CN100457104C - Alkaline salts of proton pump inhibitors - Google Patents
Alkaline salts of proton pump inhibitors Download PDFInfo
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- CN100457104C CN100457104C CNB200480020260XA CN200480020260A CN100457104C CN 100457104 C CN100457104 C CN 100457104C CN B200480020260X A CNB200480020260X A CN B200480020260XA CN 200480020260 A CN200480020260 A CN 200480020260A CN 100457104 C CN100457104 C CN 100457104C
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- pantoprazole
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Abstract
The invention relates to alkaline salts of proton pump inhibitors and to medicaments comprising these compounds.
Description
Subject matter
The present invention relates to the basic salt of proton pump inhibitor.This new salt can be applied to prepare the medical industry of medicine.
Background technology
Pyridine-2-ylmethyl sulfinyl-1H-benzimidazole, known substances from EP-A-0 005 129, EP-A-0 166 287, EP-A-0 174 726 and EP-A-0 268 956 for example is because their H
+/ K
+-adenosine triphosphatase-inhibitory action is considerable in treatment during with disease that the gastric acid secretion increase is associated.
In this class material, can commercial obtain or 5-methoxyl group-2-[(4-methoxyl group-3 has been arranged at the reactive compound example of clinical development; 5-dimethyl-2-pyridine radicals) methyl sulfinyl]-1H-benzimidazole (INN: omeprazole); (S)-5-methoxyl group-2-[(4-methoxyl group-3; 5-dimethyl-2-pyridine radicals) methylsulfinyl]-1H-benzimidazole (INN: esomeprazole); 5-difluoro-methoxy-2-[(3; 4-dimethoxy-2-pyridine radicals) methyl sulfinyl]-1H-benzimidazole (INN: pantoprazole); 2-[3-methyl-4-(2; 2; the 2-trifluoro ethoxy)-and the 2-pyridine radicals] methyl sulfinyl]-1H-benzimidazole (INN: lansoprazole); 2-{[4-(3-methoxy propoxy)-3-picoline-2-yl] methyl sulfinyl }-rabeprazole) and 5-methoxyl group-2-((4-methoxyl group-3 1H-benzimidazole (INN:; 5-dimethyl-2-pyridylmethyl) sulfinyl)-1H-imidazo [4,5-b] pyridine (INN: tenatoprazole).
Because their mechanism of action, above-mentioned sulfinyl derivant is also referred to as proton pump inhibitor, and perhaps PPI is made in abbreviation.
Prior art
For the first time, european patent application 80602 has been described some pyridine-sodium salt of 2-ylmethyl sulfinyl-1H-benzimidazole compound and the concrete preparation of calcium salt.After a while, european patent application 124495 (US4738974) is described and is required patent protection to have for example Li of cation
+, Na
+, K
+, Mg
2+, Ca
2+Or Ti
4+The new salt of cationic omeprazole.
All above-mentioned PPI have the general character (is crucial for its effectiveness) of acid labile, and they become in neutrality and particularly sour environment and very are easy to decompose, and also produce the very dark catabolite of color simultaneously.In the past, although the PPI acid labile has been carried out sizable effort and has been obtained to comprise the peroral dosage form that these PPI are stable and be easy to store.In order to be the microenvironment of 7-12 to providing pH value to the unsettled PPI of acid, it is the very common method (with reference to European patent 244380) that obtains stable oral PPI dosage form (for example tablet) that alkaline reaction chemical compound (for example sodium carbonate) is added in the peroral dosage form.Therefore, can obtain the peroral dosage form (for example tablet or capsule) of stable and anti-storage now.But the preparation of these peroral dosage forms is quite complicated, and relevant with packing, need to implement some complicated preventive measure so that even under extreme condition of storage the torrid areas of high temperature and atmosphere high humility (for example) dosage form also stable completely.In addition, the past people make great efforts to adapt to the mode that demand is preferably possible separately PPI is discharged in human body always.
International Patent Application WO 92/08716 has been described the chemical method of fractionation pyridine-2-ylmethyl sulfinyl-1H-benzimidazole optical antimer.The chemical compound mentioned for preparing in simplified method especially comprises (+) and (-)-5-difluoro-methoxy-2-[(3,4-dimethoxy-2-pyridine radicals) methyl sulfinyl]-the 1H-benzimidazole [=(+)-and (-)-pantoprazole] chemical compound.International Patent Application WO 92/08716 is mentioned the optical antimer of pyridine-2-ylmethyl sulfinyl-1H-benzimidazole; for example (+)-and (-) enantiomer or (R)-and (S)-enantiomer is useful as reactive compound in the medicine of treatment gastroenteropathy.For the dosage of administering mode and reactive compound, especially can be with reference to European patent 166287.
In the symposium that hold in JIUYUE, 1993 Montreal, the synthetic and biologic activity of pantoprazole enantiomer is disclosed in people's such as Kohl the report.
International Patent Application WO 94/24867 and WO94/25028 require patent protection chemical compound (-)-and (+)-pantoprazole be used for the treatment of the purposes of the disease of human stomach.Described each stereoisomer is compared with other stereoisomer separately has the pharmacy advantage.Also describe the possible salt of many different stereoisomers, particularly preferably be sodium salt.
In the International Patent Application WO 94/27988 (US 5693818), disclose some (+)-and (-)-form of omeprazole salts and the method for preparing them.
International Patent Application WO 97/41114 has been described some method of preparation pyridine-2-ylmethyl sulfinyl-1H-benzimidazole magnesium salt.Wherein the especially preparation of pantoprazole magnesium salt has been described to exemplify mode.According to the analytical data that provides, the salt of preparing is the pantoprazole-magnesium of anhydrous form.
International Patent Application WO 00/10995 (US 6410569) has been described the dihydrate of raceme pantoprazole magnesium salt.
United States Patent (USP) 6369085 relates to a kind of new model of omeprazole trihydrate S-enantiomer magnesium salt, and the method that is used to prepare the magnesium salt of this S-omeprazole and comprises its pharmaceutical composition.
International Patent Application WO 02/045693 (DE10061137) has been described a kind of novel formulation of suitable production pharmaceutical dosage form.Active component in novel formulation is PPI or its salt for example, is evenly dispersed in basically to comprise in one or more excipient substrate that are selected from aliphatic alcohol, triglyceride, partial glyceride and fatty acid ester.
United States Patent (USP) 5997903 relates to the oral form of pantoprazole, and it contains a core, an intermediate layer and the skin that can resist gastric juice.
International Patent Application WO 04/013126 has been described (S)-pantoprazole-magnesium and hydrate thereof.
Detailed Description Of The Invention
Have been found that now and can produce PPI alkali reaction salt that because their character and high stability, it is fit to further process highlightedly, does not even add other alkali reaction chemical compound in peroral dosage form.
Therefore, the present invention provides aspect total and has H
+/ K
+-adenosine triphosphatase-the suppress alkali reaction salt of active pyridine-2-ylmethyl sulfinyl-1H-benzimidazole.
According to the present invention, " alkali reaction salt " should be understood to include has H
+/ K
+-adenosine triphosphatase-suppress the pharmaceutically compatible slaine of active pyridine-2-ylmethyl sulfinyl-1H-benzimidazole wherein passes through at least one equivalent positive charge of hydroxyl ion balance metal ion.
According to the present invention, " has H
+/ K
+-adenosine triphosphatase-suppress active pyridine-2-ylmethyl sulfinyl-1H-benzimidazole " should be understood to include the pantoprazole of racemic form; omeprazole; lansoprazole; rabeprazole and tenatoprazole; also have the enantiomer of these chemical compounds; for example (R) of pure form-and (S)-pantoprazole; (R)-and (S)-omeprazole; (R)-and (S)-lansoprazole; (R)-and (S)-rabeprazole and (R)-and (S)-tenatoprazole; and, particularly comprise being substantially free of the enantiomer of other enantiomer separately with the mixture of any desired ratio.
Especially, has H according to the present invention
+/ K
+The alkali reaction salt of-adenosine triphosphatase-suppress active pyridine-2-ylmethyl sulfinyl-1H-benzimidazole characterizes with 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 and their enantiomer,
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.
More particularly, the invention provides the chemical compound of formula 1,
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 their enantiomer,
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.
The preferred theme of the present invention is the chemical compound of molecular formula 1,
Wherein
Me is a magnesium,
PPI is the chemical compound that is selected from pantoprazole, (R)-pantoprazole, (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.
The particularly preferred theme of the present invention is the chemical compound of formula 1,
Wherein
Me is a magnesium,
PPI is (the S)-pantoprazole that is substantially free of (R)-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.
Have been found that in International Patent Application WO 94/24867 particularly preferred (-)-or (S)-the pantoprazole sodium salt, it can not form the form of storage-stable.In for the trial that obtains stable (-)-pantoprazole peroral dosage form, have been found that the alkali reaction magnesium salt of (S)-pantoprazole, particularly, have very surprising stability property, make them in the purposes of solid or peroral dosage form, become particularly suitable candidate with the form of hydrate.Compare with (-)-Pantoprazole Sodium salt, they have the stability property of sizable improvement.For example, at the chemical compound of 70 ℃ of formulas 1, wherein Me is a magnesium, PPI is (S)-pantoprazole, X is 1, and Y is that Z is 1, be its hydrate forms, complete stability in a week, and show in fact do not have variable color or decomposition, however under identical condition, pass through the identical time cycle, the hydrate of (-)-Pantoprazole Sodium becomes brown, generates the catabolite of wanting when quantity.In addition, the chemical compound of formula 1, wherein Me is a magnesium, and PPI is (S)-pantoprazole, and X is 1, and Y is 1, and Z is 1, is its hydrate forms, and it is compared with racemic pantoprazole-magnesium dihydrate and shows surprising and unforeseeable dissolving more fast.
Can be used for the treatment of and prevent all diseases that to prevent or to treat by use PPI according to the hydrate of chemical compound of the present invention and they.The disease that particularly, can be used for the treatment of stomach according to the hydrate of chemical compound of the present invention and they.In this article, be to be noted that the hydrate according to chemical compound of the present invention and they of relative high stability.For example, under the storage of atmospheric condition, [Mg] [(S)-pantoprazole] [OH]
xH
2The sum of by-product keeps constant among the O, however under the situation of (-)-Pantoprazole Sodium, (60-70 ℃ of storage) under the same conditions, purity (according to HPLC) is reduced to 96-97% from 99.5.According to the hydrate of chemical compound of the present invention and they because quite high storage stability is particularly suitable for using in medicine.
In the presence of alkaline hydrated oxide, by with PPI and Me-reactant salt, prepare according to chemical compound of the present invention and their hydrate with concrete method, perhaps in water or at water and polar organic solvent (for example alcohols, particular methanol, ethanol or isopropyl alcohol, perhaps ketone, preferred acetone) mixture in, by easy dissolved PPI salt (for example (-)-Pantoprazole Sodium), use for example magnesium salt, for example magnesium chloride, sodium hydroxide solution prepare according to chemical compound of the present invention and their hydrate.
The Me-salt that be fit to use in the method for example has chlorination Me, bromination Me, fluoridizes Me, iodate Me, formic acid Me, acetic acid Me, propanoic acid Me, gluconic acid Me or carbonic acid Me.Can also be in the presence of alkaline hydrated oxide solution, in the alcoholates medium, use Me-alkoxide (for example methanol Me, ethanol Me, (different) propanol Me, butanols Me, hexanol Me or phenol Me) and easy dissolved PPI reactant salt, and by adding entry, alkaline PPI salt is with its hydrate forms crystallization.In addition, can be from the mixture of for example methanol will be according to chemical compound of the present invention and their hydrate recrystallization.
Following examples are to set forth the present invention rather than restriction the present invention for example.M.p represents fusing point, min. representative minute, h representative hour.
Embodiment
1.
[5-(difluoro-methoxy)]-2-[(3,4-dimethoxy-2-pyridine radicals) the methyl sulfurous Acyl group]-the 1H-benzimidazole } hydroxyl magnesium monohydrate
Molecular formula [pantoprazole
-OH
-Mg
2+H
2O]: C
16H
17F
2N
3O
6SMg
Dissolving 10.7g Pantoprazole Sodium sesquialter hydrate in 110ml water.At 25 ℃ of sodium hydroxide and agitating solution 1h that add 2.48g 40%.Dissolving 5.01g magnesium chloride hexahydrate adds to this drips of solution in the pantoprazole sodium salt solution continuous stirring 1h under 25 ℃ of stirrings in 20ml water.With the suspension sucking filtration that obtains, use the 50ml water washing precipitate.This precipitate of suspendible and filtration again once more in 100ml water in 40-45 ℃ of vacuum desiccator dry (＜50 millibars), obtain the canescence solid target chemical compound of 10.76g (94.6%) m.p.184-187 ℃ (decomposition).
Analyze:
2.
(-)-and [5-(difluoro-methoxy)]-2-[(3,4-dimethoxy-2-pyridine radicals) methyl Sulfinyl]-the 1H-benzimidazole } hydroxyl magnesium monohydrate
Molecular formula [(S)-pantoprazole
-OH
-Mg
2+H
2O]: C
16H
17F
2N
3O
6SMg
In 110ml water, dissolve 10.9g (-)-pantoprazole sodium salt.At 50 ℃ of sodium hydroxide and agitating solution 1h that add 2.48g40%.Solution is cooled to room temperature.Dissolving 5.01g magnesium chloride hexahydrate drops to magnesium chloride solution in (-)-pantoprazole sodium salt solution continuous stirring 18h under 25 ℃ of stirrings in 20ml water.With the suspension sucking filtration that obtains, use the 50ml water washing precipitate.This precipitate of suspendible and filtration again once more in 100ml water in 40-45 ℃ of vacuum desiccator dry (＜50 millibars), obtain the canescence solid target chemical compound of 10.01g (88%) m.p.164-167 ℃ (decomposition).
Specific rotation light value: α
D 20 °=-123 (c=0.5, methanol)
Analyze:
3.
(+)-and [5-(difluoro-methoxy)]-2-[(3,4-dimethoxy-2-pyridine radicals) methyl Sulfinyl]-the 1H-benzimidazole } hydroxyl magnesium sesquialter hydrate
Molecular formula [2 (R)-pantoprazole
-2OH
-2Mg
2+H
2O]: C
32H
33F
4N
6O
11S
2Mg
2
In 50ml water, dissolve 5.0g (+)-pantoprazole sodium salt.At 35 ℃ of sodium hydroxide and agitating solution 1h that add 1.23g 40%.Solution is cooled to room temperature.Dissolving 2.50g magnesium chloride hexahydrate drops to magnesium chloride solution in (+)-pantoprazole sodium salt solution continuous stirring 18h under 25 ℃ of stirrings in 15ml water.With the suspension sucking filtration that obtains,, in 50-55 ℃ of vacuum desiccator dry (＜50 millibars), obtain the canescence solid target chemical compound of 4.33g (74.6%) m.p.161-165 ℃ (decomposition) with three parts of washing precipitates of 50ml moisture.
Specific rotation light value: α
D 20 °=+112 (c=0.5, methanol)
Analyze:
4.
Three-[5-(difluoro-methoxy)]-2-[(3,4-dimethoxy-2-pyridine radicals) the methyl Asia Sulfonyl]-the 1H-benzimidazole } hydroxyl two magnesium tetrahydrates
Molecular formula [3 pantoprazole
-OH
-2Mg
2+4H
2O]: C
48H
51F
6N
9O
17S
3Mg
2
Dissolving 25.0g Pantoprazole Sodium sesquialter hydrate in 250ml water.At 25 ℃ of sodium hydroxide and agitating solution 15min that add 1.33ml 40%.Dissolving 3.92g magnesium chloride hexahydrate drops to magnesium chloride solution in the pantoprazole sodium salt solution continuous stirring 2.5h under 25 ℃ of stirrings in 31ml water.With the suspension sucking filtration that obtains, with three parts of washing precipitates of 150ml moisture.Dry this precipitate (＜50 millibars) in 40-45 ℃ of vacuum desiccator, the canescence solid target chemical compound of acquisition 12.47g (52.7%) m.p.182-185 ℃ (decomposition).
Analyze:
* calculate with tetrahydrate
5.
(-)-three-[5-(difluoro-methoxy)]-2-[(3,4-dimethoxy-2-pyridine radicals) Methyl sulfinyl]-the 1H-benzimidazole } hydroxyl two magnesium pentahydrates
Molecular formula [3 (S)-pantoprazole
-OH
-2Mg
2+5H
2O]: C
48H
53F
6N
9O
18S
3Mg
2
In 60ml water, dissolve 6.0g (-)-Pantoprazole Sodium.At 30-35 ℃ of sodium hydroxide and agitating solution 15min that adds 0.49g40%.Dissolving 1.02g magnesium chloride hexahydrate drops to magnesium chloride solution in (-) pantoprazole sodium salt solution continuous stirring 18h under 25 ℃ of stirrings in 8ml water.The suspension that sucking filtration obtains is with two parts of washing precipitates of 50ml moisture.Dry this precipitate (＜50 millibars) in 60 ℃ of vacuum desiccators, the canescence solid target chemical compound of acquisition 2.41g (48.3%) m.p.162-166 ℃ (decomposition).
Specific rotation light value: α
D 20 °=-125 (c=0.5 is in methanol)
Analyze:
* calculate with pentahydrate
6.
(+)-three-and [5-(difluoro-methoxy)]-2-[(3,4-dimethoxy-2-pyridine radicals) first The base sulfinyl]-the 1H-benzimidazole } hydroxyl two magnesium pentahydrates
Molecular formula [3 (R)-pantoprazole
-OH
-2Mg
2+5H
2O]: C
48H
53F
6N
9O
18S
3Mg
2
In 50ml water, dissolve 5.0g (+)-Pantoprazole Sodium.At 30-35 ℃ of sodium hydroxide and agitating solution 15min that adds 0.27ml40%.Dissolving 0.78g magnesium chloride hexahydrate drops to magnesium chloride solution in (+)-pantoprazole sodium salt solution continuous stirring 2 days under 25 ℃ of stirrings in 6ml water.With the suspension sucking filtration that obtains, with three parts of washing precipitates of 25ml moisture.Dry this precipitate (＜50 millibars) in 40 ℃ of vacuum desiccators, the canescence solid target chemical compound of acquisition 2.10g (40.1%) m.p.161-166 ℃ (decomposition).
Specific rotation light value: α
D 20 °=+114.5 (c=0.5 is in methanol)
Analyze:
* calculate with pentahydrate
7.
[5-(difluoro-methoxy)]-2-[(3,4-dimethoxy-2-pyridine radicals) the methyl sulfurous Acyl group]-the 1H-benzimidazole } hydroxyl calcium monohydrate
Molecular formula [pantoprazole
-OH
-Ca
2+H
2O]: C
16H
17F
2N
3O
6SCa
Dissolving 21.6g Pantoprazole Sodium sesquialter hydrate in 250ml water.Add 2.00g sodium hydroxide and agitating solution 1h at 25 ℃.Dissolving 5.55g calcium chloride (exsiccant) in 50ml water.Under 25 ℃ of stirrings, calcium chloride solution is dropped in the pantoprazole sodium solution continuous stirring 20h.With the suspension sucking filtration that obtains, use the 200ml water washing precipitate, dry this precipitate (＜50 millibars) in 40-45 ℃ of vacuum desiccator obtains 21.86g (91.8%) canescence solid target chemical compound.
Moisture (Karl-Fischer titrimetry): 7.6%
Fusing point: 157-160 ℃ (decomposition)
Analyze:
8. (-)-and [5-(difluoro-methoxy)]-2-[(3,4-dimethoxy-2-pyridine radicals) methyl
Sulfinyl]-the 1H-benzimidazole } hydroxyl calcium monohydrate
Molecular formula [pantoprazole
-OH
-Ca
2+H
2O]: C
16H
17F
2N
3O
6SCa
In 250ml water, dissolve 22.7g (-)-Pantoprazole Sodium (wet, 0.05mol).At 25 ℃ of adding 2.00g sodium hydroxide and at 40 ℃ of agitating solution 1h.Dissolving 5.55g calcium chloride (exsiccant) in 50ml water.Under 25 ℃ of stirrings, calcium chloride solution is dropped in the pantoprazole sodium solution continuous stirring 20h.With the suspension sucking filtration that obtains, use the 200ml water washing precipitate, dry this precipitate (＜50 millibars) in 40-45 ℃ of vacuum desiccator obtains 21.44g (89.9%) canescence solid target chemical compound.
Moisture (Karl-Fischer titrimetry): 7.8%
Fusing point: 137-147 ℃ (decomposition)
Analyze:
9.
[5-(difluoro-methoxy)]-2-[(3,4-dimethoxy-2-pyridine radicals) the methyl sulfurous Acyl group]-the 1H-benzimidazole } hydroxyl zinc monohydrate
Molecular formula [pantoprazole
-OH
-Zn
2+H
2O]: C
16H
17F
2N
3O
6SZn
Dissolving 21.6g Pantoprazole Sodium sesquialter hydrate in 250ml water.Add 2.00g sodium hydroxide and agitating solution 1h at 25 ℃.Dissolving 6.80g zinc chloride (exsiccant) in 50ml water.Under 25 ℃ of stirrings, liquor zinci chloridi is dropped in the pantoprazole sodium solution continuous stirring 20h.With the suspension sucking filtration that obtains, use the 200ml water washing precipitate, dry this precipitate (＜50 millibars) in 40-45 ℃ of vacuum desiccator obtains 23.08g (94.2%) canescence solid target chemical compound.
Moisture (Karl-Fischer titrimetry): 5.1%
Fusing point: 167-179 ℃ (decomposition)
Analyze:
10.
(-)-and [5-(difluoro-methoxy)]-2-[(3,4-dimethoxy-2-pyridine radicals) methyl Sulfinyl]-the 1H-benzimidazole } hydroxyl zinc monohydrate
Molecular formula [(S)-pantoprazole
-OH
-Zn
2+H
2O]: C
16H
17F
2N
3O
6SZn
In 250ml water, dissolve 22.7g (-)-Pantoprazole Sodium (wet, 0.05mol).Add 2.00g sodium hydroxide and agitating solution 1h at 25 ℃.Dissolving 6.80g zinc chloride (exsiccant) in 50ml water.Under 25 ℃ of stirrings, liquor zinci chloridi is dropped in the pantoprazole sodium solution continuous stirring 20h.With the suspension sucking filtration that obtains, use the 200ml water washing precipitate, dry this precipitate (＜50 millibars) in 40-45 ℃ of vacuum desiccator obtains 22.87g (94.2%) canescence solid target chemical compound.
Moisture (Karl-Fischer titrimetry): 4.3%
Fusing point: 169-173 ℃ (decomposition)
Analyze:
11.
(-)-and [5-(difluoro-methoxy)]-2-[(3,4-dimethoxy-2-pyridine radicals) methyl Sulfinyl]-the 1H-benzimidazole } hydroxyl magnesium monohydrate
Molecular formula [(S)-pantoprazole
-OH
-Mg
2+H
2O]: C
16H
17F
2N
3OxSMg
In 64L water, dissolve 6.20kg (-)-pantoprazole sodium salt (wet, 14.06mol).At room temperature adding 0.56kg sodium hydroxide and at 40 ℃ of agitating solution 1h.Solution is cooled to room temperature.Dissolving 2.86kg magnesium chloride hexahydrate drops to magnesium chloride solution in (-)-pantoprazole sodium solution continuous stirring 18h under 25 ℃ of stirrings in 11.4L water.The suspension that obtains is centrifugal, use the 41L water washing precipitate, in 40-45 ℃ of vacuum desiccator dry (＜50 millibars), obtain 3.97kg (58.84% canescence solid target chemical compound).
Purity (HPLC): 99.4%
ee： ＞99％
Moisture (Karl-Fischer titrimetry): 7.7%
Analyze:
Commercial use
Have useful pharmacological property according to compound of the present invention and their hydrate, this A little character are so that they commercially have utilizability. Especially, in warm-blooded animal, the spy Be not human, they present significant gastric acid secretion inhibiting effect and fabulous stomach and intestine protection is done With. Because their unique stability characteristics are according to compound of the present invention and their hydration Thing is particularly suitable for the production of stable oral PPI formulation. By at compound of the present invention In have hydroxyl ion, unstable and to the PPI of the acid-sensitive sense of trace to acid, have the storage of preventing Do not expect the self-protection that decomposes in depositing.
In this article, " protective effects of stomach and intestine " can be understood as enterogastric diseases prevention and Treatment, particularly inflammatory diseases of gastro-intestinal tract and infringement (for example gastric ulcer, duodenal ulcer, Gastritis, because produce that acid increases or medicine result's irritable bowel disease, GERD, CrohnShi disease, IBD) prevention and treatment, these diseases can by for example microorganism (for example helicobacter pylori), Bacteriotoxin, medicine (for example some anti-inflammatory agent and antirheumatic), chemicals (for example ethanol), Hydrochloric acid in gastric juice or tense situation cause.
With its advantageous property, the compound of selecting according to the present invention and their hydrate are being measured Anti-causing in the various models of ulcer and antisecretory matter is better than having earlier skill surprisingly significantly The compound of art is particularly about their stability and their pharmacological property. Because this A little character, for example compound [Mg] [(S)-Pantoprazole] [OH]xH
2O and [Mg]2[(S)-Pantoprazole]3[OH]xH
2O is suitable for the mankind and veterinary drug very much, particularly they is used for controlling Treat and/or the prevention enterogastric diseases.
Therefore, the present invention further provides be used for the treatment of and/or prevent above-mentioned disease according to this Bright compound and their hydrate.
The present invention comprises that also hydrate according to compound of the present invention and they is for the preparation for the treatment of And/or prevent purposes in the medicine of above-mentioned disease.
In addition, the hydrate that the present invention includes according to compound of the present invention and they is used for the treatment of And/or prevent the purposes of above-mentioned disease.
The present invention also provides the medicine that comprises according to compound of the present invention and their hydrate.
Can prepare described medicine by the own known method that those skilled in the art are familiar with. Do Be medicine, but use according to the hydrate former state of compound of the present invention and they, or preferred and Suitable pharmaceutic adjuvant or carrier combinations are with tablet, coated tablet, capsule, suppository, patch (example As TTS), the form of emulsion, suspension or solution uses, the amount of reactive compound wherein Preferably from 0.1 to 95% and the suitable selection by auxiliary material or carrier, can produce special Be applicable to described reactive compound and/or desired effect beginning and/or acting duration Pharmaceutical dosage form (for example form of the form of slowly-releasing or enteric).
Because its professional knowledge, those skilled in the art is known to be fit to the auxiliary of required pharmaceutical preparation Material or carrier. Except solvent, gelling agent, suppository base, additive of tablet and other activate Outside the compound carrier, also for example may use antioxidant, dispersant, emulsifying agent, froth breaking Agent, flavouring, anticorrisive agent, solubilizer, colouring agent or particularly penetration enhancer and complexant (as Cyclodextrin).
Can be oral, stomach and intestine are outer or applied dermally according to compound of the present invention and their hydration Thing.
In physianthropy, usually have been found that when oral with about 0.1 to 2mg/kg body Heavy, preferred 0.2 to 1.5mg/kg body weight and particularly 0.3 to 1.1mg/kg body weight [based on PPI] the hydrate that gives according to compound of the present invention and they of daily dose be favourable, as Fruit is fit to, and with the form of a plurality of single doses, preferred 1 to 4 single dose administration is so that the acquisition phase The result who hopes. For stomach and intestine are treated outward, can use similarly or (particularly live at vein During the property compound) normally lower dosage. Since its professional knowledge, those skilled in the art Can easily determine under every kind of situation, to give optimal dose and the class of required reactive compound Type.
Another aspect of the present invention is to comprise according to compound of the present invention or its hydrate and normal The medicine of rule auxiliary material, wherein single dose comprises 10 to 100mg PPI.
Another aspect of the present invention is to comprise according to compound of the present invention or its hydrate and normal The medicine of rule auxiliary material, wherein single dose comprises (-)-Pantoprazole of 20 to 80mg.
Another aspect of the present invention is to be used for the treatment of stomach according to compound of the present invention or its hydrate The purposes of intestines problem.
Another aspect of the present invention is to be used for the treatment of according to compound of the present invention or its hydrate The purposes of the enterogastric diseases among the chronic metabolic patient.
Another aspect of the present invention is to be used for the treatment of according to compound of the present invention or its hydrate Purposes with the enterogastric diseases among the patient of drug interaction danger.
Another aspect of the present invention be according to compound of the present invention and or its hydrate be used for the treatment of Suppress for a long time the purposes of the enterogastric diseases among the patient of acid secretion at needs.
Another aspect of the present invention is to comprise according to compound of the present invention or its hydrate and normal The medicine of rule auxiliary material is used for the treatment of the enterogastric diseases in chronic metabolic patient, its Middle single dose comprises 10 to 100mg PPI.
Another aspect of the present invention is to comprise according to compound of the present invention or its hydrate and normal The medicine of rule auxiliary material is used for the treatment of the enterogastric diseases in chronic metabolic patient, its Middle single dose comprises 20 to 80mg PPI.
Another aspect of the present invention is to comprise according to compound of the present invention or its hydrate and normal The medicine of rule auxiliary material is used for the treatment of the stomach and intestine in the patient with drug interaction danger Tract disease, wherein single dose comprises 10 to 100mg PPI.
Another aspect of the present invention is to comprise according to compound of the present invention or its hydrate and normal The medicine of rule auxiliary material is used for the treatment of the stomach and intestine in the patient with drug interaction danger Tract disease, wherein single dose comprises 20 to 80mg PPI.
Another aspect of the present invention is to comprise according to compound of the present invention or its hydrate and normal The medicine of rule auxiliary material is used for the treatment of at needs and suppresses for a long time intestines and stomach among the patient of acid secretion Disease, wherein single dose comprises 10 to 100mg PPI.
Another aspect of the present invention is to comprise according to compound of the present invention or its hydrate and normal The medicine of rule auxiliary material is used for the treatment of at needs and suppresses for a long time intestines and stomach among the patient of acid secretion Disease, wherein single dose comprises 20 to 80mg PPI.
If will be used for the treatment of above-mentioned disease, medicine according to compound of the present invention or its hydrate Preparation can also comprise the active component on one or more pharmacology of other class medicine. Can The example of mentioning is: sedative (benzodiazepine * for example
Class, diazepam), antispasmodic (example Such as bietamiverine or camylofin), anticholinergic drug (such as Oxyphencyclimine or phencarbamide), local anaesthesia Medicine (such as totokaine or procaine) randomly also comprises enzyme, vitamin or amino acid.
In this article, ben be according to compound of the present invention and buffering or in and hydrochloric acid in gastric juice or the other medicines that suppress the acid secretion for example antiacid (for example magaldrate) or H2Resistance The stagnate drug combination of agent (for example Cimetidine, ranitidine), and for increase or mistake Strengthening Main Function and/or elimination or reduction side effect or acquisition on the meaning that degree increases rises fast The effect effect is with the drug combination of gastrin antagonists. For the stomach and intestine that prevent from being caused by NSAIDs Road damage, can mention fixing or freely with NSAIDs (for example etofenamate, two chlorine Fragrant acid, Indomethacin, brufen or piroxicam) administering drug combinations, perhaps be used for controlling The antibacterial material of helicobacter pylori processed (for example cephalosporins, Tetracyclines, PCs, Macrolides, nitro glyoxaline or other bismuth salt) administering drug combinations. That can mention is anti-The member of bacterium combination has for example mezlocillin, ampicillin, Amoxicillin, cefoxitin, head Spore west fourth, CTX, Imipenem, gentamicin, amikacin, erythromycin, ring third Sha Xing, metronidazole, CLA, azithromycin and combination thereof (CLA+metronidazole for example, Amoxicillin+CLA).
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.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP03016759.7 | 2003-07-23 | ||
| EP03016760.5 | 2003-07-23 | ||
| EP03016759 | 2003-07-23 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1822835A CN1822835A (en) | 2006-08-23 |
| CN100457104C true CN100457104C (en) | 2009-02-04 |
Family
ID=34923795
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB200480020260XA Expired - Fee Related CN100457104C (en) | 2003-07-23 | 2004-07-22 | Alkaline salts of proton pump inhibitors |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN100457104C (en) |
| ZA (1) | ZA200510178B (en) |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4738974A (en) * | 1983-03-04 | 1988-04-19 | Aktiebolaget Hassle | Base addition salts of omeprazole |
| WO1994025028A1 (en) * | 1993-04-27 | 1994-11-10 | Sepracor, Inc. | Methods and compositions for treating gastric disorders using optically pure (+) pantoprazole |
| US5693818A (en) * | 1993-05-28 | 1997-12-02 | Astra Aktiebolag | Process for preparing pure salts of pyridinylmethyl-sulfinyl-1H-benzimidazole |
| CN1318065A (en) * | 1998-08-18 | 2001-10-17 | 比克·古尔顿·劳姆贝尔格化学公司 | Novel salt form of pantoprazole |
| US6369085B1 (en) * | 1997-05-30 | 2002-04-09 | Astrazeneca Ab | Form of S-omeprazole |
-
2004
- 2004-07-22 CN CNB200480020260XA patent/CN100457104C/en not_active Expired - Fee Related
-
2005
- 2005-12-14 ZA ZA200510178A patent/ZA200510178B/en unknown
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4738974A (en) * | 1983-03-04 | 1988-04-19 | Aktiebolaget Hassle | Base addition salts of omeprazole |
| WO1994025028A1 (en) * | 1993-04-27 | 1994-11-10 | Sepracor, Inc. | Methods and compositions for treating gastric disorders using optically pure (+) pantoprazole |
| US5693818A (en) * | 1993-05-28 | 1997-12-02 | Astra Aktiebolag | Process for preparing pure salts of pyridinylmethyl-sulfinyl-1H-benzimidazole |
| US6369085B1 (en) * | 1997-05-30 | 2002-04-09 | Astrazeneca Ab | Form of S-omeprazole |
| CN1318065A (en) * | 1998-08-18 | 2001-10-17 | 比克·古尔顿·劳姆贝尔格化学公司 | Novel salt form of pantoprazole |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1822835A (en) | 2006-08-23 |
| ZA200510178B (en) | 2006-12-27 |
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