LT3952B - Substituted benzimidazoles, 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 which inhibit the stimulation of gastric acid exogenously and endogenously and can therefore be used in the treatment and prophylaxis of peptic ulcers.

The present invention also relates to the use of the above compounds for inhibiting gastric juice secretion in mammals, including man. In essence, the compounds of the present invention can be used for the treatment and prophylaxis of gastrointestinal inflammatory diseases and disorders associated with gastric acidity in mammals, including man, such as gastritis, gastric ulcer, reflux oesophagitis, and Zolinger Ellison syndrome. In addition, the present compounds may be used in the treatment of other gastrointestinal disorders, for which inhibition of gastric juice secretion is desirable, such as in patients with gastric and severe gastrointestinal haemorrhages. The compounds of the present invention may also be used in intensive therapy and in preoperative or postoperative periods for aspiration acid and for the prevention of stress ulcers. These compounds can also be used for the treatment or prophylaxis of inflammatory conditions in mammals, including man, especially those requiring lysozyme enzymes. Examples of such conditions are rheumatoid arthritis and gout. The compounds of the present invention may also be used in the treatment of disorders associated with metabolic disorders and glaucoma. The present invention also relates to pharmaceutical compositions containing the aforementioned compounds as active ingredient. In another embodiment, the present invention relates to a process for the preparation of said novel compounds and to the use of the active compounds in the preparation of pharmaceutical compositions for the treatment of the aforementioned diseases.

The main object of the present invention is to obtain compounds with high bioavailability. The compounds of the present invention exhibit high stability at neutral pH and high efficacy in inhibiting gastric juice secretion. Furthermore, the compounds of the present invention do not block the uptake of iodine by the thyroid gland. Previously, several lectures read by an organization employing the present inventors have indicated that the thyroid toxicity of the compounds depends on whether the compounds are lipophilic or not. Unexpectedly, the present inventors have found that lipophilicity is not a critical parameter of the present invention. The compounds of the invention are sufficiently hydrophilic but do not exhibit any thyroid toxicity, while having a strong inhibitory effect on acid secretion, good bioavailability and stability.

Prior art

Benzimidazole derivatives for inhibiting gastric acid secretion have been described in numerous patent documents. Such documents include, for example, GB 1 500 043, GB 1 525 958, US 4 182 766, US 4 255 431 and US 4 599 347, BE 898880, EP 208452, EP 124495, EP 221041, EP 279149, EP 176308 and Dervent. reference 87-294449 / 42.

Benzimidazole derivatives provided for the treatment and prophylaxis of specific gastrointestinal inflammatory diseases, described in U.S. Patent 4,359,465.

Description of the present invention.

The compounds of Formula I are potent inhibitors of gastric juice secretion in mammals, including man, while not blocking the uptake of iodine by the thyroid gland. These compounds were also found to have high bioavailability. In addition, the compounds of the present invention have been found to exhibit high chemical stability in solutions having a neutral or acidic pH. The high chemical stability at acidic pH enables the compounds of the present invention to be used orally in the preparation of enteric-free compositions.

The compounds of the present invention have the formula I:

Wherein R and R are different and each may be H, alkyl having from 1 to 4 carbon atoms, or a -C (O) -R 0 group; furthermore one of R ¹ and R ^z must be -C (0) R ° group, where R ^ is an alkyl having 1-4 carbon atoms, or alkoxy with 1-4 carbon atoms.

7 7

R is a -CH2OCOOR group wherein R may be alkyl of 1-6 carbon atoms or benzyl;

R ⁴ and R ⁵ may be the same or different and may be selected from the group consisting of -CH 3, C ₂ H ₅ , -CH ₂ - (-CH ₂ -V) and -CH 2 CH 2 OCH 3; or R ⁴ and R ⁵ taken together with the adjacent oxygen atoms of '-O' attached to the pyridine ring and carbon atoms form a ring in this pyridine ring where R 'is CH ₂ CH ₂ CH ₂ , -CH ₂ CH ₂ -. ^{or CH} 2 It should be noted that alkyl and alkoxy are both straight and branched structures.

The structural isomers of the present invention described in Examples 1-6 can be used alone or in the form of mixtures with an equal or uneven composition of the components.

The compounds of formula I of the present invention have an asymmetric center in the sulfur atom, that is, they exist in the form of optical isomers (enantiomers), or, if these compounds also have one or more asymmetric carbon atoms, they may have two or more diastereoisomeric forms exists in the form of two enantiomers. It should be noted that the present invention encompasses both pure enantiomers and their racemic mixtures (50% of each enantiomer), as well as mixtures with an odd amount of said enantiomers. Thus, the present invention encompasses all possible forms of diastereomers (pure enantiomers or racemic mixtures).

Preferred compounds of formula I are:

Compounds wherein R 1 is -CH 2 OCOOCII 2 CH 3.

2. Compounds in which R and R ^z are selected from H, methyl, or -C (O) -R ° wherein R ° is an alkyl with 1-4 carbon atoms or alkoxy with 1-4 carbon atoms.

3. The following benzimidazole structures are particularly desirable:

4. Particularly preferred compounds wherein R ⁴ is also methyl.

5. Particularly preferred compounds of the present invention are listed in the table below:

R ¹ R ² R ³ R ⁴ R ⁵ ch ₃ qo) and ₃ CH ₂ OCOOCH ₂ CH ₃ ch ₃ ch ₃ C (O) OCH ₃ ΟΗς ch ₂ ocooch ₂ ch ₃ ch ₃ ch ₃ CH ₃ C (O) CH ₃ CH _? OCO ° C ^H 2 ^CH 3 ch ₃ ch ₃ C (O) CH _? ch ₃ ch _? ocooch ₂ ch ₃ ^ch 3 • ch ₃

It will be appreciated that in the metabolic process, the compounds of formula I may, prior to the action of these compounds, be converted to the corresponding compounds wherein R is H.

Preparation of compounds

The compounds of the present invention may be prepared by the following processes:

Z wherein R 1, R ² , R ⁴ and R ⁴ are as described above in formula I, and Z is either a metal cation such as Na ⁺ , K ⁺ , Zi ⁺ or Ag ⁺ , or a quaternary ammonium ion such as tetrabutylammonium. with alkyl chloromethyl carbonate or benzyl chloromethyl carbonate.

b) reacting a compound of formula II wherein R ¹ , R ² , R ⁴ and R ⁵ are as described above in formula I and Z is hydroxymethyl with a compound of formula III;

XC (O) -OR ⁷ wherein R is as described above and X is Cl, imidazole, p-nitrophenoxy or a functionally equivalent group in the presence of a suitable base such as triethylamine.

The reactions described in Examples a) and b) generally occur in the presence of a shielding gas and in the absence of water. Suitable solvents include hydrocarbons such as toluene or benzene; or halogenated hydrocarbons such as methylene chloride or chloroform; acetone; acetonitrile; or dimethylformamide. Said reactions may take place from room temperature to the boiling point of the reactant mixture.

c) In the presence of a compound of formula IV

OR ⁵

for an oxidation reaction wherein R

R ² , r ³ , R ⁴ and r ⁵ are as defined in formula I.

Ί

Said oxidation reaction may be carried out using an oxidizing agent such as nitric acid, hydrogen peroxide, if desired in the presence of vanadium compounds, acid, acid ether, nitrogen tetraoxide, iodobenzene, Nhalogensuccinimide, 1-chlorobenzotriazole, t , 2] -octane-bromine complex, sodium metaperiodate, selenium dioxide, manganese dioxide, chromic acid, cerium ammonium nitrate bromine, chlorine and sulfuryl chloride. The oxidation reaction usually takes place in a solvent such as halogenated hydrocarbons, alcohols, ethers and ketones.

The oxidation may also be carried out enzymatically, for example using an oxidizing enzyme, or microbiologically using the appropriate microorganism. The resulting structural isomers may be isolated by crystallization or chromatography.

The resulting racemates can be isolated by methods known in the art, for example by recrystallization from an optically active solvent. In the case of racemic mixtures of diastereomers, these may be separated into the pure enantiomers by chromatography or fractional crystallization.

In the above processes a) - c) some starting materials used are unknown. However, these materials may be obtained by methods known per se.

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

Intermediates of formula II wherein Z is hydroxymethyl are prepared by reaction of the corresponding benzylimidazole compound containing N-1 hydrogen with formaldehyde.

The starting materials of formula III may be prepared by methods known in the art, for example by treatment of 7 L of alcohol with HOR phosgene or 1,1-carbonyldiimidazole or pnitrophenyl chloroformate.

For clinical use, the compounds of the present invention may be formulated into pharmaceutical formulations for oral, rectal, parenteral or other administration. Said pharmaceutical formulations usually contain the active compounds in association with a pharmaceutically acceptable carrier. This carrier may be a solid, semi-solid or liquid diluent or capsule. The pharmaceutical preparations contemplated are also the subject of the present invention. The amount of active compound in such formulations generally ranges from 0.1 to 95% by weight. % by weight of the composition to 1-50% by weight. % for oral preparations within limits.

Pharmaceutical compositions containing the compounds of the present invention may be in the form of a single unit dosage form for oral administration. For this purpose, the compound selected is admixed with a solid, powdered carrier such as lactose, sucrose, sorbitol, mannitol, starch, amylopectin, cellulose derivatives, gelatin or other suitable carriers; with stabilizing agents such as Na, K, Ca, Mg and the like. carbonates, hydroxides or oxides, as well as wetting agents such as Mg stearate, Ca stearate, Na stearyl fumarate and polyethylene glycol. The mixture is then granulated and compressed into tablets. The granules and tablets may be coated with an enterosoluble coating to protect the active compound from catalytic acid degradation in the form of a pharmaceutical formulation in the stomach. The enteric coating material is selected from pharmaceutically acceptable materials commonly used for such applications, such as beeswax, shellac, or anionic film-forming polymers such as cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, partially methyl etherified, preferably with an appropriate plasticizer. Various dyes may be added to said coating to separate tablets or granules with various active compounds or with varying amounts of the active compound present.

Soft gelatine capsules may be prepared in the form of a capsule containing a mixture of the active compound and vegetable oil, fat or other suitable excipient commonly used in the manufacture of soft gelatine capsules. Soft gelatine capsules may also be enteric-coated as described above. The hard gelatine capsules may contain granules of the active compound coated with an enterosoluble coating. The hard gelatine capsules may also contain the active compound together with a solid powder carrier such as lactose, sucrose, sorbitol, mannitol, potato starch, amylopectin, cellulose or gelatin derivatives. Said hard gelatine capsules may be enteric-coated as described above.

Disposable dosage forms for rectal administration may be presented as suppositories, containing the active compound mixed with a neutral fat base, or in the form of gelatin rectal capsules containing the active compound mixed with vegetable oil, paraffin oil or another suitable filler commonly used for the manufacture of gelatin rectal capsules; or they may be obtained in the form of microclips ready for use; or they may be prepared in the form of microclimates in the form of dry compositions which are dissolved in the appropriate solvent just prior to administration.

Liquid compositions for oral administration may be in the form of syrups or suspensions, for example solutions or suspensions containing from 0.2 to 20% by weight. % active ingredient, and more consisting of a mixture of sugar or sugars and ethanol, water, glycerol, propylene glycol and / or polyethylene glycol. If desired, said liquid compositions may contain dyes, zequinine, carboxymethylcellulose and other thickening agents. Liquid oral formulations may also be presented as a dry powder which is dissolved in a suitable solvent before use.

The daily dose of the active compound depends on a variety of factors such as the individual needs of each patient, the route of administration and the disease. Generally, the oral dose of the active compound is between 5 and 500 mg per day.

The present invention is illustrated by the following examples:

An example.

5-carboxy-6-methyl-2 - [[(3,4-dimethoxy-2-pyridinyl) methyl] sulfinyl] -1 H -benzimidazol-1-ylmethyl ethyl carbonate and 6-carbomethoxy-5-methyl-2 - [[(3, Preparation of 4-dimethoxy-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazol-1-ylmethyl ethyl carbonate in the form of isomeric mixtures.

To a suspension of 0.45 g (1.1 mmol) of 5-carbmethoxy-6-methyl-2 - [[(3,4-dimethoxy-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazole and 0.25 g (1.8 mmol) of anhydrous potassium carbonate were added. 0.21 g (1.5 mmol) of chloromethylethyl carbonate dissolved in 5 ml of acetonitrile are added per ml of dry acetonitrile. The reaction mixture was stirred at room temperature overnight. The solvent was then removed in vacuo and the residue diluted with methylene chloride and water. The organic solvent was dried over anhydrous sodium sulfate. The solvent was removed in vacuo to give the crude product which was chromatographed on silica gel using ethyl acetate as eluent. 0.94 g of a yellow oil is obtained, which is crystallized immediately. Recrystallization from ethanol gave 0.25 g (44%) of the title compound as a mixture of isomers.

The NMR data of the resultant product are given below.

An example.

Preparation of 6-carbomethoxy-5-methyl-2 - [[(3,4-dimethoxy-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazol-1-ylmethyl ethyl carbonate

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

NMR data is provided below.

An example.

5-acetyl-6-methyl-2 - [[(3,4-dimethoxy-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazol-1-ylmethyl ethyl carbonate and 6-acetyl-5-methyl-2 - [[(3,4) - Dimethoxy-2-pyridinyl) methyl] sulfinyl] - 1 H -benzimidazol-1-ylmethyl ethyl carbonate in the form of isomeric mixtures.

To a suspension of anhydrous potassium carbonate (0.48 g, 3.47 mmol) in 80 mL of dry acetonitrile was added 0.80 g (2.14 mmol) of 5-acetyl-6-methyl-2 - [[(3,4-dimethoxy-2-pyridinyl) in a magnetic stirrer. methyl] sulfinyl] -ΪΗ-benzimidazole and 0.39 g (2.8 mmol) of chloromethylethyl carbonate dissolved in 10 ml of acetonitrile dropwise. It was then stirred at room temperature for 20 hours. The solvent was removed in vacuo, the residue diluted with methylene chloride and the methylene chloride solution was washed with water and dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the crude product obtained was chromatographed on silica gel using ethyl acetate as eluent. 0.63 g of an off-white crystalline solid is obtained. Recrystallization of the product from ethyl acetate gave 0.50 g (49%) of the title compound as a mixture of isomers.

The NMR data of the resulting product are given below.

An example.

Preparation of 5-acetyl-6-methyl-2 - [[(3,4-dimethoxy-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazol-1-ylmethyl ethyl carbonate

The title compound was isolated from the isomeric mixture described in Example 3 on a silica column eluting with a 6: 4 mixture of methylene chloride and acetonitrile. The title compound is crystallized from ethanol.

NMR data is provided below.

An example.

Preparation of 6-acetyl-5-methyl-2 - [[(3,4-dimethoxy-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazol-1-ylmethyl ethyl carbonate

The title compound is isolated from the isomeric mixture described in Example 3 on a column of silica eluting with a mixture of methylene chloride and acetonitrile (6: 4). The title compound is crystallized from ethanol.

NMR data is provided below.

An example.

5-Carboethoxy-2 - (((3,4-dimethoxy-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazol-1-ylmethyl-ethylcarbonate and 6-carboethoxy-2 - [[(3,4-dimethoxy-2-pyridinyl) ) Preparation of methyl] sulfinyl] - 1 H -benzimidazol-1-ylmethyl ethyl carbonate in the form of an isomeric mixture.

To a suspension of 0.28 g (0.72 mmol) of 5-carboethoxy-2 - [[(3,4-dimethoxy-2-pyridinyl) methyl] sulfinyl] - H -benzimidazole and 0.16 g (1.2 mmol) of anhydrous potassium carbonate in 20 ml of dry acetonitrile was added 0.16 g. g (1.2 mmol) of chloromethylethyl carbonate, dissolved

In 2 ml of dry acetonitrile. The mixture was stirred at room temperature overnight. The triturate was evaporated and the crude product obtained was chromatographed on a silica column eluting with ethyl acetate. Recrystallization of the product from ethanol gave 0.13 g (37%) of the title compound as a mixture of isomers.

The NMR data of the resultant product are given below.

Table

IP ⁷² · Solvent NMR data, parts per million 1. CDCs (300 MHz) 1.20-1.30 (m, 3H); 2.70 (s, 1.8H); 2.75 (s, 1.2H); 3.85-3.95 (m, 9H); 4.15-4.25 (m, 2H); 4.85-5.05 (m, 2H); 6.40-6.55 (m, 2H); 6.75 (d, 1H); 7.45 (s, 0.6H); 7.65 (s, 0.4 H); 8.10 (d, 1H); 8.40 (s, 0.4H); 8.40 (s, 0.6H). 2. CDCs (300 MHz) 1.30 (t, 3H); 2.70 (s, 3H); 3.90 (s, 3H); 3.90 (s, 3H) 3.95 (s, 3H); 4.25 (s. 2H); 4.95 (d, 1H); 5.05 (d, 1H); 6.50 (m, 2H); 6.75 (d, 1H); 7.65 (s, 1H); 8.10 (d, 1H); 8.20 (s, IH). 3. CDCs (300 MHz) 1.30 (t, 3H); 2.60-2.70 (m, 6H); 3.85-3.90 (m, 6H); 4.25 (kv, 2H); 4.85-5.05 (m, 2H); 6.75 (d, 1H); 7.45 (s, 0.7H); 7.60 (s, 0.3H); 8.05 (s, 0.3H); 8.10 (d, 1H); 8.20 (s, 0.7H). 4. CDCs (300 MHz) 1.30 (t, 3H); 2.60 (s, 3H); 2.70 (s, 3H); 3.90 (s, 3H); 4.20 (kv, 2H); 4.90 (d, 1H); 5.05 (d, 1H); 6.50 (m, 2H); 6.80 (d, 1H); 7.50 (s, 1H); 8.15 (d, 1H); 8.20 (s, 1H). 5. CDCL (300 MHz) 1.30 (t, 3H); 2.60 (s, 3H); 2.70 (s, 3H); 3.90 (s, 3H); 3.90 (s, 3H); 4.25 (kv, 2H); 4.90 (d, 1H); 5.05 (d, 1H); 6.55 (m, 2H); 6.80 (d, 1H); 7.60 (s, 1H); 8.05 (s, 1H); 8.15 (d, IH). 6th CDCs (300 MHz) 1.30 (m, 3H); 1.45 (m, 3H); 3.90 (s, 3H); 3.90 (s, 3H); 4.25 (m, 2H); 4.45 (m, 2H); 5.00 (m, 2H); 6.55 (m, 2H); 6.8L (d, 1H); 7.70 (d, 0.55H); 7.8L (d, 0.45H); 8.10 (m, 2H); 8.35 (s, 0.45H); 8.50 (d, 0.55H).

Preparation of Intermediates

An example

Preparation of 5-carbomethoxy-6-methyl-2 - [[{3,4-dimethoxy-2-pyridinyl) methyl] thio] -benzimidazole

5-Carboethoxy-6-methyl-2-mercapto-1 H -benzimidazole (0.67 g, 0.003 mol) and NaOH (0.12 g, 0.003 mol) in water (0.6 mL) were dissolved in CH ₃ OH (15 mL). After that added

3,4-Dimethoxy-2-chloromethylpyridine hydrochloride (= 0.0036 mol) as crude material in 10 ml CH ₃ OH and NaOH (0.144 g, 0.0036 mol) in water (0.72 ml). The mixture was heated to distillation temperature and refluxed for 1 hour. The CH ₃ OH was evaporated and the crude material was purified on a silica column eluting with CH ₂ Cl ₂ -CH ₃ OH (98-2) to give the pure title compound (1.03 g, 92%).

NMR data is provided below.

Example 1.2

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). NaHCO (0.46 g, 0.0055 mol) in water (10 mL) was added and the mixture was cooled to + 2 ° C. Then 69.5% m-chloroperbenzoic acid (0.62 g, 0.0025 mol) dissolved in CH ₂ Cl ₂ (5 mL) was added dropwise and stirred, followed by stirring again at + 2 ° C for 15 minutes. After separation, the organic layer was extracted with 0.2 M NaOH (3 x 15 mL, 0.009 mol) in aqueous solution. After separation, the aqueous solutions were combined and neutralized with methyl formate (0.56 mL, 0.009 mol) in the presence of CH ₂ Cl ₂ (25 mL). The organic layer was then 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%).

NMR data is provided below.

1.3 Example

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

5-Acetyl-6-methyl-2-mercapto-1 H -benzimidazole (4.2 g, 20 mmol) and NaOH (0.8 g, 20 mmol) were dissolved in water (1 mL) in 60 mL ethanol. 3,4-Dimethoxy-2-chloromethylpyridine hydrochloride (~ 17 mol) was added in the form of a crude product and the mixture was heated to reflux. NaOH (0.7 g, 17 mmol) in water (1 mL) 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 Na ₂ SO ₄ , and the solvent was evaporated under reduced pressure. Crystallization from acetonitrile gave the title compound (3.75 g, 62%).

NMR data is provided below.

Example 1.4

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). NaHCO ₃ (1.76 g, 21 mmol) in water (25 mL) was added and the mixture was cooled to + 3 ° C. Then 69.5% m-chloroperbenzoic acid (2.43 g, 9.8 mmol) dissolved in CH ₂ Cl ₂ (20 mL) was added dropwise and with stirring. It was then stirred again for 10 minutes. The phases were separated and the organic phase was dried over Na ₂ SO and evaporated under reduced pressure. The residue was crystallized from CH ₃ CN to give the title compound (2.25 g, 60%).

NMR data is provided below.

1.5 Example

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

5-Carbethoxy-2-mercapto-1 H -benzimidazole (2.0 g, 9 mmol) and NaOH (0.36 g, 9 mmol) were dissolved in water (1 mL) in ethanol (30 mL). 3,4-Dimethoxy-2 chloromethylpyridine hydrochloride (-6.6 mmol) was added in the form of a crude material and the mixture was heated to reflux. NaOH (0.26 g, 6.6 mmol) in water (1 mL) was then 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 Na ₂ SO ₄ and the solvent removed under reduced pressure. Crystallization from CH ₃ CN gave the title compound (1.75 g, 71%).

NMR data is provided below.

1.6 Example

Preparation of 5-carbetoxy-2 - [[(3,4-dimethoxy-2-pyridinyl) methylsulfinyl] -1H-benzimidazole

5-Carbetoxy-2 - [[(3,4-dimethoxy-2-pyridinyl) methyl] thio] -1H-benzimidazole (95.2% pure) (1.4 g, 0.0036 mmol) was dissolved in CH ₂ Cl ₂ (30 mL). NaHCO ₃ (0.6 g, 0.0072 mmol) in water (10 mL) was added and the mixture was cooled to + 2 ° C. Then 69.5% m-chloroperbenzoic acid (0.87 g, 0.0035 M) dissolved in CH ₂ Cl ₂ (5 mL) was added dropwise and with stirring. It was then stirred again for 10 minutes at + 2 ° C. The phases were separated and the organic phase was 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%).

NMR data is provided below.

Table

j Eg. Solvent NMR data, δ million. 1.1 cdci ₃ (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).

1.2 CDCl ₃ (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 (pi. 1H); 8.20 (d, 1H); 8.35 (pi. 1H). 1.3 cdci ₃ (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, 0.6 H); 7.40 (s, 0.4H); 7.85 (s, 0.4 H); 8.05 (s, 0.6H); 8.30 (m, 1H). 1.4 cdci ₃ (300 MHz) 2.60 (s, 6H); 3.85 (s, 3H); 3.85 (s, 3H); 4.70 (d, 1H); 4.80 (d, 1H); 6.80 (d, 1H); 7.30 (pi, 1H); 8.15 (d, 1H); 8.20 (pt, 1H). 1.5 cdci ₃ (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). 1.6 CDCl3 (300 MHz) 1.45 (t, 3H); 3.85 (s, 3H); 3.90 (s, 3H); 4.40 (s, 2H); 4.65 (d, 1H); 4.40 (d, 1H); 6.80 (d, 1H); 7.50, 7.80 (pl. 1H); 8.05 (d, 1H); 8.20 (d, 1H); 8.25, 8.55 (pi. 1H).

A preferred embodiment of the present invention is the use of a mixture of the compound of Example 3 and the compound of Example 4.

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Syrup

Syrup, containing 1% (m / v) of the active compound, obtained from the following ingredients:

Compound according to Example 4 1.0 g

Sugar powder 30.0 g

Saccharin 0.6 g

Glycerin 5.0 g

Twain 1.0 g

Aromatics 0.05 g

Ethanol 96% 5.0 g

Distilled water (as necessary) up to 100 ml

A solution of a mixture of the compound of Example 4 in ethanol and Tvine was obtained. Sugar and saccharin are dissolved in 60 g of warm water. After cooling, a solution of the active compound was added to the sugar and glycerol solution and flavorings dissolved in ethanol were added. The mixture was diluted to 100 ml with water. quantity.

Pills

Tablets containing 50 mg of active compound obtained from the following ingredients:

A mixture of the compound of Example 3 500 g

Lactose 700 g

Methyl cellulose 6 g

Cross-stitched polyvinylpyrrolidone 50 g Magnesium stearate 15 g

Sodium carbonate 6 g

distilled water

Π Hydroxypopylmethylcellulose Polyethylene glycol Colored titanium dioxide Purified water sufficient amount g 19g 4g 313 g

The mixture of the compound of Example 3 in powder form was mixed with lactose and granulated using an aqueous solution of methylcellulose and sodium carbonate. The untreated mass was passed through a sieve and the resulting granulate was oven dried. After drying, the granulate was mixed with polyvinylpyrrolidone and magnesium stearate. The dry mixture was compressed into tablets (i.e., kernels per 10,000 tablets), each containing 50 mg of the active compound, in a tabletting machine using a 7 mm diameter form.

II A solution of hydroxypropylmethylcellulose and polyethylene glycol in purified water was obtained. After dispersing the titanium dioxide, the solution was sprayed onto tablets I, p

using a coating unit in Acella Cota, Manesty.

The final tablet weight is 125 mg.

Capsules

Capsules containing 30 mg of active compound obtained from the following ingredients:

Compounds of Example 4 300 g

Lactose 700 g

Microcrystalline cellulose 40 g

Slightly modified hydroxypropylcellulose 62 g

Purified water in sufficient quantity

The active compound mixture was mixed with the dry ingredients and granulated using disodium bisphosphate solution. The wet mass was passed through an extruder, formed into balls and dried in a fluid bed dryer.

500 g of the resulting granules were coated with a solution of hydroxymethylcellulose (30 g) in water (600 g) using a fluid bed coater. After drying, the granules are coated with a second layer, which is described below:

Coating solution:

Hydroxypropylmethylcellulose phthalate 70 g Cetyl alcohol 4 g

Acetone 200 g

Ethanol 600 g

Finally, the coated granules are contained in capsules.

Suppositories

Using the welding procedure, from the ingredients listed below; suppositories received; each suppository contained 40 mg of the active compound.

Compounds of Example 4 4 g

Witepsol H-15 180 g

The active compound was mixed with Witepsol H-15 to homogeneity at 41 ° C. The resulting melted mass filled pre-filled suppository packages of a net weight of 1.84 g. After heating, the packages are hermetically sealed by heat welding. Each suppository contained 40 mg of active ingredient.

Biological action

Bioavailability

Bioavailability was assessed by plotting the area under the concentration-response curve of a compound of formula I (hereinafter referred to as Compound A) wherein R is H in plasma (AUC) after: and 2) intravenous (iv) administration of Compound A in rats and dogs. Low, therapeutically acceptable doses were used. The data obtained are shown in Table 4.

Ability to inhibit acid secretion

The ability to inhibit acid secretion was measured in female rats by oral administration and in dogs by oral and intraduodenal administration. The results obtained are shown in Table 4.

Effect on thyroid uptake of iodine

Effects of the compounds of formula I of the present invention on the uptake of iodine by the thyroid gland i

determined by the action of a compound of formula I wherein R is H and a metabolite of another compound of formula I on J accumulation in the thyroid gland.

Biological tests

Inhibition of gastric acid secretion in female rats without anesthesia

Female rats of the Sprague-Dawley strain were used in the experiment. To collect gastric juice in these rats into the gastric cavity. cannulae introduced. The study was initiated 14 days after cannula administration.

Animals are allowed 20 hours prior to the start of the gastric acid secretion test. only water is given. The stomach was periodically flushed through the cannula and 6.0 ml of Ringer's-Glucose solution was injected subcutaneously (s c). Acid secretion stimulated, 2.5 hrs. (1.2 ml / h, s c) with pentagastrin and carbachol (20 and 110 nmol / kg, respectively) and every 30 minutes thereafter. gastric secretory fractions were collected. 120 minutes from the onset of stimulation, orally (p o) administer 5 ml / kg of test compound or vehicle. Samples of gastric juice were titrated to pH 7.0 using NaOH 0.1 mol / l and the acid yield was determined as the volume product and the concentration of the titrated solution. Poto subtracted mean response values for a group of 4-7 rats. Percent inhibition was calculated based on absolute rates of acid release. The ED ^ p values were obtained as a result of graphical dose-response interpolation of the logarithmic curves, or as a result of single dose experiments, assuming that all dose-response curves have equal slope angles. The results were obtained on the basis of gastric acid secretion produced during the second hour after administration of the drug or the filler.

Bioavailability studies in male rats

Male rats of the Sprague-Dawley strain were used in these experiments. One day before the experiments, all rats were cannulated into the left carotid artery (with anesthesia). Rats used in experiments with intravenous administration of the substance were additionally cannulated into the jugular vein (v. Jugularis) (see Popovic and Popovic. J. Appl. Physiol. 1960, 15,727-726). the cannula was introduced into the upper duodenal region. These cannulae are brought to the surface near the neck. After this operation, rats were housed in separate cages and water-fed prior to administration of the test compounds. Test compounds were administered intravenously and intraduodenally at a single dose (4 mmol / kg) in a bolus of approximately 1 min. (2 ml / kg). Blood samples (0.1-0.4 g) were taken periodically from the carotid artery over a period of 4 hours following dosing. These samples were kept frozen as far as possible until analysis of the test compound.

Areas under the concentration-time curve (AUC) curve were calculated from the linear trapezoidal formula and extrapolated to infinity by dividing the last observed concentration of the substance in the blood by the terminal elimination rate constant.

Systemic bioavailability (F%) after intraduodenal administration was calculated as follows:

AUC (compound A) id (compound of the present invention) _{F% ae} - _x100

AUC (compound A) i v (compound A)

Inhibition of gastric acid secretion and bioavailability in non-anesthetized dogs

Harrier dogs of both genders were used in the experiments. For these dogs, duodenal openings with a Heidenhain pocket for collecting gastric juice were made to administer the test compound or the filler.

Prior to the gastric acid secretion test, the animals are fasted for approximately 18 hours without any restriction for oral administration. Stomach acid secretion stimulated, 4 hours. administering histamine dihydrochloride (12 ml / h); this is the dose that elicits approximately 80% of the maximal secretory response of the animal, and the gastric juice fractions are collected every 30 minutes. 0.5 mL / kg body weight of test compound or vehicle administered orally, intraduodenally, or intravenously to animals from the start of histamine administration. It should be noted that, when administered orally, the test compound was introduced into the acid-secreting stomach body of dogs with a Heidenhain pocket.

The acidity of the gastric juice samples was determined by titration to pH 7.0 by calculating the acid yield. Acid yield during collection periods after administration of test compound or filler is expressed as partial responses, calculated as acid release in fraction prior to compound administration as 1.0. Percent inhibition was determined by taking into account the partial responses obtained after administration of the test compound or the vehicle. ED ^ q - values obtained from the dose response graph of the logarithmic graph or by estimating the result of single dose experiments, assuming that all dose-response curves have the same slope angle. All results were obtained in 2 h acid yield. on a post-dose basis.

Blood samples were taken at intervals for analysis of plasma concentration of test compound for 3 hours. during the dose administration. Plasma separated and frozen for 30 min. after collection and then analyzed, AUC (area under the concentration-time curve) (0-3 h after compound A administration) was calculated using a linear trapezoidal formula. The systemic bioavailability (F%) of Compound A after oral or paraneral administration of the compounds of this invention was calculated according to the procedure described above in rat studies.

125

Effect on I accumulation in the thyroid gland

The accumulation of 1 ^σ 5τ in the thyroid gland was studied in male rats of the Sprague-Dawley strain, which were deprived of food for 24 hours. until the start of the experiments. The experiment was performed according to Searle CE et al. (Biochem. J 1950, 47; 77-81), which is as follows:

Test compounds were suspended in 0.5% buffer (pH 9) methylcellulose and administered orally by gavage at 5 ml / kg body weight. After 1 or. injection into the abdomen was ¹² µl (300 kBkkg, 3 ml / kg). 4 hours later after the introduction of ¹² ^ I, the animals were killed by causing COj asphyxia and bleeding. The thyroid gland, with a portion of the trachea, was then dissected and placed in a small tube for radioactivity analysis using a γ-ray counter (LKB-Wallar model 1282 Compugamhea). The percent inhibition was calculated using the formula 100 (1-T / P), where T and P are the mean values of the radioactivity of the animal's thyroid gland exposed to the test compound and the placebo of the corresponding methylcellulose buffer. Statistical reliability of the difference between the results of animals treated with the test compound and placebo is assessed using the two-sided MamWhitney U-criterion. A value of P <0.05 was considered significant.

Chemical stability

The chemical stability of the compound of the present invention was tested kinetically at low concentration and at 37 ° C in aqueous buffer at various pH. The results are shown in Table 4, showing the degradation half-life (t / 2) at pH 7, i.e.. the time interval after which half of the parent compound remained unchanged; and 10% at pH 2, i.e. the time interval after which 10% of the parent compound remained unchanged.

The bioassay and stability assay results, and Table 5 summarizes the biological assay and stability assay results for the compounds of this invention.

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Claims (16)

DEFINITION OF INVENTION 1. Compounds of formula I: wherein R ¹ and R ² are different and may each be H, alkyl of 1-4 carbon atoms, or a -C (O) -R ⁶ group; in addition, one of R ¹ and R ² must necessarily be a -C (O) -R ⁶ group in which R ⁶ is an alkyl group of 1 to 4 atoms or an alkoxy group of 1 to 4 carbon atoms. R ³ is a -CH ² OCOOR ⁷ group wherein R ⁷ may be alkyl of 1-6 carbon atoms or benzyl; -CH < R ⁴ and R ⁵ may be the same or different, and may be selected from the group consisting of -CH ₃ , -ch ₂ <°> -C 2 H 5, \ 1, ^λ -o ^7, and -CH 2 CH 2 OCH 3; or R ⁴ and R ⁵ together with neighboring oxygen atoms attached to the pyridine ring and carbon atoms in this pyridine ring form a ring wherein the portion formed by R ⁴ and R ³ 'is CH ₂ CH ₂ CH ₂ -, -CH ₂ CH ₂ - or -CH ₂ -. Compounds of formula I according to claim 1, characterized in that they are as 5-carbomethoxy-6-methyl-2 - [[(3,4-dimethoxy-2-pyridinyl) methyl] sulfinyl] - 1 H -benzimidazol-1-ylmethylethyl carbonate and 6-carbomethoxy A mixture of -5-methyl-2 - [[(3,4-dimethoxy-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazol-1-ylmethyl ethyl carbonate. Compounds of formula I according to claim 1, characterized in that they are as 5-acetyl-6-methyl-2 - [[(3,4-dimethoxy-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazol-1-ylmethyl ethylcarbonate and 6-acetyl A mixture of -5-methyl-2 - [[(3,4-dimethoxy-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazol-1-ylmethyl ethyl carbonate. 4. A compound according to claim 1, which is 5-carbomethoxy-6-methyl-2 - [[(3,4-dimethoxy-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazol-ylmethylethylcarbonate. 5. A compound according to claim 1, which is 6-carbomethoxy-5-methyl-2 - [[(3,4-dimethoxy-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazol-ylmethylethylcarbonate. 6. A compound according to claim 1, which is 5-acetyl-6-methyl-2 - [[(3,4-dimethoxy-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazol-1-ylmethyl ethyl carbonate, 7. A compound according to claim 1, which is 6-acetyl-5-methyl-2 - [[(3,4-dimethoxy-2-pyridinyl) methyl] sulfmyl] -1H-benzimidazol-1-ylmethyl ethyl carbonate. 8. A compound of the formula I as claimed in claim 1, wherein R ³ is -CH ² OCOOR ⁷ . 9. A compound according to claim 1, wherein R ¹ and R ^{2 are} each H, methyl -C (O) -R ⁶ ; wherein R ⁶ is an alkyl group containing from 1 to 4 carbon atoms or an alkoxy group containing from 1 to 4 carbon atoms. 10. A pharmaceutical composition comprising the compound of claim 1 as the active ingredient. A compound according to claim 1 for use in therapy. A compound according to claim 1 for inhibiting gastric juice secretion in a mammal, including a human. A compound according to claim 1 for 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 juice 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 diseases of the gastrointestinal tract in a mammal, including a human. 16. A process for the preparation of a compound of formula I according to claim 1, characterized in that: (a) Compound of Formula II: wherein R ¹ , R ² , R ⁴ and R ⁵ are as described above in formula I, and Z is either a metal cation such as Na ⁺ , K ⁺ , Li ⁺ and Ag ⁺ or a quaternary ammonium ion such as as tetrabutylammonium, reacts with alkyl chloromethyl carbonate or benzyl chloromethyl carbonate; or b) A compound of formula II wherein R ¹ , R ² , R ⁴ and R ⁵ are as defined above in formula I and Z is hydroxymethyl is reacted with a compound of formula III: XC (O) -OR ⁷ (III) wherein R ⁷ is as described above and X is Cl or an imidazole or pnitrobenzyloxy group or a functionally equivalent group in the presence of a suitable base such as triethylamine; or (c) executed by compound compound IV: (IV), an oxidation reaction wherein R ¹ , R ² , R ³ , R ⁴ and R ^{5 have} the meanings given for the formula