CN100457104C - Basic salts of proton pump inhibitors - Google Patents

Abstract

This invention relates to basic salts of proton pump inhibitors and pharmaceuticals containing these compounds.

Description

Basic salts of proton pump inhibitors

Invention subject

The present invention relates to basic salts of proton pump inhibitors. The new salt can be used in the pharmaceutical industry for the preparation of medicines.

Background technique

Pyridin-2-ylmethylsulfinyl-1H-benzimidazoles, for example from EP-A-0 005 129, EP-A-0 166 287, EP-A-0 174 726 and EP-A-0 268 The substances known in 956 are of considerable importance in the treatment of diseases associated with increased gastric acid secretion due to their H ⁺ /K ⁺ -adenosine triphosphatase-inhibitory action.

Examples of active compounds in this class that are already commercially available or in clinical development are 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridyl)methylidene Sulfuryl]-1H-benzimidazole (INN: omeprazole), (S)-5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridyl )methylsulfinyl]-1H-benzimidazole (INN: esomeprazole), 5-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridyl)methyl Sulphinyl]-1H-benzimidazole (INN: pantoprazole), 2-[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl Sulfuryl]-1H-benzimidazole (INN: Lansoprazole), 2-{[4-(3-methoxypropoxy)-3-methylpyridin-2-yl]methylsulfoxide Acyl}-1H-benzimidazole (INN: rabeprazole) and 5-methoxy-2-((4-methoxy-3,5-dimethyl-2-pyridylmethyl)sulfite Acyl)-1H-imidazo[4,5-b]pyridine (INN: tenatoprazole).

Due to their mechanism of action, the abovementioned sulfinyl derivatives are also known as proton pump inhibitors, or PPIs for short.

current technology

For the first time, European Patent Application 80602 describes the specific preparation of the sodium and calcium salts of certain pyridin-2-ylmethylsulfinyl-1H-benzimidazole compounds. Later, European Patent Application 124495 (US4738974) described and claimed new salts of omeprazole bearing cations such as Li ⁺ , Na ⁺ , K ⁺ , Mg ²⁺ , Ca ²⁺ or Ti ⁴⁺ cations.

All of the aforementioned PPIs have the general property of being acid-sensitive (which is very important for their effectiveness), they become very susceptible to decomposition in neutral, and especially acidic environments, while also producing highly colored decomposition products. In the past, despite the acid sensitivity of PPIs, considerable efforts have been made to obtain stable and easy-to-storage oral dosage forms containing these PPIs. In order to provide acid-labile PPIs with a microenvironment of pH 7-12, it is very common to add alkaline reactive compounds (e.g. sodium carbonate) to oral dosage forms to obtain stable oral PPI dosage forms (e.g. tablets). method (refer to European Patent 244380). Thus, stable and shelf-stable oral dosage forms such as tablets or capsules are now available. However, the preparation of these oral dosage forms is rather complex and also related to the packaging, requiring the implementation of certain complex precautions in order to make the dosage forms sufficiently stable even under extreme storage conditions, such as in tropical regions with high temperature and high atmospheric humidity. Furthermore, in the past people have struggled to adapt the release of PPIs in the human body in the best possible way for the respective needs.

International patent application WO92/08716 describes a chemical process for the resolution of the optical enantiomers of pyridin-2-ylmethylsulfinyl-1H-benzimidazoles. Compounds which may be mentioned, prepared in the exemplified process, include, inter alia, (+) and (-)-5-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridyl)methylidene Sulfonyl]-1H-benzimidazole [=(+)- and (-)-pantoprazole] compounds. International patent application WO92/08716 refers to the optical antipodes of pyridin-2-ylmethylsulfinyl-1H-benzimidazole, such as (+)- and (-) enantiomers or (R)- and The (S)-enantiomer is useful as an active compound in medicaments for the treatment of gastrointestinal disorders. With regard to the mode of administration and the dosage of the active compounds, reference is made inter alia to European Patent 166287.

In a symposium held in Montreal in September 1993, Kohl et al disclosed the synthesis and biological activity of the enantiomers of pantoprazole.

International patent applications WO94/24867 and WO94/25028 claim the use of the compounds (-)- and (+)-pantoprazole for the treatment of gastric diseases in humans. Each of the stereoisomers described has pharmaceutical advantages over the respective other stereoisomer. The possible salts of the many different stereoisomers are also described, the sodium salt being particularly preferred.

In International Patent Application WO94/27988 (US 5693818), certain (+)- and (-)-omeprazole salts and processes for their preparation are disclosed.

International patent application WO97/41114 describes certain methods for the preparation of magnesium salts of pyridin-2-ylmethylsulfinyl-1H-benzimidazoles. In particular the preparation of the magnesium salt of pantoprazole is described therein by way of example. According to the analytical data presented, the salt prepared was the anhydrous form of pantoprazole magnesium.

International patent application WO00/10995 (US 6410569) describes the dihydrate of the magnesium salt of racemic pantoprazole.

US Patent 6369085 relates to a new form of magnesium salt of the S-enantiomer of omeprazole trihydrate, and processes for the preparation of this magnesium salt of S-omeprazole and pharmaceutical compositions comprising it .

International patent application WO02/045693 (DE10061137) describes a new formulation suitable for the production of pharmaceutical dosage forms. The active ingredient in the new formulation, such as PPI or its salt, is substantially homogeneously dispersed in an excipient matrix comprising one or more selected from fatty alcohols, triglycerides, partial glycerides and fatty acid esters.

US Patent 5997903 relates to an oral form of pantoprazole comprising a core, an intermediate layer and an outer layer resistant to gastric juices.

International patent application WO04/013126 describes (S)-pantoprazole magnesium and its hydrates.

Detailed description of the invention

It has now been found that base-reactive salts of PPI can be produced which, due to their properties and high stability, are eminently suitable for further processing in oral dosage forms, even without addition of further base-reactive compounds.

Accordingly, the present invention provides, in a general aspect, base-reactive salts of pyridin-2-ylmethylsulfinyl-1H-benzimidazoles having H ⁺ /K ⁺ -ATPase-inhibiting activity.

According to the present invention, "alkali-reactive salts" are understood to include pharmaceutically acceptable salts of pyridin-2-ylmethylsulfinyl-1H-benzimidazoles having H ⁺ /K ⁺ -ATPase-inhibitory activity. Compatible metal salts wherein at least one equivalent positive charge of the metal ion is balanced by hydroxide ions.

According to the invention, "pyridin-2-ylmethylsulfinyl-1H-benzimidazoles having H ⁺ /K ⁺ -ATPase-inhibitory activity" is understood to include the racemic form of Toprazole, omeprazole, lansoprazole, rabeprazole and tenatoprazole, also enantiomers of these compounds, such as (R)- and (S)-pantoprazole in pure form Meprazole, (R)- and (S)-omeprazole, (R)- and (S)-lansoprazole, (R)- and (S)-rabeprazole and (R)- and (S)-tenatoprazole, and mixtures thereof in any desired ratios, especially include enantiomers substantially free of the respective other enantiomer.

In particular, the base-reactive salts of pyridin-2-ylmethylsulfinyl-1H-benzimidazoles having H ⁺ /K ⁺ -ATPase-inhibitory activity according to the invention are characterized by the general formula 1 .

[Me] _x [PPI] _y [OH] _z (1)

in

Me is a pharmaceutically acceptable divalent metal ion,

PPI is a compound selected from pantoprazole, omeprazole, lansoprazole, rabeprazole and tenatoprazole and their enantiomers,

OH is a hydroxide ion,

X is a positive integer from 1 to 3,

Y is a positive integer from 1 to 5 and

Z is a positive integer from 1 to 5,

The equation (Y+Z)=2X is satisfied.

More particularly, the present invention provides compounds of formula 1,

in

Me is a pharmaceutically acceptable divalent metal ion selected from magnesium, calcium and zinc,

PPI is a compound selected from pantoprazole, omeprazole, lansoprazole, rabeprazole and their enantiomers,

OH is a hydroxide ion,

X is the number 1 or 2,

Y is a positive integer from 1 to 3 and

Z is a positive integer from 1 to 3,

The equation (Y+Z)=2X is satisfied.

A preferred subject of the invention is a compound of formula 1,

in

Me is magnesium,

PPI is a compound selected from pantoprazole, (R)-pantoprazole, (S)-pantoprazole,

OH is a hydroxide ion,

X is the number 1 or 2,

Y is the number 1 or 3 and

Z is the number 1 or 3,

The equation (Y+Z)=2X is satisfied.

Particularly preferred subjects of the invention are compounds of formula 1,

in

Me is magnesium,

The PPI is (S)-pantoprazole substantially free of (R)-pantoprazole,

OH is a hydroxide ion,

X is the number 1 or 2,

Y is the number 1 or 3 and

Z is the number 1 or 3,

The equation (Y+Z)=2X is satisfied.

It has been found that (-)- or (S)-pantoprazole sodium salt is particularly preferred in International Patent Application WO 94/24867, which cannot be formed in a storage-stable form. In an attempt to obtain a stable oral dosage form of (-)-pantoprazole, it has been found that the base-reacted magnesium salt of (S)-pantoprazole, especially in the form of the hydrate, has a very surprising stable properties, making them particularly suitable candidates for use in solid or oral dosage forms. They have considerably improved stability properties compared to (-)-pantoprazole sodium salt. For example, the compound of formula 1, wherein Me is magnesium, PPI is (S)-pantoprazole, X is 1, Y is, Z is 1, is completely stable within one week at 70°C in its hydrated form, and It was shown that there was virtually no discoloration or decomposition, however over the same period of time under the same conditions, the hydrate of (-)-pantoprazole sodium turned brown, producing an equivalent amount of decomposition products. In addition, the compound of formula 1, wherein Me is magnesium, PPI is (S)-pantoprazole, X is 1, Y is 1, and Z is 1, is in the form of a hydrate thereof, which is mixed with racemic pantoprazole Magnesium azole dihydrate showed a surprising and unexpected faster dissolution than that.

The compounds according to the invention and their hydrates can be used in the treatment and prophylaxis of all diseases which can be prevented or treated by the use of PPIs. In particular, the compounds according to the invention and their hydrates can be used in the treatment of gastric diseases. In this context, particular mention should be made of the relatively high stability of the compounds according to the invention and their hydrates. For example, under storage under atmospheric conditions, the total number of by-products remains constant in [Mg][(S)-pantoprazole][OH] _x H ₂ O, whereas in (-)-pantoprazole sodium In this case, under the same conditions (storage at 60-70°C), the purity (according to HPLC) decreased from 99.5 to 96-97%. The compounds according to the invention and their hydrates are particularly suitable for use in medicine because of their rather high storage stability.

The compounds according to the invention and their hydrates are prepared in a specific manner by reacting PPI with Me-salts in the presence of alkaline hydroxides, either in water or in water with polar organic solvents such as alcohols , preferably methanol, ethanol or isopropanol, or ketones, preferably acetone), from easily soluble PPI salts (such as (-)-pantoprazole sodium), using for example magnesium salts, such as magnesium chloride, hydroxide Sodium solution to prepare the compounds according to the invention and their hydrates.

Me-salts suitable for use in this process are, for example, Me chloride, Me bromide, Me fluoride, Me iodide, Me formate, Me acetate, Me propionate, Me gluconate or Me carbonate. It is also possible to use Me-alkoxides (e.g. methanol Me, ethanol Me, (iso)propanol Me, butanol Me, hexanol Me or phenol Me) in an alcoholate medium with easily The dissolved PPI salt reacts, and by adding water, the basic PPI salt crystallizes in its hydrate form. Furthermore, the compounds according to the invention and their hydrates can be recrystallized from, for example, methanol/water mixtures.

The following examples illustrate but do not limit the invention. m.p stands for melting point, min. stands for minute, h stands for hour.

Example

1. {[5-(difluoromethoxy)]-2-[(3,4-dimethoxy-2-pyridyl)methylsulfinyl ]-1H-benzimidazole}hydroxyl magnesium monohydrate thing

Molecular formula [pantoprazole ^- OH ^- Mg ²⁺ H ₂ O]: C ₁₆ H ₁₇ F ₂ N ₃ O ₆ SMg

Dissolve 10.7 g of pantoprazole sodium sesquihydrate in 110 ml of water. 2.48 g of 40% sodium hydroxide was added at 25 °C and the solution was stirred for 1 h. 5.01 g of magnesium chloride hexahydrate was dissolved in 20 ml of water, and the solution was added dropwise to the pantoprazole sodium salt solution under stirring at 25° C., and the stirring was continued for 1 h. The resulting suspension was suction filtered and the precipitate was washed with 50 ml of water. The precipitate was resuspended in 100 ml of water and filtered again, dried (<50 mbar) in a vacuum desiccator at 40-45 °C to obtain 10.76 g (94.6%) of the target compound as an off-white solid with m.p. 184-187 °C (decomposition) .

analyze:

2. (-)-{[5-(Difluoromethoxy)]-2-[(3,4-dimethoxy-2-pyridyl) methylsulfinyl ]-1H-benzimidazole} Hydroxymagnesium monohydrate

Molecular formula [(S)-pantoprazole ^- OH ^- Mg ²⁺ H ₂ O]: C ₁₆ H ₁₇ F ₂ N ₃ O ₆ SMg

Dissolve 10.9 g of (-)-pantoprazole sodium salt in 110 ml of water. 2.48 g of 40% sodium hydroxide was added at 50 °C and the solution was stirred for 1 h. The solution was cooled to room temperature. 5.01 g of magnesium chloride hexahydrate was dissolved in 20 ml of water, and the magnesium chloride solution was added dropwise to the (-)-pantoprazole sodium salt solution under stirring at 25° C., and the stirring was continued for 18 h. The resulting suspension was suction filtered and the precipitate was washed with 50 ml of water. The precipitate was resuspended in 100 ml of water and filtered again, dried in a vacuum desiccator at 40-45°C (<50 mbar) to obtain 10.01 g (88%) of the target compound as an off-white solid with m.p.164-167°C (decomposition) .

Specific rotation value: α _D ^20° ＝-123 (c＝0.5, methanol)

analyze:

3. (+)-{[5-(Difluoromethoxy)]-2-[(3,4-dimethoxy-2-pyridyl) methylsulfinyl ]-1H-benzimidazole} Hydroxymagnesium Sesquihydrate

Molecular formula [2(R) ^{-pantoprazole-} 2OH ^- 2Mg ²⁺ H ₂ O]: C ₃₂ H ₃₃ F ₄ N ₆ O ₁₁ S ₂ Mg ₂

Dissolve 5.0 g (+)-pantoprazole sodium salt in 50 ml of water. 1.23 g of 40% sodium hydroxide was added at 35 °C and the solution was stirred for 1 h. The solution was cooled to room temperature. Dissolve 2.50 g of magnesium chloride hexahydrate in 15 ml of water, and add the magnesium chloride solution dropwise to the (+)-pantoprazole sodium salt solution at 25° C. with stirring, and continue stirring for 18 h. The resulting suspension was suction filtered, the precipitate was washed in three portions with 50 ml of water and dried in a vacuum dryer at 50-55 °C (<50 mbar) to obtain 4.33 g (74.6%) m.p. 161-165 °C (dec.) Off-white solid target compound.

Specific optical rotation value: α _D ^20° ＝+112 (c＝0.5, methanol)

analyze:

4. Tris-{[5-(difluoromethoxy)]-2-[(3,4-dimethoxy-2-pyridyl)methylsulfinyl ]-1H-benzimidazole}hydroxyl di Magnesium tetrahydrate

Molecular formula [3 pantoprazole ^- OH ^- 2Mg ²⁺ 4H ₂ O]: C ₄₈ H ₅₁ F ₆ N ₉ O ₁₇ S ₃ Mg ₂

Dissolve 25.0 g of pantoprazole sodium sesquihydrate in 250 ml of water. Add 1.33ml of 40% sodium hydroxide at 25°C and stir the solution for 15min. Dissolve 3.92g of magnesium chloride hexahydrate in 31ml of water, add the magnesium chloride solution dropwise to the pantoprazole sodium salt solution under stirring at 25°C, and continue stirring for 2.5h. The resulting suspension was suction filtered and the precipitate was washed in three portions with 150 ml of water. The precipitate was dried in a vacuum desiccator at 40-45°C (<50 mbar) to obtain 12.47 g (52.7%) of the title compound as an off-white solid with m.p. 182-185°C (dec).

analyze:

*Calculated as tetrahydrate

5. (-)-tri-{[5-(difluoromethoxy)]-2-[(3,4-dimethoxy-2-pyridyl) methylsulfinyl]-1H-benzo Imidazole}hydroxy dimagnesium pentahydrate

Molecular formula [3(S)-pantoprazole ^- OH ^- 2Mg ²⁺ 5H ₂ O]: C ₄₈ H ₅₃ F ₆ N ₉ O ₁₈ S ₃ Mg ₂

Dissolve 6.0 g (-)-pantoprazole sodium in 60 ml of water. Add 0.49g of 40% sodium hydroxide at 30-35°C and stir the solution for 15min. Dissolve 1.02 g of magnesium chloride hexahydrate in 8 ml of water, and add the magnesium chloride solution dropwise to (-) pantoprazole sodium salt solution at 25° C. with stirring, and continue stirring for 18 h. The resulting suspension was filtered with suction and the precipitate was washed in two portions with 50 ml of water. The precipitate was dried in a vacuum desiccator at 60°C (<50 mbar), yielding 2.41 g (48.3%) of the title compound as an off-white solid with m.p. 162-166°C (dec).

Specific optical rotation value: α _D ^20° = -125 (c = 0.5, in methanol)

analyze:

*Calculated as pentahydrate

6. (+)-tri-{[5-(difluoromethoxy)]-2-[(3,4-dimethoxy-2-pyridyl)methylsulfinyl ]-1H-benzo Imidazole}hydroxy dimagnesium pentahydrate

Molecular formula [3(R)-pantoprazole ^- OH ^- 2Mg ²⁺ 5H ₂ O]: C ₄₈ H ₅₃ F ₆ N ₉ O ₁₈ S ₃ Mg ₂

Dissolve 5.0 g (+)-pantoprazole sodium in 50 ml of water. Add 0.27ml of 40% sodium hydroxide at 30-35°C and stir the solution for 15min. Dissolve 0.78 g of magnesium chloride hexahydrate in 6 ml of water, add the magnesium chloride solution dropwise to the (+)-pantoprazole sodium salt solution under stirring at 25° C., and continue stirring for 2 days. The resulting suspension was suction filtered and the precipitate was washed in three portions with 25 ml of water. The precipitate was dried in a vacuum desiccator at 40°C (<50 mbar), yielding 2.10 g (40.1%) of the title compound as an off-white solid with m.p. 161-166°C (dec).

Specific optical rotation value: α _D ^20° = +114.5 (c = 0.5, in methanol)

analyze:

*Calculated as pentahydrate

7. {[5-(Difluoromethoxy)]-2-[(3,4-dimethoxy-2-pyridyl)methylsulfinyl ]-1H-benzimidazole}hydroxycalcium monohydrate thing

Molecular formula [pantoprazole ^- OH ^- Ca ²⁺ H ₂ O]: C ₁₆ H ₁₇ F ₂ N ₃ O ₆ SCa

Dissolve 21.6 g of pantoprazole sodium sesquihydrate in 250 ml of water. 2.00 g of sodium hydroxide was added at 25 °C and the solution was stirred for 1 h. Dissolve 5.55g of calcium chloride (dry) in 50ml of water. The calcium chloride solution was added dropwise to the pantoprazole sodium solution under stirring at 25°C, and the stirring was continued for 20 h. The resulting suspension was filtered with suction, the precipitate was washed with 200 ml of water and dried in a vacuum dryer at 40-45°C (<50 mbar) to obtain 21.86 g (91.8%) of the title compound as an off-white solid.

Moisture (Karl-Fischer titration method): 7.6%

Melting point: 157-160°C (decomposition)

analyze:

8. (-)-{[5-(difluoromethoxy)]-2-[(3,4-dimethoxy-2-pyridyl)methyl Sulphinyl]-1H-benzimidazole}hydroxycalcium monohydrate

Molecular formula [pantoprazole ^- OH ^- Ca ²⁺ H ₂ O]: C ₁₆ H ₁₇ F ₂ N ₃ O ₆ SCa

Dissolve 22.7 g (-)-pantoprazole sodium (wet, 0.05 mol) in 250 ml of water. 2.00 g sodium hydroxide was added at 25°C and the solution was stirred at 40°C for 1 h. Dissolve 5.55g of calcium chloride (dry) in 50ml of water. The calcium chloride solution was added dropwise to the pantoprazole sodium solution under stirring at 25°C, and the stirring was continued for 20 h. The resulting suspension was filtered with suction, the precipitate was washed with 200 ml of water and dried in a vacuum dryer at 40-45°C (<50 mbar) to obtain 21.44 g (89.9%) of the title compound as an off-white solid.

Moisture (Karl-Fischer titration method): 7.8%

Melting point: 137-147°C (decomposition)

analyze:

9. {[5-(Difluoromethoxy)]-2-[(3,4-dimethoxy-2-pyridyl)methylsulfinyl ]-1H-benzimidazole}hydroxyzinc monohydrate thing

Molecular formula [pantoprazole ^- OH ^- Zn ²⁺ H ₂ O]: C ₁₆ H ₁₇ F ₂ N ₃ O ₆ SZn

Dissolve 21.6 g of pantoprazole sodium sesquihydrate in 250 ml of water. 2.00 g of sodium hydroxide was added at 25 °C and the solution was stirred for 1 h. Dissolve 6.80 g of zinc chloride (dry) in 50 ml of water. The zinc chloride solution was added dropwise to the pantoprazole sodium solution under stirring at 25°C, and the stirring was continued for 20 h. The resulting suspension was filtered with suction, the precipitate was washed with 200 ml of water and dried in a vacuum dryer at 40-45°C (<50 mbar) to obtain 23.08 g (94.2%) of the title compound as an off-white solid.

Moisture (Karl-Fischer titration method): 5.1%

Melting point: 167-179°C (decomposition)

analyze:

10. (-)-{[5-(Difluoromethoxy)]-2-[(3,4-dimethoxy-2-pyridyl) methylsulfinyl ]-1H-benzimidazole} Hydroxyzinc monohydrate

Molecular formula [(S)-pantoprazole ^- OH ^- Zn ²⁺ H ₂ O]: C ₁₆ H ₁₇ F ₂ N ₃ O ₆ SZn

Dissolve 22.7 g (-)-pantoprazole sodium (wet, 0.05 mol) in 250 ml of water. 2.00 g sodium hydroxide was added at 25°C and the solution was stirred for 1 h. Dissolve 6.80 g of zinc chloride (dry) in 50 ml of water. The zinc chloride solution was added dropwise to the pantoprazole sodium solution under stirring at 25°C, and the stirring was continued for 20 h. The resulting suspension was filtered with suction, the precipitate was washed with 200 ml of water and dried in a vacuum dryer at 40-45°C (<50 mbar) to obtain 22.87 g (94.2%) of the title compound as an off-white solid.

Moisture (Karl-Fischer titration): 4.3%

Melting point: 169-173°C (decomposition)

analyze:

11. (-)-{[5-(Difluoromethoxy)]-2-[(3,4-dimethoxy-2-pyridyl) methylsulfinyl ]-1H-benzimidazole} Hydroxymagnesium monohydrate

Molecular formula [(S)-pantoprazole ^- OH ^- Mg ²⁺ H ₂ O]: C ₁₆ H ₁₇ F ₂ N ₃ OxSMg

Dissolve 6.20 kg (-)-pantoprazole sodium salt (wet, 14.06 mol) in 64 L of water. 0.56 kg sodium hydroxide was added at room temperature and the solution was stirred at 40 °C for 1 h. The solution was cooled to room temperature. Dissolve 2.86 kg of magnesium chloride hexahydrate in 11.4 L of water, add the magnesium chloride solution dropwise to the (-)-pantoprazole sodium solution with stirring at 25° C., and continue stirring for 18 hours. The resulting suspension was centrifuged and the precipitate was washed with 41 L of water and dried in a vacuum desiccator at 40-45°C (<50 mbar) to obtain 3.97 kg (58.84% of the target compound as an off-white solid).

Purity (HPLC): 99.4%

ee: >99%

Moisture (Karl-Fischer titration): 7.7%

analyze:

business use

The compounds according to the invention and their hydrates possess useful pharmacological properties which make them commercially available. In particular, in warm-blooded animals, especially humans, they exhibit a marked gastric acid secretion inhibitory effect and an excellent gastro-intestinal protective effect. Due to their unique stability profile, the compounds according to the invention and their hydrates are particularly suitable for the production of stable oral PPI dosage forms. By the presence of hydroxide ions in the compounds of the invention, PPI, which is acid-labile and sensitive to trace amounts of acids, has a self-protective effect against undesired decomposition during storage.

In this context, "protection of the gastrointestinal tract" can be understood as the prevention and treatment of gastrointestinal diseases, especially gastrointestinal inflammatory diseases and damage (such as gastric ulcer, duodenal ulcer, gastritis, prophylaxis and treatment of irritable bowel disease, GERD, Crohn's disease, IBD) or the result of drugs, which can be caused by, for example, microorganisms (such as Helicobacter pylori), bacterial toxins, drugs (such as certain anti-inflammatory drugs and antirheumatic Drugs), chemicals (such as alcohol), stomach acid, or stress.

With their superior properties, the compounds selected according to the present invention and their hydrates are surprisingly significantly superior to the compounds of the prior art in various models for determining antiulcerogenic and antisecretory properties, especially with regard to their Stability and their pharmacological properties. Due to these _{properties, for example the compounds [Mg][(S)-pantoprazole][OH]xH2O and} [Mg] ₂ [(S)-pantoprazole] ₃ [OH] _xH2O are very suitable For use in human and veterinary medicine, especially for their use in the treatment and/or prophylaxis of gastrointestinal diseases.

Accordingly, the present invention further provides compounds according to the invention and their hydrates for use in the treatment and/or prophylaxis of the diseases mentioned above.

The present invention also includes the use of the compounds according to the present invention and their hydrates in the preparation of medicaments for treating and/or preventing the above-mentioned diseases.

Furthermore, the present invention includes the use of the compounds according to the invention and their hydrates for the treatment and/or prophylaxis of the diseases mentioned above.

The invention also provides medicaments comprising the compounds according to the invention and their hydrates.

Said medicaments can be prepared by methods known per se which are familiar to those skilled in the art. As medicaments, the compounds according to the invention and their hydrates can be used as such or preferably in combination with suitable pharmaceutical adjuvants or carriers in the form of tablets, coated tablets, capsules, suppositories, patches (eg as TTS), It is used in the form of emulsions, suspensions or solutions, wherein the amount of active compound is preferably from 0.1 to 95% and by suitable selection of excipients or carriers, it is possible to produce special formulations suitable for the active compound and/or the desired effect. and/or duration of action of the pharmaceutical dosage form (eg sustained release form or enteric coated form).

The person skilled in the art knows by virtue of his expert knowledge suitable excipients or carriers for the desired pharmaceutical formulations. In addition to solvents, gelling agents, suppository bases, tablet excipients and other active compound carriers, it is possible to use, for example, antioxidants, dispersants, emulsifiers, antifoams, flavoring agents, preservatives, solubilizers, Colorants or especially penetration enhancers and complexing agents (eg cyclodextrins).

The compounds according to the invention and their hydrates can be administered orally, parenterally or transdermally.

In human medicine, it has generally been found that the compounds according to the invention are administered orally in a daily dosage of about 0.1 to 2 mg/kg body weight, preferably 0.2 to 1.5 mg/kg body weight and especially 0.3 to 1.1 mg/kg body weight [based on PPI]. The compounds and their hydrates are advantageously administered, if appropriate, in the form of multiple single doses, preferably 1 to 4 single doses, in order to obtain the desired result. For parenteral treatment, similar or (particularly when the active compound is administered intravenously) usually lower dosages may be used. The person skilled in the art can readily determine, owing to his expert knowledge, the optimum dosage and type of active compound to be administered in each case.

Another aspect of the invention is a medicament comprising a compound according to the invention or a hydrate thereof, together with customary excipients, wherein a single dose comprises 10 to 100 mg of PPI.

Another aspect of the invention is a medicament comprising a compound according to the invention or a hydrate thereof, together with customary excipients, wherein a single dose comprises 20 to 80 mg of (-)-pantoprazole.

Another aspect of the invention is the use of a compound according to the invention or a hydrate thereof for the treatment of gastrointestinal diseases.

Another aspect of the invention is the use of a compound according to the invention or a hydrate thereof for the treatment of gastrointestinal disorders in chronic metabolic patients.

Another aspect of the invention is the use of a compound according to the invention or a hydrate thereof for the treatment of gastrointestinal disorders in patients at risk of drug interactions.

Another aspect of the invention is the use of compounds according to the invention and hydrates thereof for the treatment of gastrointestinal disorders in patients requiring prolonged suppression of acid secretion.

Another aspect of the invention is a medicament comprising a compound according to the invention or a hydrate thereof and conventional excipients for the treatment of gastrointestinal diseases in patients with chronic metabolism, wherein a single dose comprises 10 to 100 mg of PPI.

Another aspect of the invention is a medicament comprising a compound according to the invention or a hydrate thereof and conventional excipients for the treatment of gastrointestinal diseases in patients with chronic metabolism, wherein a single dose comprises 20 to 80 mg of PPI.

Another aspect of the invention is a medicament comprising a compound according to the invention or a hydrate thereof and conventional excipients for the treatment of gastrointestinal diseases in patients at risk of drug interaction, wherein a single dose comprises 10 to 100 mg The PPI.

Another aspect of the invention is a medicament comprising a compound according to the invention or a hydrate thereof and conventional excipients for the treatment of gastrointestinal diseases in patients at risk of drug interaction, wherein a single dose comprises 20 to 80 mg The PPI.

Another aspect of the invention is a medicament comprising a compound according to the invention or a hydrate thereof and conventional excipients for the treatment of gastrointestinal diseases in patients requiring prolonged suppression of acid secretion, wherein a single dose comprises 10 to 100 mg The PPI.

Another aspect of the invention is a medicament comprising a compound according to the invention or a hydrate thereof and conventional excipients for the treatment of gastrointestinal diseases in patients requiring prolonged suppression of acid secretion, wherein a single dose comprises 20 to 80 mg The PPI.

类，如地西泮)、解痉药(例如比坦维林或卡米罗芬)、抗胆碱能药(如羟苄利明或苯卡巴胺)、局麻药(如丁卡因或普鲁卡因)，任选地还包括酶、维生素或氨基酸。If the compounds according to the invention or their hydrates are used for the treatment of the diseases mentioned above, the pharmaceutical preparations may also contain one or more pharmacologically active ingredients of other classes of drugs. Examples that may be mentioned are: sedatives (such as benzodiazepines

antispasmodics (such as diazepam), antispasmodics (such as bitanverine or carmiprofen), anticholinergics (such as oxybenzidine or benzocarbamine), local anesthetics (such as tetracaine or Caine), optionally also enzymes, vitamins or amino acids.

In this context, particular emphasis is placed on the combination of the compounds according to the invention with other drugs that buffer or neutralize gastric acid or inhibit acid secretion, such as antacids (eg magnesium aluminum hydroxide) or _H2 blockers (eg cimetidine, ranitidine), and in combination with a gastrin antagonist for the purpose of enhancing the main effect in an increased or excessively increased sense and/or eliminating or reducing side effects or obtaining a rapid onset of action. In order to prevent gastrointestinal damage caused by NSAIDs, fixed or free co-administration with NSAIDs (such as etofenamate, diclofenac, indomethacin, ibuprofen or piroxicam), or with Combined administration of antibacterial substances (such as cephalosporins, tetracyclines, penicillins, macrolides, nitroimidazoles or other bismuth salts) for the control of Helicobacter pylori. Members of antibacterial combinations that may be mentioned are, for example, mezlocillin, ampicillin, amoxicillin, cefalotin, cefoxitin, cefotaxime, imipenem, gentamicin, amikacin, erythromycin , ciprofloxacin, metronidazole, clarithromycin, azithromycin, and combinations thereof (eg, clarithromycin + metronidazole, amoxicillin + clarithromycin).

Claims (15)

1. has H ⁺/ K ⁺-adenosine triphosphatase-suppress pharmaceutically compatible slaine or its hydrate of active pyridine-2-ylmethyl sulfinyl-1H-benzimidazole is wherein used at least one equivalent positive charge of hydroxyl ion balance metal ion; Wherein has H ⁺/ K ⁺-adenosine triphosphatase-suppress active pyridine-2-ylmethyl sulfinyl-1H-benzimidazole to be selected from pantoprazole, omeprazole, lansoprazole, rabeprazole and tenatoprazole.

2. according to pharmaceutically compatible slaine or its hydrate of claim 1, wherein has H ⁺/ K ⁺-adenosine triphosphatase-suppress active pyridine-2-ylmethyl sulfinyl-1H-benzimidazole is selected from (R)-and (S)-pantoprazole, (R)-and (S)-omeprazole, (R)-and (S)-lansoprazole, (R)-and (S)-rabeprazole, (R)-and (S)-tenatoprazole.

3. according to pharmaceutically compatible slaine or its hydrate of claim 1, be characterised in that to have following general formula 1:

[Me] _x[PPI] _y[OH] _z(1)

Wherein

Me is pharmaceutically acceptable bivalent metal ion,

PPI is the chemical compound that is selected from pantoprazole, omeprazole, lansoprazole, rabeprazole and tenatoprazole,

OH is a hydroxyl ion,

X is 1 to 3 positive integer,

Y be 1 to 5 positive integer and

Z is 1 to 5 positive integer,

Satisfy equation (Y+Z)=2X.

4. according to pharmaceutically compatible slaine or its hydrate of claim 2, be characterised in that to have following general formula 1:

[Me] _x[PPI] _y[OH] _z(1)

Wherein

Me is pharmaceutically acceptable bivalent metal ion,

PPI is the chemical compound that is selected from (R)-and (S)-pantoprazole, (R)-and (S)-omeprazole, (R)-and (S)-lansoprazole, (R)-and (S)-rabeprazole, (R)-and (S)-tenatoprazole,

OH is a hydroxyl ion,

X is 1 to 3 positive integer,

Y be 1 to 5 positive integer and

Z is 1 to 5 positive integer,

Satisfy equation (Y+Z)=2X.

5. according to pharmaceutically compatible slaine or its hydrate of claim 3, wherein

Me is the pharmaceutically acceptable bivalent metal ion that is selected from magnesium, calcium and zinc,

PPI is the chemical compound that is selected from pantoprazole, omeprazole, lansoprazole, rabeprazole and tenatoprazole,

OH is a hydroxyl ion,

X is a numeral 1 or 2,

Y be 1 to 3 positive integer and

Z is 1 to 3 positive integer,

Satisfy equation (Y+Z)=2X.

6. according to pharmaceutically compatible slaine or its hydrate of claim 4, wherein

Me is the pharmaceutically acceptable bivalent metal ion that is selected from magnesium, calcium and zinc,

PPI is the chemical compound that is selected from (R)-and (S)-pantoprazole, (R)-and (S)-omeprazole, (R)-and (S)-lansoprazole, (R)-and (S)-rabeprazole, (R)-and (S)-tenatoprazole,

OH is a hydroxyl ion,

X is a numeral 1 or 2,

Y be 1 to 3 positive integer and

Z is 1 to 3 positive integer,

Satisfy equation (Y+Z)=2X.

7. according to pharmaceutically compatible slaine or its hydrate of claim 3, wherein

Me is a magnesium,

PPI is a pantoprazole,

OH is a hydroxyl ion,

X is a numeral 1 or 2,

Y be the numeral 1 or 3 and

Z is a numeral 1 or 3,

Satisfy equation (Y+Z)=2X.

8. according to pharmaceutically compatible slaine or its hydrate of claim 7, wherein

Me is a magnesium,

PPI is selected from (R)-pantoprazole and (S)-pantoprazole,

OH is a hydroxyl ion,

X is a numeral 1 or 2,

Y be the numeral 1 or 3 and

Z is a numeral 1 or 3,

Satisfy equation (Y+Z)=2X.

9. pharmaceutically compatible slaine or its hydrate according to Claim 8, wherein

Me is a magnesium,

PPI is (S)-pantoprazole,

OH is a hydroxyl ion,

X is a numeral 1 or 2,

Y be the numeral 1 or 3 and

Z is a numeral 1 or 3,

Satisfy equation (Y+Z)=2X.

10. according to pharmaceutically compatible slaine or its hydrate of claim 1, it is the Mg[pantoprazole] OH or its hydrate.

11. according to pharmaceutically compatible slaine or its hydrate of claim 1, it is Mg[(S)-pantoprazole] OH or its hydrate.

12. according to pharmaceutically compatible slaine or its hydrate of claim 1, it is Mg ₂[pantoprazole] ₃OH or its hydrate.

13. according to pharmaceutically compatible slaine or its hydrate of claim 1, it is Mg ₂[(S)-pantoprazole] ₃OH or its hydrate.

14. comprise according to claim 1 to 13 each chemical compound and the medicine of conventional adjuvant.

15. the application that each chemical compound of claim 1 to 13 is used to prepare the medicine aspect that is used for the treatment of gastrointestinal disease.