FR2744448A1 - NOVEL PIPERIDINES DERIVED FROM ARYL PIPERAZINE, AND PROCESS FOR PREPARING THEM, PHARMACEUTICAL COMPOSITIONS AND THEIR USE AS MEDICAMENTS - Google Patents

Abstract

Compounds of formula (I), wherein Ar1 is an aromatic residue such as optionally substituted phenyl, naphthyl or pyridyl, or an optionally substituted heterocyclic ring, A-B is CH-CH2 or C=CH, X is O, NH, CH2O or CH2-NH, and Ar2 is an aromatic radical such as phenyl or naphthyl to which X and the piperazine are attached on different carbons, and which itself is optionally substituted by a straight or branched C1-6 alkyl radical, alkoxy (OR4) or halogen.

Description

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

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

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

Many recent pharmacological studies have demonstrated the diversity of serotonin receptors and their respective involvement in its various modes of action (see E. Zifa, G. Fil lion, Pharm
Reviews, 44, 401, 1992 S. Langer, N. Brunello, G. Racagni, J.

Mendlecvicz, "Serotonin Receptor Subtypes: Pharmacological Significance and Clinical Implications", Karger Ed. (1992) B.E. Leonard, Int. Clin.

Psycho-pharmacology, 2, 13-21 (1992); R.W. Fuller, J. Clin. Psychiatry, 53, 36-45 (1992); Grahame-Smith, Int. Clin. Psychopharmacology, 6 Suppl.4, 6-13, (1992). These receptors are subdivided mainly into 4 major classes (5HT1, 5HT2, 5HT3 and 5HT4) which themselves include subclasses such as 5HT1 receptors which are divided mainly into 5HT1A, 5HT1B, 5HT1D (see G.R. Martin, P.A.

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

Invest. Drugs, 3 (5), 513, 1994). The 5HT1D receptors themselves contain several receptor subtypes; it is thus that the SHT1Da and 5HT1Db receptors have been cloned and then identified in humans (see, for example, E. Hamel et al., Mol., Pharmacol., 44, 242, 1993, G.W.

Rebeck et al., Proc. Natl. Acad. Sci. USA, 91, 3666, 1994). Moreover, it has recently been shown that 5HT1B auto-receptors in rodents and 5HTID in other species are able to control the release of serotonin in nerve endings (see M.

Briley, C. Moret, Cl. Neuropharm. 16, 387, 1993; B.E. Leonard, Int.

Clin. Psychopharmacol., 9.7, 1994) as well as the release of other neurotransmitters such as norepinephrine, dopamine or acetylcholine (M. Harrigton, J. Clin Psychiatry, 53, 10, 1992).

Compounds having selective antagonistic activity at the central 5HT1D receptors such as the novel compounds described in the present invention can therefore exert a beneficial effect on subjects suffering from disorders of the central nervous system. In particular, such compounds are useful in the treatment of locomotion disorders, depression, anxiety, panic attacks,
Agoraphobia, obsessive compulsive disorders, memory disorders including dementia, amnesia, and appetite disorders, sexual dysfunction, Alzheimer's disease,
Parkinson's. 5HT1D antagonists are also useful in the treatment of endocrine disorders such as hyperprolactinemia, the treatment of vasospasms, hypertension and gastrointestinal disorders involving changes in motility and secretion.

The compounds according to the present invention are potent and selective antagonists of the 5HT1D receptors and more particularly the newly identified receptors such as SHT1Da and 5HT1Db in humans and, therefore, find their utility, alone or in combination with other molecules, as medicaments and more particularly as therapeutic means for both curative and preventive treatment of serotonin-related disorders.

The prior art in this field is illustrated in particular by patents EP-0533266, EP-0533267 and EP-0533268, GB-2273930, WO-9415920, GB-2276160, GB-2276161, GB-2276162, GB- 2276163,
GB-2276164, GB-2276165, WO-9504729, WO-9506044, WO-9506637,
WO-9511243 and F 9408981 which disclose aromatic derivatives as 5HT1D antagonists and recent publications which describe GR 127,935 as a 5HT1D antagonist (see M. Skingle et al., J. of
Psychopharm. 8 (1), 14, 1994; S. Starkey, M. Skingle, Neuropharmacol., 33, 393, 1994).

The derivatives of the present invention are distinguished from the prior art not only by their original chemical structure which unambiguously distinguishes them from the previously described derivatives but also by their original biological profile, in particular as regards their selectivity for the subtypes. serotonin receptors and with respect to their antagonistic activity especially at the receptors known as 5-HTIDp.

dans laquelle Ar I représente un résidu aromatique tel qu'un phényle, un naphtyle, un pyridyle pouvant être diversement substitués par un ou plusieurs groupes choisis parmi un résidu alkyle linéaire ou ramifié comprenant de 1 à 6 atomes de carbone, trifluorométhyle, trifluorométhoxy, 2,2,2trifluoroéthyle, phényle, benzyle, cycloalkyle, hydroxyle (OH), thiol (SH), éther (OR'2), thioéther (SR'2), ester (OCOR'2), carbamate (OCONHR2), carbonate (OCO2R'2), carbonyle (COR2, COOR'2,
CONHR2), halogène (fluor, chlore, brome ou iode), amine (NR2R3), nitro (NO2), nitrile (CN), aminocarbonyle (NHCOR'2, NHCO2R'2,
NHCONR2R3), aminosulfonyle (NHSO2R'2, N(SO2R'2)2, NHSO2OR'2,
NHSO2NR2R3), sulfonyle (SO2R'2, SO2NR2R3) ou un hétérocycle pouvant éventuellement être diversement substitué tel qu'un hétérocycle à 5 membres pouvant contenir de 1 à 4 hétéroatomes tels que l'oxygène,
I'azote ou le soufre ou deux substituants sur des carbones voisins pouvant former un cycle avec le résidu aromatique auquel ils sont attachés.The present invention relates to derivatives of general formula (I)

wherein Ar I represents an aromatic residue such as phenyl, naphthyl, pyridyl which may be variously substituted by one or more groups selected from a linear or branched alkyl residue of 1 to 6 carbon atoms, trifluoromethyl, trifluoromethoxy, 2 , 2,2trifluoroethyl, phenyl, benzyl, cycloalkyl, hydroxyl (OH), thiol (SH), ether (OR'2), thioether (SR'2), ester (OCOR'2), carbamate (OCONHR2), carbonate (OCO2R 2), carbonyl (COR2, COOR'2,
CONHR2), halogen (fluorine, chlorine, bromine or iodine), amine (NR2R3), nitro (NO2), nitrile (CN), aminocarbonyl (NHCOR'2, NHCO2R'2,
NHCONR2R3), aminosulfonyl (NHSO2R'2, N (SO2R'2) 2, NHSO2OR'2,
NHSO2NR2R3), sulfonyl (SO2R'2, SO2NR2R3) or a heterocycle which may be optionally substituted, such as a 5-membered heterocycle which may contain from 1 to 4 heteroatoms such as oxygen,
Nitrogen or sulfur or two substituents on neighboring carbons which can form a ring with the aromatic residue to which they are attached.

AB represents CH-CH2 or C = CH,
X represents O, NH, CH2O or CH2-NH.

Ar 2 represents an aromatic radical such as a phenyl or a naphthyl to which X and piperazine are attached to different carbons and which may itself be variously substituted by a branched or linear alkyl radical comprising from 1 to 6 carbon atoms, an alkoxy (OR4), or a halogen (chlorine, fluorine, iodine or bromine).

R1, R2, R3 and R4, which are identical or different, represent a hydrogen, a linear or branched alkyl chain comprising from 1 to 6 carbon atoms,
R'2 represents a linear or branched alkyl chain comprising from 1 to 6 carbon atoms, and their salts, hydrates, solvates and bioprecursors physiologically acceptable for therapeutic use.

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

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

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

dans laquelle Arl, A-B, X et R1 sont définis comme dans la formule I et R5 représente un hydrogène, un radical CH3, OCH3 ou un chlore.A particularly preferred class of compounds of formula (I) corresponds to the compounds of formula (Ia)

wherein Arl, AB, X and R1 are defined as in formula I and R5 is hydrogen, CH3, OCH3 or chlorine.

dans laquelle Arl, A-B, X et R1 sont définis comme dans la formule générale (I).Another particularly preferred class of compounds of formula (I) corresponds to compounds of formula Ib

in which Ar 1, AB, X and R 1 are defined as in general formula (I).

The compounds of the present invention may be prepared by different methods which will be dependent on the nature of the substituents Ar1, A-B, Ar2, X and R1.

It will be understood that in certain reactions or sequences of chemical reactions which lead to the preparation of compounds of general formula (I) it is necessary or desirable to protect possible sensitive groups in synthetic intermediates in order to avoid undesirable side reactions. This can be achieved by the use (introduction and deprotection) of conventional protecting groups such as those described in "Protective groups in Organic Synthesis", T.W.

Greene, John Wiley & Sons, 1981 and "Protecting Groups", PJ Kocienski,
Thieme Verlag, 1994. The appropriate protecting groups will therefore be introduced and removed at the most appropriate stage to do this and using the methods and techniques described in the references cited above.

dans laquelle Ar1, A-B sont définis comme précédemment et Y représente un groupe partant tel qu'un halogène (chlore, brome ou iode), un tosylate, un mésylate ou un triflate avec une aryl pipérazine de formule générale (III):

dans laquelle X' représente O ou NH, Ar2 représente un noyau aromatique tel qu'un phényle ou un naphtyle sur lequel X' et le noyau pipérazine sont attachés en des positions différentes et R1 est décrit comme précédemment.La condensation des arylpipérazines de formule (III) avec les électrophiles de formule (II) est réalisée en présence d'une base organique ou inorganique telle que NaH, KH, DiPEA, DBU, pyridine, DMAP, K2CO3, CaCO3, Cs2CO3, en présence éventuellement d'un iodure tel que NaI, KI, Bu4NI, dans un solvant anhydre polaire tel que le THF, le DME, le n-butanol, le t-butanol, le DMF, le DMSO, la méthyléthylcétone, à une température comprise entre -10" et 800C.Les intermédiaires de formule générale (II) sont aisément préparés par condensation d'une aryl pipéridine (saturée ou insaturée) de formule générale (IV)

dans laquelle Arl, A-B sont définis comme précédemment et un chlorure d'acide de formule générale (V)
Y - CH2 - C(O)CI (v) dans laquelle Y est décrit comme précédemment en présence d'une base organique ou inorganique telle que la pyridine, la DiPEA, la DMAP, le
DBU, K2CO3, Cs2CO3 ou CaCO3 dans un solvant anhydre aprotique polaire tel que le THF, le DMF, le DME, le DMSO ou la méthyléthylcétone à une température comprise entre - 100 C et 300 C.Compounds of general formula (I) in which Ar1, AB, Ar2 and R1 are described as above and X is -CH2O- or -CH2NH are prepared by condensation of an intermediate of formula (II)

in which Ar 1, AB are defined as above and Y represents a leaving group such as a halogen (chlorine, bromine or iodine), a tosylate, a mesylate or a triflate with an aryl piperazine of general formula (III):

wherein X 'is O or NH, Ar2 is an aromatic ring such as phenyl or naphthyl on which X' and the piperazine ring are attached at different positions and R1 is described as above.The condensation of the arylpiperazines of formula ( III) with the electrophiles of formula (II) is carried out in the presence of an organic or inorganic base such as NaH, KH, DiPEA, DBU, pyridine, DMAP, K2CO3, CaCO3, Cs2CO3, optionally in the presence of an iodide such that NaI, KI, Bu4NI, in a polar anhydrous solvent such as THF, DME, n-butanol, t-butanol, DMF, DMSO, methyl ethyl ketone, at a temperature of between -10 ° and 800 ° C. intermediates of general formula (II) are easily prepared by condensation of an arylpiperidine (saturated or unsaturated) of general formula (IV)

in which Arl, AB are defined as above and an acid chloride of general formula (V)
Wherein Y is described as above in the presence of an organic or inorganic base such as pyridine, DiPEA, DMAP,
DBU, K2CO3, Cs2CO3 or CaCO3 in an aprotic polar anhydrous solvent such as THF, DMF, DME, DMSO or methyl ethyl ketone at a temperature between -100 C and 300 C.

The intermediates of general formula (III) are prepared by various methods and techniques well known to those skilled in the art for the preparation of aryl piperazines and whose choice is dependent on the nature of X ', Ar2, and R1. Thus, in the particular case where
X 'is an oxygen, the intermediates of formula (III) are accessible by condensation of an arylamine of formula (VI) ::
HO - Ar2 - NH2 (vi) wherein Ar2 is defined as above with an amine derivative of formula (VI1) R'1-N- (CH2CH2Y) 2 (vil) in which R'1, is equivalent to R1 such as defined above or R'1 represents a protecting group such as tbutoxycarbonyl or tosyl which will be converted to R1 later and Y represents a chlorine, a bromine, an iodine, a tosylate or a mesylate.

This reaction is preferably carried out in a polar anhydrous solvent such as DMF, acetonitrile, THF, n-butanol, t-butanol or DMSO, generally at the reflux temperature of the solvent used, in the presence of a base. organic or inorganic generally used for this type of reaction, such as potassium carbonate, sodium or calcium.

avec un bis-méthoxy aromatique symétrique de formule générale (IX) MeO-Ar2-OMe (Ix) dans laquelle Ar2 représente un phényle ou un naphtyle, dans les conditions décrites préalablement (cf: J. Org. Chem. 58, 5101, 1993) suivie de la déméthylation du groupement arylméthoxy avec un réactif approprié tel que BBr3 dans le dichlorométhane.In certain particular cases, the derivatives of formula (III) in which
X 'is an oxygen are preferably prepared by reaction of a lithio-piperazine of formula VIII in which R1 is defined as above

with a symmetrical aromatic bis-methoxy of the general formula (IX) MeO-Ar2-OMe (Ix) in which Ar2 represents a phenyl or a naphthyl under the previously described conditions (cf. J. Org., Chem., 58, 5101, 1993 followed by demethylation of the arylmethoxy group with a suitable reagent such as BBr3 in dichloromethane.

dans laquelle R1 est défini comme précédemment, en présence d'anhydride acétique, suivi de la réduction de la dicétopipérazine intermédiaire ainsi formée avec par exemple un borane. Dans les deux cas, le dérivé de formule (III) sera finalement obtenu après transformation du groupe représenté par X" en amine.S'il s'agit d'un groupe nitro, cette transformation sera effectuée selon les méthodes et techniques bien connues de l'homme de métier pour transformer un nitroaromatique en un dérivé d'aniline telles que par exemple l'emploi de
Nickel de Raney ou de catalyseur au rhodium en présence d'hydrazine,
I'hydrogénation sur charbon-palladium à pression atmosphérique, ou encore l'utilisation de SnC12 ou de zinc.The compounds of general formula (III) in which X 'is NH are prepared by condensation of an aromatic amine of general formula (X)
X "-Ar 2 -NH 2 (x) in which Ar 2 is defined as above and X" represents a function which may subsequently be converted into amine (such as for example a nitro group) or with a bis (haloethyl) amine derivative of formula (VII) under the conditions described above for this type of reaction, either with an amino acid of general formula (XI)

in which R 1 is defined as above, in the presence of acetic anhydride, followed by the reduction of the intermediate diketopiperazine thus formed with, for example, borane. In both cases, the derivative of formula (III) will finally be obtained after conversion of the group represented by X "to amine.If it is a nitro group, this transformation will be carried out according to the well-known methods and techniques of the skilled person to transform a nitroaromatic into an aniline derivative such as for example the use of
Raney nickel or rhodium catalyst in the presence of hydrazine,
The hydrogenation palladium on charcoal at atmospheric pressure, or the use of SnC12 or zinc.

dans laquelle X1 et X2, identiques ou différents représentent chacun un groupe partant tel qu'un halogène (en particulier le chlore), un groupe Oalkyle (en particulier le groupe OCC13), un groupe succinimyle, phtalyle ou imidazolyle. La méthode de la présente invention comprend également l'utilisation de précurseurs ou analogues bien connus des réactifs de formule générale (XII).C'est ainsi et à titre d'exemple que la condensation des intermédiaires (III) et (IV) avec le phosgène peut être avantageusement effectuée à l'aide de diphosgène ou de triphosgène selon une procédure bien connue de l'homme de l'art. The compounds of general formula (I) in which Arl, AB, Ar2 and R1 are described as above and X represents O or NH are prepared by condensation of an intermediate of general formula (III) in which X 'represents O or NH, Ar2 and R1 are defined as above, and a saturated or unsaturated arylpiperidine of formula (IV) in which Arl and AB are defined as above, with a derivative of general formula (XII):

wherein X1 and X2, which are identical or different, each represents a leaving group such as a halogen (in particular chlorine), an Oalkyl group (in particular the OCC13 group), a succinimyl, phthalyl or imidazolyl group. The method of the present invention also comprises the use of well-known precursors or analogues of the reagents of general formula (XII). Thus, and by way of example, the condensation of intermediates (III) and (IV) with the Phosgene can be advantageously carried out using diphosgene or triphosgene according to a procedure well known to those skilled in the art.

The methods and techniques chosen for carrying out the preparation of the compounds of formula (I) in which X represents O or
NH by condensation of the derivatives of formulas (III) in which X 'represents O or NH and derivatives of formula (IV) with a reagent of formula (XII) such as the choice of the order of the reactants, the reaction times, The isolation and / or purification of the intermediates, the temperature of the reaction at different stages of the condensation, the nature of the solvent (s), the presence of co-reactants (such as an organic or inorganic base, for example an amine tertiary) or catalysts and the choice of reagent (XII) (choice of X1 and X2) will be determined by the nature of Ar1, Ar2, X (O or NH) and R1.

Thus, a particularly preferred method for the preparation of derivatives of formula (I) in which X = NH and Arl, AB,
Ar2, R1 are defined as above, consists in reacting an intermediate of formula (III) in which X 'represents NH, Ar2 and R1 are defined as above with triphosgene in the presence of a base such as triethylamine in an anhydrous solvent such as dichloromethane and then adding a compound of formula (IV) wherein Arl, AB are defined as above in the presence of a base such as a tertiary amine.

avant de le condenser avec un nucléophile de formule générale (III) dans laquelle X' représente un oxygène, en présence d'une base organique ou inorganique telle que NaH, KH, t-BuOK dans un solvant aprotique polaire tel que le THF ou le DMF.In the case of the preparation of derivatives of general formula (I) in which Ar1, AB, Ar2 and R1 are defined as above and X represents oxygen, a particularly preferred method is to first condense an arylpiperidine of formula (IV ) with triphosgene in the presence of triethylamine in an anhydrous solvent such as dichloromethane and isolating the intermediate of general formula (XIII) thus formed

before condensing it with a nucleophile of general formula (III) in which X 'represents an oxygen, in the presence of an organic or inorganic base such as NaH, KH, t-BuOK in a polar aprotic solvent such as THF or DMF.

dans laquelle X1, Ar2, R1, sont définis comme précédemment et X représente O ou NH, en présence d'une base organique ou inorganique dans un solvant polaire aprotique à une température comprise entre 200 et 100" C.Also to be considered as forming part of the present invention are the methods which make it possible to prepare the products of formula (I) in which X represents O or NH by condensation of an aromatic amine of formula (IV) with a derivative of general formula ( XIV):

wherein X1, Ar2, R1, are defined as above and X is O or NH, in the presence of an organic or inorganic base in an aprotic polar solvent at a temperature between 200 and 100 ° C.

In the particular case of the compounds of general formula (I) in which R 1 represents a hydrogen, it is preferable to carry out, for certain reactions which require it, reaction intermediates in which R 1 represents a protective group such as, for example, a -butoxycarbonyl (BOC) which will be introduced beforehand by condensation of the appropriate intermediate in which R1 = H with a suitable reagent such as (BOC) 20, BOC-ON = C (CN) -Ph, BOC-ONH2.

This will make it possible, according to the methods and techniques presented previously, to prepare intermediates of general formula (I) in which R 1 = BOC and to convert these intermediates into final products of general formula (I) in which R 1 = H after deprotection of t-butyl carbonate according to methods and techniques well known for this type of transformation such as the use of acid (HCI, CF3CO2H,
H2SO4) in an organic medium.

Piperidines or unsaturated piperidines of general formula (IV) are prepared by various techniques and methods described for example in DE 2801195, EP 7067 (800123), EP 12643 (800625),
FR 2459795 (810116), EP 372776 (900613), FR 2678270 (921231),
FR 2675801 (921231), FR 2675801 (921030), EP 580398 (940126),
WO 9401403 (940120) and the recent publication of Shanklin JR

avec un organométallique de formule XVI ou XVII
Ar1 -M XVI
Ar1 - M' - Arl XVII dans laquelle M représente ZnBr, SnBu3, SnMe3 ou B(OR)2 où R représente un alkyle ou un hydrogène et M' représente Zn en présence d'un dérivé de palladium tel que par exemple Pd(Ph3)4 dans un solvant aprotique polaire tel que le THF, le DME ou le DMF à une température comprise entre 20"C et 800C suivi de la déprotection de l'azote cyclique par les méthodes bien connues de l'homme de l'art pour hydrolyser un tbutoxycarbonyle telle que par exemple l'utilisation d'acide trifluoroacétique dans le dichlorométhane.et al (J. Med Chem 34, 3011, 1991). A particularly preferred method for the preparation of unsaturated aryl piperidines is to couple the vinyl triflate of formula XV

with an organometallic of formula XVI or XVII
Ar1 -M XVI
Wherein M represents ZnBr, SnBu3, SnMe3 or B (OR) 2 where R represents an alkyl or a hydrogen and M 'represents Zn in the presence of a palladium derivative such as for example Pd (Ph3) ) 4 in a polar aprotic solvent such as THF, DME or DMF at a temperature between 20 ° C and 800C followed by the deprotection of cyclic nitrogen by methods well known to those skilled in the art for hydrolyzing a tert-butoxycarbonyl such as, for example, the use of trifluoroacetic acid in dichloromethane.

The unsaturated triflate of formula XV is prepared from N-BOC-4piperidone by reaction successively with lithium diisopropylamide in a polar anhydrous solvent such as THF at -78 ° C. and with (CF 3 SO 2) 2 N-C 6 H 5 (see Synthesis 993, 1991).

The organometallic derivatives XVI and XVII are prepared from aryl halides, more particularly from the corresponding aryl bromides by methods well known to those skilled in the art as described, for example, in "Organometallics in Synthesis , M.

Schlosser Ed .; John Wiley & Sons, 1994 "
Also to be considered as an integral part of the present invention are all the methods which make it possible to convert a derivative of formula (I) into another derivative of formula (I) in which at least one of the substituents Ar1, AB, X, Ar2 or R1 are different, by methods and techniques well known to those skilled in the art. Thus, and by way of example, the derivatives of general formula (I) in which Ar 1 represents a phenyl substituted with an NO 2 group can be converted into derivatives of formula (I) in which Ar 1 represents a phenyl substituted with same position by an NH 2 group (by methods and techniques well known for this type of reduction as described for example in "Compréhensive Organic transformation", p 412; (R.

C. Larock, VCH, 1989), among which mention may be made of atmospheric hydrogenation catalysed with palladium on carbon, the use of SnCl 2 or zinc or else of rhodium catalyst in the presence of hydrazine.

The compounds of general formula (I) in which Arl represents an aromatic substituted with an NHa group can also be converted into many other derivatives of formula (I) such as derivatives in which Arl represents an aromatic substituted with NR'2R3, NHCOR'2, NHC02R'2, NHCOR2R3, NHSO2R'2, NHSO9OR'2, NHSO2NR2R3 by methods and techniques well known for converting aniline to secondary or tertiary aromatic amine, amide, carbonate, urea, sulfonamide or sulfonylurea.

The present invention also comprises the preparation of arylpiperidines of the general formula (I) in which the piperidyl ring is saturated (AB represents CH-CH2) from the corresponding unsaturated aryl piperidines, that is to say in which AB represents C = CH which are themselves part of the present invention.

This transformation can be carried out using the methods well known to those skilled in the art for reducing a carbon-carbon double bond such as, for example, catalytic hydrogenation using atmospheric hydrogen in the presence of a catalyst such as palladium on carbon, platinum in a solvent such as methanol or methanol.

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

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

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

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

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

The infra-red spectra were recorded on a Nicolet 510P device. Absorption bands are given in cm-1
The elementary analyzes were performed on a device Fisons
EA 1108.

EXAMPLE 1
N- [4-Methoxy-3- (4-methylpiperazin-1-yl) phenyl] -4-phenyltetrahydro-1, 2,3,6-pyridin-1-ylamide Difumarate

A solution of 4-methoxy-3- (4-methylpiperazin-1-yl) aniline which can be prepared according to the method described in European Patent 0533266-11 (644mg, 2.9mmol) and triethylamine (403l, 2.9mmol) in the dichloromethane (10 ml) is slowly cannulated on a solution of triphosgene (288 mg, I.Ommol) in dichloromethane (30 ml) under a nitrogen atmosphere. During this operation, the reaction mixture is cooled with an ice bath.

It is then brought back to room temperature for 20 minutes before the addition of 4-phenyltetrahydro-2,3,6-pyridine (651 mg, 4.1 mmol) and triethylamine (403, ul, 2.9 mmol) diluted in dichloromethane ( 10mol). After 2 h at room temperature, the mixture is diluted with water and then extracted three times with ethyl acetate. The organic phases are combined, washed once with saturated sodium chloride solution, dried over magnesium sulfate and concentrated.

The crude is purified by flash chromatography with a mixture (95/5 / I) and then (90/9/1) of dichloromethane / methanol / ammonia.

Mass obtained: 1.16g (Yield: 98%)
This compound is dissolved in methanol and treated with fumaric acid to give the corresponding flimarate. This is crystallized in ether.

Elemental Analysis for. C24H30N402-2C4H404-0 45H20
Calculated: C 59.43; H, 6.06; N, 8.66; Experimental: C 58.91
H 6.02; N 8.38
Mass: 407 (MH +), 248, 160
IR (KBr): 3424, 2928, 2837, 1676, 1637, 1508
1H NMR (DMSO) 2.21 (s, 3H); 2.49 (m, 2H); 2.78 (M, 4H); 3.03 (M, 4H); 3.65 (t, 2H); 3.74 (s, 3H); 4.12 (d, 2H); 5.76 (se, 1H); 6.60 (s, 4H); 6.82 (d, 1H); 7.09-7.50 (m, 7H); 8.33 (s, 1H).

Melting point: 800C
EXAMPLE 2
N.4methoxy-3- (4-methylpiperazin-1-yl) phenyl] -4-phenylpiperidin-1-ylamide fumarate

Compound 2 is prepared according to the procedure described in Example 1 from the following reagents. triphosgene (365mg, 1.23mmol); 4-methoxy-3- (4-methylpiperazin-1-yl) aniline (81 Smg, 3.69mmol); triethylamine (510 lx2, 3.69 mmol x 2); 4phenylpiperidine (723mg, 4.49mmol); dichloromethane (80ml).

The crude is purified by flash chromatography with a mixture (93/7/1) of dichloromethane / methanol / ammonia.

Mass obtained: 1.33g (Yield: 88%)
This compound is dissolved in methanol and treated with fumaric acid to give the corresponding fumarate. This is crystallized in ether.

Elemental Analysis for: C24H32N402-C4H404-O15H20
Calculated: C, 63.78; H, 6.94; N, 10.62; Experimental: C 63.86; H, 6.98; N 10.57
Mass: 409 (MH +), 294,248,162 IR (KBr): 3416,2936,2841,1701,1637,1508,1226
1H NMR (DMSO) 1.63 (t, 2H); 1.78 (m, 2H); 2.36 (s, 3H); 2.67 (M, 4H); 2.77-2.99 (m, 7H); 3.73 (s, 3H); 4.24 (M, 2H); 6.57 (s, 2H); 6.80 (d, 1H); 7.06-7.34 (m, 7H); 8.30 (s, lH).

Melting point: 1950C
EXAMPLE 3 N- [4-Methoxy-3- (4-methylpiperazin-1-yl) phenyl] -4- (2,3-dimethylphenyl) -1,2,3,6-tetrahydropyridin-1-ylamide fumarate

Compound 3a: 1- (tert-butyloxycarbonyl) -4- (2,3-dimethylphenyl) -1,2,3,6-tetrahydropyridine
Tert-Butyllithium (10.8 ml of a 1.7 M solution in pentane, 8.4 mmol) is added dropwise to a solution of o-bromoxylene (1.24 ml, 9.18 mmol) in tetrahydrofuran (70 ml) at -78. The reaction mixture is stirred for 20 minutes at -78 ° C. and then the zinc bromide (9.2 ml of a 1M solution in tetrahydrofuran, 9.18 mmol) is added. slowly brought to room temperature and left for one hour. After this time, 1- (tert-butyloxycarbonyl) -1,2,3,6-tetrahydro-4 - [(trifluoromethyl) sulfonyloxy] pyridine prepared according to the method described by DJ Wustrow and LD Wise (Synthesis, 1991, 993 ) and tetrakis (triphenylphosphine) palladium (a spatula tip) are added and the reaction mixture is refluxed for 12 h.

After cooling, it is diluted with water and then extracted three times with ethyl acetate. The combined organic phases are then dried over magnesium sulfate and concentrated. The crude reaction product is purified by flash chromatography with a 95/5 then 90/10 mixture of petroleum ether / ethyl acetate.

Mass obtained: 1.87 g (Rt: 71%)
1H NMR (CDCl3): 1.49 (s, 9H); 2.14 (s, 3H); 2.26 (s, 3H); 2.29 (M, 2H); 3.60 (t, 5.7Hz, 2H); 4.01 (m, 2H); 5.50 (se, 1H); 6.90 (m, 1H); 7.05 (m, 2H)
Compound 3b: 4- (2,3-dimethylphenyl) -1,2,3,6-tetrahydropyridine
The trifluoroacetic acid (6 ml) is slowly added to a solution of the compound 3a (1.87 g, 6.51 mmol) in dichloromethane (30 ml) maintained at 0 C. The reaction mixture is then brought back to ambient temperature and the reaction is monitored. by thin layer chromatography. After I h, the reaction is completed. The trifluoroacetic acid is neutralized with a saturated solution of sodium hydrogencarbonate. The phases are separated and the organic phase is washed with a saturated sodium chloride solution, dried over magnesium sulphate and concentrated. The crude reaction product is purified by flash chromatography with a 85/15/1 mixture of dichloromethane / methanol / aqueous ammonia.

Mass obtained 1.04 g (Yield: 85%)
1H NMR (CDCl3): 2.20 (s, 3H); 2.25 (M, 2H); 2.28 (s, 3H); 2.51 (M, 1H); 3.11 (t, 5.6Hz, 2H); 3.69 (M, 2H); 5.56 (M, 1H); 6.95 (m, 1H); 7.06 (d, 4.8Hz, 2H).

Compound 3:
Compound 3 is prepared according to the procedure described in Example 1 from the following reagents triphosgene (238 mg, 0.80 mmol); 4-methoxy-3- (4-methylpiperazin-1-yl) aniline (532mg, 2.41mmol); triethylamine (3331Lix2.2.41mmolx2); 4- (2,3-dimethylphenyl) -1,2,3,6-tetrahydro pyridine (3b) (450mg, 2.41mmol); dichloromethane (50ml).

The crude is purified by flash chromatography with a mixture (93/7/1) of dichloromethane / methanol / ammonia.

Mass obtained: 973mg (Yield: 93%)
This compound is dissolved in methanol and treated with fumaric acid to give the corresponding fumarate. This is crystallized in ether.

Elemental Analysis for: C26H34N402-1 5C4H404
Calculated: C, 63.41; H, 6.62; N, 9.20; Experimental: C 63.12; H, 6.62; N 9.20
Mass: 435 (MH +), 248.180,136.110 IR (KBr): 3388.2993.2837.1707.1677.1277
1H NMR (DMSO) 2.13 (s, 3H); 2.23 (s, 3H); 2.28 (M, 2H); 2.39 (s, 3H); 2.71 (M, 4H); 3.00 (M, 4H); 3.64 (t, 5.4Hz, 2H); 3.73 (s, 3H); 4.06 (M, 2H); 5.54 (M, 1H); 6.58 (s, 3H); 6.81 (d, 8.7Hz, 1H); 6.90 (m, 1H); 7.00-7.14 (m, 4H); 8.30 (s, 1H).

Melting point: 1100C
EXAMPLE 4
N- [4-Methoxy-3- (4-methylpiperazin-1-yl) phenyl] -4- (2,3,4,5,6-pentamethylphenyl) -1,2,3,6-tetrahydropyridin-1 fumarate ylamide

Compound 4a: 1- (tert-butyloxycarbonyl) -4- (2,3,4,5,6-pentamethylphenyl) -1,2,3,6-tetrahydropyridine
Compound 4a is prepared according to the procedure described for compound 3a from the following reagents: 2,3,4,5,6 pentamethylbromobenzene (593 mg, 2.61 mmol); tert-butylithium (3.22 ml of a 1.7M solution in pentane, 5.48 mmol); zinc bromide (1.44 ml of a 1M solution in tetrahydrofuran, 1.4 mmol); tetrakis (triphenylphosphine) palladium (a spatula tip); 1- (tert -butyloxycarbonyl) -1,2,3,6-tetrahydro-4 - [(trifluoromethyl) sulfonyloxy] pyridine (864 mg, 2.6 mmol); tetrahydrofuran (30 ml). The reaction crude is purified by flash chromatography with a mixture (95/5) of petroleum ether / ethyl acetate.

Mass obtained: 520 mg (Yield: 61%) RMIV H (CDCl 3): 1.50 (s, 9H); 2.14 (s, 6H); 2.20 (s, 8H); 2.23 (s, 3H); 3.63 (t, 5.7Hz, 2H); 4.03 (M, 2H); 5.40 (se, 1H).

Compound 4b 4- (2,3,4,5,6-pentamethylphenyl) -1,2,3,6-tetrahydropyridine
Compound 4b is prepared according to the procedure described for compound 3b from the following reagents: compound 4a (514 mg, 1.56 mmol), trifluoroacetic acid (1.6 ml); dichloromethane (20 ml).

The crude reaction product is purified by flash chromatography with a 90/9/1 mixture of dichloromethane / methanol / aqueous ammonia.

Resulting mass: 299 mg (Yield: 84%)
1H NMR (CDCl3): 2.11-2.22 (m, 18H); 3.11 (t, 5.7Hz, 2H); 3.5 1 (m, 2H); 5.47 (se, 1H).

Compound 4:
Compound 4 is prepared according to the procedure described in Example 1 from the following reagents triphosgene (130mg, 0.44mmol); 4-methoxy-3- (4-methylpiperazin-1-yl) aniline (290mg, 1.3mmol); pyridine (106 lx 2, l, 3 mmol x 2); 4- (2,3,4,5,6-pentamethylphenyl) -1,2,3,6-tetrahydropyridine (4b) (299 mg, 1.3 mmol); dichloromethane (50ml).

The crude is purified by flash chromatography with a mixture (90/9/1) of dichloromethane / methanol / ammonia.

Mass obtained: 459mg (Yield: 74%)
This compound is dissolved in methanol and treated with fumaric acid to give the corresponding fumarate. This is crystallized in ether.

Elemental Analysis for: C29H40N402-C4H404
Calculated: C 66.87; H, 7.48; N, 9.45; Experimental: C 66.46; H, 7.71; N, 9.33 IR (KBr): 3355, 2999, 2918, 2831, 1702, 1642, 1500, 1239, 977.

1H NMR (DMSO) 2.07 (s, 6H); 2.11 (s, 8H); 2.13 (s, 3H); 2.34 (s, 3H); 2.64 (M, 4H); 2.97 (M, 4H); 3.64 (t, 5.3Hz, 2H); 3.71 (M, 3H); 4.05 (m, 2H); 5.37 (se, 1H); 6.56 (s, 2H); 6.78 (d, 8.7Hz, 1H); 7.05 (d, 2.3Hz, 1H); 7.10 (dd, 2.3 and 8.6Hz, 1H); 8.3 (s, 1H).

Melting point: 130-132 ° C
EXAMPLE 5
2- [8- (4-methylpiperazin-1-yl) naphthalen-2-yloxy] -1- [4-phenyl-1,2,3,6-tetrahydropyridin-1-yl] ethanone fumarate

Compound 5a 2-chloro-1- (4-phenyl-1,2,3,6-tetrahydropyridinyl) ethanone
Chloroacetyl chloride (1 ml, 13.0 mmol) is added dropwise to a solution of 4-phenyl-1,2,3,6-tetrahydropyridine (2.06 g, 13 mmol) and calcium carbonate (3 g, 30 mmol). in methyl ethyl ketone (50 ml) cooled to 0 C. The reaction mixture is stirred at this temperature for 1 h 30 then it is filtered on celite. The celite is rinsed several times with ethyl acetate and a 3M sodium hydroxide solution. The two phases of the filtrate are then separated and the organic phase is dried over magnesium sulphate, filtered and concentrated to give the expected product under form of an orange solid.

Mass obtained: 1.98g (Yield: 84%)
1H NMR (DMSO) 2.63 (M, 2H); 3.74 (t, 5.7Hz, 1.2H); 3.85 (t, 5.7Hz, 0.8H); 4.14 (s, 0.8H); 4.16 (s, 1.2H); 4.25 (M, 2H); 6.07 (M, 1H); 7.27-7.38 (M, 5H).

Compound 5: Compound 5a (1.36g, 5.7Smmol) and 2-hydroxy-8 (4-methylpiperazin-1-yl) naphthalene prepared according to the procedure described in French Patent No. 9408981 (1.39g, 5.75mmol) are stirred at room temperature under a nitrogen atmosphere in dimethylformamide (50 ml) in the presence of cesium carbonate (4.7 g, 14.4 mmol) for 12 h The dimethylformamide is then evaporated off under reduced pressure and the reaction mixture is taken up in the reaction mixture. The organic phase is washed three times with a saturated solution of sodium chloride before being dried over magnesium sulphate and concentrated.The crude reaction product is purified by flash chromatography with a mixture (95/5/1) of dichloromethane / methanol / ammonia.

Mass obtained: 1.57g (Yield: 62%)
This compound is dissolved in methanol and treated with fumaric acid to give the corresponding fumarate. This is crystallized in ether.

Elemental Analysis for: C28H31N3O2-C4H4O4- 0.2 H2O
Calculated: C, 68.48; H, 6.36; N 7.49; Experimental: C 68.22; H, 6.24; N 7.41
Mass (DCI / NH3): 442 (MH +) IR (KBr): 3408.2831.11629.1454
1H NMR (DMSO): 2.22 and 2.25 (s, 3H); 2.71 (M, 4H); 3.01 (M, 6H); 3.73 (M, 2H); 4.13 (s, 1.2H); 4.30 (s, 0.8H); 5.05 (s, 0.8H); 5.09 (s, 1.2H) 6.23 (se, 1H); 6.60 (s, 2H); 7.07 (d, 7.3Hz, 1H); 7.2-7.56 (m, 9H), 7.82 (d, 8.9Hz, 1H).

Melting point: 1130C
EXAMPLE 6
2- [8- (4-methylpiperazin-1-yl) naphthalene-2-oxy] -1- [4-phenylpiperidyl] ethanone fumarate

Compound 5 (782mg, 1.82mmol) is dissolved in methanol (60ml) and placed for 22h under a hydrogen atmosphere (1 atm) in the presence of palladium on charcoal. The mixture is then filtered on celite and concentrated.

Mass obtained: 664mg (Yield: 82%)
This compound is dissolved in methanol and treated with fumaric acid to give the corresponding fumarate. This is crystallized in ether.

Elemental Analysis for: C28H33N3o2-C4H4o4- 0.5 H20
Calculated: C 68.68; H, 6.66; N 7.51; Experimental: C 67.04; H, 6.63; N 7.30 Mass (DCI / NH 3): 444 (MH +), 243.204 JR (KBO: 3435.2851, 1635, 1453
1H NMR (DMSO) 1.03-1.82 (M, 4H); 2.32 (s, 3H); 2.68 (M, 6H); 2.99 (M, 4H); 3.17 (m, 1H); 4.05 (de, 1H); 4.44 (de, 1H); 4.99 (s, 2H); 6.57 (s, 2H); 7.07 (d, 7.1 Hz, 1H); 7.16-7.33 (m, 8H); 7.52 (d, 8.0Hz, 1H); 7.80 (d, 8.9 Hz, 1H).

composé 7a : i-chlorocarbonyl-4-phényl-i ,2,3,6-tétrahydropyridine
Le chlorhydrate de la 4-phényl-1,2,3,6-tétrahydropyridine (2.4g, 12mmol) est déssalifié puis mis en solution dans le dichlorométhane (40ml) en présence de pyridine (0.97ml,12mmol). Celle-ci est ensuite additionnée lentement sur une solution de triphosgène (1.19g, 4mmol) dans le dichlorométhane (60ml) à 0 C et sous atmosphère d'azote. Le mélange réactionnel est ramené à température ambiante.Après 30 minutes, il est dilué avec de l'eau
Les phases sont séparées et la phase organique est lavée avec une solution saturée en chlorure de sodium, séchée sur sulfate de magnésium, filtrée et concentrée.Melting point: 124 ° C
EXAMPLE 7
8- (4-methylpiperazin-1-yl) naphthalenec-2-4-phenyl-1,2,3,6-tetrahydropyridinyl-1-oate fumarate

Compound 7a: i-Chlorocarbonyl-4-phenyl-1,2,3,6-tetrahydropyridine
The hydrochloride of 4-phenyl-1,2,3,6-tetrahydropyridine (2.4 g, 12 mmol) is desalted and then dissolved in dichloromethane (40 ml) in the presence of pyridine (0.97 ml, 12 mmol). This is then slowly added to a solution of triphosgene (1.19 g, 4 mmol) in dichloromethane (60 ml) at 0 ° C. under a nitrogen atmosphere. The reaction mixture is brought to room temperature. After 30 minutes, it is diluted with water
The phases are separated and the organic phase is washed with a saturated solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated.

The reaction crude is purified by filtration on silica with dichloromethane.

Mass obtained: 1.22g (Yield: 49%)
1 H NMR (CDCl 3) 2.64 (M, 2H); 3.84 (t, 5.7Hz, 1H); 3.93 (t, 5.7Hz, 1H); 4.27 (M, 1H); 4.34 (M, 1H); 6.00 (M, 1H); 7.25-7.37 (m, 5H).

compound 7: A solution of 2-hydroxy-8- (4-methylpiperazin-1-yl) naphthalene (1.5 g, 6.16 mmol) in tetrahydrofuran (20 ml) is cannulated on a suspension of sodium hydride (60%, 270 mg) , 6.79 mmol) in tetrahydrofuran (20 ml) at 0 ° C. under a nitrogen atmosphere. After 15 minutes, the reaction mixture is cannulated over a solution of 7a (1.28 g, 6.16 mmol) in tetrahydrofuran (20 ml) and then it is brought to room temperature and stirred for 15 minutes. The solution is then diluted with water and extracted three times with ethyl acetate. The organic phases are combined, washed with saturated sodium chloride solution, dried over magnesium sulphate, filtered and concentrated. The crude product is purified by flash chromatography with a mixture (95/5/1) of dichloromethane / methanol / aqueous ammonia. .

Mass obtained: 1.56g (Yield: 59%)
This compound is dissolved in methanol and treated with fumaric acid to give the corresponding fumarate. This is crystallized in ether.

Elemental Analysis for: C27H29N302-C4H4 4
Calculated: C, 68.49; H 6.12; N, 7.73; Experimental: C 68.47; H, 6.13; N 7.67
Mass (DCI / NH3): 428 (MH +) JR (KBr): 3422.3052.2824.11716.1595.1400-1226
1H NMR (DMSO) 2.40 (s, 3H); 2.62 (M, 2H); 2.79 (M, 4H); 3.05 (M, 4H); 3.69 (M, 1H); 3.87 (M, 1H); 4.15 (M, 1H); 4.36 (M, 1H); 6.23 (s, 1H); 6.58 (M, 2H); 7.17 (d, 7.2Hz, 1H); 7.24-7.50 (m, 7H); 7.63 (d, 8.1Hz, 1H); 7.78 (d, 2.1HZ, 1H); 7.93 (d, 8.9 Hz, 1H).

Melting point: 2080C
EXAMPLE 8
Methylpiperazin-1-yl) -2-naphthalene 4-phenylpiperidin-1-yloate Fumarate

Compound 7 (778 mg, 1.82 mmol) is dissolved in methanol (60 ml) and placed under a hydrogen atmosphere (1 atm) for 22 h in the presence of palladium on charcoal. The mixture is then filtered on celite and concentrated.

Mass obtained: 630mg (Yield: 81%)
This compound is dissolved in methanol and treated with fumaric acid to give the corresponding fumarate. This is crystallized in ether.

Elemental Analysis for: C27H31N3 2-C4H4 4
Calculated: C, 68.24; H 6.47; N 7.70; Experimental: C 67.73; H 6.41; N 7.61
Mass (DCI / NH 3): 430 (MH +), 243.136 IR (KBr): 3422.2932.1709.1414.1205
1H NMR (DMSOI 1.68-1.87 (M, 4H), 2.40 (s, 3H), 2.79 (M, 5H), 3.04 (M, 6H), 4.15-4.38 (M, 2H), 6.57 (s, 2H); 7.15-7.36 (m, 7H), 7.42 (d, 7.6Hz, 1H), 7.62 (d, 8.2Hz, 1H), 7.75 (d, 2.1Hz, 1H), 7.90 (d, 8.9Hz, 1H).

Melting point: 172 ° C
EXAMPLE 9
2-14-Chloro-3- (4-methylpiperazin-1-yl) phenyloxy] -1- [2-cyanophenyl-1,2,3,6-tetrahydropyridin-1-yl] ethanone fumarate

Compound 9a: 1- (tert-butyloxycarbonyl) -4- (2-cyanophenyl) -1,2,3,6-tetrahydropyridine
Compound 9a is prepared according to the procedure described for compound 3a from the following reagents: 2-cyanobromobenzene (790 mg, 4.32 mmol); tert-butylithium (5.35 ml of a 1.7 M solution in pentane, 9.07 mmol); zinc bromide (2.40 ml of a 1M solution in tetrahydrofuran, 2.38 mmol); tetrakis (triphenylphosphine) palladium (a spatula tip); 1 (tert-butyloxycarbonyl) -1,2,3,6-tetrahydro-4 - [(trifluoromethyl) sulfonyloxy] pyridine (1.43 g, 4.32 mmol); tetrahydrofuran (30 ml). The reaction crude is directly engaged in the next step.

Compound 9b: 4- (2-cyanophenyl) -1,2,3,6-tetrahydropyridine
Compound 9b is prepared according to the procedure described for compound 3b from the following reagents: compound 9a (1.23 g, 4.32 mmol), trifluoroacetic acid (4.3 ml); dichloromethane (40 ml).

The crude reaction product is purified by flash chromatography with a 90/9/1 mixture of dichloromethane / methanol / aqueous ammonia.

Mass obtained: 280 mg (Yield: 35%)
1H NMR (CDCl3): 2.50 (m, 2H); 3.18 (t, 5.7Hz, 2FI); 3.61 (m, 2H); 4.70 (se, 1H); 6.01 (m, 1H); 7.28-7.37 (m, 2H); 7.49-7.66 (m, 2H).

Compound 9c 2-chloro-1- [4- (2-cyanophenyl) -1,2,3,6-tetrahydropyridyl-11-ethanone
Chloroacetyl chloride (110ml, 1.37mmol) is added dropwise to a solution of 4- (2-cyanophenyl) -1,2,3,6-tetrahydropyridine 9b (250mg, 1.37mmol) and calcium carbonate (400mg). 4 mmol) in methyl ethyl ketone (10 ml) cooled to 0 ° C. The reaction mixture is stirred at this temperature for 1 h 30 then it is filtered on celite. Celite is rinsed several times with ethyl acetate and 3M sodium hydroxide solution. The two phases of the filtrate are then separated and the organic phase is dried over magnesium sulfate, filtered and concentrated. The crude reaction product is directly engaged in the next step.

Mass obtained: 266mg (Yield: 75%)
Compound 9. 4-chloro-3- (4-methylpiperazin-1-yl) phenol prepared according to the method described in French Patent No. 9408981 (227 mg, 1.00 mmol) and the compound 9c (260 mg; room temperature under a nitrogen atmosphere in dimethylformamide (10 ml) in the presence of cesium carbonate (740 mg, 3 mmol) for 12 h The reaction mixture is then diluted with water and extracted three times with ethyl acetate The organic phases are combined and washed three times with a saturated solution of sodium chloride before being dried over magnesium sulphate and concentrated.The crude reaction product is purified by flash chromatography with a mixture (95/5/1) then (90/9/1) dichloromethane / methanol / ammonia.

Mass obtained: 58 mg (Yield: 13%) RMAI 1H (CDCl 3). 2.32 (s, 3H); 2.57 (M, 6H); 3.04 (M, 4H); 3.593.86 (m, 2H); 4.24 (M, 2H); 4.70 (s, 2H); 5.96 (M, 1H); 6.52 (m, 1H); 6.67 (d, 2.9 Hz, 1H); 7.18-7.65 (m, 5H).

The derivatives of the present invention are potent 5HTID receptor antagonists as shown by binding studies and antagonist studies of adenylate cyclase inhibition (forskolin-stimulated) by a 5HT1D agonist such as serotonin, sumatriptan or 5-CT, studies that have been performed on cloned human 5HT1D receptors.

The human receptors SHTIDa and 5HT1Db were cloned according to the sequences published by M. Hamblin and M. Metcalf, Mol. Pharmacol., 40, 143 (1991) and Weinshenk et al., Proc. Natl. Acad. Sci. 89, 3630 (1992).

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

The HeLa HA7 cell line expressing the human 5HT1A receptor was obtained from Tulco (Duke Univ., Durham, N.C., USA) and cultured according to the method of Fargin et al., J. Biol. Chem. 264, 14848 (1989).

The study of the binding of the derivatives of the present invention with human SHT1Da, 5HT1Db and 5HT1A receptors was carried out according to the method described by P. Pauwels and C. Palmier (Neuropharmacology, 33, 67, 1994).

Incubation media for these binding measurements include 0.4 ml of cell membrane preparation, 0.05 ml of tritiated ligand [[3H]
SCT (final concentration: 2nM) for the receptors SHT1Da and 5HTlDb and [3H] -80H-DPAT (final concentration 1 nM) for the receptor
SHT1A] and 0.05 ml of the test molecule (final concentrations of 0.1 nM to 1000 nM) or 10 μM (final concentration) of seretonin (SHTlDa and SHTIDb) or 1 μM (final concentration) of spiroxatrin (5HT1A).

The study of the inhibition of the formation of cyclic AMP (forskolin-stimulated) mediated by the human 5HT1Db receptor was carried out in CHO-KI cells transfected with the receptor according to the technique previously described for the 5HTIp receptor (P Pauwels and C. Palmier,
Neuropharmacology, 33, 67, 1994).

The novel compounds derived from arylpiperazines forming part of the present invention are potent and selective antagonists of SHT1D receptors and have the advantage of being particularly selective for human 5HTIDD receptors, in particular with respect to the 5HT1A, 5HT1C, 5HT2 receptors. , al, a2 and D2.

The derivatives of the present invention are further capable of inhibiting 5-hydroxytryptamine-induced contraction in rabbit saphenous vein rings and antagonizing carboxamido-tryptamine (5CT) induced inhibition at the level of of serotonin release in guinea pig brain slices. These two pharmacological models are generally recognized as particularly relevant in the functional characterization of SHT1D receptors and, in the case of the products of the present invention, make it possible to demonstrate their antagonistic activity at these receptors.

The derivatives of the present invention are unambiguously distinguished from the prior art by their original chemical structure but also by their biological profile. Indeed, the comparison of the products of the present invention with the closest prior art (patent application FR 9408981) unexpectedly demonstrates the superiority of the products of the present invention, as illustrated by the following comparative study ( table 1).

Table 1

<tb><SEP> Ki <SEP> (nM)
<tb><SEP> XY <SEP> IDa <SEP> IDp <SEP> 1A <SEP>
<tb><SEP> N-CH2 * <SEP> 340 <SEP> 18 <SEP> 450
<tb> CH-CH2 * <SEP> 160 <SEP> 4.4 <SEP> 330
<tb><SEP> C = CH ** <SEP> 76 <SEP> 4.8 <SEP> 410
<tb> * Compound claimed in the patent application FR 9408981 ** Compounds claimed in the present invention
The few illustrative examples given in Table 1 demonstrate that the products of the present invention have the advantage of having a better affinity and a better selectivity at the 5HT1Dp receptors. These novel and unexpected properties of the p-5HT1D antagonists claimed in the present invention make them particularly useful and useful for the treatment of patients with disorders in the central nervous system. Therefore, the present invention also includes a method for treating such patients, which method involves administering an active dose of a compound of the general formula (I).

Moreover, the derivatives of the present invention are also capable of controlling the growth and proliferation of C6 glial cells transfected with the receptor gene SHTIDp, stimulated by a hormonal mediator such as serotonin. For exemple. the examples of the present invention inhibit the incorporation of labeled thymidine (stimulated with 0.1 pM sumatriptan) with an IC 50 of 10 to 100 nM (method described by P. Pauwels et al., J. of Neurochemistry, in press). As such, the derivatives of the present invention are also useful in the treatment of cancers and other disorders related to cell proliferation.

Also to be considered as part of the present invention the pharmaceutical compositions containing as active ingredients, a compound of general formula (I) or a physiologically acceptable salt of a compound of formula (I) associated with one or more agents therapeutic agents, such as, for example, antidepressant agents such as tricyclic antidepressants (eg amitryptyline, clomipramine, desipramine, imipramine), monoamine oxidase inhibitors (eg isocarboxazid, moclobemide, phenelzine or tranylcyclopramine), inhibitors of uptake of serotonin (eg fluvoxamine, sertraline, fluoxetine, paroxetine or citalopram), serotonin and norepinephrine re-uptake inhibitors (eg milnacipran), or a2 antagonists (mianserin, mirtazapine, setiptiline, idazoxan, effaroxan, fluparoxan for example).

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

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

As solid compositions for oral administration may be used tablets, pills, powders (gelatin capsules, cachets) or granules. In these compositions, the active ingredient according to
The invention is mixed with one or more inert diluents, such as starch, cellulose, sucrose, lactose or silica, under an argon stream.

These compositions may also comprise substances other than diluents, for example one or more lubricants such as magnesium stearate or talc, a dye, a coating (dragees) or a varnish.

As liquid compositions for oral administration, it is possible to use pharmaceutically acceptable solutions, suspensions, emulsions, syrups and elixirs containing inert diluents such as water, ethanol, glycerol, vegetable oils or oil. of paraffin.

These compositions may comprise substances other than diluents, for example wetting agents, sweeteners, thickeners, flavoring agents or stabilizers.

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

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

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

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

In general, the doctor will determine the appropriate dosage depending on age, weight and all other factors specific to the subject to be treated. The following examples illustrate compositions according to the invention [in these examples, the term "active component" designates one or more (generally one) of the compounds of formula (I) according to the present invention:
tablets
They can be prepared by direct compression or by wet granulation. The direct compression procedure is preferred but may not be suitable in all cases depending on the doses and the physical properties of the active component.
A - By direct compression
mg per 1 tablet active component 10.0 microcrystalline cellulose PCB 89.5 magnesium stearate
100.0
The active component is passed through a sieve of 250 μm mesh size, mixed with the excipients and compressed with 6.0 mm punches. Tablets having other mechanical strengths can be prepared by modifying the compression weight using appropriate punches.

B - wet granulation
mg per active component tablet 10.0 lactose Codex 74.5 starch Codex 10.0 pregelatinized maize starch Codex 5.0 magnesium stearate
Compression weight 100.0
The active component is passed through a 250 μm mesh screen and mixed with lactose, starch and pregelatinized starch. The mixed powders are moistened with purified water, granulated, dried, sieved and mixed with magnesium stearate. The lubricated granules are tableted as for the direct compression formulas. A film of coating can be applied to the tablets by means of suitable film-forming materials, for example methylcellulose or hydroxypropyl-methyl-cellulose, according to conventional techniques. The tablets can also be coated with sugar.

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

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

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

preservative) distilled water 5.0
The active component, buffer, aroma, dye and preservative are dissolved in part of the water and the glycerin is added. The remainder of the water is heated to 80 ° C and the sucrose dissolved and cooled.

We combine the two solutions. we adjust the volume and mix. The syrup obtained is clarified by filtration.

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

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

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

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

Aerosol under pressure with metering valve
mg / dose per micronized active ingredient box 0.500 120 mg oleic acid Codex 0.050 12 mg trichlorofluoromethane for pharmaceutical use 22.25 5.34 g dichlorodifluoromethane for pharmaceutical use 60.90 14.62 g
The active component is micronized in a fluid energy mill and placed in the form of fine particles. The oleic acid is mixed with trichlorofluoromethane at a temperature of 10-15 ° C. and the micronised drug is introduced into the solution using a high-shear mixer. aluminum aerosol cans to which are attached appropriate metering valves delivering a dose of 85 mg of the suspension, the dichlorodifluoromethane is introduced into the cans by injection through the valves.

Claims (17)

1. Compounds corresponding to the general formula (I)

 wherein Ar 1 represents an aromatic residue such as phenyl, naphthyl, pyridyl which may be variously substituted by one or more groups selected from a linear or branched alkyl residue having 1 to 6 carbon atoms, trifluoromethyl, trifluoromethoxy, 2, 2,2trifluoroethyl, phenyl, benzyl, cycloalkyl, hydroxyl (OH), thiol (SH), ether (OR'2), thioether (SR'2), ester (OCOR'9), carbamate (OCONHR2), carbonate (OCO2R ' 2), carbonyl (COR2, COOR'2, CONHR2), halogen (fluorine, chlorine, bromine or iodine), amine (NR2R3), nitro (NO2), nitrile (CN), aminocarbonyl (NHCOR'2, NHCO2R'2, NHCONR2R3), aminosulfonyl (NHSO2R'2, N (SO2R'2) 2, NHSO2OR'2, NHSO2NR2R3), sulfonyl (SO2R'2, SO2NR2R3) or a heterocycle which may be optionally substituted, such as a 5-membered heterocycle which may contain from 1 to 4 heteroatoms such as oxygen, Nitrogen or sulfur or two substituents on neighboring carbons which can form a ring with the aromatic residue to which they are attached. X represents O, NH, CH2O or CH2-NH. A-B represents CH-CH2 or C = CH, Ar 2 represents an aromatic radical such as a phenyl or a naphthyl to which X and piperazine are attached to different carbons and which may itself be variously substituted by a branched or linear alkyl radical comprising from 1 to 6 carbon atoms, an alkoxy (OR4), or a halogen (chlorine, fluorine, iodine or bromine). R'2 represents a linear or branched alkyl chain comprising 1 to 6 carbon atoms, and their salts, hydrates, solvates and bioprecursors physiologically acceptable for therapeutic use. R1, R2, R3 and R4, which are identical or different, represent a hydrogen, a linear or branched alkyl chain containing from 1 to 6 carbon atoms, The compounds of general formula (I) being in isometric geometric and optical form as well as in racemic form. 2. Compounds according to claim 1, characterized in that Ar2  represents a phenyl and corresponds to the general formula (la)

 wherein R5 is H, CH3, OCH3 or C1 and the other substituents have the meanings given in claim 1. 3. Compounds according to claim 1, characterized in that Ar2  represents a naphthyl and the other substituents have the meanings  indicated in claim 1 and which correspond to formula Ib

 4. Compounds according to claim 1 characterized in that R1  represents a methyl and the other substituents have the meanings  indicated in claim 1.  claim 1.  NH and the other substituents have the meanings indicated in Compounds according to claim 1, characterized in that X represents 6. Compounds according to claim 1 characterized in that X represents  O, CH2O or CH2NH and the other substituents have the meanings  indicated in claim 1. 7. Compounds according to claim 1 characterized in that Arl  represents phenyl or phenyl substituted by one or more  residues selected from methyl, trifluoromethyl, methoxy,  trifluoromethoxy, ethyl, thiomethyl, amine, nitro, nitrile or  halogen (fluorine, chlorine, bromine or iodine) and the other substituents  the meanings indicated in claim 1. 8. Compounds according to claim 1 characterized in that Arl  represents a naphthyl or a tetrahydronaphthyl optionally  substituted by methyl or methoxy and the other substituents  the meanings indicated in claim 1. 9. Compounds according to one of claims 1 to 8 in the state of salt  acceptable for therapeutic use characterized in that these salts  are hydrochlorides, hydrobromides, sulphates, methanesulphonates,  fumarates, maleates or succinates and the other substituents have the  the meanings indicated in claim 1. 10. Process for the preparation of the compounds of formula (I) in which  Ar1, A-B, Ar2 and R1 are defined as above and X  represents CH2O or CH2NH, characterized in that one condenses  intermediate of formula (II)

 in which Ar 1 is defined as above and Y represents a leaving group such as a halogen, a tosylate, a mesylate or a triflate with an aryl piperazine of general formula (III)

 represents a precursor.  previously, R1 is defined as in formula (I) or in  where X 'is O or NH, Ar2 is defined as 11. Process for the preparation of the compounds of formula (I) in which  Ar1, A-B, Ar2, and R1 are defined as above and X  represents O or NH characterized in that one condenses a  intermediate of formula (III) defined as in claim 10  and a piperazine aryl of formula (IV) wherein Ar1 and A-B are  defined as above with an electrophile of formula (XII)

 OCC13) succinimyl, phthalyl or imidazoyl.  (in particular chlorine) an O-alkyl group (in particular the group  wherein X1 and X2 represents a leaving group such as a halogen 12. Process for the preparation of the products of formula (I) in which Ar1,  A-B, X and Ar2 are defined as before and R1 represents a  characterized in that the hydrolysis in an acidic medium is  compound of formula (I) wherein R1 represents a t  butoxycarbonyl. 13. Pharmaceutical compositions containing as active ingredients,  a compound according to one of claims 1 to 9, in combination with  an acceptable pharmaceutical vehicle, such as drugs. 14. Pharmaceutical compositions containing as active ingredients,  a compound according to one of claims 1 to 9, in combination with  an acceptable pharmaceutical vehicle, for both curative treatment  as preventive of depression and disorders or compulsive disorders  obsessive. 15. Pharmaceutical compositions containing as active ingredients,  a compound according to one of claims 1 to 9, in combination with  an acceptable pharmaceutical vehicle, for both curative treatment  that preventative of anxiety and panic attacks, of the  schizophrenia, aggression, bulimia, alcoholism,  pain and neurodegenerative diseases such as  Parkinson's or Alzheimer's. 16. Pharmaceutical compositions containing, as active ingredients,  a compound according to one of claims 1 to 9, in combination with  an acceptable pharmaceutical vehicle, for both curative treatment  than preventive cancers. 17. Pharmaceutical compositions according to one of claims 13 to  16, characterized in that they contain, in addition, at least one  second active ingredient associated with antidepressant properties,  particularly, MILNACIPRAN and / or a SHT 1A antagonist.