CA2092694C - Use of pyridylmethylsulphinyl-1h-benzimidazole derivates in the treatment of illnesses caused by helicobacter bacteria - Google Patents
Use of pyridylmethylsulphinyl-1h-benzimidazole derivates in the treatment of illnesses caused by helicobacter bacteria Download PDFInfo
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Abstract
The use of compounds of the formula 1 (see formula I) wherein the substituents and symbols have the meanings given in the description, for combating Helicobacter bacteria is described.
Description
~9~~~~
_1_ Use of ~yridylmeth l~phinyl--1H-benzimidazole derivates in the treatment of illnesses caused by helicobacter laacteria Scope of application of the invention The invention relates to new or-al drug forms. The new drug forms are employed for the treatment of diseases of the stomach and/or intestine caused by Helicobacter bacteria.
Prior art Pyridylmethylsulphinyl-1H-benzimidazoles which have gastric acid secretion-inhibiting properties-are described in a large number of patent applications.
The following patent applications and patents may be mentioned in particular here in connection with the p-resent invention: EP-A-134 400 (--- USP
4,555,518), EP-A-127 763 (= USP 4,560,693), EP-B-166 287 (= USP 4,758,579), EP-A-201 575 (_ USP 4,686,230), W089/05299 and W089/11479. - European Patent Application EP-A-382 489 describes and clay-ms the suitability of certain pyridylmethylsulphinyl-1H-benzimidazoles, which are substituted in the benzimidazole part, if desired, by methoxy or trifluoromethyl, for the treatment of infectious diseases caused by bacteria of the Campylobacter (= Helicobacter) strain. International Patent Application Wo90/09175 discloses the use of omeprazole in the treatment of infectious diseases, in particular those caused by Campylobacter pylori. -Because the pyridylmethylsulphinyl-1H-benzimidazoles have a low stability and are easily decomposed by acid, various patent applications (e.g. EP-A-244 380 or EP-A-247 983) refer to the need to administer these active compounds in a form which is resistant to gaastric juice in the case of oral administration. An "enteric coated" formulation is also used in the abovementioned EP-A-382 489 as the oral presentation form for combating Campylobacter.
Description of the invention The invention relates to the use of compounds of the formula 2 ~09~694 R3 ~ R6 /, R7 / N ~/
R8 (I) RZ-~-~\ ~ \~IH ~ N f1 wherein R1 denotes hydrogen, 1-4C-alkyl or 1-4C-alkoxy, R2 denotes hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy which is substituted completely or predominantly by fluorine, chlorodifluoromethaxy, 2-chloro-1,1,2-trifluoroethoxy or, together with R3, 1-2C-alkylenedioxy which is substituted completely ox partly by fluorine, or chlorotrifluoroethylenedioxy, R3 denotes 1-~C-alkoxy which is substituted completely or predominantly by fluorine, chlorodifluoromethoxy, 2-chloro-1,1,2-trifluoroethoxy or, together with R2, 1-2C-alkylenedioxy which is substituted completely or partly by fluorine, or chlorotrifluoroethylenedioxy, R4 denotes hydrogen or a group which can easily be split off under physiological conditions, RS denotes hydrogen or 1-4C-alkyl, R6 denotes hydrogen or 1-4C-alkyl, R7 denotes hydrogen, 1-4C-alkyl or 1-4C-alkoxy, R8 denotes 1-4C-alkoxy, 1-4C-alkoxy which is substituted completely or predominantly by fluorine. or benzyloxy and n represents the number 0 or 1, and their pharmacologically tolerated salts, for the preparation of medicaments to be administered orally for combating Helicobacter bacteria.
Z-4C-Alkyl represents straight-chain or branched alkyl radicals; examples which may be mentioned are the butyl, i-butyl, sec.-butyl, t-butyl, propyl, isopropyl, ethyl and in particular the methyl radical.
1-4C-Alkoxy represents straight-chain or branched alkoxy radicals; examples which may be mentioned are the butoxy, i-butoxy, sec.-butoxy, t-butoxy, propoxy, isopropoxy, ethoxy and in particular the methoxy radical.
Examples which may be mentioned of 1-4C-alkoxy which is substituted completely or predominantly by fluorine are the 1,2,2-trifluoroethoxy, the 2,2,3,3,3-pentafluoropropoxy, the perfluoroethoxy and in particular the 1,1,2,2-tetrafluoroethoxy, the trifluoromethoxy, the 2,2,2-trifluoroethoxy and the difluoromethoxy radical.
Examples which may be mentioned of 1-2C-alkylenedioxy which is substituted completely or partly by fluorine are the 1,1-difluoroethylenedioxy (-O-CFZ-CHZ-O-), the 1,1,2,2-tetrafluoroethylenedioxy (-O-CFZ-CFZ-O-) and in particular the difluoromethylenedioxy (-O-CFZ-O-) and the 1,1,2-trifluoroethylenedioxy radical (-O-CF2-CHF-O-).
If R2 and R3 together denote 1-2C-alkylenedioxy which is substituted completely or partly by fluorine, or chlorotrifluoroethylenedioxy, the substituents R2 and R3 are bonded in adjacent positions to the benzo part of the benzimidazole ring.
A group R4 which can easily be split off under physiological conditions is a substituent which is separated off from the nitrogen atom by hydrolysis - if appropriate under enzymatic catalysis - to form an N-H bond, the group itself -bonding a hydroxyl group - being converted into a physiologically acceptable and in particular pharmacologically tolerated compound. Groups R4 which can be split off and which may be mentioned are, in particular, all types of substituted carbonyl groups, such as the alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkoxycarbonyl, aryloxycarbonyl or aralkoxycarbonyl group, or the optionally substituted carbamoyl group. Examples which may be mentioned are the methoxycarbonyl, t-butoxycarbonyl, benzoyl, phenylcarbamoyl and the dimethylcarbamoyl group.
Preferred possible salts for compounds of 'the formula I in which n denotes the number 0 (sulphides) are all the pharmacologically tolerated acid addition salts. Salts which may be mentioned in particular are the pharmacologically tolerated salts of the inorganic and organic acids usually used in galenics.
Examples of such suitable salts are water-soluble and water-insoluble acid addition salts, such as the hydrochloride, hydrobromide, hydriodide, phosphate, nitrate, sulphate, acetate, citrate, gluconate, benzoate, hibenzate, fendizoate, butyrate, sulphosalicylate, maleate, laurate, malate, fumarate, succinate, oxalate, tartrate, amsonate, embonate, metembonate, stearate, tosylate, 2--hydroxy-3-naphthoate, 3-hydroxy-2-naphthoate or mesylate.
Preferred possible salts for compounds of the formula I in which n denotes the number 1 (sulphoxides) are pharmacologically tolerated basic salts, in particular pharmacologically tolerated salts with the inorganic and organic bases usually used in galenics. Examples of basic salts which may be mentioned are the lithium, sodium, potassium, calcium, aluminium, magnesium, titanitun, ammonium or guanidinium salts.
Of the Helicobacter strains against which the compounds of the formula I have proved to be active, the Helicobacter pylori strain may be mentioned in particular.
Examples which may be mentioned of medicaments to be administered orally are tablets, coated tablets, hard and soft capsules, for example of gelatine, dispersible powders, granules, aqueous and oily suspensions, emulsions, solutions or syrups, it being advantageous far the tablets, coated tablets, capsules or granules to be such that they readily dissolve in gastric juice and release the active compound in the stomach.
For combined treatment of gastric diseases which are based both on an increased secretion of gastric acid and on damage to the stomach by Helicobacter pylori, there may also be mentioned those drug formulations to be administered orally which contain active compounds of the formula I both in a form which ie resistant to gastric juice and in a form which is not resistant to gastric juice simultaneously in an individual dose. Examples which may be mentioned are tablets which contain the active compound both in a core which is resistant to gastric juice and in a shell which is not resistant to gastric juice, or capsules filled with pellets or (mini)tablets which are resistant to gastric juice and those which are not resistant to gastric juice.
In human medicine, the active compounds are in general administered in a daily dose of about o.05 to about 5, preferably 0.1 to 2.5 mg/kg of body weight, if appropriate in the form of several, preferably 2 to 6, individual doses, to achieve the desired result.
2~1~~6~~
If the compounds of the formula I and/or their salts are to be employed for the treatment of diseases of the stomach based on the presence of Helicobacter pylori, the medicaments to be administered can also contain one or more pharmacologically active constituents of other groups of medicaments.
Combination of compounds of the formula I and/or their salts with antimicrobial substances which have an action against Helicobacter pylori, such as, for example, penicillin G, gentamycin, erythromycin, nitrofurazone, nitrofurantoin, furazolidone, metronidazole and in particular amoxycillin, with the aim of intensifying the main action in the super-additive sense, is to be emphasized in particular in this connection. Combination of the active compound 5-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridyl)methylsulphinyl)-1H-benzimidazole [=
pantoprazole (INN)) and its salts with substances having an antimicrobial action, in particular with amoxycillin, is particularly preferred in this connection and the invention therefore furthermore relates to this combination.
It has been found, surprisingly, that the compounds of the formula I are considerably more active against Helicobacter bacteria in an acid medium than in a neutral medium, and that they accordingly - in Contrast to the doctrine to be found in the prior art - should appropriately not be administered in a form which is resistant to gastric juice.
The invention thus preferably relates to the use of compounds of the formula I
and their pharmacologically tolerated salts for the preparation of medicaments which are not in a formulation which is resistant to gastric juice and are to be administered orally for combating Helicobacter bacteria.
One embodiment of the invention which is worth mentioning (embodiment a) comprises the use, according to the invention, of compounds of the formula Ia I
(0 (Ia) RZ y\
wherein R1 denotes hydrogen or methyl, R2 denotes hydrogen, methyl, ethyl, methoxy, ethoxy, 1,1,2,2-tetrafluoroethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, difluoromethoxy, 2-chloro-1,1,2-trifluoroethoxy or, together with R3, difluoromethylenedioxy, 1,1,2-trifluoroethylenedioxy or 1-chloro-1,2,2-trifluoroethylenedioxy, R3 denotes 1,1,2,2-tetrafluoroethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, difluoromethoxy, 2-chloro-1,1,2-trifluoroethoxy or, together with R2, difluoromethylenedioxy, 1,1,2-trifluoroethylenedioxy or 1-chloro-1,2,2-trifluoroethylenedioxy, R4 denotes hydrogen, R5 denotes hydrogen, methyl or ethyl, R6 denotes hydrogen or 1-4C-alkyl, R7 denotes hydrogen or 1-4C-alkyl, R8 denotes 1-4C-alkoxy and n represents the number 0 or 1, and their pharmacologically tolerated salts.
The use, according to the invention, of the following compounds of embodiment a and their pharmacologically tolerated salts is particularly worth mentioning:
2-[(4-methoxy-2-pyridyl)methylsulphinyl]-5-trifluoromethoxy-1H-benzimidazole, 2-[(4-methoxy-3-methyl-2-pyridyl)methylsulphinyl]-5-trifluoromethoxy-1H-benzimidazole, 2-[(4-methoxy-5-methyl-2-pyridyl)methylsulphinyl]-5-trifluoromethoxy-1H-benzimidazole, 2-((4-methoxy-2-pyridyl)methylsulphinyl]-5-(1,1,2,2-tetrafluoroethaxy)-1H-benzimidazole, 2-[(4-methoxy-3-methyl-2-pyridyl)methylsulphinyl]-5-(1,1,2,2-tetrafluoroethoxy)-18-benzimidazole, 2-[(4-methoxy-3,5-dimethyl-2-pyridyl)methylsulphinyl]-5-trifluoromethoxy-1H-benzimidazole 2-[(4-methoxy-3-methyl-2-pyridyl)methylsulphinyl]-5-(2,2,2-trifluoroethoxy)-1H-benzimidazole, 5-difluoromethoxy-2-[(4-methoxy-3-methyl-2-pyridyl)-methylsulphinyl]-~1.H-benzimidazole, ~~~~~4 5,6-bis(difluoromethoxy)-2-[(4-methoxy-2-pyridyl)methylsulphinyl]-1H-benzimidazole, 5,6-bis(difluoromethoxy)-2-[(4-methoxy-3-methyl-2-pyridyl)methylsulphinyl]-1H-benzimidazole, 5-difluoromethoxy-6-methoxy-2-((4-methoxy-3-methyl-2-pyridyl)methylsulphinyl-benzimidazole, 5-chlorodifluoromethoxy-2-[(4-methoxy-2-pyridyl)methylsulphinyl]-1H-benzimidazole, 2,2-difluoro-6-[(4-methoxy-2-pyridyl)methylsulphinyl]-5H-(1,3]-dioxolo(4,5-f]
benzimidazole, 2,2-difluoro-6-((4-methoxy-3-methyl-2-pyridyl)methylsulphinyl]-5H-(1,3]-dioxolo[4,5-f]benzimidazole, 6,6,7-trifluoro-6,7-dihydro-2-[(4-methoxy-2-pyridyl)methylsulphinyl]-1H-[1,4]-dioxino[2,3-f]benzimidazole, 6,6,7-trifluoro-6,7-dihydro-2-[(4-methoxy-3-methyl-2-pyridyl)methylsulphinyl]-1H-[1,4]-dioxino[2,3-f]benzimidazole, 2,2-difluoro-6-[(4-methoxy-5-methyl-2-pyridyl)methylsulphinyl]-5H-(1,3]-dioxolo[4,5-f]benzimidazole, 6,6,7-trifluoro-6,7-dihydro-2-[(4-methoxy-3,5-dimethyl-2-pyridyl) methylsulphinyl-1H-(1,4]-dioxino[2,3-f]benzimidazole, 6-chloro-6,7,7-trifluoro-6,7-dihydro-2-((4-methoxy-3-methyl-2-pyridyl)-methylsulphinyl)-1H-[1,4]-dioxino[2,3-f]benzimidazole, 5-difluoromethoxy-2-[(4-mathoxy-3-methyl-2-pyridyl)methylsulphinyl]-4,6-dimethyl-1H-benzimidazole, 5-difluoromethoxy-6-methoxy-2-{[1-(4-methoxy-2-pyridyl)ethyl]sulphinyl}-1H-benzimidazole, 5-(1,1,2,2-tetrafluoroethoxy)-2-{1-(4-methoxy-2-pyridyl)ethyl]sulphinyl}-1H-benzimidazole, 2,2-difluoro-6-([1-(4-methoxy-2-pyridyl)ethyl]sulphinyl}-5H-[1,3]-dioxolo [4,5-f]benzimidazole, 5-(2-chloro-1,1,2-trifluoroethoxy)-2-((4-methoxy-2-pyridyl)methylsulphinyl]-1H-benzimidazole, 5-(2-chloro-1,1,2-trifluoroethoxy)-2-{[1-(4-methoxy-2-pyridyl)ethyl]sulphinyl}-1H-benzimidazole, 5-(2-chloro-1,1,2-trifluoroethoxy)-2-[(4-methoxy-3-methyl-2-pyridyl)methylsulphinyl]-1H-benzimidazole, 2[(4-methoxy-2-pyridyl)methylthio]-5-trifluoromethoxy-1H-benzimidazole, - a -2-[(4-methoxy-3-methyl-2-pyridyl)methylthio]-5-trifluoromethoxy-1H-benzimidazole, 2-[(4-methoxy-5-methyl-2-pyridyl)methylthio]-5-trifluoromethoxy-1H-benzimidazole, 2-[(4-methoxy-2-pyridyl)methyithio]-5-(x,1,2,2-tetrafluoroethoxy)-1H-benzimidazole, 2-[(4-methoxy-3-methyl-2-pyridyl)methylthio]-S-(1,1,2,2-tetrafluoroethoxy)-1H-benzimidazole, 2-[(4-methoxy-3,5-dimethyl-2-pyridyl)methylthio]-5-trifluoromethoxy-lli-benzimidazole, 2-[(4-methoxy-3-methyl-2-pyridyl)methylthio]-5-(2,2,2-trifluoroethoxy)-1H-benzimidazole, 5-difluoromethoxy-2-[(4-methoxy-3-methyl-2-pyridyl)-methylthio]-1H-benzimidazole, 5,6-bis(difluoromethoxy)-2-((4-methoxy-2-pyridyl)methylthio]-1H-benzimidazole, 5,6-bis(difluoromethoxy)-2-[(4-methoxy--3-methyl-2-pyridyl)methylthio]-1H-benzimidazole, 5-difluoromethoxy-6-methoxy-2-[(4-methoxy-3-methyl-2-pyridyl)methylthio-1H-benzimidazole, 5-chlorodifluoromethoxy-2-[(4-methoxy-2-pyridyl)methylthio]-1H-benzimidazole, 2,2-difluoro-6-[(4-methoxy-2-pyridyl)methylthio]-5H-[1,3]-dioxolo[4,5-f]
benzimidazole, 2,2-difluoro-6-[(4-methoxy-3-methyl-2-pyridyl)methylthio]-5H-[1,3]-dioxolo [4,5-f]benzimidazole, 6,6,7-trifluaro-6,7-dihydro-2-[(4-methoxy-2-pyridyl)methylthio]-1H-[1,4]-dioxino[2,3-f]benzimidazole, 6,6,7-trifluoro-6,7-dihydro-2-[(4-methoxy-3-methyl-2-pyridyl)methylthio]-1H-[1,4]-dioxino[2,3-f]benzimidazole, 2,2-difluoro-6-[(4-methoxy-5-methyl-2-pyridyl)methylthio]-5H-[1,3]-dioxolo [4,5-f]benzimidazole, 6,6,7-trifluoro-6,7-dihydro-2-[(4-methoxy-3,5-dimethyl-2-pyridyl)methylthio-1H-[1,4]-dioxino[2,3-f]benzimidazole, 6-chloro-6,7,7-trifluoro-6,7-dihydro-2-[(4-methoxy-3-methyl-2-pyridyl) methylthio]-1H-(1,4]-dioxino[2,3-f]benzimidazole, 5-difluoromethoxy-2-[(4-methoxy-3-methyl-2-pyridyl)methylthio]--4,6-dimethyl-benzimidazole, 5-difluoromethoxy-6-methoxy-2-{(1-(4-methoxy-2-pyridyl)ethyl]sulphinyl}-1H-benzimidazole, 5-(1,1,2,2-tetrafluoroethoxy)-2-{[1-(4-methoxy-2-pyridyl)ethyl]sulphinyl}-1H-i benzimidazole, 2,2-difluoro-6-{(1-(4-methoxy-2-pyridyl)ethyl]sulphinyl}-5H-(1,3]-dioxolo [4,5-f]benzimidazole, I
5-(2-chloro-1,1,2-trifluoroethoxy)-2-((4-methoxy-2-pyridyl)methylthio]-lH-benzimidazole, I
5-(2-chloro-1,1,1-trifluoroethoxy)-2-{(1-(4-methoxy-2-pyridyl)ethylj-sulphinyl}-,i 1H-benzimidazole, I
5-(2-chloro-1,1,2-trifluoroethoxy)-2-((4-methoxy-3-methyl-2-pyridyl)methylthio]-1H-benzimidazole. '.-Another embodiment of the invention which is worth mentioning (embodiment b) comprises the use, according to the invention, of compounds of the formula Ib, R
I
R3 ~ N
(Ib) R2R1~ N
wherein R1 denotes hydrogen or methyl, R2 denotes hydrogen, methyl, ethyl, methoxy, ethoxy, 1,1,2,2--tetrafluoroethoxy, trifluoromothoxy, 2,2,2-trifluoroethoxy, difluoromethoxy, 2-chloro-1,1,2-trifluoroethoxy or, together with R3, difluoromethylenedioxy, 1,1,2-trifluoroethylenedioxy or 1-chloro-1,2,2-trifluoroethylenadioxy, R3 denotes 1,1,2,2-tetrafluoroethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, difluoromethoxy, 2-chloro-1,1,2-trifluoroethoxy or, together ~:ith R2, difluoromethylenedioxy, 1,1,2-trifluoroethylenedioxy or 1-chloro-1,2,2-trifluoroethylenedioxy, R4 denotes hydrogen, R5 denotes denotes hydrogen, methyl or ethyl, R6 donotes hydrogen or 1-4C-alkyl, -R7 denotes 1-4C-alkoxy, R8 denotes 1-4C-alkoxy and n represents the number 0 or 1, and their pharmacologically tolerated salts.
The use, according to the invention, of the following compounds of embodiment b and their pharmacologically tolerated salts is particularly worth mentioning:
5-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridyl)methylsulphinyl]-4,6-dimethyl-1H-benzimidazole, 5-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridyl)methylsulphinyl]-1H-benzimidazole, 5-difluoromethoxy-2-((4,5-dimethoxy-3-methyl-2-pyridyl)methylsulphinyl]-1H-benzimidazole, 2-[(4,5-dimethoxy-3-methyl-2-pyridyl)methylsulphinyl]-5-trifluoromethoxy-1H-ben~zianidazole, 2-[(3,4-dimethoxy-2-pyridyl)methylsulphinyl]-5-(1,1,2,2-tetrafluoroethoxy)-1H-benzimidazole, 2-[(3,4-dimethoxy-2-pyridyl)methylsulphinyl]-5-(2,2,2-trifluoroethoxy)-1H-benzimidazole, 5-difluoromethoxy-6-methoxy-2-[(3,4-dimethoxy-2-pyridyl)methylsulphinyl]-iH-benzimidazole, 2,2-difluoro-6-[(3,4-dimethoxy-2-pyridyl)methylsulphinyl]-5H-[1,3]-dioxolo[4,5-f]benzimidazole, 6,6,7-trifluoro-6,7-dihydro-2-[(3,4-dimethoxy-2-pyridyl)methylsulphinyl]-1H-[1,4]-dioxino[2,3-f]benzimidazole, 2-[(4,5-dimethoxy-2-pyridyl)methylsulphinyl]-5-trifluoromethoxy-1H-benzimidazole, 2-[(4,5-dimethoxy-2-pyridyl)methylsulphinyl]-5-(1,1,2,2-tetrafluoroethoxy)-1H-benzimidazole, 2,2-difluoro-6-[(4,5-dimethoxy-2-pyridyl)methylsulphinyl]-5H-(1,3]-dioxolo[4,5-f]benzimidazole, 5-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridyl)methylthio]-4,6-dimethyl-1H-benzimidazole, 5-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridyl)methylthio]-~H-benzimidazole, 5-difluoromethoxy-2-[(4,5-dimethoxy-3-methyl-2-pyridyl)methylthio]-1H-benzimidazole, - il -2-((4,5-dimethoxy-3-methyl-2-pyridyl)methylthio]-5-trifluoromethoxy-1H-benzimidazole, 2-[(3,4-dimethoxy-2-pyridyl)methyl.thio]-5-(1,1,2,2-tetrafluoroethoxy)-iH-benzimidazole, 2-[(3,4-dimethoxy-2-pyridyl)methylthio]-5-(1,1,2,2-tetrafluoroethoxy)-1H-benzimidazole, 2-[(3,4-dimethoxy-2-pyridyl)methylthio]-5-(2,2,2-trifluoroethoxy)-1H-benzimidazole, 5-difluoromethoxy-6-methoxy-2-[(3,4-dimethoxp-2-pyridyl)methylthio]-1H-benzimidazole, 2,2-difluoro-6-[(3,4-dimethoxy-2-pyridyl)methylthio]-5H-[1,3]-dioxolo[4,5-f]benzimidazole, 6,6,7-trifluoro-6,7-dihydro-2-[(3,4-dimethoxy-2-pyridyl)methylthio]-1H-[1,4]-dioxino[2,3-f]benzimidazole, 2-[(4,5-dimethoxy-2-pyridyl)methylthio]-5-trifluoromethoxy-iH-benzimidazole, 2-[(4,5-dimethoxy-2-pyridyl)methylthio]-5-(1,1,2,2-tetrafluoroethoxy)-1H-benzimidazole, 2,2-difluoro-6-[(4,5-dimethoxy-2-pyridyl)methylthio]-5H-[1,3]-dioxolo[4,5-f]benzimidazole.
Another embodiment of the invention which is worth mentioning (embodiment c) comprises the use, according to the invention, of compounds of the formula rc N
R3 ~ (o) n ~RB (Ic) R2~ ~\ ~ \~H ~ N H
R 1 N E~5 wherein R1 denotes hydrogen, R2 denotes hydrogen, methyl, ethyl, methoxy, ethoxy, 1,1,2,2-tetrafluoroethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, difluoromethoxy, 2-chloro-1,1,2-trifluoroethoxy or, together with R3, difluoromethylenedioxy, 1,1,2-tri:cluoroethylenedioxy or i-chloro-1,2,2-trifluoroethylenedioxy, R3 denotes 1,1,2,2-tetra.fluoroethoxy, trifluoror~ethoxy, 2,2,2-trifluoroethoxy, difluoromethoxy, 2-chloro-1,1,2-trifluoroethoxy or, together with R2, difluoromethylenedioxy, 1,1,2-trifluoroethylenedioxy or 1-chloro-1,2,2-trifluoroethylenedioxy, R4 denotes hydrogen, R5 denotes hydrogen, methyl or ethyl, R6 denotes hydrogen or 1-4C-alkyl, R7 denotes i-4C-alkoxy, R8 denotes benzyloxy and n represents the number 0 or 1, and their pharmacologically talerated salts.
The use, according to the invention, of the following compounds of embodiment c and their pharmacologically tolerated salts is particularly worth mentioning:
2,2-difluoro-6-[(5-benzyloxy-4-methoxy-2-pyridyl)methylsulphinyl]-5H-[1,3]-dioxolo[4,5-f]benzimidazole, 2-((4-benzyloxy-3-methoxy-2-pyridyl)methylsulphinyl]-5-difluoromethoxy-1H-benzimidazole, 2-[(3-benzyloxy-4-methoxy-2-pyridyl)methylsulphinyl]-5-difluoromethoxy-1H-benzimidazole, 2-[(5-benzyloxy-4-methoxy-3-methyl-2-pyridyl)methylsulphinyl]-5-difluoromethoxy-1H-benzimidazole, 2-((5-benzyloxy-4-methoxy-2-pyridyl)methylsulphinyl]-5-trifluoromethoxy-1H-benzimidazole, 2,2-difluoro-6-((5-benzyloxy-4-methoxy-2-pyridyl)methylthio]-5H-[1,3]-dioxolo[4,5-f]benzimidazole, 2-[(4-benzyloxy-3-methoxy-2-pyridyl)methylthio]-5-difluoromethoxy-1H-benzimidazole, 2-[(3-benzyloxy-4-methoxy-2-pyridyl)methylthio]-5-difluoromethoxy-1H-benzimidazole, 2-[(5-benzyloxy-4-methoxy-3-methyl-2-pyridyl)methylthio]-5-difluoromethoxy-1H-benzimidazole, 2-[(5-benzyloxy-4-methoxy-2-pyridyl)methylthio]-5-trifluoromethoxy-1H-benzimidazole.
Another embodiment of the invention which is worth mentioning (embodiment d) is the use, according to the invention, of compounds of the formula Id I
(0 (Id) R2 ~\
wherein R1 denotes hydrogen, R2 denotes hydrogen, methyl, ethyl, methoxy, ethoxy, 1,1,2,2-tetrafluoroethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, difluoromethoxy, 2-chloro-1,1,2-trifluoroethoxy os, together with R3, difluoromethylenedioxy, 1,1,2-trifluoroethylenedioxy or 1-chloro-1,2,2-trifluoroethylenedioxy, R3 denotes 1,1,2,2-tetrafluoroethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, difluoromethoxy, 2-chloro-1,1,2-trifluoroethoxy or, together with R2, difluoromethylenedioxy, 1,1,2-trifluoroethylenedioxy or 1-chlora-1,2,2-trifluoroethylenedioxy, R4 denotes hydrogen, i R5 denotes hydrogen, methyl or ethyl, i R6 denotes hydrogen or i-4c-alkyl, , R7 denotes hydrogen, 1-4C-alkyl or i~-4c-alkoxy, t RS denotes 1,1,2,2-tetrafluoroethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy or difluoromethoxy and n represents the number 0 or 1, and their pharmacologically tolerated salts.
The use, according to the invention, of the following compounds of embodiment d and their pharmacologically tolerated salts is particularly worth mentioning:
5-difluoromethoxy-2-{[3-methoxy-4-(2,2,2-trifluoroethoxy)-2-pyridyl]
methylsulphinyl}-lI3-benzimidazole, 5-difluoromethoxy-2-{[3-methyl-4-(2,2,2-trifluoroethoxy)-pyridyl]
methylsulphinyl}-1H-benzimidazole, ~~~r'~~~~~
2-{[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methylsulphinyl}-5-(2,2,2-trifluoroethoxy)-1H-benzimidazole, 2,2-difluoro-6-{[3-methyl-4-(2,2,2--trifluoroethoxy)-2-pyridyl]methylsulphinyl}-5H-[1,3]-dioxolo[4,5-f]benzimidazole, 5-difluoromethoxy-2-{[3-methoxy-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methylthio}-1H-benzimidazole, 5-difluoromethoxy-2-{[3-methyl-4-(2,2,2-trifluoroethoxy)-pyridyl]methylthio}-benzimidazole, 2-{[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methylthio}-5-(2,2,2-trifluoroethoxy)-1Fi-benzimidazole, 2,2-difluoro-6-{[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methylthio}-5H-[1,3]-dioxolo[4,5-f]benzimidazole.
The compounds of the formula I and their pharmacologically tolerated salts are known from the following patent applications and patents: EP-A-134 400 (= USP
4,555,518), EP-A-127 763 (= USP 4,560,693), EP-B-166 287 (= USP 4,758,579), EP-A-201 575 (= USP 4,686,230), Wo89/05299 and WO89/11479.
The medicaments to be administered orally are prepared using the active compounds of the formula I in a manner which is known per se to the expert.
_1_ Use of ~yridylmeth l~phinyl--1H-benzimidazole derivates in the treatment of illnesses caused by helicobacter laacteria Scope of application of the invention The invention relates to new or-al drug forms. The new drug forms are employed for the treatment of diseases of the stomach and/or intestine caused by Helicobacter bacteria.
Prior art Pyridylmethylsulphinyl-1H-benzimidazoles which have gastric acid secretion-inhibiting properties-are described in a large number of patent applications.
The following patent applications and patents may be mentioned in particular here in connection with the p-resent invention: EP-A-134 400 (--- USP
4,555,518), EP-A-127 763 (= USP 4,560,693), EP-B-166 287 (= USP 4,758,579), EP-A-201 575 (_ USP 4,686,230), W089/05299 and W089/11479. - European Patent Application EP-A-382 489 describes and clay-ms the suitability of certain pyridylmethylsulphinyl-1H-benzimidazoles, which are substituted in the benzimidazole part, if desired, by methoxy or trifluoromethyl, for the treatment of infectious diseases caused by bacteria of the Campylobacter (= Helicobacter) strain. International Patent Application Wo90/09175 discloses the use of omeprazole in the treatment of infectious diseases, in particular those caused by Campylobacter pylori. -Because the pyridylmethylsulphinyl-1H-benzimidazoles have a low stability and are easily decomposed by acid, various patent applications (e.g. EP-A-244 380 or EP-A-247 983) refer to the need to administer these active compounds in a form which is resistant to gaastric juice in the case of oral administration. An "enteric coated" formulation is also used in the abovementioned EP-A-382 489 as the oral presentation form for combating Campylobacter.
Description of the invention The invention relates to the use of compounds of the formula 2 ~09~694 R3 ~ R6 /, R7 / N ~/
R8 (I) RZ-~-~\ ~ \~IH ~ N f1 wherein R1 denotes hydrogen, 1-4C-alkyl or 1-4C-alkoxy, R2 denotes hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy which is substituted completely or predominantly by fluorine, chlorodifluoromethaxy, 2-chloro-1,1,2-trifluoroethoxy or, together with R3, 1-2C-alkylenedioxy which is substituted completely ox partly by fluorine, or chlorotrifluoroethylenedioxy, R3 denotes 1-~C-alkoxy which is substituted completely or predominantly by fluorine, chlorodifluoromethoxy, 2-chloro-1,1,2-trifluoroethoxy or, together with R2, 1-2C-alkylenedioxy which is substituted completely or partly by fluorine, or chlorotrifluoroethylenedioxy, R4 denotes hydrogen or a group which can easily be split off under physiological conditions, RS denotes hydrogen or 1-4C-alkyl, R6 denotes hydrogen or 1-4C-alkyl, R7 denotes hydrogen, 1-4C-alkyl or 1-4C-alkoxy, R8 denotes 1-4C-alkoxy, 1-4C-alkoxy which is substituted completely or predominantly by fluorine. or benzyloxy and n represents the number 0 or 1, and their pharmacologically tolerated salts, for the preparation of medicaments to be administered orally for combating Helicobacter bacteria.
Z-4C-Alkyl represents straight-chain or branched alkyl radicals; examples which may be mentioned are the butyl, i-butyl, sec.-butyl, t-butyl, propyl, isopropyl, ethyl and in particular the methyl radical.
1-4C-Alkoxy represents straight-chain or branched alkoxy radicals; examples which may be mentioned are the butoxy, i-butoxy, sec.-butoxy, t-butoxy, propoxy, isopropoxy, ethoxy and in particular the methoxy radical.
Examples which may be mentioned of 1-4C-alkoxy which is substituted completely or predominantly by fluorine are the 1,2,2-trifluoroethoxy, the 2,2,3,3,3-pentafluoropropoxy, the perfluoroethoxy and in particular the 1,1,2,2-tetrafluoroethoxy, the trifluoromethoxy, the 2,2,2-trifluoroethoxy and the difluoromethoxy radical.
Examples which may be mentioned of 1-2C-alkylenedioxy which is substituted completely or partly by fluorine are the 1,1-difluoroethylenedioxy (-O-CFZ-CHZ-O-), the 1,1,2,2-tetrafluoroethylenedioxy (-O-CFZ-CFZ-O-) and in particular the difluoromethylenedioxy (-O-CFZ-O-) and the 1,1,2-trifluoroethylenedioxy radical (-O-CF2-CHF-O-).
If R2 and R3 together denote 1-2C-alkylenedioxy which is substituted completely or partly by fluorine, or chlorotrifluoroethylenedioxy, the substituents R2 and R3 are bonded in adjacent positions to the benzo part of the benzimidazole ring.
A group R4 which can easily be split off under physiological conditions is a substituent which is separated off from the nitrogen atom by hydrolysis - if appropriate under enzymatic catalysis - to form an N-H bond, the group itself -bonding a hydroxyl group - being converted into a physiologically acceptable and in particular pharmacologically tolerated compound. Groups R4 which can be split off and which may be mentioned are, in particular, all types of substituted carbonyl groups, such as the alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkoxycarbonyl, aryloxycarbonyl or aralkoxycarbonyl group, or the optionally substituted carbamoyl group. Examples which may be mentioned are the methoxycarbonyl, t-butoxycarbonyl, benzoyl, phenylcarbamoyl and the dimethylcarbamoyl group.
Preferred possible salts for compounds of 'the formula I in which n denotes the number 0 (sulphides) are all the pharmacologically tolerated acid addition salts. Salts which may be mentioned in particular are the pharmacologically tolerated salts of the inorganic and organic acids usually used in galenics.
Examples of such suitable salts are water-soluble and water-insoluble acid addition salts, such as the hydrochloride, hydrobromide, hydriodide, phosphate, nitrate, sulphate, acetate, citrate, gluconate, benzoate, hibenzate, fendizoate, butyrate, sulphosalicylate, maleate, laurate, malate, fumarate, succinate, oxalate, tartrate, amsonate, embonate, metembonate, stearate, tosylate, 2--hydroxy-3-naphthoate, 3-hydroxy-2-naphthoate or mesylate.
Preferred possible salts for compounds of the formula I in which n denotes the number 1 (sulphoxides) are pharmacologically tolerated basic salts, in particular pharmacologically tolerated salts with the inorganic and organic bases usually used in galenics. Examples of basic salts which may be mentioned are the lithium, sodium, potassium, calcium, aluminium, magnesium, titanitun, ammonium or guanidinium salts.
Of the Helicobacter strains against which the compounds of the formula I have proved to be active, the Helicobacter pylori strain may be mentioned in particular.
Examples which may be mentioned of medicaments to be administered orally are tablets, coated tablets, hard and soft capsules, for example of gelatine, dispersible powders, granules, aqueous and oily suspensions, emulsions, solutions or syrups, it being advantageous far the tablets, coated tablets, capsules or granules to be such that they readily dissolve in gastric juice and release the active compound in the stomach.
For combined treatment of gastric diseases which are based both on an increased secretion of gastric acid and on damage to the stomach by Helicobacter pylori, there may also be mentioned those drug formulations to be administered orally which contain active compounds of the formula I both in a form which ie resistant to gastric juice and in a form which is not resistant to gastric juice simultaneously in an individual dose. Examples which may be mentioned are tablets which contain the active compound both in a core which is resistant to gastric juice and in a shell which is not resistant to gastric juice, or capsules filled with pellets or (mini)tablets which are resistant to gastric juice and those which are not resistant to gastric juice.
In human medicine, the active compounds are in general administered in a daily dose of about o.05 to about 5, preferably 0.1 to 2.5 mg/kg of body weight, if appropriate in the form of several, preferably 2 to 6, individual doses, to achieve the desired result.
2~1~~6~~
If the compounds of the formula I and/or their salts are to be employed for the treatment of diseases of the stomach based on the presence of Helicobacter pylori, the medicaments to be administered can also contain one or more pharmacologically active constituents of other groups of medicaments.
Combination of compounds of the formula I and/or their salts with antimicrobial substances which have an action against Helicobacter pylori, such as, for example, penicillin G, gentamycin, erythromycin, nitrofurazone, nitrofurantoin, furazolidone, metronidazole and in particular amoxycillin, with the aim of intensifying the main action in the super-additive sense, is to be emphasized in particular in this connection. Combination of the active compound 5-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridyl)methylsulphinyl)-1H-benzimidazole [=
pantoprazole (INN)) and its salts with substances having an antimicrobial action, in particular with amoxycillin, is particularly preferred in this connection and the invention therefore furthermore relates to this combination.
It has been found, surprisingly, that the compounds of the formula I are considerably more active against Helicobacter bacteria in an acid medium than in a neutral medium, and that they accordingly - in Contrast to the doctrine to be found in the prior art - should appropriately not be administered in a form which is resistant to gastric juice.
The invention thus preferably relates to the use of compounds of the formula I
and their pharmacologically tolerated salts for the preparation of medicaments which are not in a formulation which is resistant to gastric juice and are to be administered orally for combating Helicobacter bacteria.
One embodiment of the invention which is worth mentioning (embodiment a) comprises the use, according to the invention, of compounds of the formula Ia I
(0 (Ia) RZ y\
wherein R1 denotes hydrogen or methyl, R2 denotes hydrogen, methyl, ethyl, methoxy, ethoxy, 1,1,2,2-tetrafluoroethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, difluoromethoxy, 2-chloro-1,1,2-trifluoroethoxy or, together with R3, difluoromethylenedioxy, 1,1,2-trifluoroethylenedioxy or 1-chloro-1,2,2-trifluoroethylenedioxy, R3 denotes 1,1,2,2-tetrafluoroethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, difluoromethoxy, 2-chloro-1,1,2-trifluoroethoxy or, together with R2, difluoromethylenedioxy, 1,1,2-trifluoroethylenedioxy or 1-chloro-1,2,2-trifluoroethylenedioxy, R4 denotes hydrogen, R5 denotes hydrogen, methyl or ethyl, R6 denotes hydrogen or 1-4C-alkyl, R7 denotes hydrogen or 1-4C-alkyl, R8 denotes 1-4C-alkoxy and n represents the number 0 or 1, and their pharmacologically tolerated salts.
The use, according to the invention, of the following compounds of embodiment a and their pharmacologically tolerated salts is particularly worth mentioning:
2-[(4-methoxy-2-pyridyl)methylsulphinyl]-5-trifluoromethoxy-1H-benzimidazole, 2-[(4-methoxy-3-methyl-2-pyridyl)methylsulphinyl]-5-trifluoromethoxy-1H-benzimidazole, 2-[(4-methoxy-5-methyl-2-pyridyl)methylsulphinyl]-5-trifluoromethoxy-1H-benzimidazole, 2-((4-methoxy-2-pyridyl)methylsulphinyl]-5-(1,1,2,2-tetrafluoroethaxy)-1H-benzimidazole, 2-[(4-methoxy-3-methyl-2-pyridyl)methylsulphinyl]-5-(1,1,2,2-tetrafluoroethoxy)-18-benzimidazole, 2-[(4-methoxy-3,5-dimethyl-2-pyridyl)methylsulphinyl]-5-trifluoromethoxy-1H-benzimidazole 2-[(4-methoxy-3-methyl-2-pyridyl)methylsulphinyl]-5-(2,2,2-trifluoroethoxy)-1H-benzimidazole, 5-difluoromethoxy-2-[(4-methoxy-3-methyl-2-pyridyl)-methylsulphinyl]-~1.H-benzimidazole, ~~~~~4 5,6-bis(difluoromethoxy)-2-[(4-methoxy-2-pyridyl)methylsulphinyl]-1H-benzimidazole, 5,6-bis(difluoromethoxy)-2-[(4-methoxy-3-methyl-2-pyridyl)methylsulphinyl]-1H-benzimidazole, 5-difluoromethoxy-6-methoxy-2-((4-methoxy-3-methyl-2-pyridyl)methylsulphinyl-benzimidazole, 5-chlorodifluoromethoxy-2-[(4-methoxy-2-pyridyl)methylsulphinyl]-1H-benzimidazole, 2,2-difluoro-6-[(4-methoxy-2-pyridyl)methylsulphinyl]-5H-(1,3]-dioxolo(4,5-f]
benzimidazole, 2,2-difluoro-6-((4-methoxy-3-methyl-2-pyridyl)methylsulphinyl]-5H-(1,3]-dioxolo[4,5-f]benzimidazole, 6,6,7-trifluoro-6,7-dihydro-2-[(4-methoxy-2-pyridyl)methylsulphinyl]-1H-[1,4]-dioxino[2,3-f]benzimidazole, 6,6,7-trifluoro-6,7-dihydro-2-[(4-methoxy-3-methyl-2-pyridyl)methylsulphinyl]-1H-[1,4]-dioxino[2,3-f]benzimidazole, 2,2-difluoro-6-[(4-methoxy-5-methyl-2-pyridyl)methylsulphinyl]-5H-(1,3]-dioxolo[4,5-f]benzimidazole, 6,6,7-trifluoro-6,7-dihydro-2-[(4-methoxy-3,5-dimethyl-2-pyridyl) methylsulphinyl-1H-(1,4]-dioxino[2,3-f]benzimidazole, 6-chloro-6,7,7-trifluoro-6,7-dihydro-2-((4-methoxy-3-methyl-2-pyridyl)-methylsulphinyl)-1H-[1,4]-dioxino[2,3-f]benzimidazole, 5-difluoromethoxy-2-[(4-mathoxy-3-methyl-2-pyridyl)methylsulphinyl]-4,6-dimethyl-1H-benzimidazole, 5-difluoromethoxy-6-methoxy-2-{[1-(4-methoxy-2-pyridyl)ethyl]sulphinyl}-1H-benzimidazole, 5-(1,1,2,2-tetrafluoroethoxy)-2-{1-(4-methoxy-2-pyridyl)ethyl]sulphinyl}-1H-benzimidazole, 2,2-difluoro-6-([1-(4-methoxy-2-pyridyl)ethyl]sulphinyl}-5H-[1,3]-dioxolo [4,5-f]benzimidazole, 5-(2-chloro-1,1,2-trifluoroethoxy)-2-((4-methoxy-2-pyridyl)methylsulphinyl]-1H-benzimidazole, 5-(2-chloro-1,1,2-trifluoroethoxy)-2-{[1-(4-methoxy-2-pyridyl)ethyl]sulphinyl}-1H-benzimidazole, 5-(2-chloro-1,1,2-trifluoroethoxy)-2-[(4-methoxy-3-methyl-2-pyridyl)methylsulphinyl]-1H-benzimidazole, 2[(4-methoxy-2-pyridyl)methylthio]-5-trifluoromethoxy-1H-benzimidazole, - a -2-[(4-methoxy-3-methyl-2-pyridyl)methylthio]-5-trifluoromethoxy-1H-benzimidazole, 2-[(4-methoxy-5-methyl-2-pyridyl)methylthio]-5-trifluoromethoxy-1H-benzimidazole, 2-[(4-methoxy-2-pyridyl)methyithio]-5-(x,1,2,2-tetrafluoroethoxy)-1H-benzimidazole, 2-[(4-methoxy-3-methyl-2-pyridyl)methylthio]-S-(1,1,2,2-tetrafluoroethoxy)-1H-benzimidazole, 2-[(4-methoxy-3,5-dimethyl-2-pyridyl)methylthio]-5-trifluoromethoxy-lli-benzimidazole, 2-[(4-methoxy-3-methyl-2-pyridyl)methylthio]-5-(2,2,2-trifluoroethoxy)-1H-benzimidazole, 5-difluoromethoxy-2-[(4-methoxy-3-methyl-2-pyridyl)-methylthio]-1H-benzimidazole, 5,6-bis(difluoromethoxy)-2-((4-methoxy-2-pyridyl)methylthio]-1H-benzimidazole, 5,6-bis(difluoromethoxy)-2-[(4-methoxy--3-methyl-2-pyridyl)methylthio]-1H-benzimidazole, 5-difluoromethoxy-6-methoxy-2-[(4-methoxy-3-methyl-2-pyridyl)methylthio-1H-benzimidazole, 5-chlorodifluoromethoxy-2-[(4-methoxy-2-pyridyl)methylthio]-1H-benzimidazole, 2,2-difluoro-6-[(4-methoxy-2-pyridyl)methylthio]-5H-[1,3]-dioxolo[4,5-f]
benzimidazole, 2,2-difluoro-6-[(4-methoxy-3-methyl-2-pyridyl)methylthio]-5H-[1,3]-dioxolo [4,5-f]benzimidazole, 6,6,7-trifluaro-6,7-dihydro-2-[(4-methoxy-2-pyridyl)methylthio]-1H-[1,4]-dioxino[2,3-f]benzimidazole, 6,6,7-trifluoro-6,7-dihydro-2-[(4-methoxy-3-methyl-2-pyridyl)methylthio]-1H-[1,4]-dioxino[2,3-f]benzimidazole, 2,2-difluoro-6-[(4-methoxy-5-methyl-2-pyridyl)methylthio]-5H-[1,3]-dioxolo [4,5-f]benzimidazole, 6,6,7-trifluoro-6,7-dihydro-2-[(4-methoxy-3,5-dimethyl-2-pyridyl)methylthio-1H-[1,4]-dioxino[2,3-f]benzimidazole, 6-chloro-6,7,7-trifluoro-6,7-dihydro-2-[(4-methoxy-3-methyl-2-pyridyl) methylthio]-1H-(1,4]-dioxino[2,3-f]benzimidazole, 5-difluoromethoxy-2-[(4-methoxy-3-methyl-2-pyridyl)methylthio]--4,6-dimethyl-benzimidazole, 5-difluoromethoxy-6-methoxy-2-{(1-(4-methoxy-2-pyridyl)ethyl]sulphinyl}-1H-benzimidazole, 5-(1,1,2,2-tetrafluoroethoxy)-2-{[1-(4-methoxy-2-pyridyl)ethyl]sulphinyl}-1H-i benzimidazole, 2,2-difluoro-6-{(1-(4-methoxy-2-pyridyl)ethyl]sulphinyl}-5H-(1,3]-dioxolo [4,5-f]benzimidazole, I
5-(2-chloro-1,1,2-trifluoroethoxy)-2-((4-methoxy-2-pyridyl)methylthio]-lH-benzimidazole, I
5-(2-chloro-1,1,1-trifluoroethoxy)-2-{(1-(4-methoxy-2-pyridyl)ethylj-sulphinyl}-,i 1H-benzimidazole, I
5-(2-chloro-1,1,2-trifluoroethoxy)-2-((4-methoxy-3-methyl-2-pyridyl)methylthio]-1H-benzimidazole. '.-Another embodiment of the invention which is worth mentioning (embodiment b) comprises the use, according to the invention, of compounds of the formula Ib, R
I
R3 ~ N
(Ib) R2R1~ N
wherein R1 denotes hydrogen or methyl, R2 denotes hydrogen, methyl, ethyl, methoxy, ethoxy, 1,1,2,2--tetrafluoroethoxy, trifluoromothoxy, 2,2,2-trifluoroethoxy, difluoromethoxy, 2-chloro-1,1,2-trifluoroethoxy or, together with R3, difluoromethylenedioxy, 1,1,2-trifluoroethylenedioxy or 1-chloro-1,2,2-trifluoroethylenadioxy, R3 denotes 1,1,2,2-tetrafluoroethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, difluoromethoxy, 2-chloro-1,1,2-trifluoroethoxy or, together ~:ith R2, difluoromethylenedioxy, 1,1,2-trifluoroethylenedioxy or 1-chloro-1,2,2-trifluoroethylenedioxy, R4 denotes hydrogen, R5 denotes denotes hydrogen, methyl or ethyl, R6 donotes hydrogen or 1-4C-alkyl, -R7 denotes 1-4C-alkoxy, R8 denotes 1-4C-alkoxy and n represents the number 0 or 1, and their pharmacologically tolerated salts.
The use, according to the invention, of the following compounds of embodiment b and their pharmacologically tolerated salts is particularly worth mentioning:
5-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridyl)methylsulphinyl]-4,6-dimethyl-1H-benzimidazole, 5-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridyl)methylsulphinyl]-1H-benzimidazole, 5-difluoromethoxy-2-((4,5-dimethoxy-3-methyl-2-pyridyl)methylsulphinyl]-1H-benzimidazole, 2-[(4,5-dimethoxy-3-methyl-2-pyridyl)methylsulphinyl]-5-trifluoromethoxy-1H-ben~zianidazole, 2-[(3,4-dimethoxy-2-pyridyl)methylsulphinyl]-5-(1,1,2,2-tetrafluoroethoxy)-1H-benzimidazole, 2-[(3,4-dimethoxy-2-pyridyl)methylsulphinyl]-5-(2,2,2-trifluoroethoxy)-1H-benzimidazole, 5-difluoromethoxy-6-methoxy-2-[(3,4-dimethoxy-2-pyridyl)methylsulphinyl]-iH-benzimidazole, 2,2-difluoro-6-[(3,4-dimethoxy-2-pyridyl)methylsulphinyl]-5H-[1,3]-dioxolo[4,5-f]benzimidazole, 6,6,7-trifluoro-6,7-dihydro-2-[(3,4-dimethoxy-2-pyridyl)methylsulphinyl]-1H-[1,4]-dioxino[2,3-f]benzimidazole, 2-[(4,5-dimethoxy-2-pyridyl)methylsulphinyl]-5-trifluoromethoxy-1H-benzimidazole, 2-[(4,5-dimethoxy-2-pyridyl)methylsulphinyl]-5-(1,1,2,2-tetrafluoroethoxy)-1H-benzimidazole, 2,2-difluoro-6-[(4,5-dimethoxy-2-pyridyl)methylsulphinyl]-5H-(1,3]-dioxolo[4,5-f]benzimidazole, 5-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridyl)methylthio]-4,6-dimethyl-1H-benzimidazole, 5-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridyl)methylthio]-~H-benzimidazole, 5-difluoromethoxy-2-[(4,5-dimethoxy-3-methyl-2-pyridyl)methylthio]-1H-benzimidazole, - il -2-((4,5-dimethoxy-3-methyl-2-pyridyl)methylthio]-5-trifluoromethoxy-1H-benzimidazole, 2-[(3,4-dimethoxy-2-pyridyl)methyl.thio]-5-(1,1,2,2-tetrafluoroethoxy)-iH-benzimidazole, 2-[(3,4-dimethoxy-2-pyridyl)methylthio]-5-(1,1,2,2-tetrafluoroethoxy)-1H-benzimidazole, 2-[(3,4-dimethoxy-2-pyridyl)methylthio]-5-(2,2,2-trifluoroethoxy)-1H-benzimidazole, 5-difluoromethoxy-6-methoxy-2-[(3,4-dimethoxp-2-pyridyl)methylthio]-1H-benzimidazole, 2,2-difluoro-6-[(3,4-dimethoxy-2-pyridyl)methylthio]-5H-[1,3]-dioxolo[4,5-f]benzimidazole, 6,6,7-trifluoro-6,7-dihydro-2-[(3,4-dimethoxy-2-pyridyl)methylthio]-1H-[1,4]-dioxino[2,3-f]benzimidazole, 2-[(4,5-dimethoxy-2-pyridyl)methylthio]-5-trifluoromethoxy-iH-benzimidazole, 2-[(4,5-dimethoxy-2-pyridyl)methylthio]-5-(1,1,2,2-tetrafluoroethoxy)-1H-benzimidazole, 2,2-difluoro-6-[(4,5-dimethoxy-2-pyridyl)methylthio]-5H-[1,3]-dioxolo[4,5-f]benzimidazole.
Another embodiment of the invention which is worth mentioning (embodiment c) comprises the use, according to the invention, of compounds of the formula rc N
R3 ~ (o) n ~RB (Ic) R2~ ~\ ~ \~H ~ N H
R 1 N E~5 wherein R1 denotes hydrogen, R2 denotes hydrogen, methyl, ethyl, methoxy, ethoxy, 1,1,2,2-tetrafluoroethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, difluoromethoxy, 2-chloro-1,1,2-trifluoroethoxy or, together with R3, difluoromethylenedioxy, 1,1,2-tri:cluoroethylenedioxy or i-chloro-1,2,2-trifluoroethylenedioxy, R3 denotes 1,1,2,2-tetra.fluoroethoxy, trifluoror~ethoxy, 2,2,2-trifluoroethoxy, difluoromethoxy, 2-chloro-1,1,2-trifluoroethoxy or, together with R2, difluoromethylenedioxy, 1,1,2-trifluoroethylenedioxy or 1-chloro-1,2,2-trifluoroethylenedioxy, R4 denotes hydrogen, R5 denotes hydrogen, methyl or ethyl, R6 denotes hydrogen or 1-4C-alkyl, R7 denotes i-4C-alkoxy, R8 denotes benzyloxy and n represents the number 0 or 1, and their pharmacologically talerated salts.
The use, according to the invention, of the following compounds of embodiment c and their pharmacologically tolerated salts is particularly worth mentioning:
2,2-difluoro-6-[(5-benzyloxy-4-methoxy-2-pyridyl)methylsulphinyl]-5H-[1,3]-dioxolo[4,5-f]benzimidazole, 2-((4-benzyloxy-3-methoxy-2-pyridyl)methylsulphinyl]-5-difluoromethoxy-1H-benzimidazole, 2-[(3-benzyloxy-4-methoxy-2-pyridyl)methylsulphinyl]-5-difluoromethoxy-1H-benzimidazole, 2-[(5-benzyloxy-4-methoxy-3-methyl-2-pyridyl)methylsulphinyl]-5-difluoromethoxy-1H-benzimidazole, 2-((5-benzyloxy-4-methoxy-2-pyridyl)methylsulphinyl]-5-trifluoromethoxy-1H-benzimidazole, 2,2-difluoro-6-((5-benzyloxy-4-methoxy-2-pyridyl)methylthio]-5H-[1,3]-dioxolo[4,5-f]benzimidazole, 2-[(4-benzyloxy-3-methoxy-2-pyridyl)methylthio]-5-difluoromethoxy-1H-benzimidazole, 2-[(3-benzyloxy-4-methoxy-2-pyridyl)methylthio]-5-difluoromethoxy-1H-benzimidazole, 2-[(5-benzyloxy-4-methoxy-3-methyl-2-pyridyl)methylthio]-5-difluoromethoxy-1H-benzimidazole, 2-[(5-benzyloxy-4-methoxy-2-pyridyl)methylthio]-5-trifluoromethoxy-1H-benzimidazole.
Another embodiment of the invention which is worth mentioning (embodiment d) is the use, according to the invention, of compounds of the formula Id I
(0 (Id) R2 ~\
wherein R1 denotes hydrogen, R2 denotes hydrogen, methyl, ethyl, methoxy, ethoxy, 1,1,2,2-tetrafluoroethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, difluoromethoxy, 2-chloro-1,1,2-trifluoroethoxy os, together with R3, difluoromethylenedioxy, 1,1,2-trifluoroethylenedioxy or 1-chloro-1,2,2-trifluoroethylenedioxy, R3 denotes 1,1,2,2-tetrafluoroethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, difluoromethoxy, 2-chloro-1,1,2-trifluoroethoxy or, together with R2, difluoromethylenedioxy, 1,1,2-trifluoroethylenedioxy or 1-chlora-1,2,2-trifluoroethylenedioxy, R4 denotes hydrogen, i R5 denotes hydrogen, methyl or ethyl, i R6 denotes hydrogen or i-4c-alkyl, , R7 denotes hydrogen, 1-4C-alkyl or i~-4c-alkoxy, t RS denotes 1,1,2,2-tetrafluoroethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy or difluoromethoxy and n represents the number 0 or 1, and their pharmacologically tolerated salts.
The use, according to the invention, of the following compounds of embodiment d and their pharmacologically tolerated salts is particularly worth mentioning:
5-difluoromethoxy-2-{[3-methoxy-4-(2,2,2-trifluoroethoxy)-2-pyridyl]
methylsulphinyl}-lI3-benzimidazole, 5-difluoromethoxy-2-{[3-methyl-4-(2,2,2-trifluoroethoxy)-pyridyl]
methylsulphinyl}-1H-benzimidazole, ~~~r'~~~~~
2-{[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methylsulphinyl}-5-(2,2,2-trifluoroethoxy)-1H-benzimidazole, 2,2-difluoro-6-{[3-methyl-4-(2,2,2--trifluoroethoxy)-2-pyridyl]methylsulphinyl}-5H-[1,3]-dioxolo[4,5-f]benzimidazole, 5-difluoromethoxy-2-{[3-methoxy-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methylthio}-1H-benzimidazole, 5-difluoromethoxy-2-{[3-methyl-4-(2,2,2-trifluoroethoxy)-pyridyl]methylthio}-benzimidazole, 2-{[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methylthio}-5-(2,2,2-trifluoroethoxy)-1Fi-benzimidazole, 2,2-difluoro-6-{[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methylthio}-5H-[1,3]-dioxolo[4,5-f]benzimidazole.
The compounds of the formula I and their pharmacologically tolerated salts are known from the following patent applications and patents: EP-A-134 400 (= USP
4,555,518), EP-A-127 763 (= USP 4,560,693), EP-B-166 287 (= USP 4,758,579), EP-A-201 575 (= USP 4,686,230), Wo89/05299 and WO89/11479.
The medicaments to be administered orally are prepared using the active compounds of the formula I in a manner which is known per se to the expert.
Claims (31)
1. Use of 5-difluoromethoxy-2-[3,4-dimethoxy-2-pyridyl)methylsulphinyl]-1H-benzimidazole and its pharmaceutically tolerated salts for the preparation of oral medicaments for combating Helicobacter bacteria.
2. Use of 5-difluoromethoxy-2-[3,4-dimethoxy-2-pyridyl)methylsulphinyl]-1H-benzimidazole sodium for the preparation of oral medicaments which are not in a formulation which is resistant to gastric juice and are for combating Helicobacter bacteria of the species Helicobacter pylori.
3. Drug formulation containing 5-difluoromethoxy-2-[3,4-dimethoxy-2-pyridyl)methylsulphinyl]-1H-benzimidazole or a pharmaceutically tolerated salt thereof simultaneously in a form which is resistant to gastric juice and in a form which is not resistant to gastric juice.
4. Drug formulation according to claim 3 in the form of tablets which contain difluoromethoxy-2-[3,4-dimethoxy-2-pyridyl)methylsulphinyl]-1H-benzimidazole or a pharmaceutically tolerated salt thereof both in a core which is resistant to gastric juice and in a shell which is not resistant to gastric juice.
5. Drug formulation according to claim 3 in the form of capsules which contain difluoromethoxy-2-[3,4-dimethoxy-2-pyridyl)methylsulphinyl]-1H-benzimidazole or a pharmaceutically tolerated salt thereof in pellets, mini tablets or tablets which are both resistant to gastric juice and not resistant to gastric juice.
6. A Helicobacter bacteria treatment oral composition comprising 5-difluoromethoxy-2-[3,4-dimethoxy 2-pyridyl)methylsulphinyl]-1H-benzimidazole or a pharmaceutically tolerated salt thereof, together with a pharmaceutically acceptable carrier.
7. A Helicobacter bacteria treatment oral composition comprising 5-difluoromethoxy-2-[3,4-dimethoxy-2-pyridyl)methylsulphinyl]-1H-benzimidazole or a pharmaceutically tolerated salt thereof, together with a pharmaceutically acceptable carrier, the composition comprising a first formulation which is substantially resistant to gastric juice and a second formulation which is substantially non-resistant to gastric juice.
8. A tablet comprising the composition defined in claim 7.
9. The tablet defined in claim 8, having a core comprising the first formulation and a shell comprising the second formulation.
10. A capsule comprising the composition defined in claim 7.
11. The capsule defined in claim 10, wherein at least one of the first formulation and the second formulation comprise pellets, mini tablets or tablets.
12. The capsule defined in claim 10, wherein both of the first formulation and the second formulation comprise pellets, mini tablets or tablets.
13. A Helicobacter pylori treatment oral composition comprising 5-difluoromethoxy-2-[3,4-dimethoxy-2-pyridyl)methylsulphinyl]-1H-benzimidazole sodium, together with a pharmaceutically acceptable carrier.
14. A Helicobacter pylori treatment oral composition comprising 5-difluoromethoxy-2-[3,4-dimethoxy-2-pyridyl)methylsulphinyl]-1H-benzimidazole sodium, together with a pharmaceutically acceptable carrier, the composition comprising a first formulation which is substantially resistant to gastric juice and a second formulations which is substantially non-resistant to gastric juice.
15. A tablet comprising the composition defined in claim 14.
16. The tablet defined in claim 15, having a core comprising the first formulation and a shell comprising the second formulation.
17. A capsule comprising the composition defined in claim 14.
18. The capsule defined in claim 17, wherein at least one of the first formulation and the second formulation comprise pellets, mini tablets or tablets.
19. The capsule defined in claim 17, wherein both of the first formulation and the second formulation comprise pellets, mini tablets or tablets.
20. A oral composition comprising 5-difluoromethoxy-2-[3,4-dimethoxy-2-pyridyl)methylsulphinyl]-1H-benzimidazole or a pharmaceutically tolerated salt thereof, together with a pharmaceutically acceptable carrier, the composition comprising a first formulation which is substantially resistant to gastric juice and a second formulation which is substantially non-resistant to gastric juice.
21. A tablet comprising the composition defined in claim 20.
22. The tablet defined in claim 21, having a core comprising the first formulation and a shell comprising the second formulation.
23. A capsule comprising the composition defined in claim 20.
24. The capsule defined in claim 23, wherein at least one of the first formulation and the second formulation comprise pellets, mini tablets or tablets.
25. The capsule defined in claim 23, wherein both of the first formulation and the second formulation comprise pellets, mini tablets or tablets.
26. The composition defined in claim 20 for the use of treating Helicobacter bacteria.
27. The composition defined in claim 20 for the use of treating Helicobacter pylori.
28. The tablet defined in any one of claims 21-22 for the use of treating Helicobacter bacteria.
29. The tablet defined in any one of claims 21-22 for the use of treating Helicobacter pylori.
30. The capsule defined in any one of claims 23-25 for the use of treating Helicobacter bacteria.
31. The capsule defined in any one of claims 23-25 for the use of treating Helicobacter pylori.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH299390 | 1990-09-14 | ||
| CH2993/90-9 | 1990-09-14 | ||
| CH2226/91-6 | 1991-07-25 | ||
| CH222691 | 1991-07-25 | ||
| PCT/EP1991/001689 WO1992004898A1 (en) | 1990-09-14 | 1991-09-06 | Use of pyridylmethylsulphinyl-1h-benzimidazole derivates in the treatment of illnesses caused by helicobacter bacteria |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2092694A1 CA2092694A1 (en) | 1992-03-15 |
| CA2092694C true CA2092694C (en) | 2005-04-05 |
Family
ID=25689847
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002092694A Expired - Lifetime CA2092694C (en) | 1990-09-14 | 1991-09-06 | Use of pyridylmethylsulphinyl-1h-benzimidazole derivates in the treatment of illnesses caused by helicobacter bacteria |
Country Status (13)
| Country | Link |
|---|---|
| EP (1) | EP0548103B1 (en) |
| JP (1) | JPH06500547A (en) |
| AT (1) | ATE209914T1 (en) |
| AU (1) | AU8445791A (en) |
| CA (1) | CA2092694C (en) |
| CY (1) | CY2363B1 (en) |
| DE (1) | DE59109225D1 (en) |
| DK (1) | DK0548103T3 (en) |
| ES (1) | ES2169022T3 (en) |
| IE (1) | IE913232A1 (en) |
| IL (1) | IL99471A (en) |
| NZ (1) | NZ239772A (en) |
| WO (1) | WO1992004898A1 (en) |
Families Citing this family (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IS3990A (en) * | 1992-04-24 | 1993-10-25 | Ab Astra | Method of mixing substances that inhibit gastric acid and bacterial degrading agent in an acidic environment |
| EP0683776B1 (en) * | 1993-02-17 | 1999-04-07 | Byk Gulden Lomberg Chemische Fabrik GmbH | Substituted heteroarylalkylthiopyridines for controlling helicobacter bacteria |
| WO1994027606A1 (en) * | 1993-05-28 | 1994-12-08 | Unisearch Limited | Method of treating helicobacter pylori infection |
| JPH0717971A (en) * | 1993-07-02 | 1995-01-20 | Takeda Chem Ind Ltd | Imidazole derivative, production and use thereof |
| PT711282E (en) * | 1993-07-28 | 2002-11-29 | Aventis Pharma Ltd | INHIBITOR COMPOUNDS OF PDE IV AND FNT |
| ES2145102T3 (en) | 1993-09-09 | 2000-07-01 | Takeda Chemical Industries Ltd | FORMULATION COMPRISING AN ANTIBACTERIAL SUBSTANCE AND AN ANTI-ULCER SUBSTANCE. |
| US6489346B1 (en) | 1996-01-04 | 2002-12-03 | The Curators Of The University Of Missouri | Substituted benzimidazole dosage forms and method of using same |
| US5840737A (en) | 1996-01-04 | 1998-11-24 | The Curators Of The University Of Missouri | Omeprazole solution and method for using same |
| WO1997040039A1 (en) * | 1996-04-23 | 1997-10-30 | Yoshitomi Pharmaceutical Industries, Ltd. | Pyridine compounds and medicinal uses thereof |
| US8993599B2 (en) | 2003-07-18 | 2015-03-31 | Santarus, Inc. | Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them |
| US8906940B2 (en) | 2004-05-25 | 2014-12-09 | Santarus, Inc. | Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IL85472A (en) * | 1987-03-09 | 1991-06-30 | Procter & Gamble | Pharmaceutical compositions for treating gastrointestinal disorders |
| JPH03504497A (en) * | 1988-05-25 | 1991-10-03 | ビイク グルデン ロンベルク ヒエーミツシエ フアブリーク ゲゼルシヤフト ミツト ベシユレンクテル ハフツング | New fluoroalkoxy compound |
| JP2694361B2 (en) * | 1989-02-09 | 1997-12-24 | アストラ アクチエボラグ | Antibacterial agent |
| EP0382489B1 (en) * | 1989-02-10 | 1994-11-17 | Takeda Chemical Industries, Ltd. | Use of benzimidazole derivatives as antibacterial agents |
-
1991
- 1991-09-06 DK DK91914905T patent/DK0548103T3/en not_active Application Discontinuation
- 1991-09-06 EP EP91914905A patent/EP0548103B1/en not_active Expired - Lifetime
- 1991-09-06 AU AU84457/91A patent/AU8445791A/en not_active Abandoned
- 1991-09-06 AT AT91914905T patent/ATE209914T1/en not_active IP Right Cessation
- 1991-09-06 WO PCT/EP1991/001689 patent/WO1992004898A1/en active IP Right Grant
- 1991-09-06 ES ES91914905T patent/ES2169022T3/en not_active Expired - Lifetime
- 1991-09-06 DE DE59109225T patent/DE59109225D1/en not_active Expired - Lifetime
- 1991-09-06 JP JP3514343A patent/JPH06500547A/en active Pending
- 1991-09-06 CA CA002092694A patent/CA2092694C/en not_active Expired - Lifetime
- 1991-09-12 NZ NZ239772A patent/NZ239772A/en not_active IP Right Cessation
- 1991-09-12 IL IL9947191A patent/IL99471A/en not_active IP Right Cessation
- 1991-09-13 IE IE323291A patent/IE913232A1/en not_active IP Right Cessation
-
2003
- 2003-05-30 CY CY0300045A patent/CY2363B1/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| CA2092694A1 (en) | 1992-03-15 |
| EP0548103B1 (en) | 2001-12-05 |
| NZ239772A (en) | 1997-03-24 |
| ES2169022T3 (en) | 2002-07-01 |
| DK0548103T3 (en) | 2002-04-02 |
| EP0548103A1 (en) | 1993-06-30 |
| IL99471A0 (en) | 1992-08-18 |
| WO1992004898A1 (en) | 1992-04-02 |
| CY2363B1 (en) | 2004-06-04 |
| JPH06500547A (en) | 1994-01-20 |
| ATE209914T1 (en) | 2001-12-15 |
| IE913232A1 (en) | 1992-02-25 |
| AU8445791A (en) | 1992-04-15 |
| IL99471A (en) | 1996-03-31 |
| DE59109225D1 (en) | 2002-01-17 |
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