WO1998031669A1

WO1998031669A1 - Novel arylpiperazine derived from piperidine as antidepressant medicines

Info

Publication number: WO1998031669A1
Application number: PCT/FR1998/000068
Authority: WO
Inventors: Serge Halazy; Marie Lamothe; Catherine Jorand-Lebrun
Original assignee: Pierre Fabre Medicament
Priority date: 1997-01-15
Filing date: 1998-01-15
Publication date: 1998-07-23
Also published as: FR2758327A1; AU5992198A; FR2758327B1

Abstract

The invention concerns compounds of formula (I) in which in particular, R1 represents R'1, OR'1, SR'1, NHR'1, COR'1, CHOHR'1, CH2R'1, in which R'1 represents an aryl radical selected among a phenyl, a naphthyl or a pyridyl; R2 represents a halogen (Cl, F, Br), OH, NH2, CN, NO2, R'2, OR'2, SR'2, NHR'2, COR'2, CHOHR'2, COOR'2, NHCOR'2, NHCOOR'2, NHSO2R'2, OCONHR'2, in which R'2 represents an alkyl chain linear or branched, an aryl or an arylalkyl; Z represents CO-(CH2)n-O, CO-(CH2)n-NH, (CH2)m-O,(CH2)m-NH, CO-(CH2)p-CONH-, (CH2)p-CONH, CO-(CH2)p-NHCONH-, (CH2)m-NHCONH, -CO(CH2)p-OCONH-, (CH2)m-OCONH, -CO(CH2)p-NHCOO, (CH2)m-NHCOO, in which n represents zero or a whole number ranging between 1 and 8, m represents a whole number ranging between 2 and 8 and p represents a whole number ranging between 1 and 8; Ar represents an aromatic radical such as a phenyl or a naphthyl; R3 represents an alkyl radical linear or branched containing 1 to 6 carbon atoms: These compounds are particularly useful as antidepressant drugs.

Description

NEW ARYLPIPERAZINES DERIVED FROM PIPERIDINE AS ANTIDEPRESSANT DRUGS

The present invention relates to novel disubstituted piperidines derived from aryl piperazine, as well as to their process of preparation, the pharmaceutical compositions containing them and their use as medicaments.

Serotonin or 5-hydroxytryptamine (5-HT) is a neurotransmitter and a neuromodulator of the central nervous system 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 marrow, serotonin plays an important role in the control systems of the afferent peripheral nociceptives (cf. A. Moulignier, Rev. Neurol. (Paris), 150, 3-15, 1994).

Serotonin can play an important role in various types of pathological conditions such as certain psychiatric disorders (anxiety, depression, aggression, panic attacks, obsessive compulsive disorders, schizophrenia, tendency to suicide), certain neurodegenerative disorders (dementia of the Alzheimer type, By insonism, Huntington's chorea), anorexia, bulimia, alcohol-related disorders, strokes, pain, migraine or various headaches (R. Glennon, Neurosci. Biobehavioral Reviews, 14, 5 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 0 Brunello, G. Racagni, J. ^{Mendlecvicz,;} 'Serotonin receptor subtypes. pharmacological significance and clinical implications, "Karger Ed (1992); BE Leonard, Int Clin Psycho-pharmacology, 7, 13-21.. (1992); RW Fuller, J. Clin. Psychiatry, 53, 36-45 (1992), DG Grahame-Smith, Int. Clin. Psychopharmacology, 6, suppl. 4, 6-13, (1992). mainly subdivided into 4 main classes (5HTι, 5 5HT2, 5HT3 and 5HT4) which themselves include subclasses such as for 5HTι receptors which are mainly divided into 5HTι A, 5HT] β, 5HTιr> (cf. GR Martin , PA Humphrey, Neuropharmacol., 33, 261, 1994; PR Saxena, Exp. Opin. Lnvest. Drugs, 3 (5), 513, 1994).

0 The 5HTιτj receptors themselves contain several receptor subtypes; thus the receptors 5HTιr) _a and 5HTιj b were cloned and then identified in humans (cf. for example E. Hamel et al., Mol. Pharmacol., 44, 242, 1993; GW Rebec et al. , Proc. Natl. Acad. Sci. USA, 91, 3666.1994). Furthermore, it has recently been demonstrated that the 5HTI B auto-receptors in rodents and 5HT _j r) 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; BE Léonard, Int. Clin. Psychopharmacol., 9.7, 1994) as well as the release of other neurotransmitters such as norepinephrine, dopamine or acetylcholine (M. Harrigton, J. Clin Psychiatry, 53, 10, 1992).

Compounds having a selective antagonist activity at the level of the central 5HTI TJ / IB 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, Alzheimer's disease, Parkinson's disease.

The antagonists 5HTιrj / iB also find their utility in the treatment of endocrine disorders such as hyperprolactinemia, 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 the human 5HTij) and 5-HTJB receptors and therefore find their utility, alone or in combination with other molecules, as medicaments and more particularly as therapeutic means for the treatment both curative and preventive of serotonin-related disorders.

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-9511243 and F 9408981 which describe aromatic derivatives as 5HTιr antagonists) and recent publications which describe GR127,935 as an antagonist 5HTID (cf. M. Skingle et al., J. of Psychopharm. 8 (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 chemical structure which unambiguously differentiates them from the previously described derivatives but also by their original biological profile, in particular as regards their selectivity for the subtypes of serotonin receptors and with regard to their antagonistic activity in particular at the level of the receptors known as 5-HT]) i _j or 5-HTi β human.

The present invention relates to derivatives of general formula (I)

(D in which,

Rj represents R'j, OR'i, SR'j, NHR'i, COR'i, CHOHR'j, CH ₂ R'ι, in which Ri represents an aryl residue chosen from phenyl, naphthyl or pyridyl which can optionally be substituted by one or more groups chosen from a linear or branched alkyl comprising from 1 to 5 carbon atoms, a halogen (Cl, F, Br or I), OH, OR4, SR4, CF ₃ , CH ₂ CF ₃ , NO ₂ , CN, COR4, COOR4, NHR4, NHCOR4, NHCOOR4, NHSO2R4, SO2 4 in which R4 represents a linear or branched alkyl chain comprising from 1 to 5 carbon atoms;

R ₂ represents a halogen (Cl, F, Br), OH, NH ₂ , CN, NO ₂ , R'2, OR ^* ₂ , SR ' ₂ , NHR' ₂ , COR ' ₂ , CHOHR'2, COOR', NHCOR ' ₂ , NHCOOR' ₂ , NHSO ₂ R'2, OCONHR'2, in which R'2 represents a linear or branched alkyl chain comprising from 1 to 5 carbon atoms, an aryl or an alkyiaryl in which the aryl residue is chosen from phenyl, naphthyl or pyridyl which may optionally be substituted by one or more groups chosen from linear or branched alkyl comprising from 1 to 5 carbon atoms, halogen (Cl, F, Br or I), OH, OR '4, SR', CF ₃ , CH ₂ CF ₃ , N0 ₂ , CN, COR ' ₄ , COOR'4, NHR' ₄ , NHCOR4, NHCOOR'4, NHSO2R4, Sθ2 '4 in which R'4 represents a linear or branched alkyl chain comprising from 1 to 5 carbon atoms, it being understood that when K \ represents OR'i, SR'i or NHR] then R2 necessarily represents R'2 , COOR'2, COR'2 or CHOHR ^* ₂ ;

Z represents CO- (CH ₂ ) _n -O, CO- (CH ₂ ) _n -NH, (CH ₂ ) _m -O, (CH ₂ ) _m -NH, CO- (CH ₂ ) _p -CONH-, ( CH ₂ ) _p -CONH, CO- (CH ₂ ) _p -NHCONH-, (CH ₂ ) _m -NHCONH, - CO (CH ₂ ) _p -OCONH-, (CH ₂ ) _m -OCONH, -CO (CH ₂ ) _p -NHCOO-, (CH ₂ ) _m -NHCOO, in which n represents zero or an integer between 1 and 8. m represents an integer between 2 and 8 and p represents an integer between 1 and 8 ; Ar represents an aromatic radical such as a phenyl or a naphthyl to which Z and the piperazine are attached to different carbons and which can itself be variously substituted by one or more substituents chosen from a linear or branched alkyl radical comprising from 1 to 6 carbon atoms, an alkoxy (OR5 in which R5 represents a linear or branched alkyl radical comprising from 1 to 6 carbon atoms), or a halogen (Cl, Br, F or I);

R3 represents a linear or branched alkyl radical comprising from 1 to 6 carbon atoms,

and their physiologically acceptable hydrated salts, solvates and bioprecursors 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 the addition of 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). A particularly appreciated class of compounds of formula (I) corresponds to the compounds of formula (la)

(the)

in which Ri, R2 and Z are defined as above and R'5 preferably represents H, R5, OR5 or Cl in which R5 is defined as above.

Another class also particularly appreciated of compounds of formula (I) corresponds to the compounds of formula (Ib)

(Ib) in which Ri, R ₂ and Z are defined as above.

The compounds of general formula (I) forming part of the present invention are prepared by a general method which consists in condensing a piperidine of general formula (II)

(not) in which Rj and R2 are defined as in formula (I), with an electrophile of general formula (III)

(III)

in which Ar and R3 are defined as above while Z 'represents a precursor residue of Z as defined in formula (I). The choice of techniques, methods, experimental conditions, reagents to be used for the preparation of the products of general formula (I) by condensation of the amines of formula (II) with electrophiles of formula (III), as well as the choice of Z 'will depend essentially on the nature of Z in the definition of formula (I).

Thus when Z represents CO (CH ₂ ) _n O, CO (CH ₂ ) _n NH, CO (CH ₂ ) _p CONH, CO (CH ₂ ) _p NHCONH, CO (CH ₂ ) _p OCONH or CO ( CH ₂ ) _p NHCOO (in which n is different from 0), the compounds of formula (I) are prepared by formation of an amide by condensation of an amine of formula (II) with a carboxylic acid derivative of formula (III) in which Z 'represents respectively, LCO (CH ₂ ) _n O, LCO (CH ₂ ) _n NH, LCO (CH ₂ ) _p CONH, LCO (CH ₂ ) _p NHCONH, LCO (CH ₂ ) _p OCONH or LCO (CH ₂ ) _p NHCOO, in which n and p are integers between 1 and 8, and L represents OH, Cl, or the group "LCO" represents an activated form of a carboxylic acid suitable for formation of an amide by condensation with an amine.

This condensation will be carried out by methods and techniques well known to those skilled in the art for preparing an amide from an amine and a carboxylic acid derivative. The choice of methods among the very numerous previously described will be guided by the nature of the reagents (II) and (III) present.

Thus, by way of example, this reaction can be carried out by condensation of an amine of formula (II) with a carboxylic acid derivative of formula (III) in which L (which falls within the definition Z ') represents a chlorine, in the presence of an organic or inorganic base such as pyridine, DLPEA, 4-DMAP, DBU, K2CO3, CS2CO3 in an anhydrous polar aprotic solvent such as THF, DME, dichloromethane at a temperature between - 20 ° C and 40 ° C. Another particularly preferred method of preparing the compounds of formula (I) in which the NZ bond represents an amide where Z is defined as above, consists in condensing an amine of general formula (II) with a carboxylic acid of formula ( III) in which Z ′ is defined as above (it being understood that L represents OH) by using reagents well known for this type of condensation such as for example DCC, EDCI, PyBOP, HOBT, in a polar anhydrous solvent such as THF, dichloromethane, DME, dichloroethane, in the presence of a base in stoichiometric quantities such as for example triethylamine optionally in the presence of a base in catalytic quantities such as for example 4-DMAP.

The derivatives of general formula (I) in which Z represents (CH2) _m O, (CH ₂ ) mNH, (CH ₂ ) _p CONH, (CH ₂ ) _m NHCONH, (CH ₂ ) _m OCONH or (CH2) _m NHCOO are prepared by condensation of an amine of general formula (II) with an electrophile of general formula (III) in which Z 'represents XZ in which X represents a leaving group such as a halogen (chlorine, bromine or iodine), a O-tosyle, O-mesyl or O-trifluoromethanesulfonyl.

This nucleophilic substitution reaction is carried out by methods and techniques well known to those skilled in the art for carrying out this type of transformation using a cyclic amine as a nucleophile. For example, this reaction can be carried out in the presence of an organic or inorganic base such as NaH, t-BuOK, a tertiary amine (Et3N, DiPEA, DBU or 4-DMAP), K2CO3, CS2CO3, in a polar aprotic solvent such as THF, DME, DMF or DMSO, at a temperature between 0 ° C and 80 ° C in the presence or not of catalyst such as Nal, Kl or BU4NI.

In the particular case of the compounds of general formula (I) in which Z represents CONH or CO ₂ , a particularly appreciated preparation method consists in condensing an end of general formula (II) defined as above and an aromatic piperazine derivative of formula general (IV)

(IV) in which R3 and Ar are defined as in the general formula (I) while Y represents O or NH, with an electrophile of general formula (V)

o

(V)

in which X \ and X ₂ , identical or different, each represent a leaving group such as a halogen (in particular chlorine), an O-alkyl group (in particular the group OCCI3), an O-aryl group (in particular O-pyridyl or O-phenyl groups substituted for example by a nitro residue), a succinimide, phthalimide or imidazolyl group.

The methods and techniques chosen for carrying out the preparation of the compounds of formula (I) in which Z represents CONH or COO by condensation of the piperidines of general formula (II) and aromatic derivatives of general formula (IV) with an electrophile of general formula (V) such as the choice of the order in which the reactants are brought into contact, the reaction times, the isolation and / or the purification of the intermediates, the temperature of the reactions at different stages of the condensation, the nature of the solvent (s), the presence of co-reactants (such as an organic base such as for example a tertiary amine such as triethylamine) or of catalysts and the choice of reactant (V) (nature of X] and X) will be essentially determined by the nature of (IV) and more particularly by the definition of Y.

Thus, a particularly preferred method for the preparation of derivatives of formula (I) in which Z represents CONH consists in reacting an aromatic piperazine of formula (IV) in which .Ar and R3 are defined as above and Y represents NH with triphosgene, in the presence of a base such as triethylamine in an anhydrous aprotic solvent such as dichioromethane, and. then add a compound of formula (II) in which R] and R ₂ are defined as in formula (I).

In the case of the preparation of compounds of formula (I) in which Z represents COO, a more particularly preferred method consists in first condensing in a solvent such as dichloromethane and to isolate the intermediate thus formed of general formula (VI).

(VI) before condensing it with a nucleophile of general formula (IV) in which Y represents oxygen, in the presence of an organic or inorganic base such as NaH, KH, tBuOK, in a polar aprotic solvent such as THF or the DMF.

In the particular case of the compounds of general formula (I) in which Ri, R ₂ , Ar and R3 are defined as above but Z represents (CH2) 2-CONH, an alternative but particularly appreciated method of preparation consists in condensing in a first time a cyclic amine of general formula (II) with a Michaèl acceptor corresponding to formula (VII)

(VII)

in which R represents an alkyl residue such as an ethyl, followed by the hydrolysis of the ester function of the intermediate thus formed (by methods well known to those skilled in the art for hydrolyzing an ester to an acid such as for example the use of NaOH or LiOH) to lead to a carboxylic acid derivative of general formula (VIII).

(VIII) The condensation of an aromatic amine of general formula (IV) in which Ar and R3 are defined as above but Y represents NH with an activated derivative of the carboxylic acid (VIII), according to the methods and techniques well known to man of trade for carrying out the synthesis of an amide by condensation of a carboxylic acid with an amine such as those which have been described previously leads to the compounds of formula (I) in which Z represents (CH2) 2CONH.

The synthesis intermediates of general formula (III) are prepared from the aromatic piperazines of general formula (IV) by various methods and techniques the choice of which will essentially depend on the nature of Z 'and which are summarized in the table below.

Preparation of intermediates of formula (M) by condensation of a piperazine of formula (IV) with an electrophile

in this table, P represents a protected precursor form of the leaving group X whereas p and m are defined as in the general formula (I) and n is an integer between 1 and 8, X and L 'represent a leaving group such that a halogen (Cl, Br or I), a tosylate, a mesylate or a triflate, L represents OH, Cl or, the group "COL" represents the activated form of a carboxylic acid as described above, X \, X2 are defined as in formula (V) and R represents an alkyl residue (for example methyl, ethyl, t-butyl), aryl or arylalkyl (for example benzyl). The complementary step "A" symbolizes the implementation, after the coupling of the aromatic piperazine (IV) with the electrophile, of a hydrolysis reaction of the ester function by the methods and techniques well known to man of trade for this type of transformation whereas the complementary step symbolized by "B" implements the transformation of the protective group P (in the product of condensation between (IV) and the electrophile) in leaving group X which will be carried out by different techniques and methods depending on the nature of P and X. Thus, when P represents O-benzyl, the condensation of the aromatic piperazine (IV) with the electrophile will be followed by a group cleavage reaction benzyl (for example by hydrogenation in the presence of palladium on carbon) and of a reaction of transformation of the alcohol thus formed into leaving group X. If this leaving group is a halogen, this transformation will be carried out using reacts tifs and well known methods for transforming an alcohol into halogen such as for example the use of SOCl ₂ , POCI3, PCI5, PBr ₃ , SOBr ₂ , Ph ₃ Br ₂₎ Ph ₃ I ₂ , PI3, P2I4. If the desired leaving group is a mesylate, a tosylate or a triflate, this will be obtained by reaction of the intermediate alcohol with respectively mesyl chloride, tosyl chloride or triflic anhydride in the presence of a base such than a tertiary amine, pyridine or 4-DMAP. If necessary, the electrophiles used for the preparation of the intermediates of formula (III) by reaction with a derivative of formula (IV) comprising a substituent P can also include derivatives in which P represents any other protected form of a good alcohol known to a person skilled in the art and which will be transformed into free alcohol after the condensation, followed by the transformation of this alcohol into a leaving group by the methods described above. The additional step "C" symbolizes the cleavage of the tert-butoxycarbonyl residue in an acid medium (for example HCl or TFA in ethyl ether, methanol or dichloromethane).

The intermediates of formula (IV) are prepared by various methods and techniques described such as for example in the patent applications of the Applicant (FR-2 722 788 and FR 9512218). The 4,4-disubstituted piperidines of general formula (II) in which R _j and R are defined as in general formula (I) are prepared for the most part by various methods and techniques previously described in publications such as for example J. Pharm. Sci. 61, 1316 (1972), J. Heterocyl. Chem. 23, 73 (1986), Tetrahedron Lett. 37 (8), 1297 (1996), Yaoxue Xuebao 26, 493 (1991) or in patent applications such as for example the 4-benzyl-4-hydroxypiperidines described in patent WO 9117156, the 4-anilinopiperidines described in US Patent 5106983, the 4,4-diarylpiperidines described in patent WO 9410989 and the general methods described in patents WO 9113872 and WO 9606609.

In the particular case of intermediates of formula (II) in which R \ represents R'i, COR '] or CH ₂ R'] and R ₂ represents a halogen, a particularly preferred synthesis method consists in treating a derivative of formula ( II) in which R \ represents R'i, COR'i or CH ₂ R'ι and R ₂ represents OH with an appropriate reagent such as for example DAST (diethylaminosulfur trifluoride) if R ₂ represents F in the desired product (this reaction will be carried out in a polar aprotic solvent such as dichloromethane, at a temperature between - 20 ° C and 60 ° C, in the possible presence of a base such as a tertiary amine). Likewise, a chlorinated derivative of formula (II) in which R ₂ represents Cl can be prepared by reaction of a corresponding alcohol of formula (III) in which R ₂ represents OH with SOCI2, POCI3 or (COCl2) 2i a bromine derivative analog (of formula (II), in which R2 = Br) will be prepared by reaction of the same alcohol with PBr. The intermediates of formula (II) in which Rj represents CHOHR '} are prepared by reduction, using a boron or aluminum hydride (for example LiAUi4 or NaBH_ι) of a derivative of formula (II) in wherein R \ represents COR'j, and, likewise, the derivatives of formula (II) in which R2 represents CI- ^ R'i are accessible from compounds of formula (II) in which R ₂ represents COR '\ or CHOHR 'j by reduction by means of methods and techniques well known to those skilled in the art for carrying out this type of transformation such as for example the reduction of Wolf-Kishner or the Barton method using the reduction of thioesters by Bu ₃ SnH

The intermediates of formula (II) in which R \ represents R'j or CH ₂ R'ι and R ₂ represents NHR'2, are also accessible by initial formation of an imine between 4-piperidinone comprising a protective group on l nitrogen (such as a BOC for example) followed by the reaction of this intermediate with an organometallic nucleophile (R ' _j Li, R' _j MgBr, R ' _j C ^ Li or R' jC ^ MgBr for example). An alternative method for preparing the piperidines of formula (II) which is particularly appreciated when R2 represents CN, NO2, COR'2 or Cθ2R ' ₂ consists in condensing an intermediate of formula (IX)

(IX)

in which R | preferably represents R'i, OR'i, SR '\ COR' _j and R ₂ represents CN, NO ₂ , COR ' ₂ or CO2R2 with ec a bivalent electrophile of formula (X)

Cl \

\

: ι N— P

\ /

(X) in which P represents a protective group of an amine such as for example a BOC or a TOS which will be hydrolyzed after the condensation. The condensation of the intermediates of formula (IX) with the electrophiles of formula (X) will preferably be carried out in the presence of a base, organic or inorganic, depending essentially on the nature of R] and R2, in an anhydrous aprotic solvent! than ether, THF, DME, DMF or DMSO, under phase transfer conditions at a temperature between - 40 ° and 60 ° C.

All the methods which make it possible to convert a derivative of formula (I) into another derivative of formula (I) in which at least one of the substituents R \, R ₂ , Z or R3 must also be considered as forming part of the present invention. are different, by techniques and methods well known to those skilled in the art.

Thus, by way of example, the derivatives of general formula (I) in which R ₂ represents NO2 or in which an aromatic ring is substituted by an NO2 residue can be converted into derivatives of formula (I) in which respectively R2 represents NH2 or an aromatic nucleus is substituted by an NH2 residue in the same position, by the methods and techniques well known for this type of reduction as described for example in "Comprehensive Organic Transformation", p. 412; RC Larock, VCH, 1989, among which mention may be made of atmospheric hydrogenation catalyzed with palladium on carbon, the use of SnCl2, zinc, Raney's Ni or alternatively a rhodium catalyst in the presence of hydrazine. Similarly, the derivatives of formula (I) in which R ₂ represents NH2 or in which an aromatic ring is substituted by an NH ₂ residue can be transformed into derivatives of formula (I) in which respectively NHR'2, NHCOR'2 , NHCO ₂ R ', NHSO R' or an aromatic ring is substituted by NHR4, NHCOR4, NHCO ₂ R'4, NHSO ₂ R4 by well known methods for alkylating a primary amine or for transforming an amine into amide, carbonate, urea or sulfonamide.

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 protecting groups such as those described in "Protective groups in Organic Synthesis", T.W. Greene, John Wiley & 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, using the methods and techniques described. in the references cited above.

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 stereoisomers, 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 selective enantion 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 (+ ) -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 R3 is a hydrogen comprising at least one asymmetric center can also be resolved by the formation of diastereomeric amides which are separated by chromatography and hydrolysed to release the chiral auxiliary.

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

EXAMPLE 1

IA (4-cyano-4-phenylpiperidin-1-yl) - / V- [4-methoxy-3- (4-methylpiperazin-1-yl) phenyl] amide fumarate (1)

l: A solution of triphosgene (240 mg, 0.8 mmol) in dichloromethane (30 ml) is cannulated on a solution of 4-methoxy-3- (4-methylpiperazin-l-yl) aniline (European patent 0533266-A1, 491 mg, 2.2 mmol) and pyridine (200 ml, 2.4 mmol) in dichloromethane (20 ml) under a nitrogen atmosphere and at 0 ° C. The cold bath is removed and the reaction mixture is stirred for 30 minutes at room temperature. A solution of 4-cyano-4-phenylpiperidine (A, 413 mg, 2.2 mmol) and pyridine (200 ml, 2.4 mmol) in dichloromethane (10 ml) is then added. The reaction is stirred for 12 hours at room temperature, then successively diluted in dichloromethane, washed with water, dried over magnesium sulphate and concentrated. Derivative 1 is isolated in the form of the free base after purification by flash chromatography with a mixture of eluents (95-5-1 = M OH-MeOH-CH ₂ C1 ₂ ).

Mass obtained: 558 mg (61%) This compound is dissolved in methanol and treated with fumaric acid to give the corresponding fumarate.

JH-NMR (200 MHz, dmso-d ₆ ) δ: 8.41 (s, 1H); 7.35-7.57 (m, 5H); 7.15-6.95 (m, 2H); 6.78 (d, 1 H, 8.7 Hz); 6.54 (s, fumarate); 4.34 (brd, 2H); 3.70 (s, 3H); 3 15-2.8 (m, 6H); 2.61 (brs, 4H); 2.31 (s, 3H); 2.35-2.10 (m, 2H); 2.05-1.80 (bit, 2H).

Elementary analysis: C ₂ 5H3] N5θ ₂ ; C4H4O4 Calculated: C = 63.37; H = 6.42; N = 12.74 Found: C = 63.45: H ≈ 6.46: N = 12.56

IR (TŒΓ): 3800-2400, 1689, 1642, 1521, 1514

Mass (DCI, NH ₃ ): 434 (MH +)

Rf: 0.5 (1-10-90 = NH ₄ OH-MeOH-CH ₂ Cl ₂ )

EXAMPLE 2

1- [3-chloro-2- (4-methylpiperazin-1-yl) phenyl] -3- [2-oxo-2- (4-cyano-4-phenylpiperidin-1-yl) ethyl] ureylene fumarate (2)

2A: 2-tertbutoxycarbonylamiπo-l- (4-cyano-4-phenylpiperidin-l-yl) ethan-l-one

The Λ-tert-butoxycarbonylglycine (1.8 g; 10.2 mmol) is dissolved in dichloromethane (35 ml) under a nitrogen atmosphere in the presence of A hydrochloride (2.74 g; 12.3 mmol), of triethylamine (1.57 ml; 1 1.3 mmol ), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (2.16 g; 1 1.3 mmol) and 4-NN- dimethylaminopyridine (30 mg). The reaction mixture is stirred for 24 hours at room temperature, then diluted in dichloromethane, washed twice with water and once with a saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate and concentrated. The derivative 2A is isolated in the form of the free base after purification by flash chromatography with a mixture of eluents (1-5-95

- NH ₄ OH-MeOH-CH ₂ Cl ₂ ).

Mass obtained: 3.24 g (92%)

^Ï H-NMR (200 MHz, dmso-d ₆ ) δ: 7.7-7.3 (m, 5H); 6.78 (t, 1 H, 5.5 Hz); 4.55 (brd, 1H); 4.0 (brd, 1H); 3.86 (t, 2H, 5Hz); 3.28 (bit, IH); 2.86 (bit, IH); 2.25-1.75 (m, 4H); 1.39 (s, 9H).

Elemental analysis: C19H25N3O3 Calculated: C = 66.45; H = 7.34; N = 12.24 Found: C = 66.13; H = 7.12; N ≈ 12.05

2B: 2-amino-1- (4-cyano-4-phenylpiperidin-1-yl) ethan-1-one The derivative 2A is dissolved in dichloromethane (270 ml) under a nitrogen atmosphere and trifluoroacetic acid ( 46 ml) is added. The solution is stirred for 3 hours at room temperature, then the solvent and the acid are evaporated. The oily residue is taken up in dichloromethane and washed with water. The aqueous phase is extracted 3 times with dichloromethane. The organic phases are combined, dried over MgSθ4 and concentrated. The derivative 2B is used without further purification.

Mass obtained: 1.96 g (84%)

^Ï H-NMR (200 MHz, dmso-d ₆ ) δ: 7.7-7.35 (m, 5H); 4.60 (brd, 1H); 3.95 (brd, 1H); 3.6-3.1 (m, 3H); 2.86 (bit, IH); 2.3-1.75 (m, 4H); 1.65 (brs, 2H).

Elemental analysis: C14H17N3O; 0.4 H2O Calculated: C ≈ 67.12: H = 7.16: N = 16.77 Found: C = 66.97; H = 7.27; N = 16.37

2: 3-chloro-2- (4-methylpiperazin-1-yl) aniline (French Patent No. 9512218; 500 mg; 2.2 mmol) dissolved in dichloromethane (5 ml) in the presence of pyridine (178 ml; 2.2 mmol) is cannulated on a solution cooled to 0 ° C of triphosgene (216 mg; 0.72 mmol) in dichloromethane (5 ml). The reaction mixture is stirred for 20 minutes then the derivative 2B (760 mg; 3.1 mmol) diluted in dichloromethane (5 ml) in the presence of pyridine (178 ml; 2.2 mmol) is added dropwise. The reaction no longer evolves after a few hours of stirring at 0 ° C. It is then diluted in dichloromethane, washed with a saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate and filtered. The solvent is evaporated and derivative 2 is isolated by flash chromatography with a mixture of eluents (1-5-95 = NH4OH-MeOH-CH ₂ Cl).

Mass obtained: 547 mg (50%)

This compound is dissolved in methanol and treated with fumaric acid to give the corresponding fumarate.

1H-NMR (200 MHz, dmso-d ₆ ) δ: 8.32 (s, 1H); 8.02 (dd, IH, 1.3 and 8Hz), 7.64 (brs, IH); 7.6-7.3 (m, 5H); 7.07 (t, 1H, 8Hz); 6.88 (dd, IH, 1.3 and 8Hz); 6.56 (s, fumarate); 4.56 (brd, 1H); 4.05 (brs, 3H); 3.54 (bit, 2H); 3.32 (m, 1H); 3.0-2.55 (m, 8H); 2.38 (s, 3H); 2.3-1.75 (m, 3H).

Elemental analysis: C26H31CIN6O2; 1.3 C4H4O4; 0.3 H ₂ O; 0.42 And O Calculated: C = 58.33; H = 6.01; N = 12.41 Found: C = 58.44; H = 6.03; N - 12.75

IR fKBr): 3700-2300, 1700, 1642, 1580, 1500, 1450.

Rf: 0.2 (1-3-97 = NH4θH-MeOH-CH ₂ Cl ₂ )

Mass (DCI, NH ₃ ): 495 (MH +)

EXAMPLE 3

5- [3-Chloro-2- (4-methylpiperazin-1-yl) phenylamino] -l- (4-cyano-4-phenylpiperidin-1-yl) pentan-1-one fumarate (3)

3A: 5-bromo-1- (4-cyano-4-phenylpiperidin-1-yl) pentan-1-one

A (2.1 g; 11.3 mmol) is dissolved in dichloromethane (23 ml) in the presence of triethylamine (2.35 ml; 17 mmol) under a nitrogen atmosphere. The solution is cooled to 0 ° C. and then 5-bromopentanoyl chloride (1.8 ml; 13.5 mmol) is added. The reaction is immediate. The solution is diluted in dichloromethane washed with a semi-saturated sodium bicarbonate solution and dried over magnesium sulfate. The 3A derivative is purified by flash chromatography with a 1-5-95 mixture (NH ₄ OH-MeOH-CH ₂ Cl ₂ ).

Mass obtained: 3.58 g (90%)

^Î H-NMR (200 MHz; dmso-d ₆ ) δ: 7.7-7.2 (m, 5H); 4.60 (brd, 1H); 4.07 (brd, 1H); 3.56 (t, 2H, 6.7Hz); 3.29 (bit, IH); 2.80 (bit, IH); 2.41 (t, 2H, 6.7Hz); 2.3-1.5 (m, 8H).

3B: 7V-tertbutoxycarbonyl-5- [3-chloro-2- (4-methylpiperazin-1-yl) phenylamino] -l- (4-cyano-4-phenylpiperidin-1-yl) pentan-1-one

The 7V ^r -tertbutoxycarbonyl-3-chloro-2- (4-methylpiperazin-1-yl) aniline (475 mg; 1.45 mmol) is dissolved in DMF (6 ml) at 0 ° C in the presence of sodium hydride ( 60% in oil; 138 mg; 1.7 mmol) under a nitrogen atmosphere. A solution of 3A (615 mg; 1.75 mmol) in DMF (5 ml) is added dropwise. The reaction mixture is stirred for 24 hours at room temperature and then neutralized with a few drops of water. The solvent is evaporated. The oily residue is taken up in ethyl acetate and washed twice with water. The solution is dried over magnesium sulfate, filtered and then concentrated. The derivative 3B is purified by flash chromatography with a mixture of eluents (1-7-93 = NH4θH-MeOH-CH2Cl2).

Mass obtained: 718 mg (83%)

1H-NMR (200 MHz, dmso-d ₆ ) δ: 8.41 (imp); 7.65-7.2 (m, 7H); 7.12 (t, 1H, 8Hz); 7.08 (imp); 4.61 (brd, 1H); 4.06 (brs, 1H); 4.1-3.7 (m, 1H); 3.5-2.6 (m, 7H); 2.90 and 2.74 (s, dmf); 2.38 (bs, 6H); 2.25-1.7 (m, 7H); 1.65-1.2 (m, 13H).

Mass (DCI, NH ₃ ): 594 (MH +)

3: The derivative 3 is prepared according to the method used for 2B from the following reagents: 3B (683 mg; 1.1 mmol); trifluoroacetic acid (5.2 ml) in the dichloromethane (31 ml). Derivative 3 is purified by flash chromatography with a mixture 1-3-97 (NH4θH-MeOH-CH Cl ₂ ). Mass obtained: 363 mg (64%)

1H-NMR (200 MHz, dmso-d ₆ ) δ: 7.65-7.3 (m, 5H); 6.97 (t, 1H, 8Hz); 6.59 (s, fumarate); 6.50 (t, 2H, 7Hz); 5.62 (brs, 1H); 4.62 (brd, 1H); 4.09 (brs, 1H); 3.55 (brt, 2H); 3.3 (brt, 1H); 3.11 (brs, 2H); 3.0-2.7 (m, 3H); 2.62 (brd, 2H); 2.6-2.3 (m, 7H); 2.25-1.7 (m, 4H); 1.60 (brs, 4H).

Elemental analysis: C ₂ gH3ôClN5θ; C4H4O4; 0.07 H ₂ O Calculated: C - 62.99: H = 6.61; N = 11.48 Found: C = 63.27; H = 6.61; N = 11.36

IR fKBr): 3700-2400, 1716, 1680, 1588

Rf: 0.4 (1-5-95 = NH4θH-MeOH-CH ₂ Cl ₂ )

Mass (DCI, NH ₃ ): 494 (MH +)

EXAMPLE 4

1- (4-cyano-4-phenylpiperidin-1-yl) -5- [2- (4-methylpiperazin-1-yl) phenoxy] pentan-1-onc fumarate (4)

4: Derivative 4 is prepared according to the method used for 3B from the following reagents: 3A (1.36 g; 3.9 mmol); DMF (19 ml); NaH (50%, 187 mg, 3.9 mmol); 2- (4-methyipiperazin-1-yl) phenol (French patent n ° 9408981, 500 mg, 2.6 mmol). Derivative 4 is isolated in the form of the free base after purification by flash chromatography with a mixture of eluents 1-5-95 (NH4θH-MeOH-CH ₂ Cl ₂ ).

Mass obtained: 889 mg (74%)

1H-NMR (200 MHz, dmso-d ₆ ) δ: 7.6-7.25 (m, 5H); 7.0-6.8 (m, 4H); 4.62 (brd, 1H); 4.10 (brd, 1H); 2.97 (brt, 2H); 3.31 (brt, 1H); 3.02 (brs, 4H); 2.82 (brt, 1H); 2.64 (brs, 4H); 2.50 (brt, 2H); 2.34 (s, 3H); 2.3-1.6 (m, 8H).

Elemental analysis: C gH36N4θ ₂ ; O.85C4H4O4; 0.76 H ₂ 0 Calculated: C = 66.35; H = 6.95; N = 9.60 Found: C = 66.07: H ≈ 7.04: N = 9.46

LRfKBr): 3415, 2932, 2871, 1710, 1637.

Mass (DCI, NH ₃ ): 461 (MH +)

Rf: 0.25 (1-5-95 = NH ₄ OH-MeOH-CH ₂ Cl ₂ )

EXAMPLE 5

1- (4-cyano-4-phenylpiperidin-1-yl) -5- [3-methyl-2- (4-methylpiperazin-1-yl) phenoxy] pentan-1-fumarate (5)

5: Derivative 5 is prepared according to the method used for 3B from the following reagents: 3A (1.27 g; 3.6 mmol); DMF (15 ml); NaH (60%, 145 mg, 3.6 mmol); 3-methyl-2- (4-methylpiperazin-1-yl) phenol (French Patent No. 9512218, 500 mg, 2.4 mmol). Derivative 5 is isolated in the form of a free base after purification by flash chromatography with a mixture of eluents (1-3-97 = NH4θH-MeOH- CH ₂ C1 ₂ ).

Mass obtained: 479 mg (41%)

1H-NMR (200 MHz, dmso-d ₆ ) δ: 7.6-7.3 (m, 5H); 6.99 (t, 1H, 8Hz); 6.79 (brt, 2H, 9Hz); 6.59 (s, fumarate); 4.62 (brd, 1H); 4.09 (brd, 1H); 3.95 (t, 2H, 6Hz); 3.7-3.1 (m, 2H); 3.0-2.5 (m, 4H); 2.47 (t, 2H, 6Hz); 2.38 (s, 3H); 2.25 (s, 3H); 2.5-1.5 (m, 12H).

Elemental analysis: C ₂ 9H3gN4Û ₂ ; C4H4O4; 0.07 H ₂ 0 Calculated: C = 67.10: H ≈ 1.17: N ≈ 9.48 Found: C = 66.92; H ≈ 1.18; N = 9.33

IR fKBr): 3200-2200, 1716, 1649, 1580

Mass (DCI, NH ₃ ): 475 (MH +)

Rf: 0.2 (1-4-96 = NH ₄ OH-MeOH-CH ₂ Cl ₂ )

EXAMPLE 6

1- (4-cyano-4-phenylpiperidin-1-yl) -6- [2- (4-methylpiperazin-1-yl) phenoxy] hexan 1-fumarate (6)

6A: 6-bromo-1- (4-cyano-4-phenylpiperidin-1-yl) hexan-1-one

The derivative 6A is prepared according to the method used for 3_A from the following reagents: A (667 mg; 3.6 mmol); triethylamine (748 ml; 5.3 mmol); 6-bromohexanoyl chloride (657 ml; 4.3 mmol) in dichloromethane (10 ml). Derivative 6A is purified by flash chromatography with a 30-70 mixture (EtOAc-EDP).

Mass obtained: 1.21 g (93%)

1H-NMR (200 MHz; dmso-d ₆ ) δ: 7.2-7.3 (m, 5H); 4.60 (brd, 1H); 4.07 (brd, 1H); 3.53 (t, 2H, 6.7Hz); 3.28 (brt, 1H); 2.80 (brt, 1H); 2.38 (t, 2H, 6.7Hz); 2.3-1.3 (m, 10H).

6: The derivative 6 is prepared according to the method used for 3JB from the following reagents: 6A (1.16 g; 3.2 mmol); DMF (15 ml); NaH (50%, 152 mg, 3.2 mmol); 2- (4-methylpiperazin-1-yl) phenol (French patent n ° 9408981, 407 mg, 2.1 mmol). Derivative 6 is isolated in the form of the free base after purification by flash chromatography with a mixture of eluents (1-5-95 = NH OH-MeOH-CH Cl ₂ ).

Mass obtained: 497 mg (49%)

^] H-NMR (200 MHz, dmso-d ₆ ) δ: 7.6-7.2 (m, 5H); 7.0-6.7 (m, 4H); 6.56 (s, fumarate); 4.57 (brd, 1H); 4.05 (brd, 1H); 3.93 (t, 2H, 6Hz); 3.34 (brt, 1H); 3.00 (brs, 4H); 2.9-2.5 (m, 5H); 2.5-2.25 (m, 5H); 2.2-1.3 (m, 10H).

Elemental analysis: C ₂ 9H3gN4θ ₂ ; I. I5C4H4O4; 0.34 H2O Calculated: C = 66.36; H ≈ 7.06; N = 9.21 Found: C = 66.27; H ≈ 7.21; N = 9.34

LR (KBrV 3700-2300, 1709, 1620, 1500, 1450.

Mass (DCI, NH ₃ ): 475 (MH +)

Rf: 0.3 (1-5-95 = NH ₄ OH-MeOH-CH ₂ Cl ₂ ) EXAMPLE 7

1- [4-hydroxy-4- (4-bromophenyl) piperidin-1-yl] -5- [2- (4-methylpiperazin-1-yl) phenoxy] pentan-1-one fumarate (7)

7: The derivative 7 is prepared according to the method used for 2A from the following reagents: 5- [2- (4-methylpiperazin-1-yl) phenoxy] pentanoic acid (French patent n ° 9512218, 390 mg; 1.25 mmole); 4-hydroxy-4- (4-bromophenyl) piperidine (408 mg, 1.6 mmolee); 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (280 mg; 1.46 mmolee); triethylamine (203 ml; 1.46 mmolee); 4-N, V-dimethylaminopyridine (10 mg) in dichloromethane (15 ml). Derivative 7 is isolated in the form of the free base after purification by flash chromatography with a mixture of eluents (1-7-93 ≈ NH ₄ OH-MeOH-CH ₂ Cl ₂ ).

Mass obtained: 271 mg (40%)

1H-NMR (200 MHz, dmso-d ₆ ) δ: 7.55-7.35 (m, 4H); 7.0-6.75 (m, 4H); 6.56 (s, fumarate); 4.32 (brd, 1H); 3.94 (brt, 2H); 3.77 (brd, 1H); 3.37 (brt, 1H); 2.99 (brs, 4H); 2.88 (brt, 1H); 2.59 (brs, 4H); 2.40 (bit, 2H); 2.30 (s, 3H); 2.0-1.45 (m, 8H).

Elementary analysis: C27H36N3O3; C4H4O4 Calculated: C = 57.59; H = 6.24; N ≈ 6.50 Found: C = 57.44; H = 6.24; N = 6.36

LR fKBr): 3700-2300, 1700, 1610, 1500, 1450

Mass (DCI, NH3): 530, 532 (MH +) Rf: 0.3 (1-7-93 = NH ₄ OH-MeOH-CH ₂ Cl2)

EXAMPLE 8

1- (4,4-diphenylpiperidin-1-yI) -5- [2- (4-methylpiperazin-1-yl) phenoxy] pentan-1-one fumarate (8)

8: The derivative 8 is prepared according to the method used for 2A from the following reagents: 5- [2- (4-methylpiperazin-1-yl) phenoxy] pentanoic acid (French Patent No. 9512218, 400 mg; 1.28 mmole); 4,4-diphenylpiperidine hydrochloride (446 mg, 1.6 mmol); 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (286 mg; 1.49 mmol); triethylamine (208 ml; 1.49 mmol); 4-N, N-dimethylaminopyridine (15 mg) in dichloromethane (20 ml). Derivative 8 is isolated in the form of a free base after purification by flash chromatography with a mixture of eluents (1-5-95 = NH ₄ OH-MeOH-CH ₂ Cl ₂ ).

Mass obtained: 330 mg (60%)

^Ï H-NMR (200 MHz, dmso-d ₆ ) δ: 7.5-7.1 (m, 10H); 7.0-6.8 (m, 4H); 6.58 (s, fumarate); 3.94 (brt, 2H); 3.45 (brs, 4H); 3.00 (brs, 4H); 2.60 (brs, 4H); 2.5-2.2 (m, 9H); 1.71 (brs, 4H).

Elemental analysis: C33H41N3O2; C4H4O4; 0.75 H ₂ O; 0.15 CH ₂ C1 ₂ Calculated: C = 68.19; H = 7.06; N = 6.42 Found: C = 68.22; H = 7.21; N = 6.42

IR fKBr): 3600-2300, 1700, 1640, 18500, 1450 Mass (DCI, NH ₃ ): 512 (MH +)

Rf: 0.4 (1-6-94 = NH ₄ OH-MeOH-CH ₂ Cl ₂ )

EXAMPLE 9

1- (4-hydroxy-4-benzylpiperidin-1-yl) -5- [2- (4-methylpiperazin-1-yl) phenoxy] pentan-1-one fumarate (9)

9: Derivative 9 is prepared according to the method used for 2A from the following reagents: 5- [2- (4-methylpiperazin-1-yl) phenoxy] pentanoic acid (French Patent No. 9512218, 449 mg; 1.53 mmole); 4-hydroxy-4-benzylpiperidine (350 mg, 1.8 mmol); 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (322 mg; 1.7 mmol); triethylamine (234 ml; 1.7 mmol); 4-N, N-dimethylaminopyridine (15 mg) in dichloromethane (20 ml). Derivative 9 is isolated in the form of the free base after purification by flash chromatography with a mixture of eluents (1-8-92 = NH4θH-MeOH-CH Cl ₂ ).

Mass obtained: 386 mg (54%)

^] H-NMR (200 MHz, dmso-d ₆ ) δ: 7.4-7.1 (m, 5H); 7.1-6.8 (m, 4H); 6.60 (s, fumarate); 4.08 (brd, 1H); 3.95 (brt, 2H); 3.61 (brd, 1H); 3.4-3.15 (m, 1H); 3.06 (brs. 4FI); 3.1-2.6 (m, 5H); 2.68 (s, 2H); 2.42 (s, 3H); 2.36 (brt, 2H); 1.70 (brs, 4H); 1.37 (brs, 4H).

Elemental analysis: C ₂ gH39N3U3; C4H4O4; 1.2 H 0 Calculated: C = 63.71; H = 7.39; N = 6.89 Found: C = 63.71; H = 7.58; N = 6.96 m TÇBr): 3600-2300, 1700, 1610, 1520, 1490, 1237

Mass (DCI, NH ₃ ): 466 (MH ⁺ )

Rf: 0.4 (1-8-92 = NH ₄ OH-MeOH-CH ₂ Cl ₂ )

EXAMPLE 10

1- [4- (4-fluorobenzoyl) -4-methylpiperidin-1-yl] -5- [2- (4-methylpiperazin-1-yl) phenoxy] pentan-1-one fumarate fumarate

10: The derivative 10 is prepared according to the method used for 2A from the following reagents: 5- [2- (4-methylpiperazin-1-yl) phenoxy] pentanoic acid (French Patent No. 9512218, 400 mg; 1.28 mmole); 4- (4-fluorobenzoyl) -4-methylpiperidine hydrochloride (French Patent No. 95 06825, 420 mg, 1.6 mmol); 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (286 mg; 1.5 mmol); triethylamine (208 ml; 1.5 mmol); 4-iV, Λ-dimethyiaminopyridine (15 mg) in dichloromethane (25 ml). The derivative H) is purified in the form of the free base by flash chromatography (1-7-93 = NH ₄ OH-MeOH-CH ₂ Cl2).

Mass obtained: 468 mg (73%)

^Ï H-NMR (200 MHz, dmso-d ₆ ) δ: 7.81 (dd, 2H, 5.6 and 8.7Hz); 7.27 (t, 2H, 8.8Hz); 7.0-6.8 (m, 4H); 6.56 (s, fumarate); 3.92 (brt, 2H); 3.75-3.4 (m, 2H); 3.3-3.0 (m, 2H); 2.98 (brs, 4H); 2.59 (brs, 4H); 2.33 (bit, 2H); 2.30 (s, 3H); 2.2-1.9 (m, 2H); 1.8-1.3 (m, 6H); 1.37 (s, 3H).

Elementary analysis: C29H3 FN3θ2; C4H4O4; H2O Calculated: C = 62.91; H - 6.95; N = 6.53 Found: C = 62.94; H ≈ 7.04; N = 6.67

IR fKBr): 3600-2300, 1650, 1600, 1500, 1450

Mass (DCI, NH ₃ ): 496 (MH ⁺ )

Rf: 0.3 (1-7-93 = NH ₄ OH-MeOH-CH ₂ Cl ₂ )

EXAMPLE 11

1- [4-hydroxy-4-phenylpiperidin-1-yl] -5- [2- (4-methylpiperazin-1-yl) phenoxy] pentane fumarate (1.1)

Derivative 7 (607 mg; 1.1 mmol) is dissolved in THF (6 ml) at room temperature and under a nitrogen atmosphere. LAH (1 M / THF; 2.28 ml; 2.28 mmol) is added, and the suspension is stirred for ό hours. LAH (1.15 ml; 1.15 mmol) is added and the reaction is stirred for 4 days. The reaction mixture is neutralized by successive addition of 105 ml of water, 105 ml of NaOH (15% in water) and 320 ml of water. The white precipitate is filtered, then the filtrate is concentrated. The oily residue is again treated with LAH (2.28 ml, 2.28 mmol) in THF (6 ml) under nitrogen atmosphere and heated at 63 ° C for 48 hours, then neutralized by successive addition of 70 ml of water , 70 ml of NaOH (15% in water) and 220 ml of water. The white precipitate is filtered, then the concentrated filtrate. The XJL derivative is purified in the form of a free base by flash chromatography with a mixture of eluents (1-4.5-95.5 - NH ₄ OH-MeOH-CH ₂ Cl ₂ ).

Mass obtained: 220 mg (43%)

This compound is dissolved in methanol and treated with fumaric acid to give the corresponding fumarate. ^Ï H-NMR (400 MHz, dmso-d ₆ ) δ: 7.47 (d, 2H, 7.5Hz); 7.33 (t, 2H, 7.5Hz); 7.22 (t, 1H, 7Hz); 6.90 (brs, 2H); 6.86 (brs, 2H); 6.53 (s, fumarate); 5.03 (brs, 1H, OH); 3.96 (brs, 2H); 2.98 (brs, 6H); 2.8-2.6 (m, 4H); 2.50 (brs, 4H); 2.24 (s, 3H); 2.08 (brt, 2H); 1.75 (brs, 2H); 1.69-1.62 (m, 4H); 1.49 (brs, 2H).

Elemental analysis: C27H39N3θ ₂ ; C4H4O4; 0.54 H ₂ O Calculated: C = 66.98; H = 7.78; N = 7.51 Found: C = 66.88; H = 7.96; N = 7.70

Rf: 0.3 (1-6-94 = NH ₄ OH-MeOH-CH ₂ Cl)

EXAMPLE 12

1- (4-cyano-4-phenylpiperidin-1-yl) -5- [2- (4-methylpiperazin-1-yl) phenylamino] pentan-1-one fumarate (12)

12A: ethyl N-tertbutoxycarbonyl-5- [2- (4-methylpiperazin-1-yI) phenylaminolpentanoate

The iV-tertbutoxycarbonyl-2- (4-methylpiperazin-1-yl) aniline (French Patent n ° 95012218, 1.92 g, 6.2 mmole) is dissolved in DMF (20 ml) at 0 ° C under nitrogen atmosphere in the presence sodium hydride (50% in oil; 449 mg; 9.4 mmol). Ethyl 5-bromo-pentanoate (1.28 ml, 8.1 mmol) diluted in DMF (10 ml) is added dropwise at 0 ° C. The cold bath is removed and the reaction is stirred for 5 hours at room temperature. The suspension is neutralized with a few drops of water, concentrated then diluted in ethyl acetate, washed once with water and once with a saturated aqueous solution of NaCl, dried over magnesium sulfate, filtered and concentrated. The 12A derivative is purified by flash chromatography with a mixture of eluents (NH ₄ OH-MeOH-CH Cl ₂ = 0.5-2.5-97.5).

Mass obtained: 1.91 g (73%) JH-NMR (200 MHz, dmso-d ₆ ) δ: 7.21 (brs, 1H); 7.15-6.95 (m, 3H); 4.05 (brs, 2H); 3.85-3.6 (m, 1H); 3.30 (brs, 1 H); 3.02 (brs, 2H); 2.70 (brs, 2H), 2.45 (brs, 2H); 2.40 (brs, 2H); 2.25 (brs, 2H); 2.21 (s, 3H); 1.70-1.1 (m, 16H).

12B: N-tertbutoxycarbonyI-5- [2- (4-methyIpiperazin-1-yl) phenylamino] pentanoic acid.

The 12A derivative (3.1 g, 7.4 mmol) is dissolved in THF (8 ml). A sodium hydroxide solution (1M in water, 8.1 ml, 8.1 mmol) is added and the reaction is heated at 50 ° C for 3 hours. The reaction mixture is cooled to room temperature then neutralized by addition of hydrochloric acid (IN in water, 8.1 ml, 8.1 mmol). The solvents are evaporated. The semi-solid residue is triturated in a little ethanol and filtered. The filtrate is concentrated to give a foam. The 12B derivative is used without further purification for the rest of the syntheses.

Mass obtained: 2.88 g

1H-NMR (200 MHz, dmso-d ₆ ) δ: 7.21 (brs, 1H); 7.15-6.95 (m, 3H); 3.9-3.1 (m, 3H); 3.02 (brs, 2H); 2.70 (brs, 2H); 2.45 (brs, 2H); 2.40 (brs, 2H); 2.21 (s, 3H); 2.15 (brs, 2H); 1.6-1.2 (m, 13H).

12C: La / V-tertbutoxycarbonyI-1- (4-cyano-4-phenylpiperidin-1-yI) -5- [2- (4-methylpiperazin-1-yl) phenylamino] pentan-1-one

The derivative 12C is prepared according to the method used for 2A from the following reagents: 12B (600 mg; 1.5 mmol); hydrochloride A (408 mg, 1.8 mmol); 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (322 mg; 1.7 mmol); triethylamine (234 ml; 1.7 mmol); 4-Λ / V-dimethylaminopyridine (10 mg) in dichloromethane (21 ml). The derivative 12C is isolated in the form of the free base after purification by flash chromatography with a mixture of eluents (1-4-96 = NH4θH-MeOH-CH ₂ Cl).

Mass obtained: 892 mg

iH-NMR (200 MHz, dmso-d ₆ ) δ: 7.6-7.3 (m, 6H); 7.20 (brs, 1H); 7.15-6.9 (m, 2H); 4.59 (brd, 1H); 4.03 (brd, 1H); 3.85-3.6 (m, 1H); 3.45-3.15 (m, 1H); 3.03 (brs, 3H); 2.85-2.7 (m, 3H); 2.5-2.2 (m, 6H); 2.21 (s, 3H); 2.25-2.05 (m, 2H); 2.05-1.9 (m, 2H); 1.9-1.75 (m, 2H); 1.6-1.2 (m, 11H). 12: The derivative 12C (890 mg; 1.6 mmol) is dissolved in dichloromethane (44 ml) at 0 ° C under a nitrogen atmosphere. Trifluoroacetic acid (7.5 ml) is added, the cold bath is removed and the reaction mixture is stirred until the starting material disappears. The solution is neutralized with sodium hydroxide (1 M in water) and then brought back to a slightly basic pH (approximately 8). The aqueous phase is extracted twice with dichloromethane. The organic phases are combined, dried over magnesium sulfate and the solvent is evaporated. The oily residue is purified by flash chromatography with a mixture of eluents (1-5-95 = M OH-MeOH-CH ₂ C1 ₂ ).

Mass obtained: 623 mg (85%)

* H-NMR (200 MHz, dmso-d ₆ ) δ: 7.65-7.3 (m, 5H); 7.0-6.85 (m, 2H); 6.6-6.5 (m, 2H); 4.73 (brs, 1H); 4.62 (brd, 1H); 4.08 (brd, 1H); 3.4-3.2 (m, 1H); 3.15-3.0 (m, 2H); 2.85-2.7 (m, 3H); 2.6-2.3 (m, 6H); 2.21 (s, 3H); 2.14 (brd, 2H); 2.01 (brt, 2H); 1.86 (brt, 2H); 1.61 (brs, 4H).

Elemental analysis: C gH37N5Û; 0.3 H O Calculated: C = 72.32; H = 8.15; N = 15.06 Found: C = 72.46; H = 8.1 1; N = 14.74

EXAMPLE 13

8- (4-methylpiperazin-1-yl) naphthalen-2-yl (13) 4-cyano-4-phenylpipéιïdin-l-yloate fumarate (13)

13A: 1-chloroformyl-4-cyano-4-phenylpiperidine The triphosgene (829 mg, 2.8 mmol) is dissolved at 0 ° C. under a nitrogen atmosphere in dichloromethane (26 ml). Amine A dissolved in dichloromethane (26 ml) in the presence of triethylamine (1.18 ml, 8.5 mmol) is added dropwise for 40 minutes. The reaction is stirred for 2 hours then diluted in dichloromethane, washed three times with water, dried over sodium sulfate and concentrated. The derivative 13A is isolated in the form of a free base after purification by flash chromatography with a mixture of eluents (6-94 = EDP-EtOAc).

Mass obtained: 513 mg (24%)

^Ï H-NMR (200 MHz, dmso-dô) δ: 7.65-7.3 (m, 5H); 4.45-4.25 (m, 1H); 3.55-3.4 (m, 1H); 3.4-3.15 (m, 1H); 3.15-3.0 (m, 1H); 2.45-2.25 (m, 1H); 2.25-2.05 (m, 3H).

3: 8- (4-methylpiperazin-1-yl) naphthalen-2-ol (European Patent n ° 05 33266-A1, 332 mg, 1.37 mmol) is dissolved in THF (20 ml) at 0 ° C under atmosphere nitrogen in the presence of sodium hydride (50%) in the oil; 109 mg; 2.7 mmol). The 13A derivative (513 mg, 2.06 mmol) diluted in THF (10 ml) is added dropwise at 0 ° C. The cold bath is removed and the reaction is stirred for 4 hours at room temperature. The suspension is neutralized with a few drops of water, concentrated then diluted in ethyl acetate, washed once with water and once with a saturated NaCl solution, dried over magnesium sulfate, filtered and concentrated . Derivative 13 is purified by flash chromatography with a mixture of eluents (NH4OH-MeOH-CH ₂ Cl ₂ = 1-5-95).

Mass obtained: 512 mg (82%)

1H-NMR (200 MHz, dmso-d ₆ ) δ: 7.93 (d, 1H, 8.8Hz); 7.79 (d, 1H, 1.7Hz); 7.63 (brt, 3H); 7.49 (t, 2H, 7.8 Hz); 7.43 (brt, 2H); 7.37 (dd, IH, 2.3 and 8.9 Hz); 7.18 (d, 1 H, 7.4 Hz); 6.60 (s, fumarate); 4.47 (brd, 1H); 4.27 (brd, 1H); 3.39 (brs, 1H); 3.22 (brs, 1H); 3.04 (brs, 4H); 2.74 (brs, 4H); 2.38 (s, 3H); 2.25-2.0 (m, 4H).

Elemental analysis: C28H30N4O2; C4H4O4 Calculated: C = 67.35; H ≈ 6.01; N = 9.80 Found: C = 67.45; H = 6.11; N = 9.82

IR fKBr): 3600-2300, 1703, 1550, 1540, 1490, 1470, 1400.

Rf: 0.5 (1-10-90 = NH ₄ OH-MeOH-CH ₂ Cl) EXAMPLE 14

1- (4-cyano-4-phenylpiperidin-1-yl) -2- [8- (4-methylpiperazin-1-yl) naphthalen-2-yloxy] ethanone fumarate (14)

14A: 2-chIoro-1- (4-cyano-4-phenylpiperidin-1-yl) ethanone

The hydrochloride of A (1.5 g, 6.7 mmol) is dissolved in methyl ethyl ketone (25 ml) under a nitrogen atmosphere at 0 ° C in the presence of calcium carbonate (2.02 g, 20.2 mmol). 2-chloroethanoyl chloride (536 ml; 6.7 mmol) is added dropwise. The mixture is stirred for 2 hours at room temperature, then filtered and concentrated. The derivative 14A is isolated in the form of the free base after purification by flash chromatography with a mixture of eluents (60-40 = EDP-EtOAc).

Mass obtained: 887 mg (50%)

JH-NMR (200 MHz, dmso-d ₆ ) δ: 7.55 (d, 2H, 9Hz); 7.46 (t, 2H, 7.5Hz); 7.39 (t, 1H, 7.5Hz); 4.55 (brd, 1H); 4.48 (s, 2H); 4.04 (brd, 1H); 3.35 (brt, 1H); 2.91 (brt, 1H); 2.25-1.85 (m, 4H).

H: 8- (4-methylpiperazin-1-yl) naphthalen-2-ol (European patent n ° 05 33266-A1, 392 mg, 1.62 mmoie) is dissolved in DMF (8 ml) in the presence of 14A chloride (426 mg; 1.62 mmol) and cesium carbonate (1.3 g; 2.5 mmol) under a nitrogen atmosphere. The mixture is stirred for 24 hours at room temperature, then diluted in ethyl acetate, washed three times with water, dried over magnesium sulfate and concentrated. The derivative! _4 is isolated in the form of the free base after purification by flash chromatography with a mixture of eluents (1-7-93 = NH4OH-MeOH-CH ₂ Cl ₂ ).

Mass obtained: 618 mg (81%) This compound is dissolved in methanol and treated with fumaric acid to give the corresponding fumarate.

^ -RMN (200 MHz, dmso-d ₆ ) δ: 7.82 (d, IH, 9.0Hz); 7.54 (d, 1H, 8.2Hz); 7.51 (d, 2H, 7.6Hz); 7.44 (t, 2H, 7.5Hz); 7.38 (t, 1H, 7.2Hz); 7.31 (d, 1H, 2.3Hz); 7.28 (t, 1H, 7.8Hz); 7.21 (dd, IH, 2.5 and 8.9Hz); 7.09 (d, 1H, 7.3 Hz); 6.60 (s, fumarate); 5.08 (s, 2H); 4.75 (brd, 1H); 4.58 (brd, 1H); 3.42 (brt, 1H); 3.1-2.85 (m, 5H); 2.85-2.55 (m, 4H); 2.32 (s, 3H); 2.23 (brt, 2H); 2.12 (brt, 1H); 1.88 (brt, 1H).

Elementary analysis: C ₂ 9H ₃₂ N4θ ₂ ; I.2C4H4O4; 0.3 H ₂ O Calculated: C = 66.20; H ≈ 6.15; N = 9.14 Found: C = 65.97; H = 6.29; N = 9.25

LR fKBr): 3600-2300, 1670, 1650, 1600, 1500, 1450.

Rf: 0.5 (1-10-90 = NH ₄ OH-MeOH-CH ₂ Cl ₂ )

EXAMPLE 15

2- [2- (4-methylpiperazin-1-yl) phcnoxy] -l- (4-cyano-4-pheny! Piperidin-1-yl) fumarate ethan-1-one (15)

15A: 2- [2- (4-methylpiperazin-1-yl) phenoxy] ethyl ethanoate

The derivative 15A is prepared according to the method used for 3_B from the following reagents: ethyl 2-chloroethanoate (3.39 g, 27.7 mmol); DMF (130 ml); NaH (60%, 1.27 g, 32.0 mmol); 3-methyl-2- (4-methylpiperazin-1-yl) phenol (French Patent No. 9512218, 4.1 g, 21.3 mmol). The derivative 15A is purified by flash chromatography with a mixture of eluents (1-5-95 = NH4θH-MeOH-CH ₂ C1 ₂ ). Mass obtained: 3.20 g (53%)

JH-NMR (400 MHz, dmso-d ₆ ) δ: 7.0-6.75 (m, 4H); 4.75 (s, 2H); 4.17 (q, 2H, 6.8Hz); 3.00 (brs, 4H); 2.45 (brs, 4H); 2.21 (s, 3H); 1.22 (t, 3H, 6.8Hz).

15B: 2- [2- (4-methylpiperazin-1-yl) phenoxy] ethanoic acid

The derivative 15B is prepared according to the method used for 12B from the following reagents: sodium hydroxide (1M in water, 19 ml, 19 mmol); 15A (4.81 g, 17.3 mmol); THF (19 ml).

Mass obtained: 4.25 g (90%)

^Ï H-NMR (400 MHz, dmso-d ₆ ) δ: 7.0-6.75 (m, 4H); 4.58 (s, 2H); 3.07 (brs, 4H); 2.66 (brs, 4H); 2.32 (s, 3H).

15: The derivative 15 is prepared according to the method used for 2A from the following reagents: 15B (400 mg; 1.59 mmol); A hydrochloride (424 mg, 1.9 mmol); 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (335 mg; 1.74 mmol); triethylamine (243 μl; 1.74 mmol); 4-Λ N-dimethylaminopyridine (10 mg) in dichloromethane (22 ml). The derivative 15 is isolated in the form of the free base after purification by flash chromatography (1-5-95 = NH4θH-MeOH-CH ₂ Cl2).

Mass obtained: 500 mg (75%)

H-NMR (400 MHz, dmso-d ₆ ) δ: 7.6-7.3 (m, 5H); 6.90 (brs, 4H); 6.57 (s, fumarate); 4.89 (AB, 2H); 4.56 (brd, 1H); 4.05 (brd, 1H); 3.37 (brt, 1H); 3.04 (brs, 4H); 2.90 (brt, 1H); 2.54 (brs, 4H); 2.26 (s, 3H); 2.35-2.1 (m, 3H); 1.90 (brt, 1H).

Elemental analysis: C ₂ 5H3QN4O; 1.2 C4H4O4; 0.19 H 0 Calculated: C = 64.16; H ≈ 6.29; N = 10.04 Found: C = 64.18; H = 6.38; N = 10.19

Mass (DCI, NH3): 419 (MH +)

Rf: 0.2 (1-5-95 = NH ₄ OH-MeOH-CH ₂ Cl) EXAMPLE 16

5- [5-Methoxy-2- (4-methylpiperazin-1-yl) phenylamiπo] -l- (4-cyano-4-phenylpiperidin-1-yl) pentan-1-one fumarate (16)

16A: 4- (4-methylpiperazin-1-yl) -3-nitroanisole

4-chloro-3-nitroanisole (5 g, 26.7 mmol) is heated to 100 ° C. under a nitrogen atmosphere in DMF (8 ml) in the presence of potassium carbonate (4.42 g, 32 mmol) and 1-methylpiperazine (3.5 ml, 32 mmol) for 30 hours. The reaction medium is cooled, diluted in dichloromethane and washed twice with water. The derivative 16A is extracted from the organic phase with 100 ml of IN hydrochloric acid, the aqueous phase is washed twice with ethyl acetate and then 30 ml of 30% sodium hydroxide in water are added. The derivative 16A is extracted from the aqueous phase with ethyl acetate. The solution is dried over magnesium sulfate, filtered and concentrated.

Mass obtained: 2.70 g (40%)

1H-NMR (400 MHz, dmso-d ₆ ) δ: 7.35-7.4 (m, 2H); 7.19 (dd, 1H, 3 and 9 Hz); 3.78 (s, 3H); 2.88 (brt, 4H); 2.39 (brs, 4H); 2.20 (s, 3H).

16B: 5-uιethoxy-2- (4-methylpiperazin-1-yl) aniine

In a Parr flask, compound 16A (4.77 g, 19 mmol) is dissolved in ethanol (150 ml) in the presence of palladium (5% in carbon, 2 g, 0.95 mmol). The mixture is stirred for 30 min under an initial pressure of 30 Psi. The reaction is filtered through celite and concentrated under reduced pressure.

Mass obtained: 3.74 g (89%) 1H-NMR (400 MHz, dmso-d ₆ ) δ: 6.80 (d, 1H, 8.5 Hz); 6.25 (d, 1H, 2.9 Hz); 6 09 (dd, 1H, 2.9 and 8.5 Hz); 4.76 (s, 2H); 3.62 (s, 3H); 2.71 (brt, 4H); 2.45 (brs, 4H);

2.22 (s, 3H).

16C: N-tert-butoxycarbonyl-5-methoxy-2- (4-methylpiperazin-1-yl) aniline

The derivative 16B (3.74 g; 17 mmol) is dissolved in toluene (60 ml) under a nitrogen atmosphere in the presence of di tert-butyldicarbonate (4.43 g; 20 mmol) and heated at 100 ° C for 20 hours. The solvent is evaporated and the 16C derivative is purified by flash chromatography with a mixture of eluents (0.3-3-97 = NH4OH-MeOH-CH ₂ Cl).

Mass obtained: 4.46 g (85%)

1H-NMR (400 MHz, dmso-d ₆ ) δ: 7.85 (s, 1H); 7.53 (d, 1H, 2.7 Hz); 7.15 (d, 1 H, 8.7 Hz); 6.55 (dd, IH, 2.7 and 8.7 Hz); 3.70 (s, 3H); 2.71 (brt, 4H); 2.45 (brs, 4H);

2.23 (s, 3H); 1.48 (s, 9H).

16D: 5- [N-terf-butoxycarbonyl-5-metlιoxy-2- (4-methylpiperazin-1-yl) phenylamino] -l- (4-cyano-4-phenylpiperidin-1-yI) pentan-1-one The 16D derivative is prepared according to the method used for 3_B from the following reagents: 3A (652 mg; 1.87 mmol); DMF (8 ml); NaH (50%, 125 mg, 3.1 1 mmol); 16C (500 mg, 1.56 mmol). The 16D derivative is purified by flash chromatography (0.5- 5-95 = NH ₄ OH-MeOH-CH ₂ Cl ₂ ).

Mass obtained: 948 mg (86%)

1_6: The derivative 16 is prepared according to the method used for 2 from the following reagents: 16D (945 mg; 1.33 mmol); dichloromethane (9 ml); Trifluoroacetic acid (4.5 mi). Derivative 16 is purified by flash chromatography (0.4-4-96 = NH ₄ OH-MeOH-CH ₂ Cl ₂ ).

Mass obtained: 778 mg (96%)

This compound is dissolved in methanol and treated with hydrochloric acid to give the corresponding hydrochloride.

* H-NMR (400 MHz, dmso-dό) δ: 10.70 (brs, IH); 7.54 (d, 2H, 7 6 Hz); 746 (t, 2H, 7.4 Hz); 7.38 (t, 1H, 7.2Hz); 7.00 (brs, 1H); 6.35 (brs, 2H); 4.61 (brd, 1H); 4.08 (brd, 1H); 3.70 (s, 3H); 3.49 (brd, 2H); 3.35-3.15 (m, 3H); 3.21 (brs, 2H); 3.00 (brd, 4H); 2.9-2.85 (m, 4H); 2.43 (brs, 2H); 2.15 (brd, 2H); 2.02 (brt, 1H); 1.85 (brt, 1H); 1.62 (brs, 4H).

Elementary analysis: C ₂ 9H ₃₉ N5θ ₂ ; 1.8 HC1; 0.65 CF ₃ CO ₂ H; 0.43 HO Calculated: C = 57.82; H = 6.64; N = 11.13; Cl = 10.14 Found: C = 57.65; H = 6.90; N = 1 1.13; Cl ≈ 10.23

Mass (DCI, NH ₃ ): 490 (MH +)

EXAMPLE 17

5- [5-methyl-2- (4-methylpiperazin-1-yl) phenylamino] -l- (4-cyano-4-phenylpiperidin-1-yl) pentan-1-one fumarate (17)

17A: 4- (4-methylpiperazin-1-yl) -3-nitrotoluene

4-fluoro-3-nitrotoluene (7 g, 45 mmol) is diluted under a nitrogen atmosphere in DMF (13 ml) in the presence of potassium carbonate (7.46 g, 54 mmol) and 1-methylpiperazine (6 ml, 54 mmol) for 3 hours. The reaction medium is diluted in dichloromethane and washed twice with water. The derivative 17A is extracted from the organic phase with IN hydrochloric acid, the aqueous phase is washed twice with ethyl acetate and then 30% sodium hydroxide in water is added. Derivative 17A is extracted from the aqueous phase with ethyl acetate. The solution is dried over magnesium sulfate, filtered and concentrated.

Mass obtained: 8.64 g (81%)

1H-NMR (400 MHz, dmso-d ₆ ) δ: 7.60 (brs, 1H); 7.40 (dd, IH, 1.6 and 8.4 Hz); 7.23 (d, 1H, 8.4Hz); 2.92 (brt, 4H); 2.40 (brt, 4H); 2.25 (s, 3H); 2.20 (s, 3H). 17B: 5-methyl-2- (4-methylpiperazin-1-yl) aniline

In a Pair vial, compound 17A (4.29 g, 18.2 mmol) is dissolved in methanol (200 ml) in the presence of palladium (10% in charcoal, 0.97g, 0.91 mmol). The mixture is stirred for 30 min under an initial pressure of 30 Psi. The reaction is filtered through celite and concentrated under reduced pressure.

Mass obtained: 3.47 g (93%)

JH-NMR (400 MHz, dmso-d ₆ ) δ: 6.95 (d, 1 H, 8 Hz); 6.47 (d, 1 H, 1.4 Hz); 6.09 (dd, IH, 1.4 and 8 Hz); 4.60 (brs, 2H); 2.73 (brs, 4H); 2.45 (brs, 4H); 2.21 (s, 3H); 2.12 (s, 3H).

17C: N-tert-butoxycarbonyl-5-methyl-2- (4-methylPiperazin-1-yI) aniine

The derivative 17B (6.63 g; 32 mmol) is dissolved in toluene (800 ml) under a nitrogen atmosphere in the presence of di tert-butyldicarbonate (10.74 g; 48 mmol) and heated at 80 ° C for 20 hours. The solvent is evaporated and the derivative 17C is purified by flash chromatography with a mixture of eluents (1-5-95 = ML _j OH-MeOH-CH ₂ C1 ₂ ).

Mass obtained: 9.09 g (92%)

^Ï H-NMR (400 MHz, dmso-d ₆ ) δ: 7.73 (s, 1 H); 7.68 (s, 1H); 7.07 (d, 1H, 8 Hz); 6.80 (d, 1 H, 8 Hz); 2.73 (brt, 4H); 2.46 (brs, 4H); 2.24 (s, 3H); 2.23 (s, 3H); 1.47 (s, 9H).

17D: 5- [N-tert-butoxycarbonyI-5-methyl-2- (4-methylpiperazin-1-yl) phenylamino] -l- (4-cyano-4-phenylpiperidin-1-yl) pentan-1-one

The derivative 17D is prepared according to the method used for 3B from the following reagents: 3A (766 mg; 2.19 mmol); DMF (55 ml); NaH (60%, 130 mg, 3.26 mmol); 17C (500 mg, 1.63 mmol). The 17D derivative is purified by flash chromatography (1-4-96 = NH4θH-MeOH-CH ₂ Cl ₂ ).

Mass obtained: 842 mg (90%)

17: The derivative 17 is prepared according to the method used for day 2 from the following reagents: 17D (834 mg; 1.45 mmol); dichloromethane (40 ml); Trifluoroacetic acid (6.8 ml). Derivative 17 is purified by flash chromatography (1-3-97 = NH ₄ OH-MeOH-CH ₂ Cl ₂ ). Mass obtained: 575 mg (83%)

This compound is dissolved in methanol and treated with trifluoroacetic acid to give the corresponding trifluoroacetate.

JH-NMR (400 MHz, dmso-d ₆ ) δ: 9.69 (brs, 1H); 7.54 (d, 2H, 7.6 Hz); 7.46 (t, 2H, 7.4 Hz); 7.38 (t, 1H, 7.2Hz); 6.86 (d, 1H, 7.8Hz); 6.45 (s, 1H); 6.42 (d, 1H, 7.8Hz); 4.61 (brd, 1H); 4.08 (brd, 1H); 3.48 (brd, 2H); 3.35-3.15 (m, 3H); 3.15-2.95 (m, 4H); 2.95-2.75 (m, 6H); 2.43 (brs, 2H); 2.19 (s, 3H); 2.15 (brd, 2H); 2.02 (brt, 1H); 1.85 (brt, 1H); 1.62 (brs, 4H).

EXAMPLE 18

5- [5-fluoro-2- (4-methylpiperazin-1-yl) phenylamino] -l- (4-cyano-4-phenylpiperidin-1-yl) pentan-1-one fumarate (18)

18A: 5-fluoro-2- (4-methylpiperazin-1-yl) nitrobenzene 2,5-difluoronitrobenzene (4.37 g, 27.5 mmol) is diluted under nitrogen and at 0 ° C in DMF (8 ml ) in the presence of potassium carbonate (4.55 g, 33.0 mmol) and 1-methylpiperazine (3.65 ml, 33.0 mmol) for 20 minutes. The reaction medium is diluted in dichloromethane and washed twice with water. The derivative 18A is extracted from the organic phase with IN hydrochloric acid, the aqueous phase is washed twice with ethyl acetate and then 30% sodium hydroxide in water is added. The derivative 18A is extracted from the aqueous phase with ethyl acetate. The solution is dried over magnesium sulfate, filtered and concentrated.

Mass obtained: 5.06 g (77%)

1H-NMR (400 MHz, dmso-d ₆ ) δ: 7.80 (dd, IH, 3 and 8.4 Hz); 7.51 (ddd, IH, 3 and 8 and 9 Hz Hz); 7.43 (dd, 1H, 5 and 9 Hz); 2.93 (brt, 4H); 2.40 (brt, 4H); 2.20 (s, 3H). 18B: 5-fluoro-2- (4-methylpiperazin-1-yl) aniline

In a Pair vial, compound 18A (5.06 g, 21.1 mmol) is dissolved in methanol (150ml) in the presence of palladium (10% in charcoal, 1.12 g, 1.05 mmol). The mixture is stirred for 30 minutes under an initial pressure of 30 Psi. The reaction is filtered through celite and concentrated under reduced pressure.

Mass obtained: 4.01 g (90%)

iH-NMR (400 MHz, dmso-d ₆ ) δ: 6.87 (dd, IH, 6.1 and 8.6 Hz); 6.43 (dd, IH, 3.0 and 11.1 Hz); 6.27 (td, IH, 2.9 and 8.7 Hz); 5.00 (brs, 2H); 2.74 (brs, 4H); 2.46 (brs, 4H); 2.22 (s, 3H).

18C: L N-tert-butoxycarbonyl-5-fluoro-2- (4-methylpiperazin-1-yl) aniline The derivative 18B (1.94 g; 9.27 mmol) is dissolved in toluene (230 ml) under a nitrogen atmosphere presence of di tert-butyldicarbonate (2.42 g; 11.1 mmol) and heated at 80 ° C for 48 hours. The solvent is evaporated and the derivative 18C is purified by flash chromatography (1-3-97 = NH4θH-MeOH-CH ₂ Cl2).

Mass obtained: 1.22 g (42%)

1H-NMR (400 MHz, dmso-d ₆ ) δ: 7.90 (s, 1H); 7.69 fdd, IH, 2.9 and 1 1.2 Hz); 7.26 (dd, IH, 6.0 and 8.8 Hz); 6.81 (td, IH, 3 and 5.6 Hz); 2.75 (brt, 4H); 2.48 (brs, 4H); 2.24 (s, 3H); 1.48 (s, 9H).

18D: 5- [N-tert-butoxycarbonyl-5-methyl-2- (4-methyipipέrazin-1-yl) phenylamino] -l- (4-cyano-4-phenylpiperidin-1-yl) pentan-1-one

The 18D derivative is prepared according to the method used for 3B from the following reagents: 3A (699 mg; 2.00 mmol); DMF (50 ml); NaH (60%, 123 mg, 2.00 mmol); 18C (477 mg, 1.54 mmol). The 18D derivative is purified by flash chromatography (1-3-97 = NH ₄ OH-MeOH-CH Cl2).

Mass obtained: 227 mg (25%)

18: The derivative 18 is prepared according to the method used for 1_2 from the following reagents: 18D (220 mg; 0.38 mmol); dichloromethane (10 ml); Trifluoroacetic acid (1.7 ml). Derivative 18 is purified by flash chromatography (0.5-3-97 = NH ₄ OH-MeOH-CH ₂ Cl ₂ ). Mass obtained: 129 mg (71%)

^Ï H-NMR (400 MHz, dmso-d ₆ ) δ: 7.54 (d, 2H, 7.7Hz); 7.4 (t, 2H, 7.8 Hz); 7.38 (t, 1 H, 7.2 Hz); 6.93 (dd, IH, 6.2 and 8.5 Hz); 6.34 (dd, IH, 2.8 and 1 1.8 Hz); 6.27 (td, IH, 2.8 and 8.6 Hz); 5.07 (brt, 1H); 4.62 (brd, 1H); 4.08 (brd, 1H); 3.30 (brt, 1H); 3.09 (brs, 2H); 2.81 (brt, 1H); 2.67 (brs, 4H); 2.50 (brs, 2H); 2.43 (brs, 4H); 2.21 (s, 3H); 2.15 (brd, 2H); 2.02 (brt, 1H); 1.85 (brt, 1H); 1.60 (brs, 4H).

EXAMPLE 19

5- [4-methyl-2- (4-methylpiperazin-1-yl) phenylamino] -l- (4-cyano-4-phenylpiperidin-1-yl) pentan-1-one fumarate (19)

19A: 3- (4-methylpiperazin-1-yl) -4-nitrotoluene

3-Fluoro-4-nitrotoluene (5.0 g, 32 mmol) is diluted under a nitrogen atmosphere in DMF (10 ml) in the presence of potassium carbonate (5.34 g, 39 mmol) and 1-methylpiperazine (4.3 ml, 39 mmol) for 5 minutes. The reaction medium is diluted in dichloromethane and washed twice with water. The derivative 19A is extracted from the organic phase with IN hydrochloric acid, the aqueous phase is washed twice with ethyl acetate and then 30% sodium hydroxide in water is added. The derivative 19A is extracted from the aqueous phase with ethyl acetate. The solution is dried over magnesium sulfate, filtered and concentrated.

Mass obtained: 6.89 g (90%)

^Ï H-NMR (400 MHz, dmso-d ₆ ) δ: 7.71 (d, 1 H, 8.3 Hz); 7.10 (s, 1H); 6.89 (d, 1 H 8.4 Hz); 2.97 (brt, 4H); 2.42 (brt, 4H); 2.35 (s, 3H); 2.21 (s, 3H).

19B: 4-methyl-2- (4-methylpiperazin-1-yl) aniline

In a Parr flask, compound 19A (6.8 g, 29 mmol) is dissolved in methanol (220 ml) in the presence of palladium (10% in charcoal, 1.53 g, 1.44 mmol). The mixture is stirred for 30 min under an initial pressure of 30 Psi. The reaction is filtered through celite and concentrated under reduced pressure.

Mass obtained: 5.59 g (94%)

1H-NMR (400 MHz, dmso-d ₆ ) δ: 6.69 (s, 2H); 6.65-6.50 (m, 3H); 4.45 (brs, 2H); 2.77 (brs, 4H); 2.46 (brs, 4H); 2.22 (s, 3H); 2.14 (s, 3H).

19C: N-tert-butoxycarbonyl-4-methyl-2- (4-methylpiperazin-1-yl) aniline The derivative 19B (5.0 g; 24 mmol) is dissolved in toluene (600 ml) under nitrogen atmosphere presence of di tert-butyldicarbonate (8.0 g; 37 mmol) and heated at 80 ° C for 20 hours. The solvent is evaporated and the derivative 19C is purified by flash chromatography (1-3-97 = NH4θH-MeOH-CH ₂ Cl ₂ ).

Mass obtained: 7.07 g (93%)

1H-NMR (400 MHz, dmso-d ₆ ) δ: 6.7-6.6 (m, 2H); 7.01 (s, 1H); 6.86 (d, 1 H, 8 Hz); 2.76 (brt, 4H); 2.47 (brs, 4H); 2.23 (s, 6H); 1.46 (s, 9H).

19D: 5- [N-tert-butoxycarbonyl-4-methyl-2- (4-methylpiperazin-1-yl) phenylamino] -l- (4-cyano-4-phenylpiperidin-1-yl) pentan-1-one

The derivative 19D is prepared according to the method used for 3B from the following reagents: 3A (740 mg; 2.1 1 mmol); DMF (54 ml); NaH (60%, 65 mg, 1.6 mmol); 19C (500 mg, 1.63 mmol). The derivative 19D is purified by flash chromatography (0.75-3-97 = NH ₄ OH-MeOH-CH ₂ Cl2).

Mass obtained: 606 mg (65%)

19: Derivative 9 is prepared according to the method used for 12 using the following reagents: 19D (589 mg; 1.02 mmol); dichloromethane (30 ml); Trifluoroacetic acid (5.1 ml). Derivative 19 is purified by flash chromatography (1-3-97 = NH ₄ OH-MeOH-CH ₂ Cl ₂ ).

Mass obtained: 426 mg (88%)

This compound is dissolved in methanol and treated with fumaric acid to give the corresponding fumarate. 1H-NMR (400 MHz, dmso-d ₆ ) δ: 7.54 (d, 2H, 7.6 Hz); 7.45 (t, 2H, 7.2 Hz); 7.37 (t, 1 H, 7.2 Hz); 6.80-6.65 (m, 2H); 6.59 (s, fumarate); 6.48 (d, 1 H, 8 Hz); 4.61 (brd, 1H); 4.08 (brd, 1H); 3.29 (brt, 1H); 3.04 (brs, 2H); 2.79 (brs, 5H); 2.63 (brs, 3H); 2.50 (brs, 2H); 2.42 (brs, 2H); 2.31 (s, 3H); 2.15 (s, 3H); 2.2-2.05 (m, 2H); 2.00 (brt, 1H); 1.88 (brt, 1H); 1.59 (brs, 4H).

Elemental analysis: C29H39N5O; 1.1 C4H4O4; 0.34 H ₂ O Calculated: C = 66.71; H = 7.27; N = 1 1.65 Found: C = 66.96; H = 7.25; N = 11.70

Rf: 0.41 (1-6-94 = NH ₄ OH-MeOH-CH ₂ Cl ₂ )

The derivatives of the present invention are 5HTIB / I (receptor antagonists) as shown by the binding studies and the antagonism studies of the inhibition of adenylate cyclase (stimulated by forskolin) by an agonist such as serotonin, sumatriptan or 5-CT, studies which have been carried out at the level of human receptors cloned 5HTιj3 / ιr These human receptors have been 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-Kj cell lines using an electroporator.

The HeLa HA7 cell line expressing the human 5HTι A 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 5HT I B and 5HT | rj and 5HTι ^ human 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 [3HJ-80H-DPAT (final concentration: 1 nM) for the 5HTj ^ receptor and 0.05 ml of the molecule to be tested (final concentrations from 0.1 nM to 1000 nM) or 10 μM (final concentration) serotonin (5HTjg and 5HT _dd )) or 1 μM (final concentration) of spiroxatrine (5HT _1A ).

The study of the inhibition of the formation of cyclic AMP (stimulated by forskolin) mediated by the 5HTjg and 5HT r) human 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 di-substituted piperidines forming part of the present invention are powerful and selective antagonists of the 5HTJB / IJ) receptors and have the advantage of being particularly selective for the 5HTiβ / ιj) human receptors in particular with respect to 5HTJ, 5HTJ C, 5HT, cq, α and D receptors.

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 5-carboxamidotryptamine (5CT) at the release level. of serotonin in guinea pig brain slices. These two pharmacological models are generally recognized as particularly relevant in the functional characterization of the 5HTI> / IB 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 properties of the 5HTjr) / iB antagonists claimed in the present invention make them particularly interesting and useful for the treatment of patients suffering from disorders of 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).

Furthermore, the derivatives of the present invention are also capable of controlling the growth and proliferation of glial cells of type Cg transfected by the 5HTJD receptor gene and by the 5HTι g 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 μM sumatriptan) with an IC50 of 10 to 1000 nM (method described by P. Pauwels et al., Naunyn-Schmiedeberg's Arch Pharmacol, 354, 136, 1996). 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 pharmaceutical compositions containing, as active ingredients, a compound of general formula (I) or a physiologically acceptable salt of a compound of formula (I) combined 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 receptor inhibitors (e.g. milnacipran), or _2- antagonists (e.g. mianserine, mirtazapine, setiptiline, idazoxan, effaroxan, fluparoxan).

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-HTJ 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, solutions, suspensions, emulsions, syrups and elixirs can be used pharmaceutically acceptable containing inert diluents such as water, ethanol, glycerol, vegetable oils or paraffin oil. 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 done 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 drink, 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 for 1 tablet active component 10.0 microcrystalline cellulose B.P.C. 89.5 magnesium stearate 0 £

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 component 10.0 lactose Codex 74.5 starch Codex 10.0 corn starch pregelatinized Codex 5.0 magnesium stearate 0.5

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 hydroxypropyl methylcellulose, according to conventional techniques. Sugar tablets can also be coated. Capsules

mg for one active ingredient capsule 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, United Kingdom.

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 hard gelatin capsules No. 2 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) q.s. 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 and 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 sold for Adeps Solidus of the European Pharmacopoeia.

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 1 active component 2.0 water for injection Codex supplement 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.

Cartridges for inhalation g / cartridge active ingredient micronized 1.0 lactose Codex 39.0

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 1 can micronized active component 0.500 120 mg oleic acid Codex 0.050 12 mg trichlorofluoromethane for pharmaceutical use 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 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 mixer with a high shearing effect. 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

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

(I) in which,

Rj represents], OR'i, SR'j, NHR'j, COR '}, CHOHR' CH ₂ R'ι, in which R'j represents an aryl residue chosen from phenyl, naphthyl or pyridyl which may optionally be substituted by one or more groups chosen from a linear or branched alkyl comprising from 1 to 5 carbon atoms, a halogen (Cl, F, Br or I), OH, OR4, SR4, CF ₃ , CH CF ₃ , N0,

CN, COR4, COOR4, NHR4, NHCOR4, NHCOOR4, NHSO2R4, SO2R4 in which R4 represents a linear or branched alkyl chain comprising from 1 to 5 carbon atoms;

R ₂ represents a halogen (Cl, F, Br), OH, NH ₂ , CN, NO ₂ , R'2, OR ' ₂ , SR' ₂ ,

NHR ' ₂ , COR' ₂₎ CHOHR'2, COOR ' ₂ , NHCOR' ₂ , NHCOOR ' ₂ , NHSO ₂ R'2, OCONHR'2, in which R'2 represents a linear or branched alkyl chain comprising from 1 to 5 carbon atoms, an aryl or an alkylaryl in which the aryl residue is chosen from phenyl, naphthyl or pyridyl which may optionally be substituted by one or more groups chosen from linear or branched alkyl comprising from 1 to 5 carbon atoms , halogen (Cl, F, Br or I), OH, OR ' ₄ , SR' ₄ , CF ₃ , CH ₂ CF, NO, CN, COR ' ₄ , COOR', NHR'4, NHCOR'4, NHCOOR '4, NHS0 ₂ R'4, SO ₂ R'4 in which R' ₄ represents a linear or branched alkyl chain comprising from 1 to 5 carbon atoms, it being understood that when R \ represents OR'i, SR '] or NHR'i then

R necessarily represents R'2, COOR ' ₂ , COR' ₂ or CHOHR '₂;

Z represents CO- (CH ₂ ) _n -0, CO- (CH ₂ ) _n -NH, (CH ₂ ) _m -0, (CH ₂ ) _m - H, CO- (CH ₂ ) _p -CONH-, ( CH ₂ ) _p -CONH, CO- (CH ₂ ) _p -NHCONH-, (CH ₂ ) _m -NHCONH, - CO (CH ₂ ) _p -OCONH-, (CH ₂ ) _m -OCONH, -CO (CH ₂ ) _p -NHCOO-, (CH ₂ ) _m -

NHCOO, in which n represents an integer between 1 and 8, m represents an integer between 2 and 8 and p represents an integer between 1 and 8; Ar represents an aromatic radical such as a phenyl or a naphthyl to which Z and the piperazine are attached to different carbons and which can itself be variously substituted by one or more substituents chosen from a linear or branched alkyl radical comprising from 1 to 6 carbon atoms, an alkoxy (OR5 in which R5 represents a linear or branched alkyl radical comprising from 1 to 6 carbon atoms), or a halogen (Cl, Br, F or

D;

and their physiologically acceptable hydrated salts, solvates and bioprecursors for therapeutic use,

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

2. Compounds according to Claim 1, characterized in that they correspond to the formula (la)

(the)

in which Ri, R2 and Z are defined as in formula (I) and R'5 represents H, OCH3, CH3 or Cl.

3. Compounds according to Claim 1, characterized in that they correspond to the formula (Ib)

(Ib) in which R \, R2 and Z are defined as in the general formula (I).

4. Compounds according to one of claims 1 to 3, characterized in that R3 represents a methyl.

5. Compounds according to one of claims 1 to 4, characterized in that Z represents CO (CH ₂ ) _n O or CO (CH ₂ ) _n NH.

6. Compounds according to one of claims 1 to 4, characterized in that Z represents (CH2) _m O or (CH ₂ ) _m NH.

7. Compounds according to one of claims 5 to 6, characterized in that R \ represents R '\ or CH2' 1.

8. Compounds according to one of claims 6 to 7, characterized in that 2 represents CN, OH, OR'2 or R'2.

9. Compounds according to one of claims 1 to 7, characterized in that R2 represents NH2 or NHR'2.

10. Compounds according to one of claims 1 to 9 in the form of salts acceptable for the therapeutic use, characterized in that these salts are hydrochlorides, hydrobromides, sulfates, methanesulfonates, fumarates, maleates, succinates, phosphates, acetates, benzoates, naphthoates, p-toluenesulfonates, sulfamates, ascorbates, tartrates, citrates, salicylates, lactates, glutarates or glutaconates.

1. Process for the preparation of the compounds of formula (I) in which Z represents CO (CH ₂ ) _n O, CO (CH ₂ ) _n NH, CO (CH ₂ ) _p CONH, CO (CH ₂ ) _p NHCONH, CO ( CH ₂ ) _p OCONH or CO (CH ₂ ) _p NHCOO (in which n is different from zero) according to claim 1, characterized in that a piperidine of general formula (II) is condensed

(not)

in which R \ and R2 are defined as in general formula (I), with an electrophile of general formula (III)

(or)

in which Ar and R3 are defined as in the general formula (I) and Z 'represents respectively either LCO (CH2) _n O, LCO (CH2) _n NH, LCO (CH ₂ ) _p CONH, LCO (CH ₂ ) _p NHCONH , LCO (CH ₂ ) _p OCONH or

LCO (CH2) _p NHCOO in which n and p are whole numbers between 1 and 8, and L represents OH, Cl or the group "LCO" represents an activated form of a carboxylic acid, to prepare an amide by condensation of an amine with a carboxylic acid or one of its derivatives.

12. Process for the preparation of the compounds of formula (I) in which Z represents (CH ₂ ) _m O, (CH ₂ ) _m NH, (CH ₂ ) _p CONH, (CH ₂ ) _m NHCONH, (CH ₂ ) _m OCONH or (CH ₂ ) _m NHCOO characterized in that a piperidine of formula (II) as defined in claim 1 1 is condensed with an electrophile of formula (III) in which Ar and R3 are defined as in claim 1 and Z 'represents XZ in which X represents a leaving group such as a halogen (chlorine, bromine or iodine), an O-tosyle, an O-mesyl or an O- trifluoromethanesulfonyl, in the presence of an organic or inorganic base in a polar aprotic solvent.

13. Process for the preparation of a compound of formula (I) in which Z represents COO or CONH characterized in that a piperidine of formula is condensed

(II) as defined in claim 11 and an aromatic piperazine derivative of general formula (IV)

(IV) in which R3 and Ar are defined as in claim 1 while Y represents O or NH, with an electrophile of general formula (V)

(V) in which Xj and X represent a leaving group such as for example Cl or

OCCI3, in the optional presence of an inorganic or organic base such as a tertiary amine, in a polar aprotic solvent.

14. Pharmaceutical compositions containing, as active ingredients, a compound according to one of claims 1 to 10, in combination with a pharmaceutically acceptable vehicle.

15. Pharmaceutical compositions according to claim 14, for both curative and preventive treatment of depression and obsessive compulsive disorders or disorders.

16. Pharmaceutical compositions according to claim 14, for both curative and preventive treatment of anxiety and panic attacks, schizophrenia, aggression, bulimia, alcoholism, pain and neurodegenerative diseases like Parkinson's or Alzheimer's

17. Compositions according to claim 14, for both curative and preventive treatment of cancers.

18. Pharmaceutical compositions according to one of claims 14 to 17, characterized in that they contain, in addition, at least one second associated active principle, endowed with antidepressant properties, in particular, MΓLNACIPRAN and / or a 5HT i antagonist AT-