Aminocarbonyl-substituted benzimidazoles having...

Details Aminocarbonyl-substituted benzimidazoles having... Aminocarbonyl-substituted benzimidazoles having...

2000-08-08

2003-01-28

Raymond, Richard L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S218000, C514S235800, C514S273000, C514S314000, C514S317000, C514S339000, C544S153000, C544S370000, C540S492000, C546S159000, C546S199000, C546S273400

Reexamination Certificate

active

06512000

ABSTRACT:

FIELD OF THE INVENTION
The invention relates to the use of certain aminocarbonyl-substituted benzimidazole derivatives for the treatment of diseases in which inhibition of tryptase is of therapeutic value, certain novel aminocarbonyl-substituted benzimidazole derivatives having tryptase-inhibitory activity, methods for preparing their preparation and pharmaceutical compositions containing such compounds.
BACKGROUND OF 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 used to good effect, on the basis of their thrombin-inhibiting activity, to prevent and treat venous and arterial thrombotic diseases.
In contrast to the use of benzimidazole derivatives described hereinbefore and known from the prior art, the aim of the present invention is to prepare new tryptase inhibitors which can be used, by virtue of their tryptase-inhibiting properties, to prevent and treat inflammatory and/or allergic diseases.
DETAILED DESCRIPTION OF THE INVENTION
It has been found, surprisingly, that aminocarbonyl-substituted benzimidazole derivatives of general formula (I)
 
wherein the groups R
1
, R
2
, R
3
and R
4
may have the meanings given hereinafter, 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 be of therapeutic value.
Thus, a first aspect of the invention is a method for treating diseases in which tryptase inhibitors may be of thereapeutic value, which method comprises the administration, to a host in need of such treatment, of a thereapeutic amount of a compound of the formula (I)
 
wherein:
R
1
denotes C
1
-C
10
-alkyl, which may optionally be mono-, di- or tri-substituted by one or more of the groups C
1
-C
4
-alkoxy, phenoxy, hydroxyphenoxy, C
1
-C
4
-alkoxy-phenoxy, C
3
-C
6
-cycloalkyl, —NH
2
, —NH(C
1
-C
4
-alkyl), —N(C
1
-C
4
-alkyl)
2
, —NH—CO—(C
1
-C
4
-alkyl), —CO—NH
2
, —CO—NH—(C
1
-C
4
-alkyl) or —NH—CO-benzyl, or
phenyl-C
1
-C
4
-alkyl, wherein the phenyl ring may optionally be mono-, di- or tri-substituted by one or more of the groups C
1
-C
4
-alkyl, CF
3
, fluorine, chlorine, bromine, COOH or COO—C
1
-C
4
-alkyl, or
a 5 or 6 membered, saturated or unsaturated heterocyclic group linked via a single bond or via a C
1
-C
4
-alkylene bridge, which may contain one, two or three heteroatoms selected from the group comprising oxygen, nitrogen or sulphur and which may optionally be mono-, di- or tri-substituted by one or more of the groups C
1
-C
4
-alkyl, optionally by C
1
-C
4
-alkyl substituted phenyl or optionally by C
1
-C
4
-alkyl substituted benzyl or to which a benzene ring may optionally be fused via two adjacent carbon atoms;
R
2
denotes —C(═NH)NH
2
or —CH
2
—NH
2
;
R
3
and R
4
which may be identical or different, denote hydrogen, C
1
-C
6
-alkyl, which may be mono- or disubstituted by one or more of the groups COOH, COO—C
1
-C
4
-alkyl, C
3
-C
6
-cycloalkyl, —NH
2
, —NH(C
1
-C
4
-alkyl), —N(C
1
-C
4
-alkyl)
2
, —NHphenyl, —N(phenyl)
2
, —NHbenzyl, —N(benzyl)
2
, —NH—CO—(C
1
-C
4
-alkyl), —C(═NH)NH
2
or —NH—C(═NH)NH
2
, or
phenyl-C
1
-C
4
-alkyl, wherein the C
1
-C
4
-alkylene bridge may optionally be substituted by phenyl, COOH or COO—C
1
-C
4
-alkyl and wherein the phenyl ring may optionally be mono-, di- or tri-substituted, directly or via a C
1
-C
4
-alkylene bridge, by one or more of the groups C
1
-C
4
-alkyl, C
1
-C
4
-alkoxy, CF
3
, fluorine, chlorine, bromine, COOH, COO—C
1
-C
4
-alkyl, —NH
2
, —NH(C
1
-C
4
-alkyl), —N(C
1
-C
4
-alkyl)
2
, —NHphenyl, —N(phenyl)
2
, —NHbenzyl, —N(benzyl)
2
, —NH—CO—(C
1
-C
4
-alkyl), —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, which may contain one, two, three or four heteroatoms selected from the group comprising oxygen, nitrogen or sulphur and which may optionally be mono-, di- or tri-substituted by one or more of the groups C
1
-C
4
-alkyl, phenyl or benzyl or to which a benzene ring may optionally be fused via two adjacent carbon atoms, or
C
3
-C
8
-cycloalkyl, naphthyl or phenyl, which may optionally be mono-, di- or tri-substituted by one or more of the groups C
1
-C
4
-alkyl, C
1
-C
4
-alkoxy, phenyloxy, benzyloxy, CF
3
, fluorine, chlorine, bromine, COOH or COO—C
1
-C
4
-alkyl, or
R
3
and R
4
together with the nitrogen atom form a 5-, 6- or 7-membered, saturated or unsaturated heterocyclic group, which may contain one or two further heteroatoms selected from the group comprising oxygen, nitrogen or sulphur and which may optionally be substituted by one or more of the groups C
1
-C
4
-alkyl, C
5
-C
6
-cycloalkyl, benzyl, which may optionally be substituted by C
1
-C
4
-alkyl, pyridyl or phenyl, optionally substituted by C
1
-C
4
-alkyl, C
1
-C
4
-alkoxy or hydroxy,
or a tautomer or pharmacologically acceptable acid addition salt thereof.
The phrase “a host in need of such treatment” as used herein means a patient, whether animal or human, which or who suffers from a disease which is treatable by the inhibition of tryptase.
The above-described thereapeutic method may be used to treat inflammatory and/or allergic diseases. Even more particularly, the above-described method may be used for the treatment of bronchial asthma, allergic rhinitis, allergic conjunctivitis, atopic dermatitis, urticaria, allergic otitis, allergic gastro-intestinal disorders, Crohn's disease, ulcerative colitis, anaphylactic shock, septic shock, shock lung (ARDS) and arthritis.
The compounds of formula (I) as described above for may also be used, in accordance with the invention, for the treatment of fibroses such as lung fibrosis, fibrosing alveolitis and scarring, collagenoses such as lupus erythematodes and sclerodermia as well as arteriosclerosis, psoriasis and neoplasm.
Some of the above-described compounds of the formula (I) are known and others are novel. These novel compounds of formula (I) constitute a second aspect of the invention.
The novel compounds provided by the invention are those of the formula (I)
 
wherein
R denotes C
1
-C
10
-alkyl, which may optionally be mono-, di- or tri-substituted by one or more of the groups C
1
-C
4
-alkoxy, phenoxy-, C
1
-C
4
-alkoxy-phenoxy, hydroxyphenoxy, C
3
-C
6
-cycloalkyl, —NH
2
, —NH(C
1
-C
4
-alkyl), —N(C
1
-C
4
-alkyl)
2
, —NH—CO—(C
1
-C
4
-alkyl), —CO—NH
2
, —CO—NH—(C
1
-C
4
-alkyl) or —NH—CO-benzyl, or
phenyl-C
1
-C
4
-alkyl, wherein the phenyl ring may optionally be mono-, di- or tri-substituted by one or more of the groups C
1
-C
4
-alkyl, CF
3
, fluorine, chlorine, bromine, COOH or COO—C
1
-C
4
-alkyl, or
a 5 or 6 membered, saturated or unsaturated heterocyclic group linked via a single bond or via a C
1
-C
4
-alkylene bridge, which may contain one, two or three heteroatoms selected from the group comprising oxygen, nitrogen or sulphur and
may optionally be mono-, di- or tri-substituted by one or more of the groups C
1
-C
4
-alkyl, optionally by C
1
-C
4
-alkyl substituted phenyl or optionally by C
1
-C
4
-alkyl substituted benzyl, or to which a benzene ring may optionally be fused via two adjacent carbon atoms;
R
2
denotes —C(═NH)NH
2
or —CH
2
—NH
2
;
R
3
denotes C
1
-C
6
-alkyl, which is mono- or disubstituted by one or more of the groups —NH
2
, —NH(C
1
-C
4
-alkyl), —N(C
1
-C
4
-alkyl)
2
, —NHphenyl, —N(phenyl)
2
, —NHbenzyl, —N(benzyl)
2
, —NH—CO—(C
1
-C
4
-alkyl), —C(═NH)NH
2
or —NH—C(═NH)NH
2
, or benzyl, wherein the phenyl ring is mono- or disubstituted, directly or via a C
1
-C
4
-alkylene bridge, by one or more of the groups —NH
2
, —NH(C
1
-C
4
-alkyl), —N(C
1
-C
4
-alkyl)
2
, —NHphenyl, —N(phenyl)
2
, —NHbenzyl, —N(benzyl)
2
, —NH—CO—(C
1
-C
4
-alkyl), —C(═NH)NH
2
or —NH—C(═NH)NH
2
, or
phenyl-C
2
-C
4
-alkyl, wherein the C
2
-C
4
-alkylene bridge may optionally be

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