SK5896A3 - Substituted benzimideazoles - Google Patents

Description

This invention relates to novel compounds of high optical purity, to their use in medicine, to a process for their manufacture and to their use in the manufacture of pharmaceutical compositions. The present invention also relates to novel intermediates for the preparation of these compounds of the invention.

BACKGROUND OF THE INVENTION

The compound 5-fluoro-2 - [[(4-cyclopropylmethoxy-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazole, and therapeutically acceptable salts thereof, are described in US-A 5,008,278, and EP 90901079.5. These compounds, and therapeutically acceptable salts thereof, are effective in inhibiting welting secretion in the stomach and are useful as anti-gastric ulcer agents. These sulfoxide compounds have an asymmetric center on the sulfur atom, i.e. they exist as two optical isomers (enantiomers). This is desirable to improve their pharmacological and metabolic properties, which are desirable to improve their therapeutic profile. The present invention provides such compounds having novel salts of selected 5-fluoro-2 - [(4-cyclopropylmethoxy-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazole enantiomers as well as the novel single enantiomers in neutral form.

Separation of enantiomers of therapeutically active sulfoxides such as substituted bezimidazoles, for example omeprazole (5-methoxy-2 - [(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl / sulfinyl] -ΙΗ-benzimidazole) on a preparative scale is described in ⁵ J. Chromatography, 532 (1990) _f 305-19. This isolation of the individual enantiomers of the sulfoxide reagents Ro 18-5364 is described in Euro J. Biochem. 166 (1987) 453-459). In addition, the separation of the enantiomers of omeprazole and its preparation step is described in DE 4035455. The latter preparation was carried out using a diastereomeric ether which was separated and then hydrolyzed in an acidic solution. Under the acidic conditions required for the hydrolysis of the attached group, the active omeprazole compound requires that the medium be rapidly neutralized with a base to prevent degradation of the acid-sensitive compound.

The above-mentioned efforts to prevent degradation of the resulting compound are accomplished by adding a concentrated NaOH solution to the reaction mixture containing concentrated sulfuric acid. This is advantageous because it is very risky that under these local conditions the pH reaches values between 1-6 and this can lead to the destruction of the compound. In addition, immediate neutralization causes heating that is difficult to control in a large production area.

The present invention also provides novel methods for preparing the novel compounds of the invention in a broad field and new aspects of this preparation. These new methods can be used in a wide field to obtain separate enantiomers of the compounds of the invention in neutral form as well as pharmaceutically acceptable salts.

These novel compounds of the invention, which are sulfoxides, can be expected to undergo racemization at neutral pH as well as in a basic environment. By way of example, Brandstrom et al. Acta Chemica Scandinavica 43 (1989) p 536-547. It is expected that the new enantiomers of the present invention, 5-fluoro-2 - [(4-cyclopropylmethoxy-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazole, as well as their therapeutically acceptable salts, will lead to sustained racemization.

It is not a known example of the prior art, nor is their isolation or characteristic individual enantiomers of the compounds of the invention. Likewise, the inventors are not aware that any of the isolated salts of the individual enantiomers and any of them described in the press or claimed elsewhere are described in the scientific literature.

SUMMARY OF THE INVENTION

The present invention is directed to novel individual enantiomers

5-fluoro-2 - [(4-cyclopropylmethoxy-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazole, which contact compounds Ia and Ib

(1a, Ib) 1a (+) - enantiomer Ib (-) - enantiomer as well as therapeutically acceptable salts thereof. Such salts are, for example, Na ⁺ , Mg ²⁺ , Ca ²⁺ , Li ⁺ , K ⁺ and N ⁺ , (R) ₄ salts of the individual enantiomers of said compounds, wherein R is an alkyl group having 1-4 carbon atoms, i.e. (+ ) -5-fluoro-2 - [(4-cyclopropylmethoxy-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazole and (-) - 5-fluoro-2 - [(4-cyclopropylmethoxy-2-pyridinyl) methyl] (sulfinyl) -1H-benzimidazole, such as Na ⁺ ,

Mg ²⁺ , Ca ²⁺ , Li ⁺ , K ⁺ and N ⁺ , (R) ₄ salts of the individual enantiomers of said compounds, wherein R is an alkyl group of 1-4 carbon atoms.

Particularly preferred salts of the compounds of this invention are the Na ⁺ , Mg ²⁺ , Ca ²⁺ salts and the individual enantiomers of -5-fluoro-2 - [(4-cyclopropylmethoxy-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazole.

The most preferred compounds of the invention are optically pure Na ⁺ salts of -5-fluoro-2 - [[(4-cyclopropylmethoxy-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazole relating to compounds IIa and IIb

(Ha, Ilb)

Ha (+) -enantiomer IIb (-) - enantiomer and optically pure magnesium salts of said compounds having the formula IIIa and IIIb

(Hla, Illb)

IIIa (+) - enantiomer Illb (-) - enantiomer

Interpretation of an optically pure compound of the invention means the (+) - enantiomer of said compound in the essential free form which is in accordance with the (-) enantiomer and the (-) - enantiomer in the essential form in accordance with the (+) - enantiomer and vice versa. Thus, each individual compound of the invention is obtained in high optical purity. That is, a new specific method pertaining to this aspect of the invention, i. the preparation of the individual enantiomers of the compounds of the invention is readily practicable. In addition, as mentioned above, the novel optically pure compounds are stable towards racemization in a neutral environment as well as a basic environment. Since then, an unexpected mechanism of degrading reactions in the neutral environment of these types of sulfoxides (omeprazole analogs) containing reversible reactions by means of achiral intermediates has been established. (Brandstrom et al., Acta Chemica Scandinavica 43 (1989) p 536-547, p 538). Obviously, such a reversible reaction from achiral intermediates to the sulfoxide may be the cause of the racemic product. Also, the new optically pure compounds are stable against racemization in an alkaline environment that were unexpected. Since then, the known deprotonation of the carbon atom between the pyridine ring and the chiral sulfur atom will cause racemization under alkaline conditions. This high stability to racemization in neutral and basic environments makes it possible to use the individual enantiomers of the compounds of the invention in neutral form as well as their therapeutic salts.

A specific method of making the individual enantiomers of the compounds of the invention is also the aspect of the invention mentioned above, and this can be used to obtain the individual enantiomeric compounds in neutral form as well as their salts.

The individual enantiomers of the compounds of the invention, like the racemates, exhibit extremely high biological activity, and the prior art compounds are very effective as inhibitors of gastric acid secretion and exhibit high chemical stability in a neutral pH solution.

The compounds of this invention can be used to inhibit gastric acid secretion in mammals and humans. In a more general sense, the individual enantiomers of the compounds of the invention can be used to treat diseases related to intestinal disorders in inflammatory diseases in mammals and humans, such as gastric ulcers, duodenal ulcers, esophagitis and gastritis. Such compounds can be used to treat other gastric disorders where gastric antisecretory effect is suitable, i. in patients with NSAID therapy, in patients with gastrinoma, and in patients with acute upper gastric bleeding. They can also be used in patients with a condition that is conditioned by special care and suppuration. Also, such compounds of the invention may be used for the treatment or prophylaxis of inflammatory diseases in mammals, including humans, in particular these include lysozyme enzymes. Conditionally it may be rheumatoid arthritis and gout. The compounds of the invention may be used for both psoriasis and helicobacterial infection.

An aspect of the invention is also applied in diasteromeric mixtures, regioisomeric mixtures having the formula IV, which is an intermediate used in a specific preparation method, wherein the fluoro substituent in the benzimidazole is in the 5 or 6 position.

The optically pure compounds of the invention, i.e. the individual enantiomers, are produced by separation of stereoisomers

I diastereomeric mixtures, regioisometric mixtures of type 5- and

6-Fluoro-2 - [(4-cyclopropylmethoxy-2-pyridinyl) methyl- (R / S) - (sulfinyl) -1H-benzimidazole]

wherein the fluorine substituent in the benzimidazole is in the 5 or 6 position, and wherein the acyl radical is also defined below, by subsequent solvolysis of one of the separated diastereoisomers in an alkaline solution. The individual enantiomers of the compounds of the invention formed in neutral form are then neutralized with aqueous solutions of salts called compounds with a neutralizing agent, which may be an acid or an ester such as methyl formate.

The acyl in the diastereoisometric esters may be a chiral acyl group such as mandloyl and the asymmetric center in the chiral acyl group may have the R or S configuration.

The diastereomeric esters may be separated either by chromatography or fractional crystallization.

Solvolysis is performed with a base in protic solvents such as alcohols or water, or which is a base in acetonitrile / water mixtures, but the acyl group can also be hydrolyzed in an aprotic solution which is dimethylsulfoxide or dimethylformamide. The reaction principle can be OH, or R ¹ 0 'wherein R ¹ may be alkyl or aryl.

To obtain which are the Na ⁺ salts of the invention and the ultimate base which is or with NaOR ² , wherein the R ² optically pure Na ⁺ salts of the invention, the individual enantiomeric compounds of the compound in neutral form are treated with NaOH in aqueous or anhydrous medium is an alkyl group containing 1-4 carbon atoms, or with NaNH ₂ . Also, alkali salts wherein the cation is Li ⁺ or K ⁺ can be prepared using lithium or potassium salts of the above bases. In the obtained ordered crystalline form of the individual enantiomers of the Na ⁺ salts, an optically pure amorphous Na ⁺ salt powder is added a mixture of 2-butanone and toluene. The crystalline form of the individual enantiomers of the Na ⁺ salts may also be prepared by adding NaOH to a mixture of the individual enantiomeric compounds of the invention in neutral form and with an anhydrous medium which is 2-butanone and toluene.

To obtain the optically pure Mg ²⁺ salts of the invention, the optically pure compounds of the invention in neutral form are treated with a base which is Mg (OR ³ ) 2, wherein R ³ is an alkyl group containing 1-4 carbon atoms in an anhydrous solvent such as alcohol (for alcoholates only), i.e. ROH, or in an ether such as tetrahydrofuran. Optically pure Mg ²⁺ salts can also be prepared by treating individual enantiomeric compounds of the invention, such as sodium salts with an aqueous solution of inorganic magnesium salts such as MgCl 2, where the Mg ²⁺ salts are precipitates. In an analogous manner, also alkali salts where the cation is Ca ²⁺ can be prepared by using an aqueous solution of inorganic calcium salts such as CaCl _2.

The alkali salts of the individual enantiomers of the invention mentioned above, except the sodium salts (compounds IIa and IIb) and the magnesium salts (compounds IIIa and IIIb), for example, their salts with Li ⁺ , K ⁺ , Ca ²⁺ and N ⁺ (R) ₄ , wherein R is an alkyl group having 1-4 carbon atoms.

For the clinical use of the individual enantiomers of the optically active compounds of the invention, these are comprised in pharmaceutical compositions for oral, rectal, parenteral or other modes of administration. The pharmaceutical compositions comprise the individual enantiomers of the invention in combination with pharmaceutically acceptable carriers. The carriers may be in the form of a solid, or a liquid solution, or capsules. These pharmaceutical compositions and preparations are the subject of the invention. The usual amount of active compound is between 0.1-95% by weight of the formulated medicament, between 0.2-20% by weight in the formulated medicament for parenteral use, and between 1-50% by weight in the formulation for oral administration.

The active compound with high solubility in water is desirable for parenteral treatment, it is suitable for oral treatment of active compounds with low solubility.

In the preparation of pharmaceutical compositions in dosage unit form for oral administration, the pure enantiomeric compound may be admixed with a solid powdered carrier such as lactose, sucrose, sorbitol, mannitol, starch, amylopectin, cellulose derivatives, gelatin, or other suitable carriers, stabilizing agents such as are alkaline compounds, carbonates, hydroxides and oxides of sodium, magnesium, potassium, calcium, lubricating agents such as magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethylene glycol waxes. The mixture is then converted into granules or compressed into tablets. Granules and tablets may be coated with an enteric coating to protect the active ingredient from acid catalyzed degradation as long as the dosage form remains in the stomach. The tablet coating is selected from pharmaceuticals such as beeswax, shellac, or polymers and the like, particularly preferred in combination with a suitable plasticizer. Various colorants may be added to the coatings to differentiate between tablets or granules with different amounts of the active ingredient.

acceptable materials, anionic films forming

Soft gelatin capsules can be made as capsules containing a mixture of the active compounds, vegetable oils, starch, or other acceptable vehicles for light gelatin capsules. The light gelatin capsules may also be enteric-coated as described above.

Hard gelatin capsules may contain granules or enteric coated granules of the active ingredients. Heavy gelatin capsules may also contain the active compounds in combination with solid powder carriers such as lactose, sucrose, sorbitol, mannitol, amylopectin, potato starch, cellulose derivatives, or gelatin. The capsules may be enteric-coated as described above.

The dosage unit for rectal administration may be presented in the form of suppositories containing active mixtures of neutral fat-based substances, or it may be prepared in the form of gelatin capsules for rectal administration containing the active ingredients in a mixture with vegetable oil, paraffin oil, or other acceptable vehicle. , for gelatin capsules, or may be prepared in the form of dry microclysis, reconstituted in acceptable solutions, just prior to administration.

The liquid preparation for oral administration can be prepared in the form of syrups or suspensions, i.e. solutions or suspensions containing from 0.2% to 20% by weight of the active ingredients, or sugar alcohols and a mixture of ethanol, water glycerol, propylene glycol and / or polyethylene glycol. If desired, such liquid compositions may contain coloring agents, saccharin and carboxymethyl cellulose, or other agents. The aqueous preparation for oral administration can be prepared in the form of a dry powder and is made into an acceptable solution prior to administration.

vials ready

Solutions for parenteral administration may be prepared as solutions of the optically pure compounds of the invention in pharmaceutically acceptable solutions, in particular at a concentration of from 0.1 to 10% by weight. These compounds may also contain stabilizing agents and / or buffers and may be prepared in different dosage forms, ampoules or solutions for parenteral administration may be presented as dry preparations and formulated with a suitable solvent prior to use. The typical daily dose of the active compounds will depend on various factors, such as the individual condition of the patient, the mode of administration, and the disease being treated. In general, oral and parenteral doses will range from 5 to 500 mg of active ingredient per day.

The invention is illustrated by the following examples.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

Preparation of (+) -5-fluoro-2 - [(4-cyclopropylmethoxy-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazole

Crude products of diastereomeric compounds of the two regioisomeric mandelic esters, in particular 5-fluoro-2 - [(4-cyclopropylmethoxy-2-pyridinyl) methyl- (R / S) - (sulfinyl) -1- ((R) -mandeloxymethyl)] -1H-benzimidazole and 6-fluoro-2 - [(4-cyclopropylmethoxy-2-pyridinyl) methyl- (R / S) - (sulfinyl) -1-] (R) -mandeloxymethyl] -1H-benzimidazole ( 5 g (9.8 mmol) were separated in five portions and each portion was chromatographed on the opposite column (HLPC, Kromasil C8) in the order of separated diastereomers. These stereoisomers were more readily separable with an aqueous elution mixture of 0.1 M ammonium acetate and acetonitrile (67.5 / 32.5). However, each separated diastereomer consists of a mixture of two regioisomers. These intermediates directly in their solutions during the hydrolytic acetonitrile / aqueous solution of the lipophilic diastereomer were added 1 M aqueous NaOH solution in which the pH was about 12-13. After five minutes, the solution was neutralized with a 3.0 molar aqueous solution of NH ₄ Cl, and then each was combined and extracted with methylene chloride. The organic phases were dried over Na ₂ SO ₄ and the solvent was removed by thin layer evaporation. Addition of 30 ml of acetonitrile yielded a crystallization product and after filtration 260 mg (16%) of the title compound were obtained as white crystals, m.p. 152-154 ° C. The optical purity that was analyzed was applied to the procedure. By chiral chromatography column, 99.2 = + 208.6 ° (c = 0.5% chloroform).

/ a / ²⁰ D

NMR results are shown below.

Example 2

Preparation of (-) -5-fluoro-2 - [(4-cyclopropylmethoxy-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazole

To acetonitrile / aqueous minority solution of the lipophilic diastereoisomers of 5-fluoro-2 - [(4-cyclopropylmethoxy-2-pyridinyl) methyl - (R / S) - (sulfinyl) -1- (R) -mandeloxymethyl] -1H-benzimidazole and

6-fluoro-2 - [(4-cyclopropylmethoxy-2-pyridinyl) methyl- (R / S) - (sulfinyl) -1- [(R) -mandeloxymethyl] -1H-benzimidazole (obtained from very similar reverse chromatography) of the phase described in Example 1), a 1 M aqueous solution of NaOH was added at which the pH was about 12-13. After five minutes, the solution was neutralized with a 3.0 molar aqueous solution of NH ₄ Cl, and then each was combined and extracted with methylene chloride. The organic phases were dried over Na ₂ SO ₄ , the solvent was removed by thin layer evaporation. Addition of 50 ml of acetonitrile gave a crystallization product and after filtration 460 mg (28%) of the title compound were obtained as white crystals, m.p. 152-154 C. The optical purity was analyzed by chiral chromatography column 99.0%. [.alpha.] D @ ²⁰ = -208.7 DEG (c = 0.5% chloroform).

NMR results are shown below.

Example 3

Preparation of lyophilized (-t-) -5-fluoro-2 - [(4-cyclopropylmethoxy-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazole

To a methylene chloride solution (5 mL) of (-) - 5-fluoro-2 - [[(4-cyclopropylmethoxy-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazole (100 mg, 0.25 mmol) was added aqueous solution 0, 2 M NaOH (1.4 mL, 0.28 mmol). The mixture was stirred for 30 minutes, then the layer was separated. The aqueous phase was lyophilized to yield the title product as a white amorphous powder of 83 mg (78%); [.alpha.] D @ ²⁰ = 47.2 DEG (c = 1.0%, water).

NMR results are shown below.

Example 4 i

Preparation of (+) - 5-fluoro-2 - [(4-cyclopropylmethoxy-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazole sodium salt in crystalline form

The lyophilized (+) -5-fluoro-2 - [(4-cyclopropylmethoxy-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazole sodium salt (61 mg) obtained in Example 3 was dissolved in 2-butanone (1 mL) . Toluene (2 mL) was added slowly with stirring until white crystals precipitated. The product was filtered and washed with a small amount of diethyl ether. 50 mg (82%) of the title compound were obtained in crystalline form, m.p. 230-240 ° C.

NMR results are shown below.

Example 5

Preparation of lyophilized (-) - 5-fluoro-2 - [(4-cyclopropylinethoxy-2-pyridil) methyl] sulfinyl] -1H-benzimidazole sodium salt

To a methylene chloride solution (5 mL) of (+) - 5-fluoro-2 - [(4-cyclopropylmethoxy-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazole (100 mg, 0.29 mmol) was added an aqueous solution 0.2 M NaOH (1.4 mL, 0.28 mmol). The mixture was stirred for 30 minutes, then the layer was separated. The aqueous phase was lyophilized to yield the title product as a white amorphous powder 89 mg (84%); [.alpha.] D @ ²⁰ = 46.4 DEG (c = 1.0%, water).

NMR results are shown below.

Example 6

Preparation of (-) -5-fluoro-2 - [(4-cyclopropylmethoxy-2-pyridinyl) methyl] sulfinyl-1H-benzimidazole sodium salt in crystalline form

The lyophilized (-) -5-fluoro-2 - [(4-cyclopropylmethoxy-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazole sodium salt (75 mg) obtained in Example 5 was dissolved in 2-butanone ( 1 ml). Toluene (2 mL) was added slowly with stirring until white crystals precipitated. The product was filtered and washed with a small amount of diethyl ether. 60 mg (82%) of the title compound were obtained in crystalline form, m.p. 230-240 ° C.

NMR results are shown below.

Example 7

Preparation of (+) - 5-fluoro-2 - [(4-cyclopropylmethoxy-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazole magnesium salt

The magnesium (7.1 mg, 0.29 mmol) was dissolved and treated with methanol 40 ° C warm with a small amount of a catalyst which was methylene chloride. The reaction was carried out under a nitrogen atmosphere and terminated after two hours. (+) - 5-Fluoro-2- (4-cyclopropylmethoxy-2-pyridinyl) methyl (sulfinyl) -1H-benzimidazole (200 mg, 0.58 mmol) was added to magnesium methoxide which had been pre-cooled to room temperature. . The mixture was stirred for two hours, then a small amount of water (0.05 mL) was added. The mixture was then stirred for an hour and a small amount of the inorganic salt was filtered off. The solution was concentrated using a rotary evaporator and stirring was complete and cooling to give the resulting precipitate. After filtration, the product was washed with a small amount of water, then dried under vacuum. Finally, 97 mg (47%) of the title compound was obtained as a white powder. [.alpha.] D @ ²⁰ = + 191.3 DEG (c = 1.0% DMSO).

Evaporate 2 ml of the solution. For added drop of water. then

Example 8

Preparation of (-) - 5-fluoro-2 - [(4-cyclopropylmethoxy-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazole magnesium salt

The magnesium (7.1 mg, 0.29 mmol) was dissolved and treated with methanol 40 ° C warm with a small amount of a catalyst which was methylene chloride. The reaction was carried out under a nitrogen atmosphere and terminated after two hours. (-) - 5-Fluoro-2 - [(4-cyclopropylmethoxy-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazole (200 mg, 0.58 mmol) was added to magnesium methoxide which had been pre-cooled to room temperature. temperature. The mixture was stirred for two hours, then a small amount of water (0.05 mL) was added. The mixture was then stirred for an hour and a small amount of the inorganic salt was filtered off. The solution was concentrated using a rotary evaporator and 2 ml of the total solution was evaporated. While stirring and cooling, a drop of water was added. The resulting precipitate was then formed. After filtration, the product was washed with a small amount of water, then dried under vacuum. Finally, 84 mg (41%) of the title compound was obtained as a white powder. The optical rotation was determined as (-).

Table 1

no. solution NMR Results d ppm 1. DMSO-dg 500 MHZ 0.25 (m, 2H), 0.53 (m, 2H), 13 (m, IH), 3.67 (m, IH), 3.73 (m, 1H), 4.59 (d, 1H), 4.69 (d, 1H), 6.76 (d, 1H), 6.88 (dd, 1H), 7.17 (m, 1H), 7.43 (m, 1H), 7.65 (m, 1H), 8.28 (d, 1H), ~ 13 (b, H). 2. DMSO-dg 500 MHZ 0.25 (m, 2H), 0.53 (m, 2H), 1.13 (m, 1H), 3.68 (m, 1H), 3.73 (m, 1H), 4.59 (d, 1H), 4.69 (d, 1H), 6.76 (d, 1H), 6.88 (dd, 1H), 7.17 (m 1H, 7.43 (m, 1H), 7.64 (m, 1H), 8.28 (d, 1H), ~ 13 (b, 1H). 3. _DMSO-d6 500 MHz 0.21 (m, 2H), 0.50 (m, 2H), 08 (m, IH), 3.46 (m, IH), 3.62 (m, 1H), 4.40 (d, 1H), 4.56 (d, 1H), 6.57 (d, 1H), 6.71 (m, 1H), 6.81 (m , 1H), 7.15 (dd, IH), 7.41 (m, 1 H); 8.30 (d, IH). 4. DMSO-dg 300 MHZ * 0.22 (m, 2H), 0.50 (m, 2H), 1.07 (m, 1H), 3.50 (m, 1H), 3.66 (m, 1H), 4.41 (d , H), 4.62 (d, IH), 6.59 (d, IH); 6.69 (m, 1H), 6.78 (m, 1H), 7.13 (dd, 1H), 7.39 (m, 1H), 8.29 (d, 1H). 5. DMSO-dg 500 MHz 0.22 (m, 2H), 0.50 (m, 2H), 1.08 (m, 1H), 3.46 (m, 1H), 3.62 (m, 1H), 4.40 (d 1H, 4.56 (d, 1H), 6.57 (d, 1H), 6.71 (m, 1H), 6.80 (m, 1H), 7.15 (dd, 1H), 7 40 (m, 1 H); 8.30 (d, IH).

6. DMSO-d6 0.22 (m, 2H), 0.50 (m, 2H), 1.07 (m, 1H), 3.51 (m, 1H)

300 MHz 2.66 (m, 1H), 4.41 (d, 1H), 4.62 (d, 1H), 6.60 (d, 1H),

6.69 (m, 1H), 6.78 (m, 1H), 7.13 (dd, 1H), 7.39 (m, 1H), 8.29 (d, 1H).

The preparation of intermediates of the invention will be described in the following example.

Example 9

Preparation of 5-fluoro-2 - [(4-cyclopropylmethoxy-2-pyridinyl) methyl- (R / S) - (sulfinyl) -1-1] (R) -mandeloxymethyl] -1H-benziinidazole and 6-fluoro-2- // (4-cyclopropylmethoxy-2-pyridinyl) methyl- (R / S -) - sulfinyl / -l - / (R) -mandeloxvmetvl / benzimidazole

A solution of 1.6 g (40 mmol) of sodium hydroxide in 8 ml of water was added to a mixture of 6.8 g (20 mmol) of hydrogen tetrabutylammonium sulfate and 3.0 g (20 mmol) of (R) - (-) mandelic acid. Chloroform (200 mL) and a mixture of 5-fluoro-2 - [(4-cyclopropylmethoxy-2-pyridinyl) methyl- (sulfinyl) -1- (chloromethyl)] -1H-benzimidazole and 6-fluoro-2- were added. [(4-cyclopropylmethoxy-2-pyridinyl) methyl] sulfinyl] -1- (chloromethyl) -1H-benzimidazole (as racemates) and refluxed for one hour. The reaction mixture was cooled and then partitioned between ethyl acetate and water. The base layer was separated and the organic phase was washed with water and dried under Na ₂ SO ₄ . The carrier diastereomeric mixture of the two regioisomeric mandelic esters was then separated. The crude product was chromatographed to separate the diastereomers. (Examples 1 and 2).

Yield: 9.0 g, 88%.

NMR results are shown below.

- 17 Table 2.

no. solvent NMR results in d ppm

9. CDC1 ₃ 0.3-0.4 (m, 2H), 0.6-0.7 (m, 2H), 1.1-1.3 (m, H),

3.7-3.9 (m, 2H), 4.6-4.9 (m, 2H), 5.2-5.3 (m, 1H), 6.2-6.6 (m, 2H) ), ~ 6.7 (m, 1H), 6.85 (m, 1 H);

7.0-7.8 (m, 8H), 8.1-8.2 (m, 1H).

The best known carrier of the present disclosure is the use of a magnesium salt of optically pure compounds of the invention as described in Examples 7 and 8.

Pharmaceutical compositions containing the compounds of the invention as active ingredients are described in the following paragraphs.

syrup

Syrup contains 1% (w / v) of active substance which has been prepared from the following ingredients:

Example 4 1.0 g

Powdered sugar 30.0 g

Saccharin 0.6 g

Glycerol 5.0 g

Flavoring agents 0.05 g

Ethanol 90% 5.0 g

Distilled water to make up to a final content of 100% 100 ml

The sugar and saccharin were dissolved in 60 g of hot water. After cooling, the active ingredient was added to the sugar solution and glycerol and a solution of the essential substances dissolved in ethanol were added. The mixture was diluted with water to a final volume of 100 mL.

Enteric coated tablets

Tablet containing the following 50 ingredients: mg of active compound was produced Example compound 7 500 g lactose 700 g methylcellulose 6 g Polyvinylpyrrolidone, cross-linked 50 g Magnesium stearate 15 g Sodium carbonate 6 g Distilled water as needed : Acetate phthalate 200 g

Acetylalcohol 15 g

Isopropanol 2000 g

Methylene chloride 2000 g

The compound of Example 7 in powder form was mixed with lactose and granulated with an aqueous solution of methylcellulose and sodium carbonate. The wet mass is passed through a sieve and the granulate is dried in an oven. After drying, the granules were mixed with polyvinylpyrrolidone and magnesium stearate. The dry mixture was compressed into tablets (10,000 tablets), each tablet containing 50 mg of active ingredient, which was compressed using a tabletting machine with a punch diameter of 7 mm.

A solution of cellulose acetophthalate and acetyl alcohol in isopropanol / methylene chloride was sprayed onto tablets I in an Accela Cota ^R tablet coating machine, Manesty. The final toilet was 110 mg.

Solution for intravenous use

A parenteral composition for intravenous use containing 4 mg of active ingredient per ml was prepared from the following ingredients:

Example 6 4 g

Sterilized water to a final volume of 1000 ml

The active compound was dissolved in water with a final volume of 1000 ml. The solution was filtered through a 0.22 μπ filter and sterile vials. The ampoules were dispensed into a 10 ml cap.

capsules

Capsules containing the following 30 ingredients:

Compound of Example 4 Lactose

Microcrystalline cellulose Hydroxypropyl cellulose Disodium hydrogen phosphate Purified water mg of active substance were prepared from

300 g 700 g g 62 g g

as needed

The active ingredient was mixed with the solid ingredients and the disodium hydrogen phosphate solution. Wet matter. is extruded, spheronized and dried in a fluid bed dryer.

500 g of the pellets produced as described above were first coated with a solution of 30 g of hydroxypropylmethylcellulose in 750 ml of water of the pellets with a fluid bed coating as described using a coating apparatus. After drying, the pellets were coated with a second one.

Coating solution

Cellulose hydroxypropyl methyl phthalate

acetyl

acetone

Ethanol g 4 g 200 g 600 g were filled into capsules.

The resulting pellets mentioned above

Lace * Lace was made from the welding process. Every cone in

The compound of Example 4 below contains 40 mg of active ingredient.

g

Witepsol H-15 180g

The active substance was homogeneously mixed with Witepsol H-15 at 41 ° C. The molten mass was filled into the lace packs in the necessary amount to a net weight of 1.84 g. After cooling, the lace packs were sealed. Each suppository contains 40 mg of active ingredient.

Stabilization against racemization at different pH:

The stability of the optically pure compounds of the invention towards the shoulder was measured at low concentrations (10 ^-5 M) at 37 ° C in an aqueous buffer solution having a pH between 7 and 11. Stereochemical stability was measured by comparing the optical purity of the (+) - isomer of 5-f. luoro-2 - [(4-cyclopropylmethoxy-2-pyridinyl) methyl] - (sulfinyl) -1- (chloromethyl) -1H-benzimidazole in a buffer solution immediately after dissolution and after several hours. Surprisingly, the high stereochemical stability in both neutral and inventive compounds became much more visible after 28 hours, the compounds after 28 hours.

under alkaline conditions for compounds, it shows that the racemization of the test does not reach either pH 7 or pH 11, even at least pH 7 is chemical degradation

Claims (20)

Individual enantiomeric compounds having the formulas Ia and Ib (Ia, Ib) H 1a (+) - enantiomer Ib (-) - enantiomer and therapeutically acceptable salts thereof. Compound according to claim 1, characterized in that the compound is (+) - 5-fluoro- 2 - [(4-cyclopropylmethoxy-2-pyridinyl) methyl] sulfinyl] -1- (chloromethyl) -1H-benzimidazole, or a therapeutically acceptable salt thereof, and its substantially free (-) - enantiomer. A compound according to claim 1 wherein the compound is (-) - 5-fluoro-2 - [(4-cyclopropylmethoxy-2-pyridinyl) methyl] sulfinyl] -1- (chloromethyl) -1H-benzimidazole, or its therapeutically acceptable salts and its substantially free (+) - enantiomer. Compound according to any of claims 1- 3 characterized in that the therapeutically acceptable salts are the salts of Na ^+, Li ^+, K ^+, Ca ^2+, Mg ^2+, and N ⁺ (R) _4, wherein R is an alkyl group having 1 - 4 carbon atoms. Compound according to any one of claims 1-4, characterized in that the compounds are (+) - 5-fluoro-2 - [(4-cyclopropylmethoxy-2-pyridinyl) methyl- (sulfinyl) -1- (chloromethyl)] - 1H-benzimidazole sodium salt, (-) - 5-fluoro-2 - [(4-cyclopropylmethoxy-2-pyridinyl) methyl] sulfinyl] -1- (chloromethyl) -1H-benzimidazole sodium salt, ( +) - 5-fluoro-2 - [(4-cyclopropylmethoxy-2-pyridinyl)] » methyl- (sulfinyl) -1- (chloromethyl) -1H-benzimidazole magnesium salt, (-) - 5-fluoro-2 - [(4-cyclopropylmethoxy-2-pyridinyl) methyl] sulfinyl] -1- ( chloromethyl) -1H-benzimidazole magnesium salt. A compound according to any one of claims 1-5, wherein the compound is (+) -5-fluoro-2 - [(4-cyclopropylmethoxy-2-pyridinyl) methyl] sulfinyl] -1- (chloromethyl) // 1 H -benzimidazole magnesium salt or sodium salt, (-) - 5-fluoro-2 - [(4-cyclopropylmethoxy-2-pyridinyl) methyl- (sulfinyl) -1- (chloromethyl)] - 1 H -benzimidazole magnesium a salt in crystalline form, or a sodium salt thereof. Compound according to claims 1 and 2, characterized in that the compound is (+) - 5-fluoro-2 - [(4-cyclopropylmethoxy-2-pyridinyl) methyl- (sulfinyl) -1- (chloromethyl)] - The 1H-benzimidazole magnesium salt or the sodium salt in its crystalline form as the enantiomer of the (-) - enantiomer. Compound according to claims 1 and 3, characterized in that the compound is (-) - 5-fluoro-2 - [(4-cyclopropylmethoxy-2-pyridinyl) methyl- (sulfinyl) -1- (chloromethyl)] - 1H-benzimidazole magnesium salt or sodium salt in its crystalline form as the enantiomer (+) - enantiomer. I * A process for the preparation of a compound according to claim 1, wherein the diastereoisomeric ester of formula V c. wherein the fluoro substituent of the benzimidazole moiety is in the 5 or 6 position and wherein the selected acyl is a chiral acyl group such as mandeloyl having the R or S configuration is separated and each of the separated diastereomers is subjected to solvolysis in an alkaline solution wherein the acyloxymethyl group is hydrolyzed and the enantiomeric compound is formed in neutral form upon neutralization with a neutralizing agent. wherein the enantiomeric compound in the neutral form is converted to therapeutic salts. Method according to claim 9, characterized in that the diastereoisomers are separated by chromatography or fractional recrystallization. The method according to claim 9, wherein the solvolysis is carried out in an alkaline solution consisting of a base in a protic solvent such as alcohol or water, or a base in an aprotic solution such as dimethylsulfoxide or dimethylformamide, or a mixture of bases in protic and aprotic solvents such as water and acetonitrile. I t A process for the preparation of a compound according to claim 1-4 in crystalline form, characterized in that the product obtained in claim 9 in ¢-neutral form or in the form of therapeutic salts is precipitated in anhydrous solution to the resulting precipitate. 13. Method for producing (+) - 5-fluoro-2 - [(4-cyclopropylmethoxy-2-pyridinyl) methyl- (sulfinyl) -1- (chloromethyl)] - 1H-benzimidazole sodium salt, (-) -5-fluoro-2 - [(4-cyclopropylmethoxy-2-pyridinyl) methyl] sulfinyl] -1- (chloromethyl) -1H-benzimidazole sodium salt, characterized in that in (+) -5-fluoro-2 - [(4I)] -cyclopropylmethoxy-2-pyridinyl) methyl- (sulfinyl) -1- (chloromethyl) -1H-benzimidazole sodium salt, (-) - 5-fluoro-2 - [(4-cyclopropylmethoxy-2-) pyridinyl) methyl- (sulfinyl) -1- (chloromethyl) -1H-benzimidazole sodium salt, as a crude product, is treated in an anhydrous medium such as 2-butanone and toluene. A pharmaceutical composition comprising the individual enantiomeric compounds of any one of claims 1-8 as active ingredient. The individual enantiomeric compounds of any one of claims 1-8 for use in therapy. Use of the individual enantiomeric compounds according to any one of claims 1-8 in the manufacture of a pharmaceutical composition for inhibiting gastric acid secretions. Use of the individual enantiomeric compounds according to any one of claims 1-8 in the manufacture of a pharmaceutical composition for the treatment of gastric inflammation and inflammatory diseases. ^ A method of inhibiting gastric secretion by administering to a mammal and a human in the necessary amount of an enantiomeric compound according to claim 1-8. / ^19: In a manner analogous treatment of gastric secretion by administering to mammals and d 'to a human at a suitable level enantiomeric compound according to claim 1-8. 20. Compound of 5-fluoro-2 - [(4-cyclopropylmethoxy-2-pyridinyl) methyl- (sulfinyl) -1- (chloromethyl)] - 1H-benzimidazole and 6-fluoro-2 H (4-cyclopropylmethoxy) 2-pyridinyl) methyl / sulfinyl / -l (chloromethyl) // - H-benzimidazol.