FR2756283A1 - ARY AMINES OF ARYLPIPERAZINES, THEIR PREPARATION AND THEIR APPLICATIONS AS MEDICAMENTS - Google Patents

Abstract

The invention concerns compounds of general formula (I) in which in particular, n represents zero or an integer between 1 and 3, R1 represents a hydrogen or a linear or branched alkyl containing 1 to 8 carbon atoms or an arylalkyl such as a benzyl or phenethyl, R2 represents a substituent selected between (a) and (b) in which Ar1 represents an aromatic radical such as a phenyl or a naphthyl, optionally substituted by one or several substituents selected among a halogen (F, Cl, Br), CH3 OCH3, CF3 or SCH3; Ar2 represents an aromatic radical such as a phenyl or a thienyl; X represents O, S or CH2; Ar represents an aromatic group such as a phenyl, naphthyl, indolyl, thienyl, pyridyl, pyrimidyl, benzodioxane, benzodioxolane the aromatic cycle of which can be optionally substituted; R3 and R4 different from each other, represent either a hydrogen, or an aromatic group such as a phenyl, pyridyl or pyrimidyl, capable of being diversely substituted; Z represents (CH2)j, O-(CH2)j, NH-(CH2)j, (CH2)k-C6H4-(CH2)l, O-(CH2)k-C6H4-(CH2)l or NH-(CH2)k-C6H4-(CH2)l, in which j represents an integer ranging from 2 to 10, while k and l, identical or different, represent an integer ranging from 1 to 4; Y represents CH or N. The compounds of the invention are inhibitors of serotine reuptake and antagonists of 5-HT1A receptors.

Description

Aromatic amines of arylpiperazines,
their preparation and their applications as medicines
The present invention relates to novel aromatic amines derived from arylpiperazines as well as to their method of manufacture, the pharmaceutical compositions containing them and their use as a medicament.

Serotonin or 5-hydroxytryptamine (5-HT) is a neurotransmitter and neuromodulator Liii involved in many physiological and pathological processes. Serotonin plays an important role in the nervous system as well as in the cardiovascular and gastrointestinal systems. At the central level, serotonin controls functions as varied as sleep, locomotion, food intake, learning and memory, endocrine modulations, sexual behavior, thermoregulation. In the marrow, serotonin plays an important role in peripheral nociceptive afferent control systems (see A. Moulignier, Rev. Neurol (Paris), 150, 3-15, 1994).

Serotonin may play an important role in various types of pathological conditions such as certain psychiatric disorders (anxiety, depression, aggressiveness, panic attacks, obsessive compulsive disorders, schizophrenia, tendency to suicide), certain neurodegenerative disorders (Alzheimer's dementia, Parkinsonism). , Huntington's chorea), anorexia, bulimia nervosa, alcoholism-related disorders, stroke, pain, migraine, or various headaches (R. Glennon, Neurosci, Biobehavioral Reviews, 14, 35 ,1990).

Numerous recent pharmacological studies have demonstrated the diversity of serotonin receptors and their respective involvement in its various modes of action (see E. Zifa, G. Fillion,
Pharm Reviews, 44,401,1992; S. Langer, N. Bruneilo, G. Racagni, J. Mendelecvicz, "Serotonin receptor subtypes: pharmacological significance and clinical implications", Karger Ed. (1992); BE Leonard, Int.

Clin. Psychopharmacology, 2, 13-21 (1992); R.W. Fuller; J. Clin. Psychiatrist 53, 36-45 (1992); D. G.

Grahame-Smith, Int. Clin. Psychopharmacology, Suppl.4, 6-13, (1992).

In addition, selective serotonin reuptake inhibitors (commonly known as SSRIs) have demonstrated clinical efficacy in the treatment of certain psychiatric disorders such as depression, but also panic attacks or obsessive compulsive disorders. .

Serotonin reuptake inhibitors that have been shown to be therapeutically effective in the treatment of depression (such as fluoxetine, fluvoxamine, citalopram or sertraline) are capable of increasing the synaptic availability of serotonin by reducing the recapture of serotonin. the latter by blocking its recapture site. Moreover, recent work such as those described for example by Artigas (TIPS, 14,262,1993) suggest that the efficacy of a serotonin reuptake inhibitor as an antidepressant may be impaired by activation of 5-HT1A receptors. activation which results in a reduction in the discharge frequency of serotonergic neurons. It has been shown that a 5-HT1A receptor antagonist potentiates the increase of SSRI-induced synaptic serotonin in animal models and recent clinical results have shown that the combination of a 5-HT1 antagonist Such that pindolol with a serotonin reuptake inhibitor allowed to observe a marked reduction in the latency of the antidepressant response and a significant improvement in the rapidity of action of the antidepressant (Artigas, Romero, de Montigny, Blier,
Trends Neurosci. 19378.1996). Therefore, compounds capable of simultaneously blocking the serotonin reuptake site while controlling somatodendritic 5-HT1A receptors are particularly useful as effective and fast-acting antidepressants and more broadly as therapeutic agents for treating disorders of the inergic seroton transmission.

The compounds according to the present invention are serotonin reuptake inhibitors and 5-HT1A receptor antagonists and, therefore, find their utility alone or in combination with other molecules, as medicaments and more particularly as therapeutic means for both curative and preventive treatment of serotonin-related disorders.

The prior state of the art in this field is illustrated in particular by aryl piperazines close to the general formula (I) but the compounds of the present invention are unambiguously distinguished from the derivatives of the prior art by the nature of the substituent R2 and by the biological properties of these compounds. Indeed, the previously described derivatives such as WAY-100135, WAY-100635,
WAY 100802 or MPPI are 5-HT1A receptor antagonists.

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<SEP> 0 <SEP> TO <SEP> ocH
<tb><SEP> INNNMHNÈ <SEP> N <SEP><<SEP><SEP>><SEP> INN # N <SEP> NE
<tb><SEP> HN <SEP> 0
<tb><SEP> (s) -WAY-100135
<tb> oN ,,, <SEP> 00135
<tb><SEP> OCH3 <SEP> ocH3
<tb><SEP> o
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<tb><SEP> WAY.1 <SEP> 00802 <SEP> MPPI
<tb><SEP> wAv-looso <SEP> MPPI
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The biological properties of this type of derivative as well as their characterization as antagonists
HTIA are well known to those skilled in the art (MD Ennis reviews, Curr, Opin, Ther., Patents, 1325, 1993, Fletcher A., Cliffe IA, and Dourish CT, TIPS, 14,441, 1993) and the subject of several recent patent applications such as W09616961, US 5451584, WO 9533743, US 5519025, US 5486518, US 5466688, WO 9609302.

The derivatives of the present invention are unambiguously distinguished from the prior art by their original chemical structure (definition of R2 in formula (I)) which unexpectedly confers on them novel biological properties which also distinguish them from the prior art. Indeed, the derivatives of the present invention, while being able to control the effects mediated by serotonin at the 5-HT1A receptor are also effective as inhibitors of the serotonin reuptake site which gives them different biological properties and advantageous in relation to the prior art, in particular with regard to their therapeutic use and more particularly for the preventive as well as curative treatment of disorders related to serotonin.

dans laquelle, n représente zéro ou un nombre entier compris entre 1 et 3
R1 représente un hydrogène, un alkyle linéaire ou ramifié comprenant de 1 à 8 atomes de carbone ou un arylalkyl tel qu'un benzyl ou un phénéthyl
R2 représente un substituant choisi parmi:

The present invention relates to compounds having the general formula (I)

in which, n represents zero or an integer between 1 and 3
R1 represents a hydrogen, a linear or branched alkyl comprising from 1 to 8 carbon atoms or an arylalkyl such as a benzyl or a phenethyl
R2 represents a substituent chosen from:

dans lesquels, Ar1 représente un résidu aromatique tel qu'un phényl ou un naphtyl, éventuellement substitués par un ou plusieurs substituants choisis parmi un halogène (F, Cl, Br), CH3, OCl-l3, CF3 ou SCI-13;
Ar2 représente un résidu aromatique tel qu'un phényl ou un thiényl;
Ar3 représente un phényl éventuellement substitué par un ou plusieurs substituants choisis parmi Cl, Br,
F, CF3, CH3, OCH3, OH ou CH2OH
X représente O, S ou CH2; m représente un nombre entier compris entre 1 et 4; ou encore, R1 et R2, avec l'azote auquel ils sont attachés, forment un cycle choisi parmi les résidus suivants

wherein Ar 1 represents an aromatic residue such as phenyl or naphthyl, optionally substituted by one or more substituents selected from halogen (F, Cl, Br), CH 3, OCl-13, CF 3 or SCI-13;
Ar 2 represents an aromatic residue such as phenyl or thienyl;
Ar 3 represents a phenyl optionally substituted by one or more substituents chosen from Cl, Br,
F, CF3, CH3, OCH3, OH or CH2OH
X is O, S or CH2; m represents an integer from 1 to 4; or R1 and R2 together with the nitrogen to which they are attached form a ring selected from the following residues

Ar represents an aromatic radical such as a phenyl, naphthyl, indolyl, tienienyl, pyridyl, pyrimidyl, benzodioxane, benzodioxolane whose aromatic ring may be optionally substituted with one or more substituents chosen from a linear, cyclic or branched hydrocarbon radical, saturated or unsaturated compound comprising 1 to 8 carbon atoms, a halogen (Cl, Br, F or 1), a CF 3 residue, an ether residue (ORs) or thioether (SRg) in which R 5 represents a linear or branched alkyl comprising from 1 to 6 carbon atoms,
R3 and R4, which are different from one another, represent either a hydrogen or an aromatic residue such as phenyl, pyridyl or pyrimidyl, which may be variously substituted with one or more linear, cyclic or branched, saturated or unsaturated hydrocarbon radicals; comprising 1 to 8 carbon atoms, a halogen (Cl, Br, F or I), a CF 3 residue, an ether residue (OR 6) or thioether (SR 6) in which R 6 represents a linear or branched alkyl comprising from 1 to 6 carbon atoms.

Z is (CH 2) n, O- (CH 2) n, NH- (CH 2) j, (CH 2) k-C 6 H 4 - (CH 2) 1, O- (CH 2) k-C 6 H 4 - (CH 2) 1 or NH (CH 2) k-C6H4- (CH2) 1, in which j represents an integer between 2 and 10, while k and 1, which are identical or different, represent an integer between I and 4;
Y is CH or N, with the proviso that n is not zero when Y is N; and their physiologically acceptable salts, hydrates, solvates and bioprecursors for therapeutic use.

The geometric and optical isomers of the compounds of general formula (I) are also part of the present invention as well as their mixture in racemic form. When a compound of the present invention is described without indicating the stereochemistry of its asymmetric center (s), it should be understood that all isomers are contemplated.

Among the physiologically acceptable salts of the compounds of general formula (I) are included salts obtained by addition of organic or inorganic acids such as hydrochlorides, hydrobromides, sulphates, phosphates, acetates, benzoates, naphthoates, p-toluenesulfonates, methanesulphonate. fonates, sulphamates, ascorbates, tartrates citrates oxalate, maleates, salicylates, fumarates, succinates, lactates, glutarates, glutaconates.

The term bioprecursor as used in the present invention applies to compounds whose structure differs from that of the compounds of formula (I) but which, administered to an animal or to a human being are converted into the organism to a compound of formula (1).

Another aspect of the present invention is to provide a method for controlling the serotonergic system by interaction of the compounds of formula (I) at serotonin reuptake sites and / or at the 5-HT1A receptors, which method comprises administering to a patient in need of such treatment an effective amount of a compound of formula (I), alone or in combination with other drugs, in an acceptable pharmaceutical carrier.

Also to be considered as part of the present invention is a method comprising administering a compound of formula (I) to treat a condition such as depression, obsessive-compulsive disorder, panic attacks, aggression, anxiety disorder, and the like. anxiety, pain, migraine, bulimia, alcoholism, tobacco addiction, schizophrenia, dementia
Alzheimer's, parkinsonism, Huntington's chorea, sexual dysfunction and sleep disorders.

The present invention also includes therapeutic methods involving the combination of a compound of formula (I) with another therapeutic agent.

dans laquelle Ar, Y, R3, Z, R1 et R2 sont définis comme dans la formule (I)
Une sous-classe plus particulièrement apprécié de composés de formule (la) faisant partie de la présente invention correspond aux composés de formule la dans laquelle R2 est choisi parmi un des résidus suivants:

A particularly preferred class of compounds of formula (I) corresponds to the compounds of formula (Ia)

in which Ar, Y, R3, Z, R1 and R2 are defined as in formula (I)
A more particularly preferred subclass of compounds of formula (Ia) forming part of the present invention corresponds to the compounds of formula la wherein R2 is selected from one of the following residues:

Another particularly preferred subclass of compounds of formula (I) forming part of the present invention corresponds to the compounds of formula (Ia) in which R 1 and R 2, together with the nitrogen to which they are attached, form a ring selected from one of the two following residues

dans laquelle n, R1, R2, R3, R4, Y et Z sont définis comme dans la formule générale (I)
Les composés de la présente invention sont préparés par différentes méthodes et techniques bien connues de l'homme de l'art et dont le choix dépendra en grande partie de la nature de Y et Z.Another particularly preferred class of compounds of formula (I) forming part of the present invention corresponds to the compounds of formula (Ib)

in which n, R 1, R 2, R 3, R 4, Y and Z are defined as in general formula (I)
The compounds of the present invention are prepared by various methods and techniques well known to those skilled in the art and the choice of which will depend largely on the nature of Y and Z.

dans laquelle Ar, n, R3, R4, Y et Z sont définis comme précédemment et P représente un groupe partant tel qu'un halogène (chlore, brome ou iode) un mésylate, un tosylate ou un triflate. Cette réaction de substitution nucléophile mettant en oeuvre une amine RIR2NH et un électrophile de formule (11) est préférentiellement réalisée en présence d'une base, organique ou inorganique, telle que par exemple
NaH, KH, t-BuOK, DIPEA, DMAP, DBU, Cs2C03, K2C03, dans un solvant anhydre polaire tel que le
THF, la diéthylcétone, le DMF, le DMSO, la DME en présence ou non de HMPT, à une température comprise entre - 1 50C et 900C.In general, the compounds of general formula (I) forming part of the present invention are prepared by condensation of an amine of formula HNRIR2 in which R1 and R2 are defined as in general formula (I) with an electrophile of general formula (II)

wherein Ar, n, R 3, R 4, Y and Z are defined as above and P represents a leaving group such as a halogen (chlorine, bromine or iodine) a mesylate, a tosylate or a triflate. This nucleophilic substitution reaction using an amine RIR2NH and an electrophil of formula (11) is preferably carried out in the presence of a base, organic or inorganic, such as for example
NaH, KH, t-BuOK, DIPEA, DMAP, DBU, Cs 2 CO 3, K 2 CO 3, in a polar anhydrous solvent such as
THF, diethyl ketone, DMF, DMSO, DME in the presence or absence of HMPT, at a temperature of between -150C and 900C.

dans laquelle Ar, n, R3 et R4 sont définis comme dans la formule générale (I) et un électrophile de formules générales (IVa) ou (IVb)

dans lesquels j, k et 1 sont définis comme précédemment, P' représente un groupe partant tel qu'un chlore un brome, un iode, un mésylate ou un tosylate, ou encore P' représente un précurseur d'un de ces groupes partants qui sera restauré après la condensation de (III) avec (IVa) ou (IVb) et L représente Cl, OH, Oalkyl ou encore le groupe "LCO" dans les formules (IVa) ou (IVb) représente toute forme activée issue d'un acide carboxylique propice à la préparation d'une amide par les méthodes et techniques bien connues de l'homme de l'art pour préparer une amide par condensation d'une amine avec un dérivé d'acide carboxylique. Les conditions expérimentales pour réaliser la condensation seront déterminées en fonction de la nature de L et de R3. C'est ainsi et à titre d'exemple que cette condensation entre une amine de formule (III) et un dérivé d'acide carboxylique de formule (IVa) ou (IVb) peut être réalisée à partir d'intermédiaires (IVa) ou (IVb) dans lesquels L représente un chlore, en présence d'une base organique ou inorganique telle que la pyridine, la DIPEA, la DMAP, le DBU, K2CO3, Cs2CO3 ou
Na2CO3 dans un solvant anhydre aprotique polaire tel que le THF, le dichlorométhane, à une température comprise entre - 200C et 400C. La préparation des composés de formule (II) peut également être réalisée par condensation d'une amine de formule (III) avec un ester activé de formule (IVa) ou (IVb) par les méthodes et techniques bien connues de l'homme de l'art pour ce type de transformation. A titre d'exemple complémentaire cette condensation peut également être réalisée en mettant en oeuvre une amine de formule (III) et un acide carboxylique de formule (IVa) ou (IVb) dans lesquelles L représente
OH, en présence d'une amine tertiaire telle que la triéthylamine, la diisopropyléthylamine, la pyridine, la
DMAP, la N-méthyl-morpholine, dans un solvant aprotique polaire tel que le THF, le dichlorométhane, le DCE, I'acétate d'éthyle, le chloroforme ou le DMF, par réaction préalable avec un agent activant tel que l'EDC, le DCC, le BOP ou encore le PyBOP, à une température comprise entre - 100 et 350C.When Y represents a nitrogen and Z represents (CH2) or (CH2) k-C6H4- (CH2) 1 the compounds of general formula (II) are prepared by forming an amide bond between an amine of formula (III)

in which Ar, n, R3 and R4 are defined as in general formula (I) and an electrophile of general formulas (IVa) or (IVb)

in which j, k and 1 are defined as above, P 'represents a leaving group such as a chlorine bromine, an iodine, a mesylate or a tosylate, or P' represents a precursor of one of these leaving groups which will be restored after the condensation of (III) with (IVa) or (IVb) and L represents Cl, OH, Oalkyl or the group "LCO" in the formulas (IVa) or (IVb) represents any activated form resulting from a carboxylic acid suitable for the preparation of an amide by methods and techniques well known to those skilled in the art for preparing an amide by condensation of an amine with a carboxylic acid derivative. The experimental conditions for carrying out the condensation will be determined according to the nature of L and R3. It is thus and by way of example that this condensation between an amine of formula (III) and a carboxylic acid derivative of formula (IVa) or (IVb) can be carried out from intermediates (IVa) or ( IVb) in which L represents a chlorine, in the presence of an organic or inorganic base such as pyridine, DIPEA, DMAP, DBU, K2CO3, Cs2CO3 or
Na2CO3 in an aprotic polar anhydrous solvent such as THF, dichloromethane, at a temperature between -200C and 400C. The preparation of the compounds of formula (II) can also be carried out by condensation of an amine of formula (III) with an activated ester of formula (IVa) or (IVb) by methods and techniques well known to those skilled in the art. art for this type of transformation. As a further example, this condensation can also be carried out using an amine of formula (III) and a carboxylic acid of formula (IVa) or (IVb) in which L represents
OH, in the presence of a tertiary amine such as triethylamine, diisopropylethylamine, pyridine,
DMAP, N-methyl-morpholine, in a polar aprotic solvent such as THF, dichloromethane, DCE, ethyl acetate, chloroform or DMF, by prior reaction with an activating agent such as EDC , DCC, BOP or PyBOP, at a temperature between -100 and 350C.

dans laquelle Ar, n, R3 et R4 et L sont définis comme précédemment avec un nucléophile de formule (V!)
H-Z-P' (V) dans laquelle Z représente O-(CH2)j, NH-(CH2)j-O-(CH2)k-CgHq-(CH2)1 ou NH-(CH2)k-C6H4-(CH2)1 et P' représente un groupe partant (Cl, Br, OMes, OTos) ou préférentiellement un précurseur d'un groupe partant qui sera restauré après la condensation entre (V) et (VI). Cette condensation, dépendant de la nature de Z consiste à préparer un ester par condensation d'un alcool avec un dérivé d'acide carboxylique ou, consiste à préparer un amide par condensation d'une amine avec un dérivé d'acide carboxylique. Ces transformations, bien connues de l'homme de métier sont réalisées par les méthodes et techniques en usage pour ce type de transformation telles que par exemple celles qui ont été évoquées plus haut pour la préparation des intermédiaires de formule II par condensation d'amines de formule (III) avec un dérivé d'acide carboxylique de formule (IV).When Y is CH and Z is O- (CH2), NH (CH2) j, O- (CH2) k-C6H4- (CH2) 1 or NH (CH2) k-C6H4- (CH2) 1, the intermediates of formula (II) are prepared by condensation of a carboxylic acid derivative of general formula (V)

in which Ar, n, R3 and R4 and L are defined as above with a nucleophile of formula (V!)
Wherein Z is O- (CH 2) n, NH- (CH 2) 10 -O (CH 2) k-C 6 H 4 - (CH 2) 1 or NH- (CH 2) k-C 6 H 4 - (CH 2) 1 and P 'represents a leaving group (Cl, Br, OMes, OTos) or preferentially a precursor of a leaving group which will be restored after the condensation between (V) and (VI). This condensation, depending on the nature of Z, consists in preparing an ester by condensation of an alcohol with a carboxylic acid derivative or it consists in preparing an amide by condensation of an amine with a carboxylic acid derivative. These transformations, which are well known to those skilled in the art, are carried out by the methods and techniques in use for this type of transformation, such as, for example, those which were mentioned above for the preparation of the intermediates of formula II by condensation of amines of formula (III) with a carboxylic acid derivative of formula (IV).

dans laquelle X1 et X2, identiques ou différents représentent chacun un groupe partant tel qu'un halogène (en particulier le chlore) un groupe O-alkyle (en particulier le groupe OCC13), un groupe O-aryl (en particulier le groupe O-pyridyl), un groupe succinimyle, phtalyle ou imidazolyle. Les méthodes et techniques choisies pour la mise en oeuvre de la préparation des carbamates et urées de formule (II) par condensation d'une amine de formule (III) et un intermédiaire (alcool ou amine) de formule (VI) avec un dérivé carbonylé de formule (VII) telles que le choix de l'ordre de la mise en présence des partenaires réactionnels, les temps de réaction, I'isolation ou la purification des intermédiaires, la température des réactions à différentes étapes, la nature des solvants, la présence de co-réactifs (tels qu'une base, organique ou inorganique comme par exemple une amine tertiaire telle que la triéthylamine) ou de catalyseurs seront déterminées en fonction de la nature des intermédiaires de formule (III) et (VI) et suivant les méthodes et techniques bien connues de l'homme de l'art pour préparer des carbamates et urées à partir d'amines et alcools et de réactifs de formule (VIl). In the particular case of the intermediates of formula (I1) in which Y represents a nitrogen and Z represents O- (CH2) j, NH- (CH2) j-, O (CH2) k-C6H4- (CH2) 1 or NH ( CH2) k-C6114- (CH2) 1 and which are therefore carbamates or ureas, a particularly preferred method of synthesis consists in condensing an amine of general formula (III) defined as above, and an alcohol or an amine of formula general (VI) in which P 'is defined as above and Z represents O (CH2) j,
NH (CH 2) n-, O (CH 2) k-C 6 H 4 - (CH 2) 1 or NH (CH 2) k-C 6 H 4 - (CH 2) 1, with an electrophile of general formula (VII)

wherein X1 and X2, which are the same or different, each represents a leaving group such as a halogen (in particular chlorine) an O-alkyl group (in particular the OCC13 group), an O-aryl group (in particular the O-aryl group), pyridyl), a succinimyl, phthalyl or imidazolyl group. The methods and techniques chosen for carrying out the preparation of carbamates and ureas of formula (II) by condensation of an amine of formula (III) and an intermediate (alcohol or amine) of formula (VI) with a carbonyl derivative of formula (VII) such as the choice of the order of the placing in the presence of the reaction partners, the reaction times, the isolation or the purification of the intermediates, the temperature of the reactions at different stages, the nature of the solvents, the the presence of co-reactants (such as a base, organic or inorganic, for example a tertiary amine such as triethylamine) or of catalysts will be determined according to the nature of the intermediates of formula (III) and (VI) and according to the methods and techniques well known to those skilled in the art for preparing carbamates and ureas from amines and alcohols and reagents of formula (VIl).

dans un solvant anhydre polaire tel que l'éther éthylique ou le THF à une température comprise entre 80"C et OOC. The intermediates of formula (II) in which Y represents CH and Z represents (CH 2) j or (CH 2) k
C6H4- (CH2) 1 are accessible by condensation of an organometallic of general formula (VIII)
MZ-P '
(VIII) wherein 7 represents (CH2) or (CH2) k-C6H4- (CH2) 1, P 'represents a precursor of a leaving group as defined above and M represents a metal such as Li, MgCl, MgBr , MnCl or MnBr, with an acid chloride of general formula (IX)

in a polar anhydrous solvent such as ethyl ether or THF at a temperature of between 80 ° C and 0 ° C.

en présence d'une base organique ou inorganique telle que NaH, KH, t-BuOK, DBU, DMAP, DIPEA dans un solvant aprotique anhydre tel que le THF, le DMF ou le DMSO, à une température comprise entre - 200C et 500C.In the particular case of the compounds of general formula (I) in which Z represents CH 2 CH 2, an alternative but preferred method of preparation consists in condensing an amine of general formula R 1 R 2 NH with an unsaturated α-carbonyl of general formula (X)

in the presence of an organic or inorganic base such as NaH, KH, t-BuOK, DBU, DMAP, DIPEA in an anhydrous aprotic solvent such as THF, DMF or DMSO, at a temperature between -200C and 500C.

dans laquelle Z représente (CH2)j ou (CH2)k-C6H4-(CH2)1, et R1, R2 et L sont définis comme précédemment par les méthodes et techniques décrites précédemment pour ce type de condensation. Il est bien entendu que dans certains cas, il sera nécessaire de modifier le substituant R1 de façon provisoire, pour éviter qu'une cyclisation intramoléculaire n'entre en compétition avec la condensation de l'intermédiaire (XI) avec l'amine (III). Les intermédiaires de formule (XI) sont préparés par condensation d'une amine de formule R1R2NH avec un dérivé d'acide carboxylique de formule (XII)

dans laquelle Z représente (CH2)j ou (CH2)k-C6H4-(CH2)1, P représente un groupe partant tel que défini précédemment et L' représente O-alkyl, O-benzyl, qui sera transformé en L après que la condensation entre R1R2NH et l'intermédiaire (XII) aie été réalisée.In the particular case of the compounds of formula (I) in which Y represents NH and Z represents (CH 2) j or (CH 2) k-C 6 H 4 - (CH 2) 1, an alternative method of preparation consists in condensing an intermediate of formula (III in which Ar, n, R3 and R4 are defined as above, with an electrophile of general formula (Xl)

wherein Z represents (CH2) j or (CH2) k-C6H4- (CH2) 1, and R1, R2 and L are defined as previously by the methods and techniques previously described for this type of condensation. It is understood that in certain cases, it will be necessary to modify the substituent R1 temporarily, to prevent intramolecular cyclization from competing with the condensation of the intermediate (XI) with the amine (III) . The intermediates of formula (XI) are prepared by condensation of an amine of formula R 1 R 2 NH with a carboxylic acid derivative of formula (XII)

in which Z represents (CH2) j or (CH2) k-C6H4- (CH2) 1, P represents a leaving group as defined above and L 'represents O-alkyl, O-benzyl, which will be transformed into L after the condensation between R1R2NH and intermediate (XII) has been carried out.

This type of transformation is well known to those skilled in the art and can be achieved by different methods and techniques such as those mentioned above.

dans laquelle R1 et R2 sont définis comme dans la formule (1) et Z représente O-(CH2)j, NH(CII2)j O (CH2)k-C6H4-(CH2)1 ou NH(CH2)k-C6H4-(CH2)1, avec un électrophile de formule (VII) dans laquelle X1 et X2 sont définis comme précédemment, par les méthodes et techniques bien connues de l'homme de l'art pour préparer des urées ou carbamates à partir d'amines et d'alcools, telles que par exemple celles qui ont été décrites précédemment.Finally, in the particular case of the compounds of formula (I) in which Y represents NH and Z represents O- (CH2) j, NH (CH2) j, O (CH2) k-C6H4- (CH2) 1 or NH- ( CH2) k-C6H4- (CH2) 1, an alternative method of preparation consists in condensing an amine of formula (III) in which Ar, N, R3 and R4 are defined as above and an amine or an alcohol of formula (XIII)

wherein R1 and R2 are defined as in formula (1) and Z is O- (CH2), NH (CII2), O (CH2) k-C6H4- (CH2) 1 or NH (CH2) k-C6H4- (CH 2) 1, with an electrophile of formula (VII) in which X 1 and X 2 are defined as above, by the methods and techniques well known to those skilled in the art for preparing ureas or carbamates from amines and alcohols, such as those described above.

The methods for preparing the R1R2NH amines used as reagents in the preparation of the compounds of general formula (I) have been adapted from procedures previously described in the scientific literature or in patents such as, for example, US Pat. 912743, US 4,007,196, US 4,136,193, US 4,085,225, US 4,536,518, US 4,478,836, US 4,956,388 or US 4,314,081.

It will be understood that in certain reactions or sequences of chemical reactions which lead to the preparation of the compounds of the general formula (I) it is necessary or desirable to protect possible sensitive groups in the synthesis intermediates in order to avoid undesirable side reactions. This can be achieved by the use (introduction and deprotection) of conventional protecting groups such as those described in "Protective Groups in Organic Synthesis", TW Greene, John
Wiley & Sons, 1981 and "Protecting Groups" PJ Kocienski, Thieme Verlag, 1994. The appropriate protective groups will therefore be introduced and removed at the most appropriate stage to do this and using the methods and techniques described in the cited references. previously.

When it is desired to isolate a compound according to the invention in the form of salt, for example salt by addition with an acid, this can be achieved by treating the free base of general formula (I) with an appropriate acid, preferably in equivalent amount, or by creatinine sulfate in a suitable solvent.

When the methods described above for preparing the compounds of the invention give mixtures of stereoisomers, these isomers can be separated by conventional methods such as preparative chromatography.

When the new compounds of formula (I) have one or more asymmetric centers, they can be prepared in the form of a racemic mixture or in the form of enantiomers, whether by enanheselective synthesis or by resolution. The compounds of general formula (I) have one or more asymmetric centers, they can be prepared in the form of a racemic mixture or in the form of enantiomers, whether by enantioselective synthesis or by resolution. The compounds of formula (I) having at least one asymmetric center may, for example, be separated into their enantiomers by the usual techniques such as the formation of diastereomeric pairs by formation of a salt with an optically active acid such as the acid. (-) - di-p-toluyol-1-tartaric acid, (+) di-p-toluyol-1-tartaric acid, (-1 -) - camphorsulfonic acid, (-) - camphorsulfollic acid, (+) Phenylpropionic acid, (-) - phenylpropionic acid, followed by fractional crystallization and regeneration of the free base. The compounds of formula (I) in which R 1 is hydrogen comprising at least one asymmetric center may also be resolved by forming diastereomeric amines which are separated by chromatography and hydrolyzed to liberate the chiral auxiliary.

The examples which follow illustrate the invention without, however, limiting its scope.

EXAMPLE 1
N- (2- [4- (2-Methoxy-phenyl) -piperazin-1-yl] ethyl] -3- [3-phenyl-3- (4-trifluoromethyl-phenoxy) -propylamino] -N- fumarate -pyridin-2-yl-propionamide

(2- [4- (2-Methoxy-phenyl) -piperazin-1-yl] ethyl) -pyridin-2-yl-amine (Pike V. W. et al., Med Chem.

Res. 1994, 5, 208-227) (300 mg, 0.96 mmol), dissolved in dichloromethane (6 ml) in the presence of triethylamine (0.20 ml, 1.44 mmol), is treated with OOC by acryloyl chloride (86 μL, 1.05 mL). After stirring for 10 minutes at 0 ° C., a new addition of acryloyl chloride (0.226 ml, 2.79 mmol) is carried out and the medium is stirred at 0 ° to 25 ° C. for 2 hours. dichloromethane, washed with 1N hydrochloric acid, with 2N sodium hydroxide and then with water The aqueous phases are combined and then reextracted with dichloromethane The organic phases are combined, dried over sodium sulphate, filtered and evaporated to dryness. obtained is purified by chromatography on a column of silica eluted with a dichloromethane / acetone mixture (5/1) to yield the desired amide in the form of a pale yellow syrup (191 mg, 54%).

3-Phenyl-3- (4-trifluoromethylphenoxy) propylamine (Mitchell D. et al., Synth.Comm.Comm., 1995, 1231-1238) (149 mg, 0.505 mmol) in solution in dimethylformamide (2.5 ml ) is treated at room temperature with sodium hydride (60% in oil) (24 mg, 0.60 mmol) After stirring for 30 minutes, the amide prepared above is added (185 mg, 0.505 mmol). then the mixture is stirred for 15 hours at room temperature, the medium is diluted with ethyl acetate, washed with water and then with a saturated solution of sodium chloride, the syrup obtained is purified by chromatography on a silica column. eluted with a dichloromethane / methanol / ammonia mixture (95 / 4.5 / 0.5) to yield the pure product in the form of a pale yellow syrup (94 mg, 28%). is salified by treatment with 2 equivalents of fumaric acid in methanol to give compound 1.

Elemental analysis (C 45 H 50 F 3 NuO 1/2, 2H 2 O) calculated: C 58.12 H 5.85 N 7.53% found: C <RTI
1H NMR, DMSO-d6 (ppm) 1.48-1.53m, 4H; 2.15-2.25 m, 4H; 2.40-2.50 m, 6H; 2.80-3.05 m, 8H; 3.75 s, 3H; 3.90 t, 2H; 5.60-5.70 m, 1H; 6.53 m, 4H; 6.80-6.95 m, 4H; 7.05 d, 2H; 7.30-7.40 m, 7H; 7.48 d, 1H; 7.58 d, 2H; 7.90 dt, 1H; 8.49 dd, 1H.

Melting point: 65 ° C.

EXAMPLE 3
6- [3-phenyl-3- (4-trifluoromethyl-phenoxy) -propylamino] -hexanoic acid fumarate {2- [4- (2
methoxy-phenyl) -piperazin-1-yl] ethyl) -pyridin-2-yl-amide

Compound 2 is prepared from (2- [4- (2-methoxy-phenyl) -piperazin-1-yl] ethyl) -pyridin-2-ylamine (300 mg, 0.96 mmol), 6-bromohexanoyl chloride (0.15 ml, 0.96 mmol) and 3-phenyl-3- (4-trifluoromethylphenoxy) propylamine (283 mg, 0.96 mmol) according to the procedure described for the preparation of Example 1. The syrup obtained is purified by chromatography on a column of silica eluted with a dichloromethane / methanol / ammonia mixture (90/9/1) to give the desired amide in the form of a yellow syrup which, after salification with fumaric acid, leads to compound 3 (348 mg, 44%).

Elemental analysis (C 40 H 48 N 5 O 3 F 3, 2, 2 C 4 H 4 O 4, 0.3 EtOH, 1.9 H 2 O) calculated: C 58.91H 6.24 N 6.95% found: C 59.24H 5.86 N 6 58
1H NMR, DMSO-d6 (ppm) 1.10-1.25m, 2H; 1.35-1.55 m, 4H; 2.00-2.20 m, 4H; 2.35-2.50 m, 8H; 2.75-3.03 m, 8H; 3.71 s, 3H; 3.86 t, 2H; 5.55-5.65 m, 1H; 6.49 s, 4H; 6.75-7.05 m, 6H; 7,20-7,60 m, 9
H; 7.85 dt, 1H; 8.45 dd, 1H.

Melting point: 770C.

EXAMPLE 4 2 - {[2- [4- (2-Methoxy-phenyl) -piperazin-1-yl] -ethyl} -pyridin-2-yl-carbamoyl-ethylamino] fumarate
methyl-1-phenyl-N, Nd-ethylcyclopropanecarboxam ide

Compound 4 is prepared from {2- [4- (2-methoxy-phenyl) -piperazin-1-yl] -ethyl} -pyridin-2-yl-amine (1.0 g, 3.20 mmol). ), acryloyl chloride (0.52 ml, 6.4 mmol) and 2-aminomethyl-1-phenyl-N, N-diethylcyclopropanecarboxamide (Bonnaud B et al., J. Med Chem 1987, 30, 318 -325) (482 mg, 1.96 mmol) according to the procedure described for the preparation of Example 1. The syrup obtained is purified by chromatography on a column of silica eluted with a mixture of dichloromethane / methanoammonium (97 / 2.5 / 0.5 and then 90 / 9.5 / 0.5) to yield the desired amide in the form of a yellow syrup which, after salification with fumaric acid, yields 4 (717 mg, 41%) .

Elemental analysis (C 44 H 56 N 6 O 11, 2.3H 2 O) calculated: C 59.62H 6.89 N 9.48% found: C 59.29H 6.55 N 9.20
1H NMR, DMSO-d6 (ppm): 0.69 t, 3H; 0.99 t, 3H; 1.33 s, 1H; 1.58 large s, 2H; 2.40-2.55 m, 6H; 2.602.90 m, 8H; 3.05-3.40 m, 6H; 3.71 s, 3H; 3.91 t, 2H; 6.50 s, 4H; 6.75-6.90 m, 4H; 7.19-7.35 m, 6H; 7.51 d, 1H; 7.89 dt, 1H; 8.47 dd, 1H.

Melting point: 62 C.

EXAMPLE 5
2 - {[4 - ({2- [4- (2-Methoxy-phenyl) -piperazin-1-yl] -ethyl} -pyridin-2-yl-carbamoyl fumarate)
butylamino] methyl} -1-phenyl-N, N-diéthylcyclopropanecarboxamide

Compound 5 is prepared from (2- [4- (2-methoxy-phenyl) -piperazin-1-yl] -ethyl) -pyridin-2-yl-amine (1.0 g, 3.20 mmol). ), 5-bromovaleryl chloride (0.86 ml, 6.4 mmol) and 2-aminomethyl-1-phenyl-N, N-diethylcyclopropanecarboxamide (234 mg, 0.95 mmol) according to the procedure described for Preparation of Example 1 The syrup obtained is purified by chromatography on a column of silica eluted with a dichloromethane / methanol / ammonia mixture (90 / 9.5 / 0.5 then 86/13/1) to yield the desired amide in the form of a yellow syrup which, after salification with fumaric acid, gives compound 5 (368 mg, 20%).

Elemental analysis (C38H52N6O3, 2.3C4H4O4, 2.5H2O)% calculated: C 59.50H 7.00 N 8.82% found: C 59.18H 6.91 N 8.78
1H NMR, DMSO. d6 (ppm): 0.73 t, 2H; 1.02 t, 2H; 1.30 - 1.70 m, 9M; 2.20-2.30 m, 2H; 2.44-2.50 m, 6H; 2.80-3.00 m, 6H; 3.10-3.50 m, 6H; 3.74 s, 3H; 3.90 t, 2H; 6.54 s, 4H; 6.83-6.90 m, 4H; 7.21-7.35 m, 7H; 7.48 d, 1H; 7.89 dt, 1H; 8.49 dd, 1H.

Melting point: 50 ° C.

EXAMPLE 6
6 - [(2-Diethylcarbamoyl-2-phenyl-cyclopropylmethyl) -amino] -hexanoic fumarate 2- [4- (2-Methoxy-phenyl) -piperazin-1-yl] -ethyl} -pyrid-2- yl-am ide

Compound 6 is prepared from {2- [4- (2-methoxy-phenyl) -piperazin-1-yl] -ethyl} -pyridin-2-yl-amine (1.0 g, 3.20 mmol). ), 5-bromohexanoyl chloride (0.49 ml, 3.2 mmol) and 2-aminoetllyl-1-phenyl-N, N -dietylcyclopropanecarboxamide (324 mg, 1.31 mmol) according to the procedure described for the preparation of Example 1. The syrup obtained is purified by chromatography on a column of silica eluted with a dichloromethane / methanol / ammonia mixture (95 / 4.5 / 0.5 and then 90/9/1) to give the desired amide in the form of a yellow syrup which, after salification with fumaric acid, gives compound 6 (406 mg, 24%).

Elemental analysis (C39H54 N603, 2.3C4H4O4, 2.5H2O)% Calculated: C 59.87H 7.11 N 8.69% Found: C 59.49H 7.00 N 8.78
1H NMR, DMSO-d6 (ppm): 0.73 t, 3H; 1.02 t, 3H; 1.20-1.30 m, 2H; 1.39 t, 1H; 1.50-1.70 m, 6H; 2.20 broad s, 2H; 2.45-2.47 m, 6H; 2.83-2.94 m, 6H; 3.17-3.24 in, 3H; 3.34-3.43, 3H; 3.74 s, 3H; 3.89 t, 2H; 6.53 s, 4H; 6.81-6.94 m, 4H; 7.22-7.28 m, 6H; 7.47 d, 1H; 7.89 t, 1H; 8.49 d, 1H.

Melting point: 570C.

The antagonistic properties at the 5-HT1A receptors of the derivatives of general formula (I) forming part of the present invention were determined in the HeLa HA7 cell line expressing the human 5-HT1A receptor (Tulco, Duke Univ., Durham, NC, USA) and grown according to the method of
Fargin et al. (J. Biol Chem 264, 14848, 1983). The study of the binding of the derivatives of the present invention and the study of the inhibition of the formation of cyclic AMP (forskolin-stimulated) mediated by the 5-HT1A receptors were carried out according to a previously described technique ( Pauwels, PJ,
Van Gompel, P., Leysen, JE Biochem. Pharmacol. 45,375, 1993).

The efficacy of the derivatives of the present invention as inhibitors of the serotonin reuptake site was determined by a binding study at this site, a study carried out according to the technique described by Wong et al,
Neuropsychopharmacology, 8, 23, 1993, using [3H] -paroxetine in synaptosomal preparations of rat cerebral cortex.

The study of the compounds of the present invention in the pharmacological models mentioned above makes it possible to show that they are antagonists at the 5-HT1 A receptor and also inhibitors of the serotonin reuptake site.

The present invention also relates to pharmaceutical compositions containing as active ingredient a compound of general formula I or a pharmaceutically acceptable salt thereof, mixed or combined with a suitable excipient. These compositions may, for example, be in the form of solid, liquid compositions, emulsions, lotions or creams.

As solid compositions for oral administration may be used tablets, pills, powders (gelatin capsules, cachets) or granules. In these compositions, the active ingredient according to the invention is mixed with one or more inert diluents, such as starch, cellulose, sucrose, lactose or silica, under an argon stream. These compositions may also comprise substances other than diluents, for example one or more lubricants such as magnesium stearate or talc, a dye, a coating (dragees) or a varnish.

As liquid compositions for oral administration, it is possible to use pharmaceutically acceptable solutions, suspensions, emulsions, syrups and elixirs containing inert diluents such as water, ethanol, glycerol, vegetable oils or oil. of paraffin. These compositions may comprise substances other than diluents, for example wetting agents, sweeteners, thickeners, flavoring agents or stabilizers.

The sterile compositions for parenteral administration may preferably be aqueous or nonaqueous solutions, suspensions or emulsions. As the solvent or vehicle, water, propylene glycol, polyethylene glycol, vegetable oils, in particular olive oil, injectable organic esters, for example ethyl oleate or other suitable organic solvents may be used. These compositions may also contain adjuvants, in particular wetting agents, isotonic agents, emulsifiers, dispersants and stabilizers. Sterilization can be carried out in several ways, for example by aseptic filtration, by incorporating sterilizing agents into the composition, by irradiation or by heating. They can also be prepared as sterile solid compositions which can be dissolved at the time of use in sterile water or any other sterile injectable medium.

The compositions for rectal administration are suppositories or rectal capsules which contain, in addition to the active product, excipients such as cocoa butter, semisynthetic glycerides or polyethylene glycols.

The compositions for topical administration may be, for example, creams, lotions, eye drops, mouthwashes, nasal drops or aerosols.

The doses depend on the effect sought, the duration of treatment and the route of administration used; they are generally between 0.001 g and 1 g (preferably between 0.005 g and 0.25 g) per day, preferably orally for an adult with unit doses ranging from 0.1 mg to 500 mg of active substance, preferably from 1 mg to 50 mg.

In general, the doctor will determine the appropriate dosage depending on age, weight and all other factors specific to the subject to be treated. The following examples illustrate compositions according to the invention [in these examples, the term "active component" designates one or more (generally one) of the compounds of formula (I) according to the present invention:
tablets
They can be prepared by direct compression or by wet granulation. The direct compression procedure is preferred but may not be suitable in all cases depending on the doses and physical properties of the active component.

A - By direct compression
mg for I tablet active component 10.0 microcrystalline cellulose PCB 89.5 magnesium stearate 0.5
100.0
The active component is passed through a sieve of 250 mesh side, mixed with the excipients and compressed with 6.0 mm punches. Tablets having other mechanical strengths can be prepared by modifying the compression weight using appropriate punches.

B - wet granulation
mg per active component tablet 10.0 lactose Codex 74.5 starch Codex 10.0 pregelatinized maize starch Codex 5.0 magnesium stearate 0.5
Compression weight 100.0
The active component is passed through a 250 μm mesh screen and mixed with lactose, starch and pregelatinized starch. The mixed powders are moistened with purified water, granulated, dried, sieved and mixed with magnesium stearate.

The lubricated granules are tableted as for the direct compression formulas. A coating film can be applied to the tablets using suitable film forming materials, for example methylcellulose or hydroxypropylmethylcellulose, according to conventional techniques.

The tablets can also be coated with sugar.

capsules
mg for one capsule active component 10.0 * starch 1500 89.5 magnesium stearate Codex 0 * 5
Filling weight 100.0 * a form of directly compressible starch from Colorcon Ltd, Orpington, Kent,
United Kingdom.

The active component is passed through a 250 mesh sieve and mixed with the other substances. The mixture is filled into hard gelatin capsules n02 on a suitable filling machine. Other dosage units can be prepared by changing the filling weight and, where necessary, changing the size of the capsule.

Syrup
mg per dose of 5 ml active ingredient 10,0 sucrose Codex 2750,0 glycerin Codex 500,0 buffer) aroma) dye qs

preservative) distilled water 5.0
The active component, buffer, aroma, dye and preservative are dissolved in part of the water and the glycerin is added. The remainder of the water is heated to 800 ° C. and the sucrose is dissolved therein and then cooled. We combine the two solutions, adjust the volume and mix. The syrup obtained is clarified by filtration.

suppositories
Active ingredient 10.0 mg * Witepsol H15 supplement 1.0 g * Trademark for Adeps Solidus from the European Pharmacopoeia.

A suspension of the active component in Witepsol H 15 is prepared and introduced into a suitable machine with 1 g suppository molds.

Liquid for administration by intravenous injection g / l active component 2.0 water for injection Codex supplement to 1000.0
Sodium chloride can be added to control the tonicity of the solution and adjust the pH to maximum stability and / or to facilitate the dissolution of the active component by means of a dilute acid or alkali or by adding buffer salts appropriate. The solution is prepared, clarified and filled into ampoules of appropriate size which is sealed by melting the glass. The liquid for injection can also be sterilized by autoclaving in one of the acceptable cycles. It is also possible to sterilize the solution by filtration and to introduce sterile ampoule under aseptic conditions. The solution can be introduced into the ampoules in a gaseous atmosphere.

Inhalation cartridges
g / micronized active component cartridge 1.0 lactose Codex 39.0
The active component is micronized in a fluid energy mill and placed in the form of fine particles before mixing with lactose for tablets in a high energy mixer. The powder mixture is filled into hard gelatin capsules No. 3 on a suitable encapsulating machine The contents of the cartridges are administered by means of a powder inhaler.

Aerosol under pressure with metering valve
mg / dose for micronized active ingredient box 0.500 120 mg oleic acid Codex 0.050 12 mg trichlorofluoromethane for use
Pharmaceutical 22.25 5.34 g dichlorodifluoromethane
for pharmaceutical use 60.90 14.62 g
The active component is micronized in a fluid energy mill and placed in the form of fine particles.

The oleic acid is mixed with the trichlorofluoromethane at a temperature of 10-150C and the micronized drug is introduced into the solution using a high shear mixer. The suspension is introduced in measured quantities into aluminum aerosol cans to which are attached appropriate metering valves delivering a dose of 85 mg of the suspension; dichlorodifluoromethane is introduced into the boxes by injection through the valves.

Claims (16)

1. Compounds corresponding to the general formula (I):

X is O, S or CH2; m represents an integer between I and 4; or incurred, R1 and R2, with the nitrogen to which they are attached, form a ring selected from the following residues F, CF3, CH3, OCH3, OH or CH2OH Ar 3 represents a phenyl optionally substituted by one or more substituents chosen from Cl, Br, Ar 2 represents an aromatic residue such as phenyl or thienyl; Ar 1 represents an aromatic residue such as phenyl or naphthyl, optionally substituted with one or more substituents selected from halogen (F, Cl, Br), CH 3, OCH 3, CF 3 or SCH 3;  wherein,

R2 represents a substituent chosen from:  or an arylalkyl such as benzyl or phenethyl  R1 represents a hydrogen, a linear or branched alkyl comprising from 1 to 8 carbon atoms  n represents zero or an integer between 1 and 3  in which, R3 and R4, which are different from one another, represent either a hydrogen or an aromatic residue such as phenyl, pyridyl or pyrimidyl, which may be variously substituted with one or more linear, cyclic or branched, saturated or unsaturated hydrocarbon radicals; comprising 1 to 8 carbon atoms, a halogen (Cl, Br, F or I), a CF3 residue, an ether residue (OR6) or thioether (SR6) in which R6 represents a linear or branched alkyl comprising from 1 to 6 carbon atoms. Ar represents an aromatic radical such as a phenyl, naphthyl, indolyl, thienyl, pyridyl, pyrimidyl, benzodioxane, benzodioxolane whose aromatic ring may be optionally substituted by one or more substituents chosen from a linear, cyclic or branched hydrocarbon radical, saturated or unsaturated compound comprising 1 to 8 carbon atoms, a halogen (Cl, Br, F or I), a CF3 residue, an ether residue (ORs) or thioether (SRg) in which R5 represents a linear or branched alkyl comprising from 1 to 6 carbon atoms, Y is CH or N, with the proviso that n is not zero when Y is N; and their physiologically acceptable salts, hydrates, solvates and bioprecursors for therapeutic use. Z represents (CH 2) n, O- (CH 2) n, NH- (CH 2) n, (CH 2) k-C 6 H 4 - (CH 2) l, O- (CH 2) k-C 6 H 4 - (CH 2) 1 or NH (CH 2) k-C6H4- (CH2) 1, whereinj represents an integer from 2 to 10, while k and the same or different are an integer from 1 to 4; Said compounds of general formula I may be in the form of geometric and / or optical isomers as well as racemic mixtures. 2. Compounds according to claim 1 characterized in that Ar represents an ortho-methoxy-phenyl. 3. Compounds according to claim 1 characterized in that Y represents CH and R3 represents a  phenyl. 4. Compounds according to claim 1 characterized in that Y represents N and R3 represents a 2  pyridyl. 5. Compounds according to claim 1 having the general formula la.

6. Compounds according to claim 1, characterized in that R2 represents a residue chosen from

  7. Compounds according to claim 1 characterized in that R2 represents

 8. Compounds according to claim 1 characterized in that R2 represents

 9. Compounds according to claim 1 characterized in that R1 and R2, with the nitrogen atom to which they  are attached, form a ring selected from the following two substituted piperidines

 10. Compounds according to one of claims I to 9 in the salt state acceptable for therapeutic use  characterized in that the salts are hydrochlorides, hydrobromides, sulphates, methanesulphonates,  fumarates, maleates, succinates, phosphates, acetates, benzoates, naphthoates, p-toluenesulphonates,  sulfamates, ascorbates, tartrates, citrates, salicylates, lactates, glutarates or glutaconates. 11. General process for the preparation of the compounds of formula (f) in which an R1R2NH amine in  which R1 and R2 are defined as in formula I is condensed with an electrophile of formula  general (II)

 hence such as halogen (chlorine, bromine or iodine), mesylate, tosylate or triflate.  wherein Ar, n, R3, R4, Y and Z are defined as in formula I and P is a group 12. Pharmaceutical compositions containing, as an active ingredient, a compound according to any one of  Claims I to 10 in combination with an acceptable pharmaceutical carrier, such as  drugs. 13. Pharmaceutical compositions containing, as an active ingredient, a compound according to any of  Claims 1 to 10 in combination with a pharmaceutically acceptable carrier for the treatment  both curative and preventive of serotonin-related disorders. 14. Pharmaceutical compositions containing, as an active ingredient, a compound according to any one of  Claims 1 to 10 in combination with a pharmaceutically acceptable carrier for the treatment  cure and prevention of depression, obsessive compulsive disorder and the tendency to  suicide. 15. Pharmaceutical compositions containing, as an active ingredient, a compound according to any of  Claims I to 10 in combination with a pharmaceutically acceptable carrier for the treatment  both preventive and curative of panic attacks, anxiety, alcohol-related disorders,  tobacco addiction, sexual dysfunction and sleep disorders. 16. As medicaments, the compounds of general formula I according to one of claims I to 10.