CZ21896A3 - Novel substituted benzimidazoles - Google Patents

Abstract

The novel optically pure compounds, i.e. the single enantiomeric compounds (Ia, Ib), (+)-5-fluoro-2-[[(4-cyclopropylmethoxy-2-pyridinyl)methyl]sulfinyl]-1<u>H</u>-benzimidazole and (-)-5-fluoro-2-[[(4-cyclopropylmethoxy-2-pyridinyl)methyl]sulfinyl]-1<u>H</u>-benzimidazole or a therapeutically acceptable salt thereof, such as Na<+>, Mg<2+>, Li<+>, K<+>, Ca<2+> and N<+>(R)4 salts, where R is an alkyl group with 1-4 carbon atoms, processes for the preparation thereof and pharmaceutical preparations containing the compounds as active ingredients, as well as the use of the compounds in pharmaceutical preparations and intermediates obtained by preparing the compounds.

Description

(57) New, optically pure compounds, i.e. individual enantiomers of formula (Ia, Ib), (+) - 5-fluoro-2- || (4-cycloprophylmethoxy-2-pyridinyl) methyl | sulfinyl | -1H-benzimidazole and (-) - 5-fluoro-2- || (4-cycloprophylmethoxy-2-pyridinyl) methyl | sulfinyl | -1H-benzimidazole, and (-) - 5-fluoro-2- || (4-cycloprophylmethoxy-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 having 1 to 4 carbon atoms. The process for their preparation, and pharmaceutical preparations containing them as active ingredients, as well as the use of the compounds in pharmaceutical compositions and intermediates of these compounds obtained in their preparation.

CHg — SNfo

4S.

σ o

oy <

JVMr. Ivan HOREČEK

Law and Patent Office 160 00 Prague 6. Na bašte sv. Jiří 9 P.O. BOX 275. 160 41 řraha 6 Czech Republic

New substituted benzimidazojes

FIELD • U <"3 s for ^r> ~ I w c 2 · a! XH o O Ο I; S to

CD ___ ί

This invention relates to new compounds combined with high optical purity, their use in medicine, their production and their use in the manufacture of pharmaceutical compositions. This invention also relates to novel intermediates for the preparation of the present compounds.

BACKGROUND OF THE INVENTION

The compound 5-fluoro-2 - [(4-cyclopropyl (sulfinyl) -1H-benzimidazole, and its ophylmethoxy-2-pyridinyl) methyl and apeutically acceptable salts are disclosed in US-A 5,008,278, and EP 90901079.5. These compounds and therapeutically acceptable salts thereof are effective in inhibiting acid secretion in the stomach and are useful as anti-gastric ulcer agents. These sulfoxide compounds have an asymmetric center at the sulfur atom, i.e. they exist as two optical isomers (enantiomers). This is desirable for improving their pharmacological and metabolic properties, which are desirable for improving their therapeutic profile. This invention provides those compounds having novel salts of selected enantiomers of β-fluoro-2 - [(4-cycloprophyimethoxy-2-pyridinyl) α ethyl / sulfinyl] -1H-benzimidazole, as well as new individual enantiomers in non-form. .

Separation of enantiomers of therapeutically active sulfoxides such as substituted benzimidazoles, for example, ameprazole (5-methoxy-2 - [(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl (sulfinyl) -1H benzimidazole) on a preparative scale. described in J. Chromatography, 532 (

1990), 305-19. This isolation of the separate enantiomers of sulfoxide reagents

Ro 18-5364 is described in Euro J. Biochem. 166 (1987) 453-459). Furthermore, 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 compound Omeprazole is required to rapidly neutralize the medium with a base to prevent degradation of the acid-sensitive compound.

From the aforementioned efforts to prevent degradation of the resulting compound, a concentrated NaOH solution is added to the reaction mixture containing concentrated sulfuric acid. This is disadvantageous because it is very risky that under these spinal cord conditions it reaches pH values between Ιό and this can lead to destruction of the compound. In addition, immediate neutralization causes heating which 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 aspects of this preparation. These novel methods can be used in a wide field to obtain separate enantiomers of the compounds of the invention in neutral form as well as in the form of pharmaceutically acceptable salts.

These novel compounds of the invention, which are sulfoxides, can be expected to undergo racemization at neutral pH as well as under alkaline conditions. By way of example, Biandstrom et al. Acta Chemica Scandinavica 43 (1989) p 536-547. It is unexpected that the new enantiomers of this invention 5-fluoro-2 - [(4-cycloprophylmethoxy-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazole, as therapeutically acceptable the salts are directed to permanent 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. Also, the inventors are not aware that anything in the isolated salts of the individual enantiomers of the press has been described or claimed anywhere in the scientific literature.

isomers, and whatever it is described in

Poptevynáleyu

The present invention relates to novel 4-cycloprophyimethoxy-2-pyridinyl benzimidazole units which relate to the compounds of the other enantiomers of 5-fluoro-2 - [() methyl / sulfinyl] -1H aaalb.

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

Particularly preferred salts of the compounds (C ^ ^ _{so so so} iianti) and the individual enantiomers-5-cycloprophylmethoxy-2-pyridinyl) of the present invention are Na ⁺ JMM ^ ⁺ , fluoro-2 - [(4-methyl (sulfinyl) --H-benzimidazole).

The most preferred compounds according to the invention of the fluoro-2 - [(4-cycloprophylmetho-1H-benzimidazole) are optically pure Na ⁺ salts - 5 y-2-pyridinyl) methyl (sulfinyl) urine Ha and Hb

ei-V-O

CHa-f- (

(Ha, Hb)

Na +

Ha (+) - enant omer Hb (-J-enantiomer and optically pure magnesium salts of said compounds having the formula IHa and H1b)

^CH 2— <]

Ν '

Mg 2+ (Dia, mb)

Dia (+) - enantiomer Dlb (-) - enantiomer mer

Interpretation of an optically pure compound of the invention means the (+) enantiomer of said compound in a conventional free form, sterile in accordance with the (-) enantiomer and the (-) - enantiomer in essential form in accordance with the (+) enantiomer. This means that a new specific method relating to this aspect of the invention, i.e. the preparation, of the individual enantiomers of the compounds of the invention is readily practicable. In addition, as mentioned above, the new optically pure compounds are stable towards racemization in both neutral and alkaline media. Since then, an unexpected mechanism of degrading reactions in the neutral environment of these types of sulfides (omeprazole analogs) containing reversible reactions using achiral intermediates has been established by Brandstrom et al. Acta Chemica Scandinavica 43 (1989) p 536-547, p 538). It is understood that such a reversible reaction from achiral intermediates to sulfoxide may be the cause of the racemic product. Also, the new optically pure compounds are stable against racemization in a basic environment, which 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 for racemization in neutral and basic media 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 present invention, as well as the racemates, exhibit extremely high bioavailability, and the compounds so far are highly effective as inhibitors of gastric acid secretion and exhibit high chemical stability in a neutral pH solution.

The compounds of the invention may 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 and the feet can be used to treat diseases related to internal bowel disorder inflammatory diseases in mammals and humans, such as gastric ulcers, duodenal ulcers, esophagitis and gastritis. Also, the compounds can be used for use in the treatment of other gastric disorders where appropriate; • gastric antisecretory effect, ie in patients with NS AID therapy, in patients with gistrinomy and in patients with acute upper gastric bleeding. They can also be used in patients with a condition due to special care and suppuration. Thus, the compounds of the invention can also be used for the treatment or prophylaxis of inflammatory diseases, particularly these include lysozyme diseases in mammals that also include enzymes. Conditionally it can be rheumatoid arthritis and gout. These compounds of the invention may also be used for the treatment of psoriasis, as well as for the treatment of helicobacterial infection.

wherein the fluoro substituent in the

However, also an aspect of the invention in the diaster · regioisomeric mixtures having the pattern used in the specific method for preparing benzimidazole is in position 5 or 6.

^ _CH2 - <]

Preparation of compounds

The optically pure compounds of the invention, i.e., the single enantiomers, are produced by separation of stereoisomers by diastereomeric mixtures, regioisomeric mixtures of the 5- and 6-fluoro-2 - [(4-cycloprophylmethoxy-2-pyridinyl) methyl] - (R / S) - / sulfinyl - 1H - benzimidazole of formula V

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

The acyl in the diastereoisomeric 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.

Diastereomeric esters may be separated either by chromatography or by fractional crystallization.

Solvolysis is carried out with a base in protic or water, or which is the basis of the group can also be hydrolyzed in dimethylsulfoxide or dimethylformers R 10 wherein R 1 can be alkyl or; an aryl group.

solvents such as alcohols of the acetonitrile and water but the acyl aprotic solution which is id. The reaction base may be OH ', or

To obtain an optically pure salt of the present invention which is the Na ⁺ salts of the individual enantiomeric compounds of the invention and the final compounds in neutral form are treated with a base which is NaOH in an aqueous or anhydrous medium or with NaOR 4 when R 4 is an alkyl group having 14 carbon atoms, or with NaNH 2 - Also alkali salts wherein the cation is Li ⁺ or K ⁺ can be prepared using n lithium, or potassium salts of the aforementioned bases. In the obtained ordered crystalline form of the individual enantiomers of Na ⁺ salts, an optically pure ammonium powder of Na ⁺ salts 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 the NaO enantiomeric compounds of the invention in neutral form and in a non-aqueous medium such as 2-butanone and toluene.

are optically pure

To obtain optically pure Mg @ ⁺ salts below <

The compounds of the invention in neutral form are treated with a base which is Mg (OR 3) 2, wherein R 1 is an alkyl group containing 1-4 carbon atoms in a non-aqueous solvent such as an alcohol or 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 Mg ²⁺ salts are precipitates. is Ca ²⁺ can be prepared 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 for the sodium salts (compounds IIa and IIb) and magnesium salts (compounds IIIa and 111b), for example, their salts with Li ⁺ , K ⁺ , Ca ²⁺ and N ⁺ (R) 4, wherein R is an alkyl group having () - 4 carbon atoms.

For the clinical use of the individual enantiomers of the optically active compounds of the invention, these are included 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. Carriers may be in the form of a solid, liquid, or capsule. 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 drug, between 0.2 - 20% by weight in the formulated drug for parental use and 1-50% by weight of the preparation 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. substances such as alkaline compounds, carbonates, hydroxides and oxides of sodium, magnesium, potassium, calcium, lubricants 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 that protects the active ingredient from acid catalysed degradation as long as the dosage form persists in the stomach. The tablet pack is selected from pharmaceutically acceptable materials such as Yippee

Beeswax, shellac, or anionic films forming polymers and the like, particularly preferred is a combination with a suitable plasticizer. Various colorants may be added to the coatings to differentiate between tablets or granules with different amounts of active ingredient.

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.

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

The dosage unit for rectal administration may be presented in the form of suppositories, greasy bases or which may contain active mixtures of substances, and may not be prepared in the form of gelatin tablets for rectal administration containing the active substances in a mixture with vegetable oil, paraffin oil. , or other acceptable vehicle, for gelatin kips, or may be prepared in the form of dry microclysms, reconstituted in acceptable solutions, just prior to administration.

It can be prepared in the form of syrups, containing from 0.2% to 20% alcohol and a mixture of ethanol, thylene glycol water. If desired, a coloring agent, saccharin and an aqueous preparation for oral administration of the sachet are made into an acceptable solution.

The liquid preparation for oral administration of suspensions or solutions, i.e., solutions or by weight of the active ingredients, or sugar of glycerol, propylene glycol, and / or polyes such liquid compositions may contain carboxymethyl cellulose or other agents may be prepared in dry form prior to administration.

spm

Solutions for parenteral administration may be prepared as solutions of the optically pure compounds of the invention in pharmaceutically acceptable solutions, particularly at concentrations 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 vials. Solutions for parenteral administration may be prepared as dry preparations and formulated with a suitable solvent prior to use. Typical daily dosages 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 of active ingredient.

The invention is illustrated by the following examples.

DETAILED DESCRIPTION OF THE INVENTION

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

Crude products of diastereomeric compounds of two regioisomeric mandelic esters, especially 5-fluoro-2 - [(4-cycloprophylmethoxy-2 pyridinyl) methyl - (R / S) - / sulfinyl / -1 - / (R) - mandeloxymethyl] -1H benzimidazole and 6-fluoro-2 - [(4-cycloprophylmethoxy-2-pyridinyl) methyl- (R / S) - (sulfinyl) -1 - / (R) -mandeloxymethyl] -1H-benzimidazole (5 g, 9.8 mmol) were divided into five sections and each of these sections was chromatographed on the opposite part of the column (HLPC, Kromasil C8) in the order of separated diastereomers. These stereoisomers were more readily separable with an aqueous 0.1 M ammonium acetate / acetonitrile (67.5 / 32.5) eluent mixture. However, each separated diastereomer consists of a mixture of two regioisoters. These intermediates were used directly in their solutions during the hydrolytic procedure. To an acetyl / aqueous solution

M aqueous NaOH solution in which the solution was neutralized with 3.0 molar each of them combined and extracted with the lipophilic diastereomer was added a pH of about 12-13. After five minutes with aqueous NH 4 Cl solution and then methylene chloride. The organic phases were dried over Na 2 SO 4 and the solvent was removed by evaporation to a thin layer. Addition of 30 ml of acetonitrile gave the crystallization product and after filtration by filtration 260 mg (16%) of the title compound were obtained as white crystallites, m.p. 152-154 ° C. The optical purity, which was analyzed by chiral column chromatography was 99.2% / a / ^ D - 208.6 ⁰ + (c - 0.5%, chloroform).

NMR results are shown below.

Example 2 Preparation of (-) - 5-fluoro-2

7 / (4-cycloprophylmethoxy-2-pyridinyl) methyl (sulfinyl) -1H-zimidazole

To acetonitrile / aqueous minority solution of lipophilic diastereoisomers 5 fluoro-2 - [(4-cycloprophylmethoxy-2-pyridinyl) methyl - (R / S) - (sulfinyl) -1- ((R) - mandeloxymethyl)] - // ( 4-Cycloprophylmethoxy-2-pyridine: 1- [(R) -Mangeloxymethyl] -1H-ben: similar reverse-phase aqueous NaOH solution in which the pH was ¹

1H-benzimidazole and 6-fluoro-2-yl) methyl - (R / S) - / sulfinyl / midazole (obtained from the very written example 1) were added with 1M around 12-13. After five minutes, the solution was neutralized with a 3.0 molar aqueous NH 4 Cl solution, 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 50 ml of acetonitrile gave the 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, which was analyzed using a chiral chromatography column, was 99.0% (a / 2θϋ - - 208.7 ° C - 0.5%, chloroform).

NMR results are shown below.

Example 3. Preparation of Ivophilized (+) - 5-fluoro-2 - [(4-cyclopropylmethyl-2-pyridinyl) methyl (sulfinyl) -1H-benzimidazole

To a methylene chloride solution (5 mL) of (-) - 5-fluoro-2 - [(4-cycloprophylmethoxy-2-pyridinyl) methyl (sulfinyl) -1H-benzimidazole (100 mg, 0.25 mmol) was added aqueous 0.2 M NaOH (1.4 mL). mL, 0.28 mmol). The mixture was stirred for 30 minutes, and then the layer was separated. The aqueous phase was lyophilized to give 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. Preparation of (+) - 5-fluoro-2 - [(4-cyclopropenylmethoxy) -2-pyridinyl] methyl (sulfinyl) -1 H -benzimidazole sodium salt in the tasific form

Lyophilized (+) -5-fluoro -2 - [(4-cycloprophylmethoxy-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-cyclohexylphenyl-ethoxy-2-pyridinyl) methyl] -phenyl] -2- (2-pyridinyl) methyl. IH benzimidazole sodium salts

To a methylene chloride solution (5 m cycloprophylmethoxy-2-pyridinyl) n (100 mg, 0.29 mmol) was added aqueous; mmol). The mixture was stirred for 30 min. The aqueous phase was lyophilized to yield a white amorphous powder of 89 mg (84%) / [alpha] 20 [deg.] - 46.4 [ _deg.] ( _C 10-10%, water).

j) (+) - 5 - fluoro-2 - // (4: Ethyl / sulfinyl / - IH - benzimidazole ^r 0.2 M NaOH solution (1.4 ml, 0.28 minutes, and then the layer was separated: the final product in the form of

NMR results are shown below.

Example 6, Preparation of (-) - 5 - fluoro - 2 pyridinyl) methyl (sulfinyl) - 1H - in crystalline form

7 / (4-cycloprophylmethoxy-2 lazot sodium salts in

The lyophilized (-) - 5-fluoro-2 - [(4- (cycloprophylmethoxy-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 OC.

NMR results are shown below.

Example7.Preparation of (+) -5-fluoro-2 - [(4-cyclopropylmethoxy-2-pyridinyl) methylphenyl] -1H-benzimidazole magnesium salt

Magnesium (7.1 mg, 0.29 mmol) was dissolved and treated with methanol 40 ° C warm with a small amount of catalyst, which was methylene chloride. The reaction was carried out under a nitrogen atmosphere and was complete after two hours. (+) - 5 - Fluoro -2 - [(4-cycloprophyhnethoxy-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazole (200 mg, 0.58 mmol) was added into magnesium methoxide which had previously been cooled to room temperature.

The mixture was stirred for two hours, and then a small amount of water (0.05 mL) was added. The mixture was stirred for an hour and a small amount of the inorganic salt was filtered off. The solution was concentrated using a rotary evaporator, and a total of 2 mL of solution was evaporated. A drop of water was added with stirring and cooling. The resulting precipitate was then formed. After filtration, the product was washed with a small amount of water and 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).

Example 8. Preparation of (- - 5 - fluoro -2 - [(4-cycloprophymethoxy-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 the catalyst, which was methylene chloride. The reaction was carried out under a nitrogen atmosphere and was completed after two hours (-) - 5 - Fluoro -2 - [(4-c) cloprophymethoxy-2-pyridinyl) methyl / sulfinyl] -1H-benzimidazole (200 mg, 0.58) mmol) was added to magnesium methoxide, which had been cooled to room temperature before being added. The mixture was stirred for two hours, and then a small amount of water (0.05 mL) was added. The mixture was stirred for an hour and a small amount of inorganic salt was filtered off. The flow was concentrated using a rotary evaporator, and a total of 2 ml of the solution was evaporated. A drop of water was added with stirring and cooling. The resulting precipitate was then formed. After filtration, the product was washed with a small amount of yoda, and then dried under vacuum. Finally, 84 mg (41% of the title compound) was obtained as a white powder.

Optical curl was determined as (-)

Table 1

C.

1.

Solution

NMR Results d ppm

DMSO-d6 500 MHz

0.25 (m, 2H), 3.73 (m, 1H), 6.88 (dd, 1H), 8.28 (d, 1H), = (m, 2H), 1.13 (m, 1H), 3.67 (m, 1H), .59 (d, 1H), 4.69 (d, IH), 6.76 (d, IH), 7.17 (m, IH), 7.43 (m, IH), 7.65 (m, IH), 13 (b, IH).

DMSO-d6 500 MHz

0.25 (m, 2H); 3.73 (m, 1H); 6.88 (dd, 1H); 8.28 (d, 1H). f = 53 (m, 2H), 1.13 (m, 1H), 3.68 (m, 1H), 59 (d, 1H), 4.69 (d, 1H), 6.76 (d, 1H), 7.17 (m, 1H) 7.43 (m, 1 H), 7.64 (m, 1 H),

13 (b, 1H).

DMSO-d6 500 MHz

0.21 (m, 2 H), 3.62 (m, 1 H), 4. 6.71 (m, 1 H), δ 8.30 (d, 1 H).

C50 (m, 2H), 1.08 (m, 1H), 3.46 (m, 1H), 40 (d, 1H), 4.56 (d, 1H), 6.57 (d, 1H), .81 (m, 1H), 7.15 (dd, 1 H), 7.41 (in, 1 H),

0.22 (m, 2H), δ 3.66 (m, 1H), δ 6.69 (m, 1H), δ 8.29 (d, 1H).

DMSO-d6 300 MHz (m, 2H), 1.07 (m, 1 H), 350 (m, 1 H), 41 (d, 1 H), 4.62 (d, 1 H), 659 (d, 1 H), (m, 1 H) 7.13 (dd, 1 H), 739 (m, 1 H),

4.

5. DMSO-d6 500 MHz

6. DMSO-dg 300 MHz

022 (m, 2H), [delta] JO (m, 2H), 1.08 (m, IH), 3.46 (m, 1H) / 3.62 (m, IH), 4.40 (d, IH), 4J6 (d, IH), 6 J (d, 1H), 6.71 (m, 1H), 6 JO (m, IH), 7.15 (dd, 1H), 7.40 (m, IH) 8.30 (d, 1H).

0.22 (m, 2H), 0J0 (m, 2H), 1.07 (m, IH), 3.31 (m, IH), 3.66 (m, IH), 4.41 (d, 1H) _, 4.62 (d, IH), 6.60 (d, IH), 6.69 (m, IH), 6.78 (m, IH), 7.13 (dd, IH), 739 (m, 1H), _Z 8.29 (d, IH).

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

Example 9, Preparation of 5-fluoro-2 - [(4-cyclopropenylmethoxy-2-pyridinyl) methyl - (R / S) - (sulfinyl) -1- ((R) - mandeloxylmethyl) -IH

- benzimldazole and 6-fluoro-2 - [(4-cycloprophylmethoxy-2-pyridinyl) methyl] - (R / S) - (sulfinyl) -1- / (R) - mandeloxymethyl] -IH

- 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 tetrabuhylammonium sulfate and 3.0 g (20 mmol) of (R) - (-) mandelic acid. Chloroform (200 mL) and a mixture of 5-fluoro-2 - [(4-cycloprophylmethoxy-2-pyridinyl) methyl- (sulfinyl) -1- (chloromethyl)] - 1H-benzimidazole and 6-fluoro-2- were added. // (4-cycloprophylmethoxy-2-pyridinyl) methyl- (sulfinyl) -1- (chloromethyl) -1 H -benzoimidazole (as racemates) and the mixture was 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.

Yield: 9.0 g, 88%.

NMR results are shown below.

Table 2.

solvent

CDC13

03-0.4 (m, 37-3.9 (m ,: 63-6.6 (m);

[R results d ppm

1.0.6-07 (m, 2H), 1.1-13 (m, 1H), 1.4-4-4.9 (m, 2H) _Z 53-53 (m, 1H), l = 67 (m _from 1H), 6.85 (m _from 1H).

1.8.1-83 (m _from 1H).

my description is the use of magnesium salt

7.0 - 7.8 (m, 8

It is best known to support the 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 examples.

Syrup

Syrup contains 1% (w / v was prepared from the following ingredients;

unit) of the active substance which

Example 4 compound

Icing sugar

Saccharin

Glycerol

Flavoring agents

Ethanol 90%

Distilled water for topping up;

100%

1.0 g

30.0 g

0.6 g

5-0 g

0.05 g 5-0 g 100 ml

The sugar and saccharin were dissolved in 60 g of hot water. After cooling, the active substance 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.

Enteral-coated tebíetý

A tablet containing 50 mg of active compound was made from the following ingredients:

Example 7 Compound 500 g Lactose 700g Methylcellulose 6g Polyvinylpyrrolidone, crosslinked 50 g Magnesium stearate 15 g Sodium carbonate 6g Distilled water as required

Cellulose acetate phthalate 200g Acetylalkohol 15 g Isopropanol 2000 g Methylenchlorid 2000 g

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

II Cellulose acetophthalate and methylene chloride acetophthalate solution was sprayed onto the Accela Cota R, Manesty tab.

In the tablet coating device of summer, which would be obtained by this procedure, the weight was 110 mg.

Solution for intravenous use

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

Example 6 Sterilized water to final volume

4g 1000 ml

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

Capsule

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

Example 4 300 g

Lactose 700 g

Microcrystalline cellulose 40 g

Hydroxypropyl cellulose 62 g

Disodium hydrogen phosphate 2 g

Purified water as needed

The active ingredient was mixed with solid additives and with a disodium hydrogen phosphate solution. The wet mass is passed through an extruder, 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 hydroxypropyl methylcellulose in 750 ml of water using a fluid bed pellet coating apparatus. After drying, the pellets were coated with a second coating as described below.

Coating solution

Cellulose hydroxypropyl methyl phthalate 70 g Acetylalkohol 4g Acetone 200 g Ethanol 600 g

Finally, the above pellets were filled into capsules.

Suppositories

Suppositories were made from the following admixtures using a welding process. Each suppository contains 40 mg of active ingredient.

Compound of Example 4 Witepsol H -15

4g

180 g

The active substance was homogeneously mixed with ° C. The molten mass is used in packaging, to a net weight of 1.84 g. After oc Each suppository contains 40 mg of the active ingredient with Witepsol H-15 at a temperature of 41, the suppository packages are sealed.

The stabilization against racemization in various inventions towards racemization was 10 5 M) at 37 ° C in aqueous ethyl - (sulfinyl) -1- (chloromethyl)

Stability of optically pure compounds was measured at low concentrations (buffer solution pH between 7 and 11. Stereochemical stability was measured by comparing the optical purity of the (+) - isomer of the 5-fluoro-2 - [(4-cycloprophylmethoxy-2-pyridinyl) m /] The surprisingly high stereochemical stability in both neutral and alkaline conditions for the compounds of the invention illustrates the fact that the racemization of the test compound does not reach either pH 7 or pH 11 even after 28 hours. However, at pH 7, chemical degradation of the compounds is more evident for 28 hours

Claims (17)

Patent claims A single enantiomeric compound having the formulas Ia and Ib and therapeutically acceptable salts thereof. Compound according to claim 1, characterized in that the compound is (+) - 5 fluoro-2 - [(4-cycloprophylmethoxy-2-pyridinyl) methyl- (sulfinyl) -1- (chloromethyl)] - (1H) -benzimidazole, or a therapeutically acceptable salt thereof, and a substantially free (-) enantiomer thereof. and The compound of claim 1, wherein the compound is (-) - 5-fluoro 2 - [(4-cycloprophymethoxy-2-pyridinyl) methyl- (sulfinyl) -1- (chloromethyl)] -1H-benzimidazole, or a therapeutically acceptable salt thereof, and its substantially free (+) - enantiomer. Compound according to any one of claims 1-3, characterized in that the therapeutically acceptable salts are Na ⁺ , Li ⁺ , K ⁺ , Ca 2+ _> Mg ²⁺ and N ⁺ (R) 4, wherein R is an alkyl group having 1-4 carbon atoms . A compound according to any claim 1-4 are characterized in that the compounds are (+) -5-fluoro-2 - [(4-cycloprophymethoxy-2-pyridinyl) methylbenzimidazole sodium salt, (-) - 52-pyridinyl) methyl / sulfinyl] sodium salt, - (sulfinyl) -1- (chloromethyl) / -1H1-fluoro-2 - [(4-cycloprophymethoxy) 1- (chloromethyl)] -1H-benzimidazo: (+) -5-fluoro-2 - [(4-cycloprophylmethoxy-2-pyridinyl) methyl- (sulfinyl) -1- (chloromethyl)] - (1H) benzimidazole magnesium salt, (-) - 5 fluoro-2- // (4-cycloprophylmethoxy 1- (chloromethyl)) -1H-benzimidazole 2-pyridinyl) methyl- (sulfinyl) magnesium salt. A compound according to any one of claims 1 +) - 5 - fluoro - 2 - [(4-cycloprophylsulfinyl) -1- (chloromethyl)] - (1 H - ben sodium salt, (-) - 5-fluoro-2-) (4-Cyclomethyl- (sulfinyl) -1- (chloromethyl)) salt in crystalline form, or a sodium salt thereof. 5, characterized in that the compound is (thoxy-2-pyridinyl) methyl / imidazole magnesium salt or prophylmethoxy-2-pyridinyl) -1H-benzimidazole magnesium A compound according to claim 1 and 2 characterized by fluoro-2 - [(4-cycloprophylmethoxy -> 1- (chloromethyl)] - 1H-benzimidazolo in its crystalline form as an enantiomer of (-) and in that the compound is (+) - 5 i-pyridinyl) methyl- (sulfinyl) a magnesium salt, or sodium salt, in the enantiomer. Ř Compound according to claim 1, characterized in that the compound is (-) - 5 fluoro-2 - [(4-cycloprophylmethoxy-2-pyridinyl) methyl- (sulfinyl) 1- (chloromethyl)] - 1H-benzimidazole magnesium a salt, or a sodium salt, of its crystalline form as the enantiomer of the (+) - enantiomer. A process for producing a compound according to claim 1, wherein the diastereoisomeric ester of Formula V 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 to form an enantiomeric compound, in neutral form upon neutralization with a neutralizing agent, wherein the enantiomeric compound in neutral form is converted into therapeutic salts. 10. The process of claim 9 wherein the diastereoisomers are separated by chromatography or fractional recrystallization. J f The method of claim 9, wherein the solvolysis is performed 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 a base in protic and aprotic solvents such as vpda and acetonitrile. V ' A process for the preparation of a compound of claims 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 a nonaqueous solution to the resulting precipitate. - _ 1 A process for the preparation of (+) - 5-fluoro-2H-N (4-cycloprophylmethoxy-2-pyridinyl) methyl- (sulfinyl) -1- (chloromethyl) / -1H-benzimidazole sodium salt, (-) - 5 - fluoro-2 - [(4-cycloprophylmethoxy-2-pyridinyl) methyl- (sulfinyl) -1- (chloromethyl)] -1H-benzimidazole sodium salt, characterized in that in (+) - 5-fluoro-2 - ((4-cycloprophylmethoxy-2-pyridinyl) methyl- (sulfinyl) -1- (chloromethyl)) - (1H) -benzimidazole sodium salt, (-) - 5-fluoro-2 - [(4-cycloprophylmethoxy-2 -) - pyridinyl) methyl - (sulfinyl) -1- (chloromethyl)] - [@ 1 H] benzimidazole sodium salt, as a crude product, is treated in a non-aqueous medium, which is 2 butanone and toluene. and A formulation comprising the individual enantiomeric compounds of any one of claims 1-8 as an active ingredient. The individual enantiomeric compounds of any one of claims 1-8 for use in therapy. 16. Use of the individual enantiomeric compounds according to any one of claims 1-8 in the manufacture of a pharmaceutical composition for the inhibition of gastric secretions? 14. A pharmaceutical composition for the inhibition of gastric acid secretions and inflammatory diseases, comprising the individual enantiomeric compounds of any one of claims 1-8 as active ingredients15. The individual enantiomeric compounds of any one of claims 1-8 for use in therapy. Use of the individual phenantioraeric compounds of any one of claims 1-8 in the manufacture of a pharmaceutical composition for inhibiting gastric acid secretions. 17. The compound 5-fluoro-2 - [(4-cyclopropylmethoxy-2-pyridinyl) methyl- (sulfinyl) -1-chloromethyl] -1H-benzimidazole and 6-fluoro-2H-4-cyclopropylmethoxy- 2-pyridinyl) -methyl- (sulfinyl) -1-chloro (methyl) -1H-benzimidazole.