Carboxamide-substituted benzimidazoles having...

Details Carboxamide-substituted benzimidazoles having... Carboxamide-substituted benzimidazoles having...

2000-11-02

2002-06-18

Aulakh, Charanjit S. (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C548S309700, C548S306100, C546S199000, C546S273400, C544S370000, C514S253030, C514S322000, C514S338000

Reexamination Certificate

active

06407130

ABSTRACT:

FIELD OF THE INVENTION
The invention relates to carboxamide-substituted benzimidazole derivatives, methods of their manufacture, their use in the treatment of certain disease conditions, and pharmaceutical compositions comprising such compounds.
BACKGROUND TO THE INVENTION
Benzimidazole derivatives are known from the prior art as active substances with valuable pharmaceutical properties. Thus, International Patent Application WO 98/37075 discloses, in addition to other bicyclic heterocycles, benzimidazoles which can be effectively used to prevent and treat venous and arterial thrombotic diseases by virtue of their thrombin-inhibiting activity.
SUMMARY OF THE INVENTION
In contrast to the benzimidazole derivatives as described above and known from the prior art, which are useful for the treatment of thrombotic diseases, the present invention provides compounds having tryptase-inhibitory activity which can be used to prevent and treat inflammatory and/or allergic diseases.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides carboxamide-substituted benzimidazole derivatives 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
-alkynyl, 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), —CO—NR
5
R
6
, —NR
5
R
6
or C
1
-C
4
-alkoxy-phenoxy, 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 heterocycle linked directly or via a C
1
-C
4
-alkylene bridge, which may contain one or two heteroatoms 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 C
1
-C
6
-alkyl, C
1
-C
6
-hydroxyalkyl or C
1
-C
4
-alkoxy-C
1
-C
4
-alkyl group which may be mono- or disubstituted by one, two or three of the groups —NR
5
R
6
, —C(═NH)NH
2
or —NH—C(═NH)NH
2
, or
a 5-, 6- or 7-membered, saturated or unsaturated heterocycle linked directly or via a C
1
-C
4
-alkylene bridge or a C
2
-C
4
-alkenylene bridge, which may contain one, two or three heteroatoms selected from among oxygen, nitrogen or sulphur and which may optionally be mono- or disubstituted by hydroxy, C
1
-C
4
-alkyl, —COO—C
1
-C
4
-alkyl, —CONH
2
, benzyl, diphenylmethyl, phenyl or pyridylmethyl, pyridyl, and wherein the phenyl substituent may be mono-, di- or trisubstituted by one or more groups selected from among C
1
-C
4
-alkyl, C
1
-C
4
-alkoxy, halogen, C
1
-C
4
-alkyl-halogen and —NH
2
,
cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of which may be mono- or disubstituted by one or two of the groups —NR
5
R
6
, —C(═NH)NH
2
or —NH—C(═NH)NH
2
, or phenyl-C
1
-C
4
-alkyl or naphthyl-C
1
-C
4
-alkyl, which may optionally be substituted at the alkylene bridge by —NR
5
R
6
and may be mono- or disubstituted at the phenyl ring by one or two of the groups —NO
2
, —NR
5
R
6
, —C
1
-C
4
-alkyl-NR
5
R
6
, —C(═NH)NH
2
or —NH—C(═NH)NH
2
,
R
4
denotes hydrogen or C
1
-C
6
-alkyl, which may optionally be mono- or disubstituted by one or two groups selected from among furanyl, benzofuranyl, thiophenyl, benzothiophenyl, anthracenyl, phenyl, pyridyl and naphthyl, while the substituents phenyl and naphthyl may in turn be mono-, di- or trisubstituted 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;
R
5
and R
6
, which may be identical or different, denote hydrogen, C
1
-C
4
-alkyl, phenyl, pyridyl or benzyl, which may optionally be substituted by a group selected from among halogen, halo-C
1
-C
4
-alkyl, —OH, C
1
-C
4
-alkyl, —O—C
1
-C
4
-alkyl, —O—C
1
-C
4
-alkyl, —CO—O—C
1
-C
4
-alkyl, —NO
2
, phenyl, pyrrolidin-1-yl, piperidin-1-yl, —NH
2
, —NH—C
1
-C
4
-alkyl, —N(C
1
-C
4
-alkyl)
2
and —C(═NH)NH
2
—NH
2
,
optionally in the form of the tautomers, the racemates, the enantiomers, the diastereomers and the mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.
It has been found, surprisingly, that compounds of formula I have tryptase-inhibitory activity and that they may be used to treat disease conditions in which tryptase inhibitors have therapeutic value.
Preferred compounds according to the invention are the compounds of general 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), —CO—NR
5
R
6
, —NR
5
R
6
or C
1
-C
4
-alkoxy-phenoxy, or
R
2
denotes —C(═NH)NH
2
or —CH
2
—NH
2
;
R
3
denotes a C
1
-C
6
-alkyl group, which may be mono- or disubstituted by one or two of the groups —NR
5
R
6
, —C(═NH)NH
2
or —NH—C(═NH)NH
2
, or
a 5-, 6- or 7-membered, saturated or unsaturated heterocycle linked directly or via a C
1
-C
4
-alkylene bridge, which may contain one, two or three heteroatoms selected from among oxygen, nitrogen or sulphur and may optionally be mono- or disubstituted by hydroxy, C
1
-C
4
-alkyl, benzyl, phenyl or pyridyl, and wherein the phenyl substituent may be substituted by one of the groups selected from among C
1
-C
3
-alkyl, C
1
-C
3
-alkoxy, halogen, trifluoromethyl and NH
2
,
cyclopropyl, cyclopentyl or cyclohexyl, each of which may be mono- or disubstituted by one or two of the groups —NR
5
R
6
, —C(═NH)NH
2
or —NH—C(═NH)NH
2
, or
phenyl-C
1
-C
4
-alkyl or naphthyl-C
1
-C
4
-alkyl, which may optionally be substituted by —NR
5
R
6
at the alkylene bridge and may be mono- or disubstituted at the phenyl ring by one or two of the groups —NO
2
, —NR
5
R
6
, —C
1
-C
4
-Alkyl-NR
5
R
6
, —C(═NH)NH
2
or —NH—C(═NH)NH
2
,
R
4
denotes hydrogen or C
1
-C
6
-alkyl, which may optionally be mono- or disubstituted by one or two groups selected from among phenyl, pyridyl and naphthyl, wherein the substituents phenyl and naphthyl may in turn be substituted by one 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
;
R
5
and R
6
, which may be identical or different, denote hydrogen, C
1
-C
4
-alkyl, pyridyl or benzyl, which may optionally be substituted by a group selected from among —OH, —O—C
1
-C
3
-alkyl, —NO
2
, phenyl, pyrrolidin-1-yl, —NH
2
, —NH—C
1
-C
4
-alkyl, —N(C
1
-C
4
-alkyl)
2
and —C(═NH)NH
2
,
optionally in the form of the tautomers, the racemates, the enantiomers, the diastereomers and the mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.
Also preferred are carboxamide-substituted benzimidazole derivatives of general formula (I),
wherein
R
1
denotes 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, CF
3
, phenoxy, COOH, halogen, —CO(C
1
-C
4
-alkoxy), —CO—NR
5
R
6
, —NR
5
R
6
or C
1
-C
4
-alkoxy-phenoxy, or
R
2
denotes —C(═NH)NH
2
or —CH
2
—NH
2
;
R
3
denotes a C
1
-C
4
-alkyl group, which may be mono- or disubstituted by one or two of the groups —NR
5
R
6
, —C(═NH)NH
2
or —NH—C(═NH)NH
2
, or
a 5-, 6- or 7-membered, saturated or unsaturated heterocycle linked directly or via a methylene or ethylene bridge, which may contain one or two heteroatoms selected from among oxygen or nitrogen and may optionally be substituted by methyl or benzyl; naphthylmethyl, benzyl or phenylethyl, which may optionally be substituted by —NR
5
R
6
at the alkylene bridge and may be substituted at the phenyl ring by a group selected from among

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