Magnesium salt of the (-)-enantiomer of omeprazole and its use

Field of the Invention

The invention relates to the behavior of producing novel compounds which are optically pure. The invention once again provides novel intermediates for the preparation of the compounds of the invention.

Background of the Invention

The compound 5-methoxy-2- [(4-methoxy-3'-dimethyl-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazole, which is commonly called omeprazole, and its medically acceptable alkaline salts is disclosed in EP 5129 and EP 124 495, each in this rod. Omeprazole and its basic sol are active as inhibitors of gastric acidosis and are useful as antidotes. The compounds that are sulphoxide, are at the center of the sulfur atom, i.e. found as two optical disappearances (hand woven). A pathway is desirable to get compounds with better pharmacokinetic and metabolic properties that provide better behavioral support such as the multiple versus individual abnormalities. The invention provides such compounds, which are novel salts (-) - omomer of omeprazole.

The separation of enantiomers of omeprazole in detectable scope is described, for example, in J. Chromatography, 532 (1990), 305-19, and in scope for preparation in DE 4035455. In the present invention, use has been made of a quaternary enantiomer separated from and hydrolysed in a stirring solution. In acidic acid residues that are susceptible to hydrolysis of the leaving group, omeprazole is very potent and the acid is well-neutralized with a base to prevent the metabolism of the acidic compound of the compound. In a sustained application, this is accomplished with the highest reaction rate containing condensed sulfuric acid with a condensed solution of NaOH. This is a disadvantage because it is highly dependent on certain supports, the pH will be between 1-6, which would destroy the substance.

The invention, seen from a further aspect of the invention, provides a new approach to the development of novel compounds of the invention. This new behavior can also be used extensively to obtain the single enantiomer of omeprazole in neutral form.

There is no evidence of any isolated soluble salts of optically pure omeprazole, i.e. individual enantiomers of omeprazole or any isolated acute salts of any photologically pure omeprazole silica.

DETAILED DESCRIPTION OF THE INVENTION

The invention relates to a method of producing new Na⁺, Mg²⁺, Li⁺, K⁺and Ca^{in +} salts (-) - enantiomer of omeprazole, ie Na⁺, Mg²⁺, Li⁺, K⁺ and Ca^{L +} salts (-) - 5-methoxy-2 - [[(4-methoxy-3-dimethyl-2-pyridinyl) methyl] sulfonyl] -1H-benzimidazole.

Particularly preferred salts according to the invention are Na⁺, Ca²⁺ and Mg²⁺ salts, ie sodium salt (-) - 5-methoxy-2 - [[(4-methoxy-3,4-dimethyl-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazole, magnesium salt (-) - 5-methoxy-2 - [[( 4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazole and calcium salt (-) - 5-methoxy-2 - [[(4-methoxy-3,4-dimethyl-2-pyridinyl) ) methyl] sulfinyl] benzimidazole.

The preferred salts according to the invention are optically pure Na⁺ salts (-) - enantiomer of omeprazole according to Compound 1

<img file="IS1854B_D0001.tif" />

<img file="IS1854B_D0002.tif" />

and optically pure magnesium salt (-) - enantiomer of omeprazole according to Compound IIh₃c

<img file="IS1854B_D0003.tif" />

V^CH3

N ^ CH₂-

<img file="IS1854B_D0004.tif" />

AND '3 (ID

mg

2+

With "optically pure Na⁺ which was surprisingly anticipated by the known prototype ring at the carbon atom between the pyridine ring and the hands of the brenmstein atom, triggered a rash at basfkar expo. This high degree of resistance to racemation makes it possible to use the salt (-) enantiomer of omeprazole behavior.

The specific behavior of the omeleprazole single enantiomers can be used to obtain single enantiomers of omeprazole in neutral form as well as their salts.

The compounds according to the invention may be used to inhibit gastric acidosis of mammals and humans. More generally, using the compounds of the invention in the treatment of gastric acid-related diseases and gastrointestinal and gastrointestinal diseases in mammals and mothers, such as stomach ulcers, stomach ulcers, spinal corditis and gastritis. The compounds may also be used for treatment of dyspnoea and gastrointestinal disorders over a period of time, as gastric acid erythropoiesis is impaired, for example in NSAID patients, in gastrointestinal patients, and in patients with upper gastrointestinal ulcer disease. They can also be used in patients with intensive care facilities, and before and after surgery to prevent acid retardation and stress-induced ulceration. The compound of the invention may also be used in the treatment or prevention of inflammatory conditions in mammals, including in humans, especially as solvents are involved. Special conditions include 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.

Still further aspect of the invention is Compound III, which is an intermediary used in the particular behavior of the production.

<img file="IS1854B_D0005.tif" />

production

The optically pure compounds of the invention, i.e. salts (-) - enantiomers are prepared by separating a double-bed two-dimensional mixture of the following 5-ed 6-methoxy-2 - [[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl] -1- [acyloxymethyl] -1H-benzimidazole, Formula IV

<img file="IS1854B_D0006.tif" />

wherein the methoxy shift moiety of the benzimidazole moiety is in the 6th position, and wherein the acyl group is as defined below, followed by the solvent lysis of the separated polynomials which comprise (-) enantiomer of omeprazole in alkaline solution. (-) - enantiomers of omeprazole formed is then isolated by neutralizing an aqueous solution of salt (-) - hand wrap omeprazole with neutralizing agent which may be acidic esters such as methyl formate.

The acyl half of the diastereomeric esters may have a displaced acyl group such as mandeloyl, and the non-agglomeration of the center of the acyl group may remain at the R eda S position,

The other compounds may be separated by chromatography.

The solubility is carried out together with a base in a polymeric solvent such as alcohols, but the acyl group may also be hydrolyzed with a base in an organic solvent such as dimethylfluoroxide and dimethylformamide. The incubation base can be protected by OH^]O "where R¹ may represent a straight-chain alkylated aryl group.

To this end, you will find virtually pure na⁺ salt of the invention, i.e. Na⁺ salt (-) - enantiomers of omeprazole is a derivative of a compound treated with a base such as NaOH, aqueous anhydrous, etc. with NaOR² where R² is an alkyl group containing 1-4 carbon atoms, such as NaNH₂. Alternatively, you can add a base to a basic sdlt where the cation is Li⁺ eda k⁺ with the use of lithium-potassium salts of the above base. In order to get a crystalline form Na⁺ The salt is preferably added with NaOH at anhydrous medium such as 2-butanone and toluene.

To get optically clean Mg²⁺ salt of the invention, is optically pure Na⁺salt (-) - enantiomers of omeprazole treated with aqueous solution of inorganic magnesium salts such as MgCl₂, where Mg²⁺ sdithin are precipitated. Optically pure Mg²* The salt can also be produced by treating (-) enantiomer of omeprazole with a base, such as Mg (OR³)₂, where R³ is an alkyl group containing 1-4 carbon atoms in anhydrous solvent such as alcohol (for alcohols only), for example ROH, or in ether such as tetrahydrofuran. In a slippery way, alkaline salt can be produced in which the cation is Ca²⁺, using an aqueous solution of inorganic calcium salts such as CaCl₂.

Referred to as examples of the alkaline salts (-) enantiomer of the invention, as mentioned above, the sodium salt (Compound I) and magnesium salt (Compound II), as well as their salts with Li⁺, K⁺ and Ca²*.

For clinical use, the sdlt (-) - handbag of the invention, i.e. photologically pure compounds, administered in oral, rectal, parenteral or oral administration by oral preparations. Pharmaceutical formulations typically contain the (-) enantiomer of the invention in combination with a pharmacologically acceptable carrier. Burning agent may be in the form of solid, semi-solids, of liquid form, capsule. These pharmaceutical compositions are also the subject matter of the invention. Typically, the amount of active compound of the compound is between 0.1 to 95% by weight of the composition, between 0.2 to 20% by weight in admixtures for parenteral use and between 1-50% by weight in oral compositions.

In the preparation of oral formulations in the form of oral dosage units, the optically pure compound may be mixed with solid, powdery carriers such as lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose derivative, gelatin or other suitable carriers, such as basic compounds such as carbonates, hydroxides and sodium, potassium, calcium, magnesium oxide, and so on, as well as lubricating agents such as magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethylene glycol elastomers. From the time you've done it, you've been forced out of it. The skin and throat can be coated with an enteric coating that protects the active compound from acidic nephropathy while the dosage form is in the stomach. The enteric coating is chosen from pharmacologically potent acidic coating agents, such as beeswax, flak coat, such anionic film-forming agents and such materials, if desired together with suitable softeners. Various dyes can be added to the coating to distinguish between tablets containing different amounts of active substance present.

Soft gelatin capsules can be made with capsules containing a binder of active ingredient, vegetable oil, fat, and a suitable gelatin for soft gelatin capsules. Soft gelatin capsules may also be an enteric coating as described above.

Hearing gelatin capsules can contain the granular enteric coating granules of the compound. Hearing gelatin capsules may also contain an active compound in a powdered carpet such as lactose, saccharose, sorbitol, mannitol, potato starch, amylopectin, cellulose derivatives of your gelatin. The capsule may be enteric coated as described above.

Dosage units for rectal administration can also be made in the form of active ingredient containing components with a neutral liposome, as well as in the form of a gelatin containing analgesic containing active ingredient with a vegetable flask, a paraffin oil and a suitable carrier for gelatin rectal capsules, these may be formed on the form of a rectal rectal analgesic, which may be formed in the form of an analgesic powder for dissolving in a video solvent just prior to insertion.

Liquid mixture for oral intake may be added to the form and form of syrup such as solutions containing suspensions containing from 0/02% to 20% by weight of the active ingredient and the remainder containing sugar and sugar alcohols and a mixture of ethylene, water, glyceride, propylene glycol and / or polyethylene glycol. If desired, such liquid in liquid form may contain coloring agents, flavoring agents, saccharin and carboxymethyl cellulose such as thickeners. Liquid in liquid form for oral intake may also be made in the form of a powder that dissolves a suitable solvent for use.

Solutions for parenteral administration can be made as solutions by the very best

The compounds of the invention are pharmacologically-hydrogenated, excreted free from 0.1 to 10% by weight. These solutions can also contain inhibitors that increase the ability to study and / or study pediatric patients, and may produce different unitary lameness of your vomiting. Solutions for parenteral administration can also be made as dry solutions that dissolve with a suitable solvent just prior to use.

The typical typical daily dose of the compound The compound is discussed by various factors such as, for example, individual patient threats, the pathway used in the disease and the disease. Generally, oral and gastrointestinal intake doses range from 5 to 500 mg today of the active substance.

The invention is further described with the following examples. The direction of the optical rotation of omeprazole of the enantiomers will change from (-) {(+) when sodium salt is prepared from the unsalted form and vice versa when magnesium salt is made from the sodium salt.

Example 1, Reaction of (+) - 5-Methoxy-2-yl) -4-methoxy-3,5-dimethyl-2-pyridinylmethylsulfinyl-1H-benzimidazole sodium salt

100 mg (0.3 mmol) of (-) - 5-methoxy-2 - [[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazole (contaminated with 3% of the (+) - neighborhood) were dissolved in 1 ml of 2-butanone by stirring. 60 μl of aqueous solution of 5.0 M sodium hydroxide and 2 ml of TI was added. The resulting mixture was not homogeneous. To obtain a tsar solution, more of 2-butanethanol (approximately 1 ml) was added and stirred overnight at ambient temperature. The precipitate formed was sead off and washed with ether. 51 mg (46%) of the compound were obtained according to the title of white crystals bm (decomposition) 246-248 ° C. The intelligent purity (u, h.) Analyzed by hand was approximately 2: 99.8%. [A]_D+ = + 42.8 ° (c = 0.5%; water).

NMR data are shown below.

Example 2, Reaction of (-) - 5-methoxy-2-flu (4-methoxy-35-dimethyl-2-pyridinyl) methylsulfinyl-1H-benzimidazole sodium salt

100 mg (0.3 mmol) of (+) - 5-methoxy-2 - [[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazide (mixed with 3% (-) - district) were dissolved in 1 ml of 2-butanone by stirring. 60 μl of aqueous solution of 5.0 M sodium hydroxide and 2 ml of toluene was btt dt. The resulting mixture was not homogeneous. To obtain a clear solution, more 2-butanone was poured into (approximately 1 ml) and stirred overnight at ambient temperature over night. Bottom time that was photographed was siad off and washed with ether. There were obtained 56 mg (51%) of the compound according to the title of white crystals bm (decomposition) 247-249 ° C. The cleanliness of the cleanliness (the intelligence of the hand was reduced to 99.8%._D= -44.1 ° (c = 0,%, water).

NMR data are shown below.

Example 3, Reaction of (+) - 5-methoxy-2-imido- (4-methoxy-35-dimethyl-2-pyridinylmethylsulphinyl) -1H-benzimidazole potassium salt

2.9 ml of 0.1 M solution of NaOH was added 0.10 g (0.29 mmol) of (+) - 5-methoxy-2 - [[(4-methoxy-3,5-dimethyl- 2-pyridinyl) methyl] sulfinyl] benzimidazole. Out of this bubble was added 2 ml of methylene chloride, and after mixing in a separatory funnel the aqueous solution was separated. A solution of 14 mg (0.145 mmdl) of MgCl₂ in water there was a drop in drops. The resulting film phase was separated by centrifugation and 52 mg (50%) of the product were isolated in the form of powdered powder. The optical purity (nA.) Was 98%, and the same as in the starting material. The cleanliness of the cleanliness was a dummy with a chromatic analysis of the hand analysis column. [A]_D^M= + 101.2 ° (c = 1%, methanol). The Mg content of the sample was found to be 3.0%, shown by atomic absorption spectroscopy.

EXAMPLE 4 Preparation of (+) - 5-Methoxy-2-yl (4-methoxy-3-dimethyl-2-pyridyl) methylsulfinyl] -4H-benzimidazole magnesium salt (-) - 5-methoxy-2 - [[(4-methoxy-33-dimethyl- 2-pyridinyl) methyl] sulfinyl] -1H-benzimidazole sodium salt (0300 g, 136 mmol) was dissolved in water (10 ml). To the mixture was added 10 ml of an aqueous solution of MgQ₂XH₂O (138 mg, 0.68 mmol) dropwise and the precipitate formed was isolated by centrifugation. 418 mg (86%) were obtained from the product in the form of white powder. The optical purity (utilization of the product was 99.8%, which is the same as the optical purity of the starting materials. The optical purity was determined by chromatography on the hand of the analysis column.₀^2θ= + 129.9 ° (c = 1%, metandl).

EXAMPLE 5 Preparation of f-T5-Methoxy-2-H (4-methoxy-35-dimethyl-2-pyridinyl) methylsulphinyl] -1H-benzimidazole magnesium salt (+) - 5-methoxy-2 - [[(4-methoxy-3,5-dimethyl -2-pyridinyl) methyl] sulfinyl] -1H-benzimidazole sodium salt (0.165 g, 0.45 mmol) was dissolved in water (3 mL). To the mixture was added dropwise 2 mL aqueous solution of MgCl2₂XH₂O (46 mg, 023 mmdl) and precipitate formed was isolated by centrifuge. This gave 85 mg (51%) of the product in the form of a white powder. The luminous purity (uh) of the product was 99.9%, which was the same as that of the starting material. The optical purity was determined by chromatography on the hand analysis column. -128.2 ° (c = 1%, metandl).

Tafia 1

<td>Example.</td><td>Solvent</td><td>NMRgögnðppm</td>

<td>1.</td><td>DMSO-d_e500 MHz</td><td>220 (s, 3H); 2.22 (s, 3H); 3.69 (s, 3H); 3.72 (s, 3H); 437 (d, 1 H); 4.75 (d, 1H); 634 (dd, 1H); 6.96 (d, 1H) 730 (d, 1H); 8.21 (s, 1H).</td>

<td>2.</td><td>DMSO-d₆500 MHz</td><td>220 (s, 3H); 222 (s, 3H); 3.69 (s, 3H); 3.72 (s, 3H); 438 (d, 1 H); 4.73 (d, 1H); 634 (dd, 1H); 6.96 (d, 1H); 731 (d, 1H); 821 (s, 1H).</td>

Preparation of prepared intermediates according to the invention is described in the following examples.

Example 6, Reaction of 6-methoxy-2-H (4-methoxy-35-dimethyl-2-pyridinyl) methyl (R / S) sulfinyl] -1-methyl-1-benzimidazole-1

A solution of 3.4 g of sodium hydroxide (40 ml) of water was added 14.4 g (42 mmol) of tetrabutylammonium dihydrogen sulfate and 6.4 g (R) - (-) mandelic acid. Extraction of the mixture with 400 nd of koldroform. After separation, the organic sealant was heated to reflux with 16.6 g (42 mmdl) racemate 6-methoxy-25 [[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl] -1- [ k] órmetýl] -lH-benzimidazole. Evaporation of the solvent was followed by dilution with 100 ml of dichloromethane and 700 ml of ethyl acetate. The mixture was washed with 3 x 200 ml of water and the organic solution was dried over MgSO4 and then evaporated. Crude material was purified by recrystallization from 100 ml of acetonitrile, yielding 8.1 g of the compound according to the title (38%) as a submerged mixture.

NMR data are shown below.

Example 7, Partition unit on a water-coolant medium 6-methoxy-2-fluoro-4-methoxy-3-dimethyl-2-pyridinylmethyl- (R / S) -sulfinyl-1 (R) -methyloxymethoxy] -1H-benzimidazole

The distillate of the compound according to the title of Example 6 was separated by HPLC. Approximately 300 mg of the diastereomer mixture were dissolved 10 ml of hot acetonitrile diluted with 10 ml of aq. 0.1 M ammonium acetate and acetonitrile (70/30). The solution was poured onto the column and the compounds were washed with aq. 0.1M ammonium nitrate and acetonitrile (70/30). The audience was close to the water scrubber neighborhood, cleaner than the one that was less water-resistant. Processing process for the object containing the clean neighborhood was as follows: extraction with dichloromethane, the aqueous solution washed with aqueous 5% sodium hydrogen carbonate solution, dried over Na2 SO4₄ and the solvent was evaporated with a rotary evaporator (at the end of the evaporation, the removal of acetone nitrate was determined by the amount of dichloromethane released). By using 1.2 g of the four-dimensional derivative with the above behavior, 410 mg of the water scrubber was obtained in a pure form as a colorless siltp.

NMR data are shown below.

Example 8, Reference Example 6-Methoxy-2 - [(4-methoxy-35-dimethyl-2-pyridinylmethyl) -1S-sulfonyl-1-yl] mandeloyloxymethyl-1H-benzimidazole

The product was obtained from 8.1 g (202 mmdl) of sodium hydroxide in 100 ml of water, 34.4 g (101 mmdl) of tetrabutylammonium hydrogen sulfate, 15.4 g (10 mmol) of (S) - (+) - mandelic acid and 39 , 9 g (101 mmdl) of racemate 6-methoxy-2 - [[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfonyl] -1- [methyl] -1H-benzimidazole by use sdmu behavior and in Example 6. Recrystallization from 100 ml acetone nitrate revealed 213 g. ie 41% of the compound according to the title as a polyvinyl chloride.

NMR data are shown below.

EXAMPLE 9 Analysis of Hydrophobic Enantiomers 6-Methoxy-2 - [(4-methoxy-3-dimethyl-2-pyridinylmethyl) - (R / S) -sulphinyl] -1-CS) -Mandeloyloxymethyl-1H-benzimidazole

The enantiomer of the compound according to the title of Dsmi 8 was separated by chromatography (HPLC) in the same manner as Example 7, but using the diastereomeric mixture from 6-methoxy-2 - [[(4-methoxy-33-dimethyl-2-pyridinyl) methyl] (R / S) -sulphinyl] -1 - [(S) -manyldyloxymethyl] -1H-benzimidazole in the (R) almond ester ester used in Example 7. Using 2.1 g of the diastereomeric mixture, 760 mg of a more water-efficient neighborhood in a pure form as a colorless silk.

NMR data are shown below.

Example 10. Reaction of (-) - 5-methoxy-2 - [(4-methoxy-35-dimethyl-2-pyridinyl) methylsulfinyl] -1H-benzimidazole

0.23 g (0.45 mmol) hydrophilic diastereomer 6-methoxy-2 - [[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl] -1 - [(R) -methyloxymethyl] lH-benzimidazole was dissolved in 15 ml of methanol. A solution of 36 mg (0.9 mmol) of sodium hydroxide in 0.45 ml of water was added and after 10 minutes the mixture was evaporated to evaporate in a rotary evaporator. between 15 ml of water and 15 ml of dimethimethane. Dregid was released from the organic solution with 15 ml of water and the combined aqueous solutions were essentially 85 μl (1.4 mmol) of methyl formate. After 15 minutes, the extract was withdrawn from the mixture with 3x10 ml of dichloromethane. The aqueous solution was dried over Na₂SO₄ and the steam evaporated. Pad obtained 0.12 g (77%) of the compound as the title compound as a colorless syrup. Pure purity fu.h.1. The analyzer was analyzed by 94%. [&lt;X]_D^increasingly= -155 ° (c = 03%, kldrdfoim).

NMR data are shown below.

Example 11. Reaction of (+) - 5-methoxy-2-yl (4-methoxy-33-dimethyl-2-pyridinylmethylsulphonyl) -1H-benzimidazole

0.76 g (13 mmdl) hydrophilic diastereomer 6-methoxy-2 - [[(4-methoxy-33-dimethyl-2-pyridinyl) methyl] sulfinyl] -1 - [(S) -mandeloyloxymethyl] -1H-benzimidazole was dissolved in 50 ml of methanol. A solution of 0.12 mg (3.0 mmdl) of sodium hydroxide in 13 ml of water was added and after 10 minutes the mixture was evaporated in a rotary evaporator. The residue was partitioned between 25 ml of water and 25 ml of dichloromethane. Dregid was released from the organic solution with 25 ml of water and the combined aqueous solution was about 200 μg (3/2 mmol) of methyl formate. After 15 minutes, the residue was dried with 3x25 ml dichloromethane. The organic solution was dried over Na₂SO₄ and the page ldtin evaporates. Pad yielded 0.42 g (81%) of the compound as the title compound as a colorless syrup. The light-emitting purity (uJi.) Detected by hand was approximately 98%. [A]_D^M= + 157 ° (c = 03%. Worm).

NMR data is shown below.

Tafia 2.

Dsmi, Solvent NMR Data δ ppm

CDC1₃500 MHz

CDCl3 500 MHz

CDCl3 500 MHz

2.18 (s, 3H); 2.20 (s, 3H); 2.36 (s, 3H); 2/39 (s, 3H);

3.77 (s, 3H); 3.78 (s, 3H); 3.82 (s, 3H); 3.87 (s, 3H); 4.80 (d, 1H); 4.88 (d, 1H); 5.0 (m, 2H); 534 (s, 2H); 6.43 (d, 1H); 634 (d, 1H); 6.6-6.7 (m, 2H); 6.90 (d, 1H); 6.95-6.98 (m, 2H); 7.01 (d, 1H); ¯ / 2-¯ / 3 (m, 6H); 737 (m, 2H); 7.44 (m, 2H); 738 (d, 1H); 7.62 (d, 1H); 7.95 (s, 1H); 7.97 (s, 1H).

230 (s, 3H); 236 (s, 3H); 3.78 (s, 3H); 3.82 (s, 3H);

4.80 (d, 1H); 5.00 (d, 1H); 535 (d, 1H); 6.43 (d, 1H); 6.63 (d, 1H); 6.90 (d, 1H); 6.97 (dd, 1H); 73-73 (m, 3H); 737 (m, 2H); 7.62 (d, 1H); 7.97 (s, 1H).

2.19 (s, 3H); 230 (s, 3H); 236 (s, 3H); 239 (s, 3H); 3.77 (s, 3H); 3.78 (s, 3H); 3.83 (s, 3H); 3.87 (s, 3H); 4.80 (d, 1H); 4.88 (d, 1H); 5.0 (m, 2H); 534 (s, 2H); 6.43 (d, 1H); 634 (d, 1H); 6.66 (m, 2H); 6.90 (d, 1H); 6.96-6.98 (m, 2H); 7.01 (d, 1H); 7373 (m, 6H); 737 (m, 2H); 7.44 (m, 2H); 738 (d, 1H); 7.62 (d, 1H); 7.95 (s, 1H); 7.97 (s, 1H).

9.

CDC1,

10.

230 (s, 3H); 236 (s, 3H); 3.78 (s, 3H); 3.82 (s, 3H); 430 500 MHz (d, 1H); 5.00 (d, 1H); 535 (d, 1H); 6.43 (d, 1H); 6.63 (d, 1H);

6.90 (d, 1H); 6.97 (dd, 1H); 73-73 (m, 3H); 737 (m, 2H); 7.62 (d, 1H); 737 (s, 1H).

CDCl3 2.18 (s, 3H); 232 (s, 3H); 3.68 (s, 3H); 3.83 (s, 3H);

300 MHz 4.77 (m, 2H); 6.93 (dd, 1H); -7.0 (b, 1H); = 73 (b, 1H); 8.19 (s,

IH).

11. CDC1₃ 221 (s, 3H); 2.23 (s, 3H); 3.69 (s, 3H); 3.84 (s, 3H); 4.76 (m, 2H); 6.94 (dd, 1H); = 7.0 (b, 1H); = 73 (b, 1 H); 8.20 (s, 1H).

Best Mode Known In the present invention, the sodium salts of the highly active compounds of the invention are the compounds described in Dsmi 1 and in Example 2.

Compositions containing the compounds of the invention as active substances are described in the following formulations.

syrup

Syrup containing 1% (w / v) of active substance was prepared from the following components:

Compound according to the invention 1.0 g

Sugar, powder 30.0 g

Sakkarin 03 g

Glycerol 5.0 g

Flavor 0.05 g

Etan6196% 5.0 g

Eimad water should be left so that the final volume will be 100 ml

Sugar and sachets were dissolved in 60 g of hot water. After stirring, the active substance was excreted in the sugar solution and the glycerol and solution containing flavorings were dissolved in ethyl acetate. The mixture was diluted with water to a final volume of 100 ml.

Enteric coating tablets

Enteric coating tablet containing 50 mg of active compound was prepared from the following components:

A compound according to the invention as an Mg salt 500 g

Lactose 700 g

Methyl cellulose 6 g

Polyvinylpyrrolidone, cross-linked 50 g

Magnesium stearate 15 g

Sodium carbonate 6 g

Eimad water et al.

II cellulose acetate acetate phthalate 200 g

Salty alcohol 15 g of isopropanol

methylene chloride

2000 g 2000 g

I. A compound according to the invention, powder, was mixed at lactose and made aqueous solution of methylcellulose and sodium carbonate. The wet mass was forced through a filter and the mass was dried in the oven. After drying, the granulated mass was mixed with polyvinylpyrrolidone and magnesium stearate. The dry mixture was compressed into a tablet core (10 000 tablets), each tablet containing 50 mg of active ingredient, in a tablet machine using a 7-nun diameter piston.

II. The solution of cellulose acetate trialate and cetyl alcohol in isopropanol / methylene chloride was ddad on Tablets I in Accela Cota \ Manesty coating equipment. The final weight of the tablet, 110 mg, was obtained.

Solution for intravenous injection

Intravenous, intravenous administration containing 4 mg of active compound per ml was produced by the following components:

A compound according to the invention 4 g

Sterile water to the final volume of 1000 ml

The active compound was dissolved in water until the final volume of 1000 ml was reached. The solution was filtered through 0.22 / ml and immediately dispersed 10 ml of dehydrated ampoules. The keys were sealed.

Container

Capsules containing 30 mg of active compounds were given to the following components:

A compound according to the invention lactose

Microcrystalline cellulose

Hydroxypropylcellulose, lipid-substituted Disodium hydrogen phosphate Purified water

300 g 700 g 40 g 62 gg et al.

The active substance was mixed with the dry components and made with a solution of disodium hydrogen phosphate. The wet mass was forced through dtsprautunartski and gerdur kdlaga and dried in a dry dryer.

500 g of the above pellets were first coated with a solution of hydroxypropyl methylcellulose, 30 g, in water, 750 g, using a shear coating. After drying, pellets were coated with another coating described below:

The coating solution:

Hydroxypropylmethylcellulose phthalate 70 g

Salty alcohol 4 g

Acetone 200 g

Ethanol 600 g

The final coated pellets were placed in a capsule.

suppositories

Stones are produced from the following components by combining. Each still contained 40 mg of active compound.

A compound according to the invention 4 g

Witepsol H-15 180 g

The active compound was homogeneously mixed with Witepsol H-15 at 41 ° C temperature. The molten mass was filled according to the volume of ready-made furniture so that the net weight became 1.84 g. After cooling the containers were sealed with heat. Each still contained 40 mg of active compound.

Stability against rasemeringu at different pH.

Stability of optically pure The compounds of the invention against racemation have been measured at low levels in a refrigerator. In aqueous buffered syringe at pH 8; 93; 10 and 113- The organic solvent stability was measured by comparing light-sensitive purity (-) - vapor 5-methoxy-2 - [[(4-methoxy-33-dimethyl-2-pyridinyl) methyl] cyclinyl] -1H- benzimidazole in buffer solution immediately after reconstitution and after a few days. The measurements were performed with chromatography on the hand. The high molecular weight stability of the compounds of the invention in alkaline contrast is surprising, and an example is taken as no racemation was obtained for experimental compounds at pH 11 even after 21 days. At pH 8; 9.3 and 10 is a chemical metabolism of the compound which makes detection of a racemaker inheritant in practice,

In another experiment with racemation of the optically pure compounds of the invention, aqueous phosphate buffer solution (pH = 1 l) (+) - vapor 5-methoxy

2 - [[(4-methoxy-3,4-dimethyl-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazole (c = 1 (T⁵M) heated for 26 hours at 37 ° C without any rashes being observed.