WO1998031677A1 - Novel aromatic amines derived from cyclic amines useful as medicines - Google Patents

Abstract

The invention concerns derivatives of formula (I) in which in particular, R1 represents an amino radical selected among one of the substituents (i) to (v): in which R4 and R5 identical or different, represent H or an alkyl radical linear or branched containing 1 to 6 carbon atoms, Q represents O, NH, CH2 or NCH3 and m represents a whole number ranging between 2 and 4; R2 represents H, Cl, OH, OMe, or CH3; X-Y represents N-CH2, N-CH2CH2, CR6-CH2, C=CH; Z1 represents CH2 or CO; Z2 represents O or NH and n represents zero or a whole number ranging between 1 and 6, COR'3 or CHOHR'3, in which R'3 represents an aryl or alkylaryl radical. These compounds are particularly useful as antidepressant drugs.

Description

 New aromatic amines derived from cyclic amines useful as drugs

The present invention relates to new aromatic amines derived from cyclic amines, 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, Parkinsonism , Huntington's chorea), anorexia, bulimia, alcoholism-related disorders, stroke, pain, migraine or various headaches (R. Glennon, Neurosci. Biobehavioral Reviews, | 4, 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. Mendlecvicz, "Serotonin receptor subtypes: pharmacological significance and clinical implications", Karger Ed. (1992); BE Léonard, 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). These receptors are subdivided mainly in 4 main classes (5HTι, 5HT2, HT3 and 5HT4) which themselves include subclasses such as for 5HT receptors] which are mainly divided into 5HT IA, 5HTiβ, 5HTι; p (cf. GR Martin, PA Humphrey, Neuropharmacol., 33, 261, 1994; PR Saxena, Exp. X

Opin. Invest. Drugs, 3 (5), 513, 1994). 5HTID receptors themselves contain several receptor subtypes; thus the 5HTιr _{j) α} and 5HTι 3β receptors were cloned and then identified in humans (cf. for example E. Hamel et al., Mol. Pharmacol., 44, 242, 1993; GW Rebeck et al. ., Proc. Natl. Acad. Sci. USA, 9_1, 3666.1994). Furthermore, it has recently been demonstrated that the HTIB autoreceptors in rodents and 5HTi) 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 with selective agonist activity or partial agonist at receptors 5HTJB / ID ^you ls W ^{hat are} the new compounds described in this invention can have a beneficial stress on subjects with central or peripheral disorders associated with these receptors. In particular, such compounds find their utility in the treatment of pain, various headaches and migraine.

Compounds having a selective antagonist activity at the level of the central 5B. \ \ D / \ - Q 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 5HTIΓJ) / IB also find their utility in the treatment of endocrine disorders such as hyperprolactinemia, the treatment of vasospasms, hypertension and gastrointestinal disorders in which there are changes in motility and secretion.

The compounds according to the present invention are partial agonists or selective antagonists of the human 5HTID and 5-HT] B receptors and therefore find their utility, alone or in combination with other molecules, as medicaments and more particularly as therapeutic means. for both curative and preventive treatment of serotonin-related disorders. The prior 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 5HTID antagonists and recent publications which describe GR127,935 as a 5HTi antagonist £> (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 derivatives described above but also by their original biological profile, in particular as regards their selectivity for the subtypes of serotonin receptors and with regard to their intrinsic activity in particular at the level of the receptors known as 5-HTi £) β or 5-HTI B humans.

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

(i) In which,

K \ represents an amino residue chosen from one of the substituents (i) to (v)

- Q— (CH ₂ ) _m - NR ₄ R ₅ (iii)

^ CH = CH - CH ₂ - NR ₄ R _£ (v)

in which R4 and R5, which are identical or different, represent H or a linear or branched alkyl residue comprising from 1 to 6 carbon atoms, Q represents O, NH or CHL, and m represents an integer between 2 and 4

R2 represents H, Cl, OH, OMe or CH3, it being understood that R \ is linked to the phenyl residue in ortho or meta position relative to the substituent linked via ∑2, whereas R2 can appear in any other position on the aromatic ring to which it is attached, XY represents N-CH ₂ , N-CH ₂ CH ₂ , CR6-CH ₂ , C = CH, Z \ represents CH2 or CO,

∑2 represents O or NH and n represents zero or an integer between 1 and 6; it being understood that when Z \ represents CH2 then n is different from zero R3 represents an aryl or alkylaryl residue (benzyl, phenethyl, phenylpropyl) in which the aromatic nucleus is chosen from a phenyl, a naphthyl, a pyridyl, a tetrahydronaphthyl which may possibly 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, OR ₇ , SR ₇ , CF3, CH ₂ CF ₃ , NO ₂ , CN, COR7, COOR7, NHR7, NHCOR7, NHCOOR7, NHSO2R7, SO2R7 in which R7 represents a linear or branched alkyl chain comprising from 1 to 5 carbon atoms, and, in the particular case where XY represents CRg-CH2, R3 can also represent OR'3, SR'3, NHR'3, COR'3, CHOHR'3, whereas in the particular case where XY represents C = CH, R3 can also represent COR'3 or CHOHR'3, in which R'3 represents an aryl or alkylaryl residue (benzyl, phenethyl, phenylpropyl) d in which the aromatic nucleus is chosen from a phenyl, a naphthyl, a pyridyl, a tetrahydronaphthyl 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, OR7, SR7, CF3, CH ₂ CF ₃ , NO ₂ , CN, COR7, COOR7, NHR ₇ , NHCOR7, NHCOOR7, NHSO2R7, SO2 7 in which R7 represents a hydrogen or a linear alkyl chain or branched comprising from 1 to 5 carbon atoms, R represents H or a residue chosen from a halogen (Cl, F, Br), OH, CN, NO, R'ό, OR ' ₆ , NHR' ₆ , COR ' ₆ , CHOHR ' ₆ , r

COOR ' ₆ , NHCOR'ô, NHCOOR' ₆ , NHSO ₂ R ' ₆ , OCONHR' ₆ in which R ' ₆ represents a linear or branched alkyl chain comprising from 1 to 5 carbon atoms, an aryl or alkylaryl residue in which the aromatic nucleus is chosen from phenyl, naphthyl or pyridyl which can 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 , ORg, SRg, CF3, CH2CF3, NO ₂ , CN, CORg, COORg, NHR ₈ , NHCORg, NHCOORg, NHSO ₂ R8, SO ₂ Rg in which Rg represents a linear or branched alkyl chain comprising from 1 to 5 carbon atoms , it being understood that when R3 represents OR'3, SR3 or NHR'3, then Rg necessarily represents a carbon substituent different from CN. their hydrated 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 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)

t in which R \, R2, R3, X and Y are defined as in the general formula (I).

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

in which R \, R3, X, Y, Z1, Z2 and n are defined as in formula (I).

In general, the compounds of general formula (I) are prepared by condensation of a cyclic amine of general formula (II)

in which R3, X and Y are defined in general formula (I), with an electrophile of general formula (III)

in which R \, R2, Z \, Z2 and n are defined as in formula (I) and L represents a leaving group. The choice of the nature of L as well as the choice of experimental conditions for carrying out the condensation of the cyclic amines of formula (II) with an intermediate of formula (III) to prepare the derivatives of formula (I) of the present invention will be fixed essentially by nature Z \. Thus, in the case where Z \ represents CH2, the condensation of (I) with (III) represents a nucleophilic substitution reaction which will preferably be ”Carried out with an intermediate of formula (III) in which Z \ represents a halogen (chlorine, bromine or iodine), an O-mesyl, an O-tosyl or an O-trifluoromethanesulfonyl, in a polar anhydrous solvent such as for example the THF, diethylketone, DMF, DMSO, at a temperature between 0 ° and 80 ° C, in the presence of an organic or inorganic base such as for example K2CO3, CS2CO3, NaH, tBuOK, a tertiary amine (Et3N, DiPEA, DBU or 4-DMAP) in the possible presence of a salt such as Nal, BU4NI, AgBF4 or AgClθ4.

When Zi represents CO, the condensation of a cyclic amine of formula (II) will be carried out with a carboxylic acid derivative of formula (III) in which L represents OH, Cl or also the group "LCO" represents an activated form d 'a carboxylic acid suitable for the 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 represents chlorine, in the presence of an organic or inorganic base such as pyridine, DIPEA, 4-DMAP, DBU, K2CO3, CS2CO3 in a polar aprotic anhydrous solvent such as THF, DME, dichloromethane at a temperature between - 20 ° C and 40 ° C. Another particularly appreciated method of preparing the compounds of formula (I) in which Zi represents CO consists in condensing an amine of formula (II) with a carboxylic acid of formula (III) in which L represents OH by using well reactants 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 amounts such as for example triethylamine optionally in the presence of a base in catalytic amounts such as for example 4-DMAP.

In the particular case of the compounds of formula (I) in which Z \ represents CO and n represents zero, a particularly appreciated preparation method consists in condensing an amine of general formula (II) defined as above and an aromatic amine derivative of formula general (IV) %

in which R \, R2 and Z2 are defined as in general formula (I) with an electrophile of general formula (V)

in which X \ and X2, 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 the 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 Zj represents CO and n = zero by condensation of the cyclic amines of general formula (II) and the 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 Xj and X2 ) will be determined essentially 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 CO and n = zero consists in reacting an aromatic amine of formula (IV) in which R \, R2 and Z2 are defined as above with triphosgene, in the presence of a base such as triethylamine in an aprotic anhydrous solvent such as dichloromethane, and then add a compound of formula (II) in which R3, X and Y are defined as in formula (I). In the case of the preparation of compounds of formula (I) in which Z \ represents CO, n = zero and Z represents O, a more particularly preferred method consists in first condensing a cyclic amine of formula (II) with triphosgene in the presence of triethylamine in a solvent such as dichloromethane and to isolate the intermediate thus formed of general formula (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 DMF.

The intermediates of general formula (III) are prepared by alkylation of an aromatic amine of formula (IV) with an electrophile whose nature will depend on the definition of Z1. Thus, the intermediates of formula (III) in which Z \ represents CH2 will be prepared by condensation of a derivative of formula (IV) in which R \ and R2 are defined as above and Z2 represents O or NHBOC, with a electrophile of formula (VI)

P— (CH ₂ ) _{n + 1} - L (VI)

in which n is defined as above, L represents a leaving group such as a halogen (chlorine, bromine or iodine), a mesylate, a triflate or a tosylate and P represents a protected form of a leaving group in a polar aprotic solvent , in the presence of an organic or inorganic base, at a temperature between - 10 and 80 ° C, followed by the transformation of P into a leaving group (defined as L in formula (III)), which will be carried out by different techniques and methods depending on the nature of P and L.

Thus, when P represents O-benzyl, the condensation of the aromatic amine (IV) with the electrophile will be followed by a cleavage reaction of the benzyl group (for example by hydrogenation in the presence of palladium on carbon) and of a reaction for transforming the alcohol thus formed into a leaving group Z. If this leaving group is a halogen, this transformation will be carried out using reagents and methods well known for converting an alcohol into halogen such as for example the use SOCI2, POCI3, PCI5, PBr3, SOBr ₂ , PlvjPB, PI13PI2, 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.

It is understood that the method described above for preparing intermediates of formula (III) in which Z2 represents NH using a precursor of formula (IV) in which Z2 represents NHBOC will be followed by hydrolysis in acid medium of tert-butoxycarbonyl group using for example hydrochloric acid or trifluoroacetic acid in ethyl ether, methanol or dichloromethane. Likewise, the process for the synthesis of derivatives of formula (I) in which Z2 represents NH which consists in condensing an intermediate of formula (III) in which Z2 represents NHBOC (obtained as described above) with a cyclic amine of formula (II), by the methods and techniques described above, followed by cleavage of the tbutoxycarbonyl group in acid medium.

The intermediates of formula (III) in which Z \ represents CO are prepared by condensation of a derivative of formula (IV) in which R \ and R2 are defined as above and Z2 represents O or NHBOC, with an electrophile of formula (VII )

in which n is defined as above, R 'represents a linear or branched alkyl comprising from 1 to 5 carbon atoms or a benzyl and L represents a leaving group such as a halogen (Cl, Br or I), a mesylate, a tosylate or a triflate 44 by the methods described for the condensation of (IV) or (VI), followed by the transformation of the ester function (R'OCO) into carboxylic acid (LCO) by the methods and techniques well known to those skilled in the art art to achieve this type of transformation.

The aromatic amines of general formula (IV) are prepared by different methods and techniques, the choice of which will essentially depend on the nature of Ri. Thus, in the particular case where R \ represents a piperidine, the intermediates of formula (IV) are accessible by a series of reactions illustrated in the following diagram.

1) tBuLi, ZnBr ₂

In this reaction sequence P represents a protective group and R2 is defined as above. A more particularly preferred method of preparing the compounds (IVi) from the (VIII) according to the above scheme consists in using a protective group P which will be cut simultaneously with the step of reduction by hydrogen on palladium. This is how precursors (VIII) will be used in which P represents a benzyl residue or else the group "P-Z2" represents N (benzyl) 2.

The aromatic amines of formula (IV) in which R \ represents a residue (ii) are prepared by a reaction sequence using intermediate (VIII) and proline as starting material, as illustrated in the following diagram. Kl

(IVii, R ₄ = Me) (IVii)

In this scheme, P represents a protective group such as benzyl or the group PZ2 can represent N (benzyl) 2 and in these cases the final deprotection step will implement a reduction such as for example hydrogenation on palladium. The use of proline as a starting product to introduce the pyrrolidine motif makes it possible to selectively prepare one or the other of the enantiomers of intermediates (IVii) whose asymmetric center will come from proline (D or L) chosen as product of departure. The intermediates of formula (IV) in which R \ represents a propargyl amine residue (iv) are prepared by forming an aromatic-alkyne bond according to the following scheme

The intermediates of formula (IViv) as described above allow access to ethylenic derivatives (IVv) and to derivatives of type (IViii) in which Q represents CH2 and m represents 2 according to the following scheme:

0Vv) (Z) GViii)

Finally, the intermediates of formula (IViii) in which Q represents NH or O are prepared by condensation of a phenol or an aniline of general formula (IX)

in which Q represents O or NH, R is defined as above and Z3 represents NO2 or Br, with an electrophile of formula (X)

in which m, R4, R5 and L are defined as above, in the presence of an organic or inorganic base such as CS2CO3 or NaH, in a polar aprotic solvent such as THF, DMF or DMSO at a temperature between 0 ° C and 80 ° C followed by the transformation of the remainder Z3 into Z2H. Thus the intermediates of formula (IViii) in which Z2 represents O are prepared by condensation of the precursors of formula (IX) in which Z3 represents Br with an electrophile of formula (X) followed by the reaction of the product thus formed with butyl lithium in THF at -70 ° C, addition of B (OiPr) 3 and oxidation of the boronate thus formed with hydrogen peroxide or N-methyl morpholine N-oxide.

The intermediates of formula (IViii) in which Z2 represents NH are prepared by condensation of the precursors of formula (IX) in which Z3 represents NO2 with an electrophile of formula (X), followed by the reduction of the product thus formed by the methods and techniques well known to those skilled in the art for reducing a nitro-aromatic to aniline such as for example the use of Raney nickel or SnCl ₂ .

In the particular case of intermediates of formula (IViii) in which Q represents NH, an alternative but particularly appreciated method of synthesis consists in condensing, using palladium catalysts, amines of formula (XI)

H ₂ N (CH ₂ ) _m -NR ₄ R ₅ (XI)

in which m, R4 and R5 are defined as above, with aromatic derivatives of formula (XII)

in which Z2 and R ₂ are defined as above, by the methods and techniques as described by Hartwig et al. (J. Amer. Chem. Soc, ϋ8, 7217,

1996) or Buchwald et al. (J. Amer. Chem. Soc, 118, 7215, 1996).

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 variables Ri, R2, R3, Z \, X or Y are different by the techniques and methods well known to those skilled in the art. Thus, by way of example, the derivatives of formula (I) in which R2 is different from (iv) or (v) and XY represents CH2CH2 are accessible by hydrogenation of unsaturated piperidines of formula (I) in which XY represents C = CH, using hydrogen under atmospheric pressure and platinum or palladium on carbon. The derivatives of formula (I) in which R2 represents OH can also be prepared by demethylation of an analogous derivative of formula (I) in which R2 represents OCH3 using reagents and methods suitable for this type of reaction such as for example AICI3 , BBr3 or BeCl2 (cf. Tetrahedron, 52,13623,1996). As a further example, the derivatives of formula (I) in which Z \ represents CH2 can also be prepared by reduction of an analogous derivative of formula (I) in which Z \ represents CO using reagents and methods suitable for this type of reaction such as for example LAH or BH3.

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, Thie e Verlag, 1994. The appropriate protective groups will therefore be introduced and removed during the most appropriate step for this, using 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 acid (+ ) -di - /? - 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 R4 is a hydrogen comprising at least one asymmetric center can also be resolved by 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

[4- (2,3-Dimethylphenyl) piperazin-1-yl] -N- [3- (2-dimethylaminoethylamino) -4-methoxyphenyl] amide Q) fumarate

IA: N-tert-butoxycarbonyl-2-methoxy-5-nitroaniline

The 2-methoxy-5-nitroaniline (7 g; 41.6 mmol) is dissolved in dioxane (270 ml) under a nitrogen atmosphere in the presence of di-tert-butyldicarbonate (18.1 g; 83 mmol) and heated to 95 ° C. for 18 hours. The solvent is evaporated and the derivative IA is purified by flash chromatography with dichloromethane.

Mass obtained: 9.67 g (86%)

1H-RMΝ (200 MHz, dmso-d ₆ ) δ: 8.69 (d, IH, 2.9Hz); 8.48 (brs, 1H); 7.98 (dd, IH, 2.9 and 9.1Hz); 7.21 (d, 1H, 9.1Hz); 3.94 (s, 3H); 1.49 (s, 9H).

Rf: 0.55 (CH ₂ C1 ₂ )

IB: N-tert-butoxycarbonyl-N- (2-dimethylaminoethyl) -2-methoxy-5-nitroaniline The derivative iA (9.9 g; 37 mmol) is dissolved in DMF (150 ml) at 0 ° C in the presence of sodium hydride (50% in oil; 2.1 g; 44 mmol) under a nitrogen atmosphere. In a second flask l-chloro-2-dimethylaminoethane hydrochloride

(6.4 g; 44 mmol) is desalted in DMF (150 ml) at 0 ° C using sodium hydride (50% in oil; 2.1 g; 44 mmol) under a nitrogen atmosphere. The two reaction mixtures are brought to room temperature, then the chlorine derivative is cannulated on derivative A. The suspension 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 IB derivative is purified by flash chromatography with a mixture of eluents (1-5-95 = ΝH4θH-MeOH-

CH ₂ C1 ₂ ).

Mass obtained: 6.47 g (59%)

! H-NMR (200 MHz, dmso-d ₆ ) δ: 8.19 (dd, IH, 2.8 and 9Hz); 8.1 (brs, 1H); 7.25 (d, 1H, 9.1Hz); 3.91 (s, 3H); 3.9-3.3 (m, 2H); 2.26 (brt, 2H); 2.08 (s, 6H); 1.6-1.2 (m, 9H).

Mass (DCI, NH ₃ ): 340 (MH +)

1C: 3- [N-tert-butoxycarbonyl-N- (2-dimethylaminoethyl) amino] -4-methoxyaniline The derivative IB (2 g; 5.9 mmol) is dissolved in ethanol (20 ml) under a nitrogen atmosphere. presence of a catalytic amount of Raney Nickel. Hydrazine hydrated (1.5 ml) is added dropwise. The reaction is exothermic. The reaction mixture is stirred for a few hours and then filtered. The solvent is evaporated and the derivative 1C is purified by flash chromatography with a mixture of eluents (1-5-95 = NH ₄ OH-MeOH-CH ₂ Cl2).

Mass obtained: 1.34 g (73%)

1H-NMR (200 MHz, dmso-d ₆ ) δ: 6.71 (d, 1H, 8.4Hz); 6.5-6.3 (m, 2H); 4.65 (brs, 2H); 3.62 (s, 3H); 3.7-3.1 (m, 2H); 2.4-2.2 (m, 2H); 2.08 (s, 6H); 1.6-1.2 (m, 9H).

1D: 4- (2,3-dimethylphenyl) piperazin-1-yl) -N- {3- [N-tert-butoxycarbonyl-N- (2-dimethylaminoethyl) amino] -4-methoxyphenyl} amide

A solution of triphosgene (420 mg, 1.4 mmol) in dichloromethane (10 ml) is cannulated on a solution of IÇ (1.33 g, 4.3 mmol) and TEA (600 μl, 4.3 mmol) in dichloromethane (10 ml) 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- (2,3-dimethylphenyl) piperazine (1.23 g, 6.5 mmol) and TEA (600 μl, 4.3 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. The YD derivative is isolated in the form of a free base after purification by flash chromatography with a mixture of eluents (95-5-1 = ΝPLjOH-MeOH-CH ₂ C1 ₂ ).

Mass obtained: 1.21 g (53%)

1H-NMR (200 MHz, dmso-d ₆ ) δ: 8.44 (s, 1H); 7.5-6.8 (m, 6H); 3.71 (s, 3H); 3.56 (brs, 4H); 3.8-3.2 (m, 2H); 2.77 (brs, 4H); 2.26 (brt, 2H); 2.19 (s, 3H); 2.17 (s, 3H); 2.09 (s, 6H); 1.5-1.2 (m, 9H).

i: The derivative YD (1.2 g, 2.3 mmol) is dissolved in dichloromethane (65 ml) under a nitrogen atmosphere and trifluoroacetic acid (44 ml) is added. The solution is stirred for 24 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 MgSO and concentrated. The derivative I is isolated in the form of the free base after purification by flash chromatography with a mixture of eluents (92-8-1 = NH ₄ OH-MeOH-CH ₂ Cl ₂ ). >

Mass obtained: 870 mg (89%)

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

H-NMR (200 MHz, dmso-d ₆ ) δ: 8.28 (s, 1H); 7.07 (t, 1 H, 7.6 Hz); 6.9 (brs, 2H); 6.8-6.6 (m, 3H); 6.58 (s, fumarate); 3.74 (s, 3H); 3.59 (brs, 4H); 3.17 (brt, 2H, 6Hz); 2.95-2.65 (m, 6H); 2.39 (s, 6H); 2.24 (s, 3H); 2.21 (s, 3H).

Elemental analysis: C24H35N5O2; 0.9 C4H4O4; 0.4 H ₂ O Calculated: C = 61.70; H = 7.39; N = 13.04 Found: C = 61.77; H = 7.41; N = 12.97

IR rKBr): 3356, 2945, 1650, 1612, 1522, 1234

Mass (DCI, NH ₃ ): 426 (MH +)

Rf: 0.4 (1-10-90 = NH ₄ OH-MeOH-CH ₂ Cl ₂ )

EXAMPLE 2

[4- (2,3-Dimethylphenyl) piperazin-1-yl] -N- [4-methoxy-3- (4-methylpiperidin-1-yl) phenyl] amide fumarate (2)

2A: 3-bromo-4-methoxy aniline

The 3-bromo-4-methoxy-1-nitrobenzene (7.1 g; 31 mmol) is dissolved in ethanol (103 ml) under a nitrogen atmosphere in the presence of a catalytic amount of Raney Nickel. Hydrazine hydrate (7.7 ml) is added dropwise. The reaction is exothermic. The reaction mixture is stirred for a few hours and then filtered. The solvent is evaporated and the derivative 2A is purified by flash chromatography with a mixture of eluents (40-60 = EDP-EtOAc).

Mass obtained: 5.9 g (95%)

1H-NMR Ï200 MHz, dmso-d ₆ ) δ: 6.83 (d, 1H, 8.9Hz); 6.81 (d, 1H, 2.5Hz); 6.54 (dd, IH, 8.7 and 2.6 Hz); 4.88 (s, 2H); 3.70 (s, 3H).

Elementary analysis: C7H BrNO Calculated: C = 41.61; H = 3.99; N = 6.93 Found: C = 41.77; H = 4.00; N = 6.95

IR fKBrV 3450-3300, 3000-2800 (weak), 1631, 1495, 1274, 800.

2B: N, N-dibenzyl-3-bromo-4-methoxy-aniline

Compound 2A (7.43 g, 36.8 mmol) is dissolved in 74 ml of DMF in the presence of 5 equivalents of potassium carbonate (25.4 g, 184 mmol). Benzyl bromide (21.9 ml, 184 mmol) is added to the reaction mixture. This is then heated to 80 ° C for two hours. The mixture is filtered, concentrated then diluted in dichloromethane and washed successively with water, a saturated solution of sodium chloride and a saturated solution of ammonium chloride. The aqueous phase is extracted twice with dichloromethane. The organic phase is dried over magnesium sulfate, filtered and concentrated under reduced pressure. The derivative 2B is purified by flash chromatography with a gradient of 10 to 50% of dichloromethane in petroleum ether, then by recrystallization from a mixture of ethyl ether and petroleum ether.

Mass obtained: 9.53 g (68%)

iH-RMΝ (200 MHz, dmso-d ₆ ) δ: 7.40-7.20 (m, 10H); 6.90 (d, 1 H, 8.8 Hz); 6.87 (d, 1 H, 2.6 Hz); 6.66 (dd, 1H, 9 and 3 Hz); 4.64 (s, 4H); 3.69 (s, 3H).

Elementary analysis: C2iH2 () Calculated BrΝO: C ≈ 65.98; H = 5.27; N = 3.66 Found: C = 65.96; H = 5.28; N = 3.68

IR (KBrV. 3100-2830 (weak), 1605, 1504, 1282, 743. 2Ç: 1-methyl-1,2,3,6-tetrahydropyridin-4-yl trifluoromethanesulfonate In a two-necked flask, under nitrogen, the diisopropylamine (5.5 ml, 39 mmol) is diluted in 177 ml of THF anhydrous and cooled to -78 ° C. The n-butyllithium (1.6M in hexane; 25.4 ml, 41 mmol) is added dropwise. After stirring the mixture for one hour at -78 ° C, N-methyl piperidone (4.4 ml, 35 mmol) is added. The reaction medium is stirred for one hour. The N-phenyltrifluoromethanesulfonimide (19 g, 53 mmol) is then added. After fifteen minutes of stirring at -78 ° C, the mixture is brought to room temperature, diluted in dichloromethane and washed successively twice with a saturated solution of sodium chloride and once with a saturated solution of sodium carbonate. The aqueous phase is extracted twice with dichloromethane. The organic phases are combined, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The 2C derivative is purified by flash chromatography with 2 to 3% methanol and 0.5% ammonia in dichloromethane.

Mass obtained: 6.37g (73%)

IH-RMΝ (200 MHz, dmso-d ₆ ) δ: 5.91 (m, 1H); 2.98 (m, 2H); 2.59 (t, 2H, 5.7 Hz); 2.39 (m, 2H); 2.25 (s, 3H).

IR fKBrV. 2948-2793, 1697, 1419, 1213, 875.

2D: N, N-dibenzyl-4-methoxy-3- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) aniline Under inert atmosphere of Argon, compound 2B (3 g, 7.85 mmol ) is dissolved in 79 ml of anhydrous THF and cooled to -78 ° C. Two equivalents of tert-BuLi (1.7M in pentane; 10.2 ml, 17.3 mmol) are added dropwise at this temperature. The halogen-lithium exchange carried out, zinc bromide (1M in THF; 8.7 ml, 8.7 mmol) is added at -78 ° C and then the mixture is brought to room temperature. Compound 2Ç (1.93g, 7.85 mmol), diluted in 1 ml of anhydrous THF and tetrakis (triphenylphosphine) -palladium (453 mg, 0.4 mmol) are then added. The reaction mixture is then heated at 60 ° C for three hours then diluted in dichloromethane and washed twice with a saturated solution of ammonium chloride and then a saturated solution of sodium chloride. The organic phase is dried over magnesium sulfate, filtered and concentrated under reduced pressure. The 2JD derivative is purified by flash chromatography with a gradient of 2 to 5% of methanol and 0.5% o of ammonia in dichloromethane.

Mass obtained: 2.35 g (75%) II

1H-NMR (200 MHz, dmso-d ₆ ) δ: 7.35-7.15 (m, 10H); 6.69 (d, 1 H, 8.7 Hz); 6.60 (dd, IH, 7.8 and 2.9 Hz); 6.54 (d, 1H, 3Hz); 5.6 (m, 1H); 4.52 (s, 4H); 3.69 (s, 3H); 3.02 (m, 2H); 2.67 (m, 4H); 2.36 (s, 3H).

Elemental analysis: C27H30N2O; 0.22 CH2CI2 Calculated: C ≈ 78.36; H = 7.35; N = 6.71 Found: C = 78.45; H = 7.25; N = 6.47

IR fKBrV 3050-2780, 1605, 1504, 1234, 734.

2E: 4-methoxy-3- (1-methylpiperidin-4-yl) aniline

In a Pair flask, the 2D compound (2.28 g, 5.74 mmol) is diluted in 60 ml of glacial acetic acid and 60 ml of ethanol in the presence of palladium hydroxide in catalytic amount. The mixture is stirred for five hours under a pressure of 50 Psi. The solution is filtered through celite, neutralized with a 4N sodium hydroxide solution then diluted in dichloromethane and washed with a saturated solution of sodium chloride. The organic phase is dried over magnesium sulfate, filtered and concentrated under reduced pressure. The 2E derivative is purified by flash chromatography with a gradient of 5 to 10% of methanol and 1% of ammonia in dichloromethane.

Mass obtained: 607 mg (49%)

iH-NMR (200 MHz, dmso-d ₆ ) δ: 6.68 (d, IH, 8.5 Hz), 6.59 (d, IH, 2.7Hz); 6.50 (dd, IH, 8.5 and 2.8 Hz); 3.74 (s, 3H); 3.38 (brs, 2H); 2.90 (m, 4H); 2.33 (s, 3H); 1.75 (m, 4H).

2: The triphosgene (273 mg, 0.91 mmol) is dissolved under a nitrogen atmosphere in dichloromethane (19 ml) and cooled to 0 ° C. Compound 2E (607 mg, 2.78 mmol) dissolved in 0 ° C in dichloromethane (19 ml) in the presence of an equivalent of triethylamine (390 μl, 2.78 mmol) is added dropwise. The solution is stirred at 0 ° C for twenty minutes then the cold bath is removed. The 1- (2,3-dimethylphenyl) piperazine (786.7 mg, 4.14 mmol) diluted in dichloromethane (19 ml) with an equivalent of triethylamine (390 μl, 2.78 mmol) is then added. After two hours of stirring the reaction medium is diluted in dichloromethane and washed with water and then with a saturated solution of sodium chloride. The organic phase is dried over magnesium sulfate, filtered and concentrated under pressure scaled down. Derivative 2 is then purified by flash chromatography with a mixture of 5% methanol and 0.5% ammonia in dichloromethane.

Mass obtained: 876 mg (69%)

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

1H-NMR (200 MHz, dmso-d ₆ ) δ: 8.40 (s, 1H); 7.30 (dd, 1H, 8.8 Hz); 7.23 (d, 1H); 6.85 (m, 3H); 6.49 (s, 2H, fumarate); 3.71 (s, 3H); 3.55 (brs, 4H); 2.76 (m, 2H); 2.45 (m, 8H); 2.18 (m, 9H); 1.71 (m, 3H).

Elemental analysis: C26H36N4O2; 0.4 H ₂ O; C4H4O4 Calculated: C = 64.36; H = 7.34; N = 10.01 Found: C = 64.48: H = 7.46: N = 9.92

IR rKBrV. 3397, 2950-2837, 1638, 1502, 1236, 983.

Mass (DCI, NH3): 437 (MH +)

EXAMPLE 3

[4- (2,3-Dimethylphenyl) piperazin-1-yl] -N- {4-methoxy-3 - [(2S) 1- methylpyrrolidin-2-ylmethyl] phenyl} amide fumarate

3 A: (2S) 1-tert-butoxycarbonyl-2- (N-methyl-N-methoxycarboxamido) pyrrolidine N O-dimethylhydroxylamine hydrochloride (5.44 g, 55.75 mmol) is dissolved in a nitrogen atmosphere, in 26 ml of dichloromethane and cooled to 0 ° C. N-methylpiperidine (7.8 ml, 64.1 1 mmol) is then added. In another balloon, 1 \ under a nitrogen atmosphere, the (L) BOC-proline (12 g, 55.75 mmol) is dissolved in 185 ml of dichloromethane and 39 ml of anhydrous THF at -20 ° C and N-methylpiperidine (7.45 ml, 61.32 mmol) is added quickly so as to return to a temperature of -12 ° C. The methyl chloroformate (4.18 ml, 61.32 mmol) is then quickly added to the mixture as well as, two minutes later, the NO-dimethylhydroxylamine solution prepared above. The reaction medium is brought to ambient temperature and stirred for four hours. The solution is washed successively twice with a 0 ° C solution of 0.1Ν hydrochloric acid and twice with a 0 ° C solution of 0.5Ν sodium hydroxide. The aqueous phase is extracted twice with dichloromethane. The organic phase is dried over magnesium sulfate, filtered and then concentrated under reduced pressure. The 3A derivative is used without further purification in the rest of the synthesis.

Mass obtained: 10.8g (75%)

1H-NMR (200 MHz, dmso-dô): Mixture of two diastereoisomers Majority isomer: δ: 4.56 (m, 1H); 3.67 (s, 3H); 3.31 (m, 2H); 3.10 (s, 3H); 2.17 (m, 1H); 1.77 (m, 3H); 1.31 (s, 9H). Minority isomer: δ: 4.56 (m, 1H); 3.70 (s, 3H); 3.31 (m, 2H); 3.09 (s, 3H); 2.17 (m, 1H); 1.77 (m, 3H); 1.38 (s, 9H).

3B: (2S) 1-tert-butoxycarbonyl-2-formylpyrrolidine

The aluminum and lithium hydride (1.84 g, 48.3 mmol) is suspended in 150 ml of anhydrous ethyl ether under an argon atmosphere at -45 ° C. Compound 3_A (10.39 g, 40.2 mmol) diluted in 50 ml of anhydrous ethyl ether is added to the reaction medium while maintaining the temperature at -35 ° C. When the addition is complete, the mixture is brought back to a temperature of + 5 ° C. and then again cooled to -35 ° C. A potassium bisulfate solution (2.7M in water; 15 ml) is then added very slowly to the reaction medium. The mixture is brought to room temperature and stirred for one hour. It is then filtered on celite and then concentrated under reduced pressure. The 3JB derivative is purified by flash chromatography with dichloromethane.

Mass obtained: 6.6g (82%)

H-NMR (200 MHz, dmso-d ₆ ) δ: 9.39 (s, 4H); 4.01 (m, 1H); 3.32 (s, 2H); 2.03-1.71 (m, 4H); 1.34 (d, 9H). 3Ç: (2S) N-tert-butoxycarbonyl-2- [1- (5-dibenzylamino-2-methoxyphenyl) -l- (methylsulfonylthiocarboxyoxy) methyl] pyrrolidine

Under a nitrogen atmosphere, compound 2B (11.5g, 30.1 mmol) is dissolved in 300 ml of anhydrous THF, cooled to -78 ° C, then two equivalents of / ert-BuLi (1.7M in pentane; 39 ml, 66.2 mmol) are added dropwise. The halogen-lithium exchange carried out, the compound 3B (9g, 45.1 mmol) diluted in 10 ml of anhydrous THF is added slowly using a syringe. The orange solution turns pale yellow. After ten minutes of stirring at -78 ° C, carbon sulfide (2.42 ml, 40 mmol), previously dried over calcium sulfate, is added. Thirty minutes later, methyl iodide (2.81 ml, 45.1 mmol) is added. The mixture is brought to room temperature and stirred for two hours. The red solution is then diluted in dichloromethane and washed with water and then with a saturated solution of sodium chloride. The aqueous phase is extracted twice with dichloromethane. The organic phase is dried over magnesium sulfate, filtered and concentrated under reduced pressure. The 3C derivative is purified by flash chromatography with a gradient of 1 to 7% ethyl acetate in petroleum ether.

Mass obtained: 4.28g (24%)

1H-RMΝ (200 MHz, dmso-d ₆ ) δ: 7.34-7.20 (m, 10H); 6.80 (d, 1H, 8.9 Hz); 6.63 (m, 2H); 4.59 (s, 4H); 4.13 (m, 1H); 3.64 (s, 3H); 3.30-2.95 (m, 4H); 2.45 (s, 3H); 1.56-1.30 (m, 13H).

IR CKBΓV. 3100-2820, 1692, 1512, 1223, 1058, 736.

3D: N, N-dibenzyl-4-methoxy-3 - [(2S) l-tert-butoxycarbonylpyrrolidine-2- ylmethyl] aniline

Compound 3Ç (3.85 g, 6.5 mmol) is dissolved in 217 ml of toluene, under an inert atmosphere of nitrogen. The mixture is brought to reflux of toluene. The tri-fl-butyltin hydride (182 mg, 1.1 mmol) and the AIB 8 (8.12 ml, 30.2 mmol) are added three times from the first reflux, at intervals of one hour. The reflux is maintained for an hour and a half after the last addition, then the reaction medium is brought to room temperature and stirred overnight. The mixture is concentrated under reduced pressure. The 3_D derivative is purified by flash chromatography with a gradient of 3 to 10% of ethyl acetate in petroleum ether.

Mass obtained: 2.23g (71%) H

1H-NMR (200 MHz, dmso-d ₆ ) δ: 7.34-7.19 (m, 10H); 6.72 (d, 1H, J = 8.8 Hz); 6.51 (m, 2H); 4.53 (s, 4H); 3.77 (brs, 1H); 3.62 (s, 3H); 3.14 (m, 2H); 2.78 (m, 1H); 2.34 (m, 1H); 1.24 (brs, 13H).

Elementary analysis: Cτ ιHτaN2θ, 0.2 H ₂ l2 Calculated: C = 74.41; H = 7.68; N = 5.56 Found: C = 74.24; H = 7.32; N = 5.57

IR (KBr 3200-2750, 1690, 1505, 1453, 1393, 1362

Mass (DCI, NH ₃ ): 487 (MH +)

3E: N, N-dibenzyl-4-methoxy-3 - [(2S) l-methylpyrrolidine-2-ylmethyl] aniline

Under a nitrogen atmosphere, the 3D compound (2.17 g, 4.46 mmol) is diluted in 39 ml of anhydrous THF. The mixture is stirred and cooled to -78 ° C. A solution of aluminum hydride and lithium (1M in THF; 17.8 ml, 17.8 mmol) is added to the reaction medium. This is then brought to room temperature and then heated to 60 ° C for 7 hours. When the reaction is complete, hydrated sodium sulfate is added slowly to the mixture. This is filtered through celite and then concentrated under reduced pressure. The product obtained is used without further purification in the rest of the synthesis.

Mass obtained: 1.70g (95%)

! H-RMΝ (200 MHz, dmso-d ₆ ) δ: 7.35-7.16 (m, 10H); 6.69 (d, 1 H, 8.3 Hz); 6.50 (m, 2H); 4.56 (s, 4H); 3.62 (s, 3H); 2.73 (m, 2H); 2.16 (s, 3H); 2.10-1.90 (m, 3H); 1.45-1.15 (m, 4H).

Elemental analysis: C27H32N2O; 0.05 CH2CI2 Calculated: C = 80.26: H ≈ 7.99; N = 6.92 Found: C = 80.09; H ≈ 7.87; N = 6.87

IR (KBr: 3100-2750, 1505, 1229, 735

Mass (DCI, NH3): 487 (MH +)

Rotatory power: rj ²⁴ = -33.7 (c = 1.18 g% ml, MeOH) v \

3F: 4-methoxy-3 - [(2S) 1-methylpyrrolidine-2-ylmethyl] aniline Compound 3F is prepared according to the procedure described for compound 2E from the following reagents: compound 3E (1.80g, 4.5 mmol) , 40 ml of pure acetic acid, 40 ml of ethanol, a palladium hydroxide spatula. The mixture is stirred on the Parr apparatus for 5 hours under a pressure of 45 Psi. The 3F derivative is purified by flash chromatography with a gradient of 3 to 7% of methanol and 0.5% of ammonia in dichloromethane.

Mass obtained: 712 mg (71%)

1H-NMR (200 MHz, dmso-d ₆ ) δ: 6.63 (d, 1H, 8.3 Hz); 6.38 (m, 1H); 6.34 (d, 1 H, 2.8 Hz); 4.51 (brs, 1H); 3.63 (s, 3H); 2.85 (m, 2H); 2.25 (s, 3H); 2.24-1.98 (m, 3H); 1.64-1.39 (m, 4H).

IR fKBrV. 3440-3200, 3000-2770, 1621, 1502, 1233, 805.

Elemental analysis: C13H20N2O; 0.08 CH ₂ C1 ₂ Calculated: C = 69.18; H = 9.22; N = 11.82 Found: C = 69.30; H = 9.22; N = 1 1.82

3: Compound 3 is prepared according to the procedure described for compound 2 from the following reagents: compound 3F (657 mg, 3 mmol), l- (2,3-dimethylphenyl) desalified piperazine (850 mg; 4.5 mmol), triphosgene ( 292 mg, 1 mmol, triethylamine (830 μl; 6 mmol), dichloromethane (20 ml) Derivative 3 is purified by flash chromatography with a mixture of 5% methanol and 0.5% ammonia in dichloromethane.

Mass obtained: 1.22 g (90%)

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

1H-NMR (200 MHz, dmso-d ₆ ) δ: 8.41 (s, 1H); 7.30 (m, 2H); 7.10-6.84 (m, 4H); 6.53 (s, 2H, fumarate); 3.75 (s, 3H); 3.58 (brs, 4H); 3.25-2.98 (m, 4H); 2.79 (brs, 7H); 2.19 (m, 7H); 1.65 (m, 4H).

Elemental analysis: C26H36N4O2; 0.5 H2O; 0.9 C4H4O4 Calculated: C ≈ 64.63; H = 7.44; N = 10.19 not

Found: C = 64.66; H = 7.51; N = 10.25

IR fKBr): 3420, 2950-2690, 1644, 1505, 1235, 729

Mass (DCI, NH ₃ ): 437 (MH +)

Rotatory power: αrj ²⁴ = -11 (c = 0.279 g% ml, MeOH)

EXAMPLE 4

[4- (2,3-Dimethylphenyl) piperazin-1-yl] -N- {4-methoxy-3 - [(2R) 1- methylpyrrolidin-2-ylmethyl] phenyl} amide fumarate (4)

Derivative 4 is prepared in the same way as 3 from 2B and (D) Boc-Proline. The results obtained are presented in the following table:

1 °)

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

1H-NMR (200 MHz, dmso-d ₆ ) δ: 8.42 (s, 1H); 7.4-7.25 (m, 2H); 7.06 (brt, 1H); 7.0-6.8 (m, 3H); 6.54 (s, fumarate); 3.76 (s, 3H); 3.59 (brs, 4H); 3.4-2.5 (m, 12H); 2.23 (s, 3H); 2.17 (s, 3H); 1.9-1.5 (m, 4H).

Elemental analysis: C26H36N4O2; 1.1 H2O; 0.2 C4H4O4 Calculated: C = 64.30; H = 7.24; N = 9.87 Found: C = 64 40; H = 7.61; N = 9.88

IR (K v): 3420, 2950-2690, 1644, 1505, 1235, 729

Mass (DCI, NH3): 437 (MH ⁺ )

Rotatory power: α _D ²⁶ = +10.7 (c ≈ 0.377 g% ml, MeOH) EXAMPLES 5 to 10

Derivative 5 is prepared in the same way as 3 by formation of the urea bond from the intermediate 3F and 4-phenethylpiperidine.

Derivative 6 is prepared in the same way as 2 by formation of the urea bond from the intermediate 2E and 4-phenethylpiperidine.

Derivative 7 is prepared in the same way as I by formation of the urea bond from the intermediate YD and 4-phenethylpiperidine.

Derivative 8 is prepared by alkylation of 2- (4-methylpiperidin-1-yl) phenol (itself prepared by palladium coupling of 2-bromophenol with trifluoromethane sulfonate of 1-methyl-1,2,3,6- tetrahydropyridin-4-yl followed by catalytic hydrogenation of the double bond introduced) with 5-bromo-1- (4-cyano-4-phenylpiperidin-1-yl) pentan-1 -one.

Derivative 9 is prepared by alkylation of 2- (4-methylpiperidin-1-yl) phenol with 5-bromo-1- (4-phenylpiperidin-1-yl) pentan-1-one.

The derivative 10 is prepared by alkylation of 2- (4-methylpiperidin-1-yl) phenol with 2-bromo-1 - [4- (2, 3-dimethylphenyl) piperazin-1-yl-jethan-1-one.

EXAMPLE 11

(4-Phenethylpiperazin-1-yl) -N- [4-methoxy-3- (4-methylpiperidin-1-yl) phenyl) amide hydrochloride (11)

11A: N-ter / -butoxycarbonyl-4-methoxy-3- (4-methyIpiperidin-1-yl) aniline The derivative 2E (530 mg; 2.4 mmol) is dissolved in toluene (60 ml) under nitrogen atmosphere presence of di tert-butyldicarbonate (524 mg; 2.4 mmol) and heated at 80 ° C for 7 hours. The solvent is evaporated and the derivative 11A is purified by flash chromatography (1-3-97 = ΝH4θH-MeOH-CH Cl2).

Mass obtained: 324 mg (42%) 1H-NMR (400 MHz, dmso-d ₆ ) δ: 9.05 (brs, 1H); 7.3-7.2 (m, 2H); 6.82 (d, 1 H, 8.9 Hz); 3.71 (s, 3H); 2.84 (brd, 2H); 2.75 (tt, 1H, 4Hz and 12Hz); 2.17 (s, 3H); 1.91 (brt, 2H); 1.7-1.5 (m, 4H); 1.46 (s, 9H).

11: The derivative 11A (319 mg; 0.99 mmol) is dissolved in THF (5 ml) under a nitrogen atmosphere, then cooled to 0 ° C. W-Butyllithium (740 μl; 1.2 mmol) is added dropwise. The solution is stirred for 25 minutes at 0 ° C. and then brought slowly to room temperature. 1-Phenethylpiperazine (188 mg, 1 mmol) dissolved under nitrogen atmosphere in THF (5 ml) is added, then the reaction mixture is brought to reflux of THF for 15 hrs. The solution is cooled to 25 ° C. and then neutralized slowly by adding a few drops of water. The solvent is evaporated in vacuo. The oily residue is taken up in dichloromethane, washed once with a saturated aqueous NaCl solution and a saturated aqueous sodium bicarbonate solution, dried over magnesium sulphate, filtered and concentrated. Derivative 11 is purified by flash chromatography (1-10-90 = NH4θH-MeOH-CH ₂ Cl2). Mass obtained: 120 mg (52%)

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

iH-NMR (400 MHz, dmso-d ₆ ) δ: 11.74 (brs, IH); 10.61 (brs, 1H); 8.74 (s, 1H); 7.45-7.35 (m, 7H); 6.90 (d, 1 H, 8.9 Hz); 4.25 (brd, 2H); 3.76 (s, 3H); 3.57 (brd, 2H); 3.35 (brs, 4H); 3.08 (brs, 8H); 2.8-2.65 (m, 4H); 1.89 (brs, 4H).

Elemental analysis: C26H36N4O2; 2.5 HC1; 0.96 H ₂ O Calculated: C = 59.59; H = 7.38; N = 10.69 Found: C = 59.49; H = 7.46; N = 10.45

IR (KBr): 3411, 2955, 2700-2400, 1659, 1530, 1495.

Mass (DCI, NH ₃ ): 437 (MH +)

Rf: 0.21 (0.5-10-90 = NH ₄ OH-MeOH-CH ₂ Cl ₂ ) EXAMPLE 12

(4-PhenethylPiperazin-1-yl) -N- [3- (2- diethylaminoethylamino) -4-methoxyphenyl] amide hydrochloride (12)

2: Compound 2 is prepared according to the same protocol used to synthesize derivative i by replacing l- (2,3-dimethylphenyl) piperazine with phenethylpiperazine.

Mass obtained: 511 mg

Yield for the last two stages (formation of the urea bond and deprotection of aniline): 68%

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

1 H-NMR (400 MHz, dmso-d ₆ ) δ: 11.37 (brs, 1 H); 10.23 (brs, 1H); 8.64 (s, 1H); 7.45-7.35 (m, 5H); 6.89 (brs, 1H); 6.8-6.7 (m, 2H); 5.29 (m, 1H); 4.27 (brd, 2H); 3.74 (s, 3H); 3.57 (brd, 2H); 3.5-3.2 (m, 8H); 3.2-3.0 (m, 4H); 2.8 (m, 6H).

Elemental analysis: C24H35N5O2; 2.5 HC1; 0.96 H2O Calculated: C = 53.89: H = 7.16: N = 13.09 Found: C = 53.58; H = 7.17; N = 12.88

Mass (DCI, NH ₃ ): 426 (MH ⁺ )

Rf: 0.22 (1-10-90 = NH OH-MeOH-CH ₂ Cl2) 3 ^ EXAMPLE 13

(4-PhenethylPiperazin-1-yl) -N- {3 - [(2-dimethylaminoethyl) methylamino] -4-methoxyphenyl} amide hydrochloride Q3)

13A: 3- [N-methyl-N- (2-dimethylamino) ethyl] -4-methoxyaniline

The derivative 1Ç (1.89 g, 6.10 mmol) is dissolved in anhydrous THF (30 ml) at room temperature and under a nitrogen atmosphere. Lithium aluminum hydride (1M in THF; 12.2 ml, 12.2 mmol) is added slowly and the reaction is stirred at 50 ° C for 16 hours. The reaction medium is neutralized by successive addition of 460 μl of water, 460 μl of NaOH (15% in water) and 1.38 ml of water. The aluminum salts precipitate and are removed by filtration. The filtrate is concentrated and the derivative 13A is purified by flash chromatography (1-14-86 = M OH-MeOH-CH ₂ C1 ₂ ).

Mass obtained: 41 1 mg (30%)

1H-NMR (400 MHz, dmso-d ₆ ) δ: 6.58 (d, 1H, 8.4Hz); 6.17 (d, 1H, 1.9Hz); 6.05 (dd, IH, 1.9 and 8.4Hz); 4.51 (brs, 2H); 3.62 (s, 3H); 3.05 (brt, 2H); 2.64 (s, 3H); 2.33 (brt, 2H); 2.11 (s, 6H).

13: Compound 13 is prepared according to the procedure described for compound 2 from the following reagents: compound 13A (290mg, 1.29 mmol), 1-phenethylpiperazine (368mg; 1.93 mmol), triphosgene (126mg, 0.42 mmol), triethylamine ( 360 μl; 2.60 mmol), dichloromethane (10 ml). Derivative 13 is purified by flash chromatography with a mixture of 15% methanol and 1% ammonia in dichloromethane. Mass obtained: 170 mg (30%)

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

1H-NMR (400 MHz, dmso-d ₆ ) δ: 11.33 (brs, 1H); 10.17 (brs, 1H); 8.74 (s, 1H); 7.40-7.20 (m, 6H); 7.12 (d, 1H, 8.6Hz); 6.88 (d, 1H, 8.8Hz); 5.26 (brd, 2H); 3.78 (s, 3H + Et ₂ O); 3.58 (brd, 2H); 3.4-3.2 (m, 8H); 3.2-3.0 (m, 4H); 2.81 (s, 3H); 2.80 (s, 3H); 2.71 (s, 3H); 1.03 (d, Et ₂ O).

Elemental analysis: C25H37N5O2; 2.5 HC1; 2.3 HO; 0.3 And ₂ O Calculated: C = 52.94; H = 7.99; N = 11.78; Cl = 14.91 Found: C = 52.64; H = 7.72; N = 1 1.93; Cl = 14.75

Mass (DCI, NH3): 440 (MH ⁺ )

Rf: 0.62 (1-20-80 = NH ₄ OH-MeOH-CH ₂ Cl ₂ )

EXAMPLE 14

(4-Phenethylpiperazin-1-yI) -N- [3- (3-dimethylaminoprop-1-ynyl) -4-methoxyphenylI amide Q4) hydrochloride

14A: N-tert-butoxycarbonyl-3-bromo-4-methoxyaniline

Compound 14A is prepared according to the procedure described for compound 11A from the following reagents: aniline 2A (4.99 g, 24.7 mmol); (BOQ2O (5.38 g, 24.7 mmol); Toluene (620 ml).

Mass obtained: 7.46 g (100%) ⁾ 4

1H-NMR (400 MHz, dmso-d ₆ ) δ: 9.30 (s, 1H); 7.73 (s, 1H); 7.35 (brd, 1H); 7.02 (brd, 1H); 3.78 (s, 3H); 1.46 (s, 9H).

14B: N-tert-butoxycarbonyl-3- (3-dimethylaminoprop-1-ynyl) -4-methoxyaniline In a first flask, compound 14A (5.38 g, 17.8 mmol) is dissolved in THF (15 ml) under an atmosphere of nitrogen and at room temperature. Tetrakistriphenylphosphine palladium (O) (1.02 g, 0.89 mmol) is added. In a second flask, copper iodide (341 mg, 1.79 mmol) is added at room temperature and under a nitrogen atmosphere to a solution of 3-dimethylaminopropyne (3.25 ml, 30.2 mmol) in THF (15ml). When the copper is dissolved, this solution is transferred to the first flask. The reaction mixture is then brought to reflux of THF and stirred for 22 hours, then it is cooled to room temperature and concentrated. Derivative 14B is purified by flash chromatography with a mixture of 3% methanol and 0.5% ammonia in dichloromethane.

Mass obtained: 3.36 g (61%)

1H-RMΝ (400 MHz, dmso-d ₆ ) δ: 9.29 (s, 1H); 7.48 (s, 1H); 7.35 (brd, 1H); 6.93 (d, 1H, 9Hz); 3.74 (s, 3H); 3.43 (s, 2H); 2.23 (s, 6H); 1.46 (s, 9H).

14: Compound H is prepared according to the procedure described for compound U from the following reagents: 1 -Phenethylpiperazine (936 mg, 4.92 mmol); 14B (1.5 g, 4.9 mmol); THF (50 ml); "-Buthyllitium (1.6 M in THF, 3.7 ml, 5.9 mmol).

Mass obtained: 1.14 g f55% 1

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

1H-NMR (400 MHz, dmso-d ₆ ) δ: 11.27 (brs, 1H); 10.93 (brs, 1H); 8.93 (s, 1H); 7.64 (d, 1H, 2.5Hz); 7.48 (dd, IH, 2.5 and 9 Hz); 7.4-7.3 (m, 2H); 7.3-7.2 (m, 3H); 7.02 (d, 1H, 9Hz); 4.31 (s, 3H); 4.26 (brd, 1H); 3.80 (s, 3H); 3.58 (brs, 2H); 3.35 (brs, 4H); 3.15-2.95 (m, 4H); 2.84 (s, 6H).

Elemental analysis: C25H32N4O2; 2.2 HC1; 0.55 H O Calculated: C = 59.96; H ≈ 6.88; N = 11.19 Found: C = 59.97; H = 7.02; N = 10.95

Mass (DCI, NH ₃ ): 421 (MH +) Rf: 0.17 (1-5-95 = NH ₄ OH-MeOH-CH ₂ Cl ₂ )

EXAMPLE 15

(4-PhenethylPiperazin-1-yl) -N- [3- (3-dimethylaminopropyl) -4-methoxyphenyl] amide hydrochloride Q5)

15: In a Parr flask, compound H (400 mg, 0.95 mmol) is dissolved in methanol (23 ml) in the presence of palladium hydroxide (20% in carbon, 277 mg, 0.39 mmol). The mixture is stirred for five hours under a pressure of 30 Psi. The reaction is filtered through celite and concentrated under reduced pressure. The derivative 15 is purified by flash chromatography with a gradient of 5 to 7% of methanol and 1% of ammonia in dichloromethane.

Mass obtained: 220 mg (54%)

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

^ -RMN (400 MHz, dmso-d ₆ ) δ: 11.25 (brs, IH); 10.29 (brs, 1H); 8.72 (s, 1H); 7.4-7.2 (m, 7H); 6.88 (d, 1H, 8.5Hz); 4.25 (brd, 2H); 3.75 (s, 3H); 3.58 (brd, 2H); 3.34 (brs, 2H); 3.15-2.95 (m, 6H); 2.73 (s, 3H); 2.71 (s, 3H); 2.65-2.45 (m, 4H); 1.89 (brs, 2H).

Elemental analysis: C25H36N4O2; 2.2 HC1; 1.7 H ₂ O Calculated: C = 59.48: H = 7.63; N = 11.10; Cl = 15.45 Found: C ≈ 59.59: H = 7.49; N = 11.1 1; Cl = 15.65

Mass (DCI, NH3): 425 (MH ⁺ ) EXAMPLE 16

(4-Phenylpiperidin-1-yl) hydrochloride -Λ ^ - [3- (3-dimethyla inopropyl) -

4-methoxyphenyljamide Q6)

16A: In a Parr flask, compound 14B (1.83 g, 6.04 mmol) is dissolved in methanol (90 ml) in the presence of palladium (5% in carbon, 1.28 g, 0.6 mmol). The mixture is stirred for 24 hours under a pressure of 30 Psi. The reaction is filtered through celite and concentrated under reduced pressure. The 16A derivative is purified by flash chromatography with 5% methanol and 1% ammonia in dichloromethane.

Mass obtained: 1.36 g (73%)

1H-NMR (400 MHz, dmso-d ₆ ) δ: 9.02 (s, 1H); 7.20 (brs, 2H); 6.81 (d, 1H, 8.6Hz);

3.71 (s, 3H); 2.47 (brt, 2H); 2.19 (t, 2H, 7.1Hz); 2.1 1 (s, 6H); 1.59 (p, 2H, 7.4Hz);

1.45 (s, 9H).

16: Compound 16 is prepared according to the procedure described for compound ϋ from the following reagents: 1-Phenylpiperidine (450 mg, 2.8 mmol); 16A (572 g, 1.86 mmol); THF (40 ml); n-Buthyllitium (1.6 M in THF, 3.76 ml, 2.5 mmol).

Mass obtained: 160 mg (22%)

This compound is dissolved in methanol and treated with fumaric acid to give the corresponding fumarate. 3 ^

1 H-NMR (400 MHz, dmso-d ₆ ) δ: 8.31 (brs, 1 H); 7.35-7.15 (m, 7H); 6.83 (d, 1H, 8.4Hz); 6.52 (s, fumarate); 4.25 (brd, 2H); 3.73 (s, 3H); 2.83 (brt, 2H); 2.72 (brt, 1H); 2.6-2.45 (m, 4H); 2.41 (s, 6H); 1.85-1.65 (m, 4H); 1.65-1.45 (m, 2H).

Elemental analysis: C24H33N3O2; C4H4O4; 0.33 H2O Calculated: C = 65.73; H = 7.29; N = 8.21 Found: C = 65.95; H = 7.33; N = 8.15

Mass (DCI, NH3): 396 (MH +)

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

The derivatives of the present invention are partial agonists or HTIB / ID 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, su atriptan or 5-CT, studies which have been carried out at the level of human receptors cloned 5HTJB / I). These human receptors 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-Kj cell lines using an electroporator.

The HeLa HA7 cell line expressing the human 5HTI 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 5HTJ B and 5HTιj) and 5HTJA 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-8OH-DPAT (final concentration: 1 nM) for the 5HTι ^ 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 (5HTιg and 5HTID) or 1 μM (final concentration) of spiroxatrine (5HT _{1 A} ).

The study of the inhibition of the formation of cyclic AMP (stimulated by forskolin) mediated by the human 5HTιg and 5HTιrj 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 forming part of the present invention are powerful and selective antagonists of the 5HTIB / ID receptors and have the advantage of being particularly selective for the 5HTIB / IJ) human receptors in particular with respect to the 5HTι, 5HT] Ç receptors, 5HT2, cq, ct2 and D ₂ .

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 5HTιrj) / iB receptors ^and _> in the case of the products of the present invention, make it possible to demonstrate their partial agonist or antagonist activity at the level of these receptors.

These properties of the 5HTJ] 3 / IB 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).

Furthermore, the derivatives of the present invention are also capable of controlling the growth and proliferation of type C glial cells transfected by the 5HTi> receptor gene and by the 5HTJB 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 M 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 (for example fluvoxamine, sertraline, fluoxetine, paroxetine or citalopram), serotonin and norepinephrine receptor inhibitors (for example milnacipran), or 02 antagonists (for example 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-HTι ^ 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 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 for 1 tablet active component 10.0 microcrystalline cellulose B.P.C. 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 component 10.0 lactose Codex 74.5 starch Codex 10.0 corn starch pregelatinized Codex 5.0 magnesium stearate 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 hydroxy-propyl-methyl-cellulose, according to conventional techniques. Sugar tablets can also be coated. "

Mg capsules for one active component 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.

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 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 60.90 14.62 g

The active component is micronized in a fluid energy mill and put into the state of fine particles. Oleic acid is mixed with trichlorofluoromethane at a temperature of 10-15 ° C and introduced into the solution using a high mixer. Ht shear effect the micronized drug. 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 boxes by injection through the valves.

Claims

1. The derivatives of general formula (I)

(i)

In which,

R \ represents an amino residue chosen from one of the substituents (i) to (v):

Q - (CH ₂ ) _m - NR ₄ R ₅ (ϋî)

(v) ^ CH = CH - CH ₂ - NR4R5 H in which R4 and R5, which are identical or different, represent H or a linear or branched alkyl residue comprising from 1 to 6 carbon atoms, Q represents O, NH, CH2 or NCH3 and m represents an integer between 2 and 4 R2 represents H, Cl, OH, OMe or CH3, it being understood that R \ is linked to the phenyl residue in ortho or meta position with respect to the substituent linked via Z ₂ , whereas

R2 can appear in any other position on the aromatic cycle to which it is attached,

XY represents N-CH ₂ , N-CH ₂ CH ₂ , CR ₆ -CH ₂ , C = CH, Z \ represents CH2 or CO, Z2 represents O or NH and n represents zero or an integer between

1 and 6; it being understood that when Zi represents CH2 then n is different from zero R3 represents an aryl or alkylaryl residue (benzyl, phenethyl, phenylpropyl) in which the aromatic nucleus is chosen from phenyl, naphthyl, pyridyl, tetrahydronaphthyl 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, OR7, SR7, CF3, CH ₂ CF ₃ , NO ₂ , CN , COR7, COOR7, NHR ₇ , NHCOR7, NHCOOR7, NHSO2R7, O2R7 in which R7 represents a linear or branched alkyl chain comprising from 1 to 5 carbon atoms, and, in the particular case where X- Y represents CR -CH2, R3 can also represent OR3, SR'3, NHR'3,

COR'3, CHOHR'3, whereas in the particular case where XY represents C = CH, R3 can also represent COR'3 or CHOHR'3, in which R'3 represents an aryl or alkylaryl residue (benzyl, phenethyl, phenylpropyl ) in which the aromatic nucleus is chosen from a phenyl, a naphthyl, a pyridyl, a tetrahydronaphthyl 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, OR7, SR7, CF3, CH2CF3, NO ₂ , CN, COR7, COOR7, NHR7, NHCOR7, NHCOOR7, NHSO2R7, SO2R7 in which R7 represents a hydrogen or a linear or branched alkyl chain comprising 1 to 5 carbon atoms, Rç "represents H or a residue chosen from a halogen (Cl, F, Br), OH, CN, NO ₂ , R'ό, OR'ό, NHR ' ₆ , COR'ό, CHOHR 'ô, COOR'6, NHCOR' ₆ , NHCOOR ' ₆ , NHSO ₂ R'6, OCONHR' ₆ in which R 'represents a linear or branched alkyl chain including t from 1 to 5 carbon atoms, an aryl or alkylaryl residue in which the aromatic nucleus is chosen from a phenyl, a naphthyl or pyridyl which may optionally be substituted by one or more groups chosen from? - from a linear or branched alkyl comprising from 1 with 5 carbon atoms, a halogen (Cl, F, Br or I), OH, ORg, SR ₈ , CF3, CH ₂ CF ₃ , NO ₂ , CN, CORg, COORg, ^

NHRg, NHCORg, NHCOORg, NHSO2 8, SO2R8 in which Rg represents a linear or branched alkyl chain comprising from 1 to 5 carbon atoms, it being understood that when R3 represents OR'3, SR'3 or NHR'3, then R represents obligatorily a carbon substitute and different from CN.

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

The compounds of general formula (I) which can be in the form of geometric and optical isomers as well as their mixture, in particular in racemic form.

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

in which Ri, R2, R3, X and Y are defined as in the general formula (D-

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

in which R \, R3, X, Y, Z \, Z2 and n are defined as in formula (I).

4. Compounds according to one of claims 1 to 3, characterized in that XY represents N-CH2 or CH-CH ₂ .

5. Compounds according to one of claims 1 to 4, characterized in that R3 represents a phenyl, a naphthyl, a phenethyl or a phenyl propyl in which the aromatic nucleus is optionally substituted by one or more residues chosen from CH3, OCH3, F, Cl, CF ₃ or CN.

6. Compounds according to one of claims 1 to 5, characterized in that R2 represents H, OCH3 or OH.

7. Compounds according to one of claims 1 to 6 in the form of salts acceptable for 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.

8. A method of preparing the compounds of formula (I) according to claim 1 characterized in that it involves the condensation of a cyclic amine of general formula (II)

in which R3, X and Y are defined in general formula (I), with an electrophile of general formula (III)

? Λ in which R \, R2, Zi, Z2 and n are defined as in formula (I) and L represents a leaving group such as bromine, chlorine, iodine, mesylate, triflate or tosylate when Z \ represents CH2 or Cl, OH or any activated form of a carboxylic acid conducive to the formation of an amide by condensation with an amine when Zi represents CO, by the methods and techniques well known to those skilled in the art .

Process for the preparation of a compound of formula (I) in which Z \ represents CO and n represents zero, characterized in that a cyclic amine of formula (II) defined as above and an aromatic amine of formula (IV) is condensed

in which R \, R2 and Z2 are defined as in general formula (I) with an electrophile of general formula (V)

in which X \ and X2 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.

10. Pharmaceutical compositions containing, as active ingredients, a compound according to one of claims 1 to 7, in combination with a pharmaceutical vehicle acceptable as medicaments.

1 1. Pharmaceutical compositions containing, as active ingredients, a compound according to one of claims 1 to 7, in combination with an acceptable pharmaceutical vehicle, for both curative and preventive treatment of depression and compulsive disorders or disorders obsessive. 5

12. Pharmaceutical compositions containing, as active ingredients, a compound according to one of claims 1 to 7 in combination with an acceptable pharmaceutical vehicle, 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.

13. Pharmaceutical compositions containing, as active ingredients, a compound according to one of claims 1 to 7 in combination with an acceptable pharmaceutical vehicle, for both curative and preventive treatment of cancers.

14. Pharmaceutical compositions according to one of claims 10 to 13 characterized in that they contain, in addition, at least one second associated active principle, endowed with antidepressant properties, in particular,

MILNACIPRAN and / or a 5HTJA antagonist _. .