Bispiperidines as antithrombotic agents

Details Bispiperidines as antithrombotic agents Bispiperidines as antithrombotic agents

2001-01-17

2001-12-25

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...

C546S190000, C546S189000, C546S187000, C546S186000

Reexamination Certificate

active

06333338

ABSTRACT:

The present invention relates to novel compounds which are inhibitors of the binding of fibrinogen to the Gp IIb/IIIa platelet receptors, and which can be used therapeutically as antithrombotic agents.
In the course of the pathological processes which lead to the formation of a thrombus (clot) and then to its extension, platelet aggregation represents a key step since it is the source of the seriousness of the phenomenon. Specifically, from the initiation of the thrombus, in particular in the arterial blood circulation, the intervention of several interdependent biochemical reactions induces the aggregation of an increasingly large number of platelets via the conversion of soluble fibrinogen into insoluble fibrin filaments which increase the size of the mass of platelets, first at the actual site of the arterial vascular lesion, and then increasingly in the lumen of the vessel.
In this mechanism of platelet aggregation, activation of the Gp IIb/IIIa receptors is the source of the amplification of the platelet aggregation. Fibrinogen, which can bind via its two dimers to these receptors, amplifies the binding-together of the platelets and thus induces the formation of a platelet mass forming a thrombus at the site of rupture of the atheroma plaque.
This mechanism of platelet aggregation is particularly active in all arterial thromboses, whether they appear in the course of performing interventional cardiology (transluminal percutaneous angioplasty; insertion of stents), heart surgery (aorto-coronary bypass; valve surgery), in the course of acute heart diseases (myocardial infarction, unstable angina, acute coronary syndromes, etc.) or in the course of certain cerebral ischaemias, or finally in the course of myocardial ischaemias which may complicate the follow-up of an antithrombotic treatment.
Reducing or preventing the activation of platelets in contact with a broken atherosclerotic plaque thus represents a novel and effective therapeutic approach to the treatment of thrombosis, in particular arterial thrombosis, and thus an efficient means for preventing acute coronary syndromes, including unstable angina and myocardial infarction.
The present invention is directed towards providing novel competitive inhibitors of the binding of fibrinogen to the Gp IIb/IIIa receptors.
The present invention is also directed towards providing compounds which can be administered orally, thus allowing a prolonged duration of action to be obtained and avoiding the risks of bleeding.
One subject of the present invention is compounds of general formula (I):
in which
i) either R
1
is selected from:
C
1
-C
4
alkyl, C
3
-C
12
mono- or bicyclic cycloalkyl, C
2
-C
4
alkenyl or C
2
-C
4
alkynyl groups, these groups optionally being substituted with groups selected from halogens and the hydroxyl group;
mono-, bi- or tricyclic C
6
-C
14
aryl groups,
heteroaryl groups selected from pyridyl, thienyl, furyl, quinolyl, benzodioxanyl, benzodioxolyl, benzothienyl, benzofuryl and pyrazinyl groups;
phenyl(C
1
-C
4
)alkyl and naphthyl (C
1
-C
4
)alkyl groups optionally substituted on the aryl nucleus,
the aryl and heteroaryl groups possibly being substituted with one or more groups selected independently from halogens, C
1
-C
4
alkyl, trifluoromethyl, C
1
-C
4
alkylthio, C
1
-C
4
alkylsulphonyl, C
1
-C
4
alkyloxy, nitro, and groups —COOR, —CH
2
COOR or —O— CH
2
—COOR, R being a C
1
-C
4
alkyl group,
the groups of formula:
 in which R
4
and R′
4
are selected from C
1
-C
8
alkyl and mono- or polycyclic C
3
-C
2
cycloalkyl groups, these groups optionally being substituted with groups selected from halogens and the hydroxyl group, R′
4
also possibly being hydrogen, or alternatively R
4
and R′
4
together form a tetramethylene or pentamethylene group, these last two groups themselves possibly being substituted, in particular with a C
6
-C
14
aryl or (C
6
-C
14
) aryl(C
1
-C
4
)alkyl residue;
the groups of formula:
 in which m=1 to 4 and R
5
is selected from phenyl, methoxyphenyl, indolyl, benzodioxolyl, benzodioxanyl, benzothienyl and benzofuryl groups,
and R
2
is hydrogen,
ii) or R
1
is hydrogen and R
2
is selected from the groups of formula:
—NH—CO—R
6
,
R
6
being selected from C
1
-C
4
alkoxy, C
3
-C
7
cycloalkoxy, benzyloxy, methoxyphenyl, dimethoxyphenyl, benzodioxolyl and benzodioxanyl groups,
and the groups of formula:
—NH—SO
2
—R
7
,
 R
7
being selected from:
C
1
-C
5
alkyl groups optionally substituted with one or more groups selected from halogens, hydroxyl groups and the trifluoromethyl group;
C
2
-C
5
alkenyl groups;
mono- or bicyclic C
3
-C
12
cycloalkyl groups;
mono-, bi- or tricyclic C
6
-C
14
aryl groups;
heteroaryl groups selected from pyridyl, furyl, thienyl, quinolyl, benzodioxanyl, benzodioxolyl, isoxazolyl, benzodioxinyl, benzothienyl, thiazolyl, pyrazolyl, benzofuryl and benzothiazolyl groups;
phenyl(C
1
-C
4
)alkyl and naphthyl (C
1
-C
4
)alkyl groups;
and the groups of formula:
 in which n=1, 2 or 3 and B is selected from —CH
2
—, O or S and —NH—,
 the aryl or heteroaryl groups optionally being substituted with one or more groups selected independently from halogens, C
1
-C
4
alkyl, C
3
-C
7
cycloalkyl, trifluoromethyl, C
1
-C
4
alkylthio, C
1
-C
4
alkyloxy, C
1
-C
4
alkylsulphonyl, nitro, di((C
1
-C
4
)alkyl)amino and groups —COOR, —CH
2
—COOR or —O—CH
2
COOR, R being a C
1
-C
4
alkyl group, phenyl and naphthyl groups and heteroaryl groups selected from thienyl, furyl and pyridyl groups,
iii) R
3
is selected from a hydrogen atom, a C
1
-C
4
alkyl group and a phenyl(C
1
-C
4
)alkyl group;
iv) A is selected from groups —NH—CHR
10
—, —NH—CHR
10
—CH
2
— and
 with p=1 or 2,
R
10
being selected from hydrogen, a C
1
-C
4
alkyl group and a C
6
-C
14
aryl group,
v) and Z
1
and Z
2
are hydrogen or an amine-protecting group, and the addition salts thereof with pharmaceutically acceptable acids.
One specific group of compounds of formula (I) is represented by the compounds of formula (Ia):
in which:
i) either R
1
is selected from:
C
1
-C
4
alkyl, C
3
-C
12
mono- or bicyclic cycloalkyl, C
2
-C
4
alkenyl or C
2
-C
4
alkynyl groups, these groups optionally being substituted with groups selected from halogens and the hydroxyl group;
mono-, bi- or tricyclic C
6
-C
14
aryl groups,
heteroaryl groups selected from pyridyl, thienyl, furyl, quinolyl, benzodioxanyl, benzodioxolyl, benzothienyl, benzofuryl and pyrazinyl groups;
phenyl(C
1
-C
4
)alkyl and naphthyl(C
1
-C
4
)alkyl groups optionally substituted on the aryl nucleus,
the aryl and heteroaryl groups possibly being substituted with one or more groups selected independently from halogens, C
1
-C
4
alkyl, trifluoromethyl, C
1
-C
4
alkylthio, C
1
-C
4
alkylsulphonyl, C
1
-C
4
alkyloxy, nitro and groups —COOR, —CH
2
COOR or —O— CH
2
-COOR, R being a C
1
-C
4
alkyl group,
the groups of formula:
 in which R
4
and R′
4
are selected from C
1
-C
8
alkyl and mono- or polycyclic C
3
-C
12
cycloalkyl groups, these groups optionally being substituted with groups selected from halogens and the hydroxyl group, R′
4
also possibly being hydrogen, or alternatively R
4
and R′
4
together form a tetramethylene or pentamethylene group, these last two groups themselves possibly being substituted, in particular with a C
6
-C
14
aryl or (C
6
-C
14
)aryl(C
1
-C
4
)alkyl residue;
the groups of formula:
 in which m=1 to 4 and R
5
is selected from phenyl, methoxyphenyl, indolyl, benzodioxolyl, benzodioxanyl, benzothienyl and benzofuryl groups,
 and R
2
is hydrogen,
ii) or R
1
is hydrogen and R
2
is selected from the groups of formula:
—NH—CO—R
6
,
 R
6
being selected from C
1
-C
4
alkoxy, C
3
-C
7
cycloalkoxy, benzyloxy, methoxyphenyl, dimethoxyphenyl, benzodioxolyl and benzodioxanyl groups,
 and the groups of formula:
—NH—SO
2
—R
7
,
 R
7
being selected from:
C
1
-C
5
alkyl groups optionally substituted with one or more groups selected from halogens, hydroxyl groups and the trifluoromet

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