Canadian Patents Database / Patent 2092694 Summary

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(12) Patent: (11) CA 2092694
(54) English Title: USE OF PYRIDYLMETHYLSULPHINYL-1H-BENZIMIDAZOLE DERIVATES IN THE TREATMENT OF ILLNESSES CAUSED BY HELICOBACTER BACTERIA
(54) French Title: UTILISATION DE DERIVES DE PYRIDYLMETHYLSULFINYL-1H-BENZIMIDAZOLE POUR LE TRAITEMENT DES MALADIES CAUSEES PAR HELICOBACTER BACTERIA
(51) International Patent Classification (IPC):
  • A61K 31/44 (2006.01)
(72) Inventors :
  • KLEMM, KURT (Germany)
  • KRUGER, UWE (Germany)
(73) Owners :
  • NYCOMED GMBH (Germany)
(71) Applicants :
  • BYK GULDEN LOMBERG CHEMISCHE FABRIK GMBH (Germany)
(74) Agent: GOWLING LAFLEUR HENDERSON LLP
(45) Issued: 2005-04-05
(86) PCT Filing Date: 1991-09-06
(87) PCT Publication Date: 1992-04-02
Examination requested: 1998-08-13
(30) Availability of licence: N/A
(30) Language of filing: English

(30) Application Priority Data:
Application No. Country/Territory Date
2993/90-9 Switzerland 1990-09-14
2226/91-6 Switzerland 1991-07-25

English 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.


Note: Claims are shown in the official language in which they were submitted.


WHAT IS CLAIMED IS:
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
5-
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
5-
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.

Note: Descriptions are shown in the official language in which they were submitted.



~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
- 2 -
R4
R3 ~ R6 /, R7
/ N ~/
R8 (I)
RZ-~-
~\ ~ \~IH ~ N f1
R1 N R5
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,



- 4 -
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~~
- 5 -
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
R4
I
R3
(0
(Ia)
RZ y\
R1



- 6 -
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
7
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-
1H-
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-
1H-
benzimidazole,



- 9 -
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
R4
I R6 R7
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,


- 12 -
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.




- 13 -
Another embodiment of the invention which is worth mentioning (embodiment d)
is
the use, according to the invention, of compounds of the formula Id
R4
I
R3
(0
(Id)
R2 ~\
R1
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'~~~~~
- 14 -
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}-
1H-
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.

A single figure which represents the drawing illustrating the invention.

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Admin Status

Title Date
Forecasted Issue Date 2005-04-05
(86) PCT Filing Date 1991-09-06
(87) PCT Publication Date 1992-04-02
(85) National Entry 1993-03-12
Examination Requested 1998-08-13
(45) Issued 2005-04-05
Expired 2011-09-06

Payment History

Fee Type Anniversary Year Due Date Amount Paid Paid Date
Filing $0.00 1993-03-12
Maintenance Fee - Application - New Act 2 1993-09-06 $100.00 1993-03-12
Registration of Documents $0.00 1993-09-28
Maintenance Fee - Application - New Act 3 1994-09-06 $100.00 1994-08-22
Maintenance Fee - Application - New Act 4 1995-09-06 $100.00 1995-08-16
Maintenance Fee - Application - New Act 5 1996-09-06 $150.00 1996-08-22
Maintenance Fee - Application - New Act 6 1997-09-08 $150.00 1997-08-22
Request for Examination $400.00 1998-08-13
Maintenance Fee - Application - New Act 7 1998-09-08 $150.00 1998-08-24
Maintenance Fee - Application - New Act 8 1999-09-06 $150.00 1999-08-18
Maintenance Fee - Application - New Act 9 2000-09-06 $150.00 2000-08-16
Maintenance Fee - Application - New Act 10 2001-09-06 $200.00 2001-08-23
Extension of Time $200.00 2002-07-12
Maintenance Fee - Application - New Act 11 2002-09-06 $200.00 2002-08-30
Registration of Documents $50.00 2002-10-29
Maintenance Fee - Application - New Act 12 2003-09-08 $200.00 2003-08-27
Maintenance Fee - Application - New Act 13 2004-09-07 $250.00 2004-08-17
Special Order $500.00 2004-10-13
Final $300.00 2005-01-24
Maintenance Fee - Patent - New Act 14 2005-09-06 $250.00 2005-08-05
Maintenance Fee - Patent - New Act 15 2006-09-06 $450.00 2006-08-08
Maintenance Fee - Patent - New Act 16 2007-09-06 $450.00 2007-08-08
Registration of Documents $100.00 2007-11-09
Maintenance Fee - Patent - New Act 17 2008-09-08 $450.00 2008-08-11
Maintenance Fee - Patent - New Act 18 2009-09-08 $450.00 2009-08-13
Maintenance Fee - Patent - New Act 19 2010-09-07 $450.00 2010-08-23
Current owners on record shown in alphabetical order.
Current Owners on Record
NYCOMED GMBH
Past owners on record shown in alphabetical order.
Past Owners on Record
ALTANA PHARMA AG
BYK GULDEN LOMBERG CHEMISCHE FABRIK GMBH
KLEMM, KURT
KRUGER, UWE
Past Owners that do not appear in the "Owners on Record" listing will appear in other documentation within the application.

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Abstract 1993-12-21 1 8
Cover Page 1993-12-21 1 21
Claims 1993-12-21 3 95
Description 1993-12-21 14 533
Claims 2002-02-04 4 124
Claims 2002-09-06 4 139
Claims 2003-02-24 4 123
Representative Drawing 2005-03-04 1 5
Cover Page 2005-03-04 1 32
Prosecution-Amendment 1998-08-13 1 43
PCT 1993-03-12 25 772
Prosecution-Amendment 2001-10-04 2 50
Correspondence 2001-10-29 2 69
Correspondence 2001-11-15 1 15
Correspondence 2001-11-15 1 18
Prosecution-Amendment 2002-02-04 6 212
Prosecution-Amendment 2002-03-12 2 50
Prosecution-Amendment 2002-07-12 1 46
Correspondence 2002-08-27 1 16
Prosecution-Amendment 2002-09-06 6 213
Prosecution-Amendment 2002-10-22 2 41
Correspondence 2002-12-13 1 16
Prosecution-Amendment 2003-07-29 2 72
Prosecution-Amendment 2004-10-13 1 39
Prosecution-Amendment 2004-10-27 1 13
Fees 2002-08-30 1 35
Prosecution-Amendment 2004-01-29 4 192
Prosecution-Amendment 2003-02-24 6 180
Correspondence 2005-01-25 1 44
Fees 1996-08-22 1 56
Fees 1995-08-16 1 58
Fees 1994-08-22 1 54
Fees 1993-03-13 1 45