Piperazinone derivatives and their uses

Details Piperazinone derivatives and their uses Piperazinone derivatives and their uses

2001-01-10

2002-02-05

Bernhardt, Emily (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S252130, C514S253010, C514S253060, C514S253070, C514S254110, C514S255030, C544S121000, C544S357000, C544S360000, C544S363000, C544S376000, C544S377000, C544S379000, C544S393000

Reexamination Certificate

active

06344456

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 action 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 which can be used as antithrombotic medicines.
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:
R
1
is chosen from hydrogen, a C
1
-C
4
alkyl group and a phenyl (C
1
-C
4
alkyl) group;
R
2
is chosen from hydrogen, a hydroxyl group and a protecting group for the amidino group;
R
3
is chosen from
hydrogen,
C
1
-C
5
alkyl, C
3
-C
12
mono- or bicyclic cycloalkyl, C
2
-C
4
alkenyl and C
2
-C
4
alkynyl groups, these groups optionally being substituted with groups chosen from halogens and the hydroxyl group;
mono-, bi- or tricyclic C
6
-C
14
aryl groups,
heteroaryl groups chosen from pyridyl, thienyl, furyl, quinolyl, benzodioxanyl, benzodioxolyl, benzothienyl, benzofuryl and pyrazinyl groups;
phenyl (C
1
-C
4
) alkyl and napthyl (C
1
-C
4
) alkyl groups optionally substituted on the aryl nucleus, and piperonyl groups,
R
4
and R
5
are chosen, independently of each other, from hydrogen and a C
1
-C
5
alkyl group, or form, together with the nitrogen atom, a group chosen from piperidyl and morpholinyl groups,
aryl and heteroaryl groups which may be substituted with one or more groups chosen independently from halogens, C
1
-C
4
alkyl, trifluoromethyl, C
1
-C
4
alkylthio, C
1
-C
4
alkylsulphonyl, C
1
-C
4
alkyloxy and nitro groups and groups —COOR, —CH
2
COOR and —O—CH
2
—COOR, R being a C
1
-C
4
alkyl group,
and the oxo group is in position 2 or 3 on the piperazine;
and the addition salts thereof with pharmaceutically acceptable acids.
As examples of aryl groups, mention may be made of phenyl, &agr;-naphthyl, &bgr;-naphthyl and fluorenyl groups.
The C
1
-C
5
alkyl groups may be linear or branched. Examples which may be mentioned are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl and pentyl groups.
The alkynyl groups may be, for example, ethynyl, propargyl or butynyl groups.
The alkenyl groups may be, for example, vinyl and allyl groups.
The C
1
-C
4
alkoxy groups may similarly be linear or branched. Examples which may be mentioned are methoxy, ethoxy, propoxy, isopropoxy, butoxy and isobutyoxy groups.
The halogens may be chosen from fluorine, chlorine, bromine and iodine.
As examples of protecting groups for the amidino group, mention may be made of ethoxycarbonyl, benzyloxycarbonyl, p-nitrobenzyloxycarbonyl and t-butoxycarbonyl groups.
The “addition salts with pharmaceutically acceptable acids” denote salts which give the biological properties of the free bases, without having any undesirable effect. These salts may be, in particular, those formed with mineral acids, such as hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid or phosphoric acid; acidic metal salts, such as disodium orthophosphate and monopotassium sulphate, and organic acids.
The compounds of formula I may be prepared by:
a) reacting an acid of formula
in which Z is a precursor group of a group
with an amine of formula
in which R′
1
is a C
1
-C
4
alkyl or phenyl (C
1
-C
4
alkyl) group, to give a compound of formula
b) converting the group Z into a group
and
c) optionally, converting the group R′
1
into a hydrogen atom.
The acids of formula II may be reacted with the amines of formula III in a polar solvent such as DMF, THF or ethyl acetate, in the presence of a coupling agent (DCC/HOBT, BOP, isobutyl chloroformate) at a temperature of from 15° C. to 50° C.
When Z is an N≡C— group, the group Z may be converted into an amidoxime by addition of hydroxylamine to the nitryl group in the presence of a suitable base (K
2
CO
3
, Et
3
N, NaOC
2
H
5
) in an alcoholic solvent. Hydrogenolysis, in the presence of palladium-on-charcoal in a mixture of acetic anhydride and acetic acid, of the compounds obtained gives the compounds of formula I in which R
2
is hydrogen (with direct formation of a compound in which R
1
=H when R′1 is a benzyl group).
When Z is an N≡C— group, the group Z can also be converted into an imidate by addition of ethanol in the presence of HCl in ethyl acetate. The imidate obtained is then converted into compounds of formula (I) in which R
2
is a hydrogen and —NR
4
R
5
is either a piperidyl group or a morpholinyl group, by reaction with the corresponding amine in ethanol/ethyl acetate medium.
The compounds of formula II containing a 2-piperazinone group, when Z is a nitrile group, can be obtained according to the following scheme:
4-Fluorobenzonitrile is reacted with an excess of ethylenediamine in an aprotic solvent to give 4-(2-aminoethyl)benzonitrile, which is then mono-alkylated with ethyl bromoacetate in a polar solvent such as ethanol or acetonitrile, in the presence of an inorganic base or a tertiary amine. An acylation with chloroacetyl chloride followed by a cyclization and a hydrolysis give the acid (1).
The compounds of formula II containing a 3-piperazinone group, when Z is a nitrile group, can be obtained according to the following scheme:
4-(2-Amioethyl)benzonitrile is dialkylated with ethyl bromoacetate; the cyclization is carried out in the presence of a tertiary amine, an inorganic base or a mixture thereof; after hydrolysis, the acid (2) is obtained.
The addition salts are obtained conventionally by reacting the compound of formula I with a pharmaceutically acceptable acid in a suitable solvent. Conversely, the bases may be obtained from the addition salts by treatment with a strong base.
The examples which follow illustrate the preparation of the compounds of formula I.
A—Preparation of the Compounds of Formula II
1. Synthesis of 2-[4-(4-cyanophenyl)-2-oxopiperazino]acetic acid (1)
a) 4-(2-amino

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