are as defined in formula I.

This oxidation may be carried out using an oxidizing agent such as nitric acid, hydrogen peroxide (if necessary using vanadium compounds), acid, peresters, ozone, diazotetraoxide, iodobenzene, N-halosuccinimide, 1-chlorobenzotriazole, 2-butyl hypochlorite, , 2,2] -octane-bromine complex, sodium metaperiodate, selenium dioxide, magnesium dioxide, chromic acid, cerium ammonium nitrate, bromine, chlorine and sulfuryl chloride. Oxidation usually occurs in solvents such as halogenated hydrocarbons, alcohols, ethers, ketones.

The oxidation may also be effected by enzymes using an oxidizing enzyme or microbiologically using a suitable microorganism.

Depending on the process conditions and starting materials, the invented compounds are obtained either in neutral or salt form. The invention includes both neutral compounds and their salts. Therefore, not only basic, neutral or mixed salts may be obtained, but also hemi-, mono-, sesqui- or polyhydrates.

The alkali salts of the compounds of the invention are salts of the compounds of the invention with Li ⁺ , Na ⁺ , K ⁺ , Mg ²⁺ , Ca ²⁺ and N ⁺ (R) ₄ , wherein R is (1-4C) alkyl. Especially preferred are the Na ⁺ and Mg ²⁺ salts. Of particular importance are the Na ⁺ and Mg ²⁺ salts. These salts may be prepared by reacting the compound with a base capable of releasing the required cation.

Examples of bases capable of releasing such cations and examples of reaction conditions are given below.

(a) Salts containing Li ²⁺ , Na ⁺ or K ⁺ as cation obtained by reacting the inventive compound with aqueous or anhydrous LiOH, NaOH or KOH or with LiOR, LiNH ₂ , LiNR ₂ , NaOR, NaNH ₂ , NaNR ₂ , KOR , KNH ₂ or KNR _{2 in} anhydrous medium, where R is an alkyl group having 1-4 carbon atoms.

b) Salts containing Mg ²⁺ or Ca ²⁺ as a cation, obtained by the action of the inventive compound on Mg (OR) ₂ , Ca (OR) ₂ or CaH ₂ ; wherein R is an alkyl group containing from 1 to 4 carbon atoms. The reaction takes place in an anhydrous solvent such as an alcohol (alcoholates only) such as ROH or an ether such as tetrahydrofuran.

The resulting racemates can be resolved into pure enantiomers. This can be accomplished by known methods, for example, by chromatography of the racemic diastereomeric salts or by fractional crystallization.

The starting materials described in the examples of the intermediates can be obtained by per se processes.

For clinical use, the invented compound may be incorporated into a dosage form for the oral, rectal, parenteral or other routes of administration. Typically, a compound of the invention is formulated with a pharmaceutically acceptable carrier. The carrier may be a solid, semi-solid, liquid diluent, or capsule. These medicaments are further objects of the invention. Generally, the active compounds will be present in an amount of 0.1-95% by weight of the preparation, 0.2-20% by weight of the preparation 1 for parenteral administration and 1-50% by weight for the preparation for oral administration.

For the preparation of dosage forms for oral administration containing the inventive compound, the selected compound may be mixed with a solid, powdered carrier such as lactose, sucrose, sorbitol, mannitol, starch, amylopectin, cellulose derivatives or gelatin. carriers, stabilizing agents such as alkaline compounds such as sodium, potassium, calcium, magnesium carbonates, hydroxides or oxides, and lubricating agents such as magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethylene glycol waxes. The mixture is then granulated or compressed into tablets. The granules and tablets may have an outer coating that protects the active compound from acid-promoting degradation while the dose remains in the stomach. Pharmaceutically acceptable materials such as beeswax, shellac, or anionic film-forming polymers such as cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, partially methylesterated methacrylic acid polymers are selected for the outer coating, if appropriate with a suitable plasticizer. In order to know the preparation between tablets and granules with various active compounds and various amounts of active compounds, various paints can be added to the coating.

Soft gelatine capsules may be made from a mixture of the invented compound and vegetable oil, fat or other suitable ingredients for soft gelatine capsules. The soft gelatin capsules may be coated externally in the same manner as described above. The hard gelatine capsules may contain granules of the active compound or granules with an outer coating. In hard gelatine capsules, the active compound may be combined with a solid powder carrier such as lactose, sucrose, sorbitol, mannitol, potato starch, amylopectin, cellulose derivatives or gelatin. The hard gelatin capsules may be coated externally in the same manner as described above.

Dosage units for rectal administration may be formulated as a suppository comprising the active ingredient in admixture with a neutral or fatty base, or as a mixture of the active ingredient with vegetable oil, paraffin oil, or other materials for gelatine rectal capsules; or they may be prepared as dry preparations for microclimates which are dissolved in the appropriate solvent just prior to administration.

Liquid preparations for oral administration may be in the form of syrups or suspensions, e.g., solutions or suspensions containing from 0.2 to 20% by weight of the active ingredients, the remainder being sugar or sugar alcohols and ethanol, water, glycerol, propylene glycol and / or polyethylene glycol. Coloring agents, flavoring agents, saccharine, carboxymethylcellulose or other thickening agents may be added to these liquid preparations. Liquid preparations for oral use may also be prepared as a dry powder to be reconstituted with the appropriate solvent immediately before use.

Solutions for parenteral administration may be prepared as a solution of the compound of the invention in a pharmaceutically acceptable solvent, preferably 0.1 to 10% by weight. these solutions may contain stabilizing agents. These solutions may be dispensed in different doses into ampoules or vials. Solutions for parenteral administration may be prepared as dry preparations which are dissolved in the appropriate solvent immediately before use.

The typical daily dose of the active ingredient depends on a variety of factors, such as the patient's individual need, the route of administration and the disease. Oral and parenteral doses range from 5 to 500 mg of active ingredient per day.

The invention is illustrated by the following examples.

example

Preparation of 5-Carbomethoxy-6-methyl-2 - [[(4-cyclopropyl-methoxy-3-methoxy-2-pyrimidyl) methyl] sulfinyl] -1 H -benzimidazole

5-Carbomethoxy-6-methyl-2 - [[(4-cyclopropyl-methoxy-3-methoxy-2-pyridinyl) methyl] thio]] - 1H-benzimidazole (0.42 g, 1.0 mmol) was dissolved in methylene chloride (30 mL). . Dissolved in water (5 mL) NaHCO ₃ (0.17 g, 20 mmol) was added. The mixture was cooled to + 2 ° C. 71% (0.19, 0.80 mmol) of m-chloroperbenzoic acid dissolved in methylene chloride (5 mL) was then added dropwise with stirring. Stirring is continued for 15 min. At + 2 ° C. After separation, the organic layer was washed with water, dried over Na ₂ SO ₄ and evaporated. The oily residue was added with acetonitrile (1 mL) and after cooling, the desired product was filtered off to give white crystals (0.15 g, 44%).

The NMR data are given below.

example

Preparation of 5-Acetyl-6-methyl-2 - [[(3,4-ethylenedioxy-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazole

5-Acetyl-6-methyl-2 - [[(3,4-ethylenedioxy-2-pyridinyl) methyl] thio] -1H-benzimidazole (0.17 g, 0.49 mmol) was dissolved in methylene chloride (5 mL). NaHCO ₃ (0.082 g, 0.97 mmol) dissolved in water (2 mL) was added and the mixture was cooled to + 2 ° C. 69.5% (0.11g, 0.44 mmol) of m-chloroperbenzoic acid was dissolved in methylene chloride (2 mL) with stirring.

Stir for 15 min. At + 2 ° C. After separation, the organic layer was extracted with aqueous 0.20 M NaOH (3 x 2.5 mL, 1.5 mmol). Methyl formate (0.093 mL, 1.5 mmol) was added to the combined aqueous solutions and after 15 min. the solution was extracted with methylene chloride. The organic solution was dried over H ₂ SO ₄ and evaporated. A white crystalline material remained which was washed with ether. This gave the title compound (0.050 g, 30%).

The NMR data are given below.

example

Preparation of 5-Carbomethoxy-6-methyl-2 - [[(3,4-dimethoxy-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazole

5-Carbomethoxy-6-methyl-2 - [[(3,4-dimethoxy-2-pyridinyl) methyl] thio] -1H-benzimidazole (1.03 g, 0.00276 mol) was dissolved in CH ₂ Cl ₂ (30 mL). NaHCO3 (0.46 g, 0.0055 mol) dissolved in water (10 mL) was added and the mixture was cooled to + 2 ° C. While stirring, 69.5% (0.62 g, 0.0025 mol) of m-chloroperbenzoic acid dissolved in CH ₂ Cl ₂ (5 mL) was maintained. 15 mins stirring at + 2 ° C. After separation, the organic layer was extracted with aqueous 0.2 M NaOH (3 x 15 mL, 0.009 mol). After separation, the aqueous solutions were combined and neutralized with methylpharmate (0.56 mL, 0.009 mol) in the presence of CH ₂ Cl ₂ (25 mL). After separation, the organic layer was dried over Na ₂ SO ₄ and evaporated under reduced pressure. The residue was crystallized from CH 3 CN (10 mL) to give the title compound (0.68 g, 70%).

The NMR data are given below.

example

Preparation of 5-Acetyl-6-methyl-2 - [[(3,4-dimethoxy-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazole

5-Acetyl-6-methyl-2 - [[(3,4-dimethoxy-2-pyridinyl) methyl] thio] -1H-benzimidazole (3.75 g, 10 mmol) was dissolved in CH ₂ Cl ₂ (70 mL). Was added water (25 ml) was dissolved in NaHCO ₃ (1.76 g, 21 mmol) and the mixture was cooled to "+ 3 ° C. CH ₂ Cl ₂ (20 mL) dissolved m-perbenzoic acid was added with stirring and dropwise. Stirring was continued for 10 min. The phases are separated, the organic phase is dried over Na ₂ SO ₄ and evaporated under reduced pressure. The residue was crystallized from CH ₃ CH. The title compound was obtained (2.25 g, 60%).

The NMR data are given below.

example

Preparation of 5-Carbethoxy-2 - [[(3,4-dimethoxy-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazole

5-Carbethoxy-2 - [[(3,4-dimethoxy-2-pyridinyl) methyl] thio] -1H-benzimidazole (95.2% purity) (1.4 g, 0.0036 mol) was dissolved in CH ₂ Cl ₂ (30 mL). NaHCO ₃ (0.6 g, 0.0072 mol) dissolved in water (10 mL) was added and the mixture was cooled to + 2 ° C. Thereafter, 69.5% (0.87 g, 0.0035 mol) of m-chloroperbenzoic acid dissolved in CH ₂ Cl ₂ (5 mL) was added with stirring. Stirring for another 10 min. At 2 ° C. The phases are separated, the organic phase is dried over Na ₂ SO ₄ and evaporated under reduced pressure. The residue was crystallized from CH ₃ CN (15 mL) to give the title compound (0.76 g, 54%).

The NMR data are given below.

example

Preparation of 5-Acetyl-6-methyl-2 - [[(3,4-propylenedioxy-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazole

The compound was prepared from 5-acetyl-6-methyl-2 - [[(3,4-propylenedioxy-2-pyridinyl) methyl] thio] -1H-benzimidazole and m-chloroperbenzoic acid from a 0.01 mmol sample according to standard procedures.

The NMR data are given below.

example

Preparation of 5-Acetyl-6-methyl-2 - [[(3,4-methylenedioxy-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazole

5-Acetyl-6-methyl-2 - [[(3,4-methylenedioxy-2-pyridinyl) methyl] thio] -1H-benzimidazole (140 mg, 0.41 mmol) dissolved in methylene chloride (20 mL) and sodium bicarbonate (5 ml, 1M). The mixture was stirred at room temperature and MCPBA (100 g, 0.41 mmol, 70%) dissolved in methylene chloride (10 mL) was added portionwise. Sodium thiosulfate (100 mg) was added after 10 min. phases separated. The organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was chromatographed over silica (CH ₂ Cl ₂ / MeOH / NH ₃ , 97.5: 2.5: pris). 90 mg (61%) of the title compound is obtained. Lyd. t. 178-180 ° C (dec.). The NMR data are given below.

example

Preparation of 5-Acetyl-6-methyl-2 - [[(3-methoxy-4- (5-methyl-1,3-dioxan-5-ylmethoxy) -2-pyridinyl) methyl] sulfinyl] -1H-benzimidazole

5-Acetyl-6-methyl-2 - [[(3-methoxy-4- (5-methyl-1,3-dioxan-5-ylmethoxy) -2-pyridinyl) methyl] thio] -1H-benzimidazole (87 mg, 0.19 mmol) in 20 mL of CH ₂ Cl ₂ and NaHCO ₃ (32 mg, 0.38 mL) in 5 mL of water was cooled to 0 ° C and treated with 3-chloro-perbenzoic acid (47 mg 70%, 0.19 mmol). After 10 minutes. After a period of reaction, the layers separated (the aqueous layer was washed again with 5 mL of CH ₂ Cl ₂ ) and the organic layer was extracted with 10 mL of water containing NaOH (15 mg, 38 mmol). The alkaline aqueous layer was collected and treated with several portions of methyl formate (23 mL each, 38 mmol) until the solution became cloudy. The aqueous layer was extracted with 20 + 10 mL CH ₂ Cl ₂ . The last two organic layers were combined, dried over MgSO ₄ and evaporated. The residue was chromatographed (SiO ₂ , CH ₂ Cl ₂ / MeOH, saturated NH ₃ ( _g) 93/7) to give 40 mg (44%) of pure sulfoxide.

The NMR data are given below.

example

Preparation of 5-Acetyl-6-methyl-2 - [[(3,4-dimethoxy-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazole sodium salt

5-Acetyl-6-methyl-2 - [[(3,4-dimethoxy-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazole (0.50 g, 1.3 mmol) dissolved in dichloromethane and sodium hydroxide (51 mg, 1.3 mmol) ), dissolved in water (6 ml), pour into a separating funnel. The mixture was shaken and after some time the phases separated. The aqueous solution was washed with dichloromethane and then freeze-dried.

The NMR data are given below.

example

Preparation of 5-Acetyl-6-methyl-2 - [[(cyclopropylmethoxy-3-methoxy-2-pyridinyl) methyl] sulfinyl] -1 H -benzimidazole

5-Acetyl-6-methyl-2 - [[(4-chloropropylmethoxy-3-methoxy-2-pyridinyl) methyl] thio] -benzimidazole (40 mg, 0.10 mmol) was dissolved in methylene chloride (10 mL) and sodium bicarbonate (3 ml, 1M) The mixture was stirred at room temperature and MCPBA (25 mg, 0.10 mmol, 70%) dissolved in methylene chloride (5 ml) was added portionwise and sodium thiosulphate (30 mg) was added after 10 min and the phases were separated. After drying over sodium sulfate, filtration and concentration under reduced pressure, the residue was chromatographed on silica (CH ₂ Cl ₂ / MeOH / NH ₃ , 97.54: 2.5: pris) to give 30 mg (73%) of the title compound.

table

For example, Solvent NMR data, δ million. parts 1 CDCl ₃ (300 MHz) 0.30-0.35 (m, 2H), 0.60-0.67 (m, 2H), 1.2-1.3 (m, 1H), 2.67 (s, 3H), 3.83 (d, 2H), 3.86 (s, 3H), 3.90 (s, 3H), 4.72 (d, 1H), 4.86 (d, 1H), 6.71 (d, 1H), 7.35 (b, 1H), 8.09 (d, 1H), 8.24 (b, 1H)

For example, Solvent NMR data, δ million. parts 2 CDCl ₃ (500 MHz) 2.65 (s, 3H), 2.66 (s, 3H), 3.9-4.2 (m, 4H), 4.70 (d, 1H), 4.82 (d, 1H), 6.75 (d, 1H), 7.3 (b, 1H), 7.92 (d, 1H), 8.2 (b, 1H) 3 CDCl3 (500 MHz) 2.70 (s, 3H), 3.85 (s, 3H), 3.90 (s, 3H), 3.95 (s, 3H), 4.70 (d, 1H), 4.90 (d, 1H), 6.8 (d, 1H), 7.30 (b, 1H), 8.20 (d, 1H), 8.35 (b, 1H) 4 CDCl3 (300 MHz) 2.60 (s, 6H), 3.85 (s, 3H), 3.85 (s, 3H), 4.70 (d, 1H), 4.90 (d, 1H), 6.80 (d, 1H), 7.30 (b, 1H), 8.15 (d, 1H), 8.20 (b, 1H) 5 CDCl3 (300 MHz) 1.45 (t, 3H), 3.85 (s, 3H), 3.90 (s, 3H), 4.40 (q, 2H), 4.65 (d, 1H), 4.40 (d, 1H), 6.80 (d, 1H), 7.50-7.80 (b, 1H), 8.05 (d, 1H), 8.20 (d, 1H), 8.25, 8.55 (b, 1H) 6th CDCl3 (500 MHz) 2.16 (m, 2H), 2.64 (s, 3H), 2.66 (s, 3H), 4.23 (t, 2H), 4.30 (t, 2H), 4.68 (d, 1H), 4.88 (d, 1H), 6.83 (d, 1H), 7.3-7.5 (b, 1H), 8.01 (d, 1H), 8.1-8.2 (b, 1H) 7th CDCl3 (300 MHz) 2.66 (s, 6H), 4.54 (d, 1H), 4.75 (d, 1H), 5.80 (s, 1H), 5.87 (s, 1H), 6.77 (d, 1H), 7.93 (br. 1H), 8.07 (d, 1H), 8.12 (br. 1H) 8th CDCl3 (300 MHz) 0.91 (s, 3H), 2.63 (s, 3H), 2.64 (s, 3H), 3.49 (d, 2H), 3.84 (s, 3H), 3.94 (d, 2H), 4.15 (m, 2H), 4.66 (d, 1H), 4.73 (d, 1H), 4.86 (d, 1H), 5.02 (d, 1H), 6.89 (d, 1H), 7.33 (s, 1H), 8.08 (s, 1H), 8.14 (d, 1H)

For example, Solvent NMR data, δ min. parts 9th D ₂ O (proton content in water was determined in 4.82 min fractions) (300 MHz) 2.66 (s, 3H), 2.81 (s, 3H), 3.81 (s, 3H), 4.02 (s, 3H), 4.73 (d, 1H), 4.91 (d, 1H), 7.16 (d, 1H), 7.62 (s, 1H), 8.23 (d, 1H), 8.30 (s, 1H) 10th CDCl ₃ (300 MHz) 0.33 (m, 2H), 0.65 (m, 2H), 1.24 (m, 1H), 2.63 (s, 3H), 2.64 (s, 3H), 3.84 (d, 2H), 3.88 (s, 3H), 4.73 (d, 1H), 4.83 (d, 1H), 6.73 (d, 1H), 7.35 (s, 1H), 8.08 (s, 1H), 8.11 (d, 1H)

Examples of preparation of intermediates

Example I1

Preparation of 5-Carbomethoxy-6-methyl-2 - [[(4-cyclopropyl-methoxy-3-methoxy-2-pyridinyl) methyl] thio] -1H-benzimidazole

To a solution of 5-carbomethoxy-6-methyl-2-mercapto-1H-benzimidazole (0.58 g, 2.6 mmol) in methanol (25 mL) was added aqueous NaOH (1.0 mL 5M, 5.0 mmol) and 4- cyclopropylmethoxy-3-methoxy-2-chloromethyl-pyridine hydrochloride (prepared by processes known per se) (0.03 g, 24 mmol). The mixture was refluxed for one hour and then evaporated.

The residue is sandwiched between methylene chloride and water. After separation, the organic solution was dried over Na ₂ SO ₄ and evaporated to a yellow syrup (1.0 g, 100%).

The NMR data are given below.

Example I2

Preparation of 5-Acetyl-6-methyl-2 - [[3,4-ethylenedioxy-2-pyridinyl) methyl] thio] -1H-benzimidazole

To a solution of 5-acetyl-6-methyl-2-mercapto-1H-benzimidazole (0.14 g, 0.66 mmol) in methanol (2 mL) was added successively aqueous NaOH solution (0.25 mL 5M, 1.25 mmol) and 3,4-ethylenedioxy. -2-Chloromethyl-pyridine hydrochloride (0.13 g, 0.60 mmol) dissolved in methanol (2 mL). The mixture was refluxed for one hour and then evaporated. The residue was partitioned between methylene chloride and water. After separation, the organic solution was dried over Na ₂ SO ₄ and evaporated to a yellow syrup (0.17 g, 81%).

The NMR data are given below.

Example I3

Preparation of 5-Carbomethoxy-6-methyl-2 - [[3,4-dimethoxy-2-pyridinyl) methyl] thio] -1H-benzimidazole

5-Carbomethoxy-6-methyl-2-mercapto-1H-benzimidazole (0.67 g, 0.003 mol) and aqueous (0.6 ml) NaOH (0.12 g, 0.003 mol) were dissolved in CH ₃ OH (15 ml). Then 3,4-dimethoxy-2-chloromethylpyridine hydrochloride (<0.0036 mol) (crude) and aqueous (0.72 ml) NaOH (0.144 g, 0.0036 mol) were added. The mixture is refluxed for one hour. The CH ₃ OH was evaporated and the crude material was purified by chromatography on a silica column using CH 2 Cl 2 -CH ₃ OH (982) as eluent. The pure compound (1.03 g, 92%) was obtained.

The NMR data are given below.

Example I4

Preparation of 5-Acetyl-6-methyl-2 - [[(3,4-dimethoxy-2-pyridinyl) methyl] thio] -1H-benzimidazole

5-Acetyl-6-methyl-2-mercapto-1 H -benzimidazole (4.2 g, 20 mmol) and aqueous (1 mL) NaOH (0.8 g, 20 mmol) were dissolved in 60 mL of ethanol. Then 3,4-dimethoxy-2-chloromethylpyridine hydrochloride (<17 mmol) (crude) was added and the mixture was heated to reflux. An aqueous (1 mL) solution of NaOH (0.7 g, 17 mmol) was added and refluxed for 6 hours. The solvent was evaporated and the residue was diluted with methylene chloride and water. The organic phase was dried over Na2S ₄ and evaporated under reduced pressure. The title compound was crystallized from acetonitrile (3.75 g, 62%).

The NMR data are given below.

Example I5

Preparation of 5-Carbethoxy-2 - [[(3,4-dimethoxy-2-pyridinyl) methyl] thio] -1H-benzimidazole

5-Carbethoxy-2-mercapto-1H-benzimidazole (2.0 g, 9 mmol) and aqueous (1 mL) NaOH (0.36 g, 9 mmol) were dissolved in 30 mL of ethanol. Has been added

3,4-Dimethoxy-2-chloromethylpyridine hydrochloride (~ 6.6 mmol) (crude) and heated to reflux. Aqueous (1ml) NaOH (0.26g, 6.6mmol) was then added and the mixture was refluxed for 6 hours. The solvent was evaporated and the residue was dissolved in methylene chloride and water. The organic phase was dried over Na ₂ SO ₄ and the solvent removed under reduced pressure. The desired product was crystallized from CH ₃ CN (1.75 g, 71%).

The NMR data are given below.

Example I6

Preparation of 5-Acetyl-6-methyl-2 - [[(3,4-propylenedioxy-2-pyridinyl) methyl] thio] -1H-benzimidazole

The compound was synthesized from 5-acetyl-2-mercapto-6-methyl-1H-benzimidazole and

2-chloromethyl-3,4-propylenedioxypyridine in 0.01 mmol amounts according to standard procedures.

The NMR data are given below.

Example I7

Preparation of 5-Acetyl-6-methyl-2 - [[(3,4-methylenedioxy-2-pyridinyl) methyl] thio] -1H-benzimidazole

2-Chloromethyl-3,4-methylenedioxypyridine (90 mg, 0.52 mmol) and 5-acetyl-6-methyl-2-mercaptobenzimidazole (214 mg, 1.04 mmol) were dissolved in ethanol (15 mL). The pH of the solution was adjusted to 9 (0.2 M NaOH), followed by 10 min. the solution was refluxed. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in methylene chloride (10 mL) and hydrochloric acid (2 mL). The phases are separated and the organic phase is dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue is chromatographed on silica (ethyl acetate). 140 mg (79%) of the title compound is obtained. Lyd. t. 141-143 ° C (dec.).

The NMR data are given below.

Example I8

Preparation of 5-Acetyl-6-methyl-2 - [[(3-methoxy-4- (5-methyl-1,3-dioxan-5-ylmethoxy) -2-pyridinyl) methyl] thio] -1H-benzimidazole

2- (Hydroxymethyl) -3-methoxy-4- (5-methyl-1,3-dioxan-5-ylmethoxy) pyridine (0.34 g, 1.3 mmol) dissolved in 10 mL of CH ₂ Cl ₂ cooled to 0 ° C and treated with SOCI ₂ (0:12 mL, 1.7 mmol). The solution was then allowed to warm to room temperature and reacted for 1 hour. After evaporation of the solution, a quantitative quantity of the corresponding chloromethyl derivative in the form of the hydrochloride was obtained. DI-MS, m / z (%): 289 and 287 (11 and 38). A suspension of 5-acetyl-2-mercapto-6-methyl-1H-benzimidazole (0.29 g, 1.4 mmol) in 10 mL of MeOH was treated with a solution of NaOH (0.1 Og, 26 mmol) in 1.5 mL of water. The resulting solution was treated with the resulting chloromethyl compound. The reaction was continued for 21 hours. at room temperature. The solvent was evaporated and the residue was dissolved in 20 mL of 2.5% NaOH. The aqueous layer was extracted with 50 + 25 mL CH ₂ Cl ₂ , the organic layers were combined, dried over MgSO ₄ and evaporated. 0.49 g (82%) of the desired compound is obtained in the form of a yellow-brown foam.

The NMR data are given below.

Example I9

Preparation of 5-Acetyl-6-methyl-2 - [[(4-cyclopropylmethoxy-3-methoxy-2-pyridinyl) methyl] thio] -1H-benzimidazole

2-Chloromethyl-4-cyclopropylmethoxy-3-methoxypyridine (50 mg, 0.22 mmol) and 5-acetyl-6-methyl-2-mercaptobenzimidazole (50 mg, 0.24 mmol) were dissolved in ethanol (15 mL). The pH of the solution was adjusted to 9 (0.2 M NaOH), followed by 10 min. the solution was refluxed. After concentration of the reaction mixture under reduced pressure, the residue was dissolved in methylene chloride (10 mL) and hydrochloric acid (2 mL). The phases were separated and the organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was chromatographed over silica (ethyl acetate). Yield: 40 mg (46%) of the title compound.

The NMR data are given below.

Example 110

4-Chloro-3-hydroxyethoxy-2-methylpyridine

A solution of 4-chloro-3-hydroxyethoxy-2-methylpyridine (2.78 g, 0.014 mol) in dry CDCl3 («14 ml) for 23 h. at room temperature and under Ar atmosphere was treated with TMSI (5.10 mL, 0.036 mol). The reaction mixture was partitioned between 100 mL CH 2 Cl 2 and 100 mL 1M HCl. The aqueous layer was separated by washing again with 50 mL of CH ₂ Cl ₂ and then treated with Na ₂ CO ₃ until the pH reached 10. The aqueous layer was extracted with 100 + 50 mL of CH ₂ Cl ₂ . The last two organic layers were combined, dried over MgSO ₄ and evaporated. 2.31 g of a saturated product are obtained.

Chromatography (silica gel, diethyl ether after diethyl ether / MeOH; 95/5) gave 1.06 g (40%) of the pure product.

The NMR data are given below.

Example I11

Preparation of 3,4-ethylenedioxy-2-methylpyridine

A mixture of 4-Chloro-3-hydroxyethoxy-2-methylpyridine (1.03 g, 0.0055 mol) and NaH (55%) in oil, 599 mg, 0.0138 mol) in 600 ml THF or 15 ml. boil under reflux. Excess NaH was removed with 3 mL water. The solvent was evaporated and the residue was placed between 100 mL of 1M HCl and 100 mL of CH ₂ Cl ₂ and then treated with Na ₂ CO ₃ until the pH reached 10. The aqueous layer was extracted with 150 + 100 mL of CH ₂ Cl ₂ . The last two organic layers were combined, dried over MgSO ₄ and evaporated. 720 mg of a saturated solution was obtained. Chromatography (silica gel, diethyl ether) gave 0.49 g (59%) of the pure product.

The NMR data are given below.

Example I12

Preparation of 3,4-ethylenedioxy-2-hydroxymethyl-pyridine

The required compound was obtained according to standard procedures in 3.2 mmol amounts. Yield: 395 mg (77%) of pure product.

The NMR data are given below.

Example I13

Preparation of 3- (3-Hydroxy-1-propoxy) -2-methyl-4-pyrone

A suspension of 3-hydroxy-2-methyl-4-pyrone (25 g, 200 mmol), 3-bromo-1-propanol (70 g, 500 mmol) and K ₂ CO ₃ (111 g, 800 mmol) in 600 mL acetone was stirred for 3 days. The solvent was evaporated and the residue partitioned between 300 mL of methylene chloride and 500 mL of 2.5% NaOH. The aqueous layer was separated and extracted with 2 x 300 mL methylene chloride. The organic phases were combined, dried over Na ₂ SO ₄ and evaporated at 50 ° C. Eight grams of the precipitate (24 g) was chromatographed on silica gel using methanol / methylene chloride (5: 95) as eluent to give 2.7 g (22%) of the desired product as an oil.

The NMR data are given below.

Example I14

Preparation of 3- (3-Methoxy-1-propoxy) -2-methyl-4-pyrone

A mixture of 3- (3-hydroxy-1-propoxy) -2-methyl-4-pyrone (1.4 g, 7.6 mmol), 85% KOH (0.55 g, 8.4 mmol) and methyl iodide (11 g, 76 mmol) was one day. stirred at room temperature. The red solution was partitioned between methylene chloride and semi-saturated aqueous ammonium chloride solution. The organic phase was washed with water, dried over Na ₂ SO ₄ and evaporated. The residue was purified by silica gel chromatography eluting with methanol / methylene chloride (3:97). Removal of the eluent by film evaporation afforded 0.31 g (20%) of the desired oil.

The NMR data are given below.

I Example 15

Preparation of 3- (3-Methoxy-1-propoxy) -2-methyl-4-pyrodone

3- (3-Methoxy-1-propoxy) -2-methyl-4-pyrone (0.31 g, 1.7 mmol), dissolved in 50 mL of concentrated aqueous NH ₃ , autoclaved for 2 hours. At 120 ° C. The reaction mixture was transferred to a round bottom flask and the solvent evaporated. 0.32 g (100%) of a yellow oil are obtained.

The NMR data are given below.

Example I16

Preparation of 4-Chloro-3- (3-methoxy-1-propoxy) -2-methyl-4-pyridine

A solution of 4-chloro-3- (3-methoxy-1-propoxy) -2-methyl-4-pyridone (0.32 g, 1.6 mmol) in 50 mL of POCl _{3 or} 14. reflux. The POCI _{3 was} evaporated and the residue partitioned between methylene chloride and water. The aqueous layer was separated, treated with K ₂ CO ₃ , to pH = 10, and extracted with methylene chloride. The organic layer was dried over Na ₂ SO ₄ and evaporated. The residue was purified by silica gel chromatography eluting with methanol / methylene chloride (3: 97). Evaporation of the solvent gave 0.12 g (34%) of a red oil.

The NMR data are given below.

Example I17

Preparation of 4-Chloro-3- (3-hydroxy-1-propoxy) -2-methyl-pyridine

To a solution of 4-chloro-3- (3-methoxy-1-propoxy) -2-methyl-pyridine (120 mg, 0.56 mmol) in 2 mL of CDCl3 was added trimethylsilyl iodide (0.16 mL, 1.3 mmol), which was done. In the BMR ampoule. The reaction was completed after four days, as judged by the disappearance of the OCH ₃ proton signal at 3.3 md in the NMR spectrum. To the solution was added 10 mL of 1M HCl, 10 mL of methylene chloride and everything was stirred for 5 minutes. The aqueous layer was separated, treated with K ₂ CO ₃ to pH = 10, and extracted with methylene chloride. The organic phase was dried over Na ₂ SO ₄ and evaporated. 0.049 g (43%) of the desired product is obtained in the form of a yellow oily film.

The NMR data are given below.

Example I18

Preparation of 2-Methyl-3,4-propylenedioxypyridine

A solution of 4-chloro-3- (3-hydroxy-1-propoxy) -2-methyl-pyridine (49 mg, 0.24 mmol) in 3 mL of DMSO was heated with 70% NaH for 2 h at 70 ° C (32 mg, 0.73 mmol). The mixture was cooled, diluted with water and extracted with methylene chloride. The organic solution was evaporated and the residue was chromatographed on silica gel using methylene chloride as eluent. The solvent was evaporated to give 22 mg (55%) of a yellow oil.

The NMR data are given below.

Example I19

Preparation of 2-Hydroxymethyl-3,4-propylenedioxypyridine

This product was synthesized from 2-methyl-3,4-propylenedioxypyridine according to standard procedures in an amount of 0.01 mmol. Yield: 3 mg (11%). The NMR data are given below.

I Example 20

Preparation of 2-Chloromethyl-3,4-propylenedioxypyridine

This compound was obtained in quantitative yield from 2-hydroxymethyl-3,4-propylenedioxypyridine by standard procedures in an amount of 0.01 mmol. The compound was used without purification and characterization.

I Example 21

Preparation of 2-Methyl-3,4-methylenedioxypyridine

2-Methyl-3-hydroxy-4-pyridone (1.25 g, 10 mmol) was dissolved in dry DMSO (20 mL). Dibromomethane (3.5 g, 20 mmol) and sodium hydride (1 g,> 20 mmol, 50-60% in oil) were added. The mixture was left at room temperature (stirring) for three days and then added to hydrochloric acid (50 mL). Aqueous DMSO solution Extracted with methylene chloride (3 x 50 mL) and collect the extracts directly for the next step. A sample was taken for NMR analysis.

The NMR data are given below.

I Example 22

Preparation of 2-Methyl-3,4-methylenedioxypyridine

Sodium bicarbonate (1M, 50 mL) and MCPBA (4 g, 70%) were added to a solution of the 2-methyl-3,4-methylenedioxypyridine described in Example I21 in methylene chloride. The mixture was stirred for 15 min. at ambient temperature and then excess MCPBA was removed by the addition of sodium thiosulfate (1 g). The organic phase was separated and the aqueous phase was extracted with methylene chloride (3 x 50 mL). The collected organic phases were concentrated under reduced pressure and chromatographed over silica (CHaCl2 / MeOH, 90:10). Yield: 120 mg (7.8%) of the desired product.

The NMR data are given below.

I Example 23

Preparation of 2-hydroxymethyl-3,4-methylenedioxypyridine

2-Methyl-3,4-methylenedioxypyridine-N-oxide (120 mg, 0.78 mmol) was dissolved in acetic anhydride (10 mL) and the solution heated for 15 min. 110 ° C, then the mixture was concentrated under reduced pressure. The residue was dissolved in methanol (20 mL) and sodium hydroxide (3 drops, 6M) was added. After 30 minutes the mixture was neutralized with acetic acid (pH 6) at room temperature and concentrated under reduced pressure. The residue was chromatographed over silica (hexane / ethyl acetate, 1: 1). Yield: 90 mg (75%) of the desired product.

The NMR data are given below.

I Example 24

Preparation of 2-Chloromethyl-3,4-methylenedioxypyridine

2-Hydroxymethyl-3,4-methylenedioxypyridine (90 mg, 0.59 mmol) was dissolved in methylene chloride (10 mL) and thionyl chloride (240 mg, 2 mmol) was added. After 10 minutes. at room temperature the mixture was hydrolyzed with sodium bicarbonate and the phases separated. The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. Yield: 90 mg (88%) of the title compound (crude).

The NMR data are given below.

I Example 25

Preparation of 3-Methoxy-2-methyl-4- (5-methyl-1,3-dioxan-5-yl-methoxy) pyridine-N-oxide

Deaerated solution of 5- (hydroxymethyl) -5-methyl-1,3-dioxane (1.19 g, 9 mmol) in 125 mL of dry THF for 20 min. treated with NaH (0.79 g 55% dispersion in oil, 18 mmol). 4-Chloro-3-methoxy-2-methylpyridine-oxide (1.04 g, 6 mmol) was added and the mixture was stirred for 26 h. refluxed. Excess NaH was removed in 10 mL of water and the solvent was evaporated. The residue was distributed between 150 mL CH ₂ Cl ₂ and 50 mL 5% Na ₂ CO ₃ . The organic layer was passed through phase separation paper and evaporated. 1.83 g of a saturated product are obtained. Chromatography (SiO ₂ CH ₂ Cl ₂ / MeOH, 95/5) yielded 0.39 g (24%) of a pure product as a tan oil.

The NMR data are given below.

I Example 26

Preparation of 2- (Hydroxymethyl) -3-methoxy-4- (5-methyl-1,3-dioxan-5-ylmethoxy) pyridine

3-Methoxy-2-methyl-4- (5-methyl-1,3-dioxan-5-yl-methoxy) pyridine-N-oxide (0.39 g, 1.5 mmol) in 4.5 mL (CH ₃ CO) ₂ O 4 or. heated at 100 ° C. The excess (CH ₃ CO) ₂ O was azeotropically removed 4 times using 75 mL abs. EtOH. 0.42 g (90%) of 3-methoxy-4- (5-methyl-1,3-dioxan-5-yl-methoxy) -2-pyridinyl) -methyl acetate (crude) is obtained.

Crude acetate for 1 h. 20 ml of 2M NaOH were treated at 100 ° C. The aqueous layer was extracted with 75 + 50 + 25 mL CH ₂ Cl ₂ . The organic layers were combined, dried over MgSO ₄ and evaporated. 0.34 g (97%) of pure product was obtained for further use.

The NMR data are given below.

table

For example, Solvent NMR data δ, min. parts 1 1 CDCl ₃ (300 MHz) 0.37-0.42 (m, 2H), 0.67-0.73 (m, 2H), 1.25- 1.40 (m, 1H), 2.69 (s, 3H), 3.90 (s, 3H), 3.94 (d, 2H), 3.98 (s, 3H), 4.40 (s, 2H), 6.81 (d, 1H), 7.3 (b, 1H), 8.2 (b, 1H), 8.22 (d, 1H) I2 CDCl3 (500 MHz) 2.64 (s, 3H), 2.66 (s, 3H), 4.35 (s, 2H), 4.40 (s, 4H), 6.85 (d, 1H), 7.30 (s, 1H), 8.06 (d, 1H), 8.08 (s, 1H) I3 CDCb (300 MHz) 2.70 (s, 3H), 3.90 (s, 3H), 3.95 (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) I4 CDCl3 (300 MHz) 2.60 (s, 3H), 2.65 (s, 3H), 3.90 (s, 3H), 3.90 (s, 3H), 4.35 (s, 2H), 6.85 (d, 1H), 7.25 (s, 0.6H), 7.40 (S, 0.4H), 7.85 (s, 0.4H), 8.05 (s, 6H), 8.30 (m, 1H) I5 CDCl3 (300 MHz) 1.40 (m, 3H), 3.90 (s, 3H), 3.90 (s, 3H), 4.40 (m, 4H), 6.90 (dd, 1H), 7.45 (d, 0.4H), 7.60 (d, 0.6H), 7.90 (m, 1H), 8.20 (s, 0.6H), 8.25 (m, 1H), 8.25 (s, 0.4H) I 6 CDCl3 (500 MHz) 2.32 (p, 2H), 2.64 (s, 3H), 2.66 (s, 3H), 4.37- 4.43 (m, 4H), 4.39 (s, 2H), 6.88-6.90 (m, 1H), 7.29 (s, 0.6H), 7.42 (s, 0.4H), 7.85 (s, 0.4H), 8.07 (s, 0.6H), 8.11 (m, 1H) I 7 CDCl3 (300 MHz) 2.648 (s, 3H), 2.652 (s, 3H), 4.32 (s, 2H), 6.14 (s, 2H), 6.85 (d, 1H), 7.34 (br. 1H), 8.00 (br. 1H), 8.20 (d, 1H)

For example, Solvent NMR data δ, million. parts I 8 CDCIg (300 MHz) 0.98 (s, 3H), 2.65 (s, 6H), 3.53 (d, 2H), 3.95 (s, 3H), 4.00 (d, 2H), 4.25 (s, 2H), 4.39 (s, 2H), 4.69 (m, 1H), 5.06 (m, 1H), 6.9-7.0 (2d, 1H), 7.3-7.5 (several b, 1H), 7.8-8.1 (several b, 1H), 8.2-8.3 (2d, 1H), 13.2 (b, 1H) I 9 CDCl ₃ (300 MHz) 0.38 (m, 2H), 0.69 (m, 2H), 1.31 (m, 1H), 2.63 (s, 3H), 2.636 (s, 3H), 3.93 (d, 2H), 3.98 (s, 3H), 4.40 (s, 2H), 6.81 (d, 1H), 7.33 (s, 1H), 7.98 (s, 1H), 8.22 (d, 1H) I 10 cdci ₃ (500 MHz) 2.57 (s, 3H), 2.70 (t, 1H), 3.99 (dt, 2H), 4.09 (t, 2H), 7.19 (d, 1H), 8.16 (d, 1H) I 11 CDCl3 (500 mHz) 2.41 (s, 3H), 4.30 (s, 4H), 6.65 (d, 1H), 7.90 (d, 1H) I 12 CDCl3 (500 MHz) 4.11 (b, 1H), 4.33 (m, 4H), 4.69 (b, 2H), 6.76 (d, 1H), 7.99 (d, 1H) I 13th CDCl3 (300 MHz) 1.85 (p, 2H), 2.30 (s, 3H), 3.85 (q, 2H), 4.00 (t, 2H), 4.35 (t, 1H), 6.35 (d, 1H), 7.65 (d, 1H) I 14th CDCl3 (300 MHz) 2.00 (p, 2H), 2.32 (s, 3H), 3.35 (s, 3H), 3.56 (t, 2H), 4.13 (t, 2H), 6.33 (d, 1H), 7.59 (d, 1H) I 15 CDCIg (300 MHz) 1.98 (p, 2H), 2.45 (s, 3H), 3.38 (s, 3H), 3.61 (t, 2H), 4.08 (t, 2H), 6.35 (d, 1H), 7.63 (d, 1H) I 16th CDCl3 (300 MHz) 2.09 (p, 2H), 2.54 (s, 3H), 3.38 (s, 3H), 3.63 (t, 2H), 4.04 (t, 2H), 7.16 (d, 1H), 8.13 (d, 1H) I 17th CDCl3 2.10 (p, 2H), 2.56 (s, 3H), 3.96 (t, 2H), 4.10 (t,

For example, Solvent NMR data δ, million. parts (500 MHz) 2H), 7.18 (d, 1H), 8.15 (d, 1H) 1 18 CDCl3 (300 MHz) 2.52 (p, 2H), 2.45 (s, 3H), 4.28 (t, 2H), 4.34 (t, 2H), 6.70 (d, 1H), 7.96 (d, 1H) I 19th CDCl3 (500 MHz) 2.27 (p, 2H), 4.30 (t, 2H), 4.37 (t, 2H), 4.71 (d, 2H), 6.80 (d, 2H), 8.05 (d, 1H) I 21st CDCl3 (500 MHz) 2.34 (s, 3H), 5.92 (s, 2H), 6.61 (d, 1H), 7.93 (d, 1H) I 22 CDCl3 (500 MHz) 2.42 (s, 3H), 6.12 (s, 2H), 6.59 (d, 1H), 7.90 (d, 1H) I 23 CDCl3 (300 MHz) 4.73 (s, 2H), 6.05 (s, 2H), 6.76 (d, 1H), 8.09 (d, 1H) I24 CDCl3 (300 MHz) 4.65 (s, 2H), 6.10 (s, 2H), 6.78 (d, 1H), 8.13 (d, 1H) I25 CDCl3 (300 MHz) 0.97 (s, 3H), 2.50 (s, 3H), 3.52 (d, 2H), 3.85 (s, 3H), 3.98 (d, 2H), 4.18 (s, 2H), 4.67 (d, 1H), 5.02 (d, 1H), 6.77 (d, 1H), 8.08 (d, 1H) I 26th CDCIg (300 MHz) 0.98 (s, 3H), 3.52 (d, 2H), 3.86 (s, 3H), 4.00 (d, 2H), 4.09 (m, 1H), 4.20 (s, 2H), 4.68 (d, 1H), 4.75 (d, 2H), 5.02 (d, 1H), 6.88 (d, 1H), 8.20 (d, 1H)

The best known embodiment of the present invention is the use of the compound of Example 4 or the salts thereof according to Example 9.

table

The compounds of the first formula are listed in the following table

For example, R ¹ R ² R ³ r ⁴ Yield Ident. data 1. C (O) -OCH ₃ ch ₃ ch ₃ ch ₂ 44 NMR 2. C (O) CH ₃ ch ₃ -ch ₂ ch ₂ - 30th NMR 3. C (O) -OCH ₃ ch ₃ ch ₃ ch ₃ 70 NMR 4. C (O) CH ₃ ch ₃ ch ₃ ch ₃ 60 NMR 5. C (O) OCH ₂ CH ₃ H ch ₃ ch ₃ 54 NMR 6th C (O) ch ₃ ch ₃ -ch ₂ ch ₂ ch ₂ - NMR 7th C (O) ch ₃ ch ₃ -ch ₂ - 61 NMR 8th C (O) ch ₃ ch ₃ ch ₃ ch ₂ 44 NMR 9th C (O) ch ₃ ch ₃ ch ₃ ch ₃ Sodium salt NMR 10th C (O) ch ₃ ch ₃ ch ₃ ch ₂ 73 NMR

Syrup

A syrup containing 1% by weight of the active substance was obtained from the following ingredients:

Example 1.0 describes compound 1.0 g

Sugar, powder 30.0 g

Saccharin 0.6 g

Glycerol 15.0 g

Spices 0.05 g

Ethanol 96% 5.0 g

Make up to 100 ml with distilled water

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

Tablets with outer coating

Tablets with an outer coating containing 50 mg of active ingredient were prepared from the following ingredients:

The Mg salt of the compound described in Example 4 is 500 g

Lactose 700 g

Methyl cellulose 6 g

Stitched polyvinylpyrrolidone 50 g

Magnesium stearate 15g Sodium carbonate 6g distilled water tr.k. Cellulose acetate phthalate 200 g Cetyl alcohol 15g Isopropanol 2000 yrs Methylene chloride 2000 yrs

The compound of Example I I is in powder form mixed with lactose and granulated with aqueous methylcellulose and sodium carbonate. The wet mass was squeezed through a sieve and the granulate dried in an oven. After drying, the granulate was mixed with polyvinylpyrrolidone and magnesium stearate and pressed into the tablet cores (10,000 tablets), each tablet containing 50 mg of active ingredient. The tablet used 7mm diameter shapes.

li Cellulose acetate phthalate solution and cetyl alcohol in isopropanol / methylene chloride were sprayed onto I tablets with Acela Cota®, a Manesty device for coating. The final weight of the tablets is 110 mg.

Solution for intravenous use

Parenteral preparation containing 4 mg / ml of active compound for intravenous use, obtained from the following components:

Example 4 Compound 4 g

Sterile water to a final volume of 1000 ml

The active compound was dissolved in water to a final volume of 1000 mL. The solution was filtered through a 0.22 μιτι filter and immediately dispensed into 10 ml sterile ampoules. The ampoules were then sealed.

Capsules

Capsules containing 30 mg of active ingredient were prepared from the following ingredients:

300 g of the compound described in the example

Lactose 700 g

Microcrystalline cellulose 40 g

Hydroxypropylcellulose (minor name) 62 g

Disodium hydrogen phosphate 2 g

Purified water tr.k.

The active ingredient is mixed with dry ingredients and granulated with disodium hydrogen phosphate. The wet mass was passed through an extruder, spheronized and dried in a fluid bed dryer.

500 g of the resulting granules are coated with hydroxypropylmethylcellulose, 30 g are dissolved in 750 g of water using a liquid coating device. After drying, the pellets were coated with a second layer, given below:

Coating solution:

Hydroxypropylmethylcellulose phthalate 70 g

Cetyl alcohol

4g

Acetone 200 g

Ethanol 600 g

The final coated beads were enclosed in capsules.

Suppositories

Suppositories were made from the following ingredients using a fusion procedure. Each suppository contained 40 mg of active ingredient.

Example 4 Compound 4 g

Vitepsol H-15 180 g

The active compound was homogeneously mixed with Witepsol H-15 at 41 ° C. Subsequently, the resulting melted mass was filled with pre-prepared suppository packages up to 1.84 g of net weight. After cooling, the packages are hermetically sealed. Each suppository contained 40 mg of active ingredient.

Biological effects

Bioavailability

Bioavailability is determined by calculating the ratio of the area under the plasma concentration curve of rats in introduodenal (id) and intravenous (iv) administration.

Inhibition of acid secretion

The ability to inhibit acid secretion is measured by intravenous (iv) administration to dogs and rats.

Effect of iodine delivery on thyroid gland

The effect of the invented compound of formula I on iodine uptake into the thyroid gland was measured as the effect on ¹²⁵ l accumulation in the thyroid gland.

Biological tests

Inhibition of gastric acid secretion in benarctic female rats

Female rats of the Sprague-Dawley strain were used for experiments. Cannulas were inserted into their stomach to collect gastric juice. Investigations began with a 14-day rehabilitation period after surgery.

20 or so. until secretion studies, the animals were given water only. The stomach cannula was periodically flushed and 6 ml of Ringer-glucose was administered subcutaneously (sc). Acid secretion is stimulated to 3.5 or. (1.3 ml / h, sc) with pentagastrin and carbachol (20 and 110 nmol / kg, h) respectively, at which time gastric juice was collected for 30 min. fractions. Test substances or vehicle were injected iv at 1 ml / kg 90 min. after the onset of stimulation. Gastric juice was titrated with NaOH, 0.1 mol / L to pH 7.0, and gastric juice was calculated by volume and concentration. The calculations are further based on the mean values of the 3-7 rat group. The acid content after administration of test substances or solvent is expressed as the fractional response taking the amount of acid isolated per 1.0 min prior to administration of the preparation. Percent inhibition is calculated from the fractional response induced by the test substances or solvent. ED ₅₀ values are obtained by graphically interpolating logarithmic dose-response curves or subtracting from single-dose experiments assuming all response-dose curves have the same tilt angle. Results are based on gastric acid secretion in the second hour following administration of the product / vehicle.

Bioavailability in male rats

Adult male rats of the Sprague-Davvley strain were used for experiments. One day before the experiment, all rats underwent cannulation in the left carotid artery after anesthesia. Rats used for intravenous experiments were also cannulated into the junctional vein (see V. Popovic and P. Popovic, J. Appl. Physiol. 1960; 15, 727728). Rats used for intraduodenal experiments were also injected with cannula j into the upper part of the duodenum. The cannula is derived from the back of the neck. After the operation, the rats were housed in separate cages and fed with water alone prior to administration. About 1 min. the same dose (4 µmol / kg) iv and id was administered (2 ml / kg). Blood samples (0.1-0.4 g) were periodically taken from the carotid artery for 4 hours after dosing. These samples were frozen as soon as possible and kept frozen until analysis of the test compound. The AUC of the curve plotting the blood concentration vs. time is determined by the linear trapezoidal rule and extrapolated to infinity by dividing the last measured blood concentration by the descending constant in the last phase.

The systemic bioavailability (F%) for the intraduodenal route was calculated as follows:

F (%)

AUC., Id

AUCX 100

IV

Inhibition of gastric acid secretion in a benarctic dog

Harrier dogs of both sexes were used in the experiments and had fistulas inserted into the duodenum to administer the test drug or solvent and to collect Heidenhain-pocket-stomach secretions.

Approximately 18 hours prior to examination of secretions. the animals were not fed, but water was given to them in abundance. Gastric acid secretion was stimulated for 4 hours. administration of histamine dihydrochloride (12 ml / h) at doses yielding about 80% of the maximal individual secretory response and gastric juice collected sequentially for 30 min. fractions. The test substance or solvent was administered iv, 0.5 ml / kg body weight, after 1 hour. after the start of the histamine release. The acidity of the gastric juice samples was determined by titration to pH 7.0. The acid content was calculated. The acid content of the fractions collected after administration of the test preparation or solvent was expressed as the fractional response assuming an acid content of 1.0 prior to administration. Percent inhibition is calculated based on the fractional response induced by the test substances or solvent. The ED ₅₀ values are obtained by graphically interpolating logarithmic dose response curves or subtracting from single dose experiments assuming all response-dose curves have the same tilt angle. The results are based on gastric acid secretion at the second hour after preparation / solvent administration.

Effect on ¹²⁵ l accumulation in the thyroid gland The ¹²⁵ l accumulation in the thyroid gland was studied in Sprague-Davvley rats at 24 h. were not fed prior to the experiment. Based on Searle, CE, et al. (Biochem 11950, 47: 77-81) in an experimental protocol.

Experimental materials in 0.5% buffer (pH 9) methocel were administered orally at 5 ml / kg body weight. After 1 hour, ¹²⁵ l (300 kBqKg, 3 ml / kg) was administered by intraperitoneal injection. 4 hours later after ¹²⁵ 1 administration, animals are killed (CO ₂ suffocation and bleeding). To detect radioactivity, the thyroid gland along with a piece of trachea was removed in a gamma counter (LKB-Wallac Model 1282 Compugama) and placed in a small tube.

Percent inhibition was calculated using the formula 100 (1-T / P), where T and P are the values of the animal's thyroid gland exposed to the test substance and placebo (buffer methocel), respectively. Statistical significance between the test substance and placebo treated animals was determined by the Mann-Whitney U-test. P <0.05 accepted as significant.

Chemical stability

Chemical stability kinetics of the invented compound were observed at low concentrations in aqueous buffer solutions at different pHs. The results in Table 4 show the half-life (t 1/2) at pH 7, which is the time after which half of the starting product remains unchanged.

Biological and stability test results The following table summarizes the results of the inventive compounds.

table

Data from biological experiments and stability studies

Trial compound example No. Acid secretion inhibitors Bioavailability F%, Rat 400 µmol / kg percentage inhibitory effect I access to thyroid Chemical stability at pH 7 of life half-life (t 1/2) min mas, iv umol / kg introduction of ED _SO Dog Rat 2 a) 3 0.5 0 480 4 0.74 0.9 > 100 -7 470 5 -6 270

a) 1 pmol / kg gives 14% inhibition

Claims (15)

1. Compound of Formula I: and a physiological salt thereof wherein R ¹ and R ² are different and each is H, alkyl having from 1 to 4 carbon atoms or -C (O) -R ⁵ ; wherein R ⁵ is alkyl of 1-4 carbon atoms or alkoxy of 1-4 carbon atoms and one of R ¹ or R ^{2 is} always -C (O) -R ⁵ ; R ³ and R ⁴ are the same or different and selected from -CH 3, -C 2 H 5, -CH ₂ ' ^{_ <} l, -CH ₂ -V) o and -CH 2 CH 2 OCH ³ , or R ³ and R ⁴ together with adjacent oxygen atoms attached to the pyridine ring and carbon atoms of the pyridine ring form a ring wherein the portion consisting of R ³ and R ⁴ is -CH 2 CH 2 CH 2 -, CH ₂ CH ₂ - or -CH ₂ . Compound of formula I according to claim 1, characterized in that it is 5-carbomethoxy-6-methyl-2 - [[(3,4-dimethoxy-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazole. Compound of formula I according to claim 1, characterized in that it is 5-acetyl-6-methyl-2 - [[(3,4-dimethoxy-2-pyridinyl) methyl] sulfinyl] -1 H-benzimidazole. 4. A compound of the formula I as claimed in claim 1, which is 5-acetyl-6-methyl-2 - [[(3,4-propylenedioxy-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazole. Compound of formula I according to claim 1, characterized in that it is 5-acetyl-6-methyl-2 - [[(3,4-methylenedioxy-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazole. 6. A compound according to claim 1, which is in the form of a sodium salt. 7. A compound according to claim 3, which is in the form of a sodium salt. 8. A compound according to claim 1 in the form of a magnesium salt. 9. A pharmaceutical preparation comprising the compound of claim 1 as an active ingredient. A compound according to claim 1 for use in inhibiting gastric acid secretion in a mammal, including a human. A compound according to claim 1 for use in the treatment of inflammatory diseases of the gastrointestinal tract of mammals, including man. Use of a compound according to claim 1 for the manufacture of a medicament for the inhibition of gastric acid secretion in a mammal, including a human. Use of a compound according to claim 1 for the manufacture of a medicament for the treatment of inflammatory gastrointestinal disorders in mammals and humans. 14. A process for the preparation of a compound of formula I as claimed in claim 1, which comprises oxidizing a compound of formula II (H) wherein R ¹ , R ² , R ³ and R ⁴ are as defined in claim 1 of formula I. 15. New Intermediates 2-Methyl-3,4-propylenedioxypyridine, 2-hydroxymethyl-3,4-propylenedioxypyridine, 2-methyl-3,4-methylenedioxypyridine, 2-hydroxymethyl-3,4-methylenedioxypyridine , 5-acetyl-6-methyl-2 - [[(3,4-propylenedioxy-2-pyridinyl) methyl] thio] -1H-benzimidazole and 5-acetyl-6-methyl-2 - [[3,4-methylenedioxy-2 pyridinyl) methyl] thio] -1H-benzimidazole for the preparation of a compound of formula I as claimed in claim 1.