Optically pure na+, mg2+li+, k+or sa2+salt of (-)-5-methoxy-2[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl] sulfinil]-1h-benzimidazole, the retrieval method, farmcampsite based on them and the intermediate connection

 

(57) Abstract:

Optically pure Na+, Mg2+Li+TO+or Sa2+salt of (-)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinil] -1H-benzimidazole possess inhibiting gastric acid secretion activity. 4 c. and 13 C.p. f-crystals, 2 ill., table 2.

The invention is directed to new compounds with high optical purity, their use in medicine, the method of their preparation and their use in the manufacture of a pharmaceutical preparation. The invention relates to new intermediate products for producing compounds of the present invention.

Justification of the invention

The compound 5-methoxy-2-[[(4-methoxy-3, 5-dimethyl-2 - pyridinyl)methyl]sulfinil]-1H-benzimidazole, having a common name for omeprazole and its therapeutically acceptable alkali metal salts described in EP 5129 and EP 124 495, respectively. Omeprazole and its alkaline salts are effective inhibitors of gastric acid secretion and are useful as antiulcer funds. Connection, which sulfoxidov, have a center of asymmetry at the sulfur atom, i.e. exist as two optical isomers (enantiomers). It is desirable to obtain compounds of the ical feature, such as reduced degree inside individual variability. The present invention provides such compounds, which are new salts of (-)-enantiomer of omeprazole.

Separation of the enantiomers of omeprazole on the analytical level is described, for example, in J. Chromatography, 532(1990), 305-19 and preparative level in DE 4035455. Last performed using diastereomeric simple ether, which is released and then hydrolyzed in an acidic solution. In the acidic conditions required for the hydrolysis of a related group, omeprazole is quite sensitive and acid must be quickly neutralized by a base in order to avoid decomposition of the acid-sensitive compounds. With regard to the above-mentioned occasion this is done by adding the reaction mixture containing concentrated sulfuric acid, concentrated NaOH solution. This adversely, because there is a high risk of local achievements pH in the range of 1-6, which can be destructive to substances. In addition, instant neutralization will create heat, which will be difficult to control during manufacture on a large scale.

In a further aspect the invention provides novel is for large-scale production of single enantiomers of omeprazole in a neutral way.

In prior art there is no example selected or identified optically pure salt of omeprazole, that is, a single enantiomer of omeprazole or any selected or identified any salt of optically pure analogue of omeprazole.

Detailed description of the invention

The present invention relates to new Na+, Mg2+Li+", K+and Ca2+salts of (-)-enantiomer of omeprazole, that is, Na+, Mg2+Li+, K+and Ca2+salt of (-)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2 - pyridinyl)methyl]sulfinil]-1H-benzimidazole.

Especially preferred salts according to the invention are Na+Ca2and Mg2+salt, i.e. sodium salt of (-)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] -sulfinil]-1H-benzimidazole magnesium salt of (-)-5-methoxy-2-[[ (4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinil] -1H-benzimidazole and calcium salt of (-)-5-methoxy-2-[[(4-methoxy-3, 5-dimethyl-2-pyridinyl)methyl]sulfinil]-1H-benzimidazole.

According to the invention, the most preferred salts are optically pure Na+salt of (-)-omeprazole of formula (I)

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and optically pure magnesium salt of (-)-omeprazole Fort omeprazole, substantially free of Na-salt of (+)-enantiomer of omeprazole.

The single enantiomers of omeprazole have so far been obtained only in the form of syrup, but not in the form of crystalline products. Salt defined by the present invention can easily be obtained through a new specific method, according to one aspect of the invention to obtain single enantiomers of omeprazole. Besides salt, however, is not neutral forms are obtained as crystalline products. Because optical contaminated salts of the enantiomers of omeprazole is possible to purify by crystallization, they can be obtained with very high optical purity, namely from 99.8% enantiomeric excess (e. e. even from optical contaminated drug. In addition, the optical pure salts are stable to racemization in neutral pH and alkaline pH, which was unexpected because it was assumed that the well-known deprotonization on the carbon atom between the pyridine cycle and chiral sulfur atom will cause racemization in alkaline conditions. This high stability towards racemization makes it possible to use salts of (-)-enantiomer of omeprazole therapy.

As by mentioning the t of the invention, and this method can be used to obtain single enantiomers of omeprazole in neutral form, as well as their salts.

Compounds according to the invention can be used to inhibit gastric acid secretion in mammals and man. In a more General value of the compounds of the invention can be used for the treatment of diseases of the stomach, associated with the disturbance of acid and gastrointestinal inflammatory diseases in mammals and man, such as gastric ulcer, duodenal ulcer, reflux esophagitis and gastritis. In addition, the compounds can be used for treatment of other gastrointestinal disorders where desirable gastric antisecretory effect, for example for patients on NSAID therapy, patients with ulcerative pancreas and patients with acute gastrointestinal bleeding. They can also be used on patients in cases of intensive therapy, and pre - and post-operative to prevent acid aspiration and stress ulcers. Compounds of the invention can also be used for treatment or prophylaxis of inflammatory conditions in mammals, including man, the person who by Uta such conditions as arthritis and gout. Compounds of the invention may also be useful in the treatment of psoriasis, as well as in the treatment of Helicobacter infections.

In addition, a further aspect, the compound is compound III, which is an intermediate product used in the specific way of getting.

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Getting

Optically pure compounds of the invention, i.e. salts of (-)-enantiomer is prepared by separation of the two stereoisomers diastereoisomeric mixture of the following type, 5-or 6-methoxy-2-[[ (4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinil]-1- [acyloxymethyl]-1H-benzimidazole of the formula IV

< / BR>
where the methoxy substituent in the benzimidazole component is in position 5 or 6, and the Acyl radical is as defined below, followed by solvolysis of the selected diastereoisomer containing (-)-enantiomer of omeprazole in alkaline solution. The resulting (-)-enantiomer of omeprazole and then allocate the neutralization of aqueous solutions of salts of (-)-enantiomers of omeprazole neutralizing agent, which may be acid or ester such as methylformate.

Acyl (Acyl) component in diastereomers ether may be chiral acyl group, such as Mandalay, and a center of asymmetry in hit to be separated by either chromatographic or fractional crystallization.

The solvolysis usually occurs in the presence of a base in proton solvent such as alcohols or water, but the acyl group may be removed by hydrolysis using a base in the proton solvent, such as dimethylsulfoxide or dimethylformamide. A reactive basis can be OH-or R1O-where R1can be any alkyl or aryl group.

To obtain optically pure Na+salts of the invention, that is, Na+salts of (-)-enantiomer of omeprazole, the compound obtained is treated with a base such as NaOH in an aqueous or non-aqueous medium, or with NaOR2in which R2represents an alkyl group containing 1-4 carbon atoms or with NaNH2. In addition, alkaline salts, in which the cations are Li+or+can be prepared using lithium or potassium salts of the aforementioned compounds. In order to obtain the crystalline form of Na+salt, preferably adding NaOH in non-aqueous environment, such as a mixture of 2-butanone and toluene.

To obtain optically pure Mg2+salt of the invention optically pure Na+salt of (-)-enantiomer treated with an aqueous solution of inorganic magni the salt may also be prepared by treatment of (-)- enantiomer of omeprazole base, such as Mg(OR3)2in which R3represents an alkyl group containing 1-4 carbon atoms, in a nonaqueous solvent such as alcohol (for alcoholate), for example, ROH, or in simple ether, such as tetrahydrofuran. Similarly can be prepared also alkaline salt in which the cation is Ca2+using an aqueous solution of inorganic calcium salts such as CaCl2.

Examples of the alkaline salts of the single enantiomers of the invention are, as mentioned above, in addition to the sodium salt (compound (I) and magnesium salts (compound II), are also salts with Li+TO+and Ca2+.

For clinical application of (-)-enantiomers, i.e. optically pure compounds of the invention are prepared in the form of pharmaceutical forms for oral, rectal, parenteral or other techniques. The pharmaceutical compositions contain (-)-enantiomer of the invention is usually in combination with a pharmaceutically acceptable carrier. The carrier may be in the form of solid, semi-solid product or a liquid solvent, or capsules. These pharmaceutical preparations are further purpose of the invention. Usually the number of active Saidu 1-50 wt.% in preparations for oral administration.

In the preparation of pharmaceutical compositions in the form of a standard dose for oral administration of optically pure compound can be mixed with a powdered solid carrier such as lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose derivatives, gelatin, or other suitable carriers, stabilizing agents such as alkaline compounds, such as carbonate, hydroxide or oxide of sodium, potassium, calcium, magnesium and the like, as well as with lubricating agents such as magnesium stearate, calcium stearate, sodium stearyl fumarate and polietilenglikolya paraffins. The mixture is then processed into granules or compressed into tablets. Granules and tablets can be coated intersolubility sheath, which protects the active compound from the acid-catalyzed decomposition until the dosage form remains in the stomach. Intersolubility coating is selected from pharmaceutically acceptable materials for intersolubility membranes, such as wax, shellac or anionic film-forming polymers, and the like, optionally with a suitable plasticizer. The shell may be added various dyes to distinguish tablets or granules with different the us in the form of capsules, containing a mixture of active compounds, oil, grease or other suitable filler for soft gelatin capsules. Soft gelatin capsules may also be covered intersolubility shell, as described above.

Hard gelatin capsules may contain granules or coated intersolubility shell granules of the active compound. Hard gelatin capsules may contain the active compound in combination with a powdered solid carrier such as lactose, saccharose, sorbitol, mannitol, potato starch, amylopectin, cellulose derivatives or gelatin. Capsules can be coated intersolubility shell, as described above.

The standard dose for rectal injection can be prepared in the form of suppositories containing the active substance mixed with a neutral saturated ground, or they can be prepared in the form of a gelatine rectal capsule which contains the active substance in a mixture with a vegetable oil, paraffin oil or other suitable filler for gelatin rectal capsules, or they can be prepared in the form of a ready-made micro, or they can be prigotovlenno before the introduction.

Liquid preparation for oral administration can be prepared in the form of syrups or suspensions, for example solutions or suspensions containing from 0.2% to 20% by weight of the active ingredient and the rest containing sucrose or sugar alcohols and a mixture of ethanol, water, glycerol, propylene glycol and/or polyethylene glycol. If desired, such liquid preparations may contain colouring agents, corrigentov, saccharin and carboxy - methylcellulose or other sealing agents. Liquid preparations for oral administration may also be prepared in the form of a dry powder to obtain a desired composition in a suitable solvent immediately prior to use.

Solutions for parenteral administration can be prepared as solutions of optically pure compounds of the invention in pharmaceutically acceptable solvents, preferably in a concentration of from 0.1 to 10% by weight. These solutions may also contain stabilizing agents and/or buffers, and can be produced in ampoules or vials containing standard dose. Solutions for parenteral administration can also be prepared in the form of dry preparations to obtain an improvised composition in a suitable solvent before use.

The present invention is illustrated by the following examples. The direction of optical rotation of the enantiomers of omeprazole will change from (-) to ( + ) when mesolevel forms receive sodium salt, and Vice versa, when you get the magnesium salt of sodium salt.

Example 1

Obtaining the sodium salt of (+)-5-methoxy-2-[[(4-methoxy - 3,5-dimethyl-2-pyridinyl)methyl]sulfinil]-1H-benzimidazole

100 mg (0.3 mmole) of (-)-5-methoxy-2-1[(4-methoxy-3,5-dimethyl-2 - pyridinyl)methyl]sulfinil]-1H-benzimidazole (contaminated with 3% (+)-isomer) was dissolved with stirring in 1 ml of 2-butanone. Added 60 μl of an aqueous solution of 5.0 M of sodium hydroxide and 2 ml of toluene. The resulting mixture was inhomogeneous. To obtain the true solution is additionally added 2-butanone (about 1 ml) and the mixture was stirred at ambient temperature overnight. The formed precipitate was filtered and washed with diethyl ether. Received 51 mg (46%) named in the title compound as white crystals so square (ripped. ) 246-248oC. Optical purity (e.e.), The/SUB>0=+42,8o(C=0,5%, water).

The NMR data are shown below.

Example 2

Obtaining the sodium salt of (-)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl - 2-pyridinyl)methyl]sulfinil]-1H-Beneamata

100 mg (0.3 mmole) of (+)-5-methoxy-2- [[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfonyl]-1H - benzimidazole (contaminated with 3% (-)-isomer) was dissolved with stirring in 1 ml of 2-butanone. Added 60 μl of an aqueous solution of 5.0 M of sodium hydroxide and 2 ml of toluene. The resulting mixture was inhomogeneous. To obtain the true solution is additionally added 2-butanone (about 1 ml) and the mixture was stirred at ambient temperature overnight. The formed precipitate was filtered and washed with diethyl ether. Got 56 mg (51%) named in the title compound as white crystals so square (ripped. ) 247-249oC. Optical frequency (e.e.), which was analyzed by the method of chiral column chromatography 99.8%.

[]2D0= -44,1o(C=0,5%, water).

The NMR data are shown below.

Example 3

Obtaining the magnesium salt of (+)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl] sulfinil]-1H-benzimidazole

of 2.9 ml of 0.1 M NaOH solution was added to 0.10 g (0,29 mmole) of (+)-5-meth is orida and after mixing in a separating funnel and separated aqueous solution. Added dropwise a solution of 14 mg (0,145 mmole) MgCl2in the water. The formed precipitate was separated by centrifugation and gave 52 mg (50%) of product as an amorphous powder. Optical frequency (E. E.) was 98% and thus was the same as the source material. Optical purity was determined by chromatography on analytical chiral column []2D0= = +101,2o(C=1%, methanol). The content of Mg in the sample, determined by atomic absorption spectroscopy, was 3.0%.

Example 4

Obtaining the magnesium salt of (+)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl - 2-pyridinyl)methyl]sulfinil]-1H-benzimidazole

Sodium salt of (-)-5-methoxy-2-[[(4-methoxy-N, 5-dimethyl-2-pyridinyl)methyl]sulfinil]-1H-benzimidazole (0,500 g of 1.36 mmole) was dissolved in water (10 ml). To this mixture was added dropwise 10 ml of aqueous solution of MgCl2H2O (138 mg, 0.60 mmole) and the resulting precipitate was separated by centrifugation. Received 418 mg (86%) of product as a white powder. Optical purity (E. E.) product was 99.8% and thus was the same as the original product. Optical purity was determined by chromatography on analytical chiral column.

[]2D0
Sodium salt of (+)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2 - pyridinyl)methyl]sulfinil]-1H-benzimidazole (0,165 g, 0.5 mmole) was dissolved in water (3 ml). To this mixture was added dropwise 2 ml of aqueous solution of MgCl2H2O (46 mg, 0,23 mmole) and the resulting precipitate was separated by centrifugation. Received 85 mg (51%) of product as a white powder. Optical purity (E. E.) product amounted to 99.9%, which was the same or better value in comparison with the optical purity of the starting material. Optical frequency determined chromatographic analytical chiral column.

[]2D0= -128,2o(C=1%, methanol) (see tab. 1 in the end of the description).

Example 6

The increase in optical purity by preparation of the magnesium salt of (-)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2 - pyridinyl)-methyl] sulfinil] -1H-benzimidazole in non-aqueous solution, followed by crystallization of the specified salt

Magnesium (0.11 g, 4.5 mmole) is dissolved and injected into the reaction with methanol (50 ml) at 40oC with a catalytic amount of methylene chloride. The reaction is carried out under nitrogen and finish in five hours. To a solution of magnesium methoxide added at room temperature a mixture of two enantiomers (90% of (-)-isomer and 10% of (+)-from amerivault within 12 hours, then add a small amount of water (0.1 ml) to precipitate the inorganic salt of magnesium. After 30 minutes of mixing these inorganic salts are filtered off and the solution concentrated in rotavapor. The balance now is a concentrated methanolic solution of the enantiomeric mixture (i.e., the target compounds contaminated (+)-isomer), with an optical purity (enantiomeric excess, E. E.) 80%. This mixture is diluted with acetone (100 ml) and after stirring at room temperature for 15 minutes to obtain a white precipitate. Additional stirring for 15 minutes and then filtered to give 1.3 g (50%) of target compound as white crystals. Chiral analysis of the crystals and the mother liquor carry out chromatographic analytical chiral column. It is found that the optical purity of the crystals and the mother liquor is 98,4 E. E. and 64.4% E. E. respectively. Thus, the optical purity (E. E.) increased from 80% to 98.4% simply by crystallization of salts of magnesium from a mixture of acetone and methanol. The product is crystalline, as shown by powder x-ray diffraction, and the content of magnesium is 3,44%, as shown by atomic absorption spectroscopy.

[]2Dof the magnesium salt of (+)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2 - pyridinyl)-methyl] sulfinil] -1H-benzimidazole in non-aqueous solution, followed by crystallization of the specified salt

Magnesium (0.11 g, 4.5 mmole) is dissolved and injected into the reaction with methanol (50 ml) at 40oWith a catalytic amount of methylene chloride. The reaction is carried out under nitrogen and completed in five hours. At room temperature to a solution of magnesium methoxide was added a mixture of two enantiomers (90% of (+)-isomer and 10% (-)-isomer) 5-methoxy-2- [[(4-methoxy-N,5-dimethyl-2-pyridinyl)methyl] sulfinil] -1H - benzimidazole (2, 84 g, 8.2 mmole). The mixture is stirred for 12 hours, then add a small amount of water (0.1 ml) to precipitate the inorganic salt of magnesium. After 30 minutes of mixing the inorganic salt is filtered off and the solution concentrated in rotavapor. The rest is now a methanol solution of enantiomeric mixtures (i.e., the target compounds contaminated (+)-isomer), with an optical purity (E. E.) 80%. This mixture is diluted with acetone (100 ml) and after stirring at room temperature for one hour to obtain a white precipitate. Additional stirring for 30 minutes and then filtered to give 0.35 g of the target compound as white crystals. Additional agitation of the uterine fluid for 24 hours at room temperature gives another 1.0 g (total yield = 52%). Chiral analysis definition the purity of the first crystals is 98.8% E. E. and 99.5% E. e. respectively. The optical purity of the mother liquor was found equal to 57% of E. E. Thus, the optical purity (E. E.) increased from 80% to approx. 99% just by crystallization of the magnesium salt of a mixture of acetone and methanol. The first precipitate is crystalline, as shown by powder x-ray diffraction, and content of magnesium is 3.49%, as shown by atomic adsorption spectroscopy.

[]2D0= +135,6o(C=0.5%, methanol).

In the following examples describe the production of intermediate products for the synthesis according to the invention.

Example 8

Getting 6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] -(R/S)-sulfinil]-1-[(R)-mandelbrotset]-1H - benzimidazole

A solution of 3,4 of sodium hydroxide in 40 ml of water was added to a mixture of 14.4 g (42 mmole) of acid tetrabutylammonium sulfate and 6.4 g (42 mmole) of (R)-(-)-almond acid. The mixture was extracted with 400 ml of chloroform. After separation the organic extract was heated to boiling under reflux with 16.6 g (42 mmole) of racemate 6 - methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl] sulfinil] -1-[chloromethyl] -1H-benzimidazole. After evaporation of the solvent the residue was dissolved in 100 ml dichloromethane and 700 ml of ethyl acetate. See who crystallization from 100 ml of acetonitrile, having 8,1 g named the title compound (38%) in the form diastereomeric mixture. The NMR data are shown below.

Example 9

The allocation of more hydrophilic diastereoisomer of 6-methoxy-2-[[ (4-methoxy-3,5-dimethyl-2-pyridinyl)methyl] -(R/S)-sulfinil]-1- [(R)-mandelbrotset] -1H-benzimidazole

The diastereomers named in the title compound in Example 8 was separated using reverse-phase chromatography (VGH). Approximately 300 mg diastereomeric mixture was dissolved in 10 ml of hot acetonitrile, diluted with 10 ml of a mixture of aqueous 0.1 M ammonium acetate and acetonitrile (70/30). The solution was injected into the column and was suirable a mixture of aqueous 0.1 M ammonium acetate and acetonitrile (70/30). More hydrophilic isomer was easier to get clean than less hydrophilic isomer. Developed the following methodology for the fractions containing pure isomer: extraction with dichloromethane, washing of the organic solution of 5% aqueous sodium bicarbonate solution, drying over Na2SO4and evaporation of the solvent on a rotary evaporator (at the end of the evaporation removal of acetonitrile was facilitated more by adding dichloromethane). Using the above methodology 1.2 g diastereomeric mixture received more hydro is LASS="ptx2">

Example 10

Getting 6-methoxy-2-[[(4-methoxy-N, 5-dimethyl-2 - pyridinyl)methyl] -(R/S)-sulfinil]-1-[(S)-mandelbrotset]- 1H-benzimidazole

The product obtained from 0.1 g (202 mmole) of sodium hydroxide in 100 ml of water, 34.4 g (101 mmole) of acid tetrabutylammonium sulfate, 15,4 g (101 mmole) of (S)- (+)-almond acid and 39.9 g (101 mmole) of racemate 6-methoxy-2- [[4-methoxy-N,5-dimethyl-2-pyridinyl)methyl]-sulfinil]-1- [chloromethyl]-1H-benzimidazole using the same methods as in Example 6. Recrystallization from 100 ml of acetonitrile gave 21,3 g, that is, 41% mentioned in the title compound in the form of diastereomeric mixture.

The NMR data are shown below.

Example 11

The allocation of more hydrophilic diastereoisomer of 6-methoxy-2-[[(4 - methoxy-3,5-dimethyl-2-pyridinyl) methyl]-(R/S)-sulfinil]-1- [(S)-mandelbrotset] -1H-benzimidazole

The diastereomers named in the title compound in Example 10 was separated using reverse-phase chromatography (VGH) in the same way as in Example 9, but using diastereomeric a mixture of 6-methoxy-2-[[4-methoxy-3,5-dimethyl-2-pyridinyl)methyl] - (R/S)-sulfinil]-1-[(S)-mandelbrotset] -1H-benzimidazole instead of ester (R)-almond acid used in Example 9. Ispolzovanny syrup.

The NMR data are shown below.

Example 12

Obtaining (-)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2 - pyridinyl)methyl] -sulfinil]-1H-benzimidazole

to 0.23 g (0.45 mmole) is more hydrophilic diastereoisomer of 6-methoxy-2-[[4-methoxy-3, 5-dimethyl-2-pyridinyl)methyl]-sulfinil]-1-[(R) -mandelbrotset] -1H-benzimidazole was dissolved in 15 ml of methanol. Added a solution of 36 mg (0.9 mmole) of sodium hydroxide in 0.45 ml of water, and after 10 minutes the mixture was evaporated on a rotary evaporator. The residue was distributed between 15 ml water and 15 ml of dichloromethane. The organic solution was extracted with 15 ml of water and the combined aqueous solution was added 85 μl (1.4 mmole) of methylformate. After 15 minutes the mixture was extracted with 3 x 10 ml dichloromethane. The organic solution was dried over Na2SO4and then was evaporated. Received of 0.13 g (77%) named in the title compounds as a colorless syrup. Optical purity (E. E. ), which were analyzed by chiral column chromatography was 94%.

[]2D0= -155o(C=0.5%, chloroform).

The NMR data are shown below.

Example 13

Obtain (+)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2 - pyridinyl)methyl] -sulfinil]-1H-benzimidazole

0,76 g (1.5 mmole) are more hydrophilic, diester is dissolved in 50 ml of methanol. Added a solution of 0.12 mg (3.0 mmole) of sodium hydroxide in 1.5 ml of water, and after 10 minutes the mixture was evaporated on a rotary evaporator. The residue was distributed between 25 ml of water and 25 ml of dichloromethane. The organic solution was extracted with 25 ml of water and the combined aqueous solution was added 200 μl (3.2 mmole) of methylformate. After 15 minutes the mixture was extracted with 3 x 25 ml dichloromethane. The organic solution was dried over Na2SO4and then was evaporated. Got 0,42 g (81%) named in the title compounds as a colorless syrup. Optical purity, (E. E.), which were analyzed by chiral column chromatography, was 98%.

[]2D0= +157o(C=0.5%, chloroform).

NMR data are given in table. 2 at the end of the description.

The best way to embodiments of the invention known at present is the use of sodium salts, optically pure compounds of the invention, i.e. the compounds described in Example 1 and Example 2.

Pharmaceutical preparations comprising compounds of the invention as the active ingredient, are illustrated by the following compositions.

Syrup

Syrup, containing 1% (weight. volume) of the active substance prepared from the following ingredient is - 0 g

Corrigent - 0.05 g

Ethanol 96% - 5.0 g

Distilled water q.s. (desired quantity) to a total volume of 100 ml

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

Tablets, coated intersolubility shell

Tablet covered intersolubility shell containing 50 mg of active compound prepared from the following ingredients:

I

The compound of the invention in the form of a Mg salt 500 grams

Lactose - 700 g

Methylcellulose - 6 grams

Crosslinked polyvinylpyrrolidone - 50 g

Magnesium stearate - 15 g

Sodium carbonate 6 g

Distilled water - (required number) q.s.

II

Phthalate cellulose acetate - 200 grams

Cetyl alcohol - 15g

Isopropanol - 2000

Methylene chloride - 2000

I Connection according to the invention, powdered, mixed with lactose and granulated with a water solution of methyl cellulose and sodium carbonate. Wet weight conceded under pressure through a sieve, and the granules were dried in the oven. After drying, the granulate was mixed with polyvinylpyrrolidone is 50 mg of active substance, in a machine for the manufacture of tablets using punches with a diameter of 7 mm

II Solution phthalate cellulose acetate and cetyl alcohol in isopropanol/methylene chloride deposited on the pill I Accela Cota, Manesty equipment for coating. Received the tablet with the final weight of 110 mg.

Solution for intravenous injection

Parenteral composition for intravenous administration containing 4 mg of active compound per ml, prepared from the following ingredients:

The compound of this invention is 4 grams

Sterile water to a final volume of 1000 ml

The active compound was dissolved in water to a final volume of 1000 ml, the Solution was filtered through a 0.22 μm filter and was immediately Packed up in 10 ml of sterile ampoules. Ampoules were soldered.

Capsules

Capsules containing 30 mg, prepared from the following ingredients:

The compound of the invention - 300 grams

Lactose - 700 g

Microcrystalline cellulose 40 g

Hydroxypropylcellulose with a low degree of substitution - 62 g

Disodium acid (ortho)phosphate salt 2 grams

Purified water - q.s.

The active compound was mixed with the dry ingredients and granulated with a solution of disodium sour is dried in the dryer in the fluidized layer.

The solution for coating:

Phthalate of hydroxypropylmethylcellulose - 70 g

Cetyl alcohol 4 grams

Acetone - 200 grams

Ethanol - 600 g

The finished coated tablets, filled capsules.

Suppositories

Suppositories prepared from the following ingredients using a welding method. Each suppository contained 40 mg of active compound.

The compound of this invention is 4 grams

Witepsol N-15 - 180 grams

An active connection is homogeneous mixed with Witepsol N-15 at a temperature of 41oC. the Molten mass is filled by volume of a pre-fabricated shell for suppositories to the net weight of 1.84, After cooling shell zapravljajut by heating. Each suppository contains 40 mg of active compound.

Resistance to racemization at different pH values

The stability of the optically pure compounds of the invention against racemization was determined at low concentrations in the refrigerator in aqueous buffer solutions at pH 8; 9,3; 10 and 11.2. Stereochemical stability was determined by comparing the optical purity of (-)-isomer of 5-methoxy-2-[[4-methoxy-3,5 - dimethyl-2-pyridinyl)methyl]sulfinil]-1H-benzimidazole in supersolutions chiral column. A surprisingly high stereochemical stability in alkaline environments for compounds of the invention is confirmed by the fact that even after 21 days at pH of 11.2 no observed racemization of the test compounds. At pH 8; 9.3 and 10 more apparent chemical decomposition of compounds that significantly impedes the performance measurements racemization, however, in the absence of these pH noticeable racemization was observed after 16 days.

In another experiment racemization with optically pure compounds of the invention containing phosphate buffer aqueous solution (pH 11) sodium salt of (+)-isomer of 5-methoxy-2-[[(4-methoxy-3, 5-dimethyl-2-pyridinyl)methyl] sulfinil] -1H-benzimidazole (C= 10-5M) was heated for 26 hours at 37oC without any racemization during the whole time of observation.

Clinical comparison of the pharmacokinetics of sodium salt of (-)- enantiomer of omeprazole, sodium salt (+)-enantiomer of omeprazole and sodium salt of omeprazole

In Fig. 1 and 2 presents the data of the two studies.

In Fig. 1 presents the average levels in the blood plasma of racemic omeprazole, (-)-enantiomer of omeprazole and (+)- enantiomer of omeprazole (here and below the symbol (-)-omeprazole and (+)-magogo connection. The average AUC (-)-omeprazole is in a stationary state was almost 90% higher than that for racemic omeprazole, while this indicator for (+)-omeprazole accounted for about one third of that of the racemic omeprazole.

In Fig. 2 presents the average levels of omeprazole the racemate, (+)-omeprazole and (-)-omeprazole in plasma at steady state (day 7) slow the latter to insucient buildup after the appointment of 60 mg of sodium salts of each connection. The slow of the latter to insucient buildup of average AUC at steady state (-)-omeprazole was about 30% lower compared to racemic omeprazole, while the AUC for (+)-omeprazole was higher.

After adjusting for various doses was found that the AUC (-)-omeprazole was approximately 3 times higher in the latter to insucient buildup of slow compared to fast (normal), the latter to insucient buildup. On the other hand, for (+)-omeprazole difference in AUC between slow and fast the latter to insucient buildup was more significant (about 30 times). Racemic omeprazole, being a mixture of two enantiomers, takes about 10-fold difference in AUC between slow and fast the latter to insucient buildup.

1. Optically pure Na< sulfinil]-1H-benzimidazole.

2. Connection on p. 1, representing the Na+MD2+or Sa2+salt of (-)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl] sulfinil] -1H-benzimidazole.

3. Connection on p. 1, representing MD2+salt of (-)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl] sulfinil]-1H-benzimidazole.

4. Connection on p. 1, representing Na+salt of (-)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl] sulfinil]-1H-benzimidazole in its crystalline form.

5. A method of obtaining optically pure compounds on p. 1, characterized in that diastereoisomers a mixture of ether of the formula IV

< / BR>
where the acyl means of chiral acyl group having the R-or S-configuration, share for individual diastereoisomers, after which the diastereoisomer, consisting of acyloxymethyl derived (-)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl] sulfinil] -1H-benzimidazole is dissolved in alkaline solution, where acyloxymethyl group is hydrolyzed with the formation of (-)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl] sulfinil] -1H-benzimidazole, which is then converted into Na+MD2+Li+or Sa2+Sol.

6. The method according to p. 5, characterized t is stereoisomer separated by chromatography or fractional crystallization.

8. The method according to p. 5, wherein the solvolysis is carried out in alkaline solution, consisting of a base in proton solvent, such as alcohols or water, or base in an aprotic solvent such as dimethylsulfoxide or dimethylformamide.

9. The method according to p. 5, characterized in that the salt is obtained by treatment of (-)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl] sulfinil] -1H-benzimidazole base, including Na+MD2+Li+or Sa2+in the nonaqueous solvent.

10. The method according to p. 9 obtain the sodium salt of (-)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinil]-1H-benzimidazole in its crystalline form, wherein the crude product is neutralized sodium salt followed by treatment with NaOH in a nonaqueous environment.

11. Pharmaceutical composition having inhibitory gastric acid secretion activity, containing the active ingredient and pharmaceutically acceptable carrier, characterized in that as the active ingredient it contains a compound according to any one of paragraphs. 1-4 in an effective amount.

12. Optically pure compounds according to one of paragraphs. 1-4, with inhibiting gastric acid secrets the coy composition for inhibiting gastric acid secretion.

14. Optically pure compound according to one of paragraphs. 1-4 for the preparation of pharmaceutical compositions for the treatment of gastrointestinal inflammatory diseases.

15. 6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinil]-1-(mandelbrotset)-1H-benzimidazole.

16. Connection on p. 15, representing 6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl] -(R/S)-sulfinil] -1-[(R)-mandelbrotset]-1H-benzimidazole.

17. Connection on p. 15, representing 6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl] -(R/S)-sulfinil] -1-[(S)-mandelbrotset]-1H-benzimidazole.

 

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< / BR>
where

where R is aryl, 2-, 3 - or 4-pyridinyl, unsubstituted or substituted lower alkyl, lower alkoxyl, hydroxyl or halogen, 2-, 4 - or 5-pyrimidinyl, unsubstituted or substituted lower alkyl, lower alkoxide, hydroxyl or halogen, 2-pyrazinyl, unsubstituted or substituted lower alkyl, lower alkoxyl, hydroxyl or halogen, 2 - or 3-thienyl, unsubstituted go substituted lower alkyl or halogen, 2 - or 3-furanyl, unsubstituted or substituted lower alkyl or halogen, 2-, 4 - and 5-thiazolyl, unsubstituted or substituted lower alkyl or halogen, 3-indolyl, 2-, 3 - or 4-chinoline, and m is the number 1, 2, or 3, or group

< / BR>
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< / BR>
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mixtures of their isomers or the individual is

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,

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< / BR>
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