FR2744450A1 - NOVEL NAPHTYLPIPERAZINES DERIVED FROM SUBSTITUTED CYCLOAZANES, AS WELL AS THEIR PREPARATION METHOD, PHARMACEUTICAL COMPOSITIONS AND THEIR USE AS MEDICAMENTS - Google Patents

Abstract

Compounds of formula (I), wherein, R1 is hydrogen or straight or branched C1-6 alkyl, Z2 is O, NH, CH2O or CH2NH, each of R2 and R3, which are the same or different, is hydrogen or a group selected from straight or branched alkyl, alkoxy, thioether, nitrile, trifluoromethyl or halogen (F, Cl, Br, I), X-Y is NCH2, CH-CH2, C=CH, N or NCH2CH2, and Z1 is -(CH2)n-, -(CH2)n CO-, -CO-, -CO(CH2)n-, -SO2-, -SO2(CH2)n-, -O(CH2)n-, -O(CH2)n-CO-, -OCO-, -NH(CH2)n-, -NH(CH2)nCO-, -NHCO-, -NHCO(CH2)n-, -NH(CH2)SO2-, -NHSO2-, -NHSO2(CH2)n-, -CH=CHCO-, -CCCO- -(CH2)nSO2-, -O(CH2)nSO2-, are disclosed.

Description

 The present invention relates to new naphthylpiperazines derived from substituted cycloazanes. as well as their preparation process, the pharmaceutical compositions containing them and their use as medicaments.

 Serotonin or 5-hydroxytryptamine (5-HT) is a neurotransmitter and a neuromodulator involved in many physiological and pathological processes. Serotonin plays an important role both in the nervous system and 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 medulla, serotonin plays an important role in the control systems of the afferent peripheral nociceptives (cf. A. Moulignier, Rev. Neurol. (Paris), 150,315,1994).

Serotonin can 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 (dementia of the Alzheimer type, Parkinsonism , chorea of
Huntington), anorexia, bulimia, 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 as well as their respective involvement in its various modes of action (cf. E. Zifa, G. Fillion, Pharm
Reviews, 44.401, 1992; S. Langer, N. Brunello, G. Racagni, J.

Mendelecvicz, "Serotonin receptor subtypes: pharmacological significance and clinical implications", Karger Ed. (1992); B.E. Leonard, Int. Clin.

 Psycho-pharmacology, 7, 13-21 (1992) R.W. Fuller; J. Clin. Psychiatry, 53, 36-45 (1992); D.G. Grahame-Smith, Int. Clin. Psychopharmacology, 6, suppl. 4, 6-13, (1992). These receptors are mainly subdivided into 4 main classes (5HT1, 5HT2, 5HT3 and 5HT4) which themselves have subclasses such as the 5HTI receptors which are mainly divided into 5HT1A, 5HT1B, 5HTlD (cf. G.R. Martin, P.A.

Humphrey, Neuropharmacol., 33, 261, 1994; P.R. Saxena, Exp. Opin. Invest.

Drugs, 3 (5), 513, 1994). The 5HT1D receptors themselves contain several subtypes of c receptors, as well as the 5HTIDa receptors and
SHTIDb have been cloned and then identified in humans (cf. for example E.

Hamel et al., Mol. Pharmacol., 44, 242, 1993; G.W. Rebeck et al., Proc.

Natl. Acad. Sci. USA, 91.3666, 1994). Furthermore, it has recently been demonstrated that the 5HTlB receptors in rodents and 5HTlD in other species are capable of controlling the release of serotonin in the nerve endings (cf. M. Briley, C. Moret, Cl. Neuropharm.

16,387,1993; B.E. Léonard, Int. Clin. Psychopharmacol., 9,7, 1994) as well as the release of other neurotransmitters such as norepinephrine, dopamine or acetylcholine (pal. Harrrington, J. Clin. Psychiatry, 53.10, 1992).

Compounds having a selective antagonist activity at the level of central 5HT1D receptors such as the new compounds described in the present invention can therefore exert a beneficial effect on subjects suffering from disorders of the central nervous system. In particular, such compounds find their utility in the treatment of disorders of locomotion, depression, anxiety, panic attacks,
Agoraphobia, obsessive compulsive disorders, memory disorders including dementia, amnesia, and appetite disorders, sexual dysfunctions, pain, Alzheimer's disease, Parkinson's disease. 5HT1D are also useful in the treatment of endocrine disorders such as hypcrprolactinaemia, the treatment of vasospasms, hypertension and gastrointestinal disorders in which changes in motility and secretion occur.

 The compounds according to the present invention are potent and selective antagonists of 5HT1 D receptors and more particularly receptors recently identified as 5HTIDa and 5HTIDb in humans and therefore find their utility, alone or in combination with other molecules, such as drugs and more particularly as therapeutic means for both curative and preventive treatment of disorders linked to serotonin.

The prior art in this field is illustrated in particular by patents EP-0533266, EP-0533267 and EP-0533268, GB-2273930, WO-9415920, GB-2276160, GB-2276161, GB-2276162,
GB-2276163, GB-2276164, GB-2276165, WO-9504729, WO-9506044, WO-9506637, WO-951 1243 and F 9408981 which describe aromatic derivatives as 5HT1D antagonists, and recent publications which describe GR 127,935 as 5HT1D antagonist (cf. M. Skingle et al.,
J. of Psychopharm. S (1), 14, 1994; S. Starkey, M. Skingle, Neuropharmacol., 33,393, 1994).

 The derivatives of the present invention are distinguished from the prior art not only by their new chemical structure which unambiguously distinguishes them from the previously described derivatives but also by their original biological profile, in particular as regards their selectivity and their effectiveness as antagonists at the level of the serotonin receptor subtypes (5HTlDa and p).

dans laquelle
R1 représente un hydrogène ou un alkyle linéaire ou ramifié comprenant de
1 à 6 atomes de carbone,
Z2 représente O, NH, CH2O ou CH2NH,
R2 et R3 identiques ou différents représentent un hydrogène ou un groupe choisi parmi un alkyle linéaire ou ramifié, un alcoxy, thioéther, nitrile, trifluorométhyle ou halogène (F, Cl, Br, I)
X-Y représente NCH2, CH-CH2, C=CH, N ou NCH7CH2, Z1 représente -(CH2)n-, -(CH2)n CO-, -CO-, -CO(CH2)n-, -S02-, -
S02(CH2)n-, -O(CH2)n-, -O(CH2)nCO-. -OCO-, -NH(CH2)n-,
NH(CH2)nCO-, -NHCO-, -NHCO(CH2)n-, -NH(CH2)nSO2-, -NHSO2-, - NHS02(CH2)n-, -CH CHCO-,-CCCO-,-(CH2)nSO2-, -o(CH2)nSo2-
Dans le cas particulier où X-Y représente CH-CH2, Z1 peut également représenter -O-, -NH-, -CONH-, -S02NH-, -OCONH-, -NHCOO-, -NHCONH-, -(CH2),NH-, -(CH2)nO-, -CO(CH2)nNH-, -NH(CH2)nO-, -NH(CH2) n NH-,-O (CH2)nNH-, -O(CH2)nO-, -CO(CH2)nO-, -S02(CH2)nNH-s -S02(CH2)nO- , (CH2)nS02NH-, -(CH2)nCONH-, -O(CH2)nSO2NH-, -O(CH2)nCONH-, NH(CH2)nS02NH-, -NH(CH2)nCONH-, -NHCO(CH2)nNH-,
NHSO2(CH2)nNH- dans lesquels n représente un nombre entier compris entre 1 et 6,
Dans le cas particulier où X-Y représente CH-CH2 ou C=CH Z 1 peut également représenter -CH=CH-, -CC-, Ar1 représente un reste aromatique (phényl, naphtyl ou pyridyl) pouvant être diversement substitué par exemple par un ou plusieurs groupes choisis parmi un alkyle linéaire ou ramifié comprenant de 1 à 6 atomes de carbone, un trifluorométhyle, un trifluorométhoxy, un 2,2,2-trifluoroéthyle, un phényle, un benzyle, un cycloalkyle comprenant de 3 à 7 atomes de carbone, un hydroxyle, un thiol, un alcoxy (OR4), thioéther (SR4), un nitro (NO2), un nitrile (CN), une amine (NH2 ou NR4R4'), un dérivé d'amine (NHCOR4,
NHSO2R4, NHCONR4R'4, NHCO2R4, NHSO2NR4R'4), un halogène (fluor, chlore, brome ou iode), un carbonyle (COH, COR4, COOR4, CONR4R'4) ou un hétérocycle pouvant éventuellement être substitué tel qu'un hétérocycle à 5 membres pouvant contenir de 1 à 4 hétéroatomes choisis parmi l'oxygène, le soufre ou l'azote ou par deux substituants sur des carbones voisins pouvant former un cycle avec le reste aromatique auquel ils sont attachés, ou encore, le reste Ar-Z1 représente un tétrahydronaphtyle dont la liaison avec X met en oeuvre un carbone saturé,
R4 représente un reste alkyle, linéaire ou ramifié, comprenant de 1 à 6 atomes de carbone, R'4 représente un hydrogène ou un reste alkyle, linéaire ou ramifié, comprenant de 1 à 6 atomes de carbone et leurs sels hydrates, solvates et bioprécurseurs physiologiquement acceptables pour l'usage thérapeutique.The present invention relates to products of general formula (I)

in which
R1 represents a hydrogen or a linear or branched alkyl comprising
1 to 6 carbon atoms,
Z2 represents O, NH, CH2O or CH2NH,
R2 and R3, identical or different, represent hydrogen or a group chosen from linear or branched alkyl, alkoxy, thioether, nitrile, trifluoromethyl or halogen (F, Cl, Br, I)
XY represents NCH2, CH-CH2, C = CH, N or NCH7CH2, Z1 represents - (CH2) n-, - (CH2) n CO-, -CO-, -CO (CH2) n-, -S02-, -
S02 (CH2) n-, -O (CH2) n-, -O (CH2) nCO-. -OCO-, -NH (CH2) n-,
NH (CH2) nCO-, -NHCO-, -NHCO (CH2) n-, -NH (CH2) nSO2-, -NHSO2-, - NHS02 (CH2) n-, -CH CHCO -, - CCCO -, - ( CH2) nSO2-, -o (CH2) nSo2-
In the particular case where XY represents CH-CH2, Z1 can also represent -O-, -NH-, -CONH-, -S02NH-, -OCONH-, -NHCOO-, -NHCONH-, - (CH2), NH- , - - CH2 nO-, -CO (CH2) nNH-, -NH (CH2) nO-, -NH (CH2) n NH -, - O (CH2) nNH-, -O (CH2) nO-, - CO (CH2) nO-, -S02 (CH2) nNH-s -S02 (CH2) nO-, (CH2) nS02NH-, - (CH2) nCONH-, -O (CH2) nSO2NH-, -O (CH2) nCONH -, NH (CH2) nS02NH-, -NH (CH2) nCONH-, -NHCO (CH2) nNH-,
NHSO2 (CH2) nNH- in which n represents an integer between 1 and 6,
In the particular case where XY represents CH-CH2 or C = CH Z 1 can also represent -CH = CH-, -CC-, Ar1 represents an aromatic residue (phenyl, naphthyl or pyridyl) which can be variously substituted for example by one or several groups chosen from a linear or branched alkyl comprising from 1 to 6 carbon atoms, a trifluoromethyl, a trifluoromethoxy, a 2,2,2-trifluoroethyl, a phenyl, a benzyl, a cycloalkyl comprising from 3 to 7 carbon atoms, a hydroxyl, a thiol, an alkoxy (OR4), thioether (SR4), a nitro (NO2), a nitrile (CN), an amine (NH2 or NR4R4 '), an amine derivative (NHCOR4,
NHSO2R4, NHCONR4R'4, NHCO2R4, NHSO2NR4R'4), a halogen (fluorine, chlorine, bromine or iodine), a carbonyl (COH, COR4, COOR4, CONR4R'4) or a heterocycle which can possibly be substituted such as a heterocycle with 5 members which may contain from 1 to 4 heteroatoms chosen from oxygen, sulfur or nitrogen or by two substituents on neighboring carbons which can form a ring with the aromatic residue to which they are attached, or alternatively, the remainder Ar- Z1 represents a tetrahydronaphthyl whose bond with X implements a saturated carbon,
R4 represents an alkyl residue, linear or branched, comprising from 1 to 6 carbon atoms, R'4 represents a hydrogen or an alkyl residue, linear or branched, comprising from 1 to 6 carbon atoms and their hydrate salts, solvates and bioprecursors physiologically acceptable for therapeutic use.

The geometric and optical isomers of the compounds of general formula (I) also form part of the present invention as well as their mixture in racemic form.

Among the physiologically acceptable salts of the compounds of general formula (I) are included the salts obtained by adding organic or inorganic acids such as chlorohydrates, hydrobromides, sulfates, phosphates, benzoates, acetates, naphthoates, p-toluenesulfonates, methanesulfonates, sulphamates . ascorbates, tartrates, citrates, oxalates, maleates, salicylates. fumarates, succinates, lactates, glutarates, glutaconates.

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

dans laquelle Arl, Z1, X-Y, Z2 et R1 sont définis comme dans la formule I.A particularly appreciated class of compounds of formula (I) corresponds to the compounds of formula (la)

in which Arl, Z1, XY, Z2 and R1 are defined as in formula I.

The compounds of the present invention can be prepared by different methods which will be dependent on the nature of Arl. Z1, X, Y, Z2 and R1.

It will be understood that in certain reactions or sequences of chemical reactions which lead to the preparation of compounds of 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 protective groups such as those described in "Protective groups in Organic Synthesis", TW Greene, John Wiley & BR <
Sons, 1981 and "Protecting Groups", PJ Kocienski, Thieme Verlag, 1994.

The appropriate protective groups will therefore be introduced and removed during the most appropriate step for this and using the methods and techniques described in the references cited above.

dans laquelle Arl, Z1 et X-Y sont définis comme précédemment et Y' représente un groupe partant tel qu'un halogène (chlore, brome ou iode), un tosylate, un mésylate ou un triflate avec une naphtyl-pipérazine de formule générale (III):

dans laquelle X' représente O ou NH et R1, R2 et R3 sont décrits comme précédemment.La condensation des naphtylpipérazines de formule (III) avec les électrophiles de formule (II) est réalisée en présence d'une base organique ou inorganique telle que NaH, KH, DiPEA, DBU, pyridine,
DMAP, K2CO3, CaCO3, Cs2CO3, en présence éventuellement d'un iodure tel que NaI, KI, Bu4NI, dans un solvant anhydre polaire tel que le THF, le
DME, le n-butanol, le t-butanol, le DMF, le DMSO, la méthyléthylcétone, à une température comprise entre 20" et 80". Les intermédiaires de formule générale (II) sont aisément préparés par condensation d'une amine cyclique de formule générale (IV)::

dans laquelle Arl, Z1, X-Y sont définis comme précédemment et un chlorure d'acide de formule générale (V)
Y' - CH2 - C(O)CI (v) dans laquelle Y' est décrit comme précédemment en présence d'une base organique ou inorganique telle que la pyridine, la DiPEA, la DMAP, le
DBU, K2CO3, Cs2CO3 ou CaCO3 dans un solvant anhydre aprotique polaire tel que le THF, le DMF, le DME, le DMSO ou la méthyléthylcétone à une température comprise entre - 10 C et 300 C.The compounds of general formula (I) in which Ar1, Z1, XY, R1, R2,
R3 are described as above and Z2 represents -CH2O- or -CH2NH are prepared by condensation of an intermediate of formula (II):

in which Arl, Z1 and XY are defined as above and Y 'represents a leaving group such as a halogen (chlorine, bromine or iodine), a tosylate, a mesylate or a triflate with a naphthyl-piperazine of general formula (III) :

in which X 'represents O or NH and R1, R2 and R3 are described as above. The condensation of the naphthylpiperazines of formula (III) with the electrophiles of formula (II) is carried out in the presence of an organic or inorganic base such as NaH , KH, DiPEA, DBU, pyridine,
DMAP, K2CO3, CaCO3, Cs2CO3, optionally in the presence of an iodide such as NaI, KI, Bu4NI, in a polar anhydrous solvent such as THF,
DME, n-butanol, t-butanol, DMF, DMSO, methyl ethyl ketone, at a temperature between 20 "and 80". The intermediates of general formula (II) are easily prepared by condensation of a cyclic amine of general formula (IV):

in which Arl, Z1, XY are defined as above and an acid chloride of general formula (V)
Y '- CH2 - C (O) CI (v) in which Y' is described as above in the presence of an organic or inorganic base such as pyridine, DiPEA, DMAP,
DBU, K2CO3, Cs2CO3 or CaCO3 in a polar aprotic anhydrous solvent such as THF, DMF, DME, DMSO or methyl ethyl ketone at a temperature between - 10 C and 300 C.

dans laquelle R2 et R3 sont définis comme précédemment avec un dérivé d'amine de formule (VII):: R1,-N-(CH2CH2Y)2 (vil) dans laquelle Rl est équivalent à R1 tel que défini comme précédemment ou Rl
représente un groupe protecteur tel qu'un t-butoxycarbonyle ou un tosyle (qui sera transformé en R1 ultérieurement) et Y représente un chlore, un brome, un iode, un tosylate ou un mésylate. Cette réaction est réalisée préférentiellement dans un solvant anhydre polaire tel que le DMF,
I'acétonitrile, le THF, le n-butanol, le t-butanol ou le DMSO, généralement à température de reflux du solvant utilisé, en présence d'une base organique ou inorganique généralement utilisée pour ce type de réaction, telle qu'un carbonate de potassium, de sodium ou de calcium.The intermediates of general formula (III) are prepared by various methods and techniques well known to those skilled in the art for the preparation of arylpiperazines and the choice of which depends on the nature of X 'and of R1, R2, R3. Thus, in the particular case where X 'is an oxygen, the intermediates of formula (III) are accessible by condensation of a naphthylamine of formula (Vl)

in which R2 and R3 are defined as above with an amine derivative of formula (VII) :: R1, -N- (CH2CH2Y) 2 (vil) in which R1 is equivalent to R1 as defined above or R1
represents a protective group such as a t-butoxycarbonyl or a tosyle (which will be transformed into R1 later) and Y represents a chlorine, a bromine, an iodine, a tosylate or a mesylate. This reaction is preferably carried out in a polar anhydrous solvent such as DMF,
Acetonitrile, THF, n-butanol, t-butanol or DMSO, generally at reflux temperature of the solvent used, in the presence of an organic or inorganic base generally used for this type of reaction, such as potassium, sodium or calcium carbonate.

dans laquelle R2 et R3 sont définis comme précédemment et X" représente une fonction qui pourra ultérieurement être transformée en amine (telle que par exemple un groupe nitro) soit avec un dérivé de bis(halogénoéthyl)amine de formule (VII) dans les conditions décrites précédemment pour ce type de réaction, soit avec un aminoacide de formule générale (XI)

dans laquelle R'1 est défini comme précédemment. en présence d'anhydride acétique, suivi de la réduction de la dicétopipérazine intermédiaire ainsi formée avec par exemple un borane. Dans les deux cas, le dérivé de formule (III) sera finalement obtenu après transformation du groupe représenté par
X" en amine.S'il s'agit d'un groupe nitro, cette transformation sera effectuée selon les méthodes et techniques bien connues de l'homme de métier pour transformer un nitroaromatique en un dérivé d'aniline telles que par exemple l'emploi de Nickel de Raney ou de catalyseur au rhodium en présence d'hydrazine, I'hydrogénation sur charbon-palladium à pression atmosphérique, ou encore l'utilisation de SnC12 ou de zinc.The compounds of general formula (III) in which X 'represents NH are prepared by condensation of an aromatic naphthylamine derivative of general formula (X)

in which R2 and R3 are defined as above and X "represents a function which can subsequently be converted into an amine (such as for example a nitro group) either with a bis (haloethyl) amine derivative of formula (VII) under the conditions described previously for this type of reaction, either with an amino acid of general formula (XI)

in which R'1 is defined as above. in the presence of acetic anhydride, followed by the reduction of the intermediate diketopiperazine thus formed with, for example, a borane. In both cases, the derivative of formula (III) will finally be obtained after transformation of the group represented by
X "into an amine. If it is a nitro group, this transformation will be carried out according to methods and techniques well known to those skilled in the art for transforming a nitroaromatic into an aniline derivative such as for example the use of Raney nickel or rhodium catalyst in the presence of hydrazine, hydrogenation on carbon-palladium at atmospheric pressure, or the use of SnCl2 or zinc.

dans laquelle X1 et X2, identiques ou différents représentent chacun un groupe partant tel qu'un halogène (en particulier le chlore), un groupe Oalkyle (en particulier le groupe OC13), un groupe succinimyle, phtalyle ou imidazolyle. La méthode de la présente invention comprend également l'utilisation de précurseurs ou analogues bien connus des réactifs de formule générale (XII).C'est ainsi et à titre d'exemple que la condensation des intermédiaires (III) et (IV) avec le phosgène peut être avantageusement effectuée à l'aide de diphosgène ou de triphosgène selon une procédure bien connue de l'homme de l'art. The compounds of general formula (I) in which Arl, Z1, XY, R1, R2 and
R3 are described as above and Z2 represents O or NH are prepared by condensation of an intermediate of general formula (III) in which X 'represents O or NH, and R1, R2 and R3 are defined as previously, and of an amine cyclic of formula (IV) in which Arl,
Z1, XY are defined as above, with a derivative of general formula (XII):

in which X1 and X2, identical or different, each represent a leaving group such as a halogen (in particular chlorine), an Oalkyl group (in particular the group OC13), a succinimyl, phtalyl or imidazolyl group. The method of the present invention also comprises the use of precursors or analogues well known to the reagents of general formula (XII). It is thus and by way of example that the condensation of intermediates (III) and (IV) with the phosgene can advantageously be carried out using diphosgene or triphosgene according to a procedure well known to those skilled in the art.

The methods and techniques chosen for carrying out the preparation of the compounds of formula (I) in which Z2 represents O or
NH by condensation of the derivatives of formulas (III) in which X 'represents O or NH and of derivatives of formula (IV) with a reagent of formula (XII) such as the choice of the order of the reagents, the reaction times,
The isolation and / or purification of the intermediates, the temperature of the reaction at different stages of the condensation, the nature of the solvent (s), the presence of co-reactants (such as an organic or inorganic base, for example an amine tertiary) or catalysts and the choice of reagent (XII) (choice of X1 and X2) will be determined by the nature of Arl, Z1, Z2 (O or NH), XY and R1.

Thus, a particularly appreciated method for the preparation of derivatives of formula (I) in which Z2 = NH and Arl, Z1, XY and R1, R2,
R3 are defined as above, consists in reacting an intermediate of formula (III) in which X 'represents NH with triphosgene in the presence of a base such as triethylamine in an anhydrous solvent such as dichloromethane and then adding a compound of formula (IV) in which Arl, Z1 and XY are defined as above in the presence of a base such as a tertiary amine.

avant de le condenser avec un nucléophile de formule générale (III) dans laquelle X' représente un oxygène, en présence d'une base organique ou inorganique telle que NaH, KH. t-BuOK dans un solvant aprotique polaire tel que le THF ou le DMF.In the case of the preparation of derivatives of general formula (I) in which Arl, Z1, XY and Rl, R2, R3 are defined as above and
Z2 represents oxygen, a particularly preferred method consists in first condensing a cyclic amine of formula (IV) with triphosgene in the presence of triethylamine in an anhydrous solvent such as dichloromethane and in isolating the intermediate of general formula ( XIII) thus formed

before condensing it with a nucleophile of general formula (III) in which X ′ represents oxygen, in the presence of an organic or inorganic base such as NaH, KH. t-BuOK in a polar aprotic solvent such as THF or DMF.

dans laquelle X1, R1, R2 et R3 sont définis comme précédemment et Z2 représente O ou NH, en présence d'une base organique ou inorganique dans un solvant polaire aprotique à une température comprise entre 20 et 1000
C.Also to be considered as forming part of the present invention are the methods which make it possible to prepare the products of formula (I) in which Z? represents O or NH by condensation of a cyclic amine of formula (IV) with a derivative of general formula (XIV):

in which X1, R1, R2 and R3 are defined as above and Z2 represents O or NH, in the presence of an organic or inorganic base in a polar aprotic solvent at a temperature between 20 and 1000
vs.

The intermediates of general formula IV in which Arl, Z1 and XY are defined as above are generally prepared by various methods and techniques well known to those skilled in the art, as described for example in patents DE 2801195 , EP 7067 (800123),
EP 12643 (800625), FR 2459795 (810116), EP 372776 (900613), FR 2678270 (921231), FR 2675801 (921030), EP 580398 (940126), WO 9401403 (940120) as well as the publications J. Med. Chem. 34, 3011, (1991); J. Chem. Soc. Chem. Comm. 2, 142, (1989); Tetrahedron 47 5161 (1991); Synthesis II, 1023 (1991); Izobretaniya 37, 89 (1992) and
Tetrahedron Lett. 35, 973, (1994).

A particularly preferred method for the preparation of cyclic amines of formula (IV), in the context of the present invention, consists in preparing these derivatives from precursors of general formula XV.

in which Arl, ZI and XY are defined as above and P represents a protective group usually used to protect a secondary amine such as for example a benzyl, a benzyl whose aromatic is substituted, an acetyl, a trifluoroacetyl, a benzyloxycarbonyl or a t-butoxycarbonyl. The methods used to transform the precursor of general formula (XV) into a cyclic amine IV will obviously depend on the nature of P, and are described in Protective Groups in Organic Synthesis "TW Greene, John Wiley & Sons, 1981 or even" Protecting Group "PJ Kocienski, Thieme Verlag, 1994. It is understood that the choice of the nature of the protective group P will be determined according to the methods and techniques used for the preparation of the intermediates of formula XV.

dans laquelle P représente un groupe protecteur d'une amine tel que décrit précedemment, avec un électrophile de formule XVII
Arl - Z1 - L (xvll) dans laquelle Arl et Z1 sont définis comme précédemment et L représente un groupe partant.La nature de L et les conditions expérimentales utilisées pour réaliser cette condensation dépendront surtout de la nature de Z î. C'est ainsi que, dans le cas où Z1 représente -(CH2)n, O(CH2)n-, CO(CH2)n,
NH(CH2)n, NHCO(CH2)n, SO2(CH2)n, NHSO2(CH2)n ;; cette condensation pourra être réalisée entre un intermédiaire de formule (XVI) et un électrophile de formule XVII dans laquelle L sera choisi parmi Cl, Br, I,
OTs, OMs, OTf, en présence d'une base organique (tel que par exemple une amine tertiaire) ou inorganique (tel que par exemple Cs2CO3, K2CO3 ou
Na2CO3) dans un solvant anhydre polaire tel que le THF, le DME, le DMF ou le DMSO, I'isopropanol ou le t-butanol, à une température comprise entre O"C et 80"C. Une méthode de préparation alternative mais particulièrement appréciée de ces mêmes dérivés de formule (XV) dans laquelle X représente un azote et Z1 représente (CH2)n, NH(CH2)n, O(CH2)n, SO2(CH2)n,
NHSO2(CH2)n ou NHCO(CH2)n consiste à condenser une amine cyclique de formule (XVI) dans laquelle X représente un azote avec un aldéhyde de formule XVIII:

dans laquelle Arl est défini comme précédemment et Z2 représente un reste Z1 tronqué d'un méthylène, dans les conditions bien connues sous l'appelation "amination reductrice" telles que par exemple celles décrites dans Synlett, 1079, 1995.Dans le cas où Z1 représente (CH2) nCO,
O(CH2)nCO, NH(CH2)nCO, CH = CHCO, CCCO, CO ou SO2(CH2)nCO, la condensation d'une amine cyclique de formule XVI sera effectuée avec un dérivé d'acide carboxylique de formule (XVII) dans laquelle L représente un chlore ou encore l'intermédiaire (XVII) représente une forme activée d'un acide carboxylique propice à la formation d'une amide par réaction avec une amine par les méthodes et techniques bien connues de l'homme de l'art pour ce type de transformation.Dans le cas où Z1 représente NHSO?, SO2,
O(CH2)nSO2 NH(CH2)nSO2 ou (CH2)nSO2. les intermédiaires de formule (XVI) sont condensés avec des chlorures de sulfonyle de formule XVII dans laquelle L représente Cl, par les méthodes bien connues de l'homme de l'art pour préparer une sulfonamide à partir d'un chlorure de sulfonyle et d'une amine.In the particular case where XY represents NCH2, N or NCH2CH2, a particularly appreciated method of preparing the compounds of formula
XV consists in condensing an intermediate of formula XVI

in which P represents a protective group of an amine as described above, with an electrophile of formula XVII
Arl - Z1 - L (xvll) in which Arl and Z1 are defined as above and L represents a leaving group. The nature of L and the experimental conditions used to carry out this condensation will depend mainly on the nature of Z î. Thus, in the case where Z1 represents - (CH2) n, O (CH2) n-, CO (CH2) n,
NH (CH2) n, NHCO (CH2) n, SO2 (CH2) n, NHSO2 (CH2) n ;; this condensation can be carried out between an intermediate of formula (XVI) and an electrophile of formula XVII in which L will be chosen from Cl, Br, I,
OTs, OMs, OTf, in the presence of an organic base (such as for example a tertiary amine) or inorganic (such as for example Cs2CO3, K2CO3 or
Na2CO3) in a polar anhydrous solvent such as THF, DME, DMF or DMSO, isopropanol or t-butanol, at a temperature between 0 "C and 80" C. An alternative but particularly appreciated method of preparation of these same derivatives of formula (XV) in which X represents a nitrogen and Z1 represents (CH2) n, NH (CH2) n, O (CH2) n, SO2 (CH2) n,
NHSO2 (CH2) n or NHCO (CH2) n consists in condensing a cyclic amine of formula (XVI) in which X represents a nitrogen with an aldehyde of formula XVIII:

in which Arl is defined as above and Z2 represents a truncated residue Z1 of a methylene, under the conditions well known under the name "reductive amination" such as for example those described in Synlett, 1079, 1995. In the case where Z1 represents (CH2) nCO,
O (CH2) nCO, NH (CH2) nCO, CH = CHCO, CCCO, CO or SO2 (CH2) nCO, the condensation of a cyclic amine of formula XVI will be carried out with a carboxylic acid derivative of formula (XVII) in which L represents a chlorine or else the intermediate (XVII) represents an activated form of a carboxylic acid favorable to the formation of an amide by reaction with an amine by the methods and techniques well known to the man of the art for this type of transformation. In the case where Z1 represents NHSO ?, SO2,
O (CH2) nSO2 NH (CH2) nSO2 or (CH2) nSO2. the intermediates of formula (XVI) are condensed with sulphonyl chlorides of formula XVII in which L represents Cl, by methods well known to those skilled in the art for preparing a sulphonamide from a sulphonyl chloride and d 'an amine.

In the case of the compounds of formulas (XV) in which Arl, and P are defined as above, X represents a nitrogen and Z1 represents OCO or NHCO, the preparation methods consist, for example, of condensing either a phenol (ArlOH) or a aniline (ArlNH2) and an amine of formula (XVI) with a reagent of formula XII by the methods and techniques described above for the preparation of carbamates and ureas.

In the particular case where ArlZ1 represents a tetrahydronaphthyl whose bond with X implements a saturated carbon and X represents a nitrogen, a preferred method of preparing an intermediate of formula (XV) consists in condensing the appropriate tetralone with a cyclic amine of formula
XVI, in the presence of p-toluene sulfonic acid in a solvent such as toluene at reflux, followed by the reduction of the amine thus formed for example by catalytic hydrogenation under hydrogen pressure in the presence of palladium or platinum oxide on coal.

A particularly appreciated method of preparing intermediates of formula (XV) in which XY represents NCH2, N or NCH2CH2 and Z1 represents (CH2) n, O (CH2) n, NH (CH2) n, SO2 (CH2) n consists in reducing amides of formula (XV) in which Z1 represents respectively (CH2) n ICO, O (CH2) niCO, NH (CH2) n ICO, SO2 (CH2) n ICO by known methods for reducing an amide into an amine, such as the use of an aluminum hydride (for example LiAIH4) in a solvent such as THF or ethyl ether.

en présence d'un dérivé du palladium tel que par exemple Pd(PPh3)4, éventuellement d'une base telle qu'une amine tertiaire, un carbonate de potassium, sodium ou césium, de chlorure de lithium lorsque M = SnR3 et dans un solvant aprotique polaire tel que le THF. le DME ou le DMF à une température comprise entre 20" et 80 C cf ( cf "Organometallics in synthesis",M. Schlosser, John Wiley N: son. 1994). Les triflates intermédiaires de formule XXI sont préparés par exemple par la méthode décrite dans Synthesis, 993, 1991.The intermediates of general formula (XV) in which Arl and P are defined as above and XY represents C = CH and ZI represents (CH2) n, O (CH2) n or CH = CH are prepared by coupling of an organometallic of formulas XIX or XX
Arl - ZI - M (XIX)
Arl - Z1 - M '- Z1 - Ar (XX) in which M represents ZnBr, SnR3 where R represents an alkyl group such as butyl or B (OR') 2 where R 'represents hydrogen or alkyl and M' represents Zn, with a vinyl triflate of formula (XXI)

in the presence of a palladium derivative such as for example Pd (PPh3) 4, optionally a base such as a tertiary amine, potassium carbonate, sodium or cesium, of lithium chloride when M = SnR3 and in a polar aprotic solvent such as THF. DME or DMF at a temperature between 20 "and 80 C cf (cf" Organometallics in synthesis ", M. Schlosser, John Wiley N: son. 1994). The intermediate triflates of formula XXI are prepared for example by the method described in Synthesis, 993, 1991.

The intermediates of formula XV in which ZI represents an ethynyl residue and X represents C = CH are prepared by coupling triflates of formula XXI with an aromatic acetylenic of formula XXII
Ar - CC - H (xxll) in the presence of a palladium catalyst such as Pd (PPh3) 4 or
PdC12 (PPh3) 2, a base such as a secondary or tertiary amine, potassium carbonate, sodium or cesium and optionally copper iodide in a polar solvent such as DMSO, DMF, THF (cf. Organic
Preparation and Procedures int., 27 (2), 127-160.1995).

The intermediates of general formula (XV) in which Arl and P are defined as above, XY represents CH-CH2 and Z1 represents (CH2) n, O (CH2) n can be prepared from the intermediates of general formula (XV) in which Arl and P are defined as above, XY represents C = CH and ZI represents (CH2) n, O (CH2) n,
CC or CH = CH by reduction of double and triple bonds by catalytic hydrogenation (H2, Pd / C for example).

The derivatives of formulas XV in which Z1 represents CO, (CH2) nCO or also O (CH2) nCO and XY represents C = CH, are prepared by coupling of an intermediate of formula XIX in which Z1 is omitted or represents (CH2) n, O (CH2) n and M represents SnR3 where R represents an alkyl group with a triflate of formula XXI, in the presence of a palladium catalyst such as Pd (PPh3) 4 optionally of lithium chloride and of a base such as potassium carbonate under pressure of carbon monoxide in a polar solvent such as THF according to the method described in "Organometallics in synthesis", M. Schlosser, John Wiley & son, 1994.

dans un solvant anhydre polaire tel que l'éther éthylique le THF ou le DME, à une température comprise entre - 20 C et 600 C, suivi de l'hydrolyse acide du milieu réactionnel.The intermediates of formula XV in which Z1 represents CO and XY represents CH-CH? are prepared by condensation of an aromatic derivative "ArlH" with an acid chloride, according to the methods and techniques known under the name of Friedel-Craft reaction, such as for example described in J. Med. Chem. 33, 903, 1990. An alternative method (the choice of which will essentially depend on the nature of Arl) for the preparation of compounds of formula XV in which Z1 represents CO and XY represents CH-CH2 consists in condensing an organometallic derivative Arl-M in which M represents MgCI, MgBr or Li with a nitrile of formula XXIII

in a polar anhydrous solvent such as ethyl ether THF or DME, at a temperature of between -20 ° C. and 600 ° C., followed by the acid hydrolysis of the reaction medium.

(dont une méthode de préparation est décrite dans le brevet US 4335127; 1982) avec un dérivé de formule XVII dans laquelle Z1 représente (CH2)n,
O(CH2)n, SO2(CH2)n et L est défini comme précédemment
Dans le cas particulier où Z1 représente OCO ou NHCO et X-Y représente
CH-CH2 ou C=CH, une méthode appréciée de préparation des intermédiaires de formule (I) consiste à condenser un phénol (Arl OH) ou une aniline (ArlNH2) avec un dérivé de formule (XXV)

dans laquelle L et le carboxyle auquel il est attaché constituent la forme activée d'un acide carboxylique propice à la formation d'un amide ou d'un ester par condensation avec une amine ou un alcool par les méthodes et techniques bien connues de l'homme de l'art.The intermediates of general formula (XV) in which Z1 represents (CH2) n, O (CH2) n, NH (CH2) n, SO2 (CH2) n and XY represents CH-CH2 can also be prepared by condensation of a nucleophile of general formula (XXIV)

(a preparation method of which is described in US Pat. No. 4,335,127; 1982) with a derivative of formula XVII in which Z1 represents (CH2) n,
O (CH2) n, SO2 (CH2) n and L is defined as above
In the particular case where Z1 represents OCO or NHCO and XY represents
CH-CH2 or C = CH, a popular method for preparing intermediates of formula (I) consists in condensing a phenol (Arl OH) or an aniline (ArlNH2) with a derivative of formula (XXV)

in which L and the carboxyl to which it is attached constitute the activated form of a carboxylic acid suitable for the formation of an amide or of an ester by condensation with an amine or an alcohol by the methods and techniques well known in the art. skilled in the art.

dans laquelle P est défini comme précédemment.In the particular case where Z1 represents NH and XY represents CH-CH2, the intermediates of formula XV are prepared by a reducing reaction, using for example NaBH4 or NaBH3CN as reducing agent between an aniline of formula ArlNH2 and a piperidone of formula (XXVI)

in which P is defined as above.

avec un électrophile de formule XXVIII
Arl Z'1 - L (xxvlll) dans laquelle Z'1 représente Z1 tronqué du reste NH terminal et L est défini comme précédemment. Cette condensation sera effectuée par différentes techniques et méthodes qui dépendront de la nature de Z'1 et L et qui sont similaires aux techniques et méthodes précédemment décrites pour la condensation des intermédiaires XVI et XVII (dans lequel X représente un azote).La réaction d'amination réductrice telle que décrite précédemment peut également être mise en oeuvre pour la préparation de composés de formule XV dans laquelle Z1 représente (CH2)n NH, O(CH2)nNH ou
SO2(CH2)nNH à partir des amines de formule XXVII et d'aldéhyde respectivement de formules Ari(CH2)n1CHO, ArlO(CH2)n 1CHO ou SO2(CH2)n l CHO ou à partir d'amines de formule Arî(CH2)n NH2, ArlO(CH2)nNH2 ou ArlSO2(CH2)nNH2 avec la pipéridone (XXVI).In special cases where XY represents CH-CH2 and Z1 represents
CONH, SO2NH, (CH2) nNH, CO (CH2) nNH or O (CH2) NH, the intermediates of formula XV are prepared by condensation of an amino piperidine of formula (XXVII)

with an electrophile of formula XXVIII
Arl Z'1 - L (xxvlll) in which Z'1 represents Z1 truncated from the terminal NH remainder and L is defined as above. This condensation will be carried out by different techniques and methods which will depend on the nature of Z'1 and L and which are similar to the techniques and methods previously described for the condensation of intermediates XVI and XVII (in which X represents a nitrogen). the reductive amination as described above can also be used for the preparation of compounds of formula XV in which Z1 represents (CH2) n NH, O (CH2) nNH or
SO2 (CH2) nNH from the amines of formula XXVII and aldehyde of formulas Ari (CH2) n1CHO, ArlO (CH2) n 1CHO or SO2 (CH2) nl CHO respectively or from amines of formula Arî (CH2) n NH2, ArlO (CH2) nNH2 or ArlSO2 (CH2) nNH2 with piperidone (XXVI).

Intermediaries of formula XV in which Z1 represents OCONH or
NHCONH and XY represents CH-CH? are prepared by condensing an aminopiperidine of formula XXVII and a phenol (ArlOH) or an aniline (ArlNH2) with an electrophile of formula XII according to the methods and techniques described above for the preparation of carbamates or ureas.

dans laquelle P est défini comme précédemment.In the particular case where Z1 represents O and XY represents CH-CH2, the intermediates of formula XV are prepared by a Mitsunobu reaction starting from an ArlOH derivative and from a hydroxylated piperidine derivative of formula (XXIX)

in which P is defined as above.

In the particular case where XY represents CH-CH2 and Z1 represents (CH2) nO, O (CH2) nO, NH (CH2) nO, CO (CH2) nO or SO2 (CH2) nO, the intermediates of formula XV are prepared by condensation of a hydroxy piperidine of formula (XXIX) with an electrophile of formula (XXVII I) in which Z'1 represents Z1 truncated by a terminal oxygen and L represents a leaving group such as a halogen (chlorine. bromine or iodine ), a tosylate, a mesylate or a triflate. This condensation can be carried out in the presence of a base, organic (such as a tertiary amine, potassium t-butoxide or even butyllithium) or inorganic (for example, NaH ,
KH, Cs2CO3) in a polar anhydrous solvent such as THF, DME,
DMF, DMSO, t-butanol, at a temperature between - 15 "C and 80" C.

Intermediaries of formula XV in which Z1 represents NHCOO and X
Y represents CH-CH2 are prepared by condensation of an alcohol of formula (XXIX) and an aniline derivative (ArlNH2) with a reagent of formula XII according to the methods and techniques described above for the preparation of a carbamate.

The intermediates of formula XV in which Z1 represents NHSO2, SO2, (CH2) nSO2, O (CH2) nSO2 or NH (CH2) nSO2 and XY represents CH-CH2 are prepared by condensation of a sulfonyl chloride corresponding to formula ( XXX)
Ar Z1 - Cl (xxx) with a nucleophile of formula XXIV in a polar aprotic solvent such as ethyl ether or THF at a temperature between 0 and 600
vs.

dans laquelle Z2, R1, R2 et R3 sont définis comme précédemment avec un électrophile de formule (XVII) dans laquelle Z1 et L sont définis comme précédemment et ceci, selon les méthodes et techniques décrites précédemment pour la condensation de XVI avec XVII et dont le choix dépendra essentiellement de la nature de Z î. Also to be considered as forming part of the present invention, alternative methods of synthesis of the compounds of formula (I) in which XY represents NCH2, N, NCH2CH2 which consist in condensing intermediates of general formula (XXXI)

in which Z2, R1, R2 and R3 are defined as above with an electrophile of formula (XVII) in which Z1 and L are defined as above and this, according to the methods and techniques described above for the condensation of XVI with XVII and whose choice will essentially depend on the nature of Z î.

In the particular case of the compounds of formula (I) with X = N and Z1 = OCO or NHCO, an alternative method of preparation consists in reacting a phenol of formula ArlOH or an amine of formula ArlNH2 and an amine of formula (XXXI) defined as above with a compound of formula (XII) by the methods and techniques described above for the preparation of carbamates and ureas.

In the particular case of the compounds of general formula (I) in which R1 represents a hydrogen, it is preferable to use, for certain reactions which require it, reaction intermediates in which Ri represents a protective group such as for example a tbutoxycarbonyl (BOC) which will be introduced beforehand by condensation of the appropriate intermediate in which RI = H with an appropriate reagent such as (BOC) 20, BOC-ON = C (CN) -Ph, BOC-ONH2. This will make it possible to prepare, according to the methods and techniques presented previously, intermediates of general formula (I) in which R1 = BOC and of converting these intermediates into final products of general formula (I) in which Rl = H after deprotection of t-butoxycarbonyl according to the methods and techniques well known for this type of transformation such as the use of acid (HCI, CF3CO2H, H2SO4) in an organic medium.

Also to be considered as an integral part of the present invention all the methods which make it possible to transform a derivative of formula (I) into another derivative of formula (I) in which at least one of the substituents Arl, Z1, XY, Z2, RI, R2 or R3 are different, by the methods and techniques well known to those skilled in the art. It is thus, and by way of example, that the derivatives of general formula (I) in which ArI represents a phenyl substituted by an NO2 group can be transformed into derivatives of formula (I) in which Arl represents a phenyl substituted in the same position by an NH2 group by the methods and techniques well known for this type of reduction as described for example in "Comprehensive Organic Transformation ", p. 412; R. C.

Larock, VCH, 1989, among which mention may be made of atmospheric hydrogenation catalyzed with palladium on charcoal, the use of SnCl2, zinc, Raney's Ni or else of rhodium catalyst in the presence of hydrazine. The compounds of general formula (I) in which Arl represents an aromatic substituted by an NH group? can also be transformed into numerous other derivatives of formula (I) such as derivatives in which Ari represents an aromatic substituted by NR4R4 ,, NHCOR4, NHCO2R4, NHCOR4, NHSO2R4, NHSO2OR4,
NHSO2NR4R4 'by well known methods and techniques for transforming an aromatic amine into an amide, carbonate, urea, sulfonamide, sulfonate or sulfonylurea.

When it is desired to isolate a compound according to the invention in the form of a salt, for example a 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 quantity, or with creatinine sulfate in an appropriate solvent.

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

When the new 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, either by enantion-selective synthesis or by resolution. The compounds of formula (I) having at least one asymmetric center can 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 acid (+ ) -di-p-toluoyl-l-tartaric, (+) - camphorsulfonic acid,
(-) - camphorsulfonic acid, (+) - phenylpropionic acid, (-) phenylpropionic acid, followed by fractional crystallization and regeneration of the free base.The compounds of formula (I) in which R1 is hydrogen comprising at least one asymmetric center can also be resolved by the formation of diastereomeric amides which are separated by chromatography and hydrolyzed to release the chiral auxiliary.

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

Proton NMR spectra were recorded on a Brücker device
AC 200. The chemical shifts are expressed in ppm and the following abbreviations have been used "s" for singlet; "se" for widened singlet, "d" for doublet, "dd" for doublet of doublet, "t" for triplet, "q" for quadruplet, "sx" for sextuplet, "m" for multiplet, "M" for solid .

The infrared spectra were recorded on a Nicolet 510P device.

The absorption bands are given in cm
The elementary analyzes were carried out on a Fisons EA 1108 device.

Composté la : 2chloro-1-(4-phénéthylpipérazin-î-yl)éthanone
Le chlorure de chloroacétyle (710ml, 9.0mmol) est ajouté goutte à goutte à une solution de 4-phénéthylpipérazine (1.4je, 7.5mmol) et de carbonate de calcium (2.25g, 22mmol) dans la méthyléthylcétone (40ml) refroidie à 0 C. Le mélange réactionnel est agité à cette température pendant 1/2 h puis il est filtré sur célite. La célite est rincée plusieurs fois avec de l'acétate d'éthyle et une solution de soude 3M.Les deux phases du filtrat sont ensuite séparées et la phase organique est séchée sur sulfate de magnésium, filtrée et concentrée pour donner le produit attendu sous la forme d'un solide orangé.EXAMPLE 1
2- [8- (4-methylpiperazin-1-yl) naphthalenc-2-yloxys 14-phenethylpiperazin-1-ylethanone fumarate

Composted: 2chloro-1- (4-phenethylpiperazin-î-yl) ethanone
Chloroacetyl chloride (710ml, 9.0mmol) is added dropwise to a solution of 4-phenethylpiperazine (1.4je, 7.5mmol) and calcium carbonate (2.25g, 22mmol) in methyl ethyl ketone (40ml) cooled to 0 C The reaction mixture is stirred at this temperature for 1/2 h and then it is filtered through Celite. Celite is rinsed several times with ethyl acetate and a 3M sodium hydroxide solution. The two phases of the filtrate are then separated and the organic phase is dried over magnesium sulphate, filtered and concentrated to give the expected product under the form of an orange solid.

 Niasse obtained: 1.85 g (gross yield: 93%) Rj 1H (CDC13) 2.48-2.97 (m, 8H); 3.52 (t, 5.0Hz, 2H); 3.64 (t, 5.0Hz, 2H); 4.04 (s, 2H); 7.15-7.29 (M, 5H).

Compound 1.

Compound la (550mg, 2.06mmol) and 2-hydroxy-8- (4 methylpiperazin-1-yl) naphthalene prepared according to the procedure described in French patent n ° 9408981 (500mg; 2.06mmol) are stirred at room temperature under nitrogen atmosphere in dimethylformamide (25ml) in the presence of cesium carbonate (1.0g, 3.lmmol) for 12h.

The dimethylformamide is then evaporated under reduced pressure and the reaction mixture is taken up in ethyl acetate. The organic phase is washed three times with a saturated solution of sodium chloride before being dried over magnesium sulfate and concentrated. The crude reaction product is purified by flash chromatography with a mixture (90/9/1) of dichloromethane / methanol / ammonia.

mass obtained: 820 mg (yield: 84%)
This compound is dissolved in methanol and treated with fumaric acid to give the corresponding fumarate. This is crystallized from ether.

Elementary Analysis for: C29H36N4O2-C4H4O4-0.45H2O
Calculated: C 66.41; H 6.91; N 9.42; Experimental: C 66.40; H 6.93
N 9.42 IR (KBÔ: 3429,3019,2945,2824,1642,1595
1 H NMR (DMSO) 2.41 (s, 3H); 2.50 (M, 8H); 2.75 (M, 4H); 3.01 (M, 4H); 3.47 (M, 4H); 4.99 (s, 2H); 6.60 (s, 2H); 7.24 (M, 9H); 7.51 (M, 1H); 7.80 (M, 1H).

Melting point: 1360C
EXAMPLE 2 2-18- (4-methylpiperazin-1-yl) naphthalene-2-yloxyl-1- [L1- (3-phenylpropan-1-yl) piperazin-1-yl] ethanone

Compound 2a 2-cliloro-1- [4-tert-butyloxycarbonylpiperazin-1- yl] ethanone
Compound 2a is prepared according to the procedure described for compound la from the following reagents l-tert-butyloxycarbonylpiperazine (5.15g, 27.9mmol); chloroacetyl chloride (2.42ml, 30.4mmol); calcium carbonate (8.34g, 83.4mmol); methyl ethyl ketone (60ml). The crude reaction product is purified by flash chromatography with a mixture (97/3/1) and then (95/5/1) of dichloromethane / methanol / ammonia.

Axasse obtained: 4.07g (Yield: 56%)
1 H NMR (CDCl3) 1.42 (s, 9H); 3.36-3.57 (M8H); 4.03 (s, 2H).

Compound 2b 2- [8- (4-methylpiperazin-1-yl) naphthalenc-2-yloxy] -1- [4- tert-butyloxycarbonylpiperazin-1-yllethanone
Compound 2b is prepared according to the procedure described for compound la from the following reagents 2-hydroxy-8- (4 methylpiperazin-1-yl) naphthalene prepared according to the procedure described in French patent n09408981 (2.52g; 10.0mmol) ; compound 2a (2.54g, 9.7mmol); cesium carbonate (7.74g, 14.0mmol); dimethylformamide (120ml). The crude reaction product is purified by flash chromatography with a mixture (90/9/1) of dichloromethane / methanol / ammonia.

 Mass obtained: 3.45 g (Yield: 78%) R jlzfN IH (CDC13) 1.44 (s, 9H); 2.42 (s, 3H); 2.72 (M, 4H); 3.09 (M, 4H); 3.40 (m, 4H); 3.59 (m, 4H); 4.83 (s, 2H); 7.11 (m, 2H); 7.29 (t, 7.9 Hz, 1 H); 7.48 (d, 8.1Hz, 1H); 7.56 (d, 2.5Hz, 1H); 7.74 (d, 8.9Hz, 1H).

Compound 2c 2 -18- (4-methylpiperazin-1-yl) naphthalene-2-yloxyl-1- (piperazin-1-yI) ethanone
The trifluoroacetic acid (6.7 ml) is added slowly to a solution of compound 2b (3.lg; 6.72mmol) in dichloromethane (50ml) kept at 0 C. The reaction mixture is then brought to room temperature and the reaction is followed by thin layer chromatography. After 4 hours, the reaction is completed. The trifluoroacetic acid is neutralized with a saturated solution of sodium hydrogencarbonate. The phases are separated and the organic phase is washed with a saturated sodium chloride solution, dried over magnesium sulfate and concentrated. The crude reaction product is purified by flash chromatography with a mixture (90/10/1) and then (85/15/1) of dichloromethane / methanol / ammonia.

Mass obtained: 1.45 g (Yield: 59%)
1 H NMR (CDCl3) 1.78 (sc, 1H); 2.42 (s.3H); 2.72-2.87 (M, 8H); 3.10 (M, 4H); 3.59 (t, 5.0Hz, 4H); 4.81 (s, 2H); 7.09 (d.7.8Hz, 1H); 7.14 (dd, 2.6 and 8.9Hz, 1H); 7.28 (t, 7.5Hz, 1H); 7.48 (d, 8.1Hz, 1H); 7.54 (d, 2.5Hz, 1H); 7.73 (d, 8.9Hz, 1H).

Compound 2
A solution of 1-bromo-3-phenylpropane (300m1; 1.97mmol) is stirred for 12 h at room temperature in the presence of compound 2c (605mg; 1.64mmol), potassium carbonate (340mg; 2.46mmol) and iodide of potassium (a tip of a spatula) in methyl ethyl ketone (25ml). The reaction mixture is then poured into water and extracted three times with ethyl acetate. The organic phases are combined, washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The crude reaction product is purified by flash chromatography with a mixture (90/9/1) of dichloromethane / methanol / ammonia.

Mass obtained: 427 mg (Yield: 54%) 1 H NMR (CDCl 3) 1.79 (m, 2 H); 2.40 (M, 9H); 2.63 (t.7.6Hz, 2H); 2.73 (M, 4H); 3.11 (M, 4H); 3.64 (m, 4H); 4.82 (s, 2H); 7.08-7.33 (m, 8H); 7.48 (d, 8.0Hz, 1H); 7.54 (d, 2.6Hz, 1H); 7.74 (d, 8.9 Hz, 1H).

EXAMPLE 3 2-18- (4-methylpiperazin-1-yl) naphthalene-2-yloxyJ-1-4- (2-ethoxyphenyl carbonyl) piperazin-1-yllethanonc

A solution of compound 2c (400mg, 1.09mmol) and 2ethoxyphenylacetic acid (160ml, 1.09mmol) in dichloromethane (15ml) is stirred for 16h at room temperature in the presence of 1- (3-dimethylaminopropyl) -3 hydrochloride -ethylcarbodiimide (210mg, 1.09mmol), and 4-dimethylaminopyridine (a tip of a spatula). After dilution in water, the mixture is extracted three times with ethyl acetate, then the combined organic phases are washed with a saturated solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated. purified by flash chromatography with a mixture (95/5/1) of dichloromethane / methanol / ammonia.

Mass obtained: 435 mg (Yield: 78%)
1 H NMR (CDCl3) 1.32 (m, 3H); 2.44 (s, 3H); 2.74 (M, 4H); 3.12 (M, 4H); 3.27 (M, 2H); 3.60-4.08 (m, 8H); 4.84 (s, 0.8H); 4.90 (s, 1.2H); 6.87-7.81 (m, lOH).

composé 4a : l-chiorocarbonyl-4-tert-butyloxycarbonylpipérazine
Une solution de 1-tert-butyloxycarbonylpipérazine (10g.53mmol) et de pyridine (4.77ml,59mmol) dans le dichlorométhane (100ml) est additionnée lentement sur une solution de triphosgène (5.83 g, 20mmol) dans le dichlorométhane (300ml) à 0 C et sous atmosphère d'azote. Le mélange réactionnel est ramené à température ambiante. Après 30 minutes, il est dilué avec de l'eau .Les phases sont séparées et la phase organique est lavée avec une solution saturée en chlorure de sodium, séchée sur sulfate de magnésium, filtrée et concentrée.EXAMPLE 4 4 - [(E) -styrylcarbonyl] piperazinyl-1-oate of 8- (4-methylpiperazin-1-yl) naphthalene-2

compound 4a: l-chiorocarbonyl-4-tert-butyloxycarbonylpiperazine
A solution of 1-tert-butyloxycarbonylpiperazine (10g.53mmol) and pyridine (4.77ml, 59mmol) in dichloromethane (100ml) is added slowly to a solution of triphosgene (5.83 g, 20mmol) in dichloromethane (0 C and under a nitrogen atmosphere. The reaction mixture is brought to ambient temperature. After 30 minutes, it is diluted with water. The phases are separated and the organic phase is washed with a saturated solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated.

Mass obtained: 13.3g (quantitative gross yield) RllfN 1H (CDCl3): 1.46 (s, 9H); 3.47 (M, 4H): 3.59 (M, 9H); 3.69 (M, 214).

compound 4b: 4-tert-butyloxycarbonylpiperazinyl-1-oate of 8- (4 methylpiperazin-1-yl) naphthalene-2
A solution of 2-hydroxy-8- (4-methylpiperazin- I -yl) naphthalene (6.0g, 25mmol) in tetrahydrofuran (70ml) is cannulated on a suspension of sodium hydride (60%, 1.18g, 30mmol) in tetrahydrofuran (50ml) at 0 C and under a nitrogen atmosphere. After 15 minutes, the reaction mixture is cannulated on a solution of 4a (6.16g; 25mmol) in tetrahydrofuran (70ml) then it is brought to room temperature and stirred for 12h. The solution is then diluted with water and then extracted three times with ethyl acetate. The organic phases are combined, washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered, concentrated. The crude product is purified by flash chromatography with a mixture (95/5/1) of dichloromethane / methanol / ammonia. .

Mass obtained: 7.0g (Yield: 62%)
1 H NMR (CDCl3). 1.50 (s, 9H); 2.42 (s, 3H); 2.71 (M, 4H); 3.12 (M, 4H); 3.55 (M, 6H); 3.71 (M, 2H); 7.12 (d, 6.7Hz, 1H); 7.23 (dd, 2.4 and 8.8Hz, 1H); 7.37 (t, 7.5Hz, 1H); 754 (d.8.1Hz, 1H); 7.81 (d, 8.9Hz, 1H); 7.86 (d, 2.3Hz, 1H).

compound 4c: piperazinyl-1-oate of 8- (4-methylpiperazin-1-yl) naphthalene-2
Compound 4c is prepared according to the procedure described for compound 2c from the following compounds. compound 4b (7.0g, 15mmol); trifluoroacetic acid (15.4ml); dichloromethane (110mol). The crude is purified by flash chromatography with a mixture (90/10/1) of dichloromethane / methanol / ammonia.

Mass obtained: 4.36 g (Yield: 82%)
1 H NMR (CDCl3) 2.43 (s, 3H); 2.72 (M, 4H); 2.96 (t, 5.2Hz, 4H); 3.14 (M, 4H); 3.59 (M, 2H); 3.72 (M, 2H); 7.12 (d, 6.8Hz.lH); 7.25 (dd, 2.5 and 8.8Hz, 1H); 7.38 (t, 7.5Hz, 1H); 7.55 (d, 8.îHz.IH); 7.82 (d, 8.9 Hz, 1 H); 7.87 (d, 2.3Hz, 1H).

compound 4
Compound 4 is prepared according to the procedure described for compound 3 from the following reagents. compound 4c (500mg, 1.41mmol); cinnamic acid (2 I Omg 1.41 mmo); 1- (3- dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (270mg, 1.41 mmol); 4dimethylaminopyridine (a tip of a spatula); dichloromethane (15ml). The reaction lasts 16h. The crude reaction product is purified by flash chromatography with a mixture (95/5/1) of dichloromethane / methanol / ammonia.

Mass obtained: 520mg (YId: 76%)
1 H NMR (CDCl3) 2.43 (s, 3H); 2.73 (M, 4H); 3.14 (M, 4H); 3.80 (M, 8H); 6.91 (d, 15.4Hz, 1H); 7.14 (d, 7.IHz, 1H); 7.27 (dd, 2.4 and 8.8Hz, 1H); 7.40 (m, 4H); 7.57 (m, 3H); 7.76 (d, 15.4Hz, 1H); 7.84 (d, 8.9Hz, 1H); 7.89 (d, 2.3Hz, 1H).

EXAMPLE 5 4- (2-naphthylsulfonyl) piperazinyl-1-oate of 8- (4-methylpiperazin-1-yl) naphthalene-2

A solution of 2-naphthylsulfonyl chloride (640mg, 2.82mmol) in dichloromethane (5ml) is added to a solution of compound 4c (500mg, 1.41mmol) in sodium hydroxide 1M (1.1mol) at 0 C. The two-phase mixture is then brought back to room temperature and stirred for 16h. After this time, the two phases are separated and the aqueous phase is extracted three times with dichloromethane. The combined organic phases are washed with a saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The reaction crude is purified by flash chromatography with a mixture (95/5/1) of dichloromethane / methanol / ammonia. .

Mass obtained: 441 mg (Yield: 56%)
1H NMR (CDCl3) 3.38 (s, 3H); 2.65 (M 4H): 3.07 (M.4H); 3.20 (m, 4H); 3.72 (M, 2H); 3.84 (M.2H); 7.10 (m, 2H); 7.31 (t, 8.1Hz.lH); 7.50 (d, 8.2Hz, 1H); 7.64-7.81 (m, 5H); 7.94-8.05 (m, 3H); 8.38 (s, 1H).

The derivatives of the present invention are potent 5HT1D receptor antagonists as shown by the linkage studies and the antagonism studies of the inhibition of adenylate cyclase (stimulated by forskolin) by a 5HT1 D agonist such as serotonin. , sumatriptan or 5-CT, studies which have been carried out on the cloned human receptors 5HT1D, and 5HTIDss
The human receptors 5HTîDa and 5HT1Db were cloned according to the sequences published by M. Hamblin and M. Metcalf, Mol. Pharmacol., 40,143 (1991) and Weinshenk et al., Proc. Natl. Acad. Sci. 89.3630 (1992).

Transient transfection and permanent transfection of the genes for these receptors was carried out in Cos-7 and CHO-KI cell lines using an electroporator.

The HeLa HA7 cell line expressing the human 5HTIA receptor was obtained from Tulco (Duke Univ., Durham, N.C .. USA) and cultivated according to the method of Fargin et al., J. Biol. Chem. 264.14848 (1989).

The study of the binding of the derivatives of the present invention with the human 5HTîDa, SHTIDb and SHTIA receptors was carried out according to the method described by P. Pauwels and C. Palmier (Neuropharmacology, 33,67,1994).

The incubation media for these binding measurements include 0.4 ml of cell membrane preparation, 0.05 ml of a tritiated ligand [3H] -5CT (final concentration: 2nM) for the 5HT1 Da and 5HT1 Db and [3H] receptors - 80H-DPAT (final concentration: 1 nM) for the 5HTIA receptor and 0.05 ml of the test molecule (final concentrations of 0.1 nM to 1000 nM) or 10 pM (final concentration) of seretonin (5HTîDa and 5HT1Db) or 1 pM ( final concentration) of spiroxatrine (5HT 1A).

The study of the inhibition of the formation of cyclic AMP (stimulated by forskolin) mediated by human 5HT1 Da and 5HT1 Db receptors was carried out in cells transfected by the receptor according to a technique described previously (P. Pauwels and C. Palmier, Neuropharmacology, 33,67,1994; Cell. Pharmacol. 2,183,1995; Cell. Pharmacol. 2,49,1995; Eur.

J. of Pharmacol. (Mol. Pharm.) 290, 95, 1995).

The new compounds derived from naphthyl-piperazines forming part of the present invention are powerful and selective antagonists of the 5HT1D receptors and have the advantage of being particularly selective for the human 5HT1D receptors in particular compared to the 5HT1A, SHT1C, 5HT2 receptors, al, a2 and D2
The derivatives of the present invention are further capable of inhibiting the contraction induced by 5-hydroxytryptamine in the rabbit saphenous vein rings and of antagonizing the inhibition induced by 5carboxamidotryptamine (5CT) at the level of serotonin release. in guinea pig brain slices. These two pharmacological models are generally recognized as particularly relevant in the functional characterization of the 5HT1D receptors and, in the case of the products of the present invention, make it possible to demonstrate their antagonistic activity at the level of these receptors.

These new and unexpected properties of the 5HT1D antagonists claimed in the present invention make them particularly interesting and useful for the treatment of patients suffering from disorders in the central nervous system. As a result, the present invention also comprises a method for treating such patients, a method which involves the administration of an active dose of a compound corresponding to the general formula (I). The studies of antagonist activity at the level of the cyclase mediated by the 5HT1Da and 5HT1Db receptors further demonstrate that the illustrative example of the present invention set out in table 1 above is a powerful and silent antagonist of both the 5HT1Db receptor but also 5HTIDa. These properties clearly demonstrate the unique biological characteristics of the derivatives of the present invention, in particular if we compare these data with the data obtained with the derivative GR127935 which, under the same conditions appears as a receptor agonist Human SHTIDa (cf. Pauwels and Colpaert,
Neuropharmacol., 34,235,1995).

Furthermore, the derivatives of the present invention are also capable of controlling the growth and proliferation of C6 type glial cells transfected by the 5HTIDss receptor gene and by the 5HTIDa receptor gene stimulated by a hormonal mediator such as serotonin. By way of example, the examples of the present invention inhibit the incorporation of labeled thymidine (stimulated with 0.1 pM sumatriptan) with an IC50 of 10 to 100 nM (method described by P. Pauwels et al., J. of Neurochemistry , in press). As such, the derivatives of the present invention therefore also find their utility in the treatment of cancers and other disorders linked to cell proliferation.

Also to be considered as forming part of the present invention are the pharmaceutical compositions containing, as active ingredients, a compound of general formula (I) or a physiologically acceptable salt of a compound of formula (I) associated with one or more agents therapeutic, such as, for example antidepressant agents such as tricyclic antidepressants (eg amitryptyline, clomipramine, desipramine, imipramine), monoamine oxidase inhibitors (eg isocarboxazide, moclobemide, phenelzine or tranylcyclopramine) serotonin uptake (e.g. fluvoxamine, sertraline, fluoxetine, paroxetine or citalopram) serotonin and norepinephrine re-uptake inhibitors (e.g. milnacipran), or 0 :: 2 antagonists (mianserine, mirtazapine, setiptiline, idazoxan , effaroxan, fluparoxan for example).

The derivatives of the present invention or their physiologically acceptable salts can also be administered in the form of pharmaceutical compositions, in combination with a 5-HT1A receptor antagonist (such as, for example pindolol, WAY 100135, UH-301 or WAY 100635). This association is also part of the present invention.

The present invention also relates to pharmaceutical compositions containing as active ingredient a compound of general formula I or one of its acceptable salts for pharmaceutical use, mixed or associated with a suitable excipient. These compositions can take, for example, the form of solid, liquid compositions, emulsions, lotions or creams.

As solid compositions for oral administration, tablets, pills, powders (gelatin capsules, cachets) or granules can be used. In these compositions, the active principle according to the invention is mixed with one or more inert diluents, such as starch, cellulose, sucrose, lactose or silica, under a stream of argon. These compositions can 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, use may be made of pharmaceutically acceptable solutions, suspensions, emulsions, syrups and elixirs containing inert diluents such as water, ethanol, glycerol, vegetable oils or oil paraffin. These compositions can include substances other than diluents, for example wetting, sweetening, thickening, flavoring or stabilizing products.

The sterile compositions for parenteral administration can preferably be aqueous or non-aqueous solutions. suspensions or emulsions. As solvent or vehicle, water, propylene glycol, a polyethylene glycol, vegetable oils, in particular olive oil, injectable organic esters, for example ethyl oleate or other suitable organic solvents, can be used. These compositions can also contain adjuvants, in particular wetting agents, isotonizers, 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 in the form of 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, semi-synthetic glycerides or polyethylene glycols.

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

The doses depend on the desired effect, on the duration of the treatment and on 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 based 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 passing through wet granulation. The direct compression procedure is preferred, but it may not be suitable in all cases depending on the doses and the physical properties of the active component.

A - By direct compression
mg per 1 tablet active component 10.0 microcrystalline cellulose PCB 89.5 magnesium stearate 0.5
100.0
The active component is passed through a sieve with a mesh opening of 250 μm on a side, it is mixed with the excipients and it is compressed using 6.0 mm punches. Tablets with other mechanical strengths can be prepared by varying the compression weight with the use of appropriate punches.

B - Wet granulation
mg for one tablet active ingredient 10.0 lactose Codex 74.5 starch Codex 10.0 corn starch pregelatinized Codex 5.0 magnesium stearate
Compression weight 100.0
The active component is passed through a sieve with a mesh opening of 250 µm and mixed with lactose, starch and pregelatinized starch.

The mixed powders are moistened with purified water, they are granulated, dried, sieved and mixed with magnesium stearate.

The lubricated granules are put into tablets as for the formulas by direct compression. A coating film can be applied to the tablets using suitable film-forming materials, for example methylcellulose or hydroxy-propyl-methyl-cellulose, according to conventional techniques. Sugar tablets can also be coated.

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 the firm
Colorcon Ltd, Orpington, Kent, UK.

The active component is passed through a sieve with a mesh opening of 250 µm and mixed with the other substances. The mixture is introduced into No. 2 hard gelatin capsules on an appropriate filling machine.

Other dosage units can be prepared by changing the filling weight and, if necessary, changing the size of the capsule.

Syrup
mg per 5 ml dose active ingredient 10.0 sucrose Codex 2750.0 glycerin Codex 500.0 buffer) flavor) color) qs

preservative) distilled water 5.0
The active component, the buffer, the flavor, the color and the preservative are dissolved in part of the water and the glycerin is added. The remainder of the water is heated to 80 ° C. and the sucrose is dissolved therein, then cooled. The two solutions are combined, the volume is adjusted and mixed. The syrup obtained is clarified by filtration.

Suppositories
Active ingredient 10.0 mg * Witepsol H15 supplement to 1.0 g * Brand marketed for Adeps Solidus of the Pharmacopoeia
European.

A suspension of the active component in Witepsol H15 is prepared and introduced into a suitable machine with 1 g suppository molds.

Liquid for administration by intravenous injection
g / l active ingredient 2.0 water for injection Codex complement to 1000.0
Sodium chloride can be added to adjust the tone 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 introduced into suitable size vials which are sealed by melting the glass. The liquid for injection can also be sterilized by heating in an autoclave according to one of the acceptable cycles. The solution can also be sterilized by filtration and introduced into a sterile ampoule under aseptic conditions. The solution can be introduced into the ampoules in a gaseous atmosphere.

Inhalation cartridges
g / cartridge active ingredient micronized 1.0 lactose Codex 39s0
The active component is micronized in a fluid energy mill and made into fine particles before mixing with lactose for tablets in a high energy mixer. The powder mixture is introduced into hard gelatin capsules No. 3 on an appropriate encapsulating machine. The contents of the cartridges are administered using a powder inhaler.

Pressure aerosol with metering valve
mg / dose for I box of micronized active ingredient 0.500 120 mg oleic acid Codex 0.050 12 mg trichlorofluoromethane for pharmaceutical use 22.25 5.34 g dichlorodifluoromethane for pharmaceutical use 60s90 14.62 g
The active component is micronized in a fluid energy mill and put into the state of fine particles. The oleic acid is mixed with the trichlorofluoromethane at a temperature of 10-15 ° C. and the micronized drug is introduced into the solution using a high shear mixer. The suspension is introduced in measured quantity into aluminum aerosol cans on which are fixed appropriate metering valves delivering a dose of 85 mg of the suspension; dichlorodifluoromethane is introduced into the cans by injection through the valves.

Claims (17)

1. Compounds corresponding to the general formula (I)

 in which R1 represents a hydrogen or a linear or branched alkyl comprising from 1 to 6 carbon atoms, Z2 represents O, NH, CH2O or CH2NH, R2 and R3, which are identical or different, represent a hydrogen or a group chosen from a linear or branched alkyl, an alkoxy. thioether, nitrile, trifluoromethyl or halogen (F Cl, Br, 1). X-Y represents NCH2, CH-CH2. C = CH, N or NCH2CH2, Z1 represents - (CH2) n-, - (CH2) n CO-. -CO-. -CO (CH2) n-, -SO2-, - S02 (CH2) n-, -O (CH2) n-, -O (CH2) nCO-, -OCO-, -NH (CH2) n-, NH (CH2) nCO-, -NHCO-, -NHCO (CH2) n-. -NH (CH2) nSO2-, -NHSO2-, NHSO2 (CH2) n-, -CH = CHCO -, - CCCO- - (CH2) nSO2-, -O (CH2) nSO2-. In the particular case where X-Y represents CH-CH2, Z1 can also represent -O-, -NH-, -CONH-, -S02NH-, -OCONH-, -NHCOO-. -NHCONH-, - (CH2) nNH-, - (CH2) nO-, -CO (CH2) nNH-, -NH (CH2) nO-. -NH (CH2) nNH -, -O (CH2) nNH-, -O (CH2) nO-, -CO (CH2) nO-. -SO2 (CH2) nNH-. -SO2 (CH2) nO-, (CH2) nS02NH-, - (CH2) nCONH-, O (CH2) nSO2 \ H-, -O (CH2) nCONH-, - NH (CH2) nS02NH-, -NH (CH2) nCONH-, -NHCO (CH2) nNH-, NHS02 (CH2) nNH in which n represents an integer between 1 and 6, In the particular case where XY represents CH-CH2 or C = CH, Z1 can also represent -CH = CH-, -CC-, Ar1 represents an aromatic residue (phenyl, naphthyl or pyridyl) which can be variously substituted for example by one or several groups chosen from a linear or branched alkyl comprising from 1 to 6 carbon atoms, a trifluoromethyl, a trifluoromethoxy, a 2,2,2-trifluoroethyl, a phenyl, a benzyl, a cycloalkyl comprising from 3 to 7 carbon atoms, a hydroxyl, a thiol, an alkoxy (OR4), thioether (SR4), a nitro (N02), a nitrile (CN), an amine (NHî or NR4R4 '), an amine derivative (NHCOR4, NHSO2R4, NHCONR4R'4, NHCO2R4, NHSO2NR4R'4), a halogen (fluorine, chlorine, bromine or iodine), a carbonyl (COH, COR4, COOR4, CONR4R'4) or a heterocycle which can possibly be substituted such as a heterocycle with 5 members which may contain from 1 to 4 heteroatoms chosen from oxygen, sulfur or nitrogen or by two substituents on neighboring carbons which can form a ring with the aromatic residue to which they are attached, or alternatively, the remainder Ar- Z1 represents a tetrahydronaphthyl whose bond with X implements a saturated carbon, R4 represents an alkyl residue. linear or branched, comprising from 1 to 6 carbon atoms, R'4 represents a hydrogen or an alkyl residue, linear or branched, comprising from 1 to 6 carbon atoms and their physiologically acceptable salts, hydrates, solvates and bioprecursors therapeutic use, the compounds of general formula (I) being in the form of geometric and optical isomers as well as in racemic form. 2. Compounds according to claim í, characterized in that they correspond  to the general formula the

 in which Arl, Z1, X-Y, Z2 and R1 are defined as in the  claim 1. 3. Compounds according to claim lcaractérisés in that Z2 represents O  or NH. 4. Compounds according to claim 1 characterized in that Z2 represents  CH20 or CH2NH. 5. Compounds according to Claim 1, characterized in that X-Y represents  N-CH2. 6. Compounds according to claim 1 characterized in that X-Y represents  CH-CH2 or C = CH. 7. Compounds according to claim 1 characterized in that Z1 represents (CH2) n, CO (CH2) n, SO2 (CH2) n, O (CH2) n, NH (CH2) n Or NHCO (CH2) n. 8. Compounds according to claim 1 characterized in that Z1 represents  (CH2) nCO, CO, O (CH2) nCO, NH (CH2) nCO or CH = CHCO. 9. Compounds according to claim I, characterized in that Z I represents  SO2, (CH2) nSOn. O (CH2) nSO2 or NH (CH2) nSO2. 10. Compounds according to claim 1 characterized in that X-Y represents  CH-CH2 and Z1 represents O, NH, CONH, SO2NH, OCONH, NHCOO,  NHCONH, (CH2) nNH, (CH2) nO, NH (CH2) nO, O (CH2) nNH,  NH (CH2) nNH, CO (CH2) nNH or CO (CH2) nO. 11. Process for the preparation of the compounds of formula (I) in which Arl,  Z1, X-Y, R1, Rî and R3 are defined as above and Z2  represents CH2O or CH2NH characterized in that a  intermediate of formula (II)

 in which Arl, Z1 and X-Y are defined as above and Y 'represents a leaving group such as a halogen (chlorine or bromine), a tosylate, a mesylate or a triflate, with a naphthyl-piperazine of general formula III

 in which X 'represents O or NH, and R1. R2 or R3 are defined as above in the presence of an organic or inorganic base. 12. Process for preparing the compounds of formula (I) in which Arl,  Z í, X-Y are defined as above and Z2 represents O or NH  characterized in that an intermediate of formula (III) is condensed  defined as in claim 11, and an aryl piperazine of formula  (IV)

 in which Arl, Z1 and X-Y are defined as above with an electrophile of formula (XII)

 in which X1 and X2 represent a leaving group such as a halogen  (in particular chlorine), an o-alkyl group (in particular the group  OCC13), succinimyl, phtalyl or imidiazolyl. 13. Process for the preparation of the compounds of formula (I) in which X  represents a nitrogen, characterized in that an intermediate is condensed  of formula (XXXI)

 in which R1, R2, R3 and Zx are defined as above and X-Y  represents N, N-CH2 or NCH2CH2 with an electrophile of formula  (XVII)  Arl - Z1 - L (XVII)  in which Arl and Z1 are defined as above and L represents  a leaving group whose choice and choice of conditions  experimental (to carry out the condensation) will depend on the nature of Z1. 11. Process for the preparation of products of formula (I) in which Arl, X  Y, Z1, Z2 are defined as above and R1 represents a  hydrogen characterized in that one hydrolyzes in an acid medium a  compound of formula (I) in which R1 represents a t-butoxycarbonyl. 15. Pharmaceutical compositions containing, as active ingredients, a  compound according to one of claims 1 to 9, in combination with a  pharmaceutical vehicle acceptable as a drug. 16. Pharmaceutical compositions containing, as active ingredients, a  compound according to one of claims 1 to 9, in combination with a  acceptable pharmaceutical vehicle, for both curative and  preventive of depression and compulsive disorders or disorders  obsessive.  1 7. Pharmaceutical compositions containing, as active ingredients, a  compound according to one of claims 1 to 9, in combination with a  acceptable pharmaceutical vehicle, for both curative and  preventive of anxiety and panic attacks, schizophrenia,  aggression, bulimia, alcoholism, pain and  neurodegenerative diseases like Parkinson's disease or  Alzheimer's. 18. Pharmaceutical compositions containing. as active ingredients, a  compound according to one of claims I to 9. in combination with a  acceptable pharmaceutical vehicle. for both curative and  preventive of cancers. 19. Pharmaceutical compositions according to one of claims 13 to 16  characterized in that they contain, in addition, at least one second  associated active ingredient with antidepressant properties, in particular,  MILNACIPRAN and / or a 5HT 1A antagonist.