Arylsulphonamide-substituted benzimidazoles having...

Details Arylsulphonamide-substituted benzimidazoles having... Arylsulphonamide-substituted benzimidazoles having...

2000-09-21

2002-07-02

Huang, Evelyn Mei (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S314000, C514S307000, C514S336000, C514S394000, C546S273400, C546S172000, C546S145000, C546S268400, C548S309700

Reexamination Certificate

active

06413990

ABSTRACT:

FIELD OF THE INVENTION
The invention relates to substituted arylsulphonamide-substituted benzimidazoles having tryptase-inhibiting activity, methods for preparing such compounds and their use for the treatment of inflammatory and/or allergic diseases.
BACKGROUND OF THE INVENTION
Benzimidazole derivatives are known from the prior art as active substances having valuable pharmaceutical properties. Thus, International Patent Application WO 98/37075 discloses, in addition to other bicyclic heterocycles, benzimidazoles which can be used to good effect for the prevention and treatment of venous and arterial thrombotic diseases, on the basis of their thrombin-inhibiting activity.
SUMMARY OF THE INVENTION
In contrast to the use of benzimidazole derivatives as described above and known from the prior art, the aim of the present invention is to prepare new tryptase-inhibitors which can be used, on the basis of their tryptase-inhibiting properties, for the prevention and treatment of inflammatory and/or allergic diseases.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides new benzimidazoles of general formula (I)
wherein:
R
1
denotes a group selected from among C
1
-C
6
-alkyl, C
2
-C
6
-alkenyl and C
2
-C
6
-alkinyl, which may optionally be mono-, di- or trisubstituted by one or more of the groups hydroxy, C
1
-C
4
-alkoxy, CF
3
, phenoxy, COOH, halogen, —CO(C
1
-C
4
-alkoxy), —CONH
2
, —CO—NH(C
1
-C
4
-alkyl), —CO—N(C
1
-C
4
-alkyl)
2
, —NH
2
, —NH(C
1
-C
4
-alkyl), —N(C
1
-C
4
-alkyl)
2
or C
1
-C
4
-alkoxy-phenoxy, or
a C
3
-C
8
-cycloalkyl optionally linked via a C
1
-C
4
-alkylene bridge, which may optionally be mono-, di- or trisubstituted by one or more of the groups hydroxy, C
1
-C
4
-alkoxy, carboxy, halogen, C
1
-C
4
-alkoxycarbonyl or CF
3
, or
phenyl-C
1
-C
4
-alkyl, which may optionally be mono-, di- or trisubstituted by one or more of the groups hydroxy, C
1
-C
4
-alkoxy, carboxy, halogen, C
1
-C
4
-alkoxycarbonyl or CF
3
, or
a 5- or 6-membered, saturated or unsaturated heterocyclic group linked directly or via a C
1
-C
4
-alkylene bridge, which may contain one or two hetero atoms selected from among oxygen, nitrogen or sulphur and which may optionally be substituted by C
1
-C
4
-alkyl or benzyl;
R
2
denotes —C(═NH)NH
2
or —CH
2
—NH
2
;
R
3
denotes a group selected from among phenyl, benzyl, naphthyl, furan, quinolyl, isoquinolyl, benzofuranyl, thienyl and benzothienyl, which is mono-, di- or trisubstituted in each case by one or more of the groups selected from among C
1
-C
4
-alkyl, C
1
-C
4
-alkoxy, halogen, C
1
-C
4
-alkyl-halogen, —NH
2
, —NH(C
1
-C
4
-alkyl), —N(C
1
-C
4
-alkyl)
2
, NO
2
, hydroxy, —CF
3
, —NHCO—C
1
-C
4
-alkyl, —COOH, —COO(C
1
-C
4
-alkyl), —CONH
2
, —CONH(C
1
-C
4
-alkyl), —CON(C
1
-C
4
-alkyl)
2
, —CONH(C
1
-C
4
-alkyl)—COO(C
1
-C
4
-alkyl) and phenyl-C
1
-C
6
-alkyl, wherein the substituent phenyl-C
1
-C
6
-alkyl may in turn be substituted by a group selected from among C
1
-C
6
-alkoxy, hydroxy, halogen, CF
3
and C
1
-C
6
-alkyl;
R
4
denotes hydrogen, a C
1
-C
6
-alkyl group, which may be mono- or disubstituted by one or two of the groups —NH
2
, —NH(C
1
-C
4
-alkyl), —N(C
1
-C
4
-alkyl)
2
, —C(═NH)NH
2
or —NH—C(═NH)NH
2
, or
a 5-, 6- or 7-membered, saturated or unsaturated heterocyclic group linked directly or via a C
1
-C
4
-alkylene bridge or via a C
1
-C
4
-alkylene-CO bridge which may optionally contain one, two or three hetero atoms selected from among oxygen, nitrogen or sulphur and which may optionally be substituted by C
1
-C
4
-alkyl, benzyl or pyridyl;
C
3
-C
8
-cycloalkyl, which may be mono- or disubstituted by one or two of the groups —NH
2
, —NH(C
1
-C
4
-alkyl), —N(C
1
-C
4
-alkyl)
2
, —C(═NH)NH
2
or —NH—C(═NH)NH
2
, or
phenyl, benzyl or phenylethyl, which may be mono- or disubstituted at the phenyl ring by one or two of the groups —NH
2
, —NH(C
1
-C
4
-alkyl), —N(C
1
-C
4
-alkyl)
2
, —C
1
-C
4
-alkyl-NH
2
, —C(═NH)NH
2
or —NH—C(═NH)NH
2
, ps optionally in the form of their tautomers, racemates, enantiomers, diastereomers and mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.
The compounds of formula I of the invention have a tryptase-inhibiting effect and may be used according to the invention for the prevention and treatment of diseases in which tryptase-inhibitors may develop a therapeutic effect.
Preferred are those compounds of formula I wherein:
R
1
denotes C
1
-C
6
-alkyl, which may optionally be mono-, di- or trisubstituted by one or more of the groups hydroxy, C
1
-C
4
-alkoxy, CF
3
, phenoxy, COOH, halogen, —CO(C
1
-C
4
-alkoxy), —CONH
2
, —CO—NH(C
1
-C
4
-alkyl), —CO—N(C
1
-C
4
-alkyl)
2
, —NH
2
, —NH(C
1
-C
4
-alkyl), —N(C
1
-C
4
-alkyl)
2
or C
1
-C
4
-alkoxy-phenoxy, or
a C
3
-C
8
-cycloalkyl optionally linked via a C
1
-C
4
-alkylene bridge, which may optionally be mono-, di- or trisubstituted by one or more of the groups hydroxy, C
1
-C
4
-alkoxy, carboxy, halogen, C
1
-C
4
-alkoxycarbonyl or CF
3
, or
phenyl-C
1
-C
4
-alkyl, which may optionally be mono-, di- or trisubstituted by one or more of the groups hydroxy, C
1
-C
4
-alkoxy, carboxy, halogen, C
1
-C
4
-alkoxycarbonyl or CF
3
, or
a 5- or 6-membered, saturated or unsaturated heterocyclic group linked directly or via a C
1
-C
4
-alkylene bridge, which may contain one or two hetero atoms selected from among oxygen, nitrogen or sulphur and which may optionally be substituted by C
1
-C
4
-alkyl or benzyl;
R
2
denotes —C(═NH)NH
2
or —CH
2
—NH
2
;
R
3
denotes a group selected from among phenyl, benzyl, naphthyl, quinolyl, isoquinolyl, thienyl and benzothienyl which is mono-, di- or trisubstituted in each case by one or more of the groups selected from among C
1
-C
4
-alkyl, C
1
-C
4
-alkoxy, halogen, —C
1
-C
4
-alkyl-halogen, —NH
2
, —NH(C
1
-C
4
-alkyl), —N(C
1
-C
4
-alkyl)
2
, NO
2
, hydroxy, —CF
3
, —NHCO—C
1
-C
4
-alkyl, —COOH, —COO(C
1
-C
4
-alkyl), —CONH
2
, —CONH(C
1
-C
4
-alkyl), —CON(C
1
-C
4
-alkyl)
2
, —CONH(C
1
-C
4
-alkyl)-COO(C
1
-C
4
-alkyl) and phenyl-C
1
-C
4
-alkyl, wherein the substituent phenyl-C
1
-C
4
-alkyl may in turn be substituted by a group selected from among C
1
-C
4
-alkoxy, hydroxy, halogen, CF
3
and C
1
-C
4
-alkyl;
R
4
denotes hydrogen, a C
1
-C
6
-alkyl group, which may be mono- or disubstituted by one or two of the groups —NH
2
, —NH(C
1
-C
4
-alkyl), —N(C
1
-C
4
-alkyl)
2
, —C(═NH)NH
2
or —NH—C(═NH)NH
2
, or
a 5-, 6- or 7-membered, saturated or unsaturated heterocyclic group linked directly or via a C
1
-C
4
-alkylene bridge or via a C
1
-C
4
-alkylene-CO bridge, which may optionally contain one, two or three hetero atoms selected from among oxygen, nitrogen or sulphur and may optionally be substituted by C
1
-C
4
-alkyl, benzyl or pyridyl;
C
3
-C
8
-cycloalkyl, which may be mono- or disubstituted by one or two of the groups —NH
2
, —NH(C
1
-C
4
-alkyl), —N(C
1
-C
4
-alkyl)
2
, —C(═NH)NH
2
or —NH—C(═NH)NH
2
, or
phenyl, benzyl or phenylethyl, which may be mono- or disubstituted at the phenyl ring by one or two of the groups —NH
2
, —NH(C
1
-C
4
-alkyl), —N(C
1
-C
4
-alkyl)
2
, C
1
-C
4
-alkyl-NH
2
, —C(═NH)NH
2
or —NH—C(═NH)NH
2
,
optionally in the form of their tautomers, racemates, enantiomers, diastereomers and mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.
More preferred are those compounds of formula I wherein:
R
1
denotes C
1
-C
5
-alkyl, which may optionally be mono-, di- or trisubstituted by one or more of the groups hydroxy, C
1
-C
4
-alkoxy, CF
3
, phenoxy, COOH, —CO(C
1
-C
4
-alkoxy), —CONH
2
, —CO—NH(C
1
-C
4
-alkyl), —CO—N(C
1
-C
4
-alkyl)
2
or C
1
-C
4
-alkoxy-phenoxy, or
a C
3
-C
8
-cycloalkyl optionally linked via a C
1
-C
4
-alkylene bridge, which may optionally be mono-, di- or trisubstituted by one or more of the groups hydroxy, C
1
-C
4
-alkoxy, carboxy, halogen, C
1
-C
4
-alkoxycarbonyl or CF
3
, or
phenyl-C
1
-C
4
-alkyl, which may optionally be mono-, di- or trisubstituted by one or more of the groups hydro

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