AU2004202768B2

AU2004202768B2 - New linear or cyclic ureas, a process for their preparation and pharmaceutical compositions containing them

Info

Publication number: AU2004202768B2
Application number: AU2004202768A
Authority: AU
Inventors: Marie-Pierre Bourguignon; Jean-Louis Peglion; Christophe Poitevin; Catherine Thollon; Jean-Paul Vilaine; Nicole Villeneuve
Original assignee: Laboratoires Servier SAS
Current assignee: Laboratoires Servier SAS
Priority date: 1999-12-30
Filing date: 2004-06-23
Publication date: 2007-04-05
Anticipated expiration: 2020-12-29
Also published as: AU2004202768A1

Description

P001 Section 29 Regulation 3.2(2)

AUSTRALIA

Patents Act 1990 COMPLETE SPECIFICATION STANDARD PATENT Application Number: Lodged: Invention Title: New linear or cyclic ureas, a process for their preparation and pharmaceutical compositions containing them The following statement is a full description of this invention, including the best method of performing it known to us: NEW LINEAR OR CYCLIC UREAS, A PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM The present invention relates to new linear or cyclic ureas, to a process for their preparation and to pharmaceutical compositions containing them.

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 dimethylarginine), 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 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).

Under normal conditions, NO produces major effects such as 1) regulation of arterial vasomotricity by means of its vasodilator effect (N Engl. J Med., 1993, 329, 2002; Nature, 1980, 288, 373), 2) limitation of platelet adhesion and aggregation (Trends Pharmacol.

Sci., 1991, 12, 87), 3) control of the adhesion of leukocytes and monocytes to endothelial cells (Proc. Natl Acad. Sci. USA, 1991, 88, 4651), 4) inhibition of the proliferation of vascular smooth muscle cells (Cardiovasc. Res., 1999, 43, 580, Circulation, 1993, 87 V51), which explains why the deficiency of NO in the arterial wall is favourable to pathological phenomena such as vasoconstriction, thrombosis, lipid accumulation and proliferation of vascular smooth muscle cells.

In vitro experiments have enabled it to be shown that the compounds of the present invention are capable of limiting the endothelial dysfunction and reduced vascular availability of NO that are caused by tests involving the two physiopathological mechanisms already mentioned inhibition of endothelial NO synthase and oxidative stress due to production of 02.

Besides the fact that they are new, the compounds of the present invention, by virtue of their specific pharmacological activity, which is capable of limiting the development of endothelial dysfunction, are useful in preventing the development, extension and complications of atherosclerotic lesions, especially in patients exhibiting a vascular risk factor (dyslipidaemia, diabetes, arterial hypertension), and in treating the various clinical forms of myocardial or peripheral ischaemia, cardiac insufficiency and the various forms of pulmonary arterial hypertension. The compounds are also used for preventing vascular complications (spasm, thrombosis, restenosis, accelerated atherosclerosis) in patients undergoing a bypass, vascular dilatation with or without a stent or other forms of vascular repermeabilisation and also heart transplantation.

Compounds of similar structure have been described in the literature, that being the case, more especially, for Patent Application WO 94/13659, which claims compounds containing especially a cyclic urea structure, those compounds being useful in the treatment of diseases of the central nervous system such as depression or psychosis.

Similarly, Patent Specification FR 2 338 940 describes compounds containing especially a 1-[2-hydroxy-3-(aryloxy)-propyl]-4-piperidyl}-3-aryl-imidazolidin-2-one structure and claims them for their usefulness in the treatment of vascular hypertension. Finally, Patent Specification EP 0 526 342 describes new (isoquinolin-5-yl)sulphonamides, which are useful in the treatment of myocardial ischaemia.

The compounds of the present invention are clearly distinguished from that prior art, both in their particular chemical structure and in their specific pharmacological activity of endothelial protection.

More specifically, the present invention relates to compounds of formula W-V-A E-M-Y wherein V represents a single bond or a linear or branched (Ci-C 6 )alkylene chain, M represents a single bond or a linear or branched (CI-C 6 )alkylene chain, A and E each represents a nitrogen atom or a CH group, but at least one of the two groups A or E represents a nitrogen atom, W represents a group of formula or and also may represent a group of formula (iii) but only when V represents a single bond and A represents a nitrogen atom, in which groups of formulae (ii) and (iii) R3 R 2a G2a T -X- G R 2 b 3 R2b G (ii) (iii) [This application is directed to the embodiment wherein W represents a group of formula X represents a carbonyl, sulphonyl or sulphoxide group,

G

1 represents a linear (C 2

-C

4 )alkylene chain optionally containing a double bond and/or being optionally substituted by a hydroxyl group,

G

2 represents a single bond or a methylene group,

G

3 represents *a linear (C 2

-C

3 )alkylene chain when G 2 represents a bond, *or a linear (Ci-C 2 )alkylene chain when G 2 represents a methylene group, the said alkylene chain in each of those cases optionally containing a double bond, T represents a phenyl group fused with the ring to which it is attached or a pyridyl group fused with the ring to which it is attached, RI represents a hydrogen atom, a linear or branched (Ci-C 6 )alkyl group, an aryl group or an aryl-(C 1

-C

6 )alkyl group in which the alkyl moiety is linear or branched, R2a and R2b, which are the same or different, each independently of the other represents a group selected from a hydrogen atom, a halogen atom, a linear or branched

(C

1

-C

6 )alkyl group, a hydroxy group, a linear or branched (Ci-C 6 )alkoxy group, a mercapto group, a linear or branched (Ci-C 6 )alkylthio group, a linear or branched

(C

1

-C

6 )trihaloalkyl group, a cyano group, a nitro group, an amino group, a linear or branched (C 1

-C

6 )alkylamino group, a di-(CI-C 6 )alkylamino group in which each alkyl moiety may be linear or branched, a linear or branched (Ci-C 6 )trihaloalkoxy group, an aryloxy group, an aryl-(C 1

-C

6 )alkoxy group in which the alkoxy moiety is linear or branched, a linear or branched (C 1

-C

6 )alkylsulphonate group, a linear or branched (C 1

-C

6 )trihaloalkylsulphonate group and a linear or branched (C 1

-C

6 alkylsulphonyl group, or R2a R2b, taken together in adjacent positions, represent a group selected from methylenedioxy, 1,2-ethylenedioxy, 1,3-propylenedioxy, and ethylene optionally substituted by a group selected from cyano, hydroxymethyl, linear or branched (Ci-C 6 )alkoxycarbonyl, aryloxycarbonyl and aryl-(Ci-C 6 )alkoxycarbonyl in which the alkoxy moiety is linear or branched,

R

3 represents an aryl or heteroaryl-A group, each of which groups may optionally be substituted by one or more groups, which may be the same or different, selected from among the definitions of R 2 a, Y represents an aryloxy, heteroaryloxy or heteroaryl-B group, each of which groups may optionally be substituted by one or more groups, which may be the same or different, selected from among the definitions of R 2 a, their isomers, their hydrates, their solvates and addition salts thereof with a pharmaceutically acceptable acid, wherein an aryl group is understood to mean a group selected from phenyl, biphenyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, indanyl, indenyl and benzocyclobutyl, a heteroaryl-A group is understood to mean a monocyclic aromatic or bicyclic, 5- to 12membered system containing one or two hetero atoms, which may be the same or different, selected from oxygen, nitrogen and sulphur, and wherein, in the case of a bicyclic system, one of the rings has an aromatic character and the other ring may be aromatic or partially hydrogenated, a heteroaryl-B group is understood to mean a monocyclic aromatic or bicyclic aromatic, to 12-membered system containing from 1 to 3 hetero atoms, which may be the same or different, selected from oxygen, nitrogen and sulphur, an aryloxy group is understood to mean an aryl group as defined hereinbefore attached to an oxygen atom, a heteroaryloxy group is understood to mean a heteroaryl-A group as defined hereinbefore attached to an oxygen atom, with the proviso that when V represents a single bond and W represents a group of formula wherein R 3 represents a phenyl group, then Y cannot represent a 3-indolyl group, when M represents a single bond and W represents a group of formula then if Y represents a bicyclic heteroaryl-B group wherein one of the rings represents a benzene ring the said group Y cannot be joined to M by the said benzene ring, and when M represents a single bond, V represents an ethylene group and W represents a group of formula wherein R 3 represents a phenyl group, then Y cannot represent a 1,2benzisoxazol-3-yl group.

Accordingly the primary embodiment of this application is directed to compounds of formula W-V-A E-M-Y wherein V represents a single bond or a linear or branched (Ci-C 6 )alkylene chain, M represents a single bond or a linear or branched (C 1

-C

6 )alkylene chain, A and E each represents a nitrogen atom or a CH group, but at least one of the two groups A or E represents a nitrogen atom, W represents a group of formula G J (i) X represents a carbonyl, sulphonyl or sulphoxide group,

G

1 represents a linear (C 2

-C

R

3 represents an aryl or heteroaryl-A group, each of which groups may optionally be substituted by one or more groups, which may be the same or different, selected from the definitions of R 2 a, Y represents an aryloxy, heteroaryloxy or heteroaryl-B group, each of which groups may optionally be substituted by one or more groups, which may be the same or different, selected from the definitions of R2a, R2a, represents a group selected from a hydrogen atom, a halogen atom, a linear or branched (Ci-C 6 )alkyl group, a hydroxy group, a linear or branched (Ci-C 6 )alkoxy group, a mercapto group, a linear or branched (Ci-C 6 )alkylthio group, a linear or branched (Ci-C 6 )trihaloalkyl group, a cyano group, a nitro group, an amino group, a linear or branched (Ci-C 6 )alkylamino group, a di-(C 1

-C

6 )alkylamino group in which each alkyl moiety may be linear or branched, a linear or branched (C 1

C

6 )trihaloalkoxy group, an aryloxy group, an aryl-(C 1

-C

6 )alkylsulphonate group, a linear or branched (C 1

-C

6 )trihaloalkylsulphonate group and a linear or branched (CI-C 6 )alkylsulphonyl group, their isomers, their hydrates, their solvates and addition salts thereof with a pharmaceutically acceptable acid, wherein an aryl group is understood to mean a group selected from phenyl, biphenyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, indanyl, indenyl and benzocyclobutyl, a heteroaryl-A group is understood to mean a monocyclic aromatic or bicyclic, 5- to 12membered system containing one or two hetero atoms, which may be the same or different, selected from oxygen, nitrogen and sulphur, and wherein, in the case of a bicyclic system, one of the rings has an aromatic character and the other ring may be aromatic or partially hydrogenated, a heteroaryl-B group is understood to mean a monocyclic aromatic or bicyclic aromatic, 5- to 12-membered system containing from 1 to 3 hetero atoms, which may be the same or different, selected from oxygen, nitrogen and sulphur, an aryloxy group is understood to mean an aryl group as defined hereinbefore attached to an oxygen atom, -a heteroaryloxy group is understood to mean a heteroaryl-A group as defined hereinbefore attached to an oxygen atom, with the proviso that when V represents a single bond and R 3 represents a phenyl group, then Y cannot represent a 3-indolyl group, when M represents a single bond, then if Y represents a bicyclic heteroaryl-B group wherein one of the rings represents a benzene ring the said group Y cannot be joined to M by the said benzene ring, and when M represents a single bond, V represents an ethylene group and R 3 represents a phenyl group, then Y cannot represent a 1,2-benzisoxazol-3-yl group.

Among the pharmaceutically acceptable acids there may be mentioned, without implying any limitation, hydrochloric acid, hydrobromic acid, sulphuric acid, phosphonic acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid, oxalic acid, methanesulphonic acid, camphoric acid etc.

Preferred substituents Y according to the invention are the benzofuran-3-yl group and the phenyloxy group optionally substituted by a group R 2 a as defined for formula A preferred substituent X according to the invention is the carbonyl group.

According to an advantageous embodiment of the invention, preferred compounds are compounds of formula wherein W represents a group of formula as defined for formula Especially advantageously, preferred compounds of the invention are compounds of formula (IA)

/X\

R-N N-V-A E-M-Y (IA)

G,

wherein:

R

3 represents an aryl group, and advantageously a phenyl group, optionally substituted by a group selected from a halogen atom, a hydroxy group, a linear or branched (CI-C 6 alkoxy group, an aryl-(Ci-C 6 )alkoxy group in which the alkoxy moiety is linear or branched, a nitro group, a linear or branched (Ci-C 6 )trihaloalkyl group and a cyano group, X represents a carbonyl group, Gi represents a linear (C 2

-C

3 )alkylene chain, V is as defined for formula A represents a nitrogen atom when E represents a CH group, or A represents a CH group when E represents a nitrogen atom, M represents a linear or branched (Ci-C 4 )alkylene chain, Y represents a benzofuran-3-yl group, or a phenyloxy group optionally substituted by a group selected from a halogen atom, a linear or branched (Ci-C 6 )alkylsulphonyl group and a linear or branched (C 1

-C

6 )alkylthio group.

In a very preferable manner, preferred compounds of the invention are compounds of formula (IA) as defined hereinbefore wherein A represents a nitrogen atom and E represents a CH group when Y represents an optionally substituted phenyloxy group, or A represents a CH group and E represents a nitrogen atom when Y represents a benzofuran-3-yl group.

In another preferable manner, preferred compounds of the invention are compounds of formula (IA) as defined hereinbefore wherein V represents a single bond when Y represents a benzofuran-3-yl group and V represents a linear or branched (Ci-C 4 )alkylene chain when Y represents an optionally substituted phenyloxy group.

According to another advantageous embodiment of the invention, preferred compounds are compounds of formula wherein W represents a group of formula (ii) as defined for formula Especially advantageously, preferred compounds of the invention are compounds of formula (IB)

X

R

2 b 2b N N-V-A E-M-Y (IB) R,N- Rl 2a G3 wherein R2a and R2b are as defined for formula

G

3 represents a group of formula -(CH 2 2

-(CH

2 3 or -CH=CH-, X represents a carbonyl group, RI represents a hydrogen atom, A, E and V are as defined for formula M represents a linear or branched (Ci-C 4 )alkylene chain, Y represents a benzofuran-3-yl group, or a phenyloxy group optionally substituted by a group selected from a halogen atom, a linear or branched (C 1

-C

6 )alkylsulphonyl group and a linear or branched (Ci-C 6 )alkylthio group.

In a very preferable manner, preferred compounds of the invention are compounds of formula (IB) as defined hereinbefore wherein A represents a nitrogen atom and E represents a CH group when Y represents an optionally substituted phenyloxy group, or A represents a CH group and E represents a nitrogen atom when Y represents a benzofuran-3-yl group.

In another preferable manner, preferred compounds of the invention are compounds of formula (IB) as defined hereinbefore wherein V represents a single bond when Y represents a benzofuran-3-yl group and V represents a linear or branched (Ci-C 4 )alkylene chain when Y represents an optionally substituted phenyloxy group.

According to a third advantageous embodiment of the invention, preferred compounds are compounds of formula wherein W represents a group of formula (iii) as defined for formula Especially advantageously, preferred compounds of the invention are compounds of formula (IC) X-N N-M-Y

R

2 b 2 a G (IC), wherein: R2a, R2b and M are as defined for formula

G

3 represents a group of formula -(CH 2 2 X represents a carbonyl group, Y represents a benzofuran-3-yl group, or a phenyloxy group optionally substituted by a group selected from a halogen atom and a linear or branched (C 1

-C

6 )alkylsulphonyl group.

Preferred compounds of the invention are N- 2-[4-(phenoxymethyl)- 1-piperidyl]ethyl indolinecarboxamide, 5-fluoro-N-(2- {4-[2-(4-fluorophenoxy)ethyl]-1-piperidyl }ethyl)- 1-indolecarboxamide, N- 2-[4-(p-fluorophenoxymethyl)- -piperidyl]ethyl -1-indolinecarboxamide, N- 2-[4-(phenoxymethyl)- 1-piperidyl]ethyl -1 -indolecarboxamide, and {4-[2-(4-fluorophenoxy)ethyl]-1-piperidyl }ethyl)-3-phenyl-2imidazolidinone.

The isomers, as well as the hydrates, solvates and addition salts with a pharmaceutically acceptable acid, of the preferred compounds form an integral part of the invention.

-9- The invention relates also to a process for the preparation of compounds of formula which process is characterised in that there is used as starting material: a compound offormula (II)

R

3 N C O (II), wherein R 3 is as defined for formula which is reacted 6 with a compound of formula (III) HO Gla NH Va OH (III), wherein Va represents a (C 2

-C

6 )alkylene chain and Gla represents a linear (C 2

-C

3 )alkylene chain, to yield the compounds of formula (IVa): G-OH la R3 NH N-Va-OH (IVa),

O

wherein R 3 Gla and Va are as defined hereinbefore, which compounds of formula (IVa) are converted by conventional methods of organic synthesis to yield the compounds of formula (IVb) GT -P 1 R3-NH N-V-P (IVb), wherein P 1 represents a chlorine, bromine or iodine atom or a group OSO 2

R

4 wherein R 4 represents a methyl, trifluoromethyl or tolyl group, and R 3 Va and Gla are as defined hereinbefore, which compounds of formula (IVb) are subjected to the action of heat to yield the compounds of formula (IVc): R3-N N-V--PI (IVc),

O

wherein R 3 Gla, Va and P 1 are as defined hereinbefore, which compounds of formula (IVc) are treated under basic conditions with a compound of formula HN E-M-Y wherein E, M and Y are as defined for formula to yield the compounds of formula a particular case of the compounds of formula R3-N N-V-N E-M-Y wherein R 3 Gla, Va, E, M and Y are as defined hereinbefore, 6 or with a compound of formula (VI):

H

2 N-V-A E-M-Y

(VI),

wherein A, E, M and Y have the same meanings as in formula and Vb represents a

(C

1

-C

6 )alkylene chain, to yield the compounds of formula (VII): R3-NH-CO-NH-V-A E-M-Y (VII), wherein R 3 Vb, A, E, M and Y are as defined hereinbefore, which compounds of formula (VII) are treated in the presence of a strong base with a compound of formula (VIII) P Glb P'I (VIII), wherein P 1 and P'i, which are the same or different, are as defined for P 1 hereinbefore and Gib represents a C 4 alkylene chain optionally containing a double bond, to yield the compounds of formula a particular case of the compounds of formula R-N N-V-A E-M-Y 0 11 wherein R 3 Gib, Vb, A, E, M and Y are as defined hereinbefore, 6 or with a compound of formula (IX): (R O) 2 CH-Gi-NH-V-A E-M-Y (IX), wherein G 1 c represents a linear C 1 or C 2 -alkylene chain R 5 represents a linear or branched (C 1

-C

6 )alkyl group, and V, A, E, M and Y are as defined for formula to yield the compounds of formula

G-CH(OR)

2 R-N N-V-A E-M-Y 0 wherein R 3

G

1 c, V, A, Rs, M and Y are as defined hereinbefore, which compounds of formula are placed in the presence of a strong organic acid to yield the compounds of formula a particular case of the compounds of formula

HO

GIC

R3-N N-V-A E-M-Y

Y

O

wherein R 3

G

1 c, V, A, E, M and Y are as defined hereinbefore, which compound of formula is hydrogenated according to conventional techniques of organic synthesis to yield the compounds of formula a particular case of the compounds of formula R3-N N-V-A E-M-Y

O

wherein R 3

G

1 c, V, A, E, M and Y are as defined hereinbefore, or which compounds of formula are dehydrated under conventional conditions of organic synthesis to yield the compounds of formula a particular case of the compounds of formula 12- Gic R3-N N-V-A E-M-Y 0 wherein R 3 Glc, V, A, E, M and Y are as defined hereinbefore, Sor a compound offormula (Ia)

R

3 NH S0 2 C1 (IIa), wherein R 3 is as defined for formula which is reacted with a compound of formula (ma): SHal- Gla -NH- Va -Hal (liIa), wherein Hal represents a halogen atom and Gia and Va have the same meanings as hereinbefore, to yield the compounds of formula (IIIb): la Hal R3-NH N (IIIb), S V a Hal 0 0 wherein R 3 Gia, Va and Hal are as defined hereinbefore, which compounds of formula (IIIb) are reacted to yield the compounds of formula (IIIc): R- GN--V-Hal (IIIc), 3 \I a

S

0 0 wherein R 3 Gia, Va and Hal are as defined hereinbefore, which compounds of formula (IIIc) are treated under basic conditions with a compound of formula HN E-M-Y wherein E, M and Y are as defined for formula to yield the compounds of formula a particular case of the compounds of formula 13- R-N N-V-N E-M-Y 3 S O O wherein R 3 Gla, Va, E, M and Y are as defined hereinbefore, i or a compound offormula (XV) R T H (XV), 2b 3 wherein R2a, R2b, G 2

G

3 and T have the same meanings as in formula which compound of formula (XV) is treated either with diphosgene or triphosgene, in the presence of a base, or with di-(lH-imidazol-l-yl)methanone to yield the compounds of formula (XVI) R2a 0 T jG (XVI), 2 b wherein R2a, R2b, G 2

G

3 and T are as defined hereinbefore and Ra represents a chlorine atom, a 1H-imidazol-l-yl group or a group of formula SG2

R

2 a N T 3 R 2 b wherein R2a, R2b, G 2

G

3 and T are as defined hereinbefore, which compound of formula (XVI) is reacted with a compound of formula (XVII): HRN-V-A E-M-Y (XVII), wherein R 1 V, A, E, M and Y are as defined for formula to yield the compounds of formula a particular case of the compounds of formula -14- R2a 0O T G2 A N-V-A E-M-Y

R

2 b 3

R

wherein R2a, R2b, G 2

G

3 T, R 1 V, A, E, M and Y are as defined for formula or which compound of formula (XV) is treated under basic conditions with diphosgene, with triphosgene, with S0 2 C1 2 with SOC1 2 with di-(1H-imidazol-1-yl)methanone or with di-(1H-imidazol-1-yl)sulphonyl, to yield the compounds of formula (XVIII): R T 2 G -X-Ra

(XVIII),

R2b wherein R2a, R2b, G 2

G

3 T and X have the same meanings as in formula and Ra is as defined hereinbefore, which compounds of formula (XVIII) are placed in the presence of a compound of formula as described hereinbefore to yield the compounds of formula a particular case of the compounds of formula G G -X-N E-M-Y

R

2 b wherein R2a, R2b, G 2

G

3 T, X, E, M and Y are as defined hereinbefore, or finally which compound of formula (XV) is reacted with chlorosulphonyl isocyanate, in the presence of a compound of formula (XIX) Hal V 1 OH (XIX), wherein Vi represents a linear (C 2

-C

6 )alkylene chain and Hal represents a chlorine, bromine or iodine atom, to yield the compounds of formula (XX): R2a G2-

/V

1 R a -SO -N O

(XX),

R

2 b Y

O

wherein R2a, R2b, G 2

G

3 T and V 1 are as defined hereinbefore, which compound of formula (XX) is then treated in succession with an alkali metal hydroxide and then with carbon tetrabromide in the presence of triphenylphosphine to yield the compounds of formula (XXI):

R,

T G 7-SO-NH-V-Br

(XXI),

R

2 b wherein R2a, R2b, G 2

G

3 T and Vi are as defined hereinbefore, which compounds of formula (XXI) are reacted with a compound of formula as described hereinbefore, to yield the compounds of formula a particular case of the compounds of formula T I N-SO2-NH-V-N E-M-Y R 2 3 2b wherein R2a, R2b, G 2

G

3 T, Vi, E, M and Y are as defined hereinbefore, the totality of the compounds of formulae to constituting the compounds of the invention, which are purified, if necessary, according to conventional purification techniques, are separated, where appropriate, into their isomers according to a conventional separation technique and are converted, if desired, into their hydrates, solvates or addition salts with a pharmaceutically acceptable acid.

The compounds of formulae (III), (VIII), (XVII) and (XIX) are either commercial products or are obtained according to known and conventional methods of organic synthesis.

-16- The compounds of the present invention are useful in the treatment of diseases or pathological conditions in which endothelial dysfunction is known. Accordingly, by virtue of their specific pharmacological activity, the compounds of the invention are useful in preventing the development, extension and complications of atherosclerotic lesions, in particular for patients having a vascular risk factor (dyslipidaemia, diabetes, systemic arterial hypertension), in the treatment of myocardial or peripheral ischaemia, of cardiac insufficiency and of pulmonary arterial hypertension and in the prevention of vascular complications after vascular bypass, vascular dilatation, repermeabilisation and heart transplantation.

The present invention relates also to pharmaceutical compositions comprising as active ingredient at least one compound of formula an optical isomer, hydrate, solvate or addition salt thereof with a pharmaceutically acceptable acid, alone or in combination with one or more inert, non-toxic, pharmaceutically acceptable excipients or carriers.

Among the pharmaceutical compositions according to the invention there may be mentioned more especially those that are suitable for oral, parenteral (intravenous, intramuscular or sub-cutaneous), per- or trans-cutaneous, nasal, rectal, perlingual, ocular or respiratory administration, and especially tablets or drag6es, sublingual tablets, soft gelatin capsules, hard gelatin capsules, suppositories, creams, ointments, dermal gels, injectable or drinkable preparations, aerosols, eye or nose drops etc...

The useful dosage varies according to the age and weight of the patient, the route of administration, the nature and severity of the disorder and any associated treatments taken, and ranges from 1 mg to 200 mg in one or more administrations per day.

The following Examples illustrate the invention but do not limit it in any way. The starting materials used are known products or are prepared according to known procedures. The different Preparations yield synthesis intermediates that are useful in preparation of the compounds of the invention.

The structures of the compounds described in the Examples were determined according to 17the usual spectrophotometric techniques (infrared, nuclear magnetic resonance, mass spectrometry, The melting points were determined using either a Kofler hot-plate or a hot-plate under a microscope PREPARATION 1: 4-(p-Fluorophenoxymethyl)piperidine Step N-tert-butyloxycarbonyl-4-(p-fluorophenoxymethyl)piperidine Over the course of 30 minutes, 10.5 ml of diethyl azodicarboxylate are poured onto a mixture of 13.5 g of N-tert-butyloxycarbonyl-4-hydroxymethylpiperidine, 7.45 g of pfluorophenol, 17.4 g of triphenylphosphine and 140 ml of tetrahydrofuran. After stirring for 12 hours at ambient temperature, the reaction mixture is concentrated, taken up in ether, washed with water and then 1N sodium hydroxide solution, and then washed with water. After drying, filtration and evaporation under reduced pressure, chromatography over silica gel (cyclohexane/ethyl acetate 90/10) allows the expected product to be isolated.

Meltinr point 94-98 0

C

Step 2: 4-(p-Fluorophenoxymethyl)piperidine 12.1 g of the product obtained in Step 1 are treated, at ambient temperature, with 300 ml of ethereal hydrogen chloride solution for 48 hours, allowing the title product to be obtained in the form of the hydrochloride. The free base is obtained by treating the hydrochloride with IN sodium hydroxide solution followed by extraction with dichloromethane.

PREPARATION 2 4-[2-(p-Fluorophenoxy)ethyl]piperidine The product is obtained according to the procedure of Preparation 1 using 2-(N-tertbutyloxycarbonyl-4-piperidyl)ethanol as substrate in Step 1.

PREPARATION 3 4-(Phenoxymethyl)piperidine 18 The product is obtained according to the procedure of Preparation 1 using phenol instead of p-fluorophenol in Step 1.

PREPARATION 4 4-(p-Methylsulphonylphenoxymethyl)piperidine The product is obtained according to the procedure of Preparation 1 using p-methylsuiphonyiphenol instead of p-fluorophenol in Step 1.

Melting point (hydrochloride) 230-234'C PREPARATION 5 4-[2-(p-Methylsulphonylphenoxy)ethyllpiperidine The product is obtained according to the procedure of Preparation 1 using 2-(N-tertbutyloxycarbonyl-4-piperidyl)ethanol and p-methylsulphonylphenol in Step 1.

PREPARATION 6: 2-{4-[(4-Methylsulphonylphenoxy)methyll-1-piperidyl}ethylamine Step 1I 1-tert-Butyloxycarbonyl-2-(4-[(4-methylsulphonylphenoxy)methyl-1piperidyijethylamine 11. 1 mmol of the product of Preparation 4, 11.1 mmol of 1-tert-butyloxycarbonyl-2bromoethylamine, 4.6 g of sodium carbonate and a spatula tip of potassium iodide are added to 50 ml of methyl isobutyl ketone. After 8 hours at reflux and then 12 hours at ambient temperature, a white solid is obtained which is recrystallised from acetonitrile, allowing the expected product to be isolated.

Step 2: 2-[4-[(4-Methylsulphonylphenoxy)methyl]-1-piperidyl)ethylamine The procedure is as in Step 2 of Preparation 1.

PREPARATION 7: 1-12-(Benzofuran-3-yl)ethyli-4-piperidylamine 19- Step I N-tert-butyloxycarbonyl-1-[2-(benzofuran-3-yl)ethyl]-4-piperidylamine mmol of 2-(benzofuran-3-yl)-l-bromoethane, 9.62 mmol of tert-butyl 4-piperidylcarbamate, 2.65 g of potassium carbonate and 0.65 g of tetrabutylammonium sulphate are added to 10 ml of toluene. After refluxing for 12 hours, the mixture is taken up in water.

The organic phase is then washed with water, dried and then filtered. Evaporation under reduced pressure allows the expected product to be isolated.

Step 2: 1-[2-(Benzofuran-3-yl)ethyl]-4-piperidylamine The procedure is as in Step 2 of Preparation 1.

PREPARATION 8: 1-[3-(Benzofuran-3-yl)propyl]-4-piperidylamine The product is obtained according to the procedure of Preparation 7 using 3-(benzofuran-3yl)-l-bromopropane as substrate in Step 1.

PREPARATION 9: N-{1-[2-(benzofuran-3-yl)ethyl]-4-piperidyl}-N-(2,2dimethoxyethyl)amine 12.3 mmol of the product of Preparation 7 and 12.3 mmol of glyoxal 1,1-dimethyl acetal as a 45 solution in tert-butyl methyl ether are added to 50 ml of dichloromethane. After reacting for 15 minutes, 18.45 mmol of sodium triacetoxyborohydride and then 0.69 ml of acetic acid are added. After 12 hours, the reaction mixture is poured onto 100 ml of IN sodium hydroxide solution. The organic phase is then washed with water, dried and then filtered. Evaporation under reduced pressure allows the expected product to be obtained.

PREPARATION 10 N-{1-[3-(benzofuran-3-yl)propyl]-4-piperidyl}-N-(2,2dimethoxyethyl)amine The product is obtained according to the procedure of Preparation 9 using the product of Preparation 8 instead of that of Preparation 7 as substrate PREPARATION 11 N-{1-[2-(benzofuran-3-yl)ethyl]-4-piperidyl}-N-(3,3diethoxypropyl)amine The product is obtained according to the procedure of Preparation 9 using, as substrate, the product of Preparation 7 and 3-amino-propionaldehyde diethyl acetal.

PREPARATION 12 N-{1-[3-(benzofuran-3-yl)propyl]-4-piperidyl}-N-(3,3diethoxypropyl)amine The product is obtained according to the procedure of Preparation 9 using, as substrate, the product of Preparation 8 and 3-amino-propionaldehyde diethyl acetal.

PREPARATION 13 1-[2-(Benzofuran-3-yl)ethyl]piperazine 84 mmol of 2-(benzofuran-3-yl)-1-bromoethane, 67 mmol of piperazine and 56 mmol of potassium carbonate are added to 200 ml of acetonitrile. After refluxing for 4 hours, the reaction mixture is cooled and then concentrated. The residue is taken up in dichloromethane, is washed with water, dried, filtered and then concentrated under reduced pressure. Chromatography over silica gel (dichloromethane/ethanol 90/10) allows the expected product to be isolated.

PREPARATION 14: 1-[3-(Benzofuran-3-yl)propyl]piperazine The product is obtained according to the procedure of Preparation 13 using 3-(benzofuran- 3-yl)-l-bromopropane as substrate.

PREPARATION 15 1-[2-(p-Fluorophenoxy)ethyl]piperazine The product is obtained according to the procedure of Preparation 13 using 1-bromo-2-(pfluorophenoxy)ethane as substrate.

-21- PREPARATION 16: 1-[3-(p-Fluorophenoxy)propyl]piperazine The product is obtained according to the procedure of Preparation 13 using 1-bromo-3-(pfluorophenoxy)propane as substrate.

PREPARATION 17 2-{4-[2-(p-Fluorophenoxy)ethyl]-l-piperidyl}ethylamine Step I: {4-[2-(p-Fluorophenoxy)ethyl]-l-piperidyl}acetonitrile 92.4 mmol of the product of Preparation 2, 6.5 ml of bromoacetonitrile and 39.2 g of potassium carbonate are added to 320 ml of methyl isobutyl ketone. After refluxing for 12 hours, the reaction mixture is filtered and concentrated under reduced pressure. The residue is taken up in water and dichloromethane. The organic phase is washed with water, dried, filtered and then concentrated under reduced pressure, allowing the expected product to be obtained.

Melting point 72°C Step 2: 2-{4-[2-(p-Fluorophenoxy)ethyl]-l-piperidyl}ethylamine A solution of the product obtained in Step 1 dissolved in 200 ml of tetrahydrofuran is added to a suspension of 81 mmol of LiAlH 4 in 200 ml of tetrahydrofuran, maintained at 0°C. After stirring for 12 hours at ambient temperature, the reaction mixture is hydrolysed using 2.75 ml of water, 2.2 ml of 20 sodium hydroxide solution and then 10 ml of water.

After filtration and rinsing with tetrahydrofuran, the filtrate is dried and then concentrated under reduced pressure, allowing the expected product to be isolated.

PREPARATION 18 2-[4-(p-Fluorophenoxymethyl)-l-piperidyl]ethylamine The product is obtained according to the procedure of Preparation 17 using the product of Preparation 1 as substrate.

-22- PREPARATION 19: 2-[4-(Phenoxymethyl)-1-piperidyl]ethylamine The product is obtained according to the procedure of Preparation 17 using the product of Preparation 3 as substrate.

PREPARATION 20 2-{4-[2-(Phenoxy)ethyll-1-piperidyl}ethylamine The product is obtained according to the procedure of Preparation 17 using 4-(2-phenoxyethyl)piperidine as substrate.

PREPARATION 21: 1-[3-(p-Fluorophenoxy)propyll-4-piperidyl}methylamine The product is obtained according to the procedure described in Step 2 of Preparation 17 using 1-[3-(p-fluorophenoxy)propyl]-4-piperidyl }formamide as substrate and maintaining the reaction for 3 hours at reflux and then for 12 hours at ambient temperature.

PREPARATION 22: 1-[2-(p-Fluorophenoxy)ethyl]4-piperidylamine The product is obtained according to the procedure of Preparation 7 using 1-bromo-2-(pfluorophenoxy)ethane as substrate.

PREPARATION 23: 1-(2-Chloroethyl)-3-phenyl-2-imidazolidinone Step I: 1,1-Bis(2-hydroxyethyl)-3-phenylurea 0.163 mol of diethanolamine dissolved in 160 ml of dichloromethane is added, at 10 0 C, to a solution of 0.168 mol of phenyl isocyanate. After reacting for 1 hour at 10 0 C and then for 12 hours at ambient temperature, the reaction mixture is concentrated under reduced pressure.

Step 2 1,1-Bis(2-chloroethyl)-3-phenylurea 26.44 ml of thionyl chloride are added, at 0 0 C, to a solution of 0.173 mol of the product -23obtained in Step 1 in 100 ml of dichloromethane. After reacting for 4 hours at reflux and then for 12 hours at ambient temperature, the reaction mixture is concentrated under reduced pressure.

Step 3: 1-(2-Chloroethyl)-3-phenyl-2-imidazolidinone 0.167 mol of the product obtained in Step 2 is heated for 3 hours at 120 0 C and then for 6 hours at 140 0 C. When no more gas is evolved, cooling is carried out. Chromatography over silica gel (dichloromethane) allows the expected product to be isolated.

Melting point 92 0

C

PREPARATION 24: 1-(2-Chloroethyl)-3-(p-methoxyphenyl)-2-imidazolidinone The product is obtained according to the procedure of Preparation 23 using p-methoxyphenyl isocyanate in Step 1.

Melting point 118°C PREPARATION 25 1-(2-Chloroethyl)-3-(p-hydroxyethyl)-2-imidazolidinone The product is obtained during purification of Preparation 24 over silica gel and is isolated in a ratio of 1:2.

Melting point 171 C PREPARATION 26: 1-(2-Chloroethyl)-3-(o-chlorophenyl)-2-imidazolidinone The product is obtained according to the procedure of Preparation 23 using o-chlorophenyl isocyanate in Step 1.

PREPARATION 27 1-(2-Chloroethyl)-3-(p-fluorophenyl)-2-imidazolidinone The product is obtained according to the procedure of Preparation 23 using p-fluorophenyl isocyanate in Step 1.

Melting point 105C 24 PREPARATION 28: 3-(p-Benzyloxyphenyl)-1-(2-chloroethyl)-2-imidazolidinone The product is obtained according to the procedure of Preparation 23 using pbenzyloxyphenyl isocyanate in Step 1.

Melting point 128-133'C PREPARATION 29: 1-(2-Chloroethyl)-3-(p-nitrophenyl)-2-imidazolidinone The product is obtained according to the procedure of Preparation 23 using p-nitrophenyl isocyanate in Step 1.

Melting~ point :134'C PREPARATION 30: 1 -(2-Chloroethyl)-3-(p-chlorophenyl)-2-imklazolidinone The product is obtained according to the procedure of Preparation 23 using p-chlorophenyl isocyanate in Step 1.

Meltingf point :112-114'C PREPARATION 31 4-[2-(p-Chlorophenoxy)ethyllpiperidine The product is obtained according to the procedure of Preparation 1, Steps 1 and 2, using 2-(N-tert-butyloxycarbonyl-4-piperidyl)ethanoI and p-chlorophenol as substrates.

Melting Point of the hydrochloride 205'C PREPARATION 32 4-[(p-Methylthiophenoxy)methyllpiperidine The product is obtained according to the procedure of Preparation 1, Steps 1 and 2, using p-methylthiophenol as substrate.

Meltinz Point of the hydrochloride :206-210TC PREPARATION 33 4-[2-(p-Methylthiophenoxy)ethyllpiperidine 25 The product is obtained according to the procedure of Preparation 1, Steps 1 and 2, using, as substrates, that of Preparation 2 and that of Preparation 32.

MelfinR Point of the hydrochloride 146-150'C PREPARATION 34 4-[2-(Phenoxy)ethyI]piperidine The product is obtained according to the procedure of Preparation 1, Steps 1 and 2, using 2-(N-tert-butyloxycarbonyl-4-piperidyl)ethanol and phenol as substrates.

Melting Point of the hydrochloride :155'C PREPARATION 35: 1-(2-Chloroethyl)-3-(p-trifluoromethylphenyl)-2imidazolidinone The product is obtained according to the procedure of Preparation 23, Steps 1 to 3, using ptrifluoromethyiphenyl isocyanate as substrate in Step 1.

Meltingr point PREPARATION 36: 1-(2-Chloroethyl)-3-(p-cyanophenyl)-2-im-idazolidinone The product is obtained according to the procedure of Preparation 23, Steps 1 to 3, using pcyanophenyl isocyanate as substrate in Step 1.

Melting~ point 149'C PREPARATION 37 N-(2,2-Dimethoxyethyl)-N-(2-{4-[2-(4-fluorophenoxy)ethyllpiperidyl}ethyl)amine The product is obtained in the form of an oil according to the procedure of Preparation 9 using the product of Preparation 17 as substrate.

PREPARATION 38 2-(2-Chloroethyl)-5-phenyl-1,2,5-thiadiazolidine-1 ,1-dioxide -26- Step 1: Phenylsulphamoyl chloride 25.2 g of chlorosulphonic acid are added slowly to a solution of 60.6 g of aniline in 316 ml of methylene chloride cooled to -5 0 C. When the addition is complete, the mixture is allowed to return to ambient temperature and the precipitate obtained is filtered off. After drying, the precipitate is taken up in 231 ml of toluene, and 45.1 g of phosphorus pentachloride are added gradually. The mixture is then refluxed for 3 hours 30 minutes and, after returning to ambient temperature, the precipitate formed is filtered off. The filtrate is concentrated to obtain the expected product.

Step2 N,N-bis(2-chloroethyl)-N'-phenylsulphamide 66 g of the product obtained in Step 1 above are added to a suspension of 38.6 g of N,Nbis(2-chloroethyl)amine hydrochloride in 265 ml of xylene heated to 100 0 C. The reaction mixture is heated at 140 0 C for 12 hours and, after cooling, filtered over a frit. The filtrate is concentrated and then purified by flash chromatography (eluant CH 2 C1 2 /AcOEt: 95/5) to yield the expected product.

Step3 2-(2-Chloroethyl)-5-phenyl-1,2,5-thiadiazolidine-1,l-dioxide Using a slow dropper, a solution of 12.6 g of the product obtained in Step 2 above in 25 ml of DMF is introduced onto a suspension of 1.4 g of NaH in 175 ml of DMF and stirring is carried out for 12 hours. The reaction mixture is then poured onto ice in order to bring about crystallisation of the expected product.

Melting point 45 0

C

PREPARATION 39: 2-(2-Chloroethyl)-5-(4-chlorophenyl)-1,2,5-thiadiazolidine-1,1dioxide The product is obtained according to the procedure of Preparation 38 using p-chloroaniline as substrate in Step 1.

Melting point 90 0

C

-27- PREPARATION 40 2-(2-Chloroethyl)-5-(4-fluorophenyl)-1,2,5-thiadiazolidine-1,1dioxide The product is obtained according to the procedure of Preparation 38 using p-fluoroaniline as substrate in Step 1.

Melting point PREPARATION 41: 2-[4-(p-Methylthiophenoxymethyl)-l-piperidyl]ethylamine The product is obtained according to the procedure of Preparation 17 using, as substrate, 4- (p-methylthiophenoxymethyl)piperidine, which is obtained according to the procedure of Preparation 1 using, in Step 1, p-(methylthio)-phenol instead ofp-fluorophenol.

Melting point 60-66°C PREPARATION 42 N-Methyl-2-[4-(phenoxymethyl)-l-piperidyl]ethanamine g of di-tert-butyl dicarbonate are introduced into a solution of 5 g of the product of Preparation 19 in 40 ml of methylene chloride and the mixture is stirred for 24 hours. After concentration in vacuo, the reaction mixture is purified by flash chromatography (eluant

CH

2 C1 2 /EtOH 95/5). The product obtained (5.5 g) is dissolved in 50 ml of THF and poured onto a suspension of 1.7 g lithium aluminium hydride in 70 ml of THF. The reaction mixture is refluxed for 7 hours and then, after cooling, hydrolysed at 5 0 C with, in succession, 11.7 ml of H 2 0, 6.1 ml of 20 sodium hydroxide solution and a further 6.7 ml of water. After filtration and concentration, the expected product is obtained.

PREPARATION 43 2-{4-[2-(1-Benzofuran-3-yl)ethyl]-l-piperazinyl}ethanamine The product is obtained in the form of an oil according to the procedure of Preparation 17 using the product of Preparation 13 as substrate in Step 1.

PREPARATION 44: 2-{4-[2-(4-Fluorophenoxy)ethyl]-l-piperazinyl}ethanamine The product is obtained in the form of a colourless oil according to the procedure of Preparation 17 using the product of Preparation 15 as substrate in Step 1.

-28 PREPARATION 45 5-Methoxy-1H-pyrrolo[2,3-c]pyridine Step 2-Methoxy-4-methyl-5-nitropyridine 22.3 g of 2-hydroxy-4-methyl-5-nitropyridine and 170 ml of POCl 3 are mixed together and heated at 100 0 C for 3 hours. The cooled reaction medium is poured onto ice to yield a beige precipitate of 2-chloro-4-methyl-5-nitropyridine.

Melting point 38-39 0

C

10.95 g of sodium methanolate are added, in portions, to 5 g of the resulting precipitate dissolved in 110 ml of methanol. The reaction is exothermic and, when the addition is complete, the mixture is refluxed for 2 hours. After returning to ambient temperature, the reaction mixture is poured onto a mixture of 200 g of ice and 100 ml of water. The precipitate obtained corresponds to the expected product.

Melting point 80-84°C Step 2 5-Methoxy-lH-pyrrolo[2,3-c]pyridine 10.76 g of N,N-dimethylformamide dimethyl acetal and 2.45 ml of pyrrolidine are added, in succession, to a solution of 5 g of the product obtained in Step 1 in 60 ml of dimethylformamide. The mixture obtained is first heated at 100 0 C for 8 hours and then at 150 0 C for 1 hour. Concentration is carried out under a vacuum of 10' 1 mbar and the residue is taken up in 150 ml of tetrahydrofuran. The solution obtained is hydrogenated under a pressure of 10 bars for 4 hours in the presence of 10 Pd/C. After filtration and concentration, the residue is chromatographed over silica (eluant CH 2 C12/EtOH 95/5) to yield the expected product.

Melting point 126-130°C EXAMPLE 1 1-{1-[2-(Benzofuran-3-yl)ethyl]-4-piperidyl}-3-phenyl-1,3dihydro-2H-imidazol-2-one and its hydrochloride Step 1: 1-{1-[2-(Benzofuran-3-yl)ethyl]-4-piperidyl}-1-(2,2-dimethoxyethyl)-3phenylurea -29- 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-{-[2-(Benzofuran-3-yl)ethylJ-4-piperidyl}-3-phenyl-1,3dihydro-2H-imidazol-2-one and its hydrochloride 67 mmol of the compound obtained in Step 1 are placed in the presence of 20.7 ml of trifluoroacetic acid, 20 ml of water and 132 ml of dichloromethane. After stirring for 12 hours at ambient temperature, the reaction mixture is neutralised using sodium hydroxide; the organic phase is then washed with water, dried, filtered and then evaporated. Chromatography over silica gel allows a product to be isolated, the instantaneous melting point of which is 154 0

C.

The product is converted into its hydrochloride after being dissolved in dichloromethane. It is recrystallised from ethanol.

Melting point 220-225°C Elemental microanalysis: C H N Cl %found 68.15 6.28 9.86 8.36 calculated 68.00 6.18 9.91 8.36 EXAMPLE 2: 1-{1-[3-(Benzofuran-3-yl)propyl]-4-piperidyl}-3-phenyl-1,3dihydro-2H-imidazol-2-one and its hydrochloride The product is obtained as in Example 1 using the compound of Preparation 10 as substrate in Step 1. Its hydrochloride, prepared starting from ethanolic hydrogen chloride solution, is recrystallised from isopropanol.

Melting point 210-214°C Elemental microanalysis C H N Cl %found 68.30 6.36 9.48 8.35 calculated 68.56 6.44 9.59 8.09 EXAMPLE 3 1-1-[3-(Benzofuran-3-yl)propyl]-4-piperidyl}-3-phenyl-2imidazolidinone and its hydrochloride 3.17 mmol of the compound of Example 2 are hydrogenated in acetic acid in the presence of 10 Pd/C at ambient temperature and atmospheric pressure. When the reaction is complete, the catalyst is filtered off and the filtrate is concentrated, taken up in ethyl acetate and sodium hydroxide solution, washed with water, dried and evaporated. The product obtained is converted into its hydrochloride using ethanolic hydrogen chloride.

Melting point 235-240°C Elemental microanalysis: C H N Cl %found 68.15 6.80 9.29 8.18 calculated 68.25 6.87 9.55 8.06 EXAMPLE 4: 1-{1-[2-(Benzofuran-3-yl)ethyl]-4-piperidyl}-3-phenyl-2imidazolidinone and its hydrochloride The product is obtained according to the procedure of Example 3 using the compound of Example 1 as substrate.

Melting point 224-228°C Elemental microanalysis C H N Cl %found 66.99 6.51 9.75 8.45 calculated 67.67 6.63 9.86 8.32 EXAMPLE 5 1-(2-{4-[2-(p-Fluorophenoxy)ethyl]-l-piperidyl}ethyl)-3phenyl-2-imidazolidinone and its hydrochloride -31 7.72 mmol of the product of Preparation 2 and 7.72 mmol of the product of Preparation 23 are dissolved in 70 ml of methyl isobutyl ketone, and then 3.19 g of potassium carbonate are added. After reacting for 12 hours under reflux, the mixture is filtered and then evaporated. The residue is taken up in ethyl acetate and is then washed with ethyl acetate, dried, filtered and concentrated. Chromatography over silica gel (dichloromethane/methanol/ammonium hydroxide 95/5/0.5) allows the expected product to be isolated, which is converted into its hydrochloride using ethanolic hydrogen chloride solution.

Melting point 176-180°C Elemental microanalysis C H N Cl %found 64.27 7.05 9.27 8.28 calculated 64.35 6.97 9.38 7.91 EXAMPLE 6 1-(2-{4-[2-(p-Fluorophenoxy)ethyl]-l-piperidyl}ethyl)-3-(pmethoxyphenyl)-2-imidazolidinone and its hydrochloride The product is obtained according to the procedure of Example 5 using the product of Preparation 24 instead of that of Preparation 23.

Melting point 197-203 0

C

Elemental microanalysis: C H N Cl %found 62.78 7.17 8.82 7.82 calculated 62.82 6.97 8.79 7.42 EXAMPLE 7 1-(2-{4-[2-(p-Fluorophenoxy)ethyl]-l-piperidyl}ethyl)-3-(phydroxyphenyl)-2-imidazolidinone and its hydrochloride The product is obtained according to the procedure of Example 5 using the product of Preparation 25 instead of that of Preparation 23.

Melting point 201-206°C 32 Elemental microanalvsis %found calculated

C

61.82 62.13

*H

6.73 6.73

N

8.94 9.06 Cl 7.65 7.64 EXAMELE8 1-(2-{4-[2-(p-Fluorophenoxy)ethyl]-1-piperidyllethyl)-3-(ochlorophenoxy)-2-imidazolidinone and its hydrochloride The product is obtained according to the procedure of Example 5 using the product of Preparation 26 instead of that of Preparation 23. The product is converted into the hydrochloride by the action of a solution of hydrochloric acid in acetonitrile.

Melting~ point 183-187'C Elemental microanalysis %found calculated

C

59.70 59.75

H

6.23 6.27

N

8.74 8.71 Cl 14.89 14.70 EXAM1!PJU 1-{2-[4-(Phenoxymethyl)-1-piperidyllethyl)-3- (p-hydroxyphenyl)-2-imidazolidinone and its hydrochloride The product is obtained according to the procedure of Example 5 using the compounds of Preparations 3 and 25 as substrates. The product obtained is converted into its hydrochloride by the action of ethereal hydrogen chloride solution.

Melting point 260-263'C Elemental microanalysis found calculated 63.76 63.95

H

7.05 7.00

N

9.46 9.73 Cl 8.23 8.23 EXAM-IL1.: 1-{2-[4-(p-Fluorophenoxymethyl)- 1-piperidy1]ethyl)-3-(pmethoxyphenyl)-2-imiddazolidinone and its hydrochloride The product is obtained according to the procedure of Example 5 using the compounds of -33- Preparations 1 and 24 as substrates. The product obtained is converted into its hydrochloride by the action of ethereal hydrogen chloride solution.

Melting point 287-290°C Elemental microanalysis %found calculated EXAMPLE 11: C H 62.28 6.93 62.13 6.73

N

9.02 9.06 Cl 7.81 7.64 1-(2-{4-[2-(p-Fluorophenoxy)ethyl]-l-piperidyl}ethyl)-3-(pfluorophenyl)-2-imidazolidinone and its hydrochloride The product is obtained according to the procedure of Example 5 using the compounds of Preparations 2 and 27 as substrates. The product obtained is converted into its hydrochloride by the action of ethereal hydrogen chloride solution.

Melting point 174-178°C Elemental microanalysis %found calculated

C

61.62 61.86

H

6.61 6.49

N

8.91 9.02 Cl 7.92 7.61 EXAMPLE 12 1-{2-[4-(p-Fluorophenoxymethyl)-l-piperidyl]ethyl}-3-(pbenzyloxyphenyl)-2-imidazolidinone and its hydrochloride The product is obtained according to the procedure of Example 5 using the compounds of Preparations 1 and 28 as substrates. The product obtained is converted into its hydrochloride by the action of ethereal hydrogen chloride solution.

Melting point 248-252°C Elemental microanalysis %found calculated C H 66.76 6.49 66.72 6.53

N

7.72 7.78 Cl 6.75 6.56 -34- EXAMPLIE-0: 1-{2-[4-(p-Fluorophenoxymethyl)-l-piperidyl]ethyl}-3-(phydroxyphenyl)-2-imidazolidinone and its hydrochloride The product is obtained according to the procedure of Example 5 using the compounds of Preparations 1 and 25 as substrates. The product obtained is converted into its hydrochloride by the action of ethereal hydrogen chloride solution.

Melting point 228-232°C Elemental microanalysis %found calculated EXAMPLE 14 C H 61.38 6.43 61.40 6.50

N

9.40 9.34 Cl 8.01 7.88 1-{2-[4-(p-Methylsulphonylphenoxymethyl)-1-piperidyl]ethyl}-3-(p-hydroxyphenyl)-2-imidazolidinone and its hydrochloride The product is obtained according to the procedure of Example 5 using the compounds of Preparations 4 and 25 as substrates. The product obtained is converted into its hydrochloride by the action of ethereal hydrogen chloride solution.

Melting point 265-270°C Elemental microanalysis %found calculated C H 56.19 6.38 56.52 6.32

N

8.04 8.24 Cl 5.89 6.29 EXAMPLE 15 1-(2-{4-[2-(p-Fluorophenoxy)ethyl]-l-piperidyl}ethyl)-3-(pnitrophenyl)-2-imidazolidinone and its hydrochloride The product is obtained according to the procedure of Example 5 using the compounds of Preparations 2 and 29 as substrates. The product obtained is precipitated in the form of its hydrochloride, which is recrystallised from acetonitrile.

Melting point 202-270 0

C

35 Elemental microanalysis found calculated

C

58.55 58.47

H

6.12 6.13

N

11.34 11.36 Cl 7.19 7.19 EXAh!PLE1L6 1-(2-{4-[2-(p-Fuorophenoxy)ethyl]-1-piperidyllethyl)-3-(pchlorophenyl)-2-imiddazolidinone and its hydrochloride The product is obtained according to the procedure of Example 5 using the compounds of Preparations 2 and 30 as substrates. The product obtained is precipitated in the form of the hydrochloride, which is recrystallised from acetonitrile.

Melting point 180-184'C Elemental microanalysis C H N Cl %found calculated 59.97 59.75 6.23 6.27 8.68 8.71 14.95 14.70 EXAMPLE 1: 1-{2-[4-(p-Fluorophenoxymethyl)-1-piperidyllethyl}-3-(pnitrophenyl)-2-imidazolidinone and its hydrochloride The product is obtained according to the procedure of Example 5 using the compounds of Preparations 1 and 29 as substrates. The product obtained is precipitated in the form of its hydrochloride and is recrystallised from acetonitrile.

Melting point 205-209'C Elemental microanalysis C H N Cl %found calculated 57.83 57.68 5.89 5.89 11.60 11.70 6.87 7.40 EXAMPLAE 18: 1-(2-{4-[2-(p-Methylsulphonylphenoxy)ethyl]-1piperidyl}ethyl)-3-(p-hydroxyphenyl)-2-imidazolidinone and its hydrochloride -36- The product is obtained according to the procedure of Example 5 using the compounds of Preparations 5 and 25 as substrates. The product obtained is converted into its hydrochloride by the action of ethereal hydrogen chloride solution.

Melting point 120-125°C Elemental microanalysis C H N Cl S %found 57.77 6.77 7.81 6.86 5.69 calculated 57.30 6.54 8.02 6.76 6.12 EXAMPLE 19: 1-{1-[2-(Benzofuran-3-yl)ethyl]-4-piperidyl}-3-phenyltetrahydro-2-pyrimidinone and its hydrochloride Step 1-{1-[2-(Benzofuran-3-yl)ethyl]-4-piperidyl}-4-hydroxy-3-phenyltetrahydro-2-pyrimidinone The product is obtained according to the procedure of Example 1, Steps 1 and 2, using the compound of Preparation 11 as substrate in Step 1.

Step2 1-{1-[2-(Benzofuran-3-yl)ethylJ-4-piperidyl}-3-phenyl-tetrahydro-2pyrimidinone and its hydrochloride 14.4 mmol of the compound obtained in the previous Step are hydrogenated at ambient temperature and atmospheric pressure in acetic acid in the presence of 10 Pd/C. After concentration, the residue is taken up in dichloromethane and sodium hydroxide solution.

The organic phase is dried, filtered and then evaporated. The product obtained is converted into its hydrochloride by the action of ethanolic hydrogen chloride solution.

Melting point 255-259 0

C

Elemental microanalysis C H N Cl %found 68.01 6.92 9.70 8.29 calculated 68.25 6.87 9.55 8.06 -37- EXAMPLE 20 1-{1-[3-(Benzofuran-3-yl)propyl]-4-piperidyl}-3-phenyltetrahydro-2-pyrimidinone and its hydrochloride The product is obtained according to the procedure of Example 19 using the compound of Preparation 12 instead of that of Preparation 11 as substrate in Step 1. The product obtained is converted into its hydrochloride.

Melting point 256-260°C Elemental microanalysis C H N Cl %found 68.43 7.18 9.12 7.75 calculated 68.78 7.10 9.26 7.81 EXAMPLE 21 1-(2-{4-[2-(p-Fluorophenoxy)ethyl]-l-piperidyl}ethyl)-3phenyl-1,3-diazepan-2-one and its hydrochloride Step 1-(2-f4-[2-(p-Fluorophenoxy)ethyl]-1-piperidyl}ethyl)-3-phenylurea 11 mmol of the product of Preparation 17 dissolved in 10 ml of dichloromethane are poured onto 15 mmol of phenyl isocyanate dissolved in 6 ml of dichloromethane. After stirring for 16 hours at ambient temperature, the mixture is concentrated under reduced pressure. Chromatography over silica gel (dichloromethane/methanol/ammonium hydroxide 95/5/0.5) allows the expected product to be isolated.

Melting point 140°C Step 2: 1-(2-{4-[2-(p-Fluorophenoxy)ethyl]-1-piperidyl}ethyl)-3-phenyl-1,3diazepan-2-one and its hydrochloride To a solution of 9.7 mmol of the product obtained in Step 1 in 40 ml of dimethylformamide there are added, in portions, 3 equivalents of 60% sodium hydride. They are left in contact until no more gas is evolved; 2 equivalents of 1,4-dibromobutane are added and the mixture is heated at 80 0 C for 4 hours and then left at ambient temperature for 12 hours. After evaporation, the residue is taken up in water and dichloromethane. The organic phase is washed with sodium hydroxide solution and then with water, and is dried, -38filtered and concentrated under reduced pressure. Chromatography over silica gel (dichloromethane/ methanol/ammonium hydroxide 95/5/0.5) allows the expected product to be isolated, which is converted into the hydrochloride, which is crystallised from acetonitrile.

Melting point 170-175°C Elemental microanalysis C H N Cl %found 65.22 7.37 8.74 8.07 calculated 65.60 7.41 8.83 7.45 EXAMPLE 22: 1-({1-[3-(p-Fluorophenoxy)propyl]-4-piperidyl}methyl)-3phenyl-1,3-diazepan-2-one and its hydrochloride The product is obtained according to the procedure of Example 21 using the compound of Preparation 21 instead of that of Preparation 17 as substrate in Step 1. The product obtained is converted into its hydrochloride, which is crystallised from acetonitrile.

Melting point 170-173°C Elemental microanalysis: C H N Cl %found 65.69 7.42 9.01 7.45 calculated 65.60 7.41 8.83 7.45 EXAMPLE 23: 1-{1-[2-(Benzofuran-3-yl)ethyl]-4-piperidyl}-3-phenyl-1,3diazepan-2-one and its hydrochloride The product is obtained according to the procedure of Example 21 using the compound of Preparation 7 instead of that of Preparation 17 as substrate in Step 1. The product obtained is converted into its hydrochloride by the action of ethereal hydrogen chloride solution.

Melting point 232-237°C Elemental microanalysis C H N Cl %found 69.34 7.23 9.18 8.07 calculated 68.78 7.10 9.26 7.81 -39- EXAMPLE 24: N-{1-[2-(p-Fluorophenoxy)ethyl]-4-piperidyl}indolinecarboxamide and its hydrochloride Step Indolin-1-ylcarbonyl chloride 22.5 mmol of diphosgene dissolved in 90 ml of dichloromethane are cooled to 0°C; there are then added 45 mmol of indoline, and then 67.5 mmol of triethylamine, while maintaining the temperature at 0°C. After 12 hours at ambient temperature, the mixture is filtered and the filtrate is concentrated under reduced pressure.

Step2 N-{l-[2-(p-Fluorophenoxy)ethyl]-4-piperidyl}indolinecarboxamide and its hydrochloride 12 mmol of the product obtained in Step 1 are added, in portions, to a solution of 12 mmol of the product of Preparation 22 and 36 mmol of diisopropylethylamine in 210 ml of dichloromethane. After 48 hours at ambient temperature, the mixture is diluted with water, separated, washed with water, dried, filtered and evaporated. Chromatography over silica gel (dichloromethane/ethanol 95/5) allows the expected product to be isolated, which is converted into the hydrochloride in ethanolic hydrogen chloride.

Melting point: 228-235 0

C

Elemental microanalysis C H N Cl %found 61.70 6.36 9.69 9.62 calculated 61.85 6.43 9.84 9.96 EXAMPLE 25 N-{1-[3-(Benzofuran-3-yl)propyl]-4-piperidyl}-l-indolinecarboxamide and its hydrochloride The product is obtained according to the procedure of Example 24 using the compound of Preparation 8 instead of that of Preparation 22 as substrate in Step 2. The product obtained is converted into its hydrochloride.

Melting point 253-257 0

C

Elemental microanalysis %found calculated EXAMPLE 26: C H 68.48 6.78 68.25 6.87

N

9.56 9.55 Cl 8.08 8.06 N-{1-[2-(Benzofuran-3-yl)ethyl]-4-piperidyl}-l-indolinecarboxamide and its hydrochloride The product is obtained according to the procedure of Example 24 using the compound of Preparation 7 instead of that of Preparation 22 as substrate in Step 2. The product obtained is converted into its hydrochloride by the action of ethereal hydrogen chloride solution.

Melting point 261-265°C Elemental microanalysis %found calculated EXAMPLE 27 C H 67.71 6.67 67.67 6.63

N

9.81 9.86 Cl 8.77 8.32 N-{1-[3-(Benzofuran-3-yl)propyl]-4-piperidyl}-1,2,3,4tetrahydro-1-quinolinecarboxamide and its hydrochloride The product is obtained according to the procedure of Example 24 using 1,2,3,4-tetrahydroquinoline as substrate in Step 1 and, in Step 2, the product of Preparation 8 instead of that of Preparation 22. The product obtained is converted into its hydrochloride, which is recrystallised from ethanol.

Melting point 227-231 0

C

Elemental microanalysis %found calculated

C

69.13 68.78

H

7.13 7.10

N

9.26 9.26 Cl 7.79 7.81 EXAMPL.A N-{1-[2-(Benzofuran-3-yl)ethyl]-4-piperidyl}-l,2,3,4tetrahydro-1-quinolinecarboxamide and its hydrochloride -41- The product is obtained according to the procedure of Example 27 using the compound of Preparation 7 instead of that of Preparation 8 as substrate in Step 2. The product obtained is converted into its hydrochloride, which is recrystallised from ethanol.

Melting point 215-219 0

C

Elemental microanalysis C H N Cl %found 68.27 6.85 9.44 8.26 calculated 68.25 6.87 9.05 8.06 EXAMPLE 29: 4-[2-(Benzofuran-3-yl)ethyl]-l-piperazinyl}-(2,3-dihydro-1Hindol-l-yl)methanone and its hydrochloride The product is obtained according to the procedure of Example 24 using the compound of Preparation 13 instead of that of Preparation 22 as substrate in Step 2. The product obtained is converted into its hydrochloride by the action of ethereal hydrogen chloride solution.

Melting point 284-287°C Elemental microanalysis: C H N Cl %found 67.27 6.51 10.21 8.43 calculated 67.06 6.36 10.20 8.61 EXAMPLE 30: {4-[3-(Benzofuran-3-yl)propyl]-l-piperazinyl}-(2,3-dihydro-1Hindol-1-yl)methanone and its hydrochloride The product is obtained according to the procedure of Example 24 using the compound of Preparation 14 instead of that of Preparation 22 as substrate in Step 2. The product obtained is converted into its hydrochloride and is recrystallised from acetonitrile.

Melting point 215-219°C Elemental microanalysis C H N Cl %found 67.69 6.62 9.89 7.69 calculated 67.67 6.63 9.86 8.32 -42- EXAMPLE 31: {1-[2-(p-Fluorophenoxy)ethyl]-4-piperazinyl}-(2,3-dihydro-1Hindol-l-yl)methanone and its dihydrochloride The product is obtained according to the procedure of Example 24 using the compound of Preparation 15 instead of that of Preparation 22 as substrate in Step 2. The product obtained is converted into its hydrochloride and is recrystallised from acetonitrile.

Melting point 233-236°C Elemental microanalysis C H N Cl %found 62.48 6.26 10.30 8.85 calculated 62.14 6.21 10.35 8.73 EXAMPLE 32: {1-[3-(p-Fluorophenoxy)propyl]-4-piperazinyl}-(2,3-dihydro- 1H-indol-l-yl)methanone and its hydrochloride The product is obtained according to the procedure of Example 24 using the compound of Preparation 16 instead of that of Preparation 22 as substrate in Step 2. The product obtained is converted into its hydrochloride, which is recrystallised from acetonitrile.

Melting point 250-254°C Elemental microanalysis C H N Cl %found 62.90 6.47 10.00 8.56 calculated 62.93 6.48 10.01 8.44 EXAMPLE 33 N-(2-{4-[2-(p-Fluorophenoxy)ethyl]-l-piperidyl}ethyl)-lindolinecarboxamide and its hydrochloride The product is obtained according to the procedure of Example 24 using the compound of Preparation 17 instead of that of Preparation 22 as substrate in Step 2. The product obtained is converted into its hydrochloride.

Melting point 92-95°C 43 Elemental microanalysis %found calculated EXAM1ELE314: C H 64.16 7.36 64.35 6.97

N

9.18 9.38 Cl 8.15 7.91 [4-(p-Fluorophenoxymethyl)-1-piperidyllethyl}-1indolinecarboxamide and its hydrochloride The product is obtained according to the procedure of Example 24 using the compound of Preparation 18 instead of that of Preparation 22 as substrate in Step 2. The product obtained is converted into its hydrochloride, which is recrystallised from acetonitrile.

Melting point 143-145'C Elemental microanalysis %found calculated

C

63.30 63.66

H

6.89 6.74

N

9.63 9.68 Cl 8.37 8.17 EXABMPLEM. N-{2-[4-(Phenoxymethyl)-1-piperidyllethyl}-1-indolinecarboxamide and its hydrochloride The product is obtained according to the procedure of Example 24 using the compound of Preparation 19 instead of that of Preparation 22 as substrate in Step 2. The product obtained is converted into its hydrochloride, which is recrystallised from acetonitrile.

Melting point 205-210'C Elemental microanalysis %found calculated 65.93 66.41

H

7.29 7.27

N

9.97 10.10 Cl 8.87 8.52 EXAMPI-M N-{2-14-(p-Methylsulphonylphenoxymethyl)-1-piperidyl]ethyl}-1-indolinecarboxamide and its hydrochloride -44- The product is obtained according to the procedure of Example 24 using the compound of Preparation 6 instead of that of Preparation 22 as substrate in Step 2. The product obtained is converted into its hydrochloride, which is recrystallised from acetonitrile.

Melting point 199-203°C Elemental microanalysis C H N Cl S %found 58.54 6.64 8.56 7.25 6.32 calculated 58.35 6.53 8.51 7.18 6.49 EXAMPLE 37 N-(2-{4-[(2-(Phenoxy)ethyl]-1-piperidyl}ethyl)-1-indolinecarboxamide and its hydrochloride The product is obtained according to the procedure of Example 24 using the compound of Preparation 20 instead of that of Preparation 22 as substrate in Step 2. The product obtained is converted into its hydrochloride in ethanolic hydrogen chloride.

Melting point 83-87 0

C

Elemental microanalysis: C H N Cl %found 67.69 7.96 9.82 8.03 calculated 67.04 7.50 9.77 8.25 EXAMPLE 38 N-{1-[2-(Benzofuran-3-yl)ethyl]-4-piperidyl}-l-indolecarboxamide and its hydrochloride Step 1 (Imidazol-l-yl-indol-l-yl)methanone mmol of carbonyldiimidazole and 0.24 g of 4-dimethylaminopyridine are added, in succession, to a solution of 85.4 mmol of indole in 305 ml of acetonitrile. After refluxing for 8 hours, the mixture is concentrated. The residue is taken up in a minimum of ether.

After filtration, the expected product is obtained.

Step2 N-{1-[2-(Benzofuran-3-yl)ethyl]-4-piperidyl}-l-indolecarboxamide and its hydrochloride A solution of the product obtained in Step 1 and of the product of Preparation 7 in 25 ml of acetonitrile is heated at reflux for 12 hours. After cooling, the precipitate that forms is filtered off. The filtrate is concentrated, taken up in ethyl acetate and washed with water.

The organic phase is dried, filtered and then concentrated under reduced pressure.

Chromatography over silica gel (dichloromethane/ethanol 95/5) allows the expected product to be isolated, which is converted into the hydrochloride using ethanolic hydrogen chloride solution.

Melting point 275-280 0

C

Elemental microanalysis: C H N Cl %found 67.96 6.14 9.82 8.34 calculated 68.00 6.18 9.91 8.36 EXAMPLE 39: N-{2-[4-(p-Fluorophenoxymethyl)-l-piperidyl]ethyl}-lindolecarboxamide and its hydrochloride The product is obtained according to the procedure of Example 38 using the compound of Preparation 18 instead of that of Preparation 7 as substrate in Step 2. The product obtained is converted into its hydrochloride by the action of ethereal hydrogen chloride solution.

Melting point 206-210°C Elemental microanalysis: C H N Cl %found 63.82 6.39 9.50 8.57 calculated 63.96 6.30 9.73 8.21 EXAMPLE 40: N-(2-{4-[2-(p-Fluorophenoxy)ethyl]-l-piperidyl}ethyl)-lindolecarboxamide and its hydrochloride The product is obtained according to the procedure of Example 38 using the compound of Preparation 17 instead of that of Preparation 7 as substrate in Step 2. The product obtained is converted into its hydrochloride by the action of ethanolic hydrogen chloride solution.

Melting point 214-218°C -46 Elemental microanalysis %found calculated EXAMPLEA C H 64.60 6.55 64.64 6.55

N

9.38 9.42 Cl 7.99 7.95 N-{2-[4-(Phenoxymethyl)-1-piperidyllethyl}-1-indolecarboxamide and its hydrochloride The product is obtained according to the procedure of Example 38 using the compound of Preparation 19 instead of that of Preparation 7 as substrate in Step 2. The product obtained is converted into its hydrochloride.

Melting point 171-174'C Elemental microanalysis C H N Cl %found calculated 66.41 66.74 6.88 6.82 10.01 10.15 8.85 8.56 N-{24[4-(Phenoxymethyl)-1-piperidyll-ethyl}-5,6-dimethoxy- 1-indolecarboxamide and its hydrochloride The product is obtained according to the procedure of Example 38 using 5,6-dimethoxyindole instead of indole in Step 1 and the product of Preparation 19 instead of that of Preparation 7 in Step 2. The product obtained is converted into its hydrochloride, which is crystallised from acetonitrile.

MelfinL point :204-208 0

C

EXAMPLEAn: N-(2-{4-[2-(p-Fluorophenoxy)ethyl]-1-piperidyl}ethyl)-5hydroxy-1-indolecarboxamide and its hydrochloride Step 1: (5-JBenzyloxyindol-1-yl-imidazol-1-yl)-methanone The product is obtained according to the procedure of Example 38, Step 1, using -47oxyindole instead of indole.

tep 2: N-(2-{4-[2-(p-Fluorophenoxy)ethyl]-1-piperidylethyl)--benyloxy-1indolecarboxamide The product is obtained according to the procedure of Step 2 of Example 38 using the product of Preparation 17.

tep 3: N-(2-(4-[2-(p-Fluorophenoxy)ethyl]-1-piperidylethyl)-5-hydroxy-1indolecarboxamide and its hydrochloride 3.87 mmol of the product obtained in Step 2 in 150 ml of methanol are hydrogenated in the presence of 0.4 g of 10 Pd/C. After 4 hours at ambient temperature and atmospheric pressure, the mixture is concentrated under reduced pressure. Chromatography over silica gel (dichloromethane/ethanol 95/5) allows the expected product to be isolated. The product is converted, by the action of ethereal hydrogen chloride solution, into its hydrochloride, which is crystallised from acetonitrile.

Melting point 237-241 0

C

EXAMPLE 44: N-(2-{4-[2-(p-Fluorophenoxy)ethyl]-1-piperidyl}ethyl)-5hydroxy-1-indolinecarboxamide and its hydrochloride The product is obtained according to the procedure of Example 43 using oxyindoline as substrate in Step 1. The product obtained is converted into its hydrochloride by the action of ethereal hydrogen chloride solution.

Melting point 193-196 0

C

EXAMPLE 45 N-{2-[4-(Phenoxymethyl)-1-piperidyllethyl}-5-fluoro-1indolecarboxamide and its hydrochloride Step I Bis(5-fluoroindol-1-yl)methanone -48- 78.4 mmol of carbonyldiimidazole and 0.2 g of 4-dimethylaminopyridine are added to a solution of 74 mmol of 5-fluoroindole in 300 ml of acetonitrile. After refluxing for 8 hours, and then concentrating, the residue is taken up in a minimum of ether. The solidified product, which corresponds to the expected product, is filtered off.

Step 2: N-{2-[4-(Phenoxymethyl)-l-piperidyl]ethyl}-5-fluoro-l-indolecarboxamide and its hydrochloride The product is obtained according to the procedure of Example 38 using, as substrate, the product obtained in Step 1 and the compound of Preparation 19 instead of that of Preparation 17. The product obtained is converted into its hydrochloride by the action of ethereal hydrogen chloride and is crystallised from acetonitrile.

Melting point 228-234°C Elemental microanalysis C H N Cl %found 64.04 6.32 9.71 7.88 calculated 63.96 6.30 9.73 8.21 EXAMPLE 46: N-(2-{4-[2-(p-Fluorophenoxy)ethyl]-1-piperidyl}ethyl)-5fluoro-1-indolecarboxamide and its hydrochloride The product is obtained according to the procedure of Example 45 using the compound of Preparation 17 instead of that of Preparation 19 as substrate in Step 2. The product obtained is converted into its hydrochloride by the action of ethereal hydrogen chloride and is crystallised from isopropanol.

Melting point 205-209°C Elemental microanalysis C H N Cl %found 62.12 6.17 8.93 7.39 calculated 62.13 6.08 9.06 7.64 -49- EXAMPLE 47 N-{2-[4-(p-Fluorophenoxymethyl)-l-piperidyl]ethyl}-lindolinesulphonamide and its hydrochloride Step 3-(2,3-Dihydroindol-1-ylsulphonyl)-1,3-oxazolidin-2-one 7.1 ml of 2-bromoethanol in 50 ml of dichloromethane are added to a solution of 8.72 ml of chlorosulphonyl isocyanate in 40 ml of dichloromethane. The resulting solution is then added, at 0°C, to a solution of 11.23 ml of indoline and 15.46 ml of triethylamine in 200 ml of dichloromethane. After stirring for 24 hours at ambient temperature, hydrochloric acid is added. The organic phase is then washed with hydrochloric acid and then with water, and is dried, filtered and concentrated, allowing the expected product to be obtained.

Step 2: N-(2-Hydroxyethyl)-l-indolinesulphonamide The product of Step 1 is dissolved in a solution of 3.2 g of sodium hydroxide in 80 ml of ethanol. After stirring for 48 hours at ambient temperature, the mixture is filtered. The filtrate is concentrated under reduced pressure, taken up in dichloromethane and washed with water. After drying and filtration, the organic phase is concentrated under reduced pressure, allowing the expected product to be obtained.

Step 3: N-(2-Bromoethyl)-1-indolinesulphonamide g of the product previously obtained are refluxed for 12 hours in the presence of a mixture of 4.54 g of triphenylphosphine, 5.72 g of carbon tetrabromide and 73.5 ml of ethyl ether. The reaction mixture is then concentrated under reduced pressure and chromatography over silica gel (dichloromethane/ethyl acetate 95/5) allows the expected product to be isolated.

Step 4: N-{2-[4-(p-Fluorophenoxymethyl)-l-piperidyl]ethyl}-l-indolinesulphonamide and its hydrochloride A solution containing 1.5 g of the product previously obtained, 1.2 g of the product of Preparation 1, 1.5 g of sodium carbonate and 20 ml of acetone is refluxed for 12 hours and then concentrated. The residue is taken up in dichloromethane and washed with water; the organic phase is then dried, filtered and evaporated. Chromatography over silica gel (dichloromethane/ethanol 98/2) allows the expected product to be isolated, which is converted into its hydrochloride by the action of ethereal hydrogen chloride solution.

Melting point 151-155°C Elemental microanalysis: C H N Cl S %found 56.12 6.22 8.72 7.77 6.67 calculated 56.22 6.22 8.94 7.54 6.82 EXAMPLE 48: N-(2-{4-[2-(p-Fluorophenoxy)ethyl]-l-piperidyl}ethyl)-lindolinesulphonamide and its hydrochloride The product is obtained according to the procedure of Example 47 using the compound of Preparation 2 instead of that of Preparation 1 as substrate in Step 4. The product obtained is converted into its hydrochloride.

Melting point 137-141°C Elemental microanalysis C H N Cl S %found 56.43 6.54 8.44 7.22 6.28 calculated 57.07 6.46 8.68 7.32 6.62 EXAMPLE 49 1-(4-Fluorophenyl)-3-{2-[4-(phenoxymethyl)-l-piperidyl]ethyl}-2-imidazolidinone and its hydrochloride The product is obtained according to the procedure of Example 5 using the compounds of Preparations 3 and 27 as substrates. The product is converted into its hydrochloride by the action of ethereal hydrogen chloride solution.

Melting point 239-243°C Elemental microanalysis C H N Cl %found 63.75 6.79 9.57 8.37 calculated 63.65 6.74 9.69 8.17 51 EXAMLE9. 1-(2-{4-[2-(4-Chlorophenoxy)ethylll1-piperidyllethyl)-3-(4fluorophenyl)-2-imidazolidinone and its hydrochloride The product is obtained according to the procedure of Example 5 using the compounds of Preparations 31 and 27 as substrates. The product is converted into its hydrochloride by the action of ethereal hydrogen chloride solution.

Melting point :189-193'C Elemental microanalvsis: %found calculated

C

59.31 59.75

H

6.12 6.27

N

8.61 8.71 Cl 14.74 14.70 EXAMPIEM :1 1-(4-Fluorophenyl)-3-[2-(4-{ [4-(methylthio)phenoxy]methyl}-1-piperidyl)ethyl]-2-imidazolidinone and its hydrochloride The product is obtained according to the procedure of Example 5 using the compounds of Preparations 32 and 27 as substrates. The product is converted into its hydrochloride by the action of ethereal hydrogen chloride solution.

MeltinR point (M.K.):240-245 0

C

Elemental microanalysis %found calculated

C

60.07 60.05

H

6.64 6.51

N

8.62 8.75 Cl 7.71 7.39

S

6.72 6.68 EXAMPUE52. 1-(4-Fluorophenyl)-3-[2-(4-{2-[4-(methylthio)phenoxyethyl)-1I-piperidyl)ethyl] -2-imidazolidinone and its hydrochloride The product is obtained according to the procedure of Example 5 using the compounds of Preparations 33 and 27 as substrates. The product is converted into its hydrochloride by the 52 action of ethereal hydrogen chloride solution.

Melting! point 218-223'C Elemental microanalysis %found calculated

C

61.28 60.77

H

6.88 6.73

N

8.62 8.51 Cl 7.31 7.18

S

6.06 6.49 EXAMOEU. 1-(4-Chlorophenyl)-3-{2-[4-(phenoxymethyl)-l1-piperidyl]ethyl}-2-imidazolidinone and its hydrochloride The product is obtained according to the procedure of Example 5 using the compounds of Preparations 3 and 30 as substrates. The product is converted into its hydrochloride by the action of ethereal hydrogen chloride solution.

Melting! point 277-282'C Elemental microanalysis %found calculated

EXAMPLEMA:

27 H 51.67 6.34 51.33 6.49

N

9.33 9.33 Cl 15.94 15.74 1-(4-Chlorophenyl)-3-{2-[4-(2-phenoxyethyl)-1-piperidyl]ethyl}-2-imidazolidinone and its hydrochloride The product is obtained according to the procedure of Example 5 using the compounds of Preparations 34 and 30 as substrates. The product is converted into its hydrochloride by the action of ethereal hydrogen chloride solution.

Melting point 215-219'C Elemental microanalysis %found calculated C H 62.07 6.73 62.07 6.68

N

8.98 9.05 Cl 15.47 15.27 1-(2-{4-[2-(4-Chlorophenoxy)ethyl]-1-piperidyl}ethyl)-3-(4chlorophenyl)-2-imidazolidinone and its hydrochloride -53- The product is obtained according to the procedure of Example 5 using the compounds of Preparations 31 and 30 as substrates. The product is converted into its hydrochloride by the action of ethereal hydrogen chloride solution.

Melting point 200-205 0

C

Elemental microanalysis: %found calculated EXAMPLE 56 C H 57.97 5.94 57.78 6.06

N

8.45 8.42 Cl 21.52 21.32 1-(4-Chlorophenyl)-3-(2-{4-[(4-fluorophenoxy)methyl]-lpiperidyl}ethyl)-2-imidazolidinone and its hydrochloride The product is obtained according to the procedure of Example 5 using the compounds of Preparations 1 and 30 as substrates. The product is converted into its hydrochloride by the action of ethereal hydrogen chloride solution.

Melting point 218-222°C Elemental microanalysis %found calculated EXAMPLE 57 C H 58.91 5.97 58.97 6.03

N

8.82 8.97 Cl 15.37 15.14 1-(4-Chlorophenyl)-3-[2-(4-{[4-(methylthio)phenoxy]methyl}-l-piperidyl)ethyl]-2-imidazolidinone and its hydrochloride The product is obtained according to the procedure of Example 5 using the compounds of Preparations 32 and 30 as substrates. The product is converted into its hydrochloride by the action of ethereal hydrogen chloride solution.

Melting point 288-292°C Elemental microanalysis %found calculated C H 58.26 6.40 58.06 6.29

N

8.41 8.46 Cl 14.38 14.28

S

6.69 6.46 -54- EXAMrLE M: 1-(4-Nitrophenyl)-3-{2-[4-(phenoxymethyl)-l-piperidyl]ethyl}-2-imidazolidinone and its hydrochloride The product is obtained according to the procedure of Example 5 using the compounds of Preparations 3 and 29 as substrates. The product is converted into its hydrochloride by the action of ethereal hydrogen chloride solution.

Melting point 216-220°C Elemental microanalysis %found calculated EXAMPLE 59 C H 59.51 6.36 59.93 6.34

N

11.98 12.15 Cl 7.82 7.69 [4-(Methylthio)phenoxy]methyl}-l-piperidyl)ethyl]-3-(4-nitrophenyl)-2-imidazolidinone and its hydrochloride The product is obtained according to the procedure of Example 5 using the compounds of Preparations 32 and 29 as substrates. The product is converted into its hydrochloride by the action of ethereal hydrogen chloride solution.

Melting point 243-247°C Elemental microanalysis %found calculated C H 56.57 6.09 56.85 6.16

N

10.83 11.05 Cl 6.91 6.99

S

5.99 6.32 EXAMPLE 60 1-(2-{4-[2-(4-Chlorophenoxy)ethyl]-l-piperidyl}ethyl)-3-(4nitrophenyl)-2-imidazolidinone and its hydrochloride The product is obtained according to the procedure of Example 5 using the compounds of Preparations 31 and 29 as substrates. The product is converted into its hydrochloride by the action of ethereal hydrogen chloride solution.

Melting point 196-201°

C

55 Elemental microanalysis %found calculated

C

57.02 56.59

H

5.88 5.94

N

10.91 11.00 Cl 14.26 13.92 EXAMPLER 1-(4-Hydroxyphenyl)-3-[2-(4-{ [4-(methylthio)phenoxy]methyl}-1-piperidyl)ethyl]-2-imidazolidinone and its hydrochloride The product is obtained according to the procedure of Example 5 using the compounds of Preparations 32 and 25 as substrates. The product is converted into its hydrochloride by the action of ethereal hydrogen chloride solution.

Meltin2 point (M.K.):273-277 0

C

Elemental microanalysis %found calculated 60.07 60.30

H

6.72 6.75

N

8.78 8.79 Cl 7.09 7.42

S

6.34 6.71 EXABIPLE,6. 1-{2-14-(Phenoxymethyl)-1-piperidyl]ethyl}-3- [4-(trifluoromethyl)phenyll-2-imidazolidinone and its hydrochloride The product is obtained according to the procedure of Example 5 using the compounds of Preparations 3 and 35 as substrates. The product is converted into its hydrochloride by the action of ethereal hydrogen chloride solution.

Melting point 224-228'C Elemental microanalysis %found calculated

EXAMPLL-:

C H 59.70 6.12 59.56 6.04

N

8.66 8.68 Cl 7.46 7.33 4-(2-Oxo-3-{ 2- (phenoxymethyl)- 1-piperidyll ethyl}-1 imidazolidinyl)benzonitrile and its hydrochloride -56- The product is obtained according to the procedure of Example 5 using the compounds of Preparations 3 and 36 as substrates. The product is converted into its hydrochloride by the action of ethereal hydrogen chloride solution.

Melting point 210-215°C Elemental microanalysis C H N Cl %found 64.82 6.63 12.23 7.74 calculated 65.37 6.63 12.71 8.04 EXAMPLE 64 1-(4-Fluoro-3-nitrophenyl)-3-(2-{4-[2-(4-fluorophenoxy)ethyl]- 1-piperidyl}ethyl)-1,3-dihydro-2H-imidazol-2-one and its hydrochloride The product is obtained according to the procedure of Example 1, Steps 1 and 2, using the compound of Preparation 37 and 4-fluoro-3-nitrophenyl isocyanate as substrates. The product is converted into its hydrochloride by the action of ethereal hydrogen chloride solution.

Melting point 205-209°C Elemental microanalysis: C H N Cl %found 56.58 5.23 10.95 7.06 calculated 56.64 5.35 11.01 6.97 EXAMPLE 65 1-[2-(1,1-Dioxo-5-phenyl-1,2,5-thiadiazolidin-2-yl)ethyl]-4- (phenoxymethyl)piperidine and its hydrochloride The product is obtained according to the procedure of Example 5 using the compounds of Preparations 3 and 38 as substrates. The product is converted into its hydrochloride by the action of ethereal hydrogen chloride solution.

Melting point 198-202°C 57 Elemental microanalysis found calculated

C

59.01 58.46

H

6.81 6.69

N

9.37 9.30 Cl 8.19 7.84

S

7.06 7.09 EXAMPLfi. 1-{2-[5-(4-Chlorophenyl)-1,1-dioxo-1,2,5-thiadiazolidin-2-yl]ethyl}-4-(phenoxymethyl)piperidine and its hydrochloride The product is obtained according to the procedure of Example 5 using the compounds of Preparations 3 and 39 as substrates. The product is converted into its hydrochloride by the action of ethereal hydrogen chloride solution.

Meltingi point 189-194"C Elemental microanalysis %found calculated EXAMPLE6Z: C H 54.27 5.94 54.32 6.01

N

8.47 8.64 Cl 15.12 14.58

S

6.49 6.59 1-{2-[5-(4-Fluorophenyl)-1,1-dioxo-1,2,5-thiadiazolidin-2-y]ethyl}-4-(phenoxymethyl)piperidine and its hydrochloride The product is obtained according to the procedure of Example 5 using the compounds of Preparations 3 and 40 as substrates. The product is converted into its hydrochloride by the action of ethereal hydrogen chloride solution.

Melting point 195-200'C Elemental microanalysis %found calculated EXAMIL-iB C H 56.57 6.25 56.22 6.22

N

9.02 8.94 Cl 7.51 7.54

S

6.73 6.82 1-{2-[5-(4-Chlorophenyl)-1,1-dioxo-1,2,5-thiadiazolidin-2-yl]ethyl}-4-[2-(4-fluorophenoxy)ethyllpiperidine and its hydrochloride -58- The product is obtained according to the procedure of Example 5 using the compounds of Preparations 2 and 39 as substrates. The product is converted into its hydrochloride by the action of ethereal hydrogen chloride solution.

Melting point 195-199°C Elemental microanalysis: C H N Cl S %found 53.34 5.91 8.12 13.76 6.28 calculated 53.28 5.83 8.10 13.68 6.18 EXAMPLE 69: 6-Fluoro-N-(2-{4-[(4-fluorophenoxy)methyl]-lpiperidyl}ethyl)-1H-indole-l-carboxamide and its hydrochloride The product is obtained according to the procedure of Example 45, Steps 1 and 2, using, as substrate in Step 1, 6-fluoroindole instead of 5-fluoroindole and, in Step 2, the compound of Preparation 18. The product is converted into its hydrochloride by the action of ethereal hydrogen chloride solution.

Melting point 180-184°C Elemental microanalysis C H N Cl %found 61.27 5.77 9.34 8.23 calculated 61.40 5.82 9.34 7.88 EXAMPLE 70: 6-Fluoro-N-(2-{4-[2-(4-fluorophenoxy)ethyl]-l-piperidyl}ethyl)-1H-indole-l-carboxamide and its hydrochloride The product is obtained according to the procedure of Example 45, Steps 1 and 2, using, as substrate in Step 1, 6-fluoroindole instead of 5-fluoroindole and, in Step 2, the compound of Preparation 17. The product is converted into its hydrochloride by the action of ethereal hydrogen chloride solution.

Melting point 185-190°C 59 Elemental microanalysis %found calculated EXAMPl C H 61.99 6.08 62.13 6.08

N

9.01 9.06 Cl 7.75 7.64 6-Chloro-N-{2-[4-(phenoxymethyl)-1-piperidyllethyl}-1Hindole-1-carboxamide and its hydrochloride The product is obtained according to the procedure of Example 45, Steps 1 and 2, using, as substrate in Step 1, 6-chioroindole instead of 5-fluoroindole and, in Step 2, the compound of Preparation 19. The product is converted into its hydrochloride by the action of ethereal hydrogen chloride solution.

Melting point 211-215*C Elemental microanalvsis %found calculated

C

61.72 61.61

H

6.13 6.07

N

9.39 9.37 Cl 15.91 15.81 EXAhMPLE: 6-Chloro-N-(2-{4-[2-(4-fluorophenoxy)ethyl]-1-piperidyl}ethyl)- 1H-indole- 1-carboxamide and its hydrochloride The product is obtained according to the procedure of Example 45, Steps 1 and 2, using, as substrate in Step 1, 6-chioroindole instead of 5-fluoroindole and, in Step 2, the compound of Preparation 17. The product is converted into its hydrochloride by the action of ethereal hydrogen chloride solution.

Melting~ point 1 76-180'C Elemental microanalvsis %found calculated

C

60.36 60.00

H

5.99 5.87

N

8.61 8.75 Cl 14.98 14.76 EXAMPLJE2U: 5-Chloro-N-{12- (phenoxymethyl)- 1-piperidyll ethyl}- 1Hindole-1-carboxamide and its hydrochloride The product is obtained according to the procedure of Example 45, Steps 1 and 2, using, as substrate in Step 1, 5-chloroindole instead of 5-fluoroindole and, in Step 2, the compound of Preparation 19. The product is converted into its hydrochloride by the action of ethereal hydrogen chloride solution.

Melting point 187-190°C Elemental microanalysis: C H N Cl %found 61.82 6.12 9.35 15.54 calculated 61.61 6.07 9.37 15.81 EXAMPLE 74 6-Methoxy-N-{2-[4-(phenoxymethyl)-l-piperidyl]ethyl}-lHindole-1-carboxamide and its hydrochloride The product is obtained according to the procedure of Example 38, Steps 1 and 2, using, as substrate in Step 1, 6-methoxyindole and, in Step 2, the compound of Preparation 19. The product is converted into its hydrochloride by the action of ethereal hydrogen chloride solution.

Melting point 201-207 0

C

Elemental microanalysis C H N Cl %found 64.96 6.87 9.33 8.19 calculated 64.93 6.81 9.46 7.99 EXAMPLE 75 5-Methoxy-N-{2-[4-(phenoxymethyl)-l-piperidyl]ethyl}-1Hindole-1-carboxamide and its hydrochloride The product is obtained according to the procedure of Example 38, Steps 1 and 2, using, as substrate in Step 1, 5-methoxyindole and, in Step 2, the compound of Preparation 19. The product is converted into its hydrochloride by the action of ethereal hydrogen chloride solution.

Melting point 178-182°C -61- Elemental microanalysis C H N Cl %found 65.12 7.00 9.48 8.02 calculated 64.93 6.81 9.46 7.99 EXAMPLE 76: N-(2-{4-[(4-Fluorophenoxy)methyl]-l-piperidyl}ethyl)-5methoxy-1H-indole-1-carboxamide and its hydrochloride The product is obtained according to the procedure of Example 38, Steps 1 and 2, using, as substrate in Step 1, 5-methoxyindole and, in Step 2, the compound of Preparation 18. The product is converted into its hydrochloride by the action of ethereal hydrogen chloride solution.

Melting point 186-191 C Elemental microanalysis C H N Cl %found 62.38 6.41 8.90 8.10 calculated 62.40 6.33 9.10 7.67 EXAMPLE 77: N-(2-{4-[2-(4-Fluorophenoxy)ethyl]-l-piperidyl}ethyl)-5methoxy-1H-indole-1-carboxamide and its hydrochloride The product is obtained according to the procedure of Example 38, Steps 1 and 2, using, as substrate in Step 1, 5-methoxyindole and, in Step 2, the compound of Preparation 17. The product is converted into its hydrochloride by the action of ethereal hydrogen chloride solution.

Melting point 203-207°C Elemental microanalysis C H N Cl %found 63.02 6.46 8.78 7.43 calculated 63.08 6.56 8.83 7.45 EXAMPLE 78 5-Hydroxy-N-{2-[4-(phenoxymethyl)-l-piperidyl]ethyl}-lHindole-1-carboxamide and its hydrochloride -62- The product is obtained according to the procedure of Example 43, Steps 1 to 3, using the compound of Preparation 19 as substrate in Step 2. The product is converted into its hydrochloride by the action of ethereal hydrogen chloride solution.

Melting point 210-214 0

C

Elemental microanalysis C H N Cl %found 64.42 6.73 9.86 8.54 calculated 64.25 6.56 9.77 8.25 EXAMPLE 79: 5-Chloro-N-{2-[4-(phenoxymethyl)-1-piperidyl]ethyl}-lindolinecarboxamide and its hydrochloride The product is obtained according to the procedure of Example 24, Steps 1 and 2, using, as substrate in Step 1, 5-chloroindoline and, in Step 2, the compound of Preparation 19. The product is converted into its hydrochloride by the action of ethereal hydrogen chloride solution.

Melting point 128-132 0

C

Elemental microanalysis C H N Cl %found 61.16 6.53 9.25 7.44 calculated 61.33 6.49 9.33 7.87 EXAMPLE 80: 6-Chloro-N-(2-{4-[2-(4-fluorophenoxy)ethyl]-l-piperidyl}ethyl)-l-indolinecarboxamide and its hydrochloride The product is obtained according to the procedure of Example 24, Steps 1 and 2, using, as substrate in Step 1, 6-chloroindoline and, in Step 2, the compound of Preparation 17. The product is converted into its hydrochloride by the action of ethereal hydrogen chloride solution.

Melting point 153-156°C -63- Elemental microanalysis C H N Cl %found 59.38 6.31 8.66 14.57 calculated 59.75 6.27 8.71 14.70 EXAMPLE 81: 5-Fluoro-N-(2-{4-[2-(4-fluorophenoxy)ethyl]-l-piperidyl}ethyl)-l-indolinecarboxamide and its hydrochloride The product is obtained according to the procedure of Example 24, Steps 1 and 2, using, as substrate in Step 1, 5-fluoroindoline and, in Step 2, the compound of Preparation 17. The product is converted into its hydrochloride by the action of ethereal hydrogen chloride solution.

Melting point 185-189 0

C

Elemental microanalysis C H N Cl %found 62.19 6.71 8.83 7.86 calculated 61.86 6.49 9.02 7.61 EXAMPLE 82 6-Fluoro-N-{2-[4-(phenoxymethyl)-l-piperidyl]ethyl}-lindolinecarboxamide and its hydrochloride The product is obtained according to the procedure of Example 24, Steps 1 and 2, using, as substrate in Step 1, 6-fluoroindoline and, in Step 2, the compound of Preparation 19. The product is converted into its hydrochloride by the action of ethereal hydrogen chloride solution.

Melting point 168-172°C Elemental microanalysis C H N Cl %found 63.34 6.73 9.55 8.80 calculated 63.66 6.74 9.68 8.17 EXAMPLE 83 5-Fluoro-N-{2-[4-(phenoxymethyl)-l-piperidyl]ethyl}-1indolinecarboxamide and its hydrochloride -64- The product is obtained according to the procedure of Example 24, Steps 1 and 2, using, as substrate in Step 1, 5-fluoroindoline and, in Step 2, the compound of Preparation 19. The product is converted into its hydrochloride by the action of ethereal hydrogen chloride solution.

Melting point 168-171 C Elemental microanalysis: C H N Cl %found 63.65 6.98 9.58 7.99 calculated 63.66 6.74 9.68 8.17 EXAMPLE 84: 5-Methoxy-N-{2-[4-(phenoxymethyl)-l-piperidyl]ethyl}-lindolinecarboxamide and its hydrochloride The product is obtained according to the procedure of Example 24, Steps 1 and 2, using, as substrate in Step 1, 5-methoxyindoline and, in Step 2, the compound of Preparation 19.

The product is converted into its hydrochloride by the action of ethereal hydrogen chloride solution.

Melting point 193-196 0

C

Elemental microanalysis C H N Cl %found 64.55 7.00 9.30 8.46 calculated 64.64 7.29 9.42 7.95 EXAMPLE 85 5-Methoxy-N-[2-(4-{[4-(methylthio)phenoxy]methyl}-lpiperidyl)ethyl]-l-indolinecarboxamide and its hydrochloride The product is obtained according to the procedure of Example 24, Steps 1 and 2, using, as substrate in Step 1, 5-methoxyindoline and, in Step 2, the compound of Preparation 41.

Melting point 201-205°C Elemental microanalysis %found calculated EXAMPLE 86: C H 60.96 7.15 61.02 6.96

N

8.45 8.54 Cl 7.59 7.20

S

6.53 6.52 N-[2-(4-{[4-(Methylthio)phenoxy]methyl}-l-piperidyl)ethyl]- 1-indolinecarboxamide and its hydrochloride The product is obtained according to the procedure of Example 24, Steps 1 and 2, using, as substrate in Step 1, indoline and, in Step 2, the compound of Preparation 41. The product is converted into its hydrochloride by the action of ethereal hydrogen chloride solution.

Melting point 165-170 C Elemental microanalysis: %found calculated

C

63.11 62.39

H

7.15 6.98

N

9.05 9.09 Cl 7.96 7.67

S

6.92 6.94 EXAMPLLBZM 5-Nitro-N-{2-[4-(phenoxymethyl)-l-piperidyl]ethyl}-1indolinecarboxamide and its hydrochloride The product is obtained according to the procedure of Example 24, Steps 1 and 2, using, as substrate in Step 1, 5-nitroindoline and, in Step 2, the compound of Preparation 19. The product is converted into its hydrochloride by the action of ethereal hydrogen chloride solution.

Melting point 210-220 0

C

Elemental microanalysis %found calculated 59.86 59.93

H

6.27 6.34

N

12.01 12.15 Cl 8.10 7.69 N-(2-{4-[2-(4-Fluorophenoxy)ethyl]-l-piperidyl}ethyl)-5nitro-1-indolinecarboxamide and its hydrochloride -66- The product is obtained according to the procedure of Example 24, Steps 1 and 2, using, as substrate in Step 1, 5-nitroindoline and, in Step 2, the compound of Preparation 17. The product is converted into its hydrochloride by the action of ethereal hydrogen chloride solution.

Melting point 205-210°C Elemental microanalysis: C H N Cl %found 58.22 6.15 11.25 7.85 calculated 58.47 6.13 11.36 7.19 EXAMPLE 89: 5,6-Dimethoxy-N-{2-[4-(phenoxymethyl)-l-piperidyl]ethyl}-lindolinecarboxamide and its hydrochloride The product of Example 42 is subjected to hydrogenation under the conditions described in Step 3 of Example 43, allowing the expected product to be isolated, which is converted into its hydrochloride in conventional manner.

Melting point 118-122°C Elemental microanalysis C H N Cl %found 63.50 7.39 8.79 7.71 calculated 63.08 7.20 8.83 7.45 EXAMPLE 90: N-{2-[4-(Phenoxymethyl)-l-piperidyl]ethyl}-6,7-dihydro-5H- [1,3]dioxolo[4,5-flindole-5-carboxamide and its hydrochloride The product is obtained according to the procedure of Example 24, Steps 1 and 2, using, as substrate in Step 1, 5,6-methylenedioxyindoline and, in Step 2, the compound of Preparation 19. The product is converted into its hydrochloride by the action of ethereal hydrogen chloride solution.

Melting point 215-219°C 67 Elemental microanalysis C H N Cl %found 62.80 6.56 9.05 8.03 calculated 62.67 6.57 9.14 7.71 EXAM~PLE9: N-(2-{4-[2-(4-Fluorophenoxy)ethyl]-1-piperidyllethyl)-1,3dihydro-2H-isoindole-2-carboxamide and its hydrochloride The product is obtained according to the procedure of Example 24, Steps 1 and 2, using, as substrate in Step 1, isoindoline and, in Step 2, the compound of Preparation 17. The product is converted into its hydrochloride by the action of ethereal hydrogen chloride solution.

Melting point 175-179'C Elemental microanalysis: C H N Cl %found 63.78 6.93 9.22 7.85 calculated 64.35 6.97 9.38 7.91 EXAMPLLN: [4-(Phenoxymethyl)-1-piperidyl]ethyl}-1,3-dihydro-2Hisoindole-2-carboxamide and its hydrochloride The product is obtained according to the procedure of Example 24, Steps 1 and 2, using, as substrate in Step 1, isoindoline and, in Step 2, the compound of Preparation 19. The product is converted into its hydrochloride by the action of ethereal hydrogen chloride solution.

Melting point 178-181TC Elemental microanalysis C H N Cl %found 66.03 7.26 10.00 8.57 calculated 66.41 7.27 10.10 8.52 EXAMPLE 93: N-{2-[4-(Phenoxymethyl)-1-piperidyllethyl}-1,2,3,4tetrahydroisoquinolinecarboxamide and its hemii-fumarate -68- The product is obtained according to the procedure of Example 24, Steps 1 and 2, using, as substrate in Step 1, 1,2,3,4-tetrahydroisoquinoline and, in Step 2, the compound of Preparation 19. The product is converted into its hemi-fumarate.

Melting point 150-154°C Elemental microanalysis C H N %found 68.34 7.35 9.01 calculated 68.45 7.28 9.07 EXAMPLE 94 6,7-Dimethoxy-N-{2-[4-(phenoxymethyl)-l-piperidyl]ethyl}- 1,2,3,4-tetrahydroisoquinolinecarboxamide and its fumarate The product is obtained according to the procedure of Example 24, Steps 1 and 2, using, as substrate in Step 1, 6,7-dimethoxy-l,2,3,4-tetrahydroisoquinoline and, in Step 2, the compound of Preparation 19. The product is converted into its fumarate.

Melting point 200-205°C Elemental microanalysis C H N %found 62.70 6.71 7.22 calculated 63.25 6.90 7.38 EXAMPLE 95 5-Hydroxy-N-{2-[4-(phenoxymethyl)-1-piperidyl]ethyl}-1indolinecarboxamide and its hydrochloride The product is obtained according to the procedure of Example 43, Steps 1 to 3, using the compound of Preparation 19 as substrate in Step 2. The product is converted into its hydrochloride by the action of ethereal hydrogen chloride solution.

Melting point 198-202°C Elemental microanalysis C H N Cl %found 63.80 7.33 9.64 8.38 calculated 63.95 7.00 9.73 8.21 -69- EXAMPLE 96 5-Hydroxy-N-methyl-N-{2-[4-(phenoxymethyl)-l-piperidyl]ethyl}-l-indolinecarboxamide and its hydrochloride The product is obtained according to the procedure of Example 43, Steps 1 to 3, using the compound of Preparation 42 as substrate in Step 2. The product is converted into its hydrochloride by the action of ethereal hydrogen chloride solution.

Melting point 105-110°C Elemental microanalysis C H N Cl %found 64.74 7.34 9.32 8.19 calculated 64.63 7.23 9.20 7.95 EXAMPLE 97 N-(2-{4-[2-(1-Benzofuran-3-yl)ethyl]-l-piperazinyl}ethyl)-lindolinecarboxamide and its hydrochloride The product is obtained according to the procedure of Example 24, Steps 1 and 2, using, as substrate in Step 1, indoline and, in Step 2, the compound of Preparation 43. The product is converted into its hydrochloride by the action of ethereal hydrogen chloride solution.

Melting point 195-199°C Elemental microanalysis: C H N Cl %found 61.40 6.43 11.26 14.66 calculated 61.10 6.56 11.40 14.43 EXAMPLE 98 N-{2-[4-(Phenoxymethyl)-l-piperidyl]ethyl}-l-indolinesulphonamide and its hydrochloride The product is obtained according to the procedure of Example 47, Steps 1 to 4, using the compound of Preparation 3 as substrate in Step 4. The product is converted into its hydrochloride by the action of ethereal hydrogen chloride solution.

Melting point 168-172°C Elemental microanalysis %found calculated

C

58.31 58.46

H

6.79 6.69

N

9.23 9.30

C

8.05 7.84

S

6.98 7.09 EXAMPLE 92 N-{2-[4-(2-Phenoxyethyl)-l-piperidyl]ethyl}-l-indolinesulphonamide and its hydrochloride The product is obtained according to the procedure of Example 47, Steps 1 to 4, using the compound of Preparation 34 as substrate in Step 4. The product is converted into its hydrochloride by the action of ethereal hydrogen chloride solution.

Melting point 133-135°C Elemental microanalysis: %found 5 calculated 5 EXAMPLE 100 C H *9.12 6.99 '9.28 6.92

N

8.96 9.02 Cl 7.75 7.61

S

7.09 6.88 5-Fluoro-N-{2-[4-(phenoxymethyl)-1-piperidyl]ethyl}-1indolinesulphonamide and its hydrochloride The product is obtained according to the procedure of Example 47, Steps 1 to 4, using, as substrate in Step 1, 5-fluoroindoline instead of indoline and, in Step 4, the compound of Preparation 3. The product is converted into its hydrochloride by the action of ethereal hydrogen chloride solution.

Melting point 173-176 C Elemental microanalysis: %found calculated C H 56.80 6.38 56.22 6.22

N

9.12 8.94 Cl 7.77 7.54

S

6.66 6.82 6-Chloro-N-(2-{4-[2-(phenoxy)methyl]-l-piperidyl}ethyl)-lindolinecarboxamide and its hydrochloride -71- The product is obtained according to the procedure of Example 24, Steps 1 and 2, using, as substrate in Step 1, 6-chloroindoline and, in Step 2, the compound of Preparation 19. The product is converted into its hydrochloride by the action of ethereal hydrogen chloride solution.

Melting point 175-179 C Elemental microanalysis: C H N Cl %found 61.32 6.58 9.32 16.53 calculated 61.33 6.49 9.33 15.74 EXAMPLE 102: 5-Fluoro-N-(2-{4-[2-(4-fluorophenoxy)ethyl]-l-piperazinyl}ethyl)-l-indolinecarboxamide and its dihydrochloride The product is obtained according to the procedure of Example 24, Steps 1 and 2, using, as substrate in Step 1, 5-fluororoindoline and, in Step 2, the compound of Preparation 44. The product is converted into its dihydrochloride.

Melting point 179-184°C Elemental microanalysis: C H N Cl %found 54.67 5.89 11.18 14.16 calculated 54.88 6.01 11.13 14.08 EXAMPLE 103: N-{2-[4-(Phenoxymethyl)-l-piperidyl]ethyl}-6-fluoro-1indolecarboxamide and its hydrochloride The product is obtained according to the procedure of Example 38, Steps 1 and 2, but using, in Step 1, 6-fluoroindole instead of indole and, in Step 2, the product of Preparation 19.

Melting point 184-188 0

C

EXAMPLE 104 N-Methyl-N-{2-[4-(phenoxymethyl)-l-piperidyl]ethyl}-5,6dimethoxy-1-indolinecarboxamide and its hydrochloride 72 This product is obtained according to the procedure of Example 24, Steps 1 and 2, using, as substrate in Step 1, 5,6-dimethoxyindoline and, in Step 2, the compound of Preparation 42.

Melting point :84-87'C EXAMPLE 105 N-{2-[4-(Phenoxymethyl)-1-piperidyllethyl}-4,5,6trimethoxy-1-indolecarboxamide and its hydrochloride The product is obtained according to the procedure of Example 38, Steps 1 and 2, but using, in Step 1, 4,5,6-trimethoxyindole instead of indole and, in Step 2, the product of Preparation 19.

Melting point (M.K.):217-220'C EXAMPLE 106: N-{2-[4-(Phenoxymethyl)-1..piperidyllethyl}-4,5,6triniethoxy-1-indolinecarboxamide and its hydrochloride The product is obtained according to the procedure of Example 24, Steps 1 and 2, but using, in Step 1, 4,5,6-trimethoxyindoline and, in Step 2, the product of Preparation 19.

Melting point 147-15]'C EXAMPLE 107 1-(4-Fluorophenyl)-3-(2-{4-112-(phenoxy)ethyl]-l-piperidyl}ethyl)-2-imiddazolidinone and its hydrochloride The product is obtained according to the procedure of Example 5, using the compounds of Preparations 34 and 27. The product is converted into its hydrochloride by the action of ethereal hydrogen chloride solution.

Meltins! point (M.K.):176-179 0

C

EXAMPLE 10: 1-(4-Nitrophenyl)-3-(2-{4-[2-(phenoxy)ethyl]-1 -piperidyl)ethyl)-2-imidazolidinone and its hydrochloride -73- The product is obtained according to the procedure of Example 5, using the compounds of Preparations 34 and 29. The product is converted into its hydrochloride by the action of ethereal hydrogen chloride solution.

Melting point 197-202°C EXAMPLE 109: 1-{2-[4-(Phenoxymethyl)-l-piperidyl]ethyl}-3-phenyl-2imidazolidinone and its hydrochloride The product is obtained according to the procedure of Example 5, using the compound of Preparation 3 instead of that of Preparation 2. The product is converted into its hydrochloride by the action of ethereal hydrogen chloride solution.

Melting point 214-218°C EXAMPLE 110 N-{2-[4-(Phenoxymethyl)-l-piperidyl]ethyl}-5-methoxypyrrolo[2,3-c]pyridine-l-carboxamide and its dihydrochloride The product is obtained according to the procedure of Example 45, Steps 1 and 2, using, as substrate in Step 1, the product of Preparation 45 instead of 5-fluoroindole. The product is converted into its dihydrochloride by the action of ethereal hydrogen chloride solution.

Melting point 190-195°C PHARMACOLOGICAL STUDY OF COMPOUNDS OF THE INVENTION Under standard in vitro conditions, relaxation of aortic rings caused by acetylcholine (ACh), which relaxation is entirely dependent on the presence of endothelium, is the reflection of the production of NO (stimulated by ACh), which by diffusing to smooth muscle cells brings about arterial relaxation (Nature, 1980, 288, 373).

The compounds of the invention were tested in respect of two models involving two different mechanisms implicated in the endothelial dysfunction observed in pathology the first model consists of causing inhibition of the relaxation due to ACh by blocking the enzymatic activity (endothelial NOS) responsible for the production of NO; the second model consists of causing oxidative stress in vitro using an enzymatic system that generates 02- (xanthine oxidase -XO and hypoxanthine -Hypo).

-74- EXAMPLE 11 Vascular protective effects with respect to endothelial dysfunction caused by an inhibitor of NOS The thoracic aorta of a Wistar rat (325-375 anaesthetised by the intraperitoneal route using pentobarbital sodium (30 mg/kg), is removed and dissected into rings having a length of 3 mm. Each ring is suspended from an isometric tension sensor connected to a recording system and the initial tension applied is 2.5 g. The physiological solution used, which is thermostatically maintained at 37 0 C and oxygenated (95 02 5 C0 2 comprises (in mM): NaCl 112.0; KC1 5.0; CaCl 2 2.5; KH 2

PO

4 1.0; MgSO 4 1.2; NaHCO 3 25.0; glucose 11.5; Ca-EDTA 0.016.

After a 90-minute stabilisation period, the preparations are contracted using phenylephrine (PHE 106M) and relaxed by adding 10-SM of acetylcholine in order to verify the integrity of the endothelial layer. If that is confirmed, the preparations are rinsed and a concentration of the product under test is added to the medium followed by 3x10- 7 M of NG-nitro-Larginine (LNA). The preparations are again contracted using phenylephrine and, after 30 minutes, the relaxations due to acetylcholine (ACh-10-8M to 10-sM) are assessed in the presence of indomethacin (10- 5

M).

The relaxation values are expressed as a percentage relative to the maximum contraction caused by PHE. The protective effects of the compounds with respect to the endothelial dysfunction correspond to the difference between the percentages of maximum relaxation observed in the presence or absence of product.

By way of example, the compound of Example 35 at 10- 8 3x10 8 and 10-7M inhibits, by 8, 26 and 29 respectively, the endothelial dysfunction caused by LNA.

EXAMPLE 112 Protective vascular effects with respect to endothelial dysfunction caused by a system generating 02- This protocol, carried out on aortic rings of New Zealand rabbits (2.5-3 kg), is comparable to the previous protocol except for the following points the initial tension applied is 5 g and the combination XO (3 mU/ml) -Hypo (10- 4 M) is used instead of the LNA.

By way of example, the compound of Example 35 at 3x10-8M inhibits by 17 the endothelial dysfunction caused by the XO-Hypo combination.

EXAMPLE 113: Involvement of NO in the vascular protective effects detected assessment of aortic production of cGMP By diffusing to the smooth muscle cells, the NO produced by the endothelial cells activates soluble guanylate cyclase, which brings about an increase in cyclic GMP, which is responsible for relaxation.

The content of that mediator in rat aortic rings was therefore determined in order to demonstrate that the protective effects of the compounds with respect to endothelial dysfunction are mediated by an increase in the availability of NO.

The rat aortic rings are prepared as previously. The effects of 30-minute incubation of compounds of the invention at different concentrations are assessed on the production of cGMP stimulated by ACh (10-M 1 minute) in the presence of LNA (3x10-6M). The said experiments are carried out in the presence of isobutylmethylxanthine (10- 5 M) in order to avoid degradation of the cGMP by phosphodiesterases. The rings are frozen in liquid nitrogen and maintained at -80 0 C until the assay is carried out. The cGMP content is assessed by radioimmunoassay and expressed in relation to the amount of proteins contained in the tissue (assay by the Bradford method).

By way of example, the compound of Example 35, at 10-7M, increases by 28.1 the production of cGMP stimulated by ACh in the presence of LNA.

EXAMPLE 114 Pharmaceutical composition Tablet Formulation for the preparation of 1000 tablets each containing 10 mg of active ingredient Compound of Example 10 g H ydroxypropyl g g W heat starch 10 g L actose 100 g M agnesium g Comprises/comprising and grammatical variations thereof when used in this specification are to be taken to specify the presence of stated features, integers, steps or components or groups thereof, but do not preclude the presence or addition of one or more other features, integers, steps, components or groups thereof.

Claims

1- Compounds of formula W-V-A E-M-Y wherein V represents a single bond or a linear or branched (Ci-C 6 )alkylene chain, M represents a single bond or a linear or branched (C 1 -C 6 )alkylene chain, A and E each represents a nitrogen atom or a CH group, but at least one of the two groups A or E represents a nitrogen atom, W represents a group of formula R 3 G- (i) X represents a carbonyl, sulphonyl or sulphoxide group, G 1 represents a linear (C 2 -C 4 )alkylene chain optionally containing a double bond and/or being optionally substituted by a hydroxyl group, R 3 represents an aryl or heteroaryl-A group, each of which groups may optionally be substituted by one or more groups, which may be the same or different, selected from the definitions of R 2 a, Y represents an aryloxy, heteroaryloxy or heteroaryl-B group, each of which groups may optionally be substituted by one or more groups, which may be the same or different, selected from the definitions of R 2 a, R2a, represents a group selected from a hydrogen atom, a halogen atom, a linear or branched (Ci-C 6 )alkyl group, a hydroxy group, a linear or branched (Ci-C 6 )alkoxy group, a mercapto group, a linear or branched (Ci-C 6 )alkylthio group, a linear or branched (C 1 -C 6 )trihaloalkyl group, a cyano group, a nitro group, an amino group, a linear or branched (C 1 -C 6 )alkylamino group, a di-(CI-C 6 )alkylamino group in which each alkyl moiety may be linear or branched, a linear or branched (C 1 C 6 )trihaloalkoxy group, an aryloxy group, an aryl-(Ci-C 6 )alkoxy group in which the 77 alkoxy moiety is linear or branched, a linear or branched (Ci-C 6 )alkylsulphonate group, a linear or branched (Ci-C 6 )trihaloalkylsulphonate group and a linear or branched (CI-C 6 )alkylsulphonyl group, their isomers, their hydrates, their solvates and addition salts thereof with a pharmaceutically acceptable acid, wherein an aryl group is understood to mean a group selected from phenyl, biphenyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, indanyl, indenyl and benzocyclobutyl, a heteroaryl-A group is understood to mean a monocyclic aromatic or bicyclic, 5- to 12- membered system containing one or two hetero atoms, which may be the same or different, selected from oxygen, nitrogen and sulphur, and wherein, in the case of a bicyclic system, one of the rings has an aromatic character and the other ring may be aromatic or partially hydrogenated, a heteroaryl-B group is understood to mean a monocyclic aromatic or bicyclic aromatic,

5- to 12-membered system containing from 1 to 3 hetero atoms, which may be the same or different, selected from oxygen, nitrogen and sulphur, an aryloxy group is understood to mean an aryl group as defined hereinbefore attached to an oxygen atom, a heteroaryloxy group is understood to mean a heteroaryl-A group as defined hereinbefore attached to an oxygen atom, with the proviso that when V represents a single bond and R 3 represents a phenyl group, then Y cannot represent a 3-indolyl group, when M represents a single bond, then if Y represents a bicyclic heteroaryl-B group wherein one of the rings represents a benzene ring the said group Y cannot be joined to M by the said benzene ring, and when M represents a single bond, V represents an ethylene group and R 3 represents a phenyl group, then Y cannot represent a 1,2-benzisoxazol-3-yl group.

78- 2- Compounds of formula according to claim 1, characterised in that Y represents a benzofuran-3-yl group or a phenyloxy group optionally substituted by a group selected from the definitions of R 2 a, their isomers, and hydrates, solvates and addition salts thereof with a pharmaceutically acceptable acid. 3- Compounds of formula according to claim 1, characterised in that X represents a carbonyl group, their isomers, and hydrates, solvates and addition salts thereof with a pharmaceutically acceptable acid. 4- Compounds of formula according to any one of claims 1 to 3, characterised in that they represent compounds of formula (IA): /X\ R-N N-V-A E-M-Y (IA), KG,) wherein R 3 represents an aryl group, optionally substituted by a group selected from a halogen atom, a hydroxy group, a linear or branched (Ci-C 6 )alkoxy group, an aryl-(Ci-C 6 alkoxy group in which the alkoxy moiety is linear or branched, a nitro group, a linear or branched (Ci-C 6 )trihaloalkyl group and a cyano group, X represents a carbonyl group, Gi represents a linear (C 2 -C 3 )alkylene chain, V is as defined for formula A represents a nitrogen atom when E represents a CH group, or A represents a CH group when E represents a nitrogen atom, M represents a linear or branched (C 1 -C 4 )alkylene chain, Y represents a benzofuran-3-yl group, or a phenyloxy group optionally substituted by a group selected from a halogen atom, a linear or branched (Ci-C 6 )alkylsulphonyl group and a linear or branched (C 1 -C 6 )alkylthio group, their isomers, and hydrates, solvates and addition salts thereof with a pharmaceutically acceptable acid. 79 Compounds of formula (IA) according to claim 4, characterised in that R 3 represents a phenyl group optionally substituted by a halogen atom, their isomers, and hydrates, solvates and addition salts thereof with a pharmaceutically acceptable acid. 6- Compounds of formula (IA) according to claim 4, characterised in that: A represents a nitrogen atom and E represents a CH group when Y represents an optionally substituted phenyloxy group, or A represents a CH group and E represents a nitrogen atom when Y represents a benzofuran-3-yl group, their isomers, and hydrates, solvates and addition salts thereof with a pharmaceutically acceptable acid. 7- Compounds of formula (IA) according to claim 4, characterised in that: *V represents a single bond when Y represents a benzofuran-3-yl group, *or V represents a linear or branched (Ci-C 4 )alkylene chain when Y represents an optionally substituted phenyloxy group, their isomers and hydrates, solvates and addition salts thereof with a pharmaceutically acceptable acid. 8- Compound of formula according to claim 1 which is fluorophenoxy)ethyl]-l-piperidyl }ethyl)-3-phenyl-2-imidazolidinone, its isomers, and hydrates, solvates and addition salts thereof with a pharmaceutically acceptable acid. 9- Process for the preparation of compounds of formula according to claim 1, characterised in that there is used as starting material: a compound of formula (II) R 3 N C O (II), wherein R 3 is as defined for formula which is reacted 6 with a compound of formula (III): HO Ga -NH Va -OH (III), wherein Va represents a (C 2 -C 6 )alkylene chain and Gla represents a linear (C 2 -C 3 )alkylene chain, to yield the compounds of formula (IVa): G-OH la R-NH N-V-OH (IVa), 0 wherein R 3 Gla and Va are as defined hereinbefore, which compounds of formula (IVa) are converted by conventional methods of organic synthesis to yield the compounds of formula (IVb): G-P la 1 R3 NH N-V-P, (IVb), wherein P 1 represents a chlorine, bromine or iodine atom or a group OS0 2 R 4 wherein R 4 represents a methyl, trifluoromethyl or tolyl group, and R 3 Va and Gia are as defined hereinbefore, which compounds of formula (IVb) are subjected to the action of heat to yield the compounds of formula (IVc): Rg-N N-V--P (IVc), wherein R 3 Gla, Va and P 1 are as defined hereinbefore, which compounds of formula (IVc) are treated under basic conditions with a compound of formula HN E-M-Y wherein E, M and Y are as defined for formula to yield the compounds of formula a particular case of the compounds of formula -81- GR R-N N-V-N E-M-Y 0 wherein R 3 Gla, Va, E, M and Y are as defined hereinbefore, 6 or with a compound of formula (VI): H 2 N- V-A E-M-Y (VI), wherein A, E, M and Y have the same meanings as in formula and Vb represents a (C 1 -C 6 )alkylene chain, to yield the compounds of formula (VII): R3-NH-CO-NH-V-A E-M-Y (VII), wherein R 3 Vb, A, E, M and Y are as defined hereinbefore, which compounds of formula (VII) are treated in the presence of a strong base with a compound of formula (VIII) P- Glb- P'l (VIII), wherein P 1 and P'I, which are the same or different, are as defined for Pi hereinbefore and Gib represents a C 4 alkylene chain optionally containing a double bond, to yield the compounds of formula a particular case of the compounds of formula R3-N N-V-A E-M-Y (ib), 0 wherein R 3 Gib, Vb, A, E, M and Y are as defined hereinbefore, 6 or with a compound of formula (IX) (R 5 O)CH-G-NH-V-A E-M-Y (IX), wherein G 1 c represents a linear C 1 or C 2 -alkylene chain, R 5 represents a linear or branched

82- (C 1 -C 6 )alkyl group, and V, A, E, M and Y are as defined for formula to yield the compounds of formula G- CH(ORs) 2 R-N N-V-A E-M-Y 0 wherein R 3 Glc, V, A, Rs, M and Y are as defined hereinbefore, which compounds of formula are placed in the presence of a strong organic acid to yield the compounds of formula a particular case of the compounds of formula HO G-c R3-N N-V-A E-M-Y 0 wherein R 3 G 1 c, V, A, E, M and Y are as defined hereinbefore, which compound of formula is hydrogenated according to conventional techniques of organic synthesis to yield the compounds of formula a particular case of the compounds of formula G R3-N N-V-A E-M-Y 0 wherein R 3 Gic, V, A, E, M and Y are as defined hereinbefore, or which compounds of formula are dehydrated under conventional conditions of organic synthesis to yield the compounds of formula a particular case of the compounds of formula Glc r R,-N N-V-A E-M-Y wherein R 3 Gic, V, A, E, M and Y are as defined hereinbefore, Sor a compound offormula (Ia): R3 NH S2C1 (IIa), 83 wherein R 3 is as defined for formula which is reacted with a compound of formula (IIIa) Hal Gla NH Va Hal (liIa), wherein Hal represents a halogen atom and Gla and Va have the same meanings as hereinbefore, to yield the compounds of formula (IIIb) a Hal Rj-NH N (IIIb), S\o V -Hal 0 0 wherein R 3 Gla, Va and Hal are as defined hereinbefore, which compounds of formula (IIb) are reacted to yield the compounds of formula (IIIc): 3 a R3-N N-V-Hal (IIIc), wherein R 3 Gla, Va and Hal are as defined hereinbefore, which compounds of formula (IIIc) are treated under basic conditions with a compound of formula HN E-M-Y wherein E, M and Y are as defined for formula to yield the compounds of formula a particular case of the compounds of formula G r\ R- N N-V-N E-M-Y S/ 0 0 wherein R 3 Gla, Va, E, M and Y are as defined hereinbefore, the totality of the compounds of formulae to and constituting the compounds of the invention, which are purified, if necessary, according to conventional purification techniques, are separated, where appropriate, into their isomers according to a conventional

84- separation technique and are converted, if desired, into their hydrates, solvates or addition salts with a pharmaceutically acceptable acid. Pharmaceutical compositions comprising as active ingredient at least one compound of formula according to any one of claims 1 to 8, alone or in combination with one or more inert, non-toxic pharmaceutically acceptable excipients or carriers. 11- Use of pharmaceutical compositions according to claim 10 comprising at least one active ingredient according to any one of claims 1 to 8 for use as a medicament for the treatment of diseases or pathological conditions in which endothelial dysfunction is known. 12-A method of treating diseases of pathological conditions in which endothelial dysfunction is known, which method comprises administering to a patient an effective amount of a compound according to any one of claims 1 to 8 or of a pharmaceutical composition according to claim 13- Use of pharmaceutical compositions according to claim 10 comprising at least one active ingredient according to any one of claims 1 to 8 in the manufacture of a medicament for a purpose selected from: for preventing the development, extension and complications of atherosclerotic lesions, for preventing vascular complications after vascular bypass, vascular dilatation, vascular repermeabilisation and heart transplantation and for treating a condition selected from myocardial ischaemia, peripheral ischaemia, cardiac insufficiency and pulmonary arterial hypertension. 14- Use according to claim 13 for patients having a vascular risk factor. according to claim 14 wherein the vascular risk factor is selected from dyslipidaemia, diabetes and systemic arterial hypertension. 16- A method of preventing in a patient a condition selected from the development, extension and complications of atherosclerotic lesions and vascular complications after vascular bypass, vascular dilation, vascular repermeabilisation and heart transplantation, 85 which method comprises administering to a patient an effective amount of a compound according to any one of claims 1 to 8 or of a pharmaceutical composition according to claim 17- A method according to claim 16 in patients having a vascular risk factor. 18- A method according to claim 17 wherein the vascular risk factor is selected from dyslipidaemia, diabetes and systemic arterial hypertension. 19- A method for treating a condition selected from myocardial ischaemia, peripheral ischaemia, cardiac insufficiency and pulmonary arterial hypertension, which method comprises administering to a patient an effective amount of a compound according to any one of claims 1 to 8 or of a pharmaceutical composition according to claim DATED this 17th day of June 2004 LES LABORATOIRES SERVIER WATERMARK PATENT TRADE MARK ATTORNEYS 290 BURWOOD ROAD HAWTHORN VICTORIA 3122 AUSTRALIA P18777AU01