FR2725984A1 - NOVEL AROMATIC ETHERS DERIVED FROM NAPHTYLPIPERAZINE USEFUL AS MEDICAMENTS - Google Patents

Abstract

Compounds of general formula (I), as defined in the description, therapeutically acceptable salts, solvates, hydrates and prodrugs thereof, a method for preparing same, pharmaceutical compositions containing said compounds, and the use thereof as drugs, are disclosed.

Description

The present invention relates to novel ethers derived from naphthylpiperazines, and 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 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). , chorea
Huntington), anorexia, bulimia nervosa, alcoholism-related disorders, cerebrovascular accidents, migraine or various headaches (R. Glennon, Neurosci Biobehavioral Reviews, 14, 35, 1990).

Numerous recent pharmacological studies have demonstrated the diversity of serotonin receptors and their respective involvement in its various modes of action (see E. Zifa, G. Fillion, Pharm Reviews, 44, 401, 1992; Langer, N. Brunello, G. Racagni, J. Mendlecvicz, "Serotonin Receptor Subtypes: Pharmacological Significance and Clinical Implications", Karger Ed. (1992), BE Leonard, Clinical Int Psychopharmacology, 2, 13-21 (1992) RW Fuller, J. Clin Psychiatry, 53, 3645 (1992), DG Grahame-Smith, Clinical Int Psychopharmacology, X, Suppl.4, 6-13, (1992). These receptors are subdivided mainly into 4 major classes (SHT1, 5HT2, SHT3 and 5HT4) which themselves include subclasses such as 5HT1 receptors which are mainly divided into SHT1A, 5HT1B, 5HT1D (see GR Martin, PA).

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

Invest. Drugs, 3 (5), 513, 1994). The 5HT1D receptors themselves contain several receptor subtypes; Thus, the 5HT1Da and 5HT1Db receptors have been cloned and then identified in humans (see, for example, Hamel et al., Mol.Pharmacol., 44, 242, 1993, GW Rebeck et al., Proc. Natl Acad Sci USA, 91, 3666, 1994).

The compounds according to the present invention are new compounds having a very high affinity and a very good selectivity for the receptors commonly called SHT1 and more particularly for the receptors called SHT1D, according to the new nomenclature recently proposed by P.

Humphrey, P. Hartig and D. Hoyer (TIPS, 14, 233-236, 1993)
The medicaments including (alone or in combination with other therapeutic agents) the active principles of the present invention find their use in the treatment as well as preventive treatment of diseases related to 5HT1 receptor dysfunction including SHT1A, SHT1Da and 5HT1DB receptors, their deregulation or changes in the activity of the endogenous ligand (usually serotonin).

The compounds of the present invention are potent and selective 5HT1 receptor ligands that may act as agonists, partial agonists or antagonists at these receptors, and may therefore find application in the above-mentioned serotonin-related disorders.

dans laquelle:
R1 représente un hydrogène ou un résidu alkyle linéaire ou ramifié comprenant de 1 à 6 atomes de carbone.The present invention relates to derivatives of general formula (I)

in which:
R1 represents a hydrogen or a linear or branched alkyl residue comprising from 1 to 6 carbon atoms.

R2 may be in various positions on the aromatic ring to which it is attached represents a substituent such as hydrogen, a halogen (fluorine, bromine, chlorine or iodine), a linear or branched alkyl residue comprising from 1 to 6 carbon atoms or an alkoxy radical (OR4) in which R4 represents a linear or branched alkyl comprising 1 to 6 carbon atoms, an aromatic residue such as phenyl, benzyl or phenethyl or a cycloalkyl of 4 to 10 carbon atoms.

R3 represents a hydrogen, a linear or branched alkyl residue comprising from 1 to 5 carbon atoms or an aromatic residue such as a phenyl.

X can be omitted or represent either a linear or branched alkyl chain comprising from 1 to 8 carbon atoms, or an aromatic residue such as a phenyl, a heterocycle or an arylalkyl which can be variously substituted in various positions by a linear alkyl residue or branched, an alkoxy (OR4), a halogen (chlorine, fluorine, iodine or bromine), an alcohol, an ester (CO2R4), a nitrile, a nitro, a thiol, a thioether (SR4), an amine (NHR4) or an amide (NHCOR4).

Y represents a substituent attached to the residue X selected from a linear or branched alkyl chain comprising from S to 8 carbon atoms, a carbonyl residue (COR5), sulfonylated (SO2Rs), oxygenated (OR6), amine (NR6R'6), a nitrile (CN), a nitro (NO2), a hydroxylamine (NHOH) in which R5 represents R4, OR4 or NHR4, R6 and R'6 represent hydrogen, R4, COR4, CO2R4, CONHR'4, SO2R4 or SO2NHR'4 wherein R4 is defined as above and R'4 is hydrogen, linear or branched alkyl having 1 to 6 carbon atoms, an aromatic residue such as phenyl, benzyl or phenethyl or cycloalkyl of 4 to 10 carbon atoms. carbon being understood that the group represented by O-CH (R3) -XY in the formula W can be in various positions on the aromatic ring to which it is attached.

The invention also extends to their salts, solvates, hydrates and bioprecursors acceptable for therapeutic use.

Compounds of general formula (I) containing 1 or more asymmetric centers have isomeric forms. The racemates and pure enantiomers of these compounds are also part of the present invention.

Among the salts that are acceptable for the therapeutic use of naphthylpiperazines of general formula (I), mention may be made of salts formed by addition with organic or inorganic acids and for example hydrochlorides, hydrobromides, sulphates, methanesulphonates, fumarates, maleates or succinates. Other salts may be useful in the preparation of compounds of formula (I), for example adducts with creatinine sulfate.

The term "bioprecursors" as used in the present invention applies to compounds whose structure differs from that of the compounds of formula (1), but which, administered to an animal or to a human being, are converted into the body into a compound of formula (I).

dans laquelle R2 est défini comme précédemment et R' 1 peut être équivalent à R1 ou à un précurseur de R1 (qui sera restauré en fin de synthèse par une réaction appropriée telle que par exemple la coupure d'un groupe protecteur comme l'hydrolyse en milieu acide d'un dérivé de formule (I) dans lequel
R' 1 représente un t-butoxycarbonyle pour donner le dérivé de formule (I) dans lequel R1 représente un hydrogène ou encore la transformation d'un groupe fonctionnel tel qu'une amide (R1 = COCH3 par exemple) en amine (R1 = CH2CH3) après réduction avec par exemple de l'hydrure de lithium et d'aluminium) avec un dérivé de formule générale (III)

dans laquelle X,Y et R3 sont définis comme précédemment et L représente un groupe partant tel qu'un halogène (iode, brome ou chlore), un mésylate, un tosylate ou un triflate.The compounds of the present invention are generally prepared by condensation of a naphthylpiperazine derivative of general formula (II)

in which R2 is defined as above and R '1 may be equivalent to R1 or to a precursor of R1 (which will be restored at the end of synthesis by an appropriate reaction such as, for example, the cleavage of a protecting group such as hydrolysis in acid medium of a derivative of formula (I) in which
R '1 represents a t-butoxycarbonyl to give the derivative of formula (I) in which R1 represents a hydrogen or the transformation of a functional group such as an amide (R1 = COCH3 for example) into amine (R1 = CH2CH3 after reduction with, for example, lithium aluminum hydride) with a derivative of general formula (III)

wherein X, Y and R3 are defined as above and L represents a leaving group such as halogen (iodine, bromine or chlorine), mesylate, tosylate or triflate.

The preparation of the derivatives of formula (I) by condensation of the derivatives of formula (II) with the derivatives of formula (III) can be carried out, generally, in the presence of an organic base (NaH, KH, Et3N,
DBU, DBN, DIPEA, tBuOK) or inorganic (K2CO3, KHCO3, NaHCO3, Cs2CO3, KOH, NaOH, CaCO3 ...) in an anhydrous solvent such as THF, DMF, DMSO, acetone, diethylketone, methyl ethyl ketone, acetonitrile or DME at a temperature between 20 and 140 ° C, in the presence or absence of a salt as catalyst and which may be KI, Bu4NI, LiI,
AgBF4, AgClO4 Ag2CO3, KF, Bu4NF or CsF. The choice of the experimental conditions and the reagents to carry out the condensation between the derivatives of formulas (II) and (TIR) to obtain the derivatives of formula (I) is obviously dependent on the nature of the substituents R '1, R2, X, Y, R3 and L and will be carried out according to methods and techniques well known to those skilled in the art.

par réaction en milieu basique avec un dérivé d'amine de formule générale (V)
R1 - N (CH2CH2-Z)2 (V) dans laquelle R1 est défini comme précédemment et Z représente un chlore, un brome, un iode, un mésylate ou un tosylate. Cette réaction est réalisée préférentiellement dans un solvant anhydre polaire tel que le DMF, le THF, l'acétonitrile, le n-butanol, le chlorobenzène ou le DMSO, généralement à température de reflux du solvant utilisé, en présence ou non d'une base organique ou inorganique généralement utilisée pour ce type de réaction telle qu'un carbonate de sodium, de potassium, de calcium ou de césium.The hydroxylated derivatives of naphthylpiperazines of general formula (II) are prepared from the corresponding hydroxy-naphthylamines (IV)

by reaction in basic medium with an amine derivative of general formula (V)
R1 - N (CH2CH2-Z) 2 (V) wherein R1 is defined as above and Z is chlorine, bromine, iodine, mesylate or tosylate. This reaction is preferably carried out in a polar anhydrous solvent such as DMF, THF, acetonitrile, n-butanol, chlorobenzene or DMSO, generally at the reflux temperature of the solvent used, in the presence or absence of a base organic or inorganic generally used for this type of reaction such as sodium carbonate, potassium, calcium or cesium.

dans laquelle R1 est défini comme précédement en présence d'anhydride acétique, suivi de la réduction de la dicétopipérazine intermédiaire ainsi formée avec par exemple un borane.The derivatives of general formula (II) may also be prepared from the intermediates of formula (IV) by reaction with an amino acid of formula (VI)

wherein R 1 is defined as above in the presence of acetic anhydride followed by reduction of the intermediate diketopiperazine thus formed with, for example, borane.

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 sensitive groups or functions in synthetic intermediates in order to avoid undesirable side reactions . This can be achieved by the use of conventional protecting groups such as those described in "Protective Groups in Organic Synthesis", TW Greene, J. Wiley & Jones, 1981 and "Protecting groups" of
PJ Kocienski, Thieme Verlag, 1994. The appropriate protecting groups will therefore be introduced and removed at the level of the most appropriate synthetic intermediates to do this and using the methods and techniques described in the references cited above.

Also to be considered as an integral part of the present invention are all methods which make it possible to convert a derivative of formula W into another derivative of formula (I) by the techniques and methods well known to those skilled in the art. Thus, and by way of example, the derivatives of formula (I) in which Y represents a nitrile (CN) can be converted into derivatives of formula (I) in which
Y represents CH 2 NH 2 by a hydrogenation reaction which may be carried out for example using Raney nickel.

Similarly, a derivative of formula (I) in which Y represents an ester (CORs with R5 = OR4) can also be converted to amide (Y =
CONH2) by reaction with ammonia in the presence of ammonium chloride in methanol or in alcohol (Y = CH2OH) by reduction according to methods and techniques well known for this type of transformation such as for example the use of hydride of lithium and aluminum in a solvent such as ethyl ether or THF.The compounds of general formula W in which Y is NH 2 are especially well-suited intermediates for the preparation of compounds of formula (1), in which Y represents NHR4, NHCOR4,
NHC02R4, NHCONHR'4, NHSO2R4 or NHSO2NR4R'4 wherein R4 and R'4 are defined as previously by well known methods and techniques for converting a primary amine to a secondary amine, amide, carbamate, urea, sulfonamide or sulfonated amine.

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 W with an appropriate acid, preferably in a quantity equivalent, or by creatinine sulfate in a suitable solvent.

When the methods 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 pure enantiomers, whether by enantioselective 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-ptoluoyl-1-tartaric acid, (+) - camphorsulfonic acid, (-) camphorsulfonic acid, (+) -phenylpropionic acid, (-) phenylpropionic acid, followed by a fractional crystallization and regeneration of the free base. The compounds of formula (I) in which R 1 is a hydrogen comprising at least one asymmetric center may also be resolved by forming diastereomeric amides which are separated by chromatography and hydrolyzed to liberate the chiral auxiliary.

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

For this, the absorption frequencies are given in cm-1 at their maximum intensity. For proton NMR, the chemical shifts are given in ppm and the following abbreviations were used: m (multiplet), M (Massive), s (singlet), d (doublet), dd (doublet of doublet) , t (triplet).

1A: 8-(4-méthylpipérazin-1-yl)naphtalèn-2-ol
Le 8-aminonaphtalèn-2-ol (16.1 g; 101 mmol) et le chlorhydrate de la 2chloro-N-(chloroéthyl)-N-méthyléthananine (19.5 g; 101 mmol) sont portés au reflux du butan-1-ol (300 ml) en présence de carbonate de sodium (5.36 g; 50.5 mmol). Après 48 h, le mélange réactionnel est concentré et adsorbé sur silice avant d'être purifié par chromatographie-éclair avec un mélange (95/5/1) puis (90/9/1) de dichlorométhane, méthanol, ammoniaque.EXAMPLE 1: 5- [8- (4-methylpiperazin-1-yl) naphthalen-2- fumarate fumarate
yloxy] ethyl pentanoate

1A: 8- (4-methylpiperazin-1-yl) naphthalen-2-ol
8-Aminonaphthalen-2-ol (16.1 g, 101 mmol) and 2chloro-N- (chloroethyl) -N-methylethananine hydrochloride (19.5 g, 101 mmol) are refluxed with butan-1-ol (300 g). ml) in the presence of sodium carbonate (5.36 g, 50.5 mmol). After 48 h, the reaction mixture is concentrated and adsorbed on silica before being purified by flash chromatography with a mixture (95/5/1) and then (90/9/1) of dichloromethane, methanol, ammonia.

Mass obtained: 11.8 g (Yield: 48%)
IR (KBr): 3072 (broad), 2945, 2812, 1622, 1597
1H NMR: (DMSO) 2.28 (s, 3H); 2.58 (M, 4H); 2.96 (M, 4H); 6.98-7.05 (m, 2H); 7.16 (dd, 1H); 7.37-7.46 m, 2H); 7.70 (d, 1H); 9.66 s, 1H).

 1: 8- (4-methylpiperazin-1-yl) naphthalen-2-ol 1A (519 mg, 2.14 mmol) and ethyl 5-bromopentanoate (850 μl, 5.35 mmol) are refluxed with methyl ethyl ketone ( 15 ml) in the presence of potassium carbonate (950 mg, 5.35 mmol) and potassium iodide (39 mg, 0.23 mmol). After 12 h, the reaction mixture is diluted with water and then extracted three times with ethyl acetate. The organic phases are then combined, washed with a saturated solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated.

The crude is purified by flash chromatography with a mixture (95/5/1) of dichloromethane, methanol, ammonia.

Mass obtained: 477 mg (Yield: 60%).

The fumarate is prepared by adding 0.9 equivalents of fumaric acid to a solution of the compound in hot methanol. The methanol is evaporated and the oil obtained is crystallized from ethyl ether.

Elemental Analysis for: C22H30N203-C4H404
Calculated: C 64.18, H 7.04, N 5.76; Experimental: C 64.07, H 7.13, N 5.72
Mass (DCI-NH3): 371 (MH +), 355, 325, 241
1H NMR (DMSO) 1.17 (t, 3H); 1.77 (s, 3H) 2.43 (M, 6H); 2.81 (M, 4H); 3.05 (M, 4H); 4.06 (m, 4H); 6.58 (s, 2H); 7.08-7.82 (m, 6H).

Melting point: 126-127 ° C
EXAMPLE 2: 5- [8- (4-methylpiperazin-1-yl) naphthalenedihydrochloride
2-yloxy] ethyl hexanoate

Compound 2 is prepared by the same procedure as 1 from the following reagents: 8- (4-methylpiperazin-1-yl) naphthalen-2-ol ('A) (659 mg, 2.72 mmol); Ethyl 6-bromohexanoate (1.2 ml, 6.81 mmol); potassium carbonate (1.25 g, 6.81 mmol); potassium iodide (50 mg, 0.30 mmol); methylethylketone (25 ml).

Mass obtained: 734 mg (Yield: 70%)
The hydrochloride of compound Z is obtained by adding a solution of hydrogen chloride in ethyl ether to a solution of the compound in dichloromethane.

Elemental analysis for: C23H32N203-HC1
Calculated: C 65.62, H 7.90, N 6.65, Cl, 8.42; Experimental: C 64.95, H 7.87, N 6.52; Cl 8.34 Mass (DCI-NH3>: 385 (MH +)
IR (KBr): 3458, 2939, 2664, 2586, 1730, 1626, 1597, 1460
1H NMR (DMSO) 1.17 (t, 3H); 1.47-1.83 (m, 6H); 2.35 (t, 2H); 2.85 (s, 3H); 3.34 (M, 8H); 4.09 (m, 4H); 7.12-7.36 (m, 4H); 7.58 (d, 1H); 7.83 (d, 1H); 11.17 (M, 1H).

S: 5-bromopentanoate d'isopropyle
L'isopropanol (1.4 ml; 15.0 mmol) est ajouté à une solution de chlorure de 5-bromopentanoyle (2 ml; 15 mmol) dans le dichlorométhane (50 ml) à 0 C et sous atmosphère d'azote. La triéthylamine (3.35 ml; 15 mmol) est ensuite additionnée goutte à goutte au mélange réactionnel. Celui-ci est ramené à température ambiante et agité pendant 3 h. Après ce temps, le dichlorométhane est évaporé. L'huile obtenue est diluée avec de l'acétate d'éthyle puis lavée avec de l'eau.La phase organique est séparée, séchée sur sulfate de magnésium et concentrée.Point of fusion: 86 "C
EXAMPLE 3: Isopropyl 5- [8- (4-methylpiperazin-1-yl) naphthalen-2-yloxy] pentanoate fumarate

S: Isopropyl 5-bromopentanoate
Isopropanol (1.4 ml, 15.0 mmol) is added to a solution of 5-bromopentanoyl chloride (2 ml, 15 mmol) in dichloromethane (50 ml) at 0 ° C. under a nitrogen atmosphere. Triethylamine (3.35 ml, 15 mmol) is then added dropwise to the reaction mixture. This is brought to room temperature and stirred for 3 hours. After this time, the dichloromethane is evaporated. The oil obtained is diluted with ethyl acetate and then washed with water. The organic phase is separated, dried over magnesium sulfate and concentrated.

Mass obtained: 3.2 g (Yield: 95%)
1H NMR (CDCl3): 1.22 (d, 6H); 1.43-1.55 (M, 4H); 2.26 (t, 2H); 3.40 (t, 2H), 5.00 (sep, 1H).

 Compound 3 is obtained by the same procedure as 1 from the following reagents: 8- (4-methylpiperazin-1-yl) naphthalen-2-ol 1A (520 mg, 2.15 mmol); Isopropyl 5-bromopentanoate 3A (721 mg, 3.23 mmol); potassium carbonate (720 mg, 5.2 mmol); potassium iodide (40 mg, 0.24 mmol); methyl ethyl ketone (10 ml).

Mass obtained: 473 mg (Yield: 57%)
The fumarate is obtained by the same method as for 1.

Elemental Analysis for C23H32N203-C4H404
Calculated: C 64.78, H 7.25, N 5.60; Experimental: C 63.41; H, 7.15; N 5.34
Mass (DCI / NH 3): 385 (MH +), 382, 365 JR (KBr): 3445, 1722, 1107
1H NMR: (DMSO) 1.14 (d, 6H); 1.76 (M, 4H), 2.42 (m, 5H), 2.80 (M, 4H); 3.05 (M, 4H); 4.05 (M, 2H); 4.85 (Sept. 1H); 6.57 (s, 2H); 7.07-7.81 (m, 6H).

4A: 6bromohexanoate d'isopropyle
Le composé 4A est préparé suivant la même procédure que 3A à partir des réactifs suivants : chlorure de 6-bromohexanoyle (2.15 ml; 14.05 mmol); isopropanol (1.3 ml; 14.05 mmol); triéthylamine (2.9 ml; 14.05 mmol); dichlorométhane (50 ml). Melting Point: 128-131 ° C
EXAMPLES: 6- [8- (methylpiperazin-1-yl) naphthalen-2-yloxy] hexanoate
isopropyl

4A: Isopropyl 6bromohexanoate
Compound 4A is prepared by the same procedure as 3A from the following reagents: 6-bromohexanoyl chloride (2.15 mL, 14.05 mmol); isopropanol (1.3 ml, 14.05 mmol); triethylamine (2.9 ml, 14.05 mmol); dichloromethane (50 ml).

Mass obtained: 2.93 g (Yield: 88%)
1H NMR (DMSO): 1.15 (d, 6H); 1.24-1.36 (M, 4H); 1.78 (q, 2H); 2.23 (t, 2H); 3.53 (t, 2H); 4.86 (seven, 1H).

4: Compound 4 is prepared by the same procedure as 1 from the following reagents: 8- (4-methylpiperazin-1-yl) naphthalen-2-ol 1S (508 mg, 2.1 mmol); Isopropyl bromine hexanoate (723 mg, 3.05 mmol); potassium carbonate (717 mg, 5.19 mmol); potassium iodide (41 mg, 0.25 mmol); methyl ethyl ketone (10 ml).

Mass obtained: 466 mg (Yield: 56%)
1H NMR (CDCl3): 1.22 (d, 6H); 1.30-1.95 (m, 6H); 2.32 (t, 2H); 2.42 (s, 3H); 2.71 (M, 4H); 3.12 (M, 4H); 4.09 (t, 2H); 5.00 (Sept. 1H); 7.06-7.13 (m, 2H); 7.25 (dd, 1H); 7.47 (m, 2H); 7.70 (d, 1H).

EXAMPLE 5 S [8- (4-methylpiperazin-1-yl) naphthalen-2-yloxy] hexanenitrile fumarate

Compound 9 is prepared by the same procedure as for compound 1 from the following reagents: 8- (4-methylpiperazin-1-yl) naphthalen-2-ol 1A (488 mg, 2 mmol); 6-bromohexanenitrile (750 mg, 4.26 mmol), potassium carbonate (690 mg, 5 mmol), potassium iodide (35 mg, 0.21 mmol); methyl ethyl ketone (10 ml).

Resulting mass: 361 mg (Yield: 53%)
The fumarate is obtained by the same method as for 1.

Elemental Analysis for C21H27N3 -C4H4 4
Calculated: C 66.21, H 6.89, N 9.26; Experimental: C 66.12, H 6.95; N 9.31 IR (KBr): 3433, 2936, 2864, 2828, 2473, 1701, 1622, 1597, 1460
1H NMR: (DMSO) 1.58-1.88 (m, 6H); 2.45 (s, 3H); 2.57 (t, 2H); 2.84 (M, 4H); 3.08 (M, 4H); 4.13 (t, 2H); 6.60 (s, 2H); 7.10-7.84 (m, 6H).

Point of fusion: 1600C
EXAMPLE A 6 / 5- [8- (Methylpiperazin-1-yl) naphthalen-2-yloxy] pentanenitrile fumarate

Compound 6 is prepared by the same procedure as 1 from the following reagents: 8- (4-methylpiperazin-1-yl) naphthalen-2-ol 1A (2.5 g, 10.3 mmol); 5-bromopentanenitrile (3 ml, 26 mmol), potassium carbonate (3.6 g, 26 mmol), potassium iodide (436 mg, 2.6 mmol); methyl ethyl ketone (50 ml).

Mass obtained: 1.8 g (Yield: 54%)
The fumarate is obtained by the same method as for 1.

Elemental analysis for C20H25N3O-C4H404
Calculated: C 65.59, H 6.65, N 9.56; Experimental: C 65.52; H, 6.71; N 9.44 Mass (DCI-1VH3) 324 (MH +) IR (KBr): 3429, 1680, 1624
1H NMR: (DMSO) 1.85 (M, 4H); 2.44 (s, 3H); 2.62 (t, 2H); 2.82 (M, 4H); 3.07 (M, 4H); 4.15 (t, 2H); 6.59 (s, 2H); 7.10-7.84 (m, 6H).

M.p.

A solution of lithium aluminum hydride in tetrahydrofuran (1 M, 1.62 ml, 1.62 mmol) is slowly added to a solution of compound 6 (1.05 g, 3.25 mmol) in tetrahydrofuran (20 ml) at 0 ° C. and under a nitrogen atmosphere. After 15 minutes, the reaction mixture is brought to room temperature and stirred for 2 hours. After this time, it is hydrolysed with a 1M sodium hydroxide solution and then filtered on celite. The salts are rinsed several times with ethyl acetate. The filtrate phases are then separated and the organic phase is washed twice with a saturated solution of sodium chloride, dried over magnesium sulfate and concentrated.

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

Mass obtained: 527 mg (Yield: 49%).

Difumarate is obtained by adding 1.8 equivalents of fumaric acid to a solution of compound 2 in hot methanol. After evaporation of the methanol, the salt is crystallized from ethyl ether.

Elemental analysis for: C20H29N3O-2C4H04 .0. 5:20
Calculated: C 59.14, H 6.74, N 7.39; Experimental: C 58.95; H 7.11; N 7.40 Mass (DCI / NH 3): 328 (MH +) IR (KBr): 3431, 2941, 1678, 1624, 1599, 1464
1H NMR: (DMSO) 1.07-1.83 (M, 6H); 2.37 (s, 3H); 2.71 (M, 4H); 2.84 (t, 2H); 3.05 (M, 4H); 4.11 (t, 2H); 6.53 (s, 4H); 7.10-7.84 (m, 6H).

Melting Point: 152-154 ° C
EXAMPLES: N- (5- [8- (4-methylpiperazin-1-yl) naphthalen-2-yloxy] pentyl} methanesulfonamide fumarate

A solution of the compound 2 (330 mg, 1.06 mmol) in dichloromethane (10 ml) containing triethylamine (220 Cr, 1.6 mmol) is cooled to 0 ° C. under a nitrogen atmosphere. Mesyl chloride (100 μL, 1.27 mmol) is then added to the reaction mixture. This is stirred for 15 minutes at 0 ° C. and then diluted with water. The phases are separated and the organic phase is washed twice with a saturated solution of sodium chloride. It is dried over magnesium sulfate, filtered and concentrated.

The crude product obtained is purified by flash chromatography with a mixture (95/5/1) of dichloromethane, methanol and ammonia.

Mass obtained: 300 mg (Yield: 62%)
Fumarate is obtained by the same method as 1.

Elemental Analysis for: C21H31N3O3S-C4H4O40.15SC4H10O
Calculated: C 57.56, H 6.76, N 8.06; Experimental: C 57.39, H 7.05; N 8.00 Mass (DCI / NH 3) 406 (MH +) IR (KBr): 3429, 2945, 2866, 1624, 1597, 1458
1H NMR: (DMSO) 1.52 (M, 4H); 1.79 (M, 2H); 2.38 (s, 3H) 2.74 (M, 4H); 2.86 (s, 3H); 2.96 (M, 6H); 4.08 (t, 2H); 6.57 (s, 2H); 6.93-7.80 (m, 6H).

Melting Point: 104-106 ° C
EXAMPLE 9: 4 [8- (4-methylpiperazin-1-yl) naphthalen-2-yloxy] butyl acetate fumarate

Compound 9 is prepared by the same procedure as 1 from the following reagents: 8- (4-methylpiperazin-1-yl) naphthalen-2-ol 1A (507 mg, 2.1 mmol); 4-bromobutyl acetate (606 l, 4.2 mmol); potassium carbonate (725 mg, 5.25 mmol); potassium iodide (35 mg, 0.21 mmol); methyl ethyl ketone (10 ml).

Resulting mass: 319 mg (Yield: 43%)
Fumarate is obtained by the same method as 1.

Elemental Analysis for: C21H28N203-C4H404
Calculated: C 63.55, H 6.83, N 5.93; Experimental: C 63.63; H 6.88; N 5.92
Mass (DCI / NH 3): 357 (MH +) IR (KBr): 3437, 2949, 2833, 2473, 1732, 1251 1 H NMR: (DMSO) 1.84 (M, 4H); 2.03 (s, 3H); 2.44 (s, 3H); 2.82 (M, 4H); 3.07 (M, 4H); 4.11 (M, 4H); 6.61 (s, 2H); 7.10-7.85 (m, 6H).

Melting Point: 1380C EXAMPLE 10 4 [8- (4-methylpiperazin-1-yl) naphthalen-2-yloxy] butan-1ol fumarate

A few drops of concentrated sodium hydroxide are added to an aqueous fumarate solution of compound 9. This solution is then extracted three times with dichloromethane. The organic phases are combined, dried over magnesium sulfate and concentrated.

The fumarate of the alcohol obtained is prepared according to the same method as for 1.

Elemental analysis for: C 1 9H26N2O2-C4H4O4
Calculated: C 64.17, H 7.02, N 6.51; Experimental: C 63.46; H, 6.97; N 6.39
Mass (DCI / NH 3): 314 (MH +) IR (KBr): 3406, 2953, 2866, 2687, 1686, 1624
1H NMR (DMSO) 1.58-1.86 (m, 4H); 2.43 (s, 3H); 2.82 (M, 4H); 3.05 (M, 4H); 3.48 (t, 2H); 4.10 (t, 2H); 6.58 (s, 2H); 7.08-7.82 (m, 6H).

11A: N-éthyl-6-bromohexanamide
Le chlorhydrate de l'éthylamine (1.72 g; 14.05 mmol) est ajouté à une solution de chlorure de 6-bromohexanoyle (2.15 ml; 14.05 mmol) dans le dichlorométhane (50 ml) à 0 C et sous atmosphère d'azote. La triéthylamine (5.9 ml; 42.15 mmol) est ensuite additionnée goutte à goutte au mélange réactionnel. Celuici est ramené à température ambiante et agité pendant 5 h.Melting point: 1540C EXAMPLE 11: N-ethyl + [S (4-methylpiperazin-1-yl) naphthalen-2-yloxy] hexanamide fumarate

11A: N-ethyl-6-bromohexanamide
The ethylamine hydrochloride (1.72 g, 14.05 mmol) is added to a solution of 6-bromohexanoyl chloride (2.15 ml, 14.05 mmol) in dichloromethane (50 ml) at 0 ° C. under a nitrogen atmosphere. Triethylamine (5.9 mL, 42.15 mmol) is then added dropwise to the reaction mixture. It is brought to room temperature and stirred for 5 hours.

After this time, the dichloromethane is evaporated and the oil obtained is redissolved in ethyl acetate. It is then washed with water and then with a 2N sodium hydroxide solution. The inorganic phase is dried over sodium sulfate, filtered and concentrated.

Mass obtained: 2.57 g (Yield: 83%)
1H NMR (DMSO): 0.98 (t, 3H); 1.29-1.57 (M, 4H); 1.78 (q, 2H); 2.03 (t, 2H); 3.07 (m, 2H); 3.51 (t, 2H); 7.76 (M, 1H); 11: 8- (4-methylpiperazin-1-yl) naphthalen-2-ol 1S (500 mg, 2.07 mmol) and N-ethyl-6-bromohexanamide 11S (716 mg, 3.1 mmol) are stirred at room temperature and under nitrogen atmosphere in the presence of cesium carbonate (1 g, 3.1 mmol) in dimethylformamide (30 ml). After 12 h, the reaction mixture is diluted with water and then extracted three times with ethyl acetate. The organic phases are combined and then washed twice with a saturated solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated.

The crude is purified by flash chromatography with a mixture (95/5/1) of dichloromethane, methanol, ammonia.

Mass obtained: 530 mg (Yield: 67%)
The fumarate is obtained by the same method as for 1.

Elemental Analysis for C23H33N302-C4H4 4
Calculated: C, 64.91, N, 7.46, N, 8.41; Experimental: C 64.40; H, 7.45; N 8.34
Mass (DCI / NH 3): 384 (MH +) IR (KBr): 3285, 3071, 2937, 2868, 1707, 1645
1 H NMR (DMSO) 0.98 (t, 3H): 1.42-1.81 (M, 6H); 2.07 (t, 2H); 2.42 (s, 3H); 2.80 (M, 4H); 3.04 (M, 6H); 4.07 (t, 2H); 6.57 (s, 2H); 7.07-7.81 (m, 7H).

Melting point 111-112 C
EXAMPLE 12: 1- (7-Benzyloxynaphthalen-1-yl) -4-methylpiperazine fumarate

A solution of 8- (4-methylpiperazin-1-yl) naphthalen-2-ol 1A (324 mg, 1.34 mmol) in tetrahydrofuran (5 ml) was cannulated on a suspension of sodium hydride (60%; mg, 1.47 mmol) in tetrahydrofuran (5 ml) at 0 ° C. under a nitrogen atmosphere. Before the addition of the benzyl bromide (175 μl, 1.47 mmol), the reaction mixture is stirred at 0 ° C. for 30 minutes. It is then stirred for 12 hours at room temperature. After this time, it is diluted with water and extracted three times with ethyl acetate. The combined organic phases are then washed with a saturated solution of sodium chloride, dried over magnesium sulphate, filtered and concentrated. . The crude is purified by flash chromatography with a mixture (95/5/1) of dichloromethane, methanol, ammonia.

Mass obtained: 189 mg (Yield: 42%)
The fumarate is obtained by the same method as for 1.

Elemental Analysis for: C22H24N2O-C4H404
Calculated: C 69.63, H 6.29, N 6.15; Experimental: C 68.73; H, 6.28; N 6.12
Mass (DCI / NH 3): 333 (MH +), 241 IR (KBr): 3431, 3030, 2841, 2498, 1701, 1599
1H NMR: (DMSO) 2.51 (s, 3H); 2.94 (M, 4H); 3.56 (M, 4H); 5.28 (s, 2H); 6.55 (s, 2H); 7.08-7.85 (m, 11H).

JiSion point: 218 "C
EXAMPLE 13: 1-Methyl-4- [7- (4-nitrobenzyloxy) naphthalen-1-yl] piperazine fumarate

Compound 13 is prepared by the same procedure as 12 from the following reagents: 8- (4-methylpiperazin-1-yl) naphthalen-2-ol 1A (500 mg, 2.1 mmol); 4-nitrobenzyl bromide (450 mg, 2.1 mmol); sodium hydride (60%, 90 mg, 2.27 mmol); tetrahydrofuran (10 ml).

The crude is purified by flash chromatography with a mixture (97/3/1) of dichloromethane, methanol, ammonia.

Resulting mass: 413 mg (Yield: 52%)
The fumarate is obtained with the same method as for 1.

Elemental Analysis for: C22H23N303-C4H404
Calculated: C, 63.28; H 5.51; N 8.51 Experimental: C 62.23; 5.58; N 8.59
Mass (DCI / NH3): 378 (MH +), 361, 348, 241
1H NMR: (DMSO) 2.38 (s, 3H); 2.67 (M, 4H); 2.95 (M, 4H); 5.46 (s, 2H); 6.59 (s, 2H); 7.07-8.30 (m, 10H).

Point of fusion: 228 C
EXAMPLE 14 Methyl 4- [8- (4-methylpiperazin-1-yl) naphthalen-2-yloxymethyl] benzoate fumarate

Compound 14 is prepared by the same procedure as 12 from the following reagents: 8- (4-methylpiperazin-1-yl) naphthalen-2-ol 1A (525 mg, 2.17 mmol); Methyl 4-bromomethylbenzoate (550 mg, 2.40 mmol); sodium hydride (60%, 95 mg, 2.40 mmol); tetrahydrofuran (30 ml).

The crude is purified by flash chromatography with a mixture (95/5/1) of dichloromethane, methanol, ammonia.

Mass obtained: 479 mg (Yield: 57%)
The fumarate is obtained by the same method as for 1.

Elemental Analysis for: C24H26N203-C4H404
Calculated: C 66.39, H 5.97; 5.53; Experimental: C 66.16; H, 5.93; N 5.39
Mass (DCI / NH 3): 392 (MH +), 243 IR (KBr): 3418, 2953, 2829, 2471, 1716, 1597
1H NMR: (DMSO) 2.36 (s, 3H); 2.64 (M, 4H); 2.93 (M, 4H); 3.83 (s, 3H); 5.36 (s, 2H); 6.57 (s, 2H); 7.04-8.00 (m, 10H).

Melting point: 172-173 ° C
EXAMPLE 15 Methyl 3- [8- (methylpiperazin-1-yl) naphthalen-2-yloxymethyl] henzoate fumarate

Compound 15 is prepared by the same procedure as 1 from the following reagents: 8- (4-methylpiperazin-1-yl) naphthalen-2-ol 1A (502 mg, 2.07 mmol); Methyl 3-bromomethylbenzoate (533 mg, 2.3 mmol); sodium hydride (60%, 91 mg, 2.28 mmol); tetrahydrofuran (35 ml).

The crude is purified with a mixture (95/5/1) of dichloromethane, methanol, ammonia.

Resulting mass: 364 mg (Yield: 45%)
The fumarate is obtained by the same method as for 1.

Elemental Analysis for: C24H26N2O3-1 .5CqH404
Calculated: C 63.82, H 5.71, N 4.96; Experimental: C 63.65; H, 5.90; N 5.09
Mass (1) CI / NH3): 391 (MH +) IR (KBr): 3447, 2953, 2835, 2598, 1713, 1622, 1595
1H NMR (DMSO): 2.41 (s, 3H); 2.71 (M, 4H); 2.95 (M, 4H); 3.87 (s, 3H); 5.39 (s, 2H); 6.60 (s, 3H); 7.07-7.94 (m, 9H); 8.11 (s, 1H).

Melting point: 1800 ° C (dec.) EXAMPLE 16 16: fumarate of ethyl 2- [8- (4-methylpiperazin-1-yl) naphthalen-2-yloxy] acetate

Compound 16 is prepared by the same procedure as 12 from the following reagents: 8- (4-methylpiperazin-1-yl) naphthalen-2-ol 1A (469 mg, 1.94 mmol); ethyl bromoacetate (235 μ1, 2.13 mmol); tetrahydrofuran (12 ml).

The crude is purified by flash chromatography with a mixture (97/3/1) of dichloromethane, methanol, ammonia.

Mass obtained: 475 mg (Yield: 75%)
The fumarate is obtained by the same method as for 1.

Elemental Analysis for: Cl9H24N2 3-C4H4 4
Calculated: C 62.15, H 6.35, N 6.30; Experimental: C 61.75; H 6.40; N 6.26
Mass (DCI / NH 3): 329 (MH +), 315, 241 IR (KBr): 3441, 2932, 2685, 1738, 1686
1H NMR (DMSO) 1.25 (t, 3H); 2.41 (s, 3H); 2.75 (M, 4H); 3.02 (M, 4H); 4.20 (q, 2H); 4.92 (s, 2H); 6.60 (s, 2H); 7.10-7.33 (m, 4H); 7.56 (d, 1H); 7.84 (d, 1H).

17A : 8-(4-méthylpipérazin-1-yl)naphtalèn-3-ol
Le composé 17A est préparé suivant la même procédure que 1A à partir des réactifs suivants : 8-amino-naphtalèn-3-ol (10 g; 62.2 mmol), hydrochlorure de la 2chloro-N-(chloroéthyl)-N-méthyléthylamine (11.8 g; 61.3 mmol); carbonate de sodium (3.32 g; 31.3 mmol); butan-l-ol (200 ml). Melting point: 156 ° C
EXAMPLE 17: 4 [S- (methylpiperazin-1-yl) naphthalen-Syloxy] butyl acetate fumarate

17A: 8- (4-methylpiperazin-1-yl) naphthalen-3-ol
Compound 17A is prepared by the same procedure as 1A from the following reagents: 8-amino-naphthalen-3-ol (10 g, 62.2 mmol), 2chloro-N- (chloroethyl) -N-methylethylamine hydrochloride (11.8 61.3 mmol); sodium carbonate (3.32 g, 31.3 mmol); butan-1-ol (200 ml).

The crude is purified by flash chromatography with a mixture (96/4/1) of dichloromethane, methanol, ammonia.

Mass obtained: 5.63 g (Yield: 37%)
1H NMR fDMSO): 2.27 (s, 3H); 2.57 (M, 4H); 2.97 (M, 4H); 6.83-7.36 (m, 5H); 7.93 (d, 1H); 9.66 (M, 1H).

 17: Compound 17 is prepared by the same procedure as 11 from the following reagents: 8- (4-methylpiperazin-1-yl) naphthalen-3-ol (580 mg, 2.4 mmol); 4-bromobutyl acetate (690 μl, 4.8 mmol), cesium carbonate (1.56 g, 4.8 mmol); dimethylformamide (40 ml).

The crude is purified by flash chromatography with a mixture (95/5/1) of dichloromethane, methanol, ammonia.

Resulting mass: 657 mg (Yield: 77%)
The fumarate is prepared following the same procedure as 1.

Elemental Analysis for: C21H28N2O3-C4H4O4
Calculated: C 63.55, H 6.83, N 5.93; Experimental: C 63.34; H 6.88; N 5.85 IR (KBr): 3437, 2955, 2581, 1736, 1701, 1624, 1250
1H NMR (DMSO) 1.81 (M, 4H); 2.02 (s, 3H); 2.44 (s, 3H); 2.82 (M, 4H); 3.08 (M, 4H); 4.11 (M, 4H), 6.60 (s, 2H); 6.98 (d, 1H); 7.13-7.53 (m, 4H); 8.00 (d, 1H).

PoinIdefusion: 134 "C
BIOLOGICAL RESULTS
The human 5HT1Da and 5HT1Db 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. sue, 3630 (1992).

Transient transfection and permanent transfection of the genes of these receptors was performed in Cos-7 and CHO-K1 cell lines using an electroporator.

The HeLa HA7 cell line expressing the human SHT1A receptor was obtained from Tulco (Duke Univ., Durham, N.C., USA) and cultured according to the method of Fargin et al., J. Biol. Chem. vs, 14848 (1989).

The study of the binding of the derivatives of the present invention with the receptors
Human SHT1Da, SHT1Db and 5HT1A was performed 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 a [[3 H] -SCT (2 nM final concentration) tritiated ligand for SHT1Da and SHT1Db and [3H] - 80H-DPAT (final concentration: 1 nM) for the SHT1A] receptor and 0.05 ml of the test molecule (final concentrations of 0.1 nM to 1000 nM) or 10 μM (final concentration) of serotonin (SHT1Da and SHT or 1 μM ( final concentration) of spiroxatrin (SHT1A).

The study of the inhibition of the formation of cyclic AMP (forskolin-stimulated) mediated by the human 5HT 1 Db receptor was carried out in the CHO-K1 cells transfected with the receptor according to the technique previously described for the 5HT1B receptor. (P. Pauwels and C. Palmier,
Neuropharmacology, 33, 67, 1994).

RESULTS OBTAINED

<tb><SEP> Ki (nM)
<tb> Examples <SEP> 5HTiDa <SEP><SEP> 5HT1Db <SEP> 5HT1A <SEP>
<tb><SEP> 1 <SEP> 0 <SEP> 0.2 <SEP> 0.2 <SEP> 4.3
<tb><SEP> 2 <SEP> 0.36 <SEP> 0.35 <SEP> 13
<tb><SEP> 3 <SEP> 0.34 <SEP> 0.26 <SEP> 6.4
<tb><SEP> 8 <SEP> 0.3 <SEP> 0.12 <SEP> 6.1
<tb><SEP> 9 <SEP> 0.22 <SEP> 0.1 <SEP> 8.6
<tb><SEP> 11 <SEP> 0.44 <SEP> 0.17 <SEP> 13.6
<tb><SEP> 16 <SEP> 0.86 <SEP> 0.86 <SEP> 16.4
<Tb>
The novel naphthylpiperazine derivatives forming part of this invention are novel compounds having a very high affinity and a very good selectivity for the receptors commonly known as 5HT1 and more particularly for the receptors called 5HT1D, according to the new nomenclature recently proposed by P. Humphrey. P. Hartig and D.Hoyer (TIPS, 14, 233-236, 1993).

In human therapy, the compounds of general formula (I) according to the invention are particularly useful for the treatment and prevention of disorders related to serotonin in the central nervous system and the vascular system. These compounds can therefore be used in the treatment and prevention of depression, obsessive compulsive disorders, bulimia nervosa, aggression, alcoholism, smoking, hypertension, nausea, sexual dysfunction , asocial behavior, anxiety, migraine, spasticity, Alzheimer's disease and memory disorders.

The present invention also relates to medicaments consisting of at least one compound of formula (I) in pure form or in the form of a composition in which it is combined with any other pharmaceutically compatible product, which may be inert or physiologically active. The medicaments according to the invention can be used orally, nasally, parenterally, rectally or topically.

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 a solvent or vehicle, water, propylene glycol, polyethylene glycol, vegetable oils, in particular olive oil, injectable organic esters, for example ethyl oleate or other organic solvents may be used. suitable. 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" refers to one or more (generally one) of the compounds of formula W 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 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 0.5
100.0
The active component is passed through a sieve having a mesh size of 250 m on one side, mixed with the excipients and compressed using 6.0 mm punches. Tablets having other mechanical strengths can be prepared by modifying the compression weight using appropriate punches.

B - wet granulation
mg for one active component tablet 10.0 lactose Codex 74.5 starch Codex 10.0 pregelatinized maize starch Codex 5.0 magnesium stearate 0.5
Compression weight 100.0
The active component is passed through a 250 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 methylcellulose, 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 E5
Filling weight 100.0 * a form of directly compressible starch from the firm
Colorcon Ltd, Orpington, Kent, United Kingdom.

The active component is passed through a sieve of 250 mesh size and mixed with the other substances. The mixture is filled into hard gelatin capsules No. 2 on a suitable filling machine Other dosage units can be prepared by changing the filling weight and, when 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 ingredient, buffer, flavor, color 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 is dissolved therein, then cooled, the two solutions are combined, the volume is adjusted and the mixture is mixed in. The syrup obtained is clarified by filtration.

Suooosltolres
Active ingredient 10.0 mg * Witepsol HIS 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.

Inhalatlon 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 filled into hard gelatin capsules No. 3 on a suitable encapsulating machine The contents of the cartridges are administered by means of a powder inhaler.

Aerosol under pressure with metering valve
mg / dose per 1 micronised 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 having the general formula W

 in which R1 represents a hydrogen or a linear or branched alkyl residue comprising from 1 to 6 carbon atoms, R2 may be in various positions on the aromatic ring to which it is attached represents a substituent such as hydrogen, a halogen (fluorine, bromine, chlorine or iodine), a linear or branched alkyl residue comprising from 1 to 6 carbon atoms or an alkoxy radical (OR4) in which R4 represents a linear or branched alkyl comprising from 1 to 6 carbon atoms, an aromatic residue such as phenyl, benzyl or phenethyl or a cycloalkyl of 4 to 10 carbon atoms, R3 represents a hydrogen, a linear or branched alkyl residue comprising from 1 to 5 carbon atoms or an aromatic residue such as a phenyl, X can be omitted or represent either a linear or branched alkyl chain comprising from 1 to 8 carbon atoms, or an aromatic residue such as a phenyl, a heterocycle or an arylalkyl which can be variously substituted in various positions by a linear alkyl residue or branched, an alkoxy (OR4), a halogen (chlorine, fluorine, iodine or bromine), an alcohol, an ester (CO2R4), a nitrile, a nitro, a thiol, a thioether (SR4), an amine (NHR4) or an amide (NHCOR4), Y represents a substituent attached to the residue X chosen from a linear or branched alkyl chain comprising from 5 to 8 carbon atoms, a carbonyl residue (COR5), sulphonylated (SO2Rs), oxygenated (OR6), amine (NR6R6), a nitrile ( CN), a nitro (NO 2), a hydroxylamine (NHOH) in which R 5 represents R 4, OR 4 or NHR 4, R 6 and R '6 represent a hydrogen, R 4, COR 4, CO 2 R 4, CONHR' 4, SO 2 R 4 or SO 2 NHR 4 in which R4 is defined as above and R'4 represents hydrogen, a linear or branched allyl comprising from 1 to 6 carbon atoms, an aromatic residue such as phenyl, benzyl or phenethyl or a cycloalkyl of 4 to 10 carbon atoms, it being understood that the group represented by O-CH (R 3) -XY in the formula W may be in various positions on the aromatic ring to which it is attached, their salts, solvates, hydrates and bioprecursors acceptable for therapeutic use. 2. A compound of formula (I) according to claim 1, selected from:  Ethyl 5- [8- (4-methylpiperazin-1-yl) naphthalen-2-yloxy] pentanoate,  Ethyl 5- [8- (4-methylpiperazin-1-yl) naphthalen-2-yloxy] hexanoate,  5- [8- (4-methylpiperazin-1-yl) naphthalen-2-yloxy] pentanoate  isopropyl  6- [8- (methylpiperazin-1-yl) naphthalen-2-yloxy] hexanoate, isopropyl,  6- [8- (4-methylpiperazin-1-yl) naphthalen-2-yloxy] hexanenitrile,  5- [8- (methylpiperazin-1-yl) naphthalen-2-yloxy] pentanenitrile,  5- [8- (4-methylpiperazin-1-yl) naphthalen-2-yloxy] pentylamine,  N- (5- [8- (4-methylpiperazin-1-yl) naphthalen-2-yloxy] pentyl}  methanesulfonamide, 4- [8- (4-methylpiperazin-1-yl) naphthalen-2-yloxy] butyl acetate,  4- [8- (4-methylpiperazin-1-yl) naphthalen-2-yloxy] butan-1-ol,  N-ethyl-6- [8- (4-methylpiperazin-1-yl) naphthalen-2-yloxy] hexanamide,  1- (7-benzyloxynaphthalen-1-yl) -4-methylpiperazine,  1-methyl-4- [7- (4-nitrobenzyloxycarbonyl) naphthalen-1-yl] piperazine,  4- [8- (4-methylpiperazin-1-yl) naphthalen-2-yloxymethyl] benzoate  methyl,  3- [8- (methylpiperazin-1-yl) naphthalen-2-yloxymethyl] benzoate  methyl,  2- [8- (4-methyl-piperazin-1-yl) naphthalen-2-yloxy] ethyl acetate,  4- [8- (Methylpiperazin-1-yl) naphthalen-3-yloxy] butyl acetate, 3.Compounds according to Claim 1, characterized in that R1 represents  hydrogen or methyl. 4. Compounds according to claim 1 characterized in that R2 and R3  represent a hydrogen. 5. Compounds according to claim 1, characterized in that X represents  a linear or branched alkyl chain comprising from 1 to 8 atoms of  carbon. 6. Compounds according to claim 1, characterized in that X represents  an aromatic such as a phenyl. 7. Compounds according to claim 1, characterized in that Y represents  CORs or NHS02R4. 8. Compounds according to claim 1 characterized in that they respond to  the formula Ia.

9. Compounds according to one of claims 1 to 8 in the form of salts  acceptable for therapeutic use characterized in that these salts  are selected from a hydrochloride, a hydrobromide, sulfate,  methanesulfonate, fumarate, maleate or succinate. 10. Process for the preparation of the compounds of formula (I) according to  claim 1, characterized in that an intermediate is condensed  of formula (II)

 in which R2 is defined as above and R'1 may be equivalent to R1 (or to a precursor of R1 which will be restored at the end of synthesis by an appropriate reaction) with a derivative of general formula (m)

 bromine), mesylate, tosylate or triflate.  represents a leaving group such as a halogen (chlorine, iodine or  in which X, Y, R3 are defined as above and L 11. Method according to claim 10, characterized in that one converts  a compound of formula W or a salt or derivative having a  protecting group of such a compound, into another compound of formula W.  12. Pharmaceutical combinations containing, as ingredients  active compounds, a compound according to one of claims 1 to 9,  combination with an acceptable pharmaceutical vehicle, such as  drugs. 13. Pharmaceutical compositions containing, as active ingredients, a  compound according to one of claims 1 to 9, in combination with a  acceptable pharmaceutical vehicle for both curative and  preventative disorders related to serotonin. 14. Pharmaceutical compositions containing, as active ingredients, a  compound according to one of claims 1 to 9, in combination with a  acceptable pharmaceutical vehicle for both curative and  prevention of migraine headache, cluster headache and  chronic vascular headaches. 15. Pharmaceutical compositions containing, as active ingredients, a  compound according to one of claims 1 to 9, in combination with a  acceptable pharmaceutical vehicle for both curative and  prevention of depression, obsessive compulsive disorders,  anxiety and panic attacks. 16. Pharmaceutical compositions containing, as active ingredients, a  compound according to one of claims 1 to 9, in combination with a  acceptable pharmaceutical vehicle for both curative and  prevention of schizophrenia, spasticity, aggression and / or  alcoholism and / or asocial behavior, eating disorders  such as bulimia and anorexia, sexual dysfunction. 17. Pharmaceutical compositions containing, as active ingredients, a  compound according to one of claims 1 to 9, in combination with a  acceptable pharmaceutical vehicle for both curative and  prevention and neurodegenerative diseases such as for example the  Parkinson's disease or Alzheimer's disease.