FR2761069A1 - Di:hydro benzo furan spiro:amine derivatives - Google Patents

Abstract

Novel dihydro benzo furan spiroamines of formula (I), their salts, hydrates and solvates are claimed, where A = H,H, or -CH2CH2-, or -CH=CH-; Z1 = CO, SO2, (CH2)(m+1), CO(CH2)m, SO2(CH2)m, (CH2)mCO, CO(CH2)mSO2, SO2(CH2)mSO2, CO(CH2)mCO, SO2(CH2)mCO; m = 1-6; X-Y = NCH2, NCH2CH2, C=CH, CR1-CH2; R1 = H, halogen, OH, NH2, CN, NO2, R2, OR2, SR2, NHR2, COR2, CHOHR2, COOR2, NHCOR2, NHCOOR2, NHSO2R2, OCONHR2; R2 = 11-5C alkyl, aryl or alkyl aryl in which the aryl group is selected from phenyl, naphthyl or pyridyl optionally substituted by one or more of 1-5C alkyl, halogen, OH, OR3, SR3, CF3, CH2CF3, NO2, CN, COR3, COOR3, NHR3, NHCOR3, NHCOOR3, NHSO2R3, SO2R3; R3 = H or 1-5C alkyl, Z2 is either omitted or represents (CH2)n, (CH2)nCO, CO, CO(CH2)n, O(CH2)n, O(CH2)nCO, OCO, NH(CH2)n, NH(CH2)nCO, NHCO, NHCO(CH2)n, NHSO2(CH2)n, CH=CHCO, C?=C-CO, SO2, SO2(CH2)n, NH(CH2)nSO2, NHSO2(CH2)nSO2, O(CH2)nSO2; and when X-Y = CHCH2, then Z2 may further be O, NH, CONH, SO2NH, OCONH, NHCOO, NHCONH, (CH2)nNH, (CH2)nO, CO(CH2)nNH, NH(CH2)nO, NH(CH2)nNH, O(CH2)nNH, O(CH2)nO, CO(CH2)nO, SO2(CH2)nNH, SO2(CH2)nO, (CH2)nSO2NH, (CH2)nCONH, O(CH2)nSO2NH, O(CH2)nCONH, NH(CH2)nSO2NH, NH(CH2)nCONH, NHCO(CH2)nNH, NHSO2(CH2)nNH; and when X-Y = CR1-CH2 or C=CH, Z2 may further be -CH=CH- or -C?=C-; n = 1-6; Ar = phenyl, naphthyl or pyridyl, optionally substituted by 1 or more groups selected from 1-6C alkyl, CF3, CF3O, CF3CH2, phenyl, benzyl, 3-7C cycloalkyl, OH, SH, OR4, SR4, NO2, CN, NH2, NR4R4', an amine derivative, halogen, or carbonyl, a heterocycle optionally substituted, or Ar-Z2 may represent a tetrahydronaphthyl group in which the link with X is through a saturated C atom; R4 = 1-6C alkyl; and R4' = H or 1-6C alkyl.

Description

Spiroamines derived from dihydrobenzofurans,
their preparation and their application as medicaments
The present invention relates to new spiroamines derived from dihydrobenzofurans, as well as to their process of preparation, the pharmaceutical compositions containing them and their use as medicaments.

Serotonin or 5-hydroxytryptamine (5-HT) is a neurotransmitter and a neuromodulator of the central nervous system involved in many physiological and pathological processes. Serotonin plays an important role both in the nervous system and in the cardiovascular and gastrointestinal systems. At the central level, serotonin controls functions as varied as sleep, locomotion, food intake, learning and memory, endocrine modulations, sexual behavior, thermoregulation. In the medulla, serotonin plays an important role in the control systems of the afferent peripheral nociceptives (cf. A. Moulignier,
Rev. Neurol. (Paris), 150, 3-15.1994).

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

Numerous recent pharmacological studies have demonstrated the diversity of serotonin receptors as well as their respective involvement in its various modes of action (cf. E. Zifa, G. Fillion, Pharm Reviews, 44 401, 1992; S. Langer , NOT.

Brunello, G. Racagni, J. Mendlecvicz, "Serotonin receptor subtypes: pharmacological significance and clinical implications", Karger Ed. (1992); B.E.

Leonard, Int. Clin. Psycho-pharmacology, 7 13-21 (1992); R.W. Fuller, J. Clin.

Psychiatry, 53 36-45 (1992); D.G. Grahame-Smith, Int. Clin.

Psychopharmacology, 6, suppl. 4, 6-13, (1992). These receivers are mainly divided into 4 major classes (5-HT1, 5-HT2, 5-HT3 and 5-HT4) which themselves have subclasses. The 5-HT receptors, for example, are mainly divided into 5-HT, A, 5-HT, B (former 5-HT, Db), 5-HT, D (former 5-HT, Da) (cf.

G.R. Martin, P.A. Humphrey, Neuropharmacol., 33, 261, 1994; P.R. Saxena, Exp.

Opin. Invest. Drugs, 3 (5), 513, 1994 and Hartig PR, Hoyer D., Humphrey PPA,
Martin GR :. TIPS, 17: 103-105, 1996). The 5-HT1D and 5-HTXB receptors have been cloned and then identified in humans (cf. for example E. Hamel et al., Mol.

Pharmacol., 44,242 1993; GW Rebeck et al., Proc. Natl. Acad. Sci. USA, 91, 3666, 1994). Furthermore, it has recently been shown that the 5
HT, B were able to control the release of serotonin in the nerve endings (cf. M. Briley, C. Moret, Cl. Neuropharm. 16, 387, 1993; BE Léonard,
Int. Clin. Psychopharmacol., 9,7, 1994) as well as the release of other neurotransmitters such as norepinephrine, dopamine or acetylcholine (M.

Harrigton, J. Clin. Psychiatry, 53, 10, 1992).

By their ability to control the release of neurotransmitters, presynaptic HOT receptors play a role in neurotransmission mechanisms, in particular linked to serotonin, and therefore the antagonists of these receptors can exert a beneficial effect in patients whose serotonergic transmission is impaired, such as for example patients suffering from depression, anxiety, obsessive compulsive disorders (Cf. S. Halazy, M.

Lamothe, C. Jorand-Lebrun, Exp. Op. Ther. Patents, in press, 1997).

Compounds having a selective antagonist activity at the 5 HT, D "B central receptors such as the new compounds described in the present invention can therefore exert a beneficial effect on subjects suffering from disorders of the central nervous system. In particular, such compounds find utility in the treatment of locomotion, depression, anxiety, panic attacks, agoraphobia, obsessive compulsive disorder, memory disorders including dementia, amnesia, and appetite disorders, sexual dysfunctions, Alzheimer's disease, Parkinson's disease. The 5-HTlD, 1H antagonists also find their utility in the treatment of endocrine disorders such as hyperprolactinemia, the treatment of vasospasms, hypertension and gastrointestinal disorders in which changes in motility and secretion occur.

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

The prior art in this field is illustrated in particular by patents EP-0533266, EP-0533267 and EP-0533268, GB-2273930, WO-9415920, GB2276160, GB-2276161, GB-2276162, GB-2276163, GB-2276164, GB-2276165, WO-9504729, WO-9506044, WO-9506637, WO-9511243, WO-9611934, WO9619477, WO-9631508 and FR-9408981, FR-9512218, FR-9601273, FR-9601275 describe aromatic derivatives as 5-HT antagonists, B, | D and recent publications which describe GR127,935 as a 5-HT antagonist, B "D (cf. M.

Skingle et al., J. of Psychopharm. 8 (1), 14, 1994; S. Starkey, M. Skingle,
Neuropharmacol., 33, 393, 1994).

The derivatives of the present invention are distinguished from the prior art not only by their new chemical structure which unambiguously differentiates them from the previously described derivatives but also by their original biological profile, in particular as regards their selectivity for the subtypes of serotonin receptors and as regards their antagonistic activity in particular at the level of receptors known as human 5-HTIDb or 5-HTXB.

dans laquelle
A représente H,H, ou CH2CH2 ou CH=CH;
Z, représente CO, SO2, (CH2)m+1, CO(CH2)m, SO2(CH2)m, (CH2)mCO, CO(CH2)mSO2, SO2(CH2)mSO2, (CH2)mSO2, CO(CH2)mCO, SO2(CH2)mCO; dans lesquels m représente un nombre entier compris entre 1 et 6.The present invention relates to products of general formula (I):

in which
A represents H, H, or CH2CH2 or CH = CH;
Z, represents CO, SO2, (CH2) m + 1, CO (CH2) m, SO2 (CH2) m, (CH2) mCO, CO (CH2) mSO2, SO2 (CH2) mSO2, (CH2) mSO2, CO ( CH2) mCO, SO2 (CH2) mCO; in which m represents an integer between 1 and 6.

XY represents NCH2, NCH2CH2, C = CH, CR1-CH2 where R4 represents H or a halogen (Cl, F, Br), OH, NH2, CN, NO2, R2, OR2, SR2, NHR2, COR2, CHOHR2,
COOR2, NHCOR2, NHCOOR2, NHSO2R2, OCONHR2, in which R2 represents a linear or branched alkyl chain comprising from 1 to 5 carbon atoms, an aryl or an alkylaryl in which the aryl residue is chosen from phenyl, naphthyl or pyridyl possibly optionally substituted by one or more groups chosen from a linear or branched alkyl comprising from 1 to 5 carbon atoms, a halogen (Cl, F, Br or I), OH, OR3, SR3, CF3, CH2CF3, NO2, CN , COR3, COOR3, NHR3, NHCOR3, NHCOOR3, NHSO2R3, SO2R3 in which R3 represents a hydrogen or a linear or branched alkyl chain comprising from 1 to 5 carbon atoms;
Z2 is omitted or represents (CH2) n, (CH2) nCO, CO, CO (CH2) n, O (CH2) n, O (CH2) nCO,
OCO, NH (CH2) n NH (CH2) nCO, NHCO, NHCO (CH2) n, NHSO2 (CH2) n CH = CHCO, or C = -C-CO, SO2, SO2 (CH2) n, NH (CH2) nSO2, NHSO2 (CH2) nSO2, O (CH2) nSO2; in the particular case where XY represents CHCH2, Z2 can also represent O,
NH, CONH, SO2NH, OCONH, NHCOO, NHCONH, (CH2), NH, (CH2) nO,
CO (CH2) nNH, NH (CH2) nO, NH (CH2) nNH, O (CH2) nNH, O (CH2) nO, CO (CH2) nO,
SO2 (CH2) nNH, SO2 (CH2) nO, (CH2) nSO2NH, (CH2) nCONH, O (CH2) nSO2NH,
O (CH2) nCONH, NH (CH2) nSO2NH, NH (CH2) nCONH, NHCO (CH2) nNH, NHSO2 (CH2) nNH; in the particular case where XY represents CR, -CH2 or C = CH, Z2 can also represent -CH = CH-, -CC-, n represents an integer between 1 and 6
Ar represents an aromatic residue (phenyl, naphthyl or pyridyl) which can be variously substituted
for example by one or more groups chosen from a linear or branched alkyl comprising from 1 to 6 carbon atoms, a trifluoromethyl, a trifluoromethoxy, a 2,2,2-trifluoroethyl, a phenyl, a benzyl, a cycloalkyl comprising from 3 to 7 carbon atoms, a hydroxyl, a thiol, an alkoxy (OR4), thioether (SR4), a nitro (NO2), a nitrile (CN), an amine (NH2 or NR4R4,), an amine derivative (NHCOR4 , NHSO2R4, NHCONR4R4 ', NHCO2R4, NHSO2NR4R4,), a halogen (fluorine, chlorine, bromine or iodine), a carbonyl (COH, COR4, COOR4,
CONR4R4 ')
or by a heterocycle which can optionally be substituted such as a 5-membered heterocycle which can contain from 1 to 4 heteroatoms chosen from oxygen, sulfur or nitrogen or by two substituents on neighboring carbons which can form a ring with the remainder aromatic to which they are attached,
or else, the residue Ar-Z2 represents a tetrahydronaphthyl, the bond with X of which uses a saturated carbon,
R4 represents an alkyl residue, linear or branched, comprising from 1 to 6 carbon atoms, R4 represents a hydrogen or an alkyl residue, linear or branched, comprising from 1 to 6 carbon atoms; and their hydrated salts, physiologically acceptable solvates for therapeutic use.

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

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

dans laquelle Z, représente CO, COCH2, CH2CO et Ar, X-Y, A sont définis comme dans la formule (I). Parmi les composés de formule (Ia), une sous-classe de composés plus particulièrement appréciée correspond aux produits (Ia) dans lesquels
A représente H,H ou CH2CH2 et X-Y représente NCH2 ou CH2CH2.A particularly appreciated class of compounds of formula (I) corresponds to the compounds of formula (Ia)

in which Z represents CO, COCH2, CH2CO and Ar, XY, A are defined as in formula (I). Among the compounds of formula (Ia), a subclass of compounds which is more particularly appreciated corresponds to the products (Ia) in which
A represents H, H or CH2CH2 and XY represents NCH2 or CH2CH2.

dans laquelle Z1 représente CO, COCH2, CH2CO et Ar, X-Y, A sont définis comme dans la formule (I) et n est un entier compris entre 1 et 6. Parmi les composés de formule (Ib), une sous-classe de composés plus particulièrement appréciée correspond aux produits (Ib) dans lesquels A représente H,H ou CH2CH2 et X-Y représente NCH2 ou CH2CH2.Another particularly appreciated class of compounds of formula (I) corresponds to the compounds of formula (Ib):

in which Z1 represents CO, COCH2, CH2CO and Ar, XY, A are defined as in formula (I) and n is an integer between 1 and 6. Among the compounds of formula (Ib), a subclass of compounds more particularly appreciated corresponds to the products (Ib) in which A represents H, H or CH2CH2 and XY represents NCH2 or CH2CH2.

dans laquelle A représente CH=CH, CH2-CH2 ou H,H avec un électrophile de formule générale (III)

dans laquelle Ar, Zl, Z2 et X-Y sont définis comme dans la formule générale (I) et L représente un groupe partant dont le choix dépendra de la nature de Z,.The derivatives of general formula (I) forming part of the present invention are prepared, in general, by condensation of an aromatic amine of general formula (II)

in which A represents CH = CH, CH2-CH2 or H, H with an electrophile of general formula (III)

in which Ar, Zl, Z2 and XY are defined as in the general formula (I) and L represents a leaving group whose choice will depend on the nature of Z ,.

Thus, the condensation of an aromatic amine of general formula (II) with an electrophile of general formula (III) to prepare a compound of formula (I) in which Z1 represents (CH2) m + i, CO (CH2 ) m or SO2 (CH2) m, will be produced with a derivative of formula (III) in which L will be chosen from chlorine, bromine, iodine, O-mesylate, O-triflate, O-tosylate, presence of an organic base (such as for example a tertiary amine BuOK, DBU, an amide) or inorganic (NaH, KH, K2CO3, Cs2CO3, Na2CO3) in a polar aprotic solvent such as
THF, methylethycetone, DMSO, DMF, DME, at a temperature between -10 C and 1000C.

The preparation of the derivatives of general formula (I) in which Z represents (CH2) mCO, CO (CH2) mCO or SO2 (CH2) mCO is carried out by condensation of an intermediate of formula (II) with an electrophilic agent derived from d carboxylic acid of formula (III) in which Z represents (CH2) mCO, CO (CH2) mCO or SO2 (CH2) mCO and L preferably represents chlorine or a hydroxyl, or alternatively, the "COL" group of intermediates of formula (III) represents an activated form of a carboxylic acid suitable for the formation of an amide by condensation with an amine. This condensation will be carried out by methods and techniques well known to those skilled in the art for preparing an amide from an amine and a carboxylic acid derivative. The choice of methods among the very numerous previously described will be guided by the nature of the reagents (II) and (III) present.

Thus, by way of example, this reaction can be carried out by condensation of an amine of formula (II) with a carboxylic acid derivative of formula (III) in which L represents chlorine, in the presence an organic or inorganic base such as pyridine, DIPEA, 4-DMAP, DBU, K2CO3, Cs2CO3 in a polar aprotic anhydrous solvent such as THF, DME, dichloromethane at a temperature between - 20 " C and 40 "C. Another particularly preferred method of preparing the compounds of formula (I) in which Z represents (CH2) mCO, CO (CH2) mCO or SO2 (CH2) mCO consists in condensing an amine of formula (II) with a carboxylic acid of formula (III) in which L represents OH by using reagents well known for this type of condensation such as for example DCC, EDCI, PyBOP, BOP, in a polar anhydrous solvent such as THF, dichloromethane, DME, dichloroethane, in the presence of a base in stoichiometric amounts such as for example triethylamine optionally in the presence of a base in catalytic amount such as for example 4-DMAP.

The derivatives of formula (I) of the present invention in which Z1 represents (CH2) mSO2, CO (CH2) mSO2 or SO2 (CH2) mSO2 are prepared by condensation of an amine of general formula (II) with a sulfonyl chloride of general formula (III) in which Z represents (CH2) mSO2, CO (CH2) mSO2 or SO2 (CH2) mSO2 and L represents chlorine, in a polar anhydrous solvent such as THF, DMF,
DMSO, DME, in the presence of an organic base (for example a tertiary amine) or inorganic (K2CO3, Cs2CO3 or NaH) at a temperature between - 20 "C and 80" C.

dans laquelle Ar, Z2 et X-Y sont définis comme dans la formule générale (I), avec un électrophile de formule générale (V)

dans laquelle X, et X2, identiques ou différents, représentent chacun un groupe partant tel qu'un halogène (en particulier le chlore), un groupe O-alkyle (en particulier le groupe Oc13), un groupe O-aryle (en particulier les groupes Opyridyle ou O-phényle substitué par exemple par un reste nitro), un groupe succinimide, phtalimide ou imidazolyle.In the particular case of the compounds of formula (I) in which Z1 represents CO, a particularly appreciated preparation method consists in condensing an amine of general formula (II) defined as above and a cyclic amine derivative of general formula (IV)

in which Ar, Z2 and XY are defined as in general formula (I), with an electrophile of general formula (V)

in which X, and X2, identical or different, each represent a leaving group such as a halogen (in particular chlorine), an O-alkyl group (in particular the group Oc13), an O-aryl group (in particular the Opyridyl or O-phenyl groups substituted for example by a nitro residue), a succinimide, phthalimide or imidazolyl group.

The methods and techniques chosen for carrying out the preparation of the compounds of formula (I) in which Z represents CO by condensation of the aromatic amines of general formula (II) and of the cyclic amines of general formula (IV) with an electrophilic of general formula (V) such as the choice of the order in which the reactants are brought into contact, the reaction times, the isolation and / or the purification of the intermediates, the temperature of the reactions at different stages of the condensation, the nature of the solvent (s), the presence of co-reagents (such as an organic base such as for example a tertiary amine such as triethylamine) or catalysts and the choice of reagent (V) (nature of X, and X2) will be essentially determined by the nature of (II).

Thus, a particularly preferred method for the preparation of derivatives of formula (I) in which Z represents CO consists in reacting a cyclic amine of formula (IV) in which Ar, XY and Z2 are defined as above with triphosgene, in the presence of a base such as triethylamine or pyridine in an aprotic anhydrous solvent such as dichloromethane, and then adding a compound of formula (II).

The aromatic cyclic amines of general formula (II) are obtained by the methods previously described as in patent applications WO-9611934 and WO-9619477.

dans laquelle L' représente un halogène (brome, iode ou préférentiellement C1 si Z1 représente CO(CH2)m ou SO2(CH2)m) et L sera choisi parmi un chlore, un brome, un iode, un O-mésylate, un O-triflate, un O-tosylate, en présence d'une base organique (telle que par exemple une amine tertiaire, 'BuOK, DBU, un amidure) ou inorganique (NaH, KH, K2CO3, Cs2CO3 CaCO3) dans un solvant aprotique polaire tel que le THF, le DMF, le DMSO, la DME, la méthyléthylcétone, à une température comprise entre- 10"C et 100 C dépendant de la nature de Zl. The electrophiles of general formula (III) are prepared from cyclic amines of general formula (IV) by different methods and techniques, the choice of which will essentially depend on the nature of Z 1. Thus, the intermediates of general formula (III) in which Z represents (CH2) m + "CO (CH2) m or SO2 (CH2) m are prepared by condensation of a cyclic amine of general formula (IV) with an ambident electrophile of general formula (VI)

in which L 'represents a halogen (bromine, iodine or preferably C1 if Z1 represents CO (CH2) m or SO2 (CH2) m) and L will be chosen from chlorine, bromine, iodine, O-mesylate, O -triflate, an O-tosylate, in the presence of an organic base (such as for example a tertiary amine, 'BuOK, DBU, an amide) or inorganic (NaH, KH, K2CO3, Cs2CO3 CaCO3) in a polar aprotic solvent such than THF, DMF, DMSO, DME, methyl ethyl ketone, at a temperature of between -10 "C and 100 C depending on the nature of Zl.

dans lesquels L représente un groupe partant tel qu' un halogène (chlore ,brome, iode) ou encore un O-mésylate, un 0-triflate, un O-tosylate lorsque Z, représente (CH2)mCO, m représente un nombre entier compris entre 1 et 6 et R' représente un reste alkyle comprenant de 1 à 5 atomes de carbone en chaîne droite ou ramifiée ou un phényle ou un benzoyle, suivi de l'hydrolyse de la fonction ester par les méthodes et techniques bien connues de l'homme de l'art pour transformer un ester en acide carboxylique telles que par exemple l'utilisation de LiOH ou du KOH. Les chlorures d'acide dérivés de ces acides carboxyliques sont si nécessaires, obtenus après réaction par exemple avec SOCI2, POCI3, le chlorure d'oxalyle en présence éventuelle d'une base organique telle qu'une amine tertiaire.In the particular case where Z represents (CH2) mCO, CO (CH2) mCO or SO2 (CH2) mCO, the intermediates of general formula (III) which are then carboxylic acids or derivatives of carboxylic acid (such as acid chlorides) are prepared by condensation of a cyclic amine of general formula (IV) with an ester derived from carboxylic acid of formula (VIIa), (VIIb) or (VIIc)

in which L represents a leaving group such as a halogen (chlorine, bromine, iodine) or also an O-mesylate, an 0-triflate, an O-tosylate when Z, represents (CH2) mCO, m represents an integer included between 1 and 6 and R 'represents an alkyl residue comprising from 1 to 5 carbon atoms in a straight or branched chain or a phenyl or a benzoyl, followed by the hydrolysis of the ester function by the methods and techniques well known in the art. skilled in the art to transform an ester into a carboxylic acid such as for example the use of LiOH or KOH. The acid chlorides derived from these carboxylic acids are if necessary, obtained after reaction, for example with SOCI2, POCI3, oxalyl chloride in the possible presence of an organic base such as a tertiary amine.

dans laquelle L représente un groupe partant tel qu'un halogène (brome, iode ou chlore, le chlore étant préféré si Z, représente SO2(CH2)mSO2 ou CO(CH2)mCO) ou encore un un O-mésylate, un O-triflate, un O-tosylate lorsque Z, représente (CH2)mco ou (CH2)SO2,
Z, représente (CH2)mSO2, (CH2)mCO, CO(CH2)mSO2 ou CO(CH2)mCO et A représente
H, H, CH2-CH2 ou CH=CH avec un nucléophile de formule générale (IV) dans laquelle Ar, Z2 et X-Y sont définis comme précédemment par les méthodes et techniques décrites préalablement pour ce type de condensation.In the case of derivatives of general formula (I) in which Z represents (CH2) mSO2, CO (CH2) mSO2, (CH2) mCO or CO (CH2) mCO, an alternative but particularly appreciated method of synthesis consists in condensing a intermediate of general formula (VIII)

in which L represents a leaving group such as a halogen (bromine, iodine or chlorine, chlorine being preferred if Z, represents SO2 (CH2) mSO2 or CO (CH2) mCO) or an O-mesylate, an O- triflate, an O-tosylate when Z represents (CH2) mco or (CH2) SO2,
Z represents (CH2) mSO2, (CH2) mCO, CO (CH2) mSO2 or CO (CH2) mCO and A represents
H, H, CH2-CH2 or CH = CH with a nucleophile of general formula (IV) in which Ar, Z2 and XY are defined as previously by the methods and techniques described previously for this type of condensation.

The intermediates of general formula (VIII) in which Z represents (CH2) mSO2, (CH2) mCO, CO (CH2) mSO2 or CO (CH2) mCO are prepared by condensation of an aromatic amine of formula (II) with a electrophile chosen respectively from one of the compounds (IXa) to (IXf)
L- (CH2) m CONCERN (IXa) R'OOC (CH2) m SO2CI (IXd)
L - (CH2) m COCI (IXb) R'OOC - (CH2) m COCI (IXe)
L (CH2) m COOH (lXc) R'OOC - (CH2) m COOH (lXf) in which m, R 'and L are defined as above, it being understood that the intermediate esters obtained in the case of condensation with derivatives (IXd) and (IXf) will then be transformed into carboxylic acids or acid chlorides by the methods described above.

Also to be considered as forming part of the present invention all the methods which make it possible to transform a derivative of formula (I) into another derivative of formula (I) in which at least one of the definitions of Ar, Z2, X
Y, Z, or A is different, by techniques and methods well known to those skilled in the art. Thus, by way of example, the derivatives of general formula (I) in which XY represents CH-C H2 can also be prepared by hydrogenation of the unsaturated piperidines of formula (I) in which XY represents C = CH, in using hydrogen at atmospheric pressure in the presence of palladium or platinum on carbon. Likewise, a particularly preferred method within the framework of this invention for the preparation of compounds of formula (I) in which A represents CH = CH consists in carrying out a dehydrogenation starting from a compound of general formula (I) in which A represents CH2-CH2, using agents well known for this type of preparation such as, for example, 2,3-dichloro-5,6-dicyano1,4-benzoquinone (cf. J. Bermudez, S. Dabbs, KAJoiner , FDKinsg, J. Med. Chem., 33 1929-1932, 1990).

It will be understood that in certain reactions or sequences of chemical reactions which lead to the preparation of compounds of general formula (I) it is necessary or desirable to protect possible sensitive groups in the synthesis intermediates in order to avoid undesirable side reactions. This can be achieved by the use (introduction and deprotection) of conventional protective groups such as those described in "Protective groups in Organic Synthesis", TW Greene,
John Wiley & Sons, 1981 and "Protecting Groups", PJ Kocienski, Thieme Verlag, 1994. The appropriate protective groups will therefore be introduced and removed during the most appropriate step for this, using the methods and techniques described in references cited above.

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

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

When the new compounds of general formula (I) have one or more asymmetric centers, they can be prepared in the form of a racemic mixture or in the form of enantiomers, either by enantioselective synthesis or by resolution. The compounds of formula (I) having at least one asymmetric center can for example be separated into their enatiomers by the usual techniques such as the formation of diastereomeric pairs by formation of a salt with an optically active acid such as acid (+ ) -di-p-toluoyl-l-tartaric, (+) camphorsulfonic acid, (-) - camphorsulfonic acid, (+) - phenylpropionic acid,
(-) - phenylpropionic acid, followed by fractional crystallization and regeneration of the free base.

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

In the proton NMR spectra, the chemical shifts are expressed in ppm and the following abbreviations have been used: "s" for singlet; "se" for widened singlet, "d" for doublet, "dd" for doublet of doublet, "t" for triplet, "q" for quadruplet, "sx" for sextuplet, "m" for multiplet, "M" for solid .

In the infrared spectra, the absorption bands are given in cm1
EXAMPLE 1
1-t4- (2,3-dimethylphenyl) piperazin-1-carbonyl] -1 'methyl-2,3,6,7
tetrahydrospirolfurol2,3- indole-7,4'-piperidine]

A solution of I '-methyl-2,3,6,7-tetrahydrospiro [furo [2,3 -f] indole-7,4' -piperidine] which can be prepared according to the method described in patent WO96 / 19477 (361 mg , 1.4mmol) and pyridine (113C11, 1.4mmol) in dichloromethane (1 OmI) is slowly cannulated on a solution of l-chlorocarbonyl-4- (2,3dimethylphenyl) piperazine which can be prepared according to the method described in the patent FR 9408981 (351mg, 1.4mmol) in dichloromethane (lSml) under a nitrogen atmosphere. During this operation, the reaction mixture is cooled with an ice bath. It is then brought back to room temperature and stirred for 4 hours.

After this time, the mixture is diluted with water and the aqueous phase is brought to a pH of 10-11 with sodium hydroxide. It is then extracted three times with dichloromethane. The organic phases are combined, washed once with a saturated sodium chloride solution, dried over magnesium sulfate and concentrated. The crude is purified with a mixture (90/9/1) of dichloromethane / methanol / ammonia.

Mass obtained: 523 mg (Yield: 81%) 1 H NMR (CDCI 3): 1.79 (M, 2H); 2.08 (M, 4H); 2.25 (s, 3H); 2.28 (s, 3H); 2.38 (s, 3H); 2.96 (M, 8H); 3.53 (M, 4H); 3.94 (t, 8Hz, 2H); 4.36 (s, 2H); 6.64 (s, 1H); 6.93 (m, 3H); 7.09 (t, 8.7Hz, 1H);
EXAMPLE 2
1'-methyl- [1- (4-phenethylpiperazin-1-carbonyl) -2,3,6,7- tetrahydrospirolfuro [2,3-4indole-7,4'-piperidinel dihydrochloride

A solution of phenethylpiperazine (359mg, 1.9mmol) and pyridine (155p1, 1.9mmol) in dichloromethane (15ml) is slowly cannulated over a solution of triphosgene (198mg, 0.62mmol) in dichloromethane (40ml) 'nitrogen. During this operation, the reaction mixture is cooled with an ice bath. It is then brought to room temperature for 20 min before the addition of 1'-methyl-2,3, 6,7-tetrahydrospiro [furo [2,3-fJindole-7 '-piperidine] (492mg, 1.89mmol) and the pyridine (155p1, 1.9mmol) diluted in dichloromethane (lSml).

After 2 h at room temperature, the dichloromethane is evaporated and replaced with dimethylformamide (30 ml). The reaction mixture is then heated for 48 h at 70 ° C. It is then poured into a 1 M sodium hydroxide solution and extracted three times with dichloromethane. The combined organic phases are then washed three times with a saturated solution of sodium chloride, dried over magnesium sulphate and concentrated, the crude product is purified by flash chromatography with a mixture (90/9/1) of dichloromethane / methanol / ammonia.

Mass obtained: 574 mg (Yield: 66%)
Rf: 0.32 (dichloromethane / methanol / ammonia: 90/9/1)
The dihydrochloride is prepared by adding ether / HCl to a solution of the base in dichloromethane. The precipitate obtained is filtered and then dried.

Elemental Analysis for: C28H3 6N4O2-2HCl-0.6H2O
Calculated: C 61.78; H 7.26; N 10.29; Cl 13.03; Experimental: C 62.02; H 7.66;
N 10.31; Cl 12.46
IR (KBr): 3425.2950.2691, 2572.2448.1 651.1486.1403
1H NMR (DMSO): 1.82 (d, 13.6Hz, 2H); 2.49 (m, 4H); 2.73 (d, 4.4Hz, 3H); 2.95 (t, 8.0Hz, 2H); 3.08 (m, 4H); 3.30 (m, 4H); 3.60 (m, 4H); 3.72 (d, 11.6Hz, 2H); 3.86 (t, 8.0Hz, 2H); 4.47 (s, 2H); 6.73 (s, 1H); 6.95 (s, 1H); 7.33 (m, 5H); 10.99 (sc, 1H); 11.13 (se, 1H).

Composé 3a : 2-chloro- 1 -(1 '-méthyl-2,3,6,7-tétrahydrospiro[iro[2,3-findole-7,4 ' - pipéridine]- 1 -yl)éthanone
Le chlorure de chloroacéthyle (170,u1;2.1mmol) est ajouté goutte à goutte à une solution contenant le 1'-méthyl-2,3,6,7-tétrahydrospiro[furo[2,3-findole-7,4'- pipéridine] (505mg;2.lmmol) et du carbonate de calcium (620mg;6.2mmol) dans la méthyléthylcétone (30ml) à 0 C. Dix minutes après la fin de l'addition, le mélange réactionnel est filtré sur célite. Celle-ci est rincée abondamment avec de l'acétate d'éthyle puis de la soude 1M. Les phases sont ensuite séparées . La phase organique est lavée avec une solution saturée en chlorure de sodium, séchée sur sulfate de magnésium et concentrée. Le brut réactionnel est engagé tel quel dans l'étape suivante.Melting point: 252 "C (dec.)
EXAMPLE 3
2- (4-phenethylpiperazin-1-yl) -l- (l--methyl-2,3,6,7-tetrahydrospiro [furol2,3-
f] indole-7,4'-piperidine] -1-yl) ethanone

Compound 3a: 2-chloro- 1 - (1 '-methyl-2,3,6,7-tetrahydrospiro [iro [2,3-findole-7,4' - piperidine] - 1 -yl) ethanone
Chloroacethyl chloride (170, u1; 2.1mmol) is added dropwise to a solution containing 1'-methyl-2,3,6,7-tetrahydrospiro [furo [2,3-findole-7,4'- piperidine] (505mg; 2.lmmol) and calcium carbonate (620mg; 6.2mmol) in methyl ethyl ketone (30ml) at 0 C. Ten minutes after the end of the addition, the reaction mixture is filtered through celite. This is rinsed thoroughly with ethyl acetate and then 1M sodium hydroxide. The phases are then separated. The organic phase is washed with a saturated sodium chloride solution, dried over magnesium sulfate and concentrated. The reaction crude is used as is in the next step.

Mass obtained: 620 mg (Yield: 93%)
1H NMR (CDCl3): 1.74 (m, 2H); 2.05 (m, 4H); 2.32 (s, 3H); 2.84 (m, 2H); 3.17 (t, 8.4Hz, 2H); 4.13 (s, 2H); 4.17 (t, 8.4Hz, 2H); 4.38 (s, 2H); 6.63 (s, 1H); 8.11 (s, 1H).

Compound 3: A solution containing 2-chloro-1- (1 '-methyl-2,3,6,7 tetrahydrospiro [furo [2,3-findole-7,4'-piperidine] -1-yl) ethanone ( compound W3a (617mg; 1.9mmol), phenethylpiperazine (430mg, 2.2mmol), potassium carbonate (800mg, 5.8mmol) and potassium iodide (32mg, 0.2mmol) in dimethylformamide (20ml) is heated to 80 "C for 5 h. After this time, the reaction mixture is diluted with water and then extracted three times with ethyl acetate. The combined organic phases are combined and then washed three times with a saturated chloride solution. sodium, dried over magnesium sulphate and concentrated. The crude product is purified by flash chromatography with a mixture (92/8/1) of dichloromethane / methanol / ammonia.

Mass obtained: 650mg (Yield: 72%)
Rf: 0.32 (dichloromethane / methanol / ammonia: 90/9/1) 1H NMR (CDCl3) 1.75 (m, 2H); 2.04 (m, 4H); 2.31 (s, 3H); 2.63 (M, 1OH); 2.83 (m, 4H); 3.11 (t, 8.4Hz, 2H); 3.23 (s, 2H); 4.18 (t, 8.4Hz, 2H); 4.36 (s, 2H); 6.62 (s, 1H); 7.20 (m, 3H); 7.30 (m, 2H); 8.14 (s, 1H).

EXAMPLE 4
1- (4-phenethylpiperazin-1-yl) -2- (1 '-methyl-2,3,6,7-tetrahydrospiro [furo 12.3
f] indole-7,4'-piperidine] -1-yl) ethanone

Compound 4 is prepared according to the procedure described for compound 3 from the following reagents: 2-chloro-1 - (4-phenethylpiperazin-1 -yl) ethanone (530mg; 2.0mmol) which can be prepared according to the method described in patent F 9601274; 1 '-methyl 2,3,6,7-tetrahydrospiro [furo [2,3-f] indole-7,4' -piperidine] (402 mg; 1.7 mmol); potassium carbonate (692mg; 4.9mmol); potassium iodide (50mg; 0.3mmol); dimethylformamide (20ml). The crude is purified by flash chromatography with a mixture (92/8/1) of dichloromethane / methanol / ammonia.

Mass obtained: 195 mg (Yield: 25%)
Rf: 0.36 (dichloromethane / methanol / ammonia: 90/9/1)
1H NMR (CDCI3): 1.70 (M, 2H); 2.00 (M, 4H); 2.30 (s, 3H); 2.55 (M, 4H); 2.65 (m, 2H); 2.82 (m, 4H); 3.07 (m, 2H); 3.46 (M, 2H); 3.72 (M, 2H); 4.11 (m, 2H); 4.35 (s, 2H); 4.82 (s, 2H); 6.60 (s, 1H); 7.21 (m, 3H); 7.27 (m, 2H); 7.71 (s, 1H).

EXAMPLE 5 l- (4-cyano-4-phenylpiperidin-1-carbonyl) - i '-methyl-2,3,6,7 tetrahydrospiro [furol2,3-flindole-7,4'-piperidinel

Compound 5 is prepared according to the procedure described in Example 2 from 4-phenyl-4-cyanopiperidine and 1'-methyl-2,3,6,7-tetrahydrospiro [furo [2,3-fgindole- 7,4'-piperidine]
EXAMPLE 6
1- (4-phenyltetrahydro-1,2,3,6-pyridin-1-carbonyl) -1'-methyl-2,3,6,7 tetrahydrospirolfuro [2,3-flindole-7,4'-piperidine]

Compound 6 is prepared according to the procedure described in Example 2 from 4-phenyl-1,2,5,6-tetrahydropyridine and 1 '-methyl-2,3,6,7-tetrahydrospiro [furo [ 2,3-f] indole-7,4'-piperidine]
EXAMPLE 7 l- (4-phenylpiperidin-1-carbonyl) -l--methyl-2,3,6,7-tetrahydrospiro [furo [2,3 f] indole-7,4'-piperidinel

Compound 2 is prepared according to the procedure described in Example 2 from 4-phenylpiperidine and 1 ′ -methyl-2,3,6,7-tetrahydrospiro [furo [2,3-f] indole-7, 4 '- piperidine].

EXAMPLE 8
l- (4-Inaphthalen-1-ylsulfonyljpiperazin-1-carbonyl) -l '-methyl-2,3,6,7 tetrahydrospiro [furo [2,3-fj indole-7,4'-piperidine]

Compound 8 is prepared according to the procedure described in Example 2 from 1- (naphthalen-1-ylsulfonyl) piperazine which can be prepared according to the method described in patent F 9601273 and 1'-methyl-2,3 , 6,7-tetrahydrospiro [furo [2,3-f] indole- 7,4'-piperidine]
EXAMPLE 9 1- [4- (2-naphthalen-2-yl-2-oxoethan-1-yl) piperazin-1-carbonyl] -1'-methyl-2,3,6,7-
tetrahydrospiro [furo [2,3-flindole-7,4'-piperidine]

Compound 9 is prepared according to the procedure described in Example 2 from 1 - (2-naphthalen-2-yl-2-oxoethan-1-yl) piperazine which can be prepared according to the method described in patent F 9601273 and 1'-methyl-2,3,6,7 tetrahydrospiro [furo C2,3 -fJ indole-7,4 '-pipenedine]
EXAMPLE 10
l-14- (2-fluorophenethyl) piperazin-l-carbonyljl '-methyl-2,3,6,7
tetrahydrospiro [furo [2,3-f] indole-7,4'-piperidine]

Compound 10 is prepared according to the procedure described in Example 2 from 1- (2-fluorophenethyl) piperazine which can be prepared according to the method described in patent FR-9601273 and 1'-methyl-2,3, 6,7-tetrahydrospiro [furo [2,3-fJindole- 7,4'-piperidine]
EXAMPLE 11
N- (1 '-methyl-2,3-dihydrospiro [benzofuran-3,4'-piperidinel) -4- (2,3-
dimethylphenyl) piperazin-1-ylamide

Compound 11 is prepared according to the procedure described in Example 2 from 1 - (2,3-dimethylphenyl) piperazine and 5-amino-2,3-dihydro- 1 '-methylspiro [3,4-benzofuran '-piperidine], the synthesis of which is described in patent WO96 / 11934.

EXAMPLE 12
N- (1'--methyl-2,3-dihydrospiro [benzofuran-3,4'-piperidinel) -4-phenylpiperidin-
l-ylamide

Compound 12 is prepared according to the procedure described in Example 2 from 1-phenylpiperidine and 5-amino-2,3-dihydro- l'-methylspiro [benzofuran-3,4'- piperidine], the synthesis of which is described in patent WO 96/11934.

EXAMPLE 13 N- (1'-methyl-2,3-dihydrospiro [benzofuran-3,4'-piperidinel) -4 phenethylpiperazin-l-ylamide

Compound 11 is prepared according to the procedure described in Example 2 from 1-phenethylpiperazine and 5-amino-2,3-dihydro- 1 '-methylspiro [benzofuran-3, 4'- piperidine], the synthesis of which is described in patent WO 96/11934.

The derivatives of the present invention are 5-HT1B, 1D receptor antagonists as shown by the binding studies and the antagonism studies of the inhibition of adenylate cyclase (stimulated by forskolin) by an agonist such as serotonin, sumatriptan or 5-CT, studies which have been carried out on cloned human receptors 5-HT ,,,,,. These human receptors were cloned according to the sequences published by M. Hamblin and M. Metcalf, Mol. Pharmacol., 40,143 (1991) and
Weinshenk et al., Proc. Natl. Acad. Sci 89.3630 (1992).

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

The study of the binding of the derivatives of the present invention with human 5-HT, B and 5-HTlD receptors was carried out according to the method described by P. Pauwels and C.

Palm tree (Neuropharmacology, 33,67,1994).

The study of the inhibition of the formation of cyclic AMP (stimulated by forskolin) mediated by human 5-HT, B and 5-HT, D receptors was carried out in cells transfected by the receptor according to a described technique. previously (P. Pauwels and
C. Palmier, Neuropharmacology, 33,67,1994; Cell. Pharmacol. 2.183.1995; Cell.

Pharmacol. 2.49.1995; Eur. J. ofPharmacol. (Mol. Pharm.) 290.95.1995).

The new compounds forming part of the present invention are potent and selective antagonists of 5-HT, B "D receptors and have the advantage of being particularly selective for human 5-HT, B" D receptors in particular with respect to 5-HT, A, 5-HT, c, 5-HT2, a1, a2 and D2 receptors.

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

These properties of the 5-HT, D "B antagonists claimed in the present invention make them particularly interesting and useful for the treatment of patients suffering from disorders of the central nervous system. Therefore, the present invention also comprises a method for treating such patients, a method which employs the administration of an active dose of a compound corresponding to the general formula (I).

Furthermore, the derivatives of the present invention are also capable of controlling the growth and proliferation of C6 type glial cells transfected by the 5-HTlD receptor gene and by the S-HTlB receptor gene stimulated by a hormonal mediator such as serotonin. By way of example, the examples of the present invention inhibit the incorporation of labeled thymidine (stimulated with 0.1 μM of sumatriptan) with an IC50 of 10 to 1000 nM (method described by P. Pauwels et al., Naunyn-Schmiedeberg's Arch Pharmacol., 354,136,1996). As such, the derivatives of the present invention therefore also find their utility in the treatment of cancers and other disorders linked to cell proliferation.

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

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-HT receptor antagonist, A (such as, for example pindolol, WAY 100135, UH-301 or WAY 100635). This association is also part of the present invention.

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

As solid compositions for oral administration, tablets, pills, powders (gelatin capsules, cachets) or granules can be used.

In these compositions, the active principle according to the invention is mixed with one or more inert diluents, such as starch, cellulose, sucrose, lactose or silica, under a stream of argon. These compositions can also comprise substances other than diluents, for example one or more lubricants such as magnesium stearate or talc, a dye, a coating (dragees) or a varnish.

As liquid compositions for oral administration, there may be used pharmaceutically acceptable solutions, suspensions, emulsions, syrups and elixirs containing inert diluents such as water,
Ethanol, glycerol, vegetable oils or paraffin oil. These compositions can include substances other than diluents, for example wetting, sweetening, thickening, flavoring or stabilizing products.

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

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

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

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

In general, the doctor will determine the appropriate dosage based on age, weight and all other factors specific to the subject to be treated. The following examples illustrate compositions according to the invention [in these examples, the term "active component" denotes one or more (generally one) of the compounds of formula (I) according to the present invention]:
Tablets
They can be prepared by direct compression or by passing through wet granulation. The direct compression procedure is preferred, but it may not be suitable in all cases depending on the doses and the physical properties of the active component.

A - By direct compression
mg per 1 tablet active ingredient 10.0 microcrystalline cellulose PCB 89.5 magnesium stearate 0 5
100.0
The active component is passed through a sieve with a mesh opening of 250 μm on a side, it is mixed with the excipients and it is compressed using 6.0 mm punches.

Tablets with other mechanical strengths can be prepared by varying the compression weight with the use of appropriate punches.

B - Wet granulation
mg for one tablet active ingredient 10.0 lactose Codex 74.5 starch Codex 10.0 corn starch pregelatinized Codex 5.0 magnesium stearate 0 * 5
Compression weight 100.0
The active component is passed through a sieve with a mesh size of 250 μm and mixed with the lactose, the starch and the pregelatinized starch. The mixed powders are moistened with purified water, they are granulated, dried, sieved and mixed with magnesium stearate. The lubricated granules are put into tablets as for the formulas by direct compression. A coating film can be applied to the tablets using suitable film-forming materials, for example methylcellulose or hydroxy-propyl-methyl-cellulose, according to conventional techniques. Sugar tablets can also be coated.

Capsules
mg for one capsule active component 10.0 * starch 1500 89.5 magnesium stearate Codex 0 5
Filling weight 100.0 * a form of directly compressible starch from the company Colorcon Ltd,
Orpington, Kent, United Kingdom.

The active component is passed through a sieve with a mesh opening of 250 μm and mixed with the other substances. The mixture is introduced into hard gelatin capsules No. 2 on an appropriate filling machine. Other dosage units can be prepared by modifying the filling weight and, if necessary, by changing the size of the capsule. .

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

distilled water preservative 5.0
The active component, the buffer, the flavor, the color and the preservative are dissolved in part of the water and the glycerin is added. The remainder of the water is heated to 800C and the sucrose is dissolved therein and then cooled. The two solutions are combined, the volume is adjusted and mixed. The syrup obtained is clarified by filtration.

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

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

Liquid for administration by intravenous injection
g / l active ingredient 2.0 water for injection Codex complement to 1000.0
Sodium chloride can be added to adjust the tone of the solution and adjust the pH to maximum stability and / or to facilitate the dissolution of the active component by means of a dilute acid or alkali or by adding buffer salts. appropriate. The solution is prepared, clarified and introduced into suitable size vials which are sealed by melting the glass. The liquid for injection can also be sterilized by heating in an autoclave according to one of the acceptable cycles. The solution can also be sterilized by filtration and introduced into a sterile ampoule under aseptic conditions. The solution can be introduced into the ampoules in a gaseous atmosphere.

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

Pressure aerosol with metering valve
mg / dose for 1 box of micronized active component 0.500 120 mg oleic acid Codex 0.050 12 mg trichlorofluoromethane for pharmaceutical use 22.25 5.34 g dichlorodifluoromethane for pharmaceutical use 60.90 14.62 g
The active component is micronized in a fluid energy mill and put into the state of fine particles. The oleic acid is mixed with the trichlorofluoromethane at a temperature of 10-15 ° C. and the micronized drug is introduced into the solution using a high shear mixer. The suspension is introduced in measured quantity into aluminum aerosol cans on which are fixed appropriate metering valves delivering a dose of 85 mg of the suspension; dichlorodifluoromethane is introduced into the cans by injection through the valves.

Claims (14)

1. Derivatives of general formula (I):

 in which A represents H, H, or CH2CH2 or CH = CH; Z1 represents CO, SO2, (CH2) m + "CO (CH2) m, SO2 (CH2) m, (CH2) mCO, CO (CH2) mSO2, SO2 (CH2) mSO2, (CH2) mSO2, CO (CH2) mCO , SO2 (CH2) mCO; in which m represents an integer between 1 and 6. R4 represents an alkyl residue, linear or branched, comprising from 1 to 6 carbon atoms; R4 'represents a hydrogen or an alkyl residue, linear or branched, comprising from 1 to 6 carbon atoms; and their hydrated salts, physiologically acceptable solvates for therapeutic use. X uses a saturated carbon,  or, the remainder Ar-Z2 represents a tetrahydronaphthyl, the bond with  or by a heterocycle which can optionally be substituted such as a 5-membered heterocycle which can contain from 1 to 4 heteroatoms chosen from oxygen, sulfur or nitrogen or by two substituents on neighboring carbons which can form a ring with the remainder aromatic to which they are attached,  for example by one or more groups chosen from a linear or branched alkyl comprising from 1 to 6 carbon atoms, a trifluoromethyl, a trifluoromethoxy, a 2,2,2-trifluoroethyl, a phenyl, a benzyl, a cycloalkyl comprising from 3 to 7 carbon atoms, a hydroxyl, a thiol, an alkoxy (OR4), thioether (SR4), a nitro (NO2), a nitrile (CN), an amine (NH2 or NR4R4,), an amine derivative (NHCOR4 , NHSO2R4, NHCONR4R4 ,, NHCO2R4, NHSO2NR4R4,), a halogen (fluorine, chlorine, bromine or iodine), a carbonyl (COH, COR4, COOR4, CONR4R4,) Ar represents an aromatic residue (phenyl, naphthyl or pyridyl) which can be variously substituted NHSO2 (CH2) nNH; in the particular case where X-Y represents CRl-CH2 or C = CH, Z2 can also represent -CH = CH-, -C-C-, n represents an integer between 1 and 6 O (CH2) nCONH, NH (CH2) nSO2NH, NH (CH2) nCONH, NHCO (CH2) nNH, SO2 (CH2) nNH, SO2 (CH2) nO, (CH2) nSO2NH, (CH2) nCONH, O (CH2) nSO2NH, CO (CH2) nNH, NH (CH2) nO, NH (CH2), NH, O (CH2) nNH, O (CH2) nO, CO (CH2) nO, NH, CONH, SO2NH, OCONH, NHCOO, NHCONH, (CH2) nNH, (CH2) nO, OCO, NH (CH2) n, NH (CH2) nCO, NHCO, NHCO (CH2) n, NHSO2 (CH2) n, CH = CHCO, or C = -C-CO, SO2, SO2 (CH2) n, NH ( CH2) nSO2, NHSO2 (CH2) nSO2, O (CH2) nSO2; in the particular case where X-Y represents CHCH2, Z2 can also represent O, Z2 is omitted or represents (CH2) n, (CH2) nCO, CO, CO (CH2) n, O (CH2) n, O (CH2) nCO, COOR3, NHR3, NHCOR3, NHCOOR3, NHSO2R3, SO2R3 in which R3 represents a hydrogen or a linear or branched alkyl chain comprising from 1 to 5 carbon atoms; COOR2, NHCOR2, NHCOOR2, NHSO2R2, OCONHR2, in which R2 represents a linear or branched alkyl chain comprising from 1 to 5 carbon atoms, an aryl or an alkylaryl in which the aryl residue is chosen from phenyl, naphthyl or pyridyl possibly optionally substituted by one or more groups chosen from a linear or branched alkyl comprising from 1 to 5 carbon atoms, a halogen (Cl, F, Br or I), OH, OR3, SR3, CF3, CH2CF3, NO2, CN , COR3, X-Y represents NCH2, NCH2CH2, C = CH, CR, -CH2 where R represents H or a halogen (Cl, F, Br), OH, NH2, CN, NO2, R2, OR2, SR2, NHR2, COR2, CHOHR2, 2. Compounds according to Claim 1, characterized in that they correspond to the  formula (Ia)

 as in the general formula (I).  in which Z represents CO, COCH2 or CH2CO, and Ar, X-Y and A are defined 3. Compounds according to Claim 1, characterized in that they correspond to the  formula (Ib)

 defined as in the general formula (I).  in which Z represents CO, COCH2 or CH2CO, and Ar, n, X-Y and A are 4. Compounds according to one of claims 1 to 3, characterized in that A  represents CH2CH2. 5. Compounds according to one of claims 1 to 3, characterized in that A represents  H, H. 6. Compounds according to one of claims 1 to 3, characterized in that X-Y  represents CH-CH2 or N-CH2. 7. Compounds according to one of claims 1 to 6 in the form of acceptable salts for  therapeutic use, characterized in that these salts are hydrochlorides,  hydrobromides, sulfates, methanesulfonates, fumarates, maleates, succinates,  phosphates, acetates, benzoates, naphthoates, p-toluenesulfonates, sulfamates,  ascorbates, tartrates, citrates, salicylates, lactates, glutarates or glutaconates. 8. Process for the preparation of the compounds of general formula (I) according to the  claim 1 characterized in that it consists of the condensation of an amine  aromatic of general formula (II)

 in which A represents CH = CH, CH2-CH2 or H, H with an electrophile of general formula (III)

 in which Ar, Z1, Z2 and X-Y are defined as in the general formula (I) and L represents a leaving group whose choice will depend on the nature of Z1. 9. Process for the preparation of a compound of formula (I) in which Z1 represents  CO characterized in that an aromatic amine of formula (II) is condensed  defined as in claim 8 and a cyclic amine of general formula  (IV)

 in which Ar, Z2 and X-Y are defined as in the general formula (I), with an electrophile of general formula (V)

 inorganic, such as a tertiary amine, in a polar aprotic solvent.  that for example Cl or OC Cl3 in the possible presence of an organic base or  in which X1 and X2, which are identical or different, represent a leaving group such 10. Pharmaceutical compositions containing, as active ingredients, a  compound according to one of claims 1 to 7, in combination with a vehicle  pharmaceutical acceptable, such as drugs. 11. Pharmaceutical compositions containing, as active ingredients, a  compound according to one of claims I to 7, in combination with a vehicle  pharmaceutical acceptable, for both curative and preventive treatment of  depression and obsessive-compulsive disorder or disorder. 12. Pharmaceutical compositions containing, as active ingredients, a  compound according to one of claims 1 to 7, in combination with a vehicle  pharmaceutical acceptable, for both curative and preventive treatment of  anxiety and panic attacks, schizophrenia, aggression,  bulimia, alcoholism, pain and neurodegenerative diseases  like Parkinson's or Alzheimer's disease. 13. Pharmaceutical compositions containing, as active ingredients, a  compound according to one of claims 1 to 7, in combination with a vehicle  pharmaceutical acceptable, for both curative and preventive treatment of  cancers. 14. Pharmaceutical compositions according to one of claims 10 to 13  characterized in that they contain, in addition, at least one second principle  active ingredient, endowed with antidepressant properties, in particular, the  MILNACIPRAN and / or a 5-HT antagonist, A.