WO1996012713A1

WO1996012713A1 - Novel naphthylpiperazine-derived aromatic ethers for use as drugs

Info

Publication number: WO1996012713A1
Application number: PCT/FR1995/001409
Authority: WO
Inventors: Serge Halazy; Catherine Jorand; Michel Perez
Original assignee: Pierre Fabre Medicament
Priority date: 1994-10-25
Filing date: 1995-10-24
Publication date: 1996-05-02
Also published as: FR2725984A1; AU3847595A; FR2725984B1

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 new ethers derived from naphthylpiperazines, 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 neuromodulator of the central nervous system involved in many physiological and pathological processes. Serotonin plays an important role both in the nervous system and in the cardiovascular and gastrointestinal systems. At the central level, serotonin controls functions as varied as sleep, locomotion, food intake, learning and memory, endocrine modulations, sexual behavior, thermoregulation. In the marrow, serotonin plays an important role in the control systems of the afferent peripheral nociceptives (cf. A. Moulignier, Rev. Neurol. (Paris), 150, 3-15,1994). Serotonin can play an important role in various types of pathological conditions such as certain psychiatric disorders (anxiety, depression, aggressiveness, panic attacks, obsessive compulsive disorders, schizophrenia, tendency to suicide), certain neurodegenerative disorders (dementia of the Alzheimer type, Parkinsonism , Huntington's chorea), anorexia, bulimia, alcoholism-related disorders, strokes, 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, __, 401, 1992; S. Langer, N. Brunello, G. Racagni, J. Mendlecvicz, "Serotonin receptor subtypes: pharmacological significance and clinical implications", Karger Ed. (1992); BE Léonard, Int. Clin. Psychopharmacology, 2, 13-21 ( 1992); RW Fuller, J. Clin. Psychiatry, 51, 36-45 (1992); DG Grahame-Smith, Int. Clin. Psychopharmacology, _, suppl. 4, 6-13, (1992). These receptors are subdivided mainly in 4 main classes (5HTj, 5HT2, 5HT3 and 5HT4) which themselves include subclasses such as the 5HTj receptors which are mainly divided into 5HTIA, 5HTJB »5HTJD (cf. GR Martin, PA Humphrey, Neuropharmacol., 3_3_, 261, 1994; PR Saxena, Exp. Opin. Invest. Drugs, 2 (5), 513, 1994) .The 5HTID receptors themselves contain even several receptor subtypes; thus the 5HTiD and 5HTiDβ receptors were cloned and then identified in humans (cf. for example E. Hamel et al., Mol. Pharmacol., 44, 242, 1993; GW Rebeck et al., Proc. Natl. Acad. Sci. USA, 21, 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 5HTj and more particularly for the receptors called 5HTID, according to the new nomenclature recently proposed by P. Humphrey, P. Hartig and D. Hoyer (TIPS, 14, 233-236, 1993) Medicines including (alone or in combination with other therapeutic agents) the active principles of the present invention find their use in both curative and preventive treatment of diseases related to dysfunction of the 5HTι receptors including the 5HTIA _> 5HTID _C ^and 5HTjDβ receptors, to their deregulation or to modifications of the activity of the endogenous ligand (generally serotonin).

The compounds of the present invention are powerful and selective ligands for the 5HTj receptors which can act as agonists, partial agonists or antagonists at the level of these receptors, and can therefore find application in the serotonin-related disorders mentioned above. The present invention relates to derivatives of general formula (I)

in which :

R \ represents a hydrogen or a linear or branched alkyl residue comprising from 1 to 6 carbon atoms.

R2 can be in various positions on the aromatic ring to which it is attached represents a substituent such as hydrogen, 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 arylalk 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 (COR5), sulfonylated (SO2R5), oxygenated (ORβ), amino (NR6R'6) residue, a nitrile (CN), nitro (NO2), hydroxyamine (NHOH) in which R5 represents R4, OR4 or NHR4, R and R '_ represent hydrogen, R4, COR4, CO2R4, CONHR'4, SO2R4 or Sθ2NHR' 4 in which R4 is defined as above and R'4 represents a hydrogen, a linear or branched alkyl comprising from 1 to 6 carbon atoms, an aromatic residue such as a phenyl, benzyl or phenethyl or a cycloalkyl of 4 to 10 atoms of carbon being understood that the group symbolized by O-CH (R3) -XY in the formula (I) can be in various positions on the aromatic cycle to which it is attached.

The invention also extends to their salts, solvates, hydrates and bioprecursors acceptable for therapeutic use. The 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 acceptable for the therapeutic use of naphthylpiperazines of general formula (I), mention will be made of salts formed by addition with organic or mineral acids and for example hydrochlorides, hydrobromides, sulfates, methanesulfonates, ftimarates, maleates or succinates. Other salts may be useful in the preparation of the compounds of formula (I), for example adducts with creatinine sulfate.

The expression "bioprecursors" as used in the present invention applies to compounds whose structure differs from that of the compounds of formula (I), but which, administered to an animal or to a human being, are converted in the body into a compound of formula (I). 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 'j can be equivalent to Ri or to a precursor of Rj (which will be restored at the end of the synthesis by an appropriate reaction such as for example the cleavage of a protective group such as hydrolysis in acid medium of a derivative of formula (I) in which R ′ i represents a t-butoxycarbonyl to give the derivative of formula (I) in which R 1 represents hydrogen or also the transformation of a functional group such as an amide (Rj = COCH3 for example) in amine (Ri = CH2CH3) after reduction with for example lithium aluminum hydride) with a derivative of general formula (III)

L-CH XY (III) I in which X, Y and R3 are defined as above and L represents a leaving group such as a halogen (iodine, bromine or chlorine), a mesylate, a tosylate or a 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, in general, in the presence of an organic base (NaH, KH, E13N, DBU, DBN, DIPEA, tβuOK) or inorganic (K2CO3, KHCO3, NaHC03, CS2CO3, KOH, NaOH, CaCθ3- ..) in an anhydrous solvent such as THF, DMF, DMSO, acetone, diethyl ketone, methyl ethyl ketone, acetonitrile or DME at a temperature between 20 ° and 140 ° C, in the presence or not of a salt as catalyst and which can be Kl, BU4NI, Lil, AgBF4, AgClθ4 Ag2C03, KF, BU4NF or CsF. The choice of the experimental conditions and of the reagents to carry out the condensation between the derivatives of formulas (II) and (III) 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 produced according to methods and techniques well known to those skilled in the art.

The hydroxylated naphthylpiperazine derivatives of general formula (II) are prepared from the corresponding hydroxy-naphthylamines (IV)

NH;

by reaction in basic medium with an amine derivative of general formula (V)

Ri - N (CH ₂ CH ₂ -Z) ₂ (V)

in which Ri is defined as above and Z represents a chlorine, a bromine, an iodine, a mesylate or a tosylate. This reaction is preferably carried out in a polar anhydrous solvent such as DMF, THF, acetonitrile, n-butanol, chlorobenzene or DMSO, generally at reflux temperature of the solvent used, in the presence or not of a base. organic or inorganic generally used for this type of reaction such as a sodium, potassium, calcium or cesium carbonate. The derivatives of general formula (II) can also be prepared from the intermediates of formula (IV) by reaction with an amino acid of formula (VI)

- COOH

R _Γ N (VI)

^ - COOH

in which Ri is defined as above in the presence of acetic anhydride, followed by the reduction of the intermediate dicetopiperazine thus formed with, for example, a 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 the synthesis 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", T.W. Greene, J. Wiley & Jones, 1981 and "Protecting groups" by PJ Kocienski, Thieme Verlag, 1994. The appropriate protective groups will therefore be introduced and then removed at the level of the most suitable synthetic intermediates for this purpose and using the methods and techniques. described in the references cited above.

Also to be considered as an integral 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) by 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 transformed into derivatives of formula (I) in which Y represents CH2NH2 by a hydrogenation reaction which can be carried out for example using Raney Nickel.

Similarly, a derivative of formula (I) in which Y represents an ester (COR5 with R5 = OR4) can also be converted into an amide (Y = CONH2) by reaction with ammonia in the presence of ammonium chloride in methanol or in alcohol (Y = CH2OH) by reduction according to the methods and techniques well known for this type of transformation such as for example the use of lithium aluminum hydride in a solvent such as ethyl ether or THF. The compounds of general formula (I) in which Y represents NH2 are particularly appreciated intermediates for the preparation of compounds of formula (I), in which Y represents NHR4, NHCOR4, NHCO2R4, NHCONHR'4, NHSO2R4 or NHSO ₂ NR4R ' 4 in which R4 and R'4 are defined as above by the well known methods and techniques for transforming a primary amine into a secondary amine, amide, carbamate, urea, sulfonamide or sulfonurea.

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 pure 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 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-l-tartaric, acid (+) - di-p- toluoyl-1-tartaric, acid (+) - camphorsulfonic, acid (-) - camphorsulfonic, acid (+) - phenylpropionic, (-) - phenylpropionic acid, followed by 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 can also be resolved by formation of diastereomeric amides which are separated by chromatography and hydrolysed to release the chiral auxiliary. The following examples illustrate the invention without, however, limiting its scope.

For IR, the absorption frequencies are given in cm ^_ l at their maximum intensity. Regarding the proton NMR, the chemical shifts are given in ppm and the following abbreviations have been used: m (multiplet), M (Massive), s (singlet), d (doublet), dd (doublet of doublet) , t (triplet). EXAMPLE I Ethyl 5- [8- (4-methylpiperazin-1-yI) naphthalen-2-yloxy] pentanoate fumarate

1Δ: 8- (4-methylpiperazin-1-yl) naphthalen-2-ol

8-aminonaphthalen-2-ol (16.1 g; 101 mmol) and 2-chloro-N- (chloroethyl) -N-methylethananine hydrochloride (19.5 g; 101 mmol) are brought to reflux of butan-1-ol (300 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 (wide), 2945, 2812, 1622, 1597 1 H 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 1Δ (519 mg; 2.14 mmol) and ethyl 5-bromopentanoate (850 μl; 5.35 mmol) are brought to reflux of 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 equivalent 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. Elementary analysis for: C22H30N2O3-C4H4O4

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) naphthalene hydrochloride

Ethyl 2-yloxy] hexanoate

Compound 2 is prepared according to the same procedure as 1 from the following reagents: 8- (4-methylpiperazin-1-yl) naphthalen-2-ol (1Δ) (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); methylethycetone (25 ml). Mass obtained: 734 mg (Yield: 70%) The hydrochloride of compound 2 is obtained by adding a solution of hydrogen chloride in ethyl rether to a solution of the compound in dichloromethane. Elementary analysis for: C23H32N2O3-HCI

Calculated: C 65.62; H 7.90; N 6.65; C1 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). Melting point: 86 ° C. EXAMPLE 3: fumarate of 5- [8- (4-methylpiperazin-1-yl) naphthalen-2-yloxy] isopropyl pentanoate

2Δ: 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 and under a nitrogen atmosphere. The triethylamine (3.35 ml; 15 mmol) is then added dropwise to the reaction mixture. This is brought to room temperature and stirred for 3 h. 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%) 1 H NMR (CDCI3): 1.22 (d, 6H); 1.43-1.55 (M, 4H); 2.26 (t, 2H); 3.40

(t, 2H); 5.00 (Sept., 1H).

2: Compound 2 is obtained according to the same procedure as 1 from the following reagents: 8- (4-methylpiperazin-1-yl) naphthalen-2-ol 1Δ (520 mg; 2.15 mmol); 2Δ isopropyl 5-bromopentanoate (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 f marate is obtained according to the same method as for 1. Elementary analysis for C23H32N2O3-C4H4O4

Calculated: C 64.78; H 7.25; N 5.60; Experimental: C 63.41; H 7.15; NOT

5.34

Mass (DCI / NH3): 385 (MH +), 382, 365

IR (KBr). 3445, 1722, 1107 1 H 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).

Fiction point: 128-131 ° C

EXAMPLE 4: 6- [8- (methylpiperazin-1-yl) naphthalene-2-yloxy] isopropyl hexanoate

Isopropyl 4Δ: 6-bromohexanoate

Compound 4Δ is prepared according to the same procedure as 2Δ 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%)

1 H 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 (Sept., 1H).

4: Compound 4 is prepared according to the same procedure as 1 from the following reagents: 8- (4-methylpiperazin-1-yl) naphthalen-2-ol 1Δ (508 mg; 2.1 mmol); Isopropyl 6-bromohexanoate (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%)

1 H NMR (CDCl ₃ ): 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. JH); 7.06-7.13 (m, 2H); 7.25 (dd, 1H); 7.47 (m, 2H); 7.70 (d, 1H). EXAMPLE 5 6- [8- (4-methylpiperazin-1-yl) naphthalen-2-yloxy] hexanenitrile fumarate

Compound 5 is prepared according to the same procedure as for compound 1 from the following reagents: 8- (4-methylpiperazin-1-yl) naphthalen-2-ol 1Δ

(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).

Mass obtained: 361 mg (Yield: 53%)

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

Elementary analysis for C21H27N3O-C4H4O4

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 1 H 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).

Melting point: 160 ° C

EXAMPLE 6; 5- [8- (methylpiperazin-1-yl) naphthalen-2-yloxy fumarate

Jpentanenitrile

Compound _ is prepared according to the same procedure as 1 from the following reagents: 8- (4-methylpiperazine-1-yl) naphthalen-2-ol 1Δ (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 according to the same method as for 1.

Elementary analysis for C20H25N3O-C4H4O4

Calculated: C 65.59; H 6.65; N 9.56; Experimental: C 65.52; H 6.71; NOT

9.44

Mass (DCI-NH3): 324 (MH +)

IR (KBr): 3429, 1680, 1624

1 H 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).

Melting point: 182-183 ° C EXAMPLE 7; 5- [8- (4-methylpiperazin-1-yl) naphthalen-2-y loxy] penty lamin difumarate

A solution of lithium aluminum hydride in tetrahydrofuran

(1 M; 1.62 ml; 1.62 mmol) is added slowly to a solution of compound δ (1.05 g; 3.25 mmol) in tetrahydrofuran (20 ml) at 0 ° C and under a nitrogen atmosphere. After 15 min, the reaction mixture is brought to room temperature and stirred for 2 h. After this time, it is hydrolyzed with a 1 M sodium hydroxide solution and then filtered through 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 sodium chloride solution, 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 equivalent of fumaric acid to a solution of compound 1 in hot methanol. After evaporation of the methanol, the salt is crystallized from ethyl ether.

Elementary analysis for: C20H29 3O-2C4H4O4.O.5H2O

Calculated: C 59.14; H 6.74; N 7.39; Experimental: C 58.95; H 7.11; NOT

7.40

Mass (DCI / NH3): 328 (MH +)

IR (KBr): 3431, 2941, 1678, 1624, 1599, 1464

1 H 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 EXAMPLE 8 N- {5- [8- (4-methylpiperazin-1-y 1) naphthalen-2-y loxy] pentyl} methanesulf onamide fumarate

S

A solution of compound 1 (330 mg; 1.06 mmol) in dichloromethane

(10 ml) containing triethylamine (220 μl; 1.6 mmol) is cooled to 0 ° C. under a nitrogen atmosphere. The mesyl chloride (100 μl; 1.27 mmol) is then added to the reaction mixture. This is stirred for 15 min at 0 ° C. then it is diluted with water. The phases are separated and the organic phase is washed twice with a saturated sodium chloride solution. It is dried over magnesium sulfate, filtered and concentrated. The crude obtained is purified by flash chromatography with a mixture

(95/5/1) of dichloromethane, methanol, ammonia.

Mass obtained: 300 mg (Yield: 62%)

The fumarate is obtained according to the same method as 1.

Elementary analysis for: C21H31N3O3S-C4H4O4-O.15C4H10O Calculated: C 57.56; H 6.76; N 8.06; Experimental: C 57.39; H 7.05; NOT

8.00

Mass (DCI / NH3): 406 (MH +)

IR (KBr): 3429, 2945, 2866, 1624, 1597, 1458

1 H 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 2 is prepared according to the same procedure as 1 from the following reagents: 8- (4-methylpiperazin-1-yl) naphthalen-2-ol 1Δ (507 mg; 2.1 mmol); 4-bromobutyl acetate (606 μl; 4.2 mmol); potassium carbonate (725 mg; 5.25 mmol); potassium iodide (35 mg; 0.21 mmol); methyl ethyl ketone (10 ml).

Mass obtained: 319 mg (Yield: 43%)

The fumarate is obtained according to the same method as 1. Elemental analysis for: C21H28N2O3-C4H4O4

Calculated: C 63.55; H 6.83; N 5.93; Experimental: C 63.63; H 6.88; NOT

5.92

Mass (DCI / NH3): 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: 138 ° C EXAMPLE 10 _ ^• fumarate 4- [8- (4-methylpiperazin-l-yl) naphthalen-2-yloxy] butan-l-ol

read

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

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

Elementary analysis for: C19H26N2O2-C4H4O4 Calculated: C 64.17; H 7.02; N 6.51; Experimental: C 63.46; H 6.97; NOT

6.39

Mass (DCI / NH3): 314 (MH +)

IR (KBr): 3406, 2953, 2866, 2687, 1686, 1624

1 H 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).

Melting point: 154 ° C EXAMPLE 11 N-ethyl-6- [8- (4-methylpiperazin-1-yl) naphthalen-2-yloxy] hexanamide fumarate

11

HΔ: 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 and under a nitrogen atmosphere. The triethylamine (5.9 ml; 42.15 mmol) is then added dropwise to the reaction mixture. This is brought to room temperature and stirred for 5 h. 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 organic phase is dried over sodium sulfate, filtered and concentrated. Mass obtained: 2.57 g (Yield: 83%) 1 H 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);

H: 8- (4-methylpiperazine-1-yl) naphthalen-2-ol 1Δ (500 mg; 2.07 mmol) and N-ethyl-6-bromohexanamide HΔ (716 mg; 3.1 mmol) are stirred at room temperature and under a 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 sodium chloride solution, 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 according to the same method as for 1. Elemental analysis for C23H33N3O2-C4H4O4

Calculated: C 64.91; N 7.46; N 8.41; Experimental: C 64.40; H 7.45; N 8.34

Mass (DCI / NH3): 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

12

A solution of 8- (4-methylpiperazin-1-yl) naphthalen-2-ol 1Δ (324 mg; 1.34 mmol) in tetrahydrofuran (5 ml) is cannulated on a suspension of sodium hydride (60%; 59 mg ; 1.47 mmol) in tetrahydrofuran (5 ml) at 0 ° C and under a nitrogen atmosphere. Before the addition of benzyl bromide (175 μl; 1.47 mmol), the reaction mixture is stirred at 0 ° C for

30 mins. It is then stirred for 12 h 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 sodium chloride solution, 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: 189 mg (Yield: 42%)

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

Elementary analysis for: C22H24N2O-C4H4O4

Calculated: C 69.63; H 6.29; N 6.15; Experimental: C 68.73; H 6.28; NOT

6.12

Mass (DCI / NH3): 333 (MH +), 241

IR (KBr): 3431, 3030, 2841, 2498, 1701, 1599

1 H 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.l 1H).

Melting point: 218 ° C

EXAMPLE 13 1-methyl-4- [7- (4-nitrobenzyloxy) naphthalen-1-yl] piperazine fumarate

12

Compound 12 is prepared according to the same procedure as 12 from the following reagents: 8- (4-methylpiperazin-1-yl) naphthalen-2-ol 1Δ (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.

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

Elementary analysis for: C22H23N3O3-C4H4O4

Calculated: C 63.28; H 5.51; N 8.51 Experimental: C 62.23 ;. 5.58; No. 8.59

Mass (DCI / NH3): 378 (MH +), 361, 348, 241 1 H 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).

Melting point: 228 ° C

EXAMPLE 14 Methyl 4- [8- (4-methylpiperazin-1-yl) naphthalen-2-yloxymethyl] benzoate fumarate

14

Compound 14 is prepared according to the same procedure as 12 from the following reagents: 8- (4-methylpiperazine-1-yl) naphthalen-2-ol 1Δ (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 according to the same method as for 1.

Elementary analysis for: C24H26 2O3-C4H4O4

Calculated: C 66.39; H 5.97 ;. 5.53; Experimental: C 66.16; H 5.93; NOT

5.39

Mass (DCI / NH3): 392 (MH +), 243

IR (KBr): 3418, 2953, 2829, 2471, 1716, 1597

1 H 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-yloxymethyljbenzoate fumarate

15

Compound 15 is prepared according to the same procedure as 1 from the following reagents: 8- (4-methylpiperazine-1-yl) naphthalen-2-ol 1Δ (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.

Mass obtained: 364 mg (Yield: 45%) The fumarate is obtained according to the same method as for 1.

Elementary analysis for: C24H26N2O3-I .5C4H4O4

Calculated: C 63.82; H 5.71; N 4.96; Experimental: C 63.65; H 5.90; NOT

5.09

Mass (DCI / NH3): 391 (MH +) IR (KBr): 3447, 2953, 2835, 2598, 1713, 1622, 1595

1 H 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: 180 ° C (dec.) EXAMPLE 16 Ethyl 2- [8- (4-methyl-piρérazin-1-yl) naphthalen-2-yloxyjacetate fumarate

1__

Compound 16. is prepared according to the same procedure as 12 from the following reagents: 8- (4-methylpiperazin-1-yl) naphthalen-2-ol JΔ (469 mg;

1.94 mmol); ethyl bromoacetate (235 μl; 2.13 mmol); tetrahydrofuran

(12 ml).

Mass obtained: 475 mg (Yield: 75%)

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

Elementary analysis for: C19H24N2O3-C4H4O4

Calculated: C 62.15; H 6.35; N 6.30; Experimental: C 61.75; H 6.40; NOT

6.26

Mass (DCI / NH3): 329 (MH +), 315, 241

IR (KBr): 3441, 2932, 2685, 1738, 1686

1 H 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).

Melting point: 156 ° C EXAMPLE 17: 4- [8- (methylpiperazin-1-yl) naphthalen-3-yloxy] butyl acetate fumarate

12

17A: 8- (4-methylpiperazin-1-yl) naphthalen-3-ol

Compound 12Δ is prepared according to the same procedure as 1Δ from the following reagents: 8-amino-naphthalen-3-ol (10 g; 62.2 mmol), 2-chloro-N- (chloroethyl) -N-methylethyl hydrochloride laminate (11.8 g; 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%)

1 H NMR (DMSO): 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).

12: Compound 12 is prepared according to the same procedure as H from the following reagents: 8- (4-methylpiperazin-1-yl) naphthalen-3-ol 17A (580 mg; 2.4 mmol); 4-bromobutylacetate (690 μl; 4.8 mmol), cesium carbonate (1.56 g; 4.8 mmol); dimethylformamide (40 ml).

Mass obtained: 657 mg (Yield: 77%) The fumarate is prepared according to the same procedure as 1.

Elementary analysis for: C21H28N2O3-C4H4O4

Calculated: C 63.55; H 6.83; N 5.93; Experimental: C 63.34; H 6.88; NOT

5.85 IR (KBr): 3437, 2955, 2581, 1736, 1701, 1624, 1250

1 H 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).

Melting point: 134 ° C

EXAMPLE 18 1-- [8- (4-methylpiperazin-1-yl) naphthalen-2-yloxy] nonane fumarate

18

Compound 18 is prepared according to the same procedure as 11 from the following reagents: 8- (4-methylpiperazin-1-yl) naphthalen-2-ol (1Δ) (505 mg; 2.09 mmol); 1-bromononane (480 μl; 2.5 mmol); cesium carbonate (1.02 g; 3.1 mmol); dimethylformamide (20ml).

Mass obtained: 505 mg (Yield: 66%).

The fumarate is obtained according to the same method as for compound 1.

Elementary analysis for: C24H36N2O-C4H4O4

Calculated: C 69.39; H 8.32; N 5.78; Experimental: C 69.10; H 8.33; N 5.76

Mass (DCI-NH3): 369 (MH +).

IR (KBr): 3427.2928.2855,1686,1624,1458 1 H NMR (DMSO): .84 (m, 3H); 1.25 (M, 12H); 1.73 (m, 2H); 2.37 (s, 3H); 2.73 (M, 4H); 3.28 (M, 4H); 4.07 (t, 6.3 Hz, 2H); 6.57 (s, 2H); 7.06-7.37 (m, 4H); 7.50 (d, 8.1 Hz, 1H); 7.77 (d, 8.9 Hz, 1H).

Melting point: 142 ° C

EXAMPLE 19 α- [8- (4-methylpiperazin-1-yl) naphthalen-2-yloxy] -4-bromoacetophenone fumarate

12

Compound 12 is prepared according to the same procedure as H from the following reagents: 8- (4-methylpiperazin-1-yl) naphthalen-2-ol (1Δ) (2.208 g; 9.12 mmol); 4, α-dibromoacetophenone (5.07g; 18.24 mmol); cesium carbonate (8.9 g; 27.4 mmol); dimethylformamide (80 ml). The crude is purified by flash chromatography with a mixture (95/5/1) then (90/9/1) of dichloromethane, methanol, ammonia.

Mass obtained: 2.82 g (Yield: 70%).

The fumarate is obtained according to the same method as for compound 1.

Elementary analysis for: C23H23BrN2θ2-0.7C4H4θ4-0.2 H2O Calculated: C 59.11; H 5.04; N 5.34; Experimental: C 59.28; H 4.95; N 5.29.

Mass (DCI-NH3): 439 (MH +), 361.243.

IR (KBr): 3426,3053,2833,1697,1568 1 H NMR (DMSO): 2.16 (s, 3H); 2.33 (M, 4H); 2.89 (M, 4H); 5.74 (s, 2H); 6.62 (s, 1.4H); 7.04-7.31 (m, 4H); 7.54 (d, 8 Hz, 1H); 7.84 (m, 3H); 8.05 (d, 8.5 Hz, 2H).

Melting point: 185 ° C

EXAMPLE 20 N-biphenyl-α- [8- (4-methylpiperazin-1-yl) naphthalen-2-yloxy] acetamide fumarate

2Q

2ΔΔ: 2- [8- (4-methylpiperazin-1-yl) naphthalen-2-yloxy] methyl acetate The compound 2QΔ is prepared according to the same procedure as 12 from the following reagents: 8- (4-methylpiperazin-1 -yl) naphthalen-2-ol 1Δ (1.527g; 6.31mmol); methyl bromoacetate (630μl; 6.4mmol); sodium hydride (60%; 280mg; 6.9mmol), tetrahydrofuran (50ml). The crude is purified by flash chromatography with a mixture (97/3/1) of dichloromethane, methanol, ammonia.

Mass obtained: 1.21 g (Yield: 64%).

1 H NMR (DMSO): 2.43 (s, 3H); 2.71 (M, 4H); 3.11 (M, 4H); 3.83 (s, 3H); 4.79 (s, 2H); 7.11 (d, 7.2 Hz.lH); 7.20 (dd, 2.6 and 9.0 Hz, 1H); 7.31 (d, 7.6 Hz, 1H); 4.47 (m, 2H); 7.75 (d, 8.9 Hz, 1H).

2Û: The compound 2fîΔ is brought to reflux of a sodium hydroxide solution (160 mg, 4 mmol) in a methanol / water mixture (10ml + 10ml). After 12 h, the mixture is cooled, acidified with a 5M solution of hydrochloric acid and then evaporated to dryness. The solid obtained is dissolved in pyridine (10ml) then thionyl chloride (95μl; 1.3mmol) is added dropwise at 0 ° C. The reaction mixture, brought to ambient temperature, is stirred for 2 h before the addition of 4-aminobiphenyl (220 mg; 1.3 mmol). It is then heated at 80 ° C for several days.

The crude reaction product, after evaporation of the pyridine is directly impregnated on silica and then chromatography with a 98/2 / 0.5 then 95/5/1 mixture of dichloromethane, methanol, ammonia.

Mass obtained: 185 mg (Yield: 31%).

The fumarate is obtained according to the same method as for compound 1.

Elementary analysis for: C29H29N3O2-I .5 C4H4O4-O.25 H2O Calculated: C 66.71; H 5.68; N 6.67; Experimental: C 66.62; H 5.72; N 7.04.

Mass (DCI-NH3): 452 (MH +).

IR (KBr): 3397,3030,2835, 1686, 1597, 1508

1 H NMR (DMSO): 2.22 (s, 3H); 2.57 (M, 4H); 2.94 (M.4H); 4.86 (s, 2H); 6.57 (s, 2H); 7.04-8.07 (m, 15H); 10.38 (s, 1H).

Melting point: 124 ° C

EXAMPLE 21 N-ethyl-5- [8- (4-methylpiperazin-1-yl) naphthalen-2-yloxy] pentanamide fumarate

21Δ_: N-ethyl-5-bromopentanamide 5-Bromopentanoyl chloride (4ml; 29.9mmol) is added dropwise to a solution of ethylamine (2.2ml; 33mmol) and triethylamine (4.6ml; 33mmol) in dichloromethane (150ml) at 0 ° C. After 15 min, the solution is diluted with water. The phases are then separated and the organic phase is dried over magnesium sulfate and concentrated. The crude reaction product is purified by flash chromatography with ethyl acetate.

Mass obtained: 6.2g (quantitative yield).

1 H NMR (CDCI3): 1.14 (t, 7.3 Hz, 3H); 1.85 (M, 4H); 2.20 (t, 7.3 Hz, 2H); 3.29 (qd, 7.3 and 1.5 Hz, 2H); 3.42 (t, 6.3 Hz, 2H); 5.57 (M, 1H).

21: Compound 21 is prepared according to the same procedure as 11 from the following reagents: 8- (4-methylpiperazin-1-yl) naphthalen-2-ol (1Δ) (500mg; 2.05mmol); 21Δ (640mg; 3.07mmol); cesium carbonate (1.33g; 4.1mmol); dimethylformamide (10 ml).

Mass obtained: 640 mg (Yield: 85%).

The fumarate is obtained according to the same method as for compound 1.

Elementary analysis for: C22H31N3O2-C4H4O4 Calculated: C 64.31; H 7.26; N 8.65; Experimental: C 64.09; H 7.23; N 8.60.

Mass (DCI-NH3): 370 (MH +).

IR (KBr): 3289,3063,2936,2872,1707,1639, 1458

1 H NMR (DMSO): 1.00 (t, 7.15 Hz, 3H); 1.72 (m, 4H); 2.14 (t, 6.5 Hz, 2H); 2.42 (s, 3H); 2.80 (M, 4H); 3.06 (M, 6H); 4.09 (td, 2H); 6.59 (s, 2H); 7.10 (d, 7.7 Hz, 1H); 7.15 (dd, 2.4 and 8.9 Hz, 1H); 7.26 (t, 7.5 Hz); 7.39 (d, 2.3 Hz, 1H); 7.53 (d, 8.0 Hz, 1H); 7.80 (d, 8.9 Hz, 2H).

Melting point: 102 ° C EXAMPLE 22 N- {5- [8- (4-methylpiperazin-1-yl) naphthalen- fumarate

2-yloxy] pentyl} propanamide

22

Compound 22 is prepared according to the same procedure as compound 21Δ from the following reagents: Propionyl chloride (140μl; 1.6mmol); compound 2 (434mg; 1.33mmol); triethyl lamin (275μl; 1.98mmol). The crude reaction product is purified by flash chromatography with a mixture (90/9/1) of dichloromethane, methanol, ammonia.

Mass obtained: 459 mg (Yield: 90%)

The fumarate is obtained according to the same method as for compound 1.

Elementary analysis for: C23H33N3O2-C4H4O4

Calculated: C 64.91; H 7.46; N 8.41; Experimental: C 64.39; H 7.60; N 8.33. Mass (DCI-NH3): 384 (MH +).

IR (KBr): 3302,3074,2941, 2870, 1709, 1655, 1589

1 H NMR (DMSO): .97 (t, 7.7 Hz, 3H); 1.46 (M, 4H); 1.78 (m, 2H); 2.07 (q, 7.6 Hz, 2H); 2.39 (s, 3H); 2.76 (M, 4H); 3.05 (M, 6H); 4.07 (t, 6.2 Hz, 2H); 6.58 (s, 2H); 7.09 (d, 7.8 Hz, 1H); 7.13 (dd, 2.4 and 8.9 Hz, 1H); 7.25 (t, 7.5 Hz, 1H); 7.38 (d, 2.3 Hz, 1H); 7.52 (d, 7.9 Hz, 1H); 7.76 (M, 1H); 7.78 (d, 8.9 Hz, 1H).

Melting point: 122 ° C EXAMPLE 23 N- {5- [8- (4-methylpiperazin-1-yl) naphthalen- fumarate

2-yloxy] pentyl} benzamide

22 Compound 22 is prepared according to the same procedure as compound 21Δ from the following reagents: Benzoyl chloride (90μl; 0.76mmol); compound 2 (208mg; 0.64mmol); triethylamine (132μl; 0.95mmol); dichloromethane (10ml). The crude reaction product is purified by flash chromatography with a mixture (90/9/1) of dichloromemane, me manol, ammonia.

Mass obtained: 267 mg (Yield: 97%).

The fumarate is obtained according to the same method as for compound 1.

Elementary analysis for: C27H33N3O2-C4H4O4-O.5H2O

Calculated: C 66.89; H 6.88; N 7.55; Experimental: C 66.73; H 6.67; N 7.48.

Mass (DCI-NH3): 432 (MH +).

IR (KBr): 3358,2939,1707,1626

1 H NMR (DMSO): 1.57 (M, 4H); 1.83 (M, 2H); 2.38 (s, 3H); 2.76 (M, 4H); 3.04 (M, 4H); 3.30 (m, 2H); 4.11 (t, 6.2 Hz, 1H); 6.59 (s, 2H); 7.10 (d, 7.9 Hz, 1H); 7.15 (dd, 2.4 and 8.9 Hz, 1H); 7.26 (t, 7.9 Hz, 1H); 7.39-7.55 (m, 5H); 7.78-7.86 (m, 3H); 8.49 (td, 1H).

Melting point: 70 ° C (amorphous) EXAMPLE 24 N-ethyl-α- [8- (4-methylpiperazin-1-yl) naphthalen-2-yloxy] acetamide fumarate

24 A solution of trimethylaluminum (2M in toluene; 2.5ml; 5mmol) is added dropwise to a solution of ethylamine hydrochloride (408mg; 5mmol) in dichloromethane (10ml) at -10 ° C. The reaction mixture is stirred at this temperature for 20 min and then 1 h at room temperature. A solution of compound 22Δ in dichloromethane (10ml) is then cannulated on the mixture which is then brought to reflux. After 12 hours, it is brought back to room temperature before the addition of a 3M sodium hydroxide solution. The phases are separated and the aqueous phase extracted twice with dichloromethane. The combined organic phases are washed with a saturated solution of sodium chloride and then dried over magnesium sulfate. The crude reaction product is purified by flash chromatography with a mixture (95/5/1) of dichloromethane, methanol, ammonia.

Mass obtained: 598 mg (Yield: 73%).

The fumarate is obtained according to the same method as for compound 1.

Elementary analysis for: C19H25N3O2-C4H4O4 Calculated: C 62.29; H 6.59; N 9.47; Experimental: C 62.25; H 6.70; N 9.50.

Mass (DCI-NH3): 328 (MH +).

IR (KBr): 3420.2976, 1662.1597 1 H NMR (DMSO): 1.06 (t, 7.1 Hz, 3H); 2.43 (s, 3H); 2.79 (M, 4H); 3.11 (M, 4H); 3.18 (m, 2H); 4.61 (s, 2H); 6.61 (s, 2H); 7.12 (d, 7.1 Hz, 1 H); 7.23-7.37 (m, 3H); 7.56 (d, 8 Hz.lH); 7.85 (d, 8.9 Hz, 1H); 8.23 td.lH).

Melting point: 83 ° C (amorphous)

BIOLOGICAL RESULTS

The human 5HTn) _α and 5HTiDβ receptors were cloned according to the sequences published by M. Hamblin and M. Metcalf, Mol. Pharmacol., 4Û.143 (1991) and Weinshenk et al., Proc. Natl. Acad. Sci. 82.3630 (1992). Transient transfection and permanent transfection of the genes for these receptors was carried out in Cos-7 and CHO-Kj cell lines using an electroporator. The HeLa HA7 cell line expressing the human 5HT A receptor was obtained from Tulco (Duke Univ., Durham, NC, USA) and cultivated according to the method of Fargin et al., J. Biol. Chem. 2nd, 14848 (1989). The study of the binding of the derivatives of the present invention with the 5HTι _> _α , 5HTiDβ and 5HTIA human receptors was carried out according to the method described by P. Pauwels and C. Palmier (Neuropharmacology, 22.67, 1994). The incubation media for these binding measurements include 0.4 ml of cell membrane preparation, 0.05 ml of a tritiated ligand [[3H] -5CT (final concentration: 2nM) for the 5HTi) _α and 5HTιoβ and [3H J receptors -8OH-DPAT (final concentration: 1 nM) for the 5HTι receptor and 0.05 ml of the test molecule (final concentrations from 0.1 nM to 1000 nM) or 10 μM (final concentration) of serotonin (5HTiD _α and 5HTiDβ) or 1 μM (final concentration) of spiroxatrine (5HTIA) - The study of the inhibition of the formation of cyclic AMP (stimulated by forskolin) mediated by the human 5HTij} β receptor was carried out in CHO-K1 cells transfected with the receptor according to the technique described previously for the 5HTιg receptor (P. Pauwels and C. Palmier, Neuropharmacology, 22.67, 1994). RESULTS OBTAINED

Ki (nM)

Examples 5HTι _Dα 5HTι _Dβ 5HTι _A

1 0.2 0.2 4.3

2 0.36 0.35 13

3 0.34 0.26 6.4

8 0.3 0.12 6.1

9 0.22 0.1 8.6

11 0.44 0.17 13.6

16 0.86 0.86 16.4

The new naphthylpiperazine derivatives forming part of this invention are new compounds having a very high affinity and a very good selectivity for the receptors commonly called 5HTι and more particularly for the receptors called 5HTID, 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 linked 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, aggression, alcoholism, smoking, hypertension, nausea, sexual dysfunction , asocial behavior, anxiety, migraine, spasticity, Alzheimer's disease and memory impairment. The present invention also relates to medicaments consisting of at least one compound of formula (I) in the pure state or in the form of a composition in which it is associated with any other pharmacologically 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, 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 oil paraffin. 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, polyethylene glycol, vegetable oils, in particular olive oil, injectable organic esters, for example ethyl oleate or other organic solvents can be used. suitable. These compositions can also contain adjuvants, in particular wetting agents, isotonizers, emulsifiers, dispersants and stabilizers. Sterilization can be done in several ways, for example by aseptic filtration, by incorporating sterilizing agents into the composition, by irradiation or by heating. They can also be prepared in the form of sterile solid compositions which can be dissolved at the time of use in sterile water or any other sterile injectable medium.

The compositions for rectal administration are suppositories or rectal capsules which contain, in addition to the active product, excipients such as cocoa butter, semi-synthetic glycerides or polyethylene glycols. The compositions for topical administration can be, for example, creams, lotions, eye drops, mouthwashes, nasal drops or aerosols. The doses depend on the desired effect, on the duration of the treatment and on the route of administration used; they are generally between 0.001 g and 1 g (preferably between 0.005 g and 0.25 g) per day, preferably orally for an adult with unit doses ranging from 0.1 mg to 500 mg of active substance, preferably from 1 mg to 50 mg. In general, the doctor will determine the appropriate dosage based on age, weight and all other factors specific to the subject to be treated. The following examples illustrate compositions according to the invention [in these examples, the term "active component" designates one or more

(generally one) of the compounds of formula (I) according to the present invention]:

Tablets

They can be prepared by direct compression or by passing through wet granulation. The direct compression procedure is preferred, but it may not be suitable in all cases depending on the doses and the physical properties of the active component.

A - By direct compression mg for 1 tablet active component 10.0 microcrystalline cellulose PCB 89.5 magnesium stearate 0 _r 5

100.0

The active component is passed through a sieve with a mesh opening of 250 μm on a side, it is mixed with the excipients and it is compressed using 6.0 mm punches. Tablets with other mechanical strengths can be prepared by varying the compression weight with the use of appropriate punches.

B - Wet granulation mg for one tablet active component 10.0 lactose Codex 74.5 starch Codex 10.0 corn starch pregelatinized Codex 5.0 magnesium stearate 0.5

Compression weight 100.0

The active component is passed through a sieve with a mesh opening of 250 μm and mixed with lactose, starch and pregelatinized starch. The mixed powders are moistened with purified water, they are granulated, dried, sieved and mixed with magnesium stearate. The lubricated granules are put into tablets as for the formulas by direct compression. A coating film can be applied to the tablets using suitable film-forming materials, for example methylcellulose or hydroxypropyl methylcellulose, according to conventional techniques. Sugar tablets can also be coated.

mg for one active ingredient capsule 10.0

* starch 1500 89.5 magnesium stearate Codex 0.5

Filling weight 100.0

* a form of directly compressible starch from the firm Colorcon Ltd, Orpington, Kent, United Kingdom.

The active component is passed through a sieve with a mesh opening of 250 μm and mixed with the other substances. The mixture is introduced into hard gelatin capsules No. 2 on an appropriate filling machine. Other dosage units can be prepared by changing the filling weight and, if necessary, changing the size of the capsule. Syrup mg per 5 ml dose active ingredient 10.0 ssaacccchhaarroossee CCooddeexx 2750.0 glycerin Codex 500.0 buffer) flavor) color) q.s. preservative) distilled water 5.0

The active component, the buffer, the flavor, the color and the preservative are dissolved in part of the water and the glycerin is added. The remainder of the water is heated to 80 ° C. and the sucrose is dissolved therein and then cooled. We combine the two solutions, adjust the volume and mix. The syrup obtained is clarified by filtration. Suppositories

Active ingredient 10.0 mg * Witepsol H15 supplement to 1.0 g

* Brand sold for Adeps Solidus of the European Pharmacopoeia.

A suspension of the active component in Witepsol H15 is prepared and introduced into a suitable machine with 1 g suppository molds. Liquid for administration by intravenous injection g / 1 active component 2.0 water for injection Codex supplement to 1000.0

Sodium chloride can be added to adjust the tone of the solution and adjust the pH to maximum stability and / or to facilitate the dissolution of the active component by means of a dilute acid or alkali or by adding buffer salts. appropriate. The solution is prepared, clarified and introduced into ampoules of appropriate size 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 hard gelatin capsules No. 3 on an appropriate encapsulating machine. The contents of the cartridges are administered using a powder inhaler. Pressure aerosol with metering valve mg / dose for 1 can micronized active ingredient 0.500 120 mg oleic acid Codex 0.050 12 mg trichlorofluoromethane for pharmaceutical use 22.25 5.34 g dichlorodifluoromethane for pharmaceutical use 60.90 14.62 g

The active component is micronized in a fluid energy mill and put into the state of fine particles. 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 mixer with a high shearing effect. The suspension is introduced in measured quantity into aluminum aerosol cans on which are fixed appropriate metering valves delivering a dose of 85 mg of the suspension; dichlorodifluoromethane is introduced into the boxes by injection through the valves.

Claims

1. Compounds corresponding to the general formula (I)

in which R 1 represents a hydrogen or a linear or branched alkyl residue comprising from 1 to 6 carbon atoms,

R2 can be in various positions on the aromatic ring to which it is attached represents a substituent such as hydrogen, 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 (COR5), sulfonylated (SO2R5), oxygenated (OR), amino (NRόR'é), nitrile (CN), nitro (NO2), hydroxylamine (NHOH) residue in which R5 represents R4, OR4 or NHR4, R6 and R'g represent hydrogen, R4, COR4, CO2R4, CONHR'4, SO2R4 or Sθ2NHR'4 in which R4 is defined as above and R'4 represents hydrogen, linear or branched alkyl comprising from 1 to 6 atoms of carbon, an aromatic residue such as phenyl, benzyl or phenethyl or a cycloalkyl of 4 to 10 carbon atoms, it being understood that the group symbolized by O-CH (R3) -XY in formula (I) may be in various positions on the aromatic cycle 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: 5- [8- (4-methylpiperazin-1 -y l) naphthalen-2-y loxy jpentanoate of ethyl,

5- [8- (4-methylpiperazin-1-yl) naphthalen-2-yloxy] ethyl hexanoate,

5- [8- (4-methylpiperazin-1-yl) naphthalen-2-yloxy] isopropyl pentanoate,

6- [8- (methylpiperazin-1-yl) naphthalene-2-yloxy] isopropyl hexanoate, 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, l-methyl-4- [7- (4-nitrobenzyloxy) naphthalen-1-yl] piperazine, 4- [8- (4-methylpiperazin-1) yl) methyl naphthalen-2-yloxymethyl] benzoate,

Methyl 3- [8- (methylpiperazin-1-yl) naphthalen-2-yloxymethyl] benzoate,

2- [8- (4-methyl-piperazin-1-yl) naphthalen-2-yloxy] ethyl acetate, 4- [8- (methylpiperazin-1-yl) naphthalen-3-yloxy] butyl acetate, l - [8- (4-methylpiperazin-1-yl) naphthalen-2-yloxy] nonane, α- [8- (4-methylpiperazin-1-yl) naphthalen-2-yloxy] -4-bromoacetophenone, N-biphenyl-α- [8- (4-methylpiperazin-1-yl) naphthalen-2-yloxy] acetamide , N-ethyl-5- [8- (4-methylpiperazin-1-yl) naphthalen-2-y loxy] pentanamide, N- {5- [8- (4-methylpiperazin-1-yl) naphthalen-2- yloxy] pentyl} propanamide,

N- {5- [8- (4-methylpiperazin-1-yl) naphthalen-2-yloxy] pentyl} benzamide, N-ethyl-α- [8- (4-methylpiperazin-1-yl) naphthalen-2-yloxy ] acetamide.

3. Compounds according to claim 1 characterized in that Ri represents a hydrogen or a 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 carbon atoms.

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 COR5 or NHSO2R4. 8. Compounds according to claim 1, characterized in that they correspond to formula I _a .

Compounds according to one of claims 1 to 8 in the form of salts acceptable for the therapeutic use, characterized in that these salts are chosen from a hydrochloride, a hydrobromide, sulfate, methanesulfonate, fumarate, maleate or succinate.

10. Process for preparing the compounds of formula (I) according to claim 1, characterized in that an intermediate of formula (II) is condensed

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

L-CH X-Y (III) I

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

11. Method according to claim 10, characterized in that a compound of formula (I) or a salt or a derivative comprising a protecting group of such a compound is converted into another compound of formula

(D.

12. Pharmaceutical combinations containing, as active ingredients, a compound according to one of claims 1 to 9, in combination with an acceptable pharmaceutical vehicle, as medicaments.

13. Pharmaceutical compositions containing, as active ingredients, a compound according to one of claims 1 to 9, in combination with an acceptable pharmaceutical vehicle, for both curative and preventive treatment of disorders related to serotonin.

14. Pharmaceutical compositions containing, as active ingredients, a compound according to one of claims 1 to 9, in combination with an acceptable pharmaceutical vehicle, for both curative and preventive treatment of migraine, cluster headache. face and chronic vascular headache.

15. Pharmaceutical compositions containing, as active ingredients, a compound according to one of claims 1 to 9, in combination with an acceptable pharmaceutical vehicle, for both curative and preventive treatment 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 an acceptable pharmaceutical vehicle, for both curative and preventive treatment of schizophrenia, spasticity, l aggression and / or alcoholism and / or asocial behavior, eating disorders such as bulimia and anorexia, sexual dysfunctions.

17. Pharmaceutical compositions containing, as active ingredients, a compound according to one of claims 1 to 9, in combination with an acceptable pharmaceutical vehicle, for both curative and preventive treatment and neurodegenerative diseases such as for example disease Parkinson's or Alzheimer's disease.