| Title of Invention | SUBSTITUTED 1-PIPERAZINYL ACYL PIPERIDINYL DERIVATIVE COMPOUNDS. |
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| Abstract | The present invention relates to 1-substituted 1-piperazinylacylpiperidine derivative of general formula (I), wherein: n is 1 or 2, p is 1 or 2; R1 represents a halogen atom, a trifluoromethyl radical, C1-C4 alkyl, a C1-C4 alkoxy, a trifluoromethoxy radical; R2 represents a hydrogen atom or a halogen atom; R3 represents a hydrogen atom, an -OR5 group, a -CH2OR5 group, a -NR6R7 group; a -NR8COR9 group; a -NR8CONR10R11 group; a -CH2NR12R13 group, a -CH2NR8CONR14R15 group; a C1-C4 alkoxycarbonyl; a -CONR16R17 group; or R3 forms a double bond between the carbon atom whereto it is bound and the neighbouring carbon atom of the piperidine cycle; R4 represents an aromatic group selected among (II), said aromatic groups being unsubstituted, monosubstituted or disubstituted by a substituent selected independently among a halogen atom, a C1-C4 alkyl, a C1-C4 alkoxy, a trifluoromethyl radical. The invention also concerns a method for preparing said compounds and their therapeutic use. |
| Full Text | " SUBSTITUTED 1 -PIPERAZINYLACYLPIPERIDINE DERIVATIVES; The present invention relates to substituted 1 -piperazinylacylpipendine derivatives, their preparation and their therapeutic application. The compounds according to the present invention exhibit affinity for the neurotropbin receptor p75NTR. Neurotrophins belong to a family of proteins which possess a similar structure and similar functions and include nerve growth factor (NGF), BDNF (Brain Derived Neurotrophic Factor), neurotrophin-3 (NT-3), neurotrophin-4/5 (NT-4/5) and neurotrophin-6 (NT-6). The biological effects of these proteins (survival and differentiation) are exerted through interaction with membrane receptors having tyrosine kinase activity (trk-A, trk-B and trk-C) (H. THOENEN, Science, 1995, 270, 593-598; G.R. LEWIN and Y.A. BARDE, Annu. Rev. Neurosci., 1996, 19, 289-317; M.V. CHAO, J., Neurobiol., 1994, 25, 1373-1385; M. BOTHWELL, Annu. Rev. Neurosci., 1995, 18, 223-253; G. DECHANT and Y.A. BARDE, Curr. Opin. Neurobiol., 1997, 7, 413-418). However, many studies show the preponderant role of the p75NTR receptor in the activity of neurotrophins. The p75NTR receptor, the receptor for all neurotrophins. is a transmembrane glycoprotein of the tumour necrosis factor (TNF) receptor family (WJ. FRIEDMAN and L.A. GREENE, Exp. Cell. Res., 1999, 253, 131-142; J. MELDOSIS et al., Trends Pharmacol. Sci., 2000, 21, 242-243). A number of biological functions are attributed to the p75NTR receptor: on the one hand, the modulation of the affinity of neurotrophins for trk receptors; on the other hand, in the absence of trk, induction of a signal for cell death by apoptosis which occurs through homodimerization of the receptor and activation of the ceramide pathway. Apoptosis, or programmed cell death, is a physiological mechanism for elimination of cells in numerous tissues. In particular, apoptosis plays a preponderant role in embryogenesis, morphogenesis and cell renewal. Apoptosis is a genetically controlled phenomenon which only occurs at an advanced and irreversible stage of cell lesion. Many studies show that apoptosis occurs in several pathologies of the central nervous system such as amyotrophic lateral sclerosis, multiple sclerosis, Alzheimer's, Parkinson's and Huntington's diseases and prion diseases. Furthermore, neuronal death through apoptosis also occurs very early after cerebral and cardiac ischaemia. 2 Cell death is also a preponderant phenomenon in atherosclerosis; indeed, the necrosis zones in primary atherosclerotic lesions in humans are evaluated at 80% (ML. BOCHATON-PIALAT et al., Am. J. Pathol., 1995, 146, 1-6; H. PERLMAN, Circulation, 1997, 95, 981-987). Apoptosis is also involved in mechanisms leading to cell death following cardiac ischaemia-reperfusion (H. YAOITA et al., Cardiovasc. Res., 2000,45, 630-641). Several studies show that the p75NTR-dependent pro-apoptotic signal is observed in various cell types including neuronal cells, oligodendrocytes, Schwann cells and also hepatic, cardiac and smooth muscle cells (J.M. FRADE et al,, Nature, 1996, 383, 166-168; P. LASACCIA-BONNEFIL et al., Nature, 1996, 383, 716-719; M. SOILU-HANNINEN et al., J. Neurosci., 1999, 19, 4828-4838; N. TRIM et al., Am. J. Pathol., 2000, 156, 1235-1243; S.Y. WANG et al., Am. J. Pathol., 2000, 157, 1247-1258). Moreover, a number of experiments carried out in vivo show an increase in the expression of p75NTR following ischaemia in regions of the brain and of the heart in which massive apoptosis is recorded. These results therefore suggest that p75NTR may play a preponderant role in the mechanisms leading to neuronal death through apoptosis post ischaemia (P.P. ROUX et al., J. Neurosci., 1999, 19, 6887-6896; J.A. PARK et al., J. Neurosci., 2000, 20, 9096-9103). The p75 receptor is described as a cellular target for the prion peptide (V. DELLA-BIANCA et al., J. Biol. Chem., 2001, in press) and for the p-amyloid peptide (S. RABIZADEH et al., Proc. Natl. Acad. Sci. USA, 1994, 91 10703-10706) and would thus be involved in apoptotic phenomena induced by these compounds. These results support the hypothesis according to which p75NTR would play an important role in neuronal death induced by the infectious prion protein (transmissible spongiform encephalopathy) or by the beta-amyloid protein (Alzheimer's disease). Recent studies suggest that the p75NTR receptor might also play an important role in axonal regeneration, via its function as co-receptor for the Nogo receptor (WONG et al., Nature Neurosci., 2002, 5, 1302-1308; Kerracher and Winton, Neuron, 2002, 36, 345-348). Indeed, several myelin-associated proteins (myelin-associated glycoprotein, MAG, Nogo-A and oligodendrocyte myelin glycoprotein OMgp) inhibit nerve regeneration at the central level during medullary or cranial trauma. These proteins are located in the membrane of the oligodendrocytes directly adjacent to the axon and inhibit neuritic growth by binding with a high affinity to the Nogo receptor located on the axonal membrane. The p75NTR receptor is associated with the Nogo receptor and is involved in the signalling of the inhibitory effects of these myelin proteins in relation to axonal growth. As a result, the p75NTR receptor plays a major 3 role in the regulation of neuronal plasticity and in neuron-glia interactions and represents a therapeutic target of choice for promoting nerve regeneration. At the peripheral level, recent studies show an increase in the expression of p75 and of neurotrophins and a massive apoptosis in atherosclerotic lesions. Furthermore, a pro-angiogenic and vasodilative effect of NGF is also recorded. Finally, a novel form of p75 which is truncated in the extracellular part has been identified as well as its major role in established vasculogenesis (D. VON SHACK et al., Nature Neuroscience, 2001, 4, 977-978). All these recent data suggest that p75NTR in its whole or truncated form could also play a preponderant role in vascular pathologies. A number of compounds are known to interact with the trkA/NGF/p75NTR system or to possess an NGF-type activity. Thus, patent application WO 00/59893 describes substituted pyrimidine derivatives which demonstrate an NGF-type activity and/or which increase the activity of NGF on PC 12 cells. Patent applications WO 00/69828 and WO 00/69829 describe polycyclic compounds which inhibit the binding of NGF to the p75 receptor in cells which do not express the trkA receptor. Application WO 94/11373 describes pyridazinoquinazolone derivatives which bind to the neurotrophin receptor p75NTR. Application WO 94/22866 describes pyrazoloquinazolone derivatives which specifically bind to NGF so as to avoid its attachment to the p75NTR receptor but allowing it to interact with the trk receptor. Application WO 01/49684 describes substituted tetrahydropyridine derivatives which possess activity vis-a-vis the modulation of TNF-alpha. New 1-piperazinylacylpiperidine derivatives have now been found which exhibit affinity for the receptor p75NTR. The present invention provides compounds of the formula (I): in which: - n is 1 or 2; - p is 1 or 2; - R1 represents a halogen atom; a trifluoromethyl radical; a (C1-C4)alkyl; a (C1-C4)alkoxy; a trifluoromethoxy radical; 4 R2 represents a hydrogen atom or a halogen atom; R3 represents a hydrogen atom; a group -OR5; a group -CH2OR5; a group -NR5R7; a group -NRgCOR9; a group -NR8CONR10R11; a group -CH2NR12R13; a group -CH2NR8CONR14R15; a (C1-C4)alkoxycarbonyl; a group -CONR16R17; or else R3 constitutes a double bond between the carbon atom to which it is attached and the adjacent carbon atom of the piperidine ring; R4 represents an aromatic group selected from: - the said aromatic groups being unsubstituted or being mono- or disubstituted by a substituent selected independently from a halogen atom; a (C1-C4)alkyl; a (C1-C4)alkoxy; a trifluoromethyl radical; R5 represents a hydrogen atom ; a (C1-C4)alkyl; a (C1-C4)alkylcarbonyl; - R5 and R7 represent each independently a hydrogen atom or a (C1-C4)alkyl; - Rg represents a hydrogen atom or a (C1-C4)alkyl; - R9 represents a (C1-C4)alkyl or a group -(CH2)m-NR6R7; - mis 1,2 or 3; R10 and R11 represent each independently a hydrogen atom or a (C1-C4)alkyl; - R12 and R13 represent each independently a hydrogen atom or a (C1-C5)alkyl; R13 may also represent a group -(CH2)q-OH or a group -(CH2)q-S-CH3- - or else R12 and R13, together with the nitrogen atom to which they are attached, constitute a heterocycle selected from aziridine, azetidine, pyrrolidine, piperidine and morpholine; q is 2 or 3; - R14 and R15 represent each independently a hydrogen atom or a (C1-C4)alkyl; - R16 and R17 represent each independently a hydrogen atom or a (C1-C4)alkyl; R17 may also represent a group -(CH2)q-NR6R7; - or else R16 and R17, together with the nitrogen atom to which they are attached, constitute a heterocycle selected from azetidine, pyrrolidine, piperidine, 5 morpholine and piperazine which is unsubstituted or substituted in position 4 by a (C1-C4)alkyl. The compounds of formula (I) may exist in the form of bases or addition salts with acids. Such addition salts form part of the invention. These salts are advantageously prepared with pharmaceutically acceptable acids, although the salts of other acids useful for the purification or isolation of compounds of formula (I) also form part of the invention. The compounds of formula (I) may also exist in the form of hydrates or solvates, specifically in the form of associations or combinations with one or more molecules of water or with a solvent. Such hydrates and solvates also form part of the invention. A halogen atom is an atom of bromine, chlorine, fluorine or iodine. (C1-C4)Alkyl or (C1-C5)alkyl respectively is a linear or branched alkyl radical of one to four carbon atoms or one to five carbon atoms, respectively, such as the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl or tert-pentyl radical. (C1-C4)Alcoxy is a linear or branched alkoxy radical of one to four carbon atoms, such as the methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy o tert-butoxy radical. Among the compounds of formula (I) provided by the invention mention may be made of the preferred compounds which are defined as follows: - R1 is in position 2, 3 or 4 of the phenyl and represents a trifluoromethyl radical, a chlorine atom, a methyl, a methoxy or a trifluoromethoxy radical and R2 represents a hydrogen atom; or else R1 is in position 3 of the phenyl and represents a trifluoromethyl radical and R2 is in position 4 of the phenyl and represents a chlorine atom; - and/or R3 represents a hydrogen atom, a hydroxyl, a methoxy, an (acetyloxy)methyl, a hydroxymethyl, a dimethylamino, an acetylamino, an aminomethyl, a (methylamino)methyl, a (dimethylamino)methyl, a (diethylamino)methyl, an (isopropyl amino)methyl, an (N-methyl- isopropylamino)methyl, an (isobutylamino)methyl; an (N-methyl- isobutylamino)methyl, an (isopentylamino)methyl, an (N-methylisopentylamino)methyl, an aminocarbonyl, an azetidin-1-ylcarbonyl; or else R3 constitutes a double bond between the carbon atom to which it is attached and the adjacent carbon atom of the piperidine ring; - and/or R4 represents a 2-pyridyl, a 6-methyl-2-pyridyl, a 3-(trifluoromethyI)- 2-pyridyl, a 5-(trifluoromethyl)-2-pyridyl, a 3-chloro-5-(trifluoromethyl)-2-pyridyl, 6 a 3-pyridyl, a 4-pyridyl, a 3,5-dichloro-4-pyridyl? a 2-pyrazinyl, a 5-chloro-2-pyrazinyl, a 6-chloro-2-pyrazinyl, a 2-pyrimidinyl, a 4-(trifluoromethyl)-2-pyrimidinyl, a 6-chloro-2-pyrimidinyl, a 4-pyrimidinyl, a 6-chloro-4-pyrimidinyl, a 5-pyrimidinyl, a 3-pyridazinyl, a 6-chloro-3-pyridazinyl, a 4-pyridazinyl, a 3(2H)-pyridazinone-5-yl or a 3(2H)-pyridazinone-4-yI. Particular preference is given to the compounds of formula (I) wherein: - n is 1 or 2; - p is 1 or 2; - Rj is in position 2, 3 or 4 of the phenyl and represents a trifluoromethyl radical, a chlorine atom, a methyl, a methoxy or a trifluoromethoxy radical and R.2 represents a hydrogen atom; or else K\ is in position 3 of the phenyl and represents a trifluoromethyl radical and R.2 is in position 4 of the phenyl and represents a chlorine atom; - R3 represents a hydrogen atom, a hydroxyl, a methoxy, an (acetyloxy)methyl, a hydroxymethyl, a dimethyl amino, an acetylamino, an aminomethyl, a (methylamino)m ethyl, a (dimethylamino)methyl, a (diethylamino)methyl, an (isopropylamino)methyl, an (N-methylisopropylamino)methyl; an (isobutylamino)methyl; an (N-methylisobutylamino)rnethyl, an (isopentylamino)methyl, an (N-methylisopentylamino)methyl, an aminocarbonyl, an azetidin-1-ylcarbonyl; or else R3 constitutes a double bond between the double bond between the carbon atom to which it is attached and the adjacent carbon atom of the piperidine ring; - R4 represents a 2-pyridyl, a 6-methyl-2-pyridyl, a 3-(trifluoromethyl)-2-pyridyl, a 5-(trifluoromethyl)-2-pyridyl, a 3-chloro-5-(trifluoromethyl)-2-pyridyl, a 3-pyridyl, a 4-pyridyl, a 3,5-dichloro-4-pyridyl, a 2-pyrazinyl, a 5-chloro~2-pyrazinyl, a 6-chloro-2-pyrazinyl, a 2-pyrimidinyl, a 4-(trifluoromethyl)-2-pyrimidinyl, a 6-chloro-2-pyrimidinyl, a 4-pyrimidinyl, a 6-chloro-4-pyrimidinyl, a 5-pyrimidinyl, a 3-pyridazinyl, a 6-chloro-3-pyridazinyl, a 4-pyridazinyl, a 3(2//)-pyridazinone-5- yl, a 3(2//)-pyridazinone-4-yl; in the form of a base or an addition salt with an acid, and also in the form of a hydrate or solvate. More preference is given to the compounds of formula (I) wherein : - n is 1 ; - p is 1 ; - K\ is in position 2, 3 or 4 of the phenyl and represents a trifluoromethyl radical, a chlorine atom, a methoxy or a trifluoromethoxy radical and R2 represents a 7 hydrogen atom; or else R1 is in position 3 of the phenyl and represents a trifluoromethyl radical and R2 is in position 4 of the phenyl and represents a chlorine atom; - R3 represents a hydroxyl, a dimethylamino, an aminomethyl, a (methylamino)methyl, a (dimethylamino)methyl, a (diethylamino)methyl, an (isopropylamino)methyl, an (isobutylamino)methyl, an (isopcntylamino)methyl, an (N-methylisopentylamino)methyl or an aminocarbonyl; or else R3 constitutes a double bond between the carbon atom to which it is attached and the adjacent carbon atom of the piperidine ring; - R4 represents a 2-pyrazinyl, a 4-pyrimidinyl, a 3(2//)-pyridazinone-5-yl or a 5-(trifluoromethyl)-2-pyridyl; in the form of a base or an addition salt with an acid, and in the form of a hydrate or solvate. Among the compounds of formula (I) provided by the invention particular mention may be made of the following compounds: - l-[4-(aminomethyl)-4-[3-(tritluoromethyl)phenyI]-l-piperidyl]-2-[4-(2-pyrazinyl)- 1 -piperazinyl] -1 -ethanone; - 5-[4-[2-[4-hydroxy-4-[3-(trifluoromethyl)phenyl]-l-piperidyl]-2-oxoethyl]- l-piperazinyl]-3(2//)-pyndazinone; 1 -[4~hydroxy-4-[2-(trifluoromethyl)phenyl]-1 -piperidyl]-2-[4-(2-pyrazinyl)-1 -piperazinyl]-1 -ethanone; - 2-[4-(4-pyrimidinyl)-l-piperazinyl]-l-[4-[3-(trifluoromethyl)phenyl]-3}6-dihydro- 1 (2#)-pyridyl]-l -ethanone; - 2-[4-(2-pyrazinyl)-1 -piperazinyl]-1 -[4-[2-(trifluoromethyl)phenyl]-3,6-dihydro- 1 (2//)-pyridyl] -1 -ethanone; l-[2-[4-(2-pyrazinyl)-l-piperazinyI]acetyl]-4-[3-(trifluoromethyl)phenyl]-4-piperidinecarboxamide; l-[4-(dimethylamino)-4-[3-(trifluoromethyl)phenyl]-l-piperidyl]-2-[4-(2-pyrazinyl)-l-piperazinyl]-l-ethanone; - l-[4-hydroxy-4-[3-(trifluoromethyl)phenyl]-l-piperidyl]-2-[4-(2-pyrazinyl)- l-piperazinyl]-l-ethanone; - l-[4-[(dimethylamino)methyl]-4-[3-(trifluoromethyl)phenyl]-l-piperidyl]- 2-[4-(2-pyrazinyl)-l-piperazinyI]-l-ethanone; - l-[4-(4-chlorophenyl)-3,6-dihydro-l(2//)-pyridyl]-2-[4-(2-pyrazinyl)- l-piperazinyl]-l-ethanone; 8 - 1 -[4-hydroxy-4-(3-methoxyphenyl)-1 -piperidyl]-2-[4-(2-pyrazinyl)- 1 -piperazinyl]-1 -ethanone; . l-[4-[4-chloro-3-(trifluoromethyl)phenyI]-3,6-dihydro-l(2//)-pyridyl]-2-[4-(2-pyrazinyl)-l-piperazinyI]-l-ethanone; - l-[4-[4-chloro-3-(trifluoromethy!)phenyl]-3,6-dihydro-l(2//)-p>Tidyl]- 2-[4-[5-(trifluoromethyl)-2-pyridyl] 1 -piperazinyl]-1 -ethanone; - l-[4-[(methylamino)methyl]-4-[3-(trifluoromethyl)phenyl]-l-piperidyl]- 2-[4-(2-pyrazinyl)-1 -piperazinyl]-1 -ethanone; l-[4-[(diethylamino)methyl]-4-[3-(trifluoromethyl)phenyI]-l-piperidyI]-2-[4-(2-pyrazinyl)-1 -piperazinyl]-1 -ethanone; l-[4-[(isopropylamino)methyl]-4-[3-(trifluoromethyl)phenyl]-l-piperidyI]-2-[4-(2-pyrazinyI)-l-piperazinyl]-l-ethanone; l-[4-[(isobutylamino)methyl]-4-[3-(trifluoromethyl)phenyl]-l-piperidyl]-2-[4-(2-pyrazinyl)-l-piperazinyl]-l-ethanone; l-[4-[(isopentylamino)methyl]-4-[3-(trifluoromethyl)phenyl]-l-piperidyl]-2-[4-(2-pyrazinyl)-l-piperazinyl]-l-ethanone; l-[4-[(N-methylisopentylamino)methyl]-4-[3-(trifluoromethyl)phenyl]-l-piperidyl]-2-[4-(2-pyrazinyl)-l-piperazinyl]-l-ethanone; l-[4-hydroxy-4-[3-(trifiuoromethoxy)phenyl]-l-piperidyl]-2-[4-(2-pyrazinyl)-1 -piperazinyl]-1 -ethanone; in the form of base or an addition salt of an acid, and in the form of a hydrate or solvate. In another of its aspects the present invention provides a process for preparing compounds of formula (I) in which n = 1, characterized in that: al) a compound of the formula in which R1, R2 and R3 are as defined for a compound of formula (I) and Hal represents a halogen atom, preferably chlorine or bromine, with the proviso that when R3 contains a hydroxyl or amine function these functions may be protected, is reacted with a compound of formula 9 in which p and R4 are as defined for a compound of formula (I); bl) and, after deprotection of the hydroxyl or amine functions present in R3 where appropriate, the compound of formula (I) is obtained. Where appropriate, the compound of formula (I) is converted into one of its addition salts with an acid. In another of its aspects the present invention provides a process for preparing compounds of formula (I) in which n = 2, characterized in that: a2) a compound of formula in which R1, R2 and R3 are as defined for a compound of formula (I), with the proviso that when R3 contains a hydroxyl or amine function these functions may be protected, is reacted with a compound of formula in which p and R4 are as defined for a compound of formula (I); b2) and, after deprotection of the hydroxyl or amine functions present in R3 where appropriate, the compound of formula (I) is obtained. Where appropriate, the compound of formula (I) is converted into one of its addition salts with an acid. In step al) or in step a2), when a compound of formula (IIa) or (IIb) is reacted with a compound of formula (III), the reaction is carried out in the presence of a base selected from organic bases such as triethylamine, N,N-diisopropylethylamine or N-methylmorpholine or from alkali metal carbonates or bicarbonates such as potassium carbonate, sodium carbonate or sodium bicarbonate and in the absence or presence of an alkali metal iodide such as potassium iodide or sodium iodide. The reaction is carried out in a solvent such as acetonitrile, N,N-dimethylformamide, toluene or propan-2-ol and at a temperature between the ambient temperature and the reflux temperature of the solvent. Where appropriate, in step bl) or in step b2), the hydroxyl or amine functions present in R3 are deprotected in accordance with the conventional methods well known to the person skilled in the art. 10 10 15 20 In one version of the process and when R3 represents a group -CH2NR12R-13 in which R12 and R13 each represent hydrogen in which R1, R2 and R3 are as defined for a compound of formula (I) and Hal represents a halogen atom, preferably chlorine or bromine, is reacted with a compound of formula in which p and R4 are as defined for a compound of formula (I), to give a compound of formula b3) the cyano group of the compound of formula (Ia) is reduced to give a compound of formula (I) in which R3 = CH2NH2. Where appropriate the compound of formula (I) is converted into one of its addition salts with an acid. In step a3) the reaction between the compound of formula (IIc) or (IId) and the compound of formula (III) is carried out as described above in step al) or a2) of the process according to the invention. In step b3) the reduction of the cyano group of the compound of formula (la) is carried out in accordance with conventional methods. Thus, for example, the reduction is carried out by hydrogenation in the presence of a catalyst such as Raney nickel or rhodium on alumina and in the presence or absence of ammonia in a solvent such as methanol, N,N-dimethylformamide or tetrahydrofuran or a mixture of these solvents and at a temperature between ambient temperature and 60°C. 10 15 20 25 In another version of the process and when R3 constitutes a double bond between the carbon atom to which it is attached and the adjacent carbon atom of the piperidine ring a compound of formula in which R1, R2, n, p and R4 are as defined for a compound of formula (I) is dehydrated to give a compound of formula Where appropriate the compound of formula (I) is converted into one of its addition salts with an acid. The dehydration is carried out using for example an acetic acid/hydrochloric acid mixture or an acetic acid/sulphuric acid mixture at a temperature between the ambient temperature and 140°C. The reaction can also be carried out using p-toluenesulphonic acid, in a solvent such as toluene and at a temperature between the ambient temperature and the reflux temperature. A compound of formula (I) in which R3 represents a group -CH2NR12R13 in which R12 - H and R13 = (C1-C5)alkyl may also be prepared by reacting a compound of formula (I) in which R3 = -CH2NH2 with a (C1-C5)alkyl halide in the presence of a base such as an alkali metal carbonate such as potassium carbonate in a solvent such as acetonitrile, N,N-dimethylformamide or tetrahydrofuran at a temperature between the ambient temperature and the reflux temperature of the solvent. An identical reaction is used to prepare the compounds of formula (I) in which R12 et R13 each represent the same or a different (Cj-C5)alkyl. A compound of formula (I) in which R3 represents a group -CH2NR12R13 in which R12 = H or (C1-C5)alkyl and R13 - (C1-C5)alkyl, a group -(CH2)q-OH or a group -(CH2)q-S-CH3 respectively may also be prepared by reacting a compound of formula (I) in which R3 = -CH2-NHR12 with formaldehyde or with an aldehyde of formula OHC-(C1-C4)alkyl, OHC-(CH2)q. 1 -OH or OHC-(CH2)q-1-S-CH3 respectively, or with a corresponding ketone, in the presence of a reducing agent such as sodium borohydride or sodium triacetoxyborohydride and in the presence of an 12 acid such as acetic acid in a solvent such as dichloromethane or tetrahydrofiiran at a temperature between 0°C and the ambient temperature. A compound of formula (I) in which R3 represents a group -CH2NR12R13 in which R12 et Rl3, together with the nitrogen atom to which they are attached, constitute aziridine may also be prepared by cyclizing a corresponding intermediate in which R3 represents a group -CH2NH-CH2CH2-CI in the presence of a base such as an alkali metal carbonate such as potassium carbonate and in the presence of an alkali metal iodide such as potassium iodide in a solvent such as acetonitrile and at a temperature between the ambient temperature and the reflux temperature of the solvent; the corresponding intermediate is prepared by reacting a compound of formula (I) in which R3 = -CH2NH2 with chloroacetaldehyde by the method described above. A compound of formula (I) in which R3 represents a group -CH2NR12R13 in which R12 and R13, together with the nitrogen atom to which they are attached, constitute azetidine, pyrrolidine, piperidine or morpholine, respectively, may also be prepared by reacting a compound of formula (I) in which R3 = -CH2NH2 with a compound of formula HaI-(CH2)3-Hal, Hal-(CH2)4-Hal, Hal-(CH2)s-Hal or Hal-CH2CH2-O-CH2CH2-Hal respectively, in which Hal represents a halogen atom, preferably chlorine or bromine, in the presence of a base such as an alkali metal carbonate such as potassium carbonate or in the presence of an alkali metal iodide such as potassium iodide in a solvent such as acetonitrile, ethylene glycol or a mixture of these solvents and at a temperature between the ambient temperature and the reflux temperature of the solvent. A compound of formula (I) in which R3 represents a group -CH2NRgCONRi4Rj5 in which Rg = R14 = R15 = H may also be prepared by reacting a compound of formula (I) in which R3 = -CH2NH2 with trimethylsilyl isocyanate in a solvent such as dichloromethane at a temperature between the ambient temperature and the reflux temperature of the solvent, followed by hydrolysis in an acidic medium. A compound of formula (I) in which R3 represents a group -CONR16R17 may also be prepared by reacting a corresponding intermediate in which R3 represents a carboxyl with a compound of formula HNR16R17 by conventional methods of peptide coupling; the corresponding intermediate is prepared by conventional methods by acid or base treatment of a compound of formula (I) in which R3 represents a (C|-C4)alkoxycarbonyl or by reacting a compound of formula (la) with a strong base such as an alkali metal hydroxide such as potassium hydroxide in a solvent such as 13 toluene or ethylene glycol at a temperature between the ambient temperature and the reflux temperature of the solvent. A compound of formula (I) in which R3 represents a group -NRgCOR.9 in which R9 = -(CH2)m-NR5R7 may also be prepared by reacting a corresponding intermediate in which R3 represents a group -NRgCO(CH2)m-Hal and Hal represents a halogen atom, preferably chlorine, with an excess of a compound of formula HNR6R7 in a solvent such as dichloromethane or ethanol at a temperature between the ambient temperature and the reflux temperature of the solvent; the corresponding intermediate is prepared by reacting a compound of formula (I) in which R3 = -NHRg with a compound of formula Hal-CO-(CH2)m-Hal in which Hal represents a halogen atom, preferably chlorine or bromine, in the presence of a base such as triethylamine or N,N-diisopropylethylamine in a solvent such as dichloromethane and at a temperature between 0°C and the ambient temperature. A compound of formula (I) in which R3 represents a group -CH2OR5 in which R5 represents a hydrogen atom may also be prepared by acid or base treatment of a compound of formula (I) in which R3 represents a group -CH2OR5 in which R5 represents a (Ci-C4)alkylcarbonyl. The compounds of formula (I) thus obtained may be subsequently separated from the reaction medium and purified by conventional methods, for example by crystallization or chromatography. The compounds of formula (I) thus obtained are isolated in the form of the free base or a salt, by conventional techniques. The compounds of formula (Ila) are prepared by reacting a piperidine derivative of formula in which R\, R2 and R3 are as defined for a compound of formula (I) with a compound of formula in which Hal and Hal' represent each independently a halogen atom, preferably chlorine or bromine. The reaction is carried out in the presence of a base such as triethylamine, N,N-diisopropylethylamine or N-methylmorpholine in a solvent such as 14 dichloromethane, chloroform, tetrahydrofuran, dioxane or a mixture of these solvents and at a temperature between 0°C and the ambient temperature. The compounds of formula (lib) are prepared by reacting the compound of formula (IV) with a compound of formula in which Hal and Hal' are as defined above under the operating conditions mentioned above. Similarly the compounds of formula (IIc) or (IId) respectively are prepared by reacting a compound of formula in which R1 and R-2 are as defined for a compound of formula (I) with a compound of formula (V) or (VI) respectively in accordance with the same operating conditions as above. The compounds of formula (V) or (VI) are available commercially, are known or are prepared by known methods. The compounds of formula (III) are available commercially or are prepared by known methods such as those described in J. Org. Chem., 1953, 18, 1484-1488, J. Med. Chem., 1978, 21 (6), 536-542, Chem. Pharm. Bull., 1991, 39 (9), 2288-2300, Tetrahedron Letters, 1998, 39, 617-620 or in WO 97/28129. For example, a compound of formula (III) is prepared by reacting a compound of formula in which p is as defined for a compound of formula (I) and W represents hydrogen or an N-protective group with a compound of formula Hal-R4 (VIII) in which R4 is as defined for a compound of formula (I) and Hal represents a halogen atom, preferably chlorine, bromine or iodine. 15 The reaction is carried out i]n the presence or absence of a base, in an inert solvent such as ethanol, propan-2-ol, n-butanol, acetonitrile or toluene at a temperature between 0°C and the reflux temperature of the solvent. When a base is used it is selected from organic bases such as diisopropylethylamine or from alkali metal carbonates such as sodium or potassium carbonate. In the absence of a base the reaction is carried out using an excess of the compound of formula (VII). The reaction may also be carried out without solvent, by heating the mixture of compounds (VII) and (VIII) at temperatures of the order of from 140°C to 180°C. Where appropriate, when W represents an N-protective group, it is eliminated by conventional methods to give the expected compounds of formula (III). The compounds of formula (VII) or of formula (VIII) are known or are prepared by known methods. The compounds of formula (IV) are available commercially, are known or are prepared by known methods such as those described in EP-0 474 561, EP-0 673 928 or WO 96/23787. The compounds of formula (IV) are generally prepared in a form in which they are protected on the nitrogen atom of the piperidine; after a step of deprotection the compounds of formula (IV) themselves are obtained. In particular a compound of formula (IV) in which R3 represents a group -OR5 in which R5 = H is prepared by reacting an organomagnesium derivative of formula in which R1 and R2 are as defined for a compound of formula (I) and Hal represents a halogen atom, preferably bromine, with l-benzyl-4-piperidinone in a solvent such as diethyl ether or tetrahydrofuran at a temperature between the ambient temperature and reflux temperature of the solvent. The organomagnesium derivatives of formula (IX) are prepared by conventional methods well known to the person skilled in the art from the corresponding halogenated derivatives. From compounds of formula (IV) in which R3 = -OH the compounds of formula (IV) in which R3 = -OR5 in which R5 represents a (C1-C4)alkyl or a (C1-C4)alkylcarbonyl, respectively, are prepared by an alkylation or acylation reaction, respectively, by methods which are known to the person skilled in the art. 16 The compounds of formula (IV) in which R3 - -OH and which carry a protective group on the nitrogen atom of the piperidine may undergo a Ritter reaction by the action of acetonitrile in an acidic medium in order to prepare the compounds of formula (IV) in which R3 = -NHCOCH3 by the method described in EP-0 474 561. Hydrolysis in a strong acidic medium is then used to prepare the compounds of formula (IV) in which R3 = -NR5R7 in which R5 = R7 = H. The methods described in EP-0 673 928 or WO 96/23787 are used to prepare the compounds of formula (IV) in which R3 = -NR5R7 in which R6 and/or R7 represents a (C1-C4)alkyl. The compounds of formula (IV) in which R3 = -NRgCORo in which R9 is a (C1-C4)alkyl, or else R3 = -NRgCONR10Rl 1, or else R3 = -CH2NR12R13 in which R12 and R13 represent each independently a hydrogen or a (C1-C4)alkyl, or else R3 = -CH2NR.gCONR.14R15, or else R3 - (C1-C4)alkoxycarbonyl, or else R3 = -CONR16R17 are prepared by the methods described in WO 96/23787. A compound of formula (IV) in which R3 = -CH2NR12R13 in which R12 = R13 = H is prepared from the compound of formula (IVa) by the method described above for a compound of formula (I). A compound of formula (IV) in which R3 = -NRgCORo in which R9 = -(CH2)mNR6R7 is prepared by the method described above for a compound of formula (I). A compound of formula (IV) in which R3 = -CH2NR12R13 in which R12 = H or (C1-C5)alkyl and R13 = (C1-C5)alkyl, a group -(CH2)q-OH or a group -(CH2)n-S-CH3 is prepared by the method described above for a compound of formula (I). A compound of formula (IV) in which R3 = -CH2NR12R13 "n which R12 = H and R13 = -CH3 may also be prepared by reducing a corresponding intermediate in which R3 = -CH2NHCHO using a reducing agent such as lithium aluminium hydride in a solvent such as ether or tetrahydroruran at a temperature between the ambient temperature and the reflux temperature of the solvent. The corresponding intermediate is prepared by reacting a compound of formula (IV) in which R3 = -CH2NH2 with ethyl formate at a temperature between the ambient temperature and 60°C A compound of formula (IV) in which R3 = -CH2NR12R13 in which R12 and Rl3, together with the nitrogen atom to which they are attached, constitute aziridine, azetidine, pyrrolidine, piperidine or morpholine is prepared by the methods described above for a compound of formula (I). A compound of formula (IV) in which R3 = -CONRjgR^ in which Rjg = K\j -H may also be prepared by reacting a compound of formula (IVa), protected on the 17 nitrogen atom of the piperidine, with hydrogen peroxide in the presence of a strong base such as an alkali metal hydroxide such as sodium hydroxide and a phase transfer catalyst such as a substituted quaternary ammonium salt, triethylammonium chloride for example, in a solvent such as toluene in a mixture with water, at a temperature between the ambient temperature and the reflux temperature of the solvent. The compounds of formula (IVa) are prepared by known methods such as those described in Bioorg. Med. Chem. Lett., 1999, 9, 3273-3276 and in J. Med. Chem., 1999,42 (23), 4778-4793. From compounds of formula (IV) in which R3 = -CH2OH the compounds of formula (IV) in which R3 = -CH2OR5 in which R5 represents a (Cj-C^alkyl or a (Cj-C4)alkylcarbonyl, respectively, are prepared by an alkylation or acylation reaction, respectively, by the methods known to the person skilled in the art. The compounds of formula (IV) in which R3 - -CH2OR5 in which R5 represents a hydrogen atom are prepared by reducing a compound of formula (IV) in which R3 represents a methoxycarbonyl by methods known to the person skilled in the art. The compounds of formula (IV) in which R3 represents a (C1 -C4)alkoxycarbonyl are prepared by esterification reaction of a corresponding intermediate in which R3 represents a carboxyl by methods known to the person skilled in the art; the corresponding intermediate is prepared by reacting a compound of formula (Via) with a strong base such as an alkali metal hydroxide such as potassium hydroxide, in a solvent such as toluene or ethylene glycol at a temperature between the ambient temperature and the reflux temperature of the solvent. During any of the steps of preparing the compounds of formula (I), or of the intermediates of formula (la), (Ila), (lib), (He), (lid), (III) or (IV), it may be necessary and/or desirable to protect the sensitive or reactive functional groups, such as the amine, hydroxyl or carboxyl groups, which are present on any of the molecules concerned. This protection may be carried out using the conventional protective groups, such as those described in Protective Groups in Organic Chemistry, J.F.W. McOmie, Ed., Plenum Press, 1973, in Protective Groups in Organic Synthesis, T.W. Greene and P.G.M. Wuts, Ed., John Wiley & Sons, 1991 or in Protecting Groups, Kocienski P.J., 1994, Georg Thieme Verlag. The protective groups can be eliminated in an appropriate subsequent step, using the methods which are known to the person skilled in the art and which are not to the detriment of the rest of the molecule in question. The N-protective groups used where appropriate are conventional N-protective groups which are well known to the person skilled in the art, such as, for example, the 18 tert-butoxycarbonyl, fluorenylmethoxycarbonyl, benzyl, benzhydrylidene or benzyloxycarbonyl group. The invention, in another of its aspects, further provides the compounds of formula (la). These compounds are useful as synthesis intermediates for the compounds of formula (I). Accordingly, in another of its aspects, the invention provides compounds of formula in which - n is 1 or 2; - p is 1 or 2; - R1 represents a halogen atom; a trifluoromethyl radical; a (C1-C4)alkyl; a (C1-C4)alkoxy; a trifluoromethoxy radical; - R2 represents a hydrogen atom or a halogen atom; - R4 represents an aromatic group selected from the said aromatic groups being unsubstituted or mono- or disubstiruted by a substituent selected independently from a halogen atom, a (C1-C4)alkyl, a (C1-C4)alkoxy, a trifluoromethyl radical; in the form of a base or an addition salt with an acid, and in the form of a hydrate or solvate. The following examples describe the preparation of certain compounds in accordance with the invention. These examples are not limitative and merely illustrate the present invention. The numbers of the compounds exemplified refer to those given in Table I below, which illustrates the chemical structures and the physical properties of some compounds according to the invention. 19 In the preparations and in the examples the following abbreviations are used: ether: diethyl ether iso ether: diisopropyl ether DMSO: dimethyl sulphoxide DMF: N,N-dimethylformamide THF: tetrahydrofuran DCM: dichloromethane AcOEt: ethyl acetate DIPEA: diisopropyl ethyl amine TFA: trifluoroacetic acid BOP: benzotriazol-l-yloxytris(dimethylamino)phosphonium hexafluorophosphate PyBOP: benzotriazol-l-yloxytripyrrolidinophosphonium hexafluorophosphate 2N hydrochloric ether: 2N solution of hydrochloric acid in diethyl ether m.p.: melting point AT: ambient temperature b.p.: boiling temperature HPLC: high performance liquid chromatography Silica H: Silica gel 60 H sold by Merck (Darmstadt) Buffer solution pH = 2: solution of 16.66 g of KHSO4 and 32.32 g of K2SO4 in one litre of water. The proton magnetic resonance (1H NMR) spectra are recorded at 200 MHz in DMSO-d^, using the DMSO-d6 peak as reference. The chemical shifts 5 are expressed in parts per million (ppm). The signals observed are expressed as follows: s: singlet; bs: broad singlet; d: doublet; sd: split doublet; t: triplet; st: split triplet; q; quadruplet; unres. comp.: unresolved complex; mt: multiple!. The NMR spectra confirm the structures of the compounds. The compounds according to the invention are analysed by LC/UV/MS (liquid chromatography/UV detection/mass spectrometry) coupling. For the compounds a check is made that their mass spectra as obtained in the positive electrospray mode (ESI+) are compatible with the calculated molar mass. The mass spectra of the compounds according to the invention generally have as their base peak the molecular ion MH+. PREPARATIONS 1. Preparations of compounds of formulae (IV) and (IVa) Preparation 1.1 20 4-[3-(Trifluoromethyl)phenyl]-4-piperidinolhydrochloride. (IV), HC1: Rj = 3-CF3; R2 = H; R3 = -OH. A) l-Benzyl-4-[3-(trifluoromethyl)phenyl]-4-piperidinolhydrochIoride. A mixture of 180 g of magnesium in 2670 ml of THF is heated to 30°C and admixed with 33 ml of a solution of 1670 g of l-bromo-3-(trifluoromethyl)benzene in 1330 ml of THF and then, slowly, with the remainder of the solution so as to bring about and subsequently maintain reflux of the THF, and is left at reflux with stirring for 2 hours. Subsequently a solution of 1000 g of l-benzyl-4-piperidinone in 3200 ml of THF is added slowly and the mixture is heated at reflux for 2 hours. After cooling to AT, the reaction mixture is introduced over 30 minutes into a solution of 1870 g of ammonium chloride in 6700 ml of water and the mixture is left with stirring at 20-25°C for 2 hours. After decanting, the organic phase is washed with 5330 ml of water and the solvent is evaporated under vacuum. The residue is taken up in 5330 ml of ether, a solution of 210 g of HC1 gas in 800 ml of propan-2-ol is added slowly, the temperature being kept below 25°C, the mixture is left with stirring for 40 minutes and the crystals formed are isolated with suction. The crystals are taken up in 2000 ml of ether and again isolated with suction. 1080 g of the expected product are obtained following recrystallization from a propan-2-ol/EtOH (70/30; v/v) mixture. B) 4-[3-(Trifluoromethyl)phenyl]-4-piperidinol hydrochloride. A mixture of 1000 g of the compound obtained in the preceding step and 83 g of 10% palladium on carbon (50% moisture content) in 2910 ml of EtOH and 2910 ml of MeOH is hydrogenated at 50°C under a pressure of 2 bars. The catalyst is filtered off and washed twice with 660 ml of MeOH and the filtrate and washings are concentrated under vacuum. The residue is taken up in 3320 ml of ether and is left with stirring at AT for 1 hour 30 minutes. The precipitate formed is isolated with suction, washed with 280 ml of ether and dried under vacuum at 40°C. This gives 726 g of the expected product. Preparation 1.2 4-Methoxy-4-[3-(trifluoromethyI)phenyl]piperidine. (IV): R! = 3-CF3; R2 = H; R3 = -OCH3. A) ?err-Butyl4-hydroxy-4-[3-(trifluoromethyl)phenyl]-l-piperidinecarboxylate. 20 g of the compound obtained in Preparation 1.1 in 80 ml of DCM is admixed at AT with 17.92 g of triethylamine and then, dropwise, with a solution of 16.3 g of di-tert-butyl dicarbonate in 20 ml of DCM and the mixture is left with stirring at AT for 18 hours. Water is added to the reaction mixture, which is then extracted with DCM, the organic phase is washed with water and a 5% KHSO4 solution and dried over 21 Na2SO4 and the solvent is evaporated under vacuum. This gives 13 g of the expected product following recrystallization from an iso ether/hexane mixture. B) /e/";-Butyl4-methoxy-4-[3-(trifluoromethyl)phenyl]-l-piperidinecarboxylate. A solution of 2 g of the compound obtained in the preceding step in 15 ml of DMF and 20 ml of THF is admixed, in portions and at AT, with 0.277 g of sodium hydride at a concentration of 60% in oil and the mixture is left with stirring for 40 minutes. Subsequently 1.3 g of methyl iodide are added and the mixture is left with stirring for 2 hours. The reaction mixture is concentrated under vacuum, the residue is taken up with water and extracted with AcOEt, the organic phase is washed with water and dried over Na2SO4 and the solvent is evaporated under vacuum. This gives 2 g of the expected product in the form of a yellow oil. C) 4-Methoxy-4-[3-(trifluoromethyl)phenyl]piperidine. A mixture of 2 g of the compound obtained in the preceding step and 5 ml of TFA in 15 ml of DCM is left with stirring at AT for 1 hour. The reaction mixture is concentrated under vacuum, the residue is extracted with DCM, the organic phase is washed with a 5% Na2CO3 solution and dried over Na2SO4 and the solvent is evaporated under vacuum. This gives 1.7 g of the expected product in the form of an orange-coloured oil. Preparation 1.3 N,N-Dimethyl-4-[3-(trifluoromethyl)phenyl]-4-piperidineamine. (IV): R1 = 3-CF3; R2 = H; R3 - -N(CH3)2. A) l-Benzyl-4-[3-(trifluoromethyl)phenyl]-4-piperidinol. An icebath is used to cool a solution of 20 g of the compound obtained in Preparation 1.1 (free base) and 11.3 ml of triethylamine in 200 ml of DCM, 11 ml of benzyl bromide are added dropwise and the mixture is left with stirring at AT overnight. It is concentrated under vacuum, the residue is taken up in saturated K2CO3 solution and extracted with AcOEt, the organic phase is washed with saturated K2CO3 solution and with saturated NaCl solution and dried over Na2SO4 and the solvent is evaporated under vacuum. The oily residue is taken up in pentane and the precipitate formed is isolated with suction. This gives 17 g of the expected product. B) N-[l-Benzyl-4-[3-(trifluoromethyl)phenyl]-4-piperidyl]acetamide. An icebath is used to cool 60 ml of concentrated H2SO4, a solution of 16 g of the compound obtained in the preceding step in 120 ml of acetonitrile is added dropwise, during which the temperature of the reaction medium is kept below 30°C and the mixture is left with stirring overnight, during which the temperature is allowed to 22 return to AT. The reaction mixture is poured onto ice and rendered alkaline by addition of concentrated NaOH solution and the precipitate formed is isolated with suction. The precipitate is dissolved in DCM, the organic phase is washed with water and dried over Na2SO4 and the solvent is evaporated under vacuum. This gives 9.7 g of the expected product following recrystallization from acetonitrile. C) l-Benzyl-4-[3-(trifluoromethyl)phenyl]-4-piperidineamine. A mixture of 9.6 g of the compound obtained in the preceding step, 250 ml of concentrated HC1 solution and 250 ml of water is heated at 150°C overnight. Half of the reaction mixture is concentrated under vacuum, the resulting acidic aqueous phase is rendered alkaline by addition of concentrated NaOH solution and extracted with DCM, the organic phase is dried over Na2SO4 and the solvent is evaporated under vacuum. This gives 8.1 g of the expected product, which is used as it is. D) l-Benzyl-N,N-dimethyl-4-[3-(trifluoromethyl)phenyl]-4-piperidineamine. A mixture of 8.1 g of the compound obtained in the preceding step, 3.5 ml of a 37% solution of formaldehyde in water and 10 ml of acetic acid in 250 ml of THF is admixed in portions and at AT with 50 g of sodium triacetoxyborohydride and the mixture is left with stirring at AT overnight. 200 ml of MeOH are added and the reaction mixture is heated at 70°C for 1 hour and concentrated under vacuum. The residue is taken up with IN NaOH solution and extracted with DCM, the organic phase is washed with water and dried over Na2SO4 and the solvent is evaporated under vacuum. This gives 8.7 g of the expected product in the form of an oil which solidifies. E) N,N-Dimethyl-4-[3-(trifluoromethyl)phenyl]-4-piperidineamine. A mixture of 8.2 g of the compound obtained in the preceding step, 5 g of ammonium formate and 2 g of 10% palladium on carbon in 100 ml of MeOH is left with stirring at AT for 1 hour. The catalyst is filtered off and the filtrate is concentrated under vacuum. The residue is taken up with saturated K2CO3 solution and extracted with AcOEt, the organic phase is dried over Na2SO4 and the solvent is evaporated under vacuum. This gives 4.8 g of the expected product. Preparation 1.4 4-[3-(Trifluoromethyl)phenyl]-4-piperidinecarbonitrilehydrochloride. (IVa), HC1: R] = 3-CF3; R2 - H. A) 2-(2,2-Diethoxyethyl)-4,4-diethoxy-2-[3-(trifluoromethyl)phenyl]butanenitrile. A mixture of 30 g of 3-trifluoromethyl)phenylacetonitrile and 14.4 g of sodium amide in 400 ml of toluene is left with stirring at AT for 5 minutes, 66 ml of bromoacetaldehyde diethyl acetal are added and the mixture is then heated at 60°C for 23 3 hours. It is concentrated under vacuum, the residue is taken up in water and extracted with ether, the organic phase is dried over Na2SO4 and the solvent is evaporated under vacuum. The residue is chromatographed on silica gel H, eluting with a DCM/AcOEt (100/5; v/v) mixture. This gives 26 g of the expected product. B) 4-Oxo-2-(2-oxoethyl)-2-[3-(trifluoromethyI)phenyl]butanenitrile. A mixture of 23.9 g of the compound obtained in the preceding step in 90 ml of formic acid is left with stirring at 50°C for 1 hour. Water is added to the reaction mixture, which is then extracted with AcOEt, the organic phase is washed with water and with 10% NaHCO3 solution and dried over Na2SO4 and the solvent is evaporated under vacuum. This gives 16 g of the expected product, which is used immediately in the following step. C) l-BenzyM-[3-CtrifluoromethylJphenyll^-piperidinecarbonitrilehydrochloride. A mixture of 16 g of the compound obtained in the preceding step, 6.25 ml of benzylamine, 48.6 g of sodium triacetoxyborohydride and 5 drops of acetic acid in 150 ml of DCM is left with stirring at AT overnight. Subsequently 40 ml of MeOH are added dropwise and the mixture is then heated at 60°C for 1 hour. The reaction mixture is concentrated under vacuum, the residue is extracted with AcOEt, the organic phase is washed with 10% NaHCO3 solution and with water and dried over Na2SO4 and the solvent is evaporated under vacuum. The residue is taken up in a saturated solution of HC1 gas in ether and the precipitate formed is isolated with suction. This gives 18 g of the expected product. D) 4-[3-(Trifluoromethyl)phenyl]-4-piperidinecarbonitrilehydrochloride. A mixture of 2 g of the compound obtained in the preceding step and 0.2 g of 10% palladium on carbon in 30 ml of MeOH is hydrogenated at AT at atmospheric pressure for 3 hours. The catalyst is filtered off on Celite® and the filtrate is concentrated under vacuum. This gives 1.5 g of the expected product. This compound can also be prepared by following the three steps below: A1) tert-Butyl bis(2-chloroethyl)carbamate. A mixture of 106 g of N,N-bis(2-chloroethyl)amine hydrochloride and 130 g of di-terf-butyl dicarbonate in 1 500 ml of DCM is admixed dropwise over 1 hour 30 minutes at AT with 83 ml of triethylamine, then left with stirring at AT overnight. The reaction mixture is washed with water and the organic phase is dried over Na2SO4 and evaporated under vacuum. This gives 150 g of the expected product, which is used as it is. 24 B') terf-Butyl 4-cyano-4-[3-(trifluoromethyl)phenyl]-l-piperidine carboxylate. A suspension of 56 g of sodium hydride at a concentration of 60% in oil in 750 ml of DMSO and 250 ml of THF is admixed dropwise under an inert atmosphere and at AT with a solution of 120 g of 3-(trifluoromethyl)phenylacetonitrile in 250 ml of DMSO and then, slowly with a solution of 150 g of the compound obtained in the preceding step in 250 ml of DMSO and heated at 60°C overnight. The reaction mixture is poured into an ice/H2O mixture and extracted with ether, the organic phase is washed with water and with saturated NaCl solution and dried over Na2SO4 and the solvent is evaporated under vacuum. The residue is chromatographed on silica gel, eluting with DCM and then with a DCM/AcOEt (80/20; v/v) mixture. This gives 191 g of the expected product, which crystallizes; m.p. = 72-73°C. C) 4-[3-(Trifluoromethyl)phenyl]-4-piperidinecarbonitrilehydrochIoride. A mixture of 115 g of the compound obtained in the preceding step, 500 ml of a 2N solution of HC1 in ether and 150 ml of MeOH is left with stirring at AT for 4 hours. The crystalline product formed is isolated with suction and dried. This gives 75 g of the expected product, m.p. = 259°C. Preparation 1.5 tert-Butyl [4-[3-(trifluoromethyl)phenyl]-4-piperidyl]methylcarbamate. (IV): R1 = 3-CF3; R2 = H; R3 = -CH2NH-COOC(CH3)3. A) [l-Benzyl-4-[3-(trifluoromethyl)phenyl]-4-piperidyl]methylamine. A mixture of 1.5 g of the compound obtained in step C of preparation 1.4, 0.15 g of Raney® nickel and 5 ml of aqueous ammonia in 20 ml of MeOH is hydrogenated at AT under atmospheric pressure overnight. The catalyst is filtered off and the filtrate is concentrated under vacuum. This gives 1.45 g of the expected product. B) tert-Buty\ [ 1 -benzyl-4-[3-(trifluoromethyl)phenyl]-4-piperidyl]methylcarbamate. A mixture of 1.45 g of the compound obtained in the preceding step and 20 ml of AcOEt is heated to 40°C, 0.9 g of d\-tert-buty\ dicarbonate is added and the mixture is then heated at reflux for 30 minutes. After cooling to AT it is admixed with water and extracted with AcOEt, the organic phase is dried over Na2SO4 and the solvent is evaporated under vacuum. This gives 1.86 g of the expected product. C) tert-Buty\ [4-[3-(trifluoromethyl)phenyl]-4-piperidyl]methylcarbamate. A mixture of 1.8 g of the compound obtained in the preceding step and 0.18 g of 10% palladium on carbon in 20 ml of MeOH is hydrogenated at AT at atmospheric pressure overnight. The catalyst is filtered off and the filtrate is concentrated under vacuum. This gives 1.3 g of the expected product in the form of an oil. 25 Preparation 1.6 4-[3-(Trifluoromethyl)phenyl]-4-piperidinecarboxamide. (IV): R1 = 3-CF3; R2 - H; R3 = -CONH2. A) l-Benzyl-4-[3-(trifluoromethyl)phenyl]-4-piperidinecarboxamide. A mixture of 5 g of the compound obtained in step C of preparation 1.4, 30 ml of toluene, 30 ml of 30% H2O2 solution, 30 ml of 30% NaOH solution and 0.5 g of aliquot 336 (trioctylmethylammonium chloride) is heated at 100°C for 48 hours. It is concentrated under vacuum, the residue is taken up in water and extracted with DCM, the organic phase is dried over Na2SC>4 and the solvent is evaporated under vacuum. The residue is chromatographed on silica gel H, eluting with a DCM/MeOH (100/3; v/v) mixture. This gives 2.5 g of the expected product. B) 4-[3-(Trifluoromethyl)phenyl]-4-piperidinecarboxamide. A mixture of 2.5 g of the compound obtained in the preceding step and 0.25 g of 10% palladium on carbon in 30 ml of MeOH is hydrogenated at AT under atmospheric pressure for 48 hours. The catalyst is filtered off and the filtrate is concentrated under vacuum. This gives 1.7 g of the expected product. Preparation 1.7 4-[2-(Trifluoromethyl)phenyl]-4-piperidinol. (IV): Rj = 2-CF3; R2 = H; R3 = -OH. A) l-Benzyl-4-[2-(trifluoromethyl)phenyI]-4~piperidinol. A mixture of 1.52 g of magnesium in 25 ml of THF is admixed dropwise over 20 minutes with a solution of 14.25 g of l-brorno-2-(trifluoromethyl)benzene in 15 ml of THF and the mixture is heated at reflux for 30 minutes. After it has cooled on an ice bath, it is admixed slowly with a solution of 10 g of 1-benzyl-4-piperidinone in 30 ml of THF and left with stirring at AT for 3 hours. The reaction mixture is poured into saturated aqueous ammonium chloride solution and extracted with AcOEt, the combined organic phases are washed with water and dried over Na2SO4 and the solvents are evaporated under vacuum. The residue is chromatographed on silica gel, eluting with a DCM/AcOEt (70/30; v/v) mixture. This gives 4.5 g of the expected product. B) 4-[2-(TrifluoromethyI)phenyl]-4-piperidinoI. A mixture of 4.5 g of the compound obtained in the preceding step and 0.5 g of 10% palladium on carbon in 100 ml of MeOH is hydrogenated at 35°C under atmospheric pressure overnight. The catalyst is filtered off and the filtrate is concentrated under vacuum. This gives 2.7 g of the expected product following recrystallization from iso ether. 26 Preparation 1.8 4-[2-(trifluoromethyl)phenyl]-4-piperidinecarbonitrilehydrochloride. (IVa), HC1: R1 = 2-CF3; R2 = H. A) tert-Buty\ 4-cyano-4-[2-(trifluoromethyl)phenylj-1 -piperidinecarboxylate. A suspension of 9 g of sodium hydride at a concentration of 60% in oil in 125 ml of DMSO and 125 ml of THF is admixed dropwise and at AT with a solution of 20 g of 2-(trifluoromethyl)phenylacetonitrile in 50 ml of DMSO and then, slowly, with a solution of 25 g of the compound obtained in step A' of preparation 1.4 in 70 ml of DMSO and the mixture is heated at 60°C for 24 hours. The reaction mixture is poured into 2 litres of water and extracted with ether, the organic phase is washed with water and dried over Na2SO4 and the solvent is evaporated under vacuum. The residue is chromatographed on silica gel, eluting with DCM and then with a DCM/AcOEt (70/30; v/v) mixture. This gives 16 g of the expected product. B) 4-[2-(TrifluoromethyI)phenyl]-4-piperidinecarbonitrilehydrochloride. A mixture of 6 g of the compound obtained in the preceding step, 150 ml of 2N hydrochloric ether and 20 ml of MeOH is left with stirring at AT for 2 hours. It is concentrated under vacuum, the residue is taken up in ether and the precipitate formed is isolated with suction. This gives 2.3 g of the expected product. Preparation 1.9 Methyl 4-[3-(trifluoromethyl)phenyl]-4-piperidinecarboxylatehydrochloride. (IV), HC1: Ri = 3-CF3; R2 = H; R3 = -COOCH3. A) l-Benzyl-4-[3-(trifluoromethyl)phenyl]-4-piperidinecarboxylicacid. A mixture of 5 g of the compound obtained in step C of preparation 1.4 and 4.25 g of KOH pellets in 80 ml of ethylene glycol is heated at reflux for 3 hours. It is cooled to AT and admixed with 100 ml of water, acidified to pH = 6.5 by addition of 10% HC1 solution, and the precipitate formed is isolated with suction and dried under vacuum. This gives 3.9 g of the expected product, m.p. = 243°C. B) Methyl l-benzyl-4-[3-(trifluoromethyl)phenyl]-4-piperidinecarboxylate hydro- chloride. A mixture of 3 g of the compound obtained in the preceding step and 50 ml of thionyl chloride in 100 ml of DCM is heated at 60°C for 3 hours. It is concentrated under vacuum and the residue is taken up in 100 ml of MeOH and heated at 60°C overnight. Concentration under vacuum gives 4 g of the expected product, m.p. = 230°C. C) Methyl 4-[3-(trifluoromethyI)phenyl]-4-piperidinecarboxylate hydrochloride. 27 A mixture of 4 g of the compound obtained in the preceding step and 0.4 g of 10% palladium on carbon in 200 ml of MeOH is hydrogenated at AT under atmospheric pressure overnight. The catalyst is filtered off and the filtrate is concentrated under vacuum. This gives 2.5 g of the expected product. Preparation 1.10 [4-[3-(TrifluoromethyI)phenyl]-4-piperidyl]methyl acetate. (IV): R1 = 3-CF3; R2 - H; R3 = -CH2-O-CO-CH3. A) l-(tert-Butyl)-4-methyl 4-[3-(trifluoromethyl)phenyl]-l,4-piperidinedicarboxylate. A mixture of 7 g of the compound obtained in preparation 1.9, 5.33 g of di-tert- butyldicarbonate and 3.5 ml of triethylamine in 100 ml of DCM is left with stirring at AT for 2 hours. It is concentrated under vacuum, the residue is taken up in water and extracted with ether, the organic phase is washed with water and dried over Na2SC>4 and the solvent is evaporated under vacuum. This gives 9.3 g of the expected product. B) tert-Butyl 4-(hydroxymethyl)-4-[3-(trifluoromethyl)phenyl]-1 -piperidine- carboxylate. A mixture of 9.27 g of the compound obtained in the preceding step in 150 ml of ether is cooled to 0°C, 1 g of lithium aluminium hydride is added and the mixture is left with stirring at 0°C for 4 hours. The reaction mixture is admixed with saturated NH4CI solution, the mineral salts are filtered off, the filtrate is extracted with AcOEt, the organic phase is dried over Na2SC>4 and the solvent is evaporated under vacuum. This gives 5.5 g of the expected product following recrystallization from ether. C) tert-Butyl 4-[(acetyIoxy)methyl]-4-[3-(trifluoromethyl)phenyl]-l-piperidine- carboxylate. A mixture of 5.5 g of the compound obtained in the preceding step and 2 ml of triethylamine in 50 ml of DCM is cooled to -70°C, 1.1 ml of acetyl chloride are added and the mixture is left with stirring overnight, during which the temperature is allowed to return to AT. Ice is added to the reaction mixture, which is then extracted with DCM, the organic phase is dried over Na2SO4 and the solvent is evaporated under vacuum. This gives 6 g of the expected product. D) [4-[3-(Trifluoromethyl)phenyl]-4-piperidyl]methyl acetate. A mixture of 6 g of the compound obtained in the preceding step and 30 ml of TFA in 50 ml of DCM is left with stirring at AT for 1 hour. It is concentrated under vacuum, the residue is taken up with ice and then with 10% NaHCO3 solution and extracted with DCM, the organic phase is dried over Na2SO4 and the solvent is evaporated under vacuum. This gives 4.5 g of the expected product. Preparation 1.11 28 4-[4-(Trifluoromethyl)phenyI]-4-piperidmol. (IV): R1 - 4-CF3; R2 = H; R3 - -OH. A) l-Benzyl-4-[4-(trifluoromethyl)phenyl]-4-piperidinol. This compound is prepared by the procedure described in step A of preparation 1.7, from 1.55 g of magnesium in 25 ml of THF, a solution of 14.25 g of 1-bromo-4-(trifluoromethyl)benzene in 15 ml of THF and a solution of 10 g of 1-benzyl-4-piperidinone in 30 ml of THF. This gives 7.3 g of the expected product. B) 4-[4-(Trifluoromethyl)phenyl]-4-piperidinoI. A mixture of 4.8 g of the compound obtained in the preceding step and 2 g of 10% palladium on carbon in 50 ml of MeOH is hydrogenated at 30°C under atmospheric pressure for 2 hours. The catalyst is filtered off and the filtrate is concentrated under vacuum. This gives 2.4 g of the expected product following recrystallization from iso ether. Preparation 1.12 4-(4-Chlorophenyl)-4-piperidinecarbonitrilehydrochloride. (IVa),HCl:R1=4-Cl;R2 = H. A) tert-Butyl 4-(4-chlorophenyl)-4-cyano-1 -piperidinecarboxylate. A suspension of 4.4 g of sodium hydride at a concentration of 60% in oil in 300 ml of THF is admixed rapidly at AT with 7.51 g of 4-chlorophenyIacetonitrile and then with 12 g of tert-butyl bis(2-chloroethyl)carbamate, heated at 40°C for 28 hours and then left with stirring at AT overnight. Saturated ammonium chloride solution is added to the reaction mixture, which is then concentrated under vacuum to remove the THF, after which the aqueous phase which remains is extracted with ether, the organic phase is washed with a buffer solution pH = 2 and with saturated NaCl solution and dried over Na2SO4 and the solvent is evaporated under vacuum. This gives 12 g of the expected product, which is used as it is. B) 4-(4-Chlorophenyl)-4-piperidinecarbonitrile hydrochloride. A mixture of 18 g of the compound obtained in the preceding step in 100 ml of MeOH and 20 ml of concentrated HC1 solution is heated at 40-50°C for 3 hours. The reaction mixture is concentrated under vacuum, the residue is taken up twice in MeOH and each time the solvent is evaporated under vacuum. This gives 5.85 g of the expected product following recrystallization from acetone. Preparation 1.13 4-(3-Methylphenyl)-4-piperidinol. (IV): R1 = 3-CH3; R2 = H; R3 = -OH. A) l-Benzyl-4-(3-methylphenyl)-4-piperidinol. 29 This compound is prepared by the procedure described in step A of preparation 1.7, from 1.55 g of magnesium in 25 ml of THF, a solution of 11 g of 3-bromotoluene in 15 ml of THF and a solution of 10 g of 1 -benzyl-4-piperidone in 30 ml of THF. The product obtained is chromatographed on silica gel, eluting with a DCM/MeOH (97/3; v/v) mixture. This gives 14.5 g of the expected product. B) 4-(3-Methylphenyl)-4-piperidinol. A mixture of 14.5 g of the compound obtained in the preceding step and 2 g of 10% palladium on carbon in 500 ml of MeOH is hydrogenated at 25°C under atmospheric pressure for 48 hours. The catalyst is filtered off and the filtrate is concentrated under vacuum. This gives 8.9 g of the expected product. Preparation 1.14 4-(3-Methoxyphenyl)-4-piperidinoI. (IV): R! - 3-OCH3; R2 = H; R3 = -OH. A) 1 -Benzyl-4-(3-methoxyphenyl)-4-piperidinol. This compound is prepared by the procedure described in step A of preparation 1.7, from 1.55 g of magnesium in 25 ml of THF, a solution of 12 g of 3-bromoanisole and 15 ml of THF and a solution of 10 g of 1-benzyl-4-piperidone in 30 ml of THF. The product obtained is chromatographed on silica gel, eluting with a DCM/MeOH (97/3 to 95/5; v/v) mixture. This gives 13.7 g of the expected product. B) 4-(3-Methoxyphenyl)-4-piperidinol. A mixture of 13.7 g of the compound obtained in the preceding step and 2 g of 10% palladium on carbon in 500 ml of EtOH is hydrogenated at 25°C under atmospheric pressure for 48 hours. The catalyst is filtered off and the filtrate is concentrated under vacuum. This gives 10.8 g of the expected product. Preparation 1.15 N-[4-[4-Chloro-3-(trifluoromethyl)phenyl]-4-piperidyl3acetamidehydrochloride. (IV), HC1: Ri = 3-CF3; R2 = 4-C1; R3 - -NHCOCH3. A) l-Benzyl-4-[4-chloro-3-(trifluoromethyl)phenyl]-4-piperidinoI. A mixture of 15 g of 4-[4-chloro-3-(trifluoromethyl)phenyl]-4-piperidinol, 8.3 g of K2CO3 and 7.18 ml of benzyl bromide in 80 ml of DMF is left with stirring at AT for 2 days. The reaction mixture is poured into water and extracted with AcOEt, an insoluble product is filtered off, the organic phase is washed with water and with saturated NaCl solution and dried over Na2SO4 and the solvent is evaporated under vacuum. The residue is chromatographed on silica gel, eluting with a DCM/MeOH (95/5; v/v) mixture. This gives 14.6 g of the expected product. B) N-[l-Benzyl-4-[4-chloro-3-(trifluoromethyl)phenyl]-4-piperidyl]acetamide. 30 An ice bath is used to cool 30 ml of concentrated H2SO4, a solution of 7.98 g of the compound obtained in the preceding step in 60 ml of acetonitrile is added dropwise at a temperature of less than 15°C and the mixture is left with stirring at 15°C for 2 days. The reaction mixture is poured onto ice, rendered alkaline by addition of NaOH pellets and extracted with AcOEt, the organic phase is dried over Na2SC>4 and the solvent is evaporated under vacuum to give an impure solid (7.86 g). The residue is chromatographed on silica gel, eluting with a DCM/MeOH (97/3 to 95/5; v/v) mixture. This gives 4.26 g of the expected product following recrystallization from a DCM/iso ether mixture; m.p. = 198-199°C. C) N-[4-[4-Chloro-3-(trifluoromethyl)phenyI]-4-piperidyl3acetamidehydrochloride. A mixture of 3.1 g of the compound obtained in the preceding step, and 1.05 g of K2CO3 in 25 ml of DCM is left with stirring at AT for 15 minutes, then cooled with an ice bath, admixed dropwise with a solution of 1.2 ml of 1 -chloroethyl chloroformate in 5 ml of DCM and left with stirring at 4°C for 2 hours. An insoluble product is filtered off, the filtrate is concentrated under vacuum, the residue is taken up in MeOH and the solvent is evaporated under vacuum. The residue is taken up with 80 ml of MeOH and heated at reflux for 15 minutes and the solvent is evaporated under vacuum. This gives 2.7 g of the expected product. D) tert-Butyl 4-(acetylamino)-4-[4-chloro-3 -(trifluoromethyl)phenyl]-1 -piperidine- carboxylate. A mixture of 2.7 g of the compound obtained in the preceding step, 1.9 ml of DIPEA and 1.64 g of di-tert-buty\ dicarbonate in 20 ml of DCM is left with stirring at AT for 2 hours. The mixture is concentrated under vacuum and the residue is chromatographed on silica gel, eluting with a DCM/MeOH (98/2; v/v) mixture. This gives 1.4 g of the expected product. E) N-[4-[4-chloro-3-(trifluoromethyI)phenyl]-4-piperidyl]acetamidehydrochloride. A suspension of 1.4 g of the compound obtained in the preceding step in 20 ml of dioxane is admixed with 4 ml of 2N hydrochloric ether solution and left with stirring at AT for 2 hours. The reaction mixture is concentrated under vacuum to give the expected product, which is used as it is. Preparation 1.16 4-[3-(Trifluoromethoxy)phenyl]-4-piperidinolhydrochloride. (IV), HC1: Ri - 3-OCF3; R2 = H; R3 = -OH. A) l-Benzyl-4-[3-(trifluoromethoxy)phenyl]-4-piperidinolhydrochloride. This compound is prepared by the procedure described in step A of preparation 1.7, from 2g of magnesium in 25 ml of THF, a solution of 20 g of 1-bromo- 31 3-(trifluoromethoxy)benzene in 15 ml of THF and a solution of 13 g of 1-benzyl-4-piperidone in 30 ml of THF. The hydrochloride of the product obtained is formed in 2N hydrochloric ether solution. This gives 24.4 g of the expected product. B) 4-[3-(trifluoromethoxy)phenyl]-4-piperidinol hydrochloride. A mixture of 24 g of the compound obtained in the preceding step, 16 g of ammonium formate and 2 g of 10% palladium on carbon in 500 ml of MeOH is left with stirring at AT for 4 hours. The catalyst is filtered off and the filtrate is concentrated under vacuum. The residue is taken up with saturated K2CO3 solution and extracted with ether, the organic phase is washed with saturated NaCl solution and dried over Na2SC>4 and the solvent is evaporated under vacuum. The residue is taken up with 2N hydrochloric ether solution and the precipitate formed is isolated with suction. This gives 6.2 g of the expected product, m.p. = 145-146°C. Preparation 1.17 teT-r-Butylmethyl [[4-[3-(trifluoromethyl)phenyl]piperidin-4-yl]methyl]carbamate. (IV): Rj = 3-CF3; R2 = H; R3 = -CH2N(CH3)-COOC(CH3)3 A) N,N-Bis(2-chloroethyl)benzylamine. An ice bath is used to cool a mixture of 150 g of N,N-bis(2-chloroethyl)amine hydrochloride and 100 ml of benzyl bromide in 1 000 ml of DMF and then 120 ml of triethylamine are added dropwise and the mixture is left with stirring at AT overnight. The reaction mixture is concentrated under vacuum, the residue is taken up in water and extracted 3 times with ether, the organic phases are dried over Na2SC>4 and the solvent is evaporated under vacuum. This gives 113 g of the expected product. B) l-Benzyl-4-[3-(trifluoromethyl)phenyl]-4-piperidinecarbonitrile hydrochloride. A suspension of 23.24 g of sodium hydride at a concentration of 60% in oil in 100 ml of DMSO and 100 ml of THF is admixed dropwise under an inert atmosphere and at AT with a solution of 50 g of 3-(trifluoromethyl)phenylacetonitrile in 150 ml of DMSO and the mixture is left with stirring for 15 minutes. A solution of 62.43 g of the compound obtained in the preceding step in 150 ml of DMSO is subsequently added over 1 hour and the mixture is left with stirring at AT overnight. An ice/water mixture is added, the system is extracted with ether, the organic phase is dried over Na2SO4 and the solvent is evaporated under vacuum. The residue is taken up in 1 000 ml of hot EtOH, the system is left with stirring at AT for 48 hours and the crystalline product formed is isolated with suction. This gives 50 g of the expected product. C) [ 1 -Benzyl-4-[3-(trifluoromethyl)phenyl]-4-piperidyl]methylamine. 32 30 g of the compound obtained in the preceding step are dissolved in 10% NaOH solution and extracted with ether, the organic phase is dried over Na2SO4 and the solvent is evaporated under vacuum. The product, in the form of the free base, is taken up in 500 ml of MeOH and 30 ml of 20% aqueous ammonia solution, 3 g of Raney® nickel are added and the system is hydrogenated at AT under atmospheric pressure overnight. The catalyst is filtered off and the filtrate is concentrated under vacuum. The residue is taken up in water and extracted with AcOEt, the organic phase is dried over Na2SO4 and the solvent is evaporated under vacuum. This gives 27 g of the expected product. D) [[l-Benzyl-4-[3-(trifluoromethyl)phenyl3-4-piperidyI]methyI]formamide. A mixture of 27 g of the compound obtained in the preceding step and 300 ml of ethyl formate is left with stirring at AT overnight, then heated at 60°C for 6 hours and left with stirring at AT for 48 hours. It is concentrated under vacuum, the residue is taken up with 10% HC1 solution, the acidic aqueous phase is washed with ether, ice is added and the mixture is rendered alkaline by addition of 10% NaOH solution and extracted with ether, the organic phase is dried over Na2SO4 and the solvent is evaporated under vacuum. The residue is chromatographed on silica gel H, eluting with DCM and then with a DCM/MeOH (100/4; v/v) mixture. This gives 20 g of the expected product. E) [[l-Benzyl-4-[3-(trifluoromethyl)phenyl]-4-piperidyl]methyl]methylamine. A suspension of 4 g of lithium aluminium hydride in 400 ml of ether is admixed at AT with 20 g of the compound obtained in the preceding step and then left with stirring at AT for 16 hours. Subsequently, in succession, 3 ml of water, 3 ml of 30% NaOH and 1 ml of water are added and the mixture is left with stirring. The mineral salts are filtered off on Celite, the filtrate is decanted, the organic phase is dried over Na2SO4 and the solvent is evaporated under vacuum. This gives 18 g of the expected product. F) tert-Butyl [[l-benzyl-4-[3-(trifluoromethyl)phenyl]-4-piperidyl]methyl]methyl- carbamate. A mixture of 18 g of the compound obtained in the preceding step and 9.6 g of di'tert-butyl dicarbonate in 300 ml of DCM is left with stirring at AT for 1 hour. Water is added to the reaction mixture, which is then extracted with DCM, the organic phase is dried over Na2SO4 and the solvent is evaporated under vacuum. The residue is chromatographed on silica gel H, eluting with a DCM/MeOH (100/2; v/v) mixture. This gives 21 g of the expected product. G) tert-Butylmethyl[4-[3-(trifluoromethyl)phenyl]piperidin-4-yl]methyl]carbamate. 33 A mixture of 21 g of the compound obtained in the preceding step in 2 g of 10% palladium on carbon in 300 ml of MeOH is hydrogenated at AT under atmospheric pressure for 12 hours. The catalyst is filtered off and the filtrate is concentrated under vacuum. This gives 16 g of the expected product. Preparation 1.18 4-(3-Chlorophenyl)-4-piperidinecarbonitrilehydrochloride. (IVa),HCl:R]=3-Cl;R2=H. A) tert-ButyI-4-(3-chlorophenyl)-4-cyanopiperidine-l-carboxylate. A suspension of 15.8 g of sodium hydride of a concentration of 60% in oil in 400 ml of DMSO is admixed dropwise at AT under an inert atmosphere with a solution of 30 g of 3-chlorophenylacetonitrile in 200 ml of THF and then with a solution of 45.5 g of tert-butyl bis(2-chloroethyl)carbamate in 200 ml of DMSO and is heated at 60°C overnight. The reaction mixture is poured into an ice/water mixture and extracted with ether, the organic phase is washed with water and dried over Na2SO4 and the solvent is evaporated under vacuum. The residue is chromatographed on silica gel, eluting with DCM. This gives 33 g of the expected product. B) 4-(3-Chlorophenyl)-4-piperidinecarbonitrilehydrochloride. A mixture of 6.7 g of the compound obtained in the preceding step, 100 ml of 2N hydrochloric ether solution and 20 ml of MeOH is left with stirring at AT for 3 hours. It is concentrated under vacuum, the residue is taken up in ether and the precipitate formed is isolated with suction. This gives 4.65 g of the expected product, m.p. = 198°C. Preparation 1.19 4-(3 -methoxyphenyl)-4-piperidinecarbonitrile hydrochloride. (IVa), HC1: R1 = 3-OCH3; R2 =H. A) tert-Buty\ 4-(3-methoxyphenyl)-4-cyanopiperidine-l-carboxylate. This compound is prepared by the procedure described in step A of preparation 1.8, from 16.3 g of sodium hydride at a concentration of 60% in oil in 400 ml of DMSO, 30 g of 3-methoxyphenylacetonitrile in 150 ml of THF and 47 g of tert-butyl bis(2-chloroethyl)carbamate in 100 ml of DMSO. This gives 54 g of the expected product. B) 4-(3-Methoxyphenyl)-4"piperidinecarbonitriIe hydrochloride. A mixture of 48 g of the compound obtained in the preceding step, 300 ml of 2N hydrochloric ether solution and 50 ml of MeOH is left with stirring at AT for 2 hours. The precipitate formed is isolated with suction to give 30.5 g of the expected product, m.p. = 172°C. 34 Preparation 1.20 4-(Azetidin-1 -ylcarbonyl)-4-[3-(trifluoromethyl)phenyl]piperidine. A) 4-(Chloroformyl)-4-[3-(trifluoromethyI)phenyl]piperidinehydrochloride. A mixture of 1 g of the compound obtained in step A of preparation 1.9 and 10 ml of thionyl chloride in 10 ml of DCM is heated at 60°C for 2 hours. It is concentrated under vacuum to give 1.05 g of the expected product, which is used as it is. B) 4-(Azetidin-l-yIcarbonyl)-l-benzyl-4-[3-(trifluoromethyl)phenyl]piperidine. A mixture of 1.05 g of the compound obtained in the preceding step, 0.283 g of azetidine and 1.15 ml of triethylamine in 10 ml of DCM is left with stirring at AT overnight. Saturated K2CO3 solution is added to the reaction mixture, which is then extracted with DCM, the extract is dried over Na2SO4 and the solvent is evaporated under vacuum. The residue is chromatographed on silica gel, eluting with a DCM/MeOH (97/3; v/v) mixture. This gives 0.43 g of the expected product. C) 4-(Azetidin-1 -ylcarbonyl)-4-[3-(trifluoromethyl)phenyl]piperidine. A mixture of 0.43 g of the compound obtained in the preceding step, 1 g of 10% palladium on carbon and 20 ml of MeOH is hydrogenated at 25°C under atmospheric pressure overnight. The catalyst is filtered off and the filtrate is concentrated under vacuum. This gives 0.33 g of the expected product, which is used as it is. 2. Preparations of compounds of formula (II) Preparation 2.1 2-Chloro-1 -[4-[3-(trifluoromethyI)phenyl]-1 -piperidyl]-1 -ethanone. (Ha): Ri = 3-CF3; R2 = H; R3 = H; Hal = Cl. An ice bath is used to cool a mixture of 2.5 g of 4-[3-(trifluoromethyl)-phenyljpiperidine and 4 ml of triethylamine in 30 ml of DCM, which is then admixed dropwise with 0.85 ml of 2-chloroacetyl chloride and left with stirring for 3 hours, during which the temperature is allowed to return to AT. It is concentrated under vacuum, the residue is taken up with aqueous IN HC1 solution and extracted with AcOEt, the organic phase is washed with saturated NaCl solution and dried over Na2SO4 and the solvent is evaporated under vacuum. This gives 3.1 g of the expected product, which is used as it is. Preparation 2.2 2-Chloro-1 -[4-hydroxy-4-[3-(trifluoromethyl)phenyl]-1 -piperidyl]-1 -ethanone. (Ha): Ri = 3-CF3; R2 = H; R3 = -OH; Hal = Cl. 35 A mixture of 5 g of the compound obtained in preparation 1.1 and 10 ml of DIPEA in 40 ml of DCM is admixed dropwise and at AT with 1.63 ml of 2-chloroacetyl chloride and left with stirring for 30 minutes. The reaction mixture is washed with water, the organic phase is dried over Na2SO4 and the solvent is evaporated under vacuum. The residue is chromatographed on silica gel, eluting with a DCM/MeOH (97/3; v/v) mixture. This gives 5.5 g of the expected product, which is used as it is. Preparation 2.3 l-[4-Hydroxy-4-[3-(trifluoromethyl)phenyl]-l-piperidyl]-2-propen-l-one. (lib): R\ " 3-CF3; R2 == H; R3 = -OH. An ice bath is used to cool a mixture of 5 g of the compound obtained in preparation 1.1 and 8 ml of triethylamine in 50 ml of DCM which is then admixed dropwise with 2.07 ml of 3-bromopropionyl chloride and left with stirring for 2 hours, during which the temperature is allowed to return to AT. The reaction mixture is washed with saturated K2CO3 solution and with water, the organic phase is dried over Na2SC>4 and the solvent is evaporated under vacuum. The residue is chromatographed on silica gel, eluting with a DCM/MeOH (98.5/1.5 to 97/3; v/v) mixture. This gives 4.6 g of the expected product, which is used as it is. Preparation 2.4 2-Chloro-l-[4-methoxy-4-[3-(trifluoromethyl)phenyl]-l-piperidyI]-l-ethanone. (Ha): R! = 3-CF3; R2 = H; R3 = -OCH3; Hal = Cl. A mixture of 1 g of the compound obtained in preparation 1.2 and 1.4 ml of triethylamine in 20 ml of DCM is admixed dropwise and at AT with 0.3 ml of 2-chloroacetyl chloride and left with stirring at AT for 3 hours. It is concentrated under vacuum, the residue is taken up with aqueous IN HC1 solution and extracted with AcOEt, the organic phase is washed with NaCl solution and dried over Na2SO4 and the solvent is evaporated under vacuum. This gives 1.2 g of the expected product, which is used as it is. Preparation 2.5 2-Chloro-l-[4-(dimethylamino)-4-[3-(trifluoromethyl)phenyI]-l-piperidyl]-1-ethanone. (Ha): Ri = 3-CF3; R2 = H; R3 = -N(CH3)2; Hal - Cl. An ice bath is used to cool a mixture of 1 g of the compound obtained in preparation 1.3 and 1 ml of triethylamine in 20 ml of DCM which is then admixed dropwise with 0.35 ml of 2-chloroacetyl chloride and left with stirring, during which the temperature is allowed to return to AT. It is concentrated under vacuum, the residue is extracted with AcOEt, the organic phase is washed with saturated K2CO3 solution and dried over Na2SO4 and the mixture is evaporated under vacuum. This gives 1.4 g of the expected product, which is used as it is. Preparation 2.6 l-(2~Chloroacetyl)-4-[3-(trifluoromethyl)phenyl]-4-piperidinecarbomtrile. (IIc): R1 = 3-CF3; R2 - H; Hal = Cl. A mixture of 4.8 g of the compound obtained in preparation 1.4, free base, and 2.7 ml of triethylamine in 50 ml of DCM is admixed dropwise and at AT with 1.5 ml of 2-chloroacetyl chloride and is left with stirring at AT for 1 hour. 10% HCI solution is added to the reaction mixture, which is then decanted, the organic phase is washed with 10% NaOH solution and dried over Na2SO4 and the solvent is evaporated under vacuum. This gives 3.42 g of the expected product following recrystallization from ether; m.p. = 120°C. Preparation 2.7 tert-Butyl [l-(2-chloroacetyl)-4-[3-(trifluoromethyl)phenyl]-4-piperidyl]methyl-carbamate. (IIa): R1 = 3-CF3; R2 = H; R3 - -CH2NHCOOC(CH3)3, Hal - Cl. An ice bath is used to cool a mixture of 4.95 g of the compound obtained in preparation 1.5 and 6.8 ml of triethylamine in 50 ml of DCM which is then admixed dropwise with 1.65 ml of 2-chloroacetyl chloride and left with stirring, during which the temperature is allowed to return to AT. It is concentrated under vacuum, the residue is taken up with saturated K2CO3 solution and extracted with AcOEt, the organic phase is washed with saturated K2CO3 solution, with buffer solution pH = 2 and with saturated NaCI solution and dried over Na2SO4 and the mixture is evaporated under vacuum. The residue is chromatographed on silica gel, eluting with DCM/AcOEt (80/20; v/v) mixture. This gives 1.8 g of the expected product, which is used as it is. Preparation 2.8 l-(2-ChIoroacetyl)-4-[3-(trifluoromethyl)phenyI]-4-piperidinecarboxamide. (Ila): Rj = 3-CF3; R2 = H; R3 = -CONH2; Hal = Cl. A mixture of 0.7 g of the compound obtained in preparation 1.6 and 0.37 ml of triethylamine in 10 ml of DCM and 10 ml of dioxane is admixed dropwise and at AT with 0.21 ml of 2-chloroacetyl chloride and is left with stirring at AT for 2 hours. It is concentrated under vacuum, the residue is taken up in water, and the precipitate formed is isolated with suction and dried. This gives 0.82 g of the expected product, m.p.= l95-198°C. 37 Preparation 2.9 2-Chloro-l-[4-hydroxy-4-[2-(trifluoromethyI)phenyl]-l-piperidyl]-l-ethanone. 01a): R1 = 2-CF3; R2 = H; R3 - -OH; Hal = Cl. An ice bath is used to cool a mixture of 1.8 g of the compound obtained in preparation 1.7 and 1 ml of triethylamine in 20 ml of DCM which is then admixed dropwise with 0.65 ml of 2-chloroacetyl chloride and left with stirring for 1 hour, during which the temperature is allowed to return to AT. Water is added to the reaction mixture, which is concentrated under vacuum to remove the DCM and subjected to extraction with AcOEt, the organic phase is washed with water and with saturated NaCI solution and dried over Na2SO4 and the solvent is evaporated under vacuum. This gives 1.8 g of the expected product, which is used as it is. Preparation 2.10 l-(2-Chloroacetyl)-4-[2-(trifluoromethyl)phenyl]-4-piperidinecarbonitrile. (IIc): R] = 2-CF3; R2 - H; Hal = Cl. A mixture of 2.1 g of the compound obtained in preparation 1.8 and 2 ml of triethylamine in 20 ml of DCM is admixed at AT with 0.6 ml of 2-chloroacetyl chloride and left with stirring for 30 minutes. It is concentrated under vacuum, and the residue is taken up with 10% HC1 solution and extracted with AcOEt, the organic phase is washed with water, with saturated K2CO3 solution and with saturated NaCI solution and dried over Na2SO4 and the solvent is evaporated under vacuum. This gives 2.3 g of the expected product. Preparation 2.11 [l-(2-Chloroacetyl)-4-[3-(trifluoromethyl)phenyl]-4-piperidyl]methyl acetate. (Ila): KX = 3-CF3; R2 = H; R3 - -CH2OCOCH3; Hal = Cl. A mixture of 1 g of the compound obtained in preparation 1.10 and 0.46 ml of triethylamine in 20 ml of DCM is cooled to 0°C, 0.27 ml of 2-chloroacetyl chloride is added and the mixture is left with stirring at 0°C for 30 minutes. Water is added to the reaction mixture, which is extracted with DCM, the organic phase is dried over Na2SO4 and the solvent is evaporated under vacuum. This gives 0.9 g of the expected product. Preparation 2.12 2-Chloro- l-[4-hydroxy-4-[4-(trifluoromethyl)phenyl]-1 -piperidyl)-1 -ethanone. (Ila): Ri = 4-CF3; R2 - H; R3 = -OH; Hal = Cl. An ice bath is used to cool a mixture of 1.2 g of the compound obtained in preparation 1.11 and 1.2 ml of triethylamine in 20 ml of DCM which is then admixed dropwise with 0.38 ml of 2-chloroacetyl chloride and left with stirring for 1 hour, 38 during which the temperature is allowed to return to AT. Water is added to the reaction mixture, which is extracted with DCM, the organic phase is dried over Na2SO4 and the solvent is evaporated under vacuum. This gives 1.36 g of the expected product, which is used as it is. Preparation 2.13 2-Chloro-1 -[4-(4-chlorophenyl)-4-hydroxy-1 -piperidyl]-l -ethanone. (Ila): R{ = 4-C1; R2 - H; R3 = -OH; Hal - Cl. This compound is prepared by the procedure described in preparation 2.12, from 4-(4-chlorophenyl)-4-piperidinol (available commercially) and 2-chloroacetyl chloride. Preparation 2.14 l-(2-Chloroacetyl)-4-(4-chIorophenyl)-4-piperidinecarbonitrile. (He): Ri = 4-C1; R2 = H; Hal = Cl. This compound is prepared by the procedure described in preparation 2.1, from the compound obtained in preparation 1.12 and 2-chloroacetyl chloride. Preparation 2.15 2-Chloro-l-[4-hydroxy-4-(3-methylphenyI)-l-piperidyl]-l-ethanone. (Ila): Ki - 3-CH3; R2 = H; R3 = -OH; Hal = Cl. This compound is prepared by the procedure described in preparation 2.1, from the compound obtained in preparation 1.13 and 2-chloroacetyl chloride. Preparation 2.16 2-Chloro-1 -[4-hydroxy-4-(3-methoxyphenyl)-1 -piperidyl]-l -ethanone. (Ila): R] = 3-OCH3; R2 = H; R3 = -OH; Hal = Cl. This compound is prepared by the procedure described in preparation 2.1, from the compound obtained in preparation 1.14 and 2-chloroacetyl chloride. Preparation 2.17 2-Chloro-1 -[4-[4-chloro-3-(trifluoromethyl)phenyl}-4-hydroxy-1 -piperidyl]-1-ethanone. (Ila): Rj = 3-CF3; R2 = 4-C1; R3 = -OH; Hal = Cl. This compound is prepared by the procedure described in preparation 2.1, from 4-[4-chloro-3-(trifluoromethyl)phenyl]-4-piperidinol and 2-chloroacetyl chloride. Preparation 2.18 N-[l-(2-Chloroacetyl)-4-[4-chloro-3-(trifluoromethyl)phenyl]-4-piperidyl]-acetamide. (Ua): R\ = 3-CF3; R2 = 4-C1; R3 = -NHCOCH3; Hal = Cl. 39 This compound is prepared by the procedure described in preparation 2.2, from the compound obtained in preparation 1.15 and 2-chloroacetyl chloride. Preparation 2.19 2-Chloro-l-[4-hydroxy-4-f3-(trifiuoromethoxy)phenyl]-l-piperidyI]-l-ethanone. (Ha): R\ = 3-OCF3; R2 = H; R3 = -OH; Hal = Cl. This compound is prepared by the procedure described in preparation 2.1, from the compound obtained in preparation 1.16 and 2-chtoroacetyl chloride. Preparation 2.20 tert-Butyl [[l-(2-chloroacetyl)-4-[3-(trifluoromethyl)phenyI]-4-piperidyl]methyl]-methylcarbamate. (Ha): Rt - 3-CF3; R2 = H; R3 = -CH2N(CH3)COOC(CH3)3; Hal = Cl. A solution of 14 g of the compound obtained in preparation 1.17 and 5.5 ml of triethylamine in 300 ml of DCM is cooled to -40°C, 3.1 ml of 2-chloroacetyl chloride are added slowly and the mixture is left with stirring, during which the temperature is allowed to return to AT. It is concentrated under vacuum, the residue is taken up in water and extracted with AcOEt, the organic phase is washed with buffer pH = 2 and water and dried over Na2SC>4 and the solvent is evaporated under vacuum. This gives 15.33 g of the expected product. Preparation 2.21 l-(2-ChIoroacetyl)-4-(3-chlorophenyl)-4-piperidinecarbonitrile. (lie): Ri = 3-C1; R2 = H; Hal = Cl. This compound is prepared by the procedure described in preparation 2.1, from the compound obtained in preparation 1.18 and 2-chloroacetyl chloride. Preparation 2.22 l-(2-Chloroacetyl)-4-(3-methoxyphenyl)-4-piperidinecarbonitrile. (He): Ri - 3-OCH3; R2 = H; Hal = Cl. This compound is prepared by the procedure described in preparation 2.1, from the compound obtained in preparation 1.19 and 2-chloroacetyl chloride. Preparation 2.23 4-(Azetidin-l-ylcarbonyl)-l-(2-chloroacetyl)-4-[3-(trifluoromethyl)phenyl]-piperidine. This compound is prepared by the procedure described in preparation 2.1, from the compound obtained in preparation 1.20 and 2-chloroacetyl chloride. 40 3. Preparations of compounds of formula (III). Preparation 3.1 A mixture of 3 g of piperazine, 1.04 ml of 2-chIoropyrazine and 1.85 g of K2CO3 in 100 ml of EtOH is heated at reflux for 48 hours. The reaction mixture is concentrated under vacuum, the residue is taken up in water, the system is rendered alkaline to pH = 10 by addition of 10% NaOH and subjected to extraction with chloroform, the organic phase is washed with water and dried over Na2SO4 and the solvent is evaporated under vacuum. This gives 1.8 g of the expected product following recrystallization from hexane. Preparation 3.2 This compound is prepared by the procedure described in Tetrahedron Letters, 1998,39,617-620. Preparation 3.3 A) ter/-Butyl 4-(6-chloro-3-pyridazinyl)-l-piperazinecarboxylate. A mixture of 13.52 g of tert-butyl 1-piperazinecarboxylate, 10.81 g of 3,6-dichloropyridazine and 20 ml of triethylamine in 100 ml of n-butanol is heated at reflux for 5 hours. It is concentrated under vacuum and the residue is chromatographed on silica gel, eluting with a DCM/AcOEt (90/10; v/v) mixture. This gives 14 g of the expected product, which is used as it is. B) tert-Butyl 4-(3-pyridazinyl)-1 -piperazinecarboxylate. A mixture of 10.5 g of the compound obtained in the preceding step and 2.5 g of 10% palladium on carbon in 30 ml of DMF and 250 ml of EtOH is hydrogenated at AT under atmospheric pressure overnight. The catalyst is filtered off and the filtrate is concentrated under vacuum. The residue is chromatographed on silica gel, eluting 41 with a DCM/MeOH (97/3 to 90/10; v/v) mixture. This gives 9.1 g of the expected product, which is used as it is. C) 3-(l-piperazinyl)pyridazine trihydrochloride. A mixture of 3.8 g of the compound obtained in the preceding step, 50 ml of a 2N solution of HC1 in ether and 20 ml of MeOH is left with stirring at AT overnight. It is concentrated under vacuum, the residue is taken up in ether and the precipitate formed is isolated with suction. This gives 3 g of the expected product, which is used as it is. A mixture of 2.96 g of the compound obtained in step A of preparation 3.3 and 30 ml of a 6N solution of HC1 in MeOH is left with stirring in AT overnight. The reaction mixture is concentrated under vacuum, the residue is taken up in DCM a number of times and each time the solvent is evaporated under vacuum. This gives 2.6 g of the expected product, which is used as it is. A) tert-Butyl 4-(2-chIoro-4-pyrimidinyl)-1 -piperazinecarboxylate. A mixture of 9.55 g of tert-bntyl 1-piperazinecarboxylate, 7.64 g of 2,4-dichloropyrimidine and 8.6 g of NaHCO3 in 50 ml of EtOH is heated at reflux for 1 hour. It is concentrated under vacuum, the residue is taken up in water and extracted with DCM, the organic phase is dried over Na2SO4 and the solvent is evaporated under vacuum. The residue is chromatographed on silica gel, eluting with a DCM/AcOEt (90/10 to 60/40; v/v) mixture. Two compounds are separated: - the less polar compound, corresponding to tert-butyl 4-(4-chloro- 2-pyrimidinyl)-l-piperazinecarboxylate, of which 1.75 g are obtained; - the more polar compound, corresponding to the compound of step A), of which 12.9 g are obtained, and which is used as it is. B) terf-Butyl 4-(4-pyrimidinyI)-l -piperazinecarboxylate hydrochloride. A mixture of 12.9 g of the compound obtained in the preceding step and 3.2 g of 10% palladium on carbon in 300 ml of MeOH and 100 ml of DMF is hydrogenated at AT under atmospheric pressure for 2 hours. The catalyst is filtered off and the filtrate 42 is concentrated under vacuum. This gives 13 g of the expected product, which is use as it is. C) 4-(l-Piperazinyl)pyrimidine dihydrochloride. A mixture of 4 g of the compound obtained in the preceding step, 50 ml of a 21 solution of HC1 in ether and 30 ml of MeOH is left with stirring at AT for 2 hour; The precipitate formed is isolated with suction and washed with ether. This gives 3 of the expected product, which is used as it is. A) tert-Butyl 4-(5-pyrimidinyl)-1 -piperazinecarboxylate. Argon is bubbled for 15 minutes into a mixture of 9.3 g of tert-buty 1-piperazinecarboxylate, 7.95 g of 5-bromopyrimidine and 6.5 g of sodium ten butoxide in 250 ml of toluene, which is then heated at reflux, 0.277 g of palladiun acetate and 1.7 ml of tri-terf-butylphosphine are added and reflux is continued fo 24 hours. 0.277 g of palladium acetate is added and the mixture is heated at reflux fo 8 hours. The reaction mixture is cooled to AT, water is added, the mixture is subjectei to extraction with AcOEt, the organic phase is filtered and dried over Na2SC>4 and thi solvent is evaporated under vacuum. The residue is chromatographed on silica ge] eluting with DCM, then with a DCM/AcOEt (50/50; v/v) mixture and finally with ; DCM/MeOH (95/5; v/v) mixture. This gives 3.95 g of the expected product followinj recrystallization from a DCM/hexane/iso ether mixture. B) 5-(l-Piperazinyl)pyrimidine x hydrochloride. A mixture of 3.5 g of the compound obtained in the preceding step in 20 ml o dioxane is admixed at AT with 50 ml of a 2N solution of HC1 in ether, which is Ie1 with stirring at AT for 1 hour and concentrated under vacuum. This gives a yello\ solid which is used as it is. A) 5-(4-Benzyl-l-piperazinyI)-4-chloro-3(2i/)-pyridazinone. 43 A mixture of 7 g of 1-benzylpiperazine, 6.55 g of 4,5-dichloro-3(2//)-pyridazinone and 11 g of K2CO3 in 150 ml of DMF is heated at 110°C for 4 hours and then concentrated under vacuum. The residue is chromatographed on silica gel, eluting with a DCM/MeOH (95/5; v/v) mixture. The product obtained is taken up in iso ether and triturated and the precipitate formed is isolated with suction. This gives 7 g of the expected product, which is recrystallized from iso ether; m.p. = 173-175°C. B) 5-(4-Benzyl-l-piperazmyl)-3,4-dichloropyridazine. A mixture of 1.7 g of the compound obtained in the preceding step and 20 ml of phosphorus oxychloride is heated at 85°C for 4 hours. After cooling to AT the reaction mixture is poured onto ice, the aqueous phase is rendered alkaline by addition of concentrated NaOH solution and extracted with DCM, the organic phase is dried over Na2SO4 and the solvent is evaporated under vacuum. The residue is chromatographed on silica gel, eluting with a DCM/MeOH (97/3 to 90/10; v/v) mixture. This gives 1.5 g of the expected product, which is used as it is. C) 4-(l -Piperazinyl)pyridazine. A mixture of 1.3 g of the compound obtained in the preceding step and 0.13 g of 10% palladium on carbon in 20 ml of MeOH is hydrogenated at 30°C under atmospheric pressure for 3 hours. The catalyst is filtered off and the filtrate is concentrated under vacuum. This gives 0.85 g of the expected product, which is used as it is. A mixture of 0.8 g of the compound obtained in step A of preparation 3.8 and 0.3 g of 10% palladium on carbon in 30 ml of MeOH is hydrogenated at 30°C under atmospheric pressure for 2 hours. The catalyst is filtered and the filtrate is concentrated under vacuum. This gives 0.38 g of the expected product, which is used as it is. 44 A) 4-(4-BenzyI-l-piperazinyl)-5-chloro-3(2//)-pyridazinone and 5-(4-benzyI- 1 -piperazinyl)-4-chloro-3 (2//)-pyridazinone. A mixture of 2.77 g of 1-benzylpiperazine, 1.3 g of NaHCC>3 and 2.6 g . 4,5-dichIoro-3(2//)-pyridazinone in 300 ml of dioxane is heated at 100°C ovemig and then concentrated under vacuum. The residue is chromatographed on silica ge eluting with a DCM/MeOH (98/2; v/v) mixture. Two compounds are separated: - the less polar compound, 4-(4-berizyl-l-piperazinyl)-5-chloro-3(2//)-pyridazinon of which 0.8 g is obtained; - the more polar compound, 5-(4-benzyl-l-piperazinyl)-4-chloro-3(2fl pyridazinone, of which 1.2 g are obtained. B) 4-(l ~Piperazmyl)-3(2//)-pyridazinone hydrochloride. A mixture of 0.75 g of the less polar compound obtained in the preceding ste and 0.2 g of 10% palladium on carbon in 20 ml of MeOH and 10 ml of DMF hydrogenated at 30°C under atmospheric pressure for 3 hours. The catalyst is filters off and the filtrate is concentrated under vacuum. This gives 0.46 g of the expecte product, which is used as it is. Preparation 3.10 An ice bath is used to cool a solution of 3 g of 2-chloropyrimidine in 20 ml Preparation 3.11 A) tert-Butyl 4-(6-chloropyrazin-2-yI)-1 -piperazinecarboxylate. A mixture of 5 g of ten-butyl 1-piperazinecarboxylate, 4 g of 2,6-dichIoro-pyrazine and 9.5 ml de DIPEA in 40 ml of n-butanol is heated at reflux for 3 hours. It is concentrated under vacuum, the residue is taken up in 100 ml of EtOH, the system is left to stand overnight and the crystalline product formed is isolated with suction. This gives 4.7 g of the expected product, m.p. = 108°C. B) 2-Chloro-6-(l -piperazinyl)pyrazine hydrochloride. A mixture of 1.5 g of the compound obtained in the preceding step and 100 ml of 2N hydrochloric ether solution in 10 ml of MeOH is left with stirring at AT overnight. The precipitate formed is isolated with suction and washed with ether. This gives 1.2 g of the expected product. Preparation 3.12 4-Chloro-2-(l-piperazinyl)pyrimidine x hydrochloride. A) tert-Butyl 4-(4-chloropyrirnidin-2-yl)-l -piperazinecarboxylate and tert-butyl 4-(2-chloropyrimidin-4-yl)-1 -piperazinecarboxylate. A mixture of 9.55 g of tert-butyl 1-piperazinecarboxylate, 7.64 g of 2,4-dichloropyrimidine and 8.6 g of NaHCO3 in 90 ml of EtOH is heated at 100°C for one hour. It is concentrated under vacuum, the residue is taken up in water and extracted with DCM, the organic phase is dried over Na2SC>4 and the solvent is evaporated under vacuum. The residue is chromatographed on silica gel, eluting with a DCM/AcOEt (90/10 to 60/40; v/v) mixture. Two compounds are separated: -the less polar compound, tert-butyl 4~(4-chloropyrimidin-2-yI)-1-piperazinecarboxylate, of which 1.75 g are obtained; - the more polar compound, tert-butyl 4-(2-chloropyrimidin~4-yl)-1-piperazinecarboxylate, of which 12.9 g are obtained. B) 4-Chloro-2-(l-piperazinyl)pyrimidine x hydrochloride. A mixture of 1.75 g of the less polar compound obtained in the preceding step and 100 ml of 2N hydrochloric ether solution in 10 ml of MeOH is left with stirring at AT for 18 hours. It is concentrated under vacuum, the residue is taken up in ether and the crystalline product formed is isolated with suction. This gives 1.6 g of the expected product. 46 Preparation 3.13 6-ChIoro-4-(l-piperazinyl)pyrimidine hydrochloride. A solution of 14.8 g of 4,6-dichIoropyrimidine in 100 ml of acetonitrile is cooled to 0~5°C, a solution of 20 g of anhydrous piperazine in 200 ml of acetonitrile is added over 30 minutes and the mixture is left with stirring at 0-5°C for 2 hours. It is concentrated under vacuum, the residue is taken up with 100 ml of 2N NaOH and extracted with ether, the organic phase is dried over Na2SC>4 and the solvent is evaporated under vacuum. The hydrochloride is formed, giving 15 g of the expected product. EXAMPLE 1: Compound No. 1 2-[4-(2-Pyrazinyl)-1 -piperazinyl]-1 -[4-[3-(trifluorornethyi) phenyl]-1 -piperidyl]-1-ethanone hvdrochloride, 2H->O. A mixture of 0.7 g of the compound obtained in preparation 2.1, 0.39 g of the compound obtained in preparation 3.1, 0.39 g of potassium iodide and 0.635 g of K2CO3 in 30 ml of acetonitrile is left with stirring at AT overnight. Water is added to the reaction mixture, which is extracted with AcOEt, the organic phase is washed with water and with saturated NaCl solution and dried over Na2SC>4 and the solvent is evaporated under vacuum. The residue is chromatographed on silica gel, eluting with a DCM/MeOH (97/3; v/v) mixture. The product obtained is taken up in 2N hydrochloric ether solution and, after trituration, the precipitate formed is isolated with suction. This gives 0.42 g of the expected product. Mass spectrum: MH = 434.3. EXAMPLE 2: Compound No. 2 l-[4-Hydroxy-4-[3-(trifluoromethyl)phenyl]-l-piperidyl]-2-[4-[5-trifluorornethyI)-2-pyridyl]~l-piperazinyl]-!-ethanone dioxalate. A mixture of 0.8 g of the compound obtained in preparation 2.2, 0.575 g of l-[5-(trifluoromethyI)-2-pyridyl]piperazine, 0.413 g of potassium iodide and 0.688 g 47 of K2CO3 in 20 ml of acetonitrile is left with stirring at AT for 2 hours. Saturated K2CO3 solution is added, the mixture is extracted with AcOEt, the organic phase is washed with water and with saturated NaCl solution and dried over Na2SC>4 and the solvent is evaporated under vacuum. The residue is chromatographed on silica gel, eluting the DCM/MeOH (96/4; v/v) mixture. The product obtained is taken up in ether, 0.384 g of oxalic acid is added, the system is triturated and the precipitate formed is isolated with suction. This gives 1.27 g of the expected product, m.p. = 173°C. EXAMPLE 3: Compound No. 3 1 -[4-Hydroxy-4-[3-(trifluoromethyl)phenyl]-1 -piperidyI]-3-[4-(2-pyrazinyl]-l-piperazinyl]-l-propanone 1.5 oxalate, 1.5 H2O. A mixture of 0.5 g of the compound obtained in preparation 2.3, 0.660 g of the compound obtained in preparation 3.1, 0.4 ml of triethylamine and 0.23 g of potassium iodide in 10 ml of acetonitrile is heated at 70°C for 60 hours. Water is added to the reaction mixture, which is extracted with AcOEt, the organic phase is washed with saturated K2CO3 solution, with water and with saturated NaCl solution and dried over Na2SO4 and the solvent is evaporated under vacuum. The residue is chromatographed on silica gel, eluting with a DCM/MeOH (94/6; v/v) mixture. 0.77 g of the product obtained is taken up in ether, 0.28 g of oxalic acid is added, and the precipitate formed is isolated with suction. This gives 0.762 g of the expected product, m.p. = 113°C. EXAMPLE 4: Compound No. 4 1 -[4-(Aminomethyl)-4-[3-(trifluoromethyl)phenyl]-1 -piperidyl]-2-[4-(2-pyrazinyl)-1 -piperazinvli-1 -ethanone. A) l-[2-[4-(2-PyrazinyI)-l-piperazinyl]acetyl]-4-[3-(trifluoromethyl)phenyl]- 4-piperidinecarbonitrile. A mixture of 3.42 g of the compound obtained in preparation 2.6, 1.7 g of the compound obtained in preparation 3.1, 1.7 g of potassium iodide and 1.42 g of K2CO3 in 50 ml of acetonitrile is left with stirring at AT for 18 hours. The mixture is concentrated under vacuum, the residue is taken up in water and extracted with 48 AcOEt, the organic phase is dried over Na2SO4 and the solvent is evaporated under vacuum. The residue is taken up in absolute EtOH, and the crystals formed are isolated with suction and washed with ether. This gives 3.5 g of the expected product, m.p. = 138°C. B) l-[4-(ArnrnomethyI)-4-[3-(trifluoromethyI)phenyl]-l-piperidyl]-2-[4-(2-pyrazinyl)- 1 -piperazinyl]-1 -ethanone. A mixture of 3 g of the compound obtained in the preceding step, 0.3 g of Raney® nickel, 20 ml of 20% aqueous ammonia and 200 ml of MeOH is hydrogenated at AT under atmospheric pressure for 16 hours. The catalyst is filtered off and the filtrate is concentrated under vacuum. The residue is taken up in water and extracted with AcOEt, the organic phase is dried over Na2SO4 and the solvent is evaporated under vacuum. This gives 2.17 g of the expected product following recrystallization from AcOEt; m.p. = 155°C. Mass spectrum: MH = 463.4. lH NMR: DMSO-d6: 5 (ppm): 1.0 to 1.2: m: 2H; 1.6 to 2.2: m: 4H; 2.4 to 4.0: m: 16H; 7.4 to 7.7: m: 4H; 7.79: d: 1H; 8.06: dd: 1H; 8.29: d: 1H. Compound No. 4 of Example 4 can also be obtained by following the two steps below: A*) tert-Buty\ [l-[2-[4-(2-pyrazinyl)-l-piperazinyl]acetyI]-4-[3-(trifluoromethyl)- phenyl]-4-piperidyl]methylcarbamate. A mixture of 2.8 g of the compound obtained in preparation 2.7, 1.25 g of the compound obtained in preparation 3.1, 1.1 g of potassium iodide and 1.8 g of K2CO3 in 30 ml of acetonitrile is left with stirring at AT for 3 hours. Saturated K2CO3 solution is added, the mixture is extracted with AcOEt, the organic phase is dried over Na2SO4 and the solvent is evaporated under vacuum. The residue is chromatographed on silica gel, eluting with a DCM/MeOH (97/3: v/v) mixture. This gives 1.75 g of the expected product. B') l-[4-(Aminomethyl)-4-[3-(trifluoromethyl)phenyl]-l-piperidyl]-2-[4-(2- pyrazinyl)-1 -piperazinylj-1 -ethanone. A mixture of 1.7 g of the compound obtained in the preceding step, 50 ml of a 2N solution of HC1 in ether and 30 ml of MeOH is left with stirring at AT for 4 hours. It is concentrated under vacuum, the residue is taken in water, the aqueous phase is washed with AcOEt, the aqueous phase is rendered alkaline by addition of K2CO3, the mixture is subjected to extraction with AcOEt, the organic phase is washed with saturated NaCl solution and dried over Na2SO4 and the solvent is evaporated under 49 vacuum. The product crystallizes on evaporation in AcOEt and the crystals formed are isolated with suction. This gives 1.05 g of the expected product, m.p. = 152-153°C. Mass spectrum: MH =463.3. EXAMPLE 5: Compound No. 5 l-[4-(Aminomethyl)-4-[3-(trifluoromethyl)phenyI]-l-piperidyl]-2-[4-(2-pyrimidinyl)-1 -piperazinyl]-1 -ethanone trihydrochloride. A) l-[2-[4-(2-P>Timidinyl)-l-piperazinyl]acetyl]-4-[3-(trifluoromethyl)phenyl]- 4-piperidinecarbonitrile. A mixture of 1.28 g of the compound obtained in preparation 2.6, I.I g of 2-(l-piperazinyl)pyrimidineJ 1.23 g of K2CO3 and 0.79 g of potassium iodide in 30 ml of acetonitrile is left with stirring at AT for 4 hours. It is concentrated under vacuum, the residue is taken up in water and extracted with DCM, the organic phase is dried over Na2SO4 and the solvent is evaporated under vacuum. The residue is chromatographed on silica gel H, eluting with a DCM/MeOH (100/1; v/v) mixture. This gives 0.9 g of the expected product. B) l-[4-(Aminomethyl)-4-[3-(trifluoromethyl)phenyI]-l-piperidyl]-2-[4-(2- pyrimidinyl)-1 -piperazinyl]-1 -ethanone trihydrochloride. A mixture of 0.9 g of the compound obtained in the preceding step, 0.1 g of Raney® nickel, 10 ml of 20% aqueous ammonia and 50 ml of MeOH is hydrogenated at AT under atmospheric pressure for 4 hours. The catalyst is filtered off and the filtrate is concentrated under vacuum. The residue is taken up in water and extracted with DCM, the organic phase is dried over Na2SO4 and the solvent is evaporated under vacuum. The residue is taken up in a 2N solution of HC1 in ether and the precipitate formed is isolated with suction. This gives 0.74 g of the expected product after drying under vacuum; m.p. = 198-202°C. EXAMPLE 6: Compound No. 27 2-[4-(4-PyrimidinyI)-l-piperazinyl]-l-[4-[3-(trifiuoromethyl) phenyl]-3,6-dihydro-l(2#)-pyridyl]-l -ethanone dioxalate. 50 A mixture of 0.87 g of Compound No. 11, 5 ml of 35% HCI solution and 9 ml of acetic acid is heated at 110°C for 1 hour. After cooling to AT, 5% K2CO3 solution is added, the mixture is extracted with AcOEt, the organic phase is washed with saturated NaCl and dried over Na2SO4 and the solvent is evaporated under vacuum. The residue is chromatographed on silica gel, eluting with a DCM/MeOH (95/5; v/v) mixture. 0.7 g of the product obtained is taken up in MeOH, 0.12 g of oxalic acid is added, the system is left in crystallization and the precipitate formed is isolated with suction. This gives 0.502 g of the expected product, m.p. = 160°C. Mass spectrum: MH = 432.3. EXAMPLE 7: Compound No. 30 1 -[4-(Aminomethyl)-4-[2-(trifluoromethyl)phenyl]-1 -piperidyl]~2-[4-(2-pyrazinyl)-l-piperazinyl]-l-ethanone 1.5 oxalate, 0.5 H2O. A) l-[2-[4-(2-Pyrazinyl)-l-piperazinyl]acetyl]-4-[2-(trifluoromethyl) phenyl]- 4-piperidinecarbonitrile 1.5 oxalate. A mixture of 1 g of the compound obtained in preparation 2.10, 0.496 g of the compound obtained in preparation 3.1, 0.51 g of potassium iodide and 0.836 g of K2CO3 in 20 ml of acetonitrile is left with stirring at AT overnight. It is concentrated under vacuum, the residue is taken up in water and extracted with AcOEt, the organic phase is washed with water and with saturated NaCl solution and dried over Na2SO4 and the solvent is evaporated under vacuum. The residue is chromatographed on silica gel, eluting with a DCM/MeOH (97/3; v/v) mixture. 0.29 g of the product obtained is taken up in MeOH, 0.057 g of oxalic acid is added and the precipitate formed is isolated with suction. This gives 0.081 g of the expected product, m.p. = 125-126°C. B) l-[4-(Aminomethyl)-4-[2-(trifluoromethyl)phenyl]-l-piperidyl]-2-[4-(2- pyrazinyl)-l-piperazinyl]-l-ethanone 1.5 oxalate, 0.5 H2O. A mixture of 0.8 g of the compound obtained in the preceding step, 0.08 g of Raney® nickel, 20 ml of 20% aqueous ammonia and 100 ml of MeOH is hydrogenated at AT under atmospheric pressure for 36 hours. The catalyst is filtered off and the filtrate is concentrated under vacuum. The residue is taken up in water and extracted with AcOEt, the organic phase is washed with saturated NaCl solution and dried over Na2SO4 and the solvent is evaporated under vacuum. The product is chromatographed on silica gel, eluting with a DCM/MeOH (90/10; v/v) mixture. 0.28 g of the product obtained is taken up in AcOEt, 0.054 g of oxalic acid is added 51 and the precipitate formed is isolated with suction. This gives 0.26 g of the expected product. Mass spectrum: MH = 463.4. EXAMPLE 8: Compound No. 32 1 -[4-(Hydroxymethyl)-4-[3-(trifluoromethyl)phenyl]-1 -piperidyl]-2-[4-(2-pyrazinyl)- 1 -piperazinyll-1 -ethanone. A mixture of 0.6 g of Compound No. 31 and 0.14 g of KOH pellets in 10 ml of MeOH and 5 ml of water is heated at 70°C for 10 minutes. After cooling to AT, the crystalline product formed is isolated with suction, washed with water and dried. This gives 0.3 g of the expected product, m.p. = 223°C. Mass spectrum: MH = 464.4. EXAMPLE 9: Compound No. 33 l-[4-[(Dimethylamino)methyl]-4-[3-(trifluoromethyI)phenyl]-l-piperidyl]-2-[4-(2-pyrazinyI)-1 -piperazinyl]-1 -ethanone. A mixture of 0.85 g of Compound No. 4 obtained in Example 4, 0.28 ml of 37% aqueous formaldehyde solution, 3.8 g of sodium triacetoxyborohydride and 3 drops of acetic acid in 50 ml of THF is left with stirring at AT overnight. The reaction mixture is concentrated under vacuum, the residue is taken up in 100 ml of water and the system is heated at 80°C for 30 minutes. After cooling to AT, the reaction mixture is rendered alkaline to pH = 9 by addition of 10% NaOH solution and extracted with DCM. The organic phase is dried overNa2SC>4 and the solvent is evaporated under vacuum. This gives 0.55 g of the expected product following recrystallization from ether; m.p. - 118°C. Mass spectrum: MH =491.4. !H NMR: DMSO-d6: 5 (ppm): 1.6-2.3: m: 10 H; 2.35-2.7: m: 6H; 2.8-3.3: m: 4H; 3.4-4.0: m: 6H; 7.4-8.4: m: 7H. EXAMPLE 10: Compound No. 36 l-[4-(4-Chlorophenyl)-3,6-dihydro-l(2//)-pyridyl]-2-[4-(2-pyrazinyI)- 1 -piperazinyl]-1 -ethanone. 52 A mixture of 0.907 g of Compound No. 35 and 0.91-3 g of p-toluenesulphonic acid in 20 ml of toluene is heated at 118°C for 24 hours. After cooling to AT, 5% K2CO3 solution is added, the system is extracted with AcOEt, the organic phase is dried over Na2SO4 and the solvent is evaporated under vacuum. The residue is chromatographed on silica gel, eluting with a DCM/MeOH (97/3; v/v) mixture. This gives 0.55 g of the expected product following recrystallization from a DCM/iso ether mixture; m.p. = 139-141°C. EXAMPLE 11: Compound No. 37 l-[4-(Aminomethyl)-4-(4-chlorophenyl)-l-piperidyl]-2-[4-(2-pyrazinyl)-1 -piperazinyl]-1 -ethanone trifluoroacetate. A) 4-(4-Chlorophenyl)-1 -[2-[4-(2-pyrazmyl)-1 -piperazinyl]acetyl]-4-pipendine- carbonitrile. A mixture of 1 g of the compound obtained in preparation 2.14, 0.56 g of the compound obtained in preparation 3.1, 0.56 g of potassium iodide and 0.47 g of K2CO3 in 20 ml of acetonitrile is left with stirring at AT overnight. It is concentrated under vacuum, the residue is taken up in water and extracted with AcOEt, the organic phase is dried over Na2SC>4 and the solvent is evaporated under vacuum. This gives 1.51 g of the expected product, which is used as it is. B) l-[4-(Aminomethyl)-4-phenyl-l-piperidyl]-2-[4-(2-pyrazinyl)-l-piperazinyl]- 1 -ethanone trifluoroacetate and 1 -[4-(aminomethyl)-4-(4-chlorophenyl)-l-piperidyl]-2-[4-(2-pyrazinyl)-l-piperazinyl]-l-ethanone trifluoroacetate. A mixture of 1.51 g of the compound obtained in the preceding step, and 0.15 g of rhodium on alumina in 100 ml of MeOH is hydrogenated at AT under atmospheric pressure for 36 hours. The catalyst is filtered off and the filtrate is concentrated under vacuum. The residue is chromatographed on silica gel H, eluting with a DCM/MeOH (100/5; v/v) mixture and then with a DCM/MeOH/H2O (100/5/0.5; v/v/v) mixture. The product obtained is taken up, in the form of a mixture of two compounds, in EtOH, 2N hydrochloric ether solution is added and the precipitate formed is isolated with suction. The precipitate is dissolved in water, the aqueous phase is washed with DCM, the aqueous phase is rendered alkaline by addition of 10% NaOH solution and 53 extracted with DCM, the organic phase is dried over Na2SO4 and the solvent is evaporated under vacuum. The residue is recrystallized from AcOEt to give 0.14 g of the mixture of the two compounds, containing 21.6% of one compound and 75.5% of Compound No. 37. Preparative HPLC is used to separate the two compounds. A Delta Prep 4000 preparative HPLC apparatus with a PROCHROM column with dynamic axial compression, with a diameter of 50 mm, and 380 g of Kromasil®C18 stationary phase, compressed under a pressure of 70 bars, are used. The mobile phase is a gradient of the mixture of an eluent A (H2O + TFA 0.1%) and of an eluent B (acetonitrile/^O (90% + 10%) + TFA 0.1%) and the flow rate is 122 ml/min. UV detection is carried out at a wavelength of 254 nm. After 0.122 g of the mixture has been separated, the product is: - 0.037 g of a compound identified as being l-[4-(aminomethyl)-4-phenyl- l-piperidyl]-2-[4-(2-pyrazinyl)-l-piperazinyl]-1-ethanone trifluoroacetate: RT=13min; Mass spectrum MH = 395.4. - 0.15 g of Compound No. 37: RT = 15.9 min; Mass spectrum MH = 429.4. EXAMPLE 12: Compound No. 57 l-[4-[(Methylamino)methyl]-4-[3-(trifluoromethyl)phenyl]-l-piperidyl]-2-[4-(2-pyrazinyl)-1 -piperazinyl]-1 -ethanone. A) tert-Butylmethyl [[l-[2-[4-(2-pyrazinyI)-l-piperazinyl]acetyl]- 4-[3-(trifluoromethyl)phenyl]-4-piperidyl]methyl]carbamate. A mixture of 10 g of the compound obtained in preparation 2.20, 3.7 g of the compound obtained in preparation 3.1, 3.7 g of potassium iodide and 6.2 g K2CO3 in 200 ml of acetonitrile is left with stirring at AT for 5 hours. It is concentrated under vacuum, the residue is taken up in water and extracted with AcOEt, the organic phase is dried over Na2SO4 and the solvent is evaporated under vacuum. The residue is chromatographed on silica gel H, eluting with DCM and then with a DCM/MeOH (100/2; v/v) mixture. This gives 10.7 g of the expected product. B) l-[4-[(Methylamino)methyl]-4-[3-(trifluoromethyl)phenyl]-l-piperidyl]-2-[4-(2- pyrazinyl)-1 -piperazinyl] -1 -ethanone. A solution of 8 g of the compound obtained in the preceding step in 100 ml of MeOH is imixed with 300 ml of 2N hydrochloric ether solution and left with stirring at AT 54 overnight. It is concentrated under vacuum, the residue is taken up with 10% NaOH solution and extracted with AcOEt, the organic phase is dried over Na2SO4 and the solvent is evaporated under vacuum. The residue is chromatographed on silica gel H, eluting with a DCM/MeOH (100/2; v/v) mixture and then with a DCM/MeOH/water (100/5/0.5; v/v/v) mixture. This gives 4.5 g of the expected product following recrystallization from iso ether; m.p.= 137-139°C. Mass spectrum MH = 477.4. !H NMR: DMSO-dg: 8 (ppm): 1.10: s: 1H; 1.6-2.3: m: 7H; 2.4-3.8: m: 16H; 7.4-7.75: m: 4H; 7.8: d: 1H; 8.15: dd: 1H; 8.3: d: 1H. EXAMPLE 13: Compound No. 58 l-[4-(Isopropylamino)methyl]-4-[3-(trifluoromethyl)phenyl]-l-piperidyl]-2-[4-(2- A mixture of 1 g of Compound No. 4, 0.16 ml of acetone and 5 drops of acetic acid in 10 ml of THF is admixed at AT with 0.5 g of sodium triacetoxyborohydride and is left with stirring at AT overnight. Subsequently 20 ml of MeOH are added and the mixture is heated at 55°C for 1 hour. It is concentrated under vacuum, the residue is taken up with 30% NaOH solution and extracted with DCM, the organic phase is dried over Na2SO4 and the solvent is evaporated under vacuum. The residue is chromatographed on silica gel, eluting with a DCM/MeOH (93/7; v/v) mixture. This gives 0.511 g of the expected product following recrystallization from ether; m.p. = 140-141°C. Mass spectrum: MH = 505.3. EXAMPLE 14: Compound No. 59 l-[4-[(N-methylisopropylamino)methyl]-4-[3-(trifluoromethyl) phenyl]- A mixture of 0.36 g of Compound No. 58, 0.08 ml of 37% aqueous formaldehyde solution and 5 drops of acetic acid in 10 ml of THF is admixed at AT with 0.605 g of sodium triacetoxyborohydride and is left with stirring at AT for 4 hours. Subsequently 10 ml of MeOH are added and the mixture is heated at 60°C for 1 hour. It is concentrated under vacuum, the residue is taken up with 30% NaOH solution and 55 extracted with DCM, the extract is dried over Na2SO4 and the solvent is evaporated under vacuum. The residue is chromatographed using a DCM/MeOH (96/4; v/v) mixture. The product obtained is taken up in 2N hydrochloric ether solution and the precipitate formed is isolated with suction. This gives 0.233 g of the expected product, m.p. = 185-200°C. Mass spectrum: MH = 519.3. EXAMPLE 15: Compound No. 65 1 -[4-(Aminomethyl)-4-(3-chIorophenyl)-1 -piperidyl]-2-[4-(2-pyrazinyl)- A) 4-(3-Chlorophenyl)-1 -[2-[4-(2-pyrazinyl)-1 -piperazinyl]acetyl]-4-piperidine-carbonitrile. A mixture of 2.3 g of the compound obtained in preparation 2.21, 1.3 g of the compound obtained in preparation 3.1, 1.3 g of potassium iodide and 2.2 g of K2CO3 in 40 ml of acetonitrile is left with stirring at AT overnight. Water is added to the reaction mixture, which is extracted with AcOEt, the organic phase is washed with saturated K2CO3 solution and with water and dried over Na2SC>4 and the solvent is evaporated under vacuum. The residue is chromatographed on silica gel, eluting with a DCM/MeOH (97/3; v/v) mixture. This gives 2.3 g of the expected product. B) 1 -[4-(Aminomethyl)-4-(3-chlorophenyl)-1 -piperidyl]-2-[4-(2-pyrazinyl)- 1 -piperazinyl]- 1-ethanone. A mixture of 0.62 g of the compound obtained in the preceding step and 0.6 g of Raney® nickel in 30 ml of MeOH is hydrogenated at 28°C under atmospheric pressure for 8 hours. The catalyst is filtered off and the filtrate is concentrated under vacuum. The residue is chromatographed under alumina, eluting with a DCM/MeOH (97/3; v/v) mixture. This gives 0.121 g of the expected product following recrystallization from the DCM/iso ether mixture; m.p. = 138-139°C. Mass spectrum: MH = 429.3. EXAMPLE 16: Compound No. 69 1 -[4-(Aminomethyl)-4-(3-methoxyphenyl)-1 -piperidyl]-2-[4-(2-pyrazinyl)-1 -piperazinyl]-1 -ethanone dioxalate. A) 4-(3-Methoxyphenyl)-l -[2-[4-(2-pyrazinyl)-1 -piperazinyl]acetyl]-4-piperidine- carbonitrile. A mixture of 1.2 g of the compound obtained in preparation 2.22, 0.675 g of the compound obtained in preparation 3.1, 0.68 g of potassium iodide and 1.2 g of K2CO3 in 30 ml of acetonitrile is left with stirring at AT for 4 hours. Water is added, the mixture is extracted with DCM, the organic phase is washed with saturated K2CO3 solution and water and dried over Na2SO4 and the solvent is evaporated under vacuum. The residue is chromatographed on silica gel, eluting with a DCM/MeOH (97/3; v/v) mixture. This gives 1.5 g of the expected product, of which a portion is recrystallized from iso ether; m.p. = 108°C. B) 1 -[4-(Aminomethyl)~4-(3-methoxyphenyl)-1 -piperidyl]-2-[4-(2-pyrazinyl)- 1 -piperazinyl]-1 -ethanone dioxalate. A mixture of 1.3 g of the compound obtained in the preceding step, 0.2 g of Raney® nickel and 10 ml of concentrated aqueous ammonia solution in 70 ml of MeOH is hydrogenated at 31°C under atmospheric pressure for 30 hours. The catalyst is filtered off and the filtrate is evaporated under vacuum. The residue is taken up in IN HC1 solution, the aqueous phase is washed with AcOEt, the aqueous phase is rendered alkaline by addition of 10% NaOH solution, the mixture is extracted with DCM, the organic phase is dried over Na2SC>4 and the solvent is evaporated under vacuum. 0.2 g of the product obtained is taken up in ether, 0.042 g of oxalic acid is added and the precipitate formed, following trituration, is isolated with suction. This gives 0.19 g of the expected product, m.p. = 120°C. Mass spectrum: MH = 425.4. The table below illustrates the chemical structures and physical properties of some examples of compounds according to the invention. In this table - the value R3 = double bond indicates that R3, together with the adjacent carbon atom of the piperidine ring, forms a double bond, as illustrated in Example 6; - Me, Et, n-Pr, i-Pr, n-Bu, i-Bu, n-Pe and i-Pe represent, respectively, the groups methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl and isopentyl. 57 TABLE I (I) 58 59 60 61 62 64 10 (a) Compound prepared by the procedure described in Example 1, from the compound obtained in preparation 2.2 and the corresponding compound of formula (in). (b) Compound prepared by the procedure described in Example 2, from the compound obtained in preparation 2.2 and the corresponding compound of formula (III). (c) Compound prepared by the procedure described in Example 3, from the compound obtained in preparation 2.3 and the corresponding compound of formula (III). (d) Compound prepared by the procedure described in Example 1, from the compound obtained in preparation 2.4 and the corresponding compound of formula (III). (e) Compound prepared by the procedure described in Example 2, from the compound obtained in preparation 2.5 and the corresponding compound of formula (III). (f) Compound prepared by the procedure described in Example 1, from the compound obtained in preparation 2.8 and the corresponding compound of formula (III). (g) Compound prepared by the procedure described in Example 1, from the compound obtained in preparation 2.9 and the corresponding compound of formula (III). (h) Compound prepared by the procedure described in Example 6, from Compound No. 11. 65 (i) Compound prepared by the procedure described in Example 6, from Compound No. 12. (j) Compound prepared by the procedure described in Example 6, from Compound No. 26. (k) Compound prepared by the procedure described in Example 1, from the compound obtained in preparation 2.11 and the corresponding compound of formula (III). (1) Compound prepared by the procedure described in Example 1, from the compound obtained in preparation 2.12 and the corresponding compound of formula (III). (m) Compound prepared by the procedure described in Example 1, from the compound obtained in preparation 2.13 and the corresponding compound of formula (III). (n) Compound prepared by the procedure described in Example 1, from the compound obtained in preparation 2.15 and the corresponding compound of formula (III). (o) Compound prepared by the procedure described in Example 6, from Compound No. 38. (p) Compound prepared by the procedure described in Example 1, from the compound obtained in preparation 2.16 and the corresponding compound of formula (III). (q) Compound prepared by the procedure described in Example 6, from Compound No. 40. (r) Compound prepared by the procedure described in Example 1, from the compound obtained in preparation 2.17 and the corresponding compound of formula (111). (s) Compound prepared by the procedure described in Example 6, from Compound No. 42. (t) Compound prepared by the procedure described in Example 10, from Compound No. 44. (u) Compound prepared by the procedure described in Example 10, from the compound from Example 46. (v) Compound prepared by the procedure described in Example 6, from Compound No. 48. 66 (w) Compound prepared by the procedure described in Example 2, from the compound obtained in preparation 2.18 and the corresponding compound of formula (III). (x) Compound prepared by the procedure described in Example 1, from the compound obtained in preparation 2.19 and the corresponding compound of formula (III). (y) Compound prepared by the procedure described in Example 6, from Compound No. 52. (z) Compound prepared by the procedure described in steps A' and then B' from Example 4, from the compound obtained in preparation 2.7 and the corresponding compound of formula (III). (k) Compound prepared by the procedure described in Example 13, from Compound No. 4 and the corresponding aldehyde. (l) Compound prepared by the procedure described in Example 14. (m) Compound prepared by the procedure described in Example 1, from the compound obtained in preparation 2.23 and the corresponding compound of formula (III). The compounds according to the invention were subjected to biochemical studies. Cell culture: The SH-SY-5Y strain (human neuroblastoma) is cultured conventionally in a DMEM culture medium (Dulbecco's Modified Eagle's Medium) (Gibco BRL, France) containing FCS (5%) (foetal calf serum) (Boehringer Mannheim, Germany), sodium pyruvate (1 mM), anti-PPLO (5 ml) (antimycoplasma agent: Tylocine® prepared in a normal saline solution, 6 000 ug/ml), gentamycin (0.1 mg/ml) and glutamine (4 mM) in collagen-coated culture flasks (Becton Dickinson, France). The stock strain SK-N-BE (human neuroblastoma) and the clone Bep 75 expressing the human p75NTR receptor (SK-N-BE Bep 75) are conventionally cultured in a DMEM culture medium containing FCS (5%), sodium pyruvate (1 mM), anti-PPLO (5 ml), gentamycin (0.1 mg/ml) and glutamine (4 mM). Study of the binding of 125I-NGF to the pl5mR receptor The study of the binding of 125I-NGF (neuronal growth factor radiolabelled with iodine-125) is carried out on a cellular suspension of the two strains SH-SY-5Y and SK-N-BE Bep 75 in accordance with the method described by Weskarnp (Neuron, 1991, 6, 649-663). Nonspecific binding is determined by measuring the total binding after one hour of preincubation with the cells at 37°C in the presence of nonradiolabelled NGF (1 uM). The specific binding is calculated by the difference 67 between the measurement of total binding and the measurement of nonspecific binding. The competition experiments are carried out using a 125I-NGF concentration of 0.3 nM. The concentrations inhibiting by 50% (IC50) the binding of 125I-NGF to the p75NTR receptor of the compounds according to the invention are low and vary from 10"6tol0"nM. Measurement of apoptosis: The cells (human neuroblastoma strains SH-SY-5Y and SK-N-BE Bep 75) are established in Petri dishes 35 mm in diameter (Biocoat collagen I) (105 cells/well) in a DMEM culture medium containing 5% FCS for 24 h. The culture medium is then removed, the cells are rinsed with PBS (Dulbecco's phosphate buffered saline) and either fresh medium containing 5% FCS or medium containing NGF at the concentration of lOng/ml is added in the presence or absence of the compounds according to the invention. The levels of apoptosis are measured 48 hours after the treatments in the case of the strain SH-SY-5Y and 24 hours later in the case of the strain SK-N-BE Bep 75 by quantifying the cytoplasmic histones associated with the DNA fragments (cell death detection ELISA, Boehringer Mannheim, Germany). The levels of apoptosis are expressed as quantity of oligonucleosomes/105 cells ± SD. Each value corresponds to the mean of 9 experimental points distributed over 3 independent experiments. The compounds of formula (I) exhibit NGF-induced apoptosis inhibitory activity with IC50 values varying from 10"6 to 10*11 M. Thus the binding of the compounds according to the invention to the p75 receptor results, on the one hand, at the biochemical level, in the inhibition of the dimerization of the receptor induced by neurotrophins, and, on the other hand, at the cellular level, in the inhibition of the proapoptotic effect mediated by the p75NTR receptor. The compounds according to the invention can therefore be used for the preparation of medicaments, in particular of medicaments intended for the prevention or treatment of any pathology where the p75 receptor is involved. Thus, in another of its aspects, the invention provides medicaments comprising a compound of formula (I), or an addition salt thereof with a pharmaceutically acceptable acid, or alternatively a solvate or a hydrate of the compound of formula (I). Thus the compounds according to the invention may be used, in humans or in animals, in the treatment or prevention of various p75NTR-dependent conditions such as central and peripheral neurodegenerative diseases such as senile dementia, epilepsy, Alzheimer's disease, Parkinson's disease, Huntingdon's chorea, Down's syndrome, prion diseases, amnesia, schizophrenia; amyotrophic lateral sclerosis, multiple 68 sclerosis; cardiovascular conditions such as post-ischaemic cardiac damage, cardiomyopathies, myocardial infarction, cardiac insufficiency, cardiac ischaemia, cerebral infarction; peripheral neuropathies (of diabetic, traumatic or iatrogenic origin); damage to the optic nerve and to the retina; spinal cord trauma and cranial trauma; atherosclerosis; stenoses; cicatrization; alopecia. The compounds according to the invention may also be used in the treatment of cancers such as that of the lung, of the thyroid, of the pancreas, of the prostate, of the small intestine and of the colon, of the breast, in the treatment of tumours, of metastases and of leukaemias. The compounds according to the invention may also be used in the treatment of chronic neuropathic and inflammatory pain and in the treatment of autoimmune diseases such as rheumatoid arthritis. The compounds according to the invention may also be used in the treatment of bone fractures and in the treatment or prevention of bone diseases such as osteoporosis. In another of its aspects, the present invention relates to pharmaceutical compositions comprising, as active principle, a compound according to the invention. These pharmaceutical compositions contain an effective dose of at least one compound according to the invention, or a pharmaceutically acceptable salt, a solvate or a hydrate of the said compound, and at least one pharmaceutically acceptable excipient. The said excipients are selected, according to the pharmaceutical form and the desired mode of administration, from the customary excipients which are known to the person skilled in the art. In the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, intratracheal, intranasal, transdermal or rectal administration, the active principle of formula (I) above, or its salt, solvate or hydrate where appropriate, may be administered in unit form for administration, as a mixture with conventional pharmaceutical excipients, to animals and to human beings for the prophylaxis or treatment of the above disorders or diseases. The appropriate unit forms for administration comprise the forms for oral administration such as tablets, soft or hard gelatin capsules, powders, granules and oral solutions or suspensions, forms for sublingual, buccal, intratracheal, intraocular or intranasal administration, forms for administration by inhalation, forms for topical, transdermal, subcutaneous, intramuscular or intravenous administration, forms for 69 rectal administration and implants. For topical application, the compounds according to the invention may be used in creams, gels, ointments or lotions. By way of example, a unit form for administration of a compound according to the invention in tablet form may comprise the following components: Compound of the invention : 50.0 mg Mannitol : 223.75 mg Croscaramellose sodium : 6.0 mg Cornstarch : 15.0 mg Hydroxypropylmethylcellulose : 2.25 mg Magnesium stearate : 3.0 mg For oral administration, the dose of active principle administered per day may be up to 0.01 to 100 mg/kg, in single or divided doses, preferably 0.02 to 50 mg/kg. There may be particular cases in which higher or lower dosages are appropriate; such dosages are not outside the scope of the invention. According to the customary practice, the dosage appropriate for each patient is determined by the doctor according to the mode of administration, the weight and the response of the said patient. The present invention, in another of its aspects, also relates to a method of treating the pathologies indicated above which comprises the administration, to a patient, of an effective dose of a compound according to the invention, or one of its pharmaceutically acceptable salts or its hydrates or solvates. 70 1. Substituted 1-piperazinyl acyl piperidinyl derivative compounds of the formula (I): in which: - n is 1 or 2; - p is 1 or 2; - Rl represents a halogen atom; a trifluoromethyl radical; a (Cj-C^alkyl; a (Cj-C4)alkoxy; a trifhioromethoxy radical; - R-2 represents a hydrogen atom or a halogen atom; - R3 represents a hydrogen atom; a group -OR5; a group -CH2OR5; a group -NR6R7; a group -NRgCORf}; a group -NRgCONRioR-li; a group -CH2NR12R13; a group -CH2NRgCONR14R15; a (Ci-C4)alkoxycarbonyl; a group-CONRi6R17. - or else R3 constitutes a double bond between the carbon atom to which it is attached and the adjacent carbon atom of the piperidine ring; - R4 represents an aromatic group selected from: - the said aromatic groups being unsubstituted or being mono- or disubstituted by a substituent selected independently from a halogen atom; a (Cj-C4)alkyl; a (Ci-C4)a!koxy; a trifluoromethyl radical; - R5 represents a hydrogen atom ; a (Cj-C^alkyl; a (Cj-C4)alkylcarbonyl; - Rg and R7 represent each independently a hydrogen atom or a (C^-C4)alkyl; - Rg represents a hydrogen atom or a (Ci-C4)alkyl; - R9 represents a (Cj-C4)alkyl or a group -(CH2)m-NR6^-7J 71 - m is 1, 2 or 3; - R10 and R11 represent each independently a hydrogen atom or a (C1-C4)alkyl; - R12 and R13 represent each independently a hydrogen atom or a (C1-C5)alkyl; Rl3 may also represent a group -(CH2)q-OH or a group -(CH2)n-S-CH3- - or else Rj2 and R13, together with the nitrogen atom to which they are attached, constitute a heterocycle selected from aziridine, azetidine, pyrrolidine, piperidine and morpholine; - q is 2 or 3; - R14 and R15 represent each independently a hydrogen atom or a (Ci-C4)alkyl; - Rl6 and R17 represent each independently a hydrogen atom or a (Ci-C4)alkyl; Rl7 may also represent a group -(CH2)q-NR6R7; - or else R16 and R17, together with the nitrogen atom to which they are attached, constitute a heterocycle selected from azetidine, pyrrolidine, piperidine, morpholine and piperazine which is unsubstituted or substituted in position 4 by a (Ci-C4)alkyl; in the form of a base or an addition salt with an acid, or in the form of a hydrate or solvate. 2. Compound of formula (I) as claimed in claim I, wherein - R] is in position 2, 3 or 4 of the phenyl and represents a trifluoromethyl radical, a chlorine atom, a methyl, a methoxy or a trifluoromethoxy radical and R2 represents a hydrogen atom; or else K\ is in position 3 of the phenyl and represents a trifluoromethyl radical and R2 is in position 4 of the phenyl and represents a chlorine atom; in the form of a base or an addition salt with an acid, or in the form of a hydrate or solvate. 3. Compound of formula (I) as claimed in claim 1, wherein; - R3 represents a hydrogen atom, a hydroxyl, a methoxy, an (acetyloxy)methyl, a hydroxymethyl, a dimethylamino, an acetylamino, an aminomethyl, a (methylamino)methyl, a (dimethylamino)methyl, a (diethylamino)methyl, an (isopropylamino)methyl, an (N-methylisopropylarnino)methyl, an (isobutylamino)methyl; an (N-methyl isobutylamino)methyl, an (isopentylamino)methyl, an (N-methylisopentylamino)methyl, an aminocarbonyl, an azetidin-1-ylcarbonyl; or else R3 constitutes a double bond between the carbon atom to which it is attached and the adjacent carbon atom of the piperidine ring; in the form of a base or an addition salt with an acid, or in the form of a hydrate or solvate. 72 4. Compound of formula (I) as claimed in claim 1 wherein - R4 represents a 2-pyridyl, a 6-methyl-2-pyridyl, a 3-(trifruoromethyl)-2-pyridyl, a 5-(trifruoromethyl)-2-pyridyl, a 3-chloro-5-(trifluoromethyl)-2-pyridyl, a 3-pyridyl, a 4-pyridyl, a 3,5-dichloro-4-pyridyl, a 2-pyrazinyl, a 5-chloro-2- pyrazinyl, a 6-chloro-2-pyrazinyl, a 2-pyrimidinyI, a 4-(trifluoromethyl)-2- pyrimidinyl, a 6-chloro-2-pyrimidinyl, a 4-pyrimidinyl, a 6-chloro-4-pyrimidinyl, a 5-pyrimidinyl, a 3-pyridazinyl, a 6-chloro-3-pyridazinyl, a 4-pyridazinyl, a 3(2//)-pyridazinone-5-yl or a 3(2tf)-pyridazinone-4-yl; in the form of a base or an addition salt with an acid, or in the form of a hydrate or solvate. 5. Compound of formula (I) as claimed in claim 1, wherein - n is 1 or 2; - p is 1 or 2; - Rj is in position 2, 3 or 4 of the phenyl and represents a trifluoromethyl radical, a chlorine atom, a methyl, a methoxy or a trifluoromethoxy radical and R2 represents a hydrogen atom; or else Rj is in position 3 of the phenyl and represents a trifluoro methyl radical and R2 is in position 4 of the phenyl and represents a chlorine atom; - R3 represents a hydrogen atom, a hydroxyl, a methoxy, an (acetyloxy)methyl, a hydroxym ethyl, a dimethylamino, an acetylamino, an aminomethyl, a (methyl amino)methyl, a (dimethylamino)methyl, a (di ethyl ami no) methyl, an (isopropylamino)methyl, an (N-methylisopropylamino)methyl; an (isobutylamino)methyl; an (N-methylisobutylamino)m ethyl, an (isopentylamino)methyl, an (N-methylisopentylamino)methyl, an aminocarbonyl, an azetidin-1-ylcarbonyl; or else R3 constitutes a double bond between the carbon atom to which it is attached and the adjacent carbon atom of the piperidine ring; - R4 represents a 2-pyridyl, a 6-methyl-2-pyridyl, a 3-(trifluoromethyl)-2-pyridyl, a 5-(trifluoromethyl)-2-pyridyl, a 3-chloro-5-(trifluoromethyl)-2-pyridyI, a 3-pyridyl, a 4-pyridyl, a 3,5-dichloro-4-pyridyl, a 2-pyrazinyl, a 5-chloro-2- pyrazinyl, a 6-chloro-2-pyrazinyl, a 2-pyrimidinyl, a 4-(trifluoromethyl)-2- pyrimidinyl, a 6-chloro-2-pyrimidinyl, a 4-pyrimidinyl, a 6-chloro-4-pyrimidinyl, a 5-pyrimidinyl, a 3-pyridazinyl, a 6-chloro-3-pyridazinyl, a 4-pyridazinyl, a 3(2/f)-pyridazinone-5-yl, a 3(2//)-pyridazinone-4-yl; in the form of a base or an addition salt with an acid, or in the form of a hydrate or solvate. 6. Compound of formula (I) as claimed in claim 1, wherein 73 - n is 1; -pis 1; - R_i is in position 2, 3 or 4 of the phenyl and represents a trifluoromethyl radical, a chlorine atom, a methoxy or a trifluoromethoxy radical and R.2 represents a hydrogen atom; or else Rj is in position 3 of the phenyl and represents a trifluoromethyl radical and R2 is in position 4 of the phenyl and represents a chlorine atom; - R3 represents a hydroxyl, a dimethyl amino, an aminomethyl, a (methylamino)methyl, a (dimethylamino)methyl, a (diethylamino)methyl, an (isopropylamino)methyl, an (isobutylamino)methyl, an (isopentylamino)methyl, an (N-methylisopentylamino)methyl or an aminocarbonyl; or else R3 constitutes a double bond between the carbon atom to which it is attached and the adjacent carbon atom of the piperidine ring; - R4 represents a 2-pyrazinyl, a 4-pyrimidinyl, a 3(2//)-pyridazinone-5-yl or a 5 - (trifluoromethyl)-2 -pyridy 1; in the form of a base or an addition salt with an acid, or in the form of a hydrate or solvate. 7. Process for preparing compounds of formula (I) as claimed in claim 1, in which n = 1, wherein al) a compound of formula in which R\, R2 and R3 are as defined for a compound of formula (I) in Claim 1 and the reaction between compound of formula (Ila) with compound of formula (III) is carried out in the presence of a base selected from triethyl amine or potassium carbonate and in the presence of potassium iodide in a solvent such as acetonitrile and at a temperature between the ambient temperature and the reflux temperature of the solvent, bl) and, after deprotection of the hydroxyl or amine functions present in K3 where appropriate, the compound of formula (I) is obtained. 74 8. Process for preparing compounds of formula (I) as claimed in claim !, in which n = 2, wherein a2) a compound of formula in which R1, R-2 and R3 are as defined for a compound of formula (I) in Claim 1, with the proviso that when R3 contains a hydroxyl or amine function these functions may be protected, is reacted with a compound of formula in which p and R4 are as defined for a compound of formula (I) in Claim 1; and the reaction between compound of formula (lib) with compound of formula (III) is carried out in the presence of a base selected from triethyl amine or potassium carbonate and in the presence of potassium iodide in a solvent such as acetonitrile and at a temperature between the ambient temperature and the reflux temperature of the solvent, b2) and, after deprotection of the hydroxyl or amine functions present in R3 where appropriate, the compound of formula (I) is obtained. 9. Process for preparing compounds of formula (I) as claimed in claim 1, in which R3 represents a group -CH2NR12R13 in which Rj2 and R13 each represent hydrogen, wherein a3) a compound of formula in which Rj and R2 arc as defined for a compound of formula (I) in Claim 1 and Hal represents a halogen atom, preferably chlorine or bromine, is reacted with a compound of formula in which p and R4 are as defined for a compound of formula (I) in Claim 1 to give a compound of formula 75 and the reaction between compound of formulaKjifi^ith compound of formula (III) is carried out in the presence of a base selected from triethyl amine or potassium carbonate and in the presence of potassium iodide in a solvent such as acetonitrile and at a temperature between the ambient temperature and the reflux temperature of the solvent b3) the cyano group of the compound of formula (la; is reduced to give a compound of formula (I) according to Claim 1 in which R3 = CH2NH? wherein the reduction of the cyano group of the compound of formula (la) is carried out by hydrogenation in the presence of a catalyst such as Raney® nickel or rhodium on alumim in the presence or absence of ammonia, in a solvent such as methanol and at a temperature between ambient temperature and 60°C. 10. Compound of formula in which: - n is 1 or 2; - p is 1 or 2; - Ri represents a halogen atom; a trifluoromethyl radical; a (C j-C4)alkyl; a (C1 -C4)alkoxy; a trifluoromethoxy radical; - R-2 represents a hydrogen atom or a halogen atom; - R4 represents an aromatic group selected from: the said aromatic groups being unsubstituted or mono- or disubstituted by a substituent selected independently from a halogen atom, a (Cj-C^alkyl, a (Cj-C4)alkoxy, a trifluoromethoxy radical; in the form of a base or an addition salt with an acid, or in the form of a hydrate or solvate. 76 11. Pharmaceutical composition; C'o^ravv^v^ dLcompound of formula (I)G&cWwcV\nany one of Claims 1 to 6, or a pharmaceutically acceptable salt, a hydrate or a solvate of this compound, and at least one pharmaceutically acceptable excipient. 12. A pharmaceutical composition, as claimed in claim 11, for the preparation of a medicament intended for the prevention or treatment of central or peripheral neurodegenerative diseases; amyotrophic lateral sclerosis, multiple sclerosis; cardiovascular conditions; peripheral neuropathies; damage to the optic nerve and to the retina; spinal cord trauma and cranial trauma; atherosclerosis; stenoses; cicatrization; alopecia; cancers; tumours; metastases; leukaemias; chronic neuropathic and inflammatory pain; autoimmune diseases; bone fractures; bone diseases. The present invention relates to 1-substituted 1-piperazinylacylpiperidine derivative of general formula (I), wherein: n is 1 or 2, p is 1 or 2; R1 represents a halogen atom, a trifluoromethyl radical, C1-C4 alkyl, a C1-C4 alkoxy, a trifluoromethoxy radical; R2 represents a hydrogen atom or a halogen atom; R3 represents a hydrogen atom, an -OR5 group, a -CH2OR5 group, a -NR6R7 group; a -NR8COR9 group; a -NR8CONR10R11 group; a -CH2NR12R13 group, a -CH2NR8CONR14R15 group; a C1-C4 alkoxycarbonyl; a -CONR16R17 group; or R3 forms a double bond between the carbon atom whereto it is bound and the neighbouring carbon atom of the piperidine cycle; R4 represents an aromatic group selected among (II), said aromatic groups being unsubstituted, monosubstituted or disubstituted by a substituent selected independently among a halogen atom, a C1-C4 alkyl, a C1-C4 alkoxy, a trifluoromethyl radical. The invention also concerns a method for preparing said compounds and their therapeutic use. |
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| Patent Number | 210828 | ||||||||||||||||||||||||
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| Indian Patent Application Number | 01862/KOLNP/2004 | ||||||||||||||||||||||||
| PG Journal Number | 50/2007 | ||||||||||||||||||||||||
| Publication Date | 14-Dec-2007 | ||||||||||||||||||||||||
| Grant Date | 14-Dec-2007 | ||||||||||||||||||||||||
| Date of Filing | 06-Dec-2004 | ||||||||||||||||||||||||
| Name of Patentee | SANOFI-AVENTIS | ||||||||||||||||||||||||
| Applicant Address | 174, AVENUE DE FRANCE, F-75013 PARIS | ||||||||||||||||||||||||
Inventors:
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| PCT International Classification Number | C07D417/14 | ||||||||||||||||||||||||
| PCT International Application Number | PCT/FR03/01685 | ||||||||||||||||||||||||
| PCT International Filing date | 2003-06-05 | ||||||||||||||||||||||||
PCT Conventions:
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