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AssigneeLes Laboratoires Servier
InventorsJean-Louis Peglion, Christophe Poitevin, Jean-Paul Vilaine, Nicole Villeneuve, Marie-Pierre Bourguignon, Catherine Thollon
Estimating the term…
Compound of formula (I): 1 wherein: V represents a single bond or an alkylene chain, M represents a single bond or an alkylene chain, A and E each represents nitrogen or CH, but at least one of the two groups A or E represents nitrogen, W represents a group of formula (i), (ii) or (iii): 2 wherein: X represents carbonyl, sulphonyl or sulphoxide, G1, G2 and G3 are as defined in the description, T represents a fused phenyl group or a fused pyridyl group, R1 represents hydrogen, linear or branched (C1-C6)alkyl, aryl or aryl-(C1-C6)alkyl in which the alkyl moiety is linear or branched, R2a and R2b, which are the same or different, are as defined in the description, R3 represents aryl or heteroaryl-A as defined in the description, each of which groups may optionally be substituted, Y represents aryloxy, heteroaryloxy or heteroaryl-B as defined in the description, each of which groups may optionally be substituted, its isomers, its hydrates, its solvates and addition salts thereof with a pharmaceutically acceptable acid. Medicinal products containing the same which are useful in the treatment of diseases or pathological conditions in which endothelial dysfunction is known.
1- A compound selected from those of formula (I):
2- A compound of claim 1, characterised in that Y represents benzofuran-3-yl or phenyloxy optionally substituted by a group R2a as defined for formula (I), its isomers, and hydrates, solvates and addition salts thereof with a pharmaceutically acceptable acid.
3- A compound of claim 1, characterised in that X represents carbonyl, its isomers, and hydrates, solvates and addition salts thereof with a pharmaceutically acceptable acid.
4- A compound of claim 1, characterised in that W represents a group of formula (i) as defined for formula (I), its isomers, and hydrates, solvates and addition salts thereof with a pharmaceutically acceptable acid.
5- A compound of claim 1, characterised in that it represents a compound of formula (IA):
6- A compound of claim 5, characterised in that R3 represents phenyl optionally substituted by halogen, its isomers, and hydrates, solvates and addition salts thereof with a pharmaceutically acceptable acid.
7- A compound of claim 5, characterised in that:
8- A compound of claim 5, characterised in that:
9- A compound of claim 1, characterised in that W represents a group of formula (ii) as defined for formula (I), its isomers, and hydrates, solvates and addition salts thereof with a pharmaceutically acceptable acid.
10- A compound of claim 1, characterised in that it represents a compound of formula (IB):
11- A compound of claim 10, characterised in that:
12- A compound of claim 10, characterised in that:
13- A compound of claim 1, characterised in that W represents a group of formula (iii) as defined for formula (I), its isomers, and hydrates, solvates and addition salts thereof with a pharmaceutically acceptable acid.
14- A compound of claim 1, characterised in that it represents a compound of formula (IC):
15- Compounds of claim 1 which are:
16- Compound of formula (I) according to claim 1 which is 1-(2-{4-[2-(4-fluorophenoxy)ethyl]-1-piperidyl}ethyl)-3-phenyl-2-imidazolidinone, its isomers, and hydrates, solvates and addition salts thereof with a pharmaceutically acceptable acid.
17- Method for treating a living body afflicted with a disease or pathological condition in which endothelial dysfunction is known, comprising the step of administering to the living body an amount of a compound of claim 1 which is effective for alleviation of said disease or condition.
18- Pharmaceutical composition useful for treatment of a disease or pathological condition in which endothelial dysfunction is known, comprising as active principle an effective amount of a compound as claimed in claim 1, together with one or more inert, non-toxic pharmaceutically acceptable excipients or vehicles.
19- Method for treating a living body afflicted with myocardial or peripheral ischaemia, cardiac insufficiency or pulmonary arterial hypertension, comprising the step of administering to the living body an amount of a compound of claim 1 which is effective for alleviation of said conditions.
20- Pharmaceutical composition useful for treatment of myocardial or peripheral ischaemia, cardiac insufficiency or pulmonary arterial hypertension, comprising as active principle an effective amount of a compound as claimed in claim 1, together with one or more inert, non-toxic pharmaceutically acceptable excipients or vehicles.
21- Method for preventing a living body from the development, extension and complications of atherosclerotic lesions, particularly for patients having a vascular risk factor (dyslipidaemia, diabetes, systemic arterial hypertension), or for preventing vascular complications after vascular bypass, vascular dilatation, vascular repermeabilisation and heart transplantation, comprising the step of administering to the living body an amount of a compound of claim 1 which is effective for said preventions.
22- Pharmaceutical composition useful for prevention of the development, extension and complications of atherosclerotic lesions, particularly for patients having a vascular risk factor (dyslipidaemia, diabetes, systemic arterial hypertension), or for prevention of vascular complications after vascular bypass, vascular dilatation, vascular repermeabilisation and heart transplantation, comprising as active principle an effective amount of a compound as claimed in claim 1, together with one or more inert, non-toxic pharmaceutically acceptable excipients or vehicles.
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From the US filing history. Foreign family members aren’t listed.
Backward citations are indexed for grants only.
Containing two hetero rings: linked by a carbon chain containing only aliphatic carbon atoms
Drugs for disorders of the metabolism: antihyperlipidemics
For glucose homeostasis: for hyperglycaemia, e.g. antidiabetics
Drugs for disorders of the cardiovascular system
Term end not estimated
The compounds of the present invention are useful in the treatment of diseases or pathological conditions in which endothelial dysfunction is known to be a pathogenic and/or aggravating mechanism. Such pathologies are: atherosclerosis, the existence of vascular risk factors (dyslipidaemia, diabetes, systemic arterial hypertension), the various clinical forms of myocardial or peripheral ischaemia, cardiac insufficiency and the various forms of pulmonary arterial hypertension. The said compounds are also useful in the treatment of patients undergoing heart transplantation or vascular repermeabilisation such as a bypass, thrombolysis or arterial dilatation with or without a stent.
A reduction in the vascular availability of nitrogen monoxide (NO) constitutes the major mechanism of endothelial dysfunction observed in the diseases and pathological conditions mentioned above and explains its pathogenic role (Cardiovasc. Res., 1999, 43, 572; Coronary. Art. Dis. 1999, 10, 277; Coronary. Art. Dis., 1999, 10 301; Coronary. Art. Dis., 1999, 10, 287; Coronary. Art. Dis., 1999, 10, 295).
In the said pathological conditions, the endothelial dysfunction may in fact result from two main mechanisms: 1) inadequate production of NO associated with inhibition of endothelial NO synthase by endogenous inhibitors such as ADMA (asymmetric dimethyl-arginine), the plasma concentration of which increases in patients exhibiting cardiovascular risk factors (Cardiovasc. Res., 1999, 43, 542; Hypertension, 1997, 29, 242; Circulation, 1997, 95, 2068), 2) inactivation of the NO by the superoxide anion (O2−), the production of which is increased in pathological conditions (Cardiovasc. Res., 1999, 43, 562; Eur. J. Biochem. 1997, 245, 541; J. Clin. Invest., 1993, 91 2546).
Step 1: 1-{1-[2-(Benzofuran-3-yl)ethyl]-4-piperidyl}-1-(2,2-dimethoxyethyl)-3-phenylurea
6 mmol of phenyl isocyanate are added to a mixture of 6 mmol of the compound of Preparation 9 and 3.14 ml of diisopropylethylamine in 72 ml of dichloromethane. After stirring for 12 hours at ambient temperature and dilution with water, the organic phase is washed with water, dried, filtered and then concentrated under reduced pressure, allowing the expected product to be obtained.
Step 2: 1-{1-[2-(Benzofuran-3-yl)ethyl]-4-piperidyl}-3-phenyl-1,3-dihydro-2H-imidazol-2-one and its Hydrochloride