Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-09-21
2002-04-02
Huang, Evelyn Mei (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S218000, C514S254080, C514S307000, C514S314000, C514S322000, C514S338000, C514S394000, C514S415000, C514S336000, C540S575000, C540S603000, C544S139000, C544S370000, C546S145000, C546S172000, C546S199000, C546S273400, C546S268400, C548S309700, C548S310100, C548S465000, C548S503000, C548S509000
Reexamination Certificate
active
06365584
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 the group 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 the group 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 phenyl, benzyl, naphthyl, furanyl, benzofuranyl, quinolyl, isoquinolyl, thienyl or benzothienyl;
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 the group oxygen, nitrogen or sulphur and which may optionally be substituted by C
1
-C
4
-alkyl, C
1
-C
4
-hydroxyalkyl, 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, diastereorners and mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.
According to the invention, the preferred arylsulphonamide-substituted benzimidazole derivatives of general formula (I) are those 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 hydroxy, C
1
-C
4
-alkoxy, carboxy, C
1
-C4-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 the group 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 phenyl, benzyl, quinolyl, benzothienyl or naphthyl;
R
4
denotes a C
1
-C
6
-alkyl group, which is mono- or disubstituted by one or two of the groups —NH
2
, —NHmethyl, —N(methyl)
2
, —NHethyl, —N(ethyl)
2
, —NH(n-propyl), —N(n-propyl)
2
, —NH(iso-propyl), —N(iso-propyl)
2
, —C(═NH)NH
2
or —NH—C(═NH)NH
2
, or
a 5-, 6- or 7-membered, saturated or unsaturated nitrogen-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 or two other hetero atoms selected from the group oxygen, nitrogen or sulphur and which may optionally be substituted by C
1
-C
4
-alkyl, C
1
-C
4
-hydroxyalkyl, benzyl or pyridyl;
cyclopropyl, cyclopentyl or cyclohexyl, each of which is mono- or disubstituted by one or two of the groups —NH
2
, —NHmethyl, —N(methyl)
2
, —NHethyl, —N(ethyl)
2
, —NH(n-propyl), —N(n-propyl)
2
, —NH(iso-propyl), —N(iso-propyl)
2
, —C(═NH)NH
2
or —NH—C(═NH)NH
2
, or
phenyl, benzyl or phenylethyl, which are mono- or disubstituted at the phenyl ring by one or two of the groups —NH
2
, —NHmethyl, —N(methyl)
2
, —NHethyl, —N(ethyl)
2
, —NH(n-propyl), —N(n-propyl)
2
, —NH(iso-propyl), —N(iso-propyl)
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.
Preferred are arylsulphonamide-substituted benzimidazole derivatives of general formula (I), wherein
R
1
denotes methyl, ethyl, propyl, butyl or pentyl, each of which may be substituted by one of the groups hydroxy, methoxy, ethoxy, propoxy, CF
3
, phenoxy, COOH, CONH
2
, CONHMe or methoxy-phenoxy, or
benzyl, phenylethyl or phenylpropyl, which may be mono- or disubstituted at the phenyl ring by one or two of the groups hydroxy, methoxy, ethoxy, carboxy, methoxycarbonyl, ethoxycarbonyl 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 the group oxygen or nitrogen and may optionally be substituted by methyl, ethyl, propyl or benzyl;
R
2
denotes —C(═NH)NH
2
or —CH
2
—NH
2
;
R
3
denotes phenyl, benzyl, quinolyl, benzothienyl or naphthyl;
R
4
denotes a group selected from the group ethyl, propyl, butyl, pentyl and hexyl, each of which is mono- or disubstituted by one or two of the groups —NH
2
, —NHmethyl, —N(methyl)
2
, —NHethyl, —N(ethyl)
2
, —NH(n-propyl), —N(n-propyl)
2
, —NH(iso-propyl), —N(iso-propyl)
2
, —C(═NH)NH
2
or —NH—C(═NH)NH
2
, or
a 5-, 6- or 7-membered, saturated or unsaturated nitrogen-heterocyclic group linked directly or via a C
1
-C
4
-alkylene bridge or via a C
1
-C
3
-alkylene-CO bridge, which may optionally contain one or two other hetero atoms selected from the group oxygen or nitrogen and may optionally be substituted by methyl, ethyl, propyl, 3-hydroxypropyl or benzyl, or
cyclopentyl or cyclohexyl, each of which is mono- or disubstituted by one or two of the groups —NH
2
, —NHmethyl, —N(methyl)
2
, —NHethyl, —N(ethyl)
2
, —NH(n-propyl), —N(n-propyl)
2
, —NH(iso-propyl), —N(iso-propyl)
2
, —C(═NH)NH
2
or —NH—C(═NH)NH
2
, or
benzyl or phenylethyl, which are mono- or disubstituted at the
Anderskewitz Ralf
Braun Christine
Briem Hans
Disse Bernd
Hoenke Christoph
Boehringer Ingelheim Pharma KG
Devlin Mary-Ellen M.
Huang Evelyn Mei
Raymond Robert P.
Stempel Alan R.
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