WO1993016057A1 - 1,4-dialkylpiperazine derivatives, method for obtaining them and pharmaceutical compositions containing them - Google Patents

Abstract

The invention relates to derivatives of 1,4-dialkylpiperazine having formula (I) wherein X is an atom of oxygen, of sulfur, a methylene group or an unsubstituted amino group or an amino group substituted by a phenyl, paratoluenesulfonyl or nitropyridine group; n is an integer from 0 to 3; Z is a methyl group, a phenyl group (1), a phtalimide group or a group (2) when A is an oxygen atom, a ketone function, a group CHOH, or an unsubstituted vinyl group or a vinyl group substituted by a phenyl group; R1?, R2? and R3?, which are similar or different, represent a hydrogen atom, a halogen atom, a C1?-C6? alkyl, a C1?-C6? alkoxy or a trifluoromethyl group, or yet R2? and R3? represent together an alkylenedioxy group wherein the alkyl group is from C1? to C6?, and the pharmaceutically acceptable salts thereof. Said derivatives are active as antidepressing neuroleptic, anxiolytic, antihistaminic and spasmolytic agents.

Description

1,4-dialkylpiperazine derivatives, processes for obtaining them and pharmaceutical compositions containing them

The present invention relates to 1,4-dialkylpiperazine derivatives, methods for obtaining them and pharmaceutical compositions containing them. The derivatives of the invention exhibit interesting pharmacological properties on the central nervous system, in particular antidepressant, neuroleptic and anxiolytic properties, as well as anti histamine and spasmolytic activities.

 The compounds of the invention correspond to the following general formula (I):

in which

 - X represents an oxygen or sulfur atom, a methylene group, or an amino group unsubstituted or substituted by a phenyl, paratoluenesulfonyl or nit ropyridine group,

 - n is an integer from 0 to 3,

- Z represents a methyl group, a phenyl group a

phthalimide group or a group in which

 - A is an oxygen atom, a ketone function, a CHOH group, or a vinyl group unsubstituted or substituted by a phenyl group,

- R ₁ , R ₂ and R ₃ , identical or different, represent a hydrogen or halogen atom, a C ₁ -C ₆ alkyl, a C ₁ -C ₆ alkoxy or a trifluoromethyl group, or alternatively R ₂ and R ₃ together represent an alkylenedioxy group in which the alkyl group is in In the present description, C ₁ -C ₆ alkoxy denotes a hydroxy group substituted by a C ₁ -C ₆ alkyl and, by C ₁ -C ₆ alkyl, the residues of saturated aliphatic hydrocarbons with straight chain or branched, containing 1 to 6 carbon atoms. The preferred alkyl group for the purposes of the invention is the methyl group.

 The term "halogen" designates the four halogens F, Cl,

Br and I. Preferably, R ₁ , R ₂ and / or R ₃ , when they represent a halogen, are F or Cl.

 Advantageous compounds of formula (I) are those in which at least one of the following conditions is met:

- X is a methylene group;

 - X is an amino group unsubstituted or substituted by a phenyl, paratoluenesulfonyl or nitropyridine group;

- Z is a group in which A is an oxy atom

 ketone gene or function;

 - n = 2 or 3.

The compound of formula (I) in which X is a methylene group, R ₁ represents hydrogen, Z is a group in which A is a ketone function, R ₂ represents

feels a fluorine atom in position 4 and R ₃ represents hydrogen, is a preferred compound according to the invention.

 The compounds of formula (I) can be obtained by various synthetic methods, called methods A, B, C, D, E and F which are explained below.

 In the following description, the substituents which have not all the meanings given for the compounds of formula (I) have been assigned an index (lowercase letter corresponding to the capital letter designating their process of preparation). The general formulas of the compounds obtained by the various synthesis processes have been assigned the same index.

The compounds of formula (la) below in which: - Xa is an oxygen or sulfur atom, a methylene group or an amino group unsubstituted or substituted by a paratoluenesulfonyl group,

- R ₂ , n and Z being as defined above,

 can be obtained by condensation of the monosubstituted piperazine (II) on the chlorinated derivative (III), in the presence of potassium carbonate and a catalytic amount of potassium or sodium iodide, in a ketonic solvent such as methyl ethyl ketone ( 2-butanone) or diethyl ketone, as indicated in the reaction scheme below (Method A):

 The conëensation can also be carried out in an aromatic solvent such as benzene, toluene or xylene, but in this case an additional equivalent of piperazine (II) must replace the potassium carbonate in order to trap the hydrochloric acid formed.

 The chlorinated derivative (III) can easily be prepared by chlorination of the alcohol (IV), in which Xa is defined as above, by thionyl chloride in an aromatic solvent such as benzene or toluene or in a chlorinated solvent such as methylene chloride or chloroform, as shown in the diagram below:

L'alcool (IV) est obtenu par réduction par le borohydrure de sodium de la cetone correspondante (V) dans un alcool inférieur, tel que le méthanol ou l'éthanol.

The alcohol (IV) is obtained by reduction by sodium borohydride of the corresponding ketone (V) in a lower alcohol, such as methanol or ethanol.

 The piperazines (II) other than the born Ipiperazi pheny

(n = O, Z = and that methylpiperazi does not (n = O, Z = CH ₃ )

 are conventionally prepared by condensing four equivalents of anhydrous piperazine (VII) on the halogenated or tosylated derivatives (VI) in an aromatic solvent (hereinafter symbolized by ArH) such as toluene or xylene, according to the diagram below:

The compounds of formula (Va) in which Xa is a unit, are conventionally prepared according to the scheme described by

 Johnson and Glenn (JACS 71, 1949, 1092-6), explained below.

Les cétones (Va) pour lesquelles

Ketones (Va) for which

R ₁ is a hydrogen or halogen atom, in particular fluorine or chlorine,

 Xa is an N-paratoluenesulfonyl motif,

 are prepared according to the reaction scheme described below:

 The compounds of formula (Ib) below in which

- Zb represents a methyl group, a phenyl group

 a phthalimide group or a group - *

dans lequel A est un atome d'oxygène, un groupe CHOH ou un groupe vinyle non substitué ou substitué par un groupe phényle,

in which A is an oxygen atom, a CHOH group or a vinyl group which is unsubstituted or substituted by a phenyl group,

- R ₁ , R ₂ , R ₃ , n and X are as defined above for the compounds of formula (I)

can also be obtained by reduction of enamine (XVIII) by sodium borohydride, in the presence of formic acid in a solvent such as tetrahydrof uranium (THF) according to the method described in application GB 1 249 375, as indicated in the diagram below (Method B):

 One can also use other reduction methods known to those skilled in the art, in particular using formic acid (Leucart reaction described in P.L. de Benville et al., J.A.C.S, 1950, 72, 3073).

 Enamines (XVIII), in which:

Zb represents a methyl group, a phenyl group,

 a phthalimide group or a group

dans lequel A est un atome d'oxygène, un groupe CHOH ou un groupe vinyle non substitué ou substitué par un groupe phényle, - R₁, R₂, R₃, n et X sont tels que définis plus haut pour les composés de formule (I)

in which A is an oxygen atom, a CHOH group or a vinyl group which is unsubstituted or substituted by a phenyl group, - R ₁ , R ₂ , R ₃ , n and X are as defined above for the compounds of formula (I)

are obtained by condensation of the substituted piperazine (IIb), on the ketone (V) in the presence of TiCl ₄ in an aromatic solvent such as benzene or toluene according to the method described by Rossi et al., in Synthesis 1978, 465- 7, as shown in the diagram below:

In the case where X represents: ente a motif or N-paratoluènesulfonyle,

R ₁ , R ₂ , R ₃ , n, Zb and A being as defined above for the derivatives of formula (Ib), the enamine (XVIII) can also be prepared by heating the ketone (V) and three equivalents of the amine (IIb) previously described in an aromatic solvent such as benzene, toluene or xylene in the presence of a catalytic amount of paratoluene sulfonic acid, and by distilling the water by azeotropic entrainment.

The enamines of formula (XVIII) in which X is a unit are new compounds and represent a

 another object of the invention.

 The derivatives of formula (le) below in which

- R ₁ , R ₂ , R ₃ and X are as defined above for the derivatives of formula (I),

 - n ≠ 0,

^X ou un g roupe — da ns l eque l A est une f onct i on c e tone ,

- Zc represents a phenyl group / a phthalimide unit

^X or a group - in which the A is a function on this tone,

an oxygen atom, or a vinyl group unsubstituted or substituted by a phenyl group, are hereinafter called compounds of formula (Ie). These compounds can easily be obtained by condensation of the halogen derivative (XIX) with the piperazine (XX) in a keto solvent, such as methyl ethyl ketone (2-butanone) or diethyl ketone, in the presence of an equivalent of potassium carbonate or sodium and a catalytic amount of sodium or potassium iodide. This synthesis process (Method C) is described in the diagram below:

 The compounds of formula (XX) can be prepared by hydrogenolysis of the benzyl analogs (XXI) with hydrogen in the presence of palladium in an alcohol such as methanol or ethanol as described below:

Les composés de formule (XIX) pour lesquels A est une fonction cetone, et ceux pour lesquels Z est un phtalimide, sont disponibles commercialement.

The compounds of formula (XIX) for which A is a ketone function, and those for which Z is a phthalimide, are commercially available.

 The derivatives (XIX) in which A represents an oxygen atom and n is equal to 3 are easily accessible by reaction of the dihalogenoalkanes with the corresponding phenates in a ketonic solvent, such as acetone or methyl ethyl ketone, according to the diagram below. -after:

The compounds of formula (XX) for which R ₁ is as defined above and X is an oxygen or sulfur atom or a methylene unit, can also be obtained by condensation of the chlorinated compounds (III) with four equivalents of anhydrous piperazine (VII), in an aromatic solvent such as benzene or toluene as described below:

The derivatives of formula (Id) below are compounds of formula (I) in which X is a compound unit

can be synthesized by the N-phenylation method described by Barton et al., (Tetrahedron letters 1987, 28, 887-90; Ibid 1988, 29, 1115-8). The phenyl nucleus is introduced onto compound XXII using triphenylbismuth diacetate in the presence of copper in a chlorinated solvent such as methylene chloride or chloroform according to the reaction scheme below (Method C):

Condensation of compound (XXII) with 2-chloro-5-nitropyridine in a ketone solvent such as methyl ethyl ketone, in the presence of potassium or sodium carbonate and a catalytic amount of sodium or potassium iodide also leads to the derivatives of formula (I) in which X is a unit according to the reaction scheme below (Method E)

 to prepare the compounds of formula (le) below

The derivatives of formula (XXII) above are synthesized from the compounds of formula (I), in which X represents a amino group substituted by a paratoluenesulfonyl radical by cleavage of the paratoluenesulfonyl radical, using naphthalene / sodium in dimethoxyethane (DME) as indicated below:

 The compounds of formula (I) in which

- Z is a group in which A is a CHOH group,

 - n = 3,

- R ₁ , R ₂ , R ₃ and X are as defined above

 are hereinafter called compounds of formula (If). These compounds are preferably prepared by reduction of the corresponding ketone with a reducing agent such as sodium borohydride in an alcoholic solvent such as methanol or ethanol, according to the scheme indicated below (Method F):

Les composés de formule (I) dans laquelle X représente un groupe méthylène peuvent être préparés alternativement par les procédés de synthèse A, B ou C.

The compounds of formula (I) in which X represents a methylene group can be prepared alternately by the methods of synthesis A, B or C.

 To prepare the compounds of formula (I) in which X is an amino group unsubstituted or substituted by a phenyl, paratoluenesulfonyl or nit ropyridine group, one of the routes A, B, C will be used, according to the choice of the other substituents. ,

Crazy.

 The acid addition salts of the derivatives of formula (I) according to the invention can be obtained by conventional methods with acids commonly used to obtain pharmaceutically acceptable salts, such as maleic acid, hydrochloric acid, methane sulfonic acid or fumaric acid.

 The derivatives according to the invention have advantageous pharmacological properties on the central nervous system, in particular antidepressant, anxiolytic, neuroleptic properties, as well as spasmolytic and antihistamine activities.

 A subject of the invention is also the pharmaceutical compositions containing, as active principle, a derivative according to the invention in association with a pharmaceutically acceptable vehicle as well as the inclusion complexes such as those described in particular in Chem. Pharm. Bull., 1975, 23, 6, 1205; 1975, 23, 12, 3062; 1978, 26, 10, 2952. Advantageously, use will be made of the inclusion complexes of the compounds of the invention in β-cyc lodext rine.

 The compositions according to the invention can be compositions administered orally, sublingually, subcutaneously, intramuscularly, intravenously, transdermally, locally or rectally.

Suitable administration forms include in particular oral forms such as tablets, capsules, powders, granules and oral solutions or suspensions, sublingual and oral administration forms, as well as administration forms -cutaneous, intramuscular, intravenous, intranasal or intraocular and forms of rectal administration. The invention will now be described in more detail by the following illustrative examples. In the examples, the derivatives prepared were identified and characterized by studying their NMR and infrared spectra as well as their elementary analysis.

Example 1

 Preparation of di hydrochloride of N [4-fluoro-phenyl-1) oxo-1 butyl- 4] N '[tetrahydro-1,2,3,4 naphthyl-1] piperazine (Compound 21)

Method A

A mixture composed of 4.68 g (0.028 mole) of chloro-1 tetralin, 7 g (0.028 mole) of (4-fluoro-phenyl-1) oxo-1 butyl-4 piperazine, 5.81 g (0.042 mole) of K ₂ CO ₃ and 0.42 g (0.0028 mole) -de Nal in 50 ml of methyl ethyl ketone (butanone-2) is heated at reflux for 12 h. After cooling. the insolubles are filtered and the solvent is evaporated off under reduced pressure. The residue is taken up in 200 ml of toluene. The toluene phase is washed with 50 ml of water, 5 times 5 ml of 7% acetic acid, then 50 ml of water. After drying the organic phase over MgSO ₄ and evaporation of the solvent, an oil is obtained which is purified by chromatography on silica (solvent CH ₂ Cl ₂ / EtOH: 95/5). 7.2 g of pure product with a melting point of 205 C are obtained.

 Yield: 68%

H NMR spectrum (60 MHz, solvent CDCl ₃ , reference TMS): 1.3 to 1.9 ppm (m, 18H); 3.0 ppm (t, J = 7Hz, 2H); 3.6-4.0 ppm (m, 1H); 6.5 to 8.2 ppm (m, 8H).

Formation of dihydrochloride:

The compound obtained is dissolved in 30 ml of absolute ethanol. In this solution, gaseous hydrochloric acid is bubbled. After cooling, the product is drained and then dried in a vacuum oven the crystals obtained. Melting point 195ºC. E x emp le 2

 Preparation of N (benzyl) N 'hydrochloride (1,2,3,4-naphthyl-1-tetrahydro) piperazine (Compound 12) Method B

 Step 1: Enamine formation

To a mixture of 9 g (0.0062 mole) of cx-tetralone and 66 g (0.037 mole) of benzylpiperazine dissolved in 750 ml of benzene, previously cooled to 5ºC, is added dropwise, under a nitrogen atmosphere , a solution of 7.2 g (0.0038 mole) of TiCl ₄ in 25 ml of benzene. After addition, the reaction mixture is stirred at 20 ° C for 15 h. The precipitate formed is filtered through a bed of Celite. The filtrate is concentrated to dryness under reduced pressure. The red oil obtained is thrown into 100 ml of water and the mixture obtained is stirred until precipitation of a yellow solid.

The solid is drained, then recrystallized from absolute ethanol. 17.2 g of pure enamine with a melting point are thus obtained:

 Yield: 91%

¹ H NMR spectrum (60 MHz, solvent CDCl ₃ , reference TMS): 1.7 to 3.0 ppm (m, 12H); 3.4 ppm (s, 2H); 5.0 ppm (t, J = 4Hz, 1H); 6.7 to

7.3 ppm (m, 9H).

Step 2: Enamine reduction

To a solution of 8 g (0.00263 mole) of the enamine previously described, in 100 ml of tetrahydrof uranium, cooled to 0ºC, 22.8 ml (0.0028 mole) of 98% formic acid are slowly added . Then add, in small amounts, 4 g (0.0106 mole) of sodium borohydride, keeping the temperature at 0ºC. A strong gas evolution is observed (B ₂ H ₆ ). After addition, the reaction mixture is stirred for 5 h at room temperature. The solution is then neutralized with dilute sodium hydroxide, then extracted with chloroform. The organic phase is dried over MgSO ₄ , then concentrated to dryness under reduced pressure. The oil obtained is triturated in petroleum ether, until a white solid precipitates which is wrung out, then dried in an oven. 5.5 g of pure product are thus obtained. Yield: 68%

 Spectrum of R.M.N. H (60 MHz, solvent CDCl, reference TMS): 1.3 to 2.9 ppm (m, 14H); 3.4 ppm (s, 2H); 3.3-3.9 ppm (m, 1H); 6.7 to 7.7 ppm (m, 9H).

Formation of dihydrochloride:

 We operate as described previously in Example 1

Melting point: 210 ° C Example 3

 Preparation of tri hydrochloride of N [benzy l] N '[1-phenyl-1,2,3,4-tetrahydro-quinolinyl-4] piperazine (Compound 3)

Method B

Step 1: Enamine formation

 A mixture of 10 g (0.0448 mole) of N-phenyl tetrahydro-1,2,3,4 quinolinone-4, 24 g (0.1345 mole) of N-benzylpiperazine and 6 g (0 is brought to reflux. , 0315 mole) of p-toluene sulfonic acid, dissolved in 180 ml of toluene. The water formed is removed by azeotropic entrainment (Dean-Stark). When the theoretical amount of water is obtained (16 h), the reaction mixture is cooled and the toluene is evaporated under reduced pressure. The solid is dissolved in 50 ml of methanol at 30ºC. The solution is cooled in an ice bath and the pure enamine crystallizes. The solid is drained, washed with 20 ml of methanol, then dried under vacuum at 20 ° C.

 Efficiency: 85%

NMR spectrum H (60 MHz, solvent CDCl ₃ reference TMS): 2.3 to 2.9 ppm (m, 8H); 3.4 ppm (s, 2H); 4.0 ppm (d, 2H); 4.9 ppm (t, 1H); 6.3 to 7.3 ppm (m, 14H).

Step 2: Enamine reduction

The reduction of enamine is carried out according to the procedure described in Example 2 (step 2). The oil obtained is purified by chromatography on silica (elution solvent CH ₂ Cl ₂ 100%). Yield: 66%

Specter of R .M. NOT . ¹ H (60 MHz, so far CDCl ₃ , TMS reference)

1.9 ppm (q, 2H); 2.2 to 2.6 ppm (m, 8H); 3.3 ppm (s, 2H); 3, 3 to

3.7 ppm (m, 3H); 6.3 to 7.3 ppm ⁽ m, 14H).

Formation of trichlorhydrate:

 The procedure is as described above in Example 1 for the formation of the di hydrochloride. Melting point of the hydrochloride: 196 ° C.

Example 4

 Preparation of N dimaleate [4-fluoro-phenyl-1) oxo-1 butyl-4]

N '[2,3-methoxy-tetrahydro-2,3,4-naphthyl-1] piperazine (Compound 23) Method C

Preparation of N [(4-fluoro-phenyl-1) oxo-1 butyl-4] piperazine (Derivative II: R ₂ = 4-F, R ₃ = H, A = C = 0, n = 3)

 A mixture composed of 30 g (0.015 mole) of ω-chloro 4-fluoro buty rophenone, 51.7 g (0.06 mole) of anhydrous piperazine and 200 ml of toluene is heated for 24 h at reflux. After cooling, the solution is filtered, washed with 50 ml of water, then extracted with 7 times 25 ml of 7% acetic acid. The acetic phases are combined, then neutralized with sodium carbonate in the presence of 100 ml of methylene chloride. The organic phase is isolated, then dried over MgSO 4. After evaporation of the solvent, it is collected

28.4 g of pure oil.

 Efficiency: 76%

¹ H NMR spectrum (60 MHz, solvent CDCl ₃ , reference TMS):

2.0 ppm (q, 2H); 2.2 to 3.0 ppm (m, 10H); 2.9 ppm (t, 2H); 6.7 to 8.0 ppm (m, 4H).

Condensation on chloro-1-methoxy-6-tetrahydro-1,2,3,4-naphthalene

 The procedure is as described previously in Example 1.

Yield: 47% H NMR spectrum (60 MHz, solvent CDCl ₃ , reference TMS): 1.4 to

3.5 ppm (m, 19H) 2.9 ppm (t, 2H); 3.7 ppm (s, 3H) 6.4 8.1 ppm (m, 7H). Dimaleate formation:

 The compound obtained is dissolved in anhydrous ethanol. A solution of two equivalents of maleic acid previously dissolved in a minimum of ethanol is added at 5 ° C., then the mixture is refluxed for 30 min. The crystals are obtained after cooling the mixture in an ice bath, draining and drying under vacuum. Dimaleate melting point: 134 ° C.

Example 5

Preparation of N [benzyl] N 'hydrochloride N' [1-phenyl-1,2,3,4-quinolinyl-4] piperazine (Compound 3)

Method D

Preparation of the N [benzy l] N '[tét rahydro-1, 2,3,4 qui no léi ny l-4] pi pérazi ne (Déri vé XXII: R ₁ = H, n = 1, R. ₂ , R ₃ = H)

 4.44 g (0.0192 mole) of sodium are placed in 250 ml of

DME. The mixture is placed under a nitrogen atmosphere. 24.7 g (0.0192 mole) of naphthalene dissolved in 250 ml of

DME. The mixture is left stirring for 1 hour at room temperature. 11.13 g (0.0024 mole) of sulfonamide I (R ₁ = H, X = N-pTs, n = 1, Z = Ph) dissolved in 100 ml of DME are then added dropwise. The temperature rises to 30 C. Stirring is continued for 4 h. Water is then added until the solid formed has completely dissolved. It is evaporated to dryness and the residue is taken up in 200 ml of methylene chloride. The solution is washed with water and the organic phase is dried over MgSO _4. After evaporation of the solvent, an oil is collected which is purified by chromatography on silica (elution solvent: 100% CH ₂ Cl ₂ ), thus obtaining 6.81 g of amine.

Efficiency: 93% NMR spectrum H (60 MHz, solvent CDCl ₃ , reference TMS): 1.6 to 2.2 ppm (m, 2H); 2.2 to 2.8 ppm (m, 8H); 3.1 to 3.4 ppm (m, 2H); 3.5 ppm (s, 2H); 3.4 to 3.8 ppm (m, 3H); 6.2 to 7.3 ppm (m, 9H). N-phenylation reaction in the presence of triphenylbismuth diacetate

 A mixture of 3.65 g (0.012 mole) of NCbenzyl] N '[1,2,3,4-tetrahydro-4-quinolinyl] piperazine, 7.3 g

(0.0132 mole) of triphenylbismuth diacetate, 0.07 g (0.0012 mole) of copper powder and 100 ml of methylene chloride is stirred

24 h at room temperature. After filtration of the insolubles and washing with water, the organic phase is dried over magnesium sulfate, then evaporated to dryness. The oil obtained is purified by chromatography on silica (elution solvent CH ₂ Cl ₂ / MeOH 98/2). 2.41 g of pure product are thus obtained.

 Yield: 52%

¹ H NMR spectrum (60 MHz, solvent CDCl ₃ , reference TMS):

1.9 ppm (q, 2H); 2.2 to 2.6 ppm (m, 8H); 3.3 ppm (s, 2H); 3.3 to

3.7 ppm (m, 3H); 6.3 to 7.3 ppm (m, 14H).

Formation of trichlorhydrate:

 The procedure is as described above in Example 1 for the formation of the di hydrochloride. Melting point of the tri hydrochloride: 195-198 ° C.

Example 6

 Preparation of N [benzyl] N '[5-nitro-2-pyridyl) 1,2,3,4-tetrahydro-4-quinolinyl] piperazine (Compound 7)

Process E

To a solution of 4.05 g of derivative XXII (R ₁ = H, n = 1, R ₂ and

R ₃ = H) previously described in Example 5, in 100 ml of methyl ethyl ketone, 1.62 g of 2-chloro-5-pyridine, 2.7 g of Na 2 CO, and 0.15 g of Nal are added. . The reaction mixture is heated at reflux for 18 h, then filtered and the solvent is evaporated off under reduced vacuum. The residual oil is taken up in 100 ml of toluene and we wash with water. Extraction is carried out using 10% acetic acid, then the fractions are combined and basified in the presence of 100 ml of CH ₂ Cl ₂ . The organic phase is isolated, dried, then the solvent is evaporated. A solid with a melting point of 126 ° C. is obtained which is recrystallized from ethanol.

 Yield: 18%

¹ H NMR spectrum (60 MHz, solvent CDCl ₃ , reference TMS); 2.3 a

2.8 ppm (m, 6H); 3.5 ppm (s, 2H); 3.4-4.0 ppm (m, 7H); 6.5 ppm

(d, 1H); 6.8 to 7.5 ppm (m, 9H); 8.1 ppm (dd, 1H); 8.9 ppm (d, 1H).

Dimaleate formation

 The procedure is as described above in Example 4. Melting point 120 ° C.,

Example 7

 Preparation of N [(4-fluorophenyl-1) hydroxy-1-butyl- 4] N 'dimaleate N' [1,2,3,4-naphthyl-tetrahydro-1] piperazine (Compound 28) Method F

2.9 g (0.00765 mole) of NCfluoro-4 phenyl-1) 1-oxo-butyl-4] N 'Cététrahydro-1,2,3,4 naphtyl-1] piperazine (compound 21) are placed in 100 ml methanol. The mixture is cooled to 0ºC, then the sodium borohydride is added in parts. At the end of the addition, the mixture is stirred for 2 h at 0 ° C. The methanol is evaporated under reduced pressure, hydrolysis, then extracted with methylene chloride. The organic phase is dried over MgSO ₄ , then evaporated to dryness. The residual oil is purified by chromatography on silica (elution solvent CH ₂ Cl ₂ 100%). 1.82 g of pure alcohol are thus obtained.

Yield: 63%

NMR spectrum H (60 MHz, solvent CDCl ₃ , reference TMS): 1.4 to 3.0 ppm (m, 21H); 3.8 ppm (m, 14H); 4.6 ppm (m, 1H); 6.8 to 7.8 ppm (m, 8H). Dimaleate formation

 The procedure is as described above in Example 4. Melting point 160 ° C, Example 8

Preparation of NCphenyl-1, tetrahydro-1,2,3,4 quinolinyl-4] piperazine (Derivative XX: R ₁ = H, X = N-Ph)

To a solution of 17.5 g (0.0046 mole) of N (benzyl) N 'di hydrochloride (1,2,3,4-naphthyl-1) tetrahydro-piperazine (Compound 12) in 300 ml of absolute ethanol , 1.75 g of Pd / C at 10% are added. The mixture is vigorously stirred under a hydrogen atmosphere for 1 h at room temperature, then 5 min at 40 ° C. The solution is then filtered, then evaporated to dryness under reduced vacuum to give 16.6 g of solid which is then placed in 200 ml of methylene chloride. The solution is made alkaline with 2N sodium hydroxide. The organic phase is isolated, then dried over MgSO ₄ .

After evaporation of the solvent, 7.1 g of pure amine are obtained.

 Efficiency: 71%

NMR spectrum H (60 MHz, solvent CDCl ₃ , reference TMS): 1.9 ppm (q, 2H); 2.0 to 2.3 ppm (m, 10H); 3.2 ppm (s, 2H);

3.4 ppm (m, 1H); 6.2 to 7.2 ppm (m, 14H).

 The compounds prepared according to Examples 1 to 7, as well as other compounds prepared according to the synthetic routes A, B, C, D,

E or F are collated in Table 1 below with their elementary analyzes and the synthetic routes which can be used for their preparation.

Pharmacological trials

 A. In a first series of tests, the pharmacological activity of the products of the invention was tested in the 17 experimental models described below:

1 - Study of spontaneous motility (actimetry)

 The motor activity of the animals was determined using the photoelectric actuator from BOISSIER and SIMON.

 The mice are placed in pairs in a box closed by a lid, and crossed by two perpendicular light rays which the mice cut while moving.

 These trips are counted by a meter read after 30 min and 1 h.

An effective dose 50 (DE.- _n ) can be calculated based on the results obtained.

2 - Action on hypermotility by dexamphetamine

 The product to be tested is injected intraperitoneally 10 min before the administration of 6 mg / kg of dexamphetamine. The motor activity of mice is determined using photoelectric activity.

3 - Exploration behavior (hole board)

 Thirty minutes after the intraperitoneal administration of the derivatives of the invention, each mouse is placed on an automated hole board for 5 min. We note, minute by minute, the number of holes explored.

An effective dose 50 (ED ₅₀ ) can be calculated based on the results obtained.

4 - Motor coordination (traction test)

 This test assesses the presence or absence of adjustments of a mouse presented by its front legs to a horizontal metal wire.

We note the number of mice which cannot hang one of their hind legs before 5 s. An effective dose 50 (ED ₅₀ ) can be calculated based on the results obtained.

5 - Rectal temperature

 The rectal temperature of the mice is measured using an electric thermometer.

A first reading is carried out immediately before the injection of the product.

 The temperature is noted 30 min, 1, 2, 3 and 4 h after the injection.

6 - Group toxicity to dexamphetamine

 The administration of the product to be tested is carried out intraperitoneally 30 min before the injection of dexamphetamine. Mortality is detected 24 h after the injection.

7 - Group toxicity to yohimbine

 The product to be tested is administered 30 min before the injection of yohimbine (25 mg / kg PI).

 The number of deaths is counted 24 hours after the injection of yohimbine.

8 and 9 - Apomorphine tests

 The product to be tested is administered intraperitoneally 30 min before the injection of apomorphine. Apomorphine is injected subcutaneously at 1.6 or 16 mg / kg.

 The mice are then isolated in small cages. We note the adjustments, stereotypes and rectal temperature of the animals.

Neuroleptics generally antagonize syndromes induced by apomorphine at a low dose (1.6 mg / kg). Some antidepressants act on the symptoms induced by a high dose of apomorphine (16 mg / kg). 10 - Reserpine test

 The product to be tested is administered intraperitoneally. The mice are placed in individual cages.

 Thirty minutes after injection of the product to be tested, 2.5 mg / kg of reserpine is injected intraperitoneally.

 The eyelid occlusion is noted every 30 min and the rectal temperature is taken 2 h, 3 h and 4 h after the injection of reserpine. 11 - Test of the suspension by the tail (Tail Suspension Test or T. S. T.)

 A rodent subjected to an unpleasant and obviously dead end situation (hooked by the tail) tends to decrease very quickly its motor activity of escape.

12 - Forced swimming test

 The test product is administered intraperitoneally 60 minutes before the start of the test. The mice are then placed in a beaker half filled with tap water for 6 min.

 The movement time of the animals in the water is calculated. The results are expressed in "Minimum active dose" (p <0.01).

13 - Search for catalepsy

 The search for the cataleptigenic action of the product to be tested is carried out by the cross-leg homolateral test, after intraperitoneal injection.

14 - Search for an anti cataleptic action with prochlorperazine (PCPZ)

 The neuroleptic prochlorperazine induces catalepsy at a dose of 25 mg / kg. Typical neuroleptics potentiate this catalepsy, certain antidepressants antagonize it.

The product to be tested is injected and each rat is placed in individual cages. Thirty minutes later, 25 mg / kg of PCPZ is injected. Every 30 min, each rat is placed on a sheet of filter paper and is subjected to the crossing of the forelegs with the homolateral hind legs.

 The device includes two hanging units, a central unit and a microcomputer which integrates operator controls and static calculations.

 The product is administered intraperitoneally, 30 min before the mouse hooks. The measurement of the various parameters (immobility time, total energy, power of the movements) is carried out automatically for 6 min. The results are expressed in "Minimum active dose" (p <0.01).

15 - Test of the four plates

 The product is injected intraperitoneally, 30 min before the start of the experiment. Note the number of electric shocks that the mouse receives when switching from one plate to another for 1 min.

16 - Interaction with oxotrémori ne

As oxotremori is not a cholinergic receptor agonist, it can be thought that the substances which antagonize the tremors, hypothermia and peripheral signs (salivation, pi lo-erection ⁾ induced by this product are anticholinergics.

 The product to be tested is administered 30 min before the intraperitoneal injection of oxotremorine.

 The derivatives of the invention having demonstrated no action on the tremors and the peripheral signs, only the effects on hypothermia will be reported in the table.

17 - Bicuculline test

The product to be tested is administered 30 min before the injection of bicuculline. We note the latency of convulsions, lethality and the percentage of dead animals. 18 and 19 - Study of the antagonism vis-à-vis the contractions induced by histamine and barium chloride

Barium chloride and histamine are stimulants of smooth muscle fiber and cause muscle spasm on rat duodenum. We are looking for an antagonism of this spasm by the product to be tested. The results are expressed in IC ₅₀ (μM).

Notes:

 The results are reported in Table 2 below, in which the following indications appear:

The "effective doses 50" (ED ₅₀ in mg / kg) and the "inhibition constants 50" (IC ₅₀ in μM) are mentioned.

An arrow indicates that the derivative tested has a

stimulating activity or that it potentiates the effect of another substance (example: potentiating the toxicity of yohimbine, worsening of induced hypothermia ...).

indique que le dérivé testé présente une activité inhibitrice ou qu'il antagonise l'effet d'une autre substance (exemple : antagonisme de l ' hypermoti lité induite par la dexamphétamine, antagonisme des hypothermies, d'un ptôsis induits...). An arrow

indicates that the derivative tested has an inhibitory activity or that it antagonizes the effect of another substance (example: antagonism of hypermotility induced by dexamphetamine, antagonism of hypothermia, of induced ptosis ...).

Two arrows or indicate that the product

to try has biphasic activity on the test.

 When an Effective Dose 50 cannot be calculated, the results are expressed as follows:

+ Active dose (p <0.01) greater than or equal to 1/5 LD ₅₀

++ Active dose (p <0.01) greater than or equal to 1/10 LD ₅₀

+++ Active dose (p <0.01) greater than or equal to 1/20 LD ₅₀ npd Significant activity not proportional to the dose

0 No activity

- Not tested

B. Conditioning test (Vogel test) (Table 3)

 The product to be tested is injected intraperitoneally 30 min before the start of the experiment.

 Male rats (Wistar-cerj) are deprived of water, then placed in individual cages where they have free access to a bottle of water whose teat is electrified.

 We count the number of shocks received during 3 min.

Anxiolytics reduce this punishing effect and increase the number of shocks received.

 The results are expressed as a percentage of activity as a function of the dose studied, (ns = not significant, ** = p <0.01).

 This test was carried out on compound 21 of Example 1 in comparison with BUSPIRONE (reference compound).

 C. Receorology study (Table 4)

Correlations between the anxiolytic activity of new derivatives such as BUSPIRONE or IPSAPIRONE and, their affinity for the 5-HT _1A serotonergic receptors having been demonstrated, the inventors reported the results found for compound 21 and compound 8. The values found on other receivers are given for information.

The study of the displacement curves of the specific radioligands of the sites or receptors studied makes it possible to determine the I C ₅₀ of the product to be tested, which is the concentration inhibiting 50% of the total specific binding of the radioligand, and the coefficient of CHENG PRUSOFF when the product has an affinity at a concentration less than or equal to 10 M. The values of IC ₅₀ and K _i are expressed in nM (10 ^-9 M)

Claims

1. 1,4-diaIkyIpiperazine derivatives of formula (I)

in which :  X represents an oxygen or sulfur atom, a methylene group, or an amino group unsubstituted or substituted by a phenyl, paratoluenesulfonyl or nitropyridine group,  - n is an integer from 0 to 3, - Z represents a methyl group, a phenyl group a

a phthalimide group or a group in which A is

an oxygen atom, a ketone function, a CHOH group, or a vinyl group unsubstituted or substituted by a phenyl group, - R ₁ , R ₂ and R ₃ , identical or different, represent a hydrogen or halogen atom, a C ₁ -C ₆ alkyl, a C ₁ -C ₆ alkoxy or a trifluoromethyl group or alternatively R ₂ and R ₃ , together represent an alkylenedioxy group in which the alkyl group is C ₁ -C ₆ , and their pharmaceutically acceptable salts.  2. Derivatives according to claim 1, of general formula (la):

in which  - Xa is an oxygen or sulfur atom, a methylene group or an amino group unsubstituted or substituted by a paratoluenesulfonyl group, - R ₁ , n and Z are as defined in claim 1, and their pharmaceutically acceptable salts.  3. Derivatives according to claim 1, of formula (Ib):

in which  - Zb represents a methyl group, a pheny group.

a phthalimide group or a group in which A is

an oxygen atom, a CHOH group or a vinyl group unsubstituted or substituted by a phenyl group, - R ₁ , R ₂ , R ₃ , n and X are as defined in claim 1, and their pharmaceutically acceptable salts.  4. Derivatives according to claim 1, of formula (Ie):

in which - X, n, R ₁ , R ₂ and R ₃ are as defined in claim 1, - Zc represents a phenyl group, a phthalimide unit

or a group α in which A is a ketone function,

or a vinyl group unsubstituted or substituted by a phenyl group, and their pharmaceutically acceptable salts.  5. Derivatives according to claim 1, of formula (Id):

wherein R ₁ , n and Z are as defined in claim 1, and their pharmaceutically acceptable salts.  6. Derivatives according to claim 1, of formula (Ie):

wherein R ₁ , n and Z are as defined in claim 1, and their pharmaceutically acceptable salts.  7. Derivatives according to claim 1, of formula (If):

wherein X, R ₁ , R ₂ , R ₃ and n are as defined in claim 1, and their pharmaceutically acceptable salts.  8. Derivatives according to claim 1, of formula (I), in which at least one of the following conditions is met:  - X is a methylene group;  - X is an amino group unsubstituted or substituted by a phenyl, paratoluenesulfonyl or nit ropyridine group; - Z is a group in which A is an oxy atom

ketone gene or function; - n = 2 or 3.  9. Derivatives according to claim 1, of formula (I), in which X is a methylene group, R ₁ represents hydrogen, Z is a group in which A is a ketone function, R ₂

represents a fluorine atom in position 4 and R ₃ represents hydrogen. 10. Process for the preparation of the compounds of formula (la) in which

 - Xa is an oxygen or sulfur atom, a methylene group or an amino group unsubstituted or substituted by a paratoluenesulfonyl group,  - n is an integer from 0 to 3, - Z represents a methyl group, a phthalimide group or a group in which A is an oxygen atom, a function

 ketone, a CHOH group, or a vinyl group unsubstituted or substituted by a phenyl group, - R ₁ , R ₂ and R ₃ , identical or different, represent a hydrogen or halogen atom, a C ₁ -C ₆ alkyl, a C ₁ -C ₆ alkoxy or a trifluoromethyl group, or alternatively R ₂ and R ₃ together represent an alkylenedioxy group in which the alkyl group is C ₁ -C ₆ ,  characterized in that a substituted piperazine of formula (II) is condensed:

on a chlorinated derivative (III)

in which Xa, Z, n and R ₁ are as defined above, in the presence of potassium carbonate and a catalytic amount of potassium or sodium iodide, in a ketone solvent.  11. Process for the preparation of the compounds of formula (Ib):

in which Zb represents a methyl group, a phthalimide group or a group in which A is an oxygen atom, a

CHOH group or a vinyl group unsubstituted or substituted by a phenyl group,  - X represents an oxygen or sulfur atom, a methylene group, or an amino group unsubstituted or substituted by a phenyl, paratoluenesulfonyl or nit ropyridine group,  - n is an integer from 0 to 3, - R ₁ , R ₂ and R ₃ , identical or different, represent a hydrogen or halogen atom, a C ₁ -C ₆ alkyl, a C ₁ -C ₆ alkoxy or a trifluoromethyl group, or alternatively R _? and R, together represent an alkylenedioxy group in which the alkyl is C ₁ -C ₆ , characterized in that a substituted piperazine of formula (Ilb) is condensed:

on a cetone of formula (V)

in which n, R ₁ and Zb are as defined above, in an aromatic solvent in the presence of TiCl ₄ , to obtain an enamine of formula (XVIII):

which is then subjected to reduction with sodium borohydride in the presence of formic acid.  12. Process for the preparation of the compounds of formula (Ie):

in which  - X represents an oxygen or sulfur atom, a methylene group, or a group unsubstituted or substituted by a phenyl, paratoluenesulfonyl or nit ropyridine group,  n ≠ 0, Zc represents a phenyl group, a phthalimide unit

or a group in which A is a ketone function

 or a vinyl group unsubstituted or substituted by a phenyl group, - R ₁ , R ₂ and R ₃ , identical or different, represent a hydrogen or halogen atom, a C ₁ -C ₆ alkyl, a C ₁ -C ₆ alkoxy or a trifluoromethyl group, or alternatively R ₂ and R ₃ together represent an alkylenedioxy group in which the alkyl group is characterized in that a halogen derivative of formula (XIX) is condensed: Zc - (CH ₂ ) _n - Hal (XIX) with a piperazine of formula (XX)

in which A, X, n, R ₁ , R ₂ and R ₃ are as defined above, in the presence of potassium or sodium carbonate and a catalytic amount of sodium or potassium iodide, in a ketone solvent. 13. Process for the preparation of the compounds of formula (Id)

 in which :  - n is an integer from 0 to 3, - Z represents a methyl group, a phthalimide group or a group in which A is an oxygen atom, a function

 ketone, a CHOH group, or a vinyl group unsubstituted or substituted by a phenyl group, - R ₁ , R ₂ and R ₃ , identical or different, represent a hydrogen atom, a halogen atom, a C ₁ -C ₆ alkyl, a C ₁ -C ₆ alkoxy or a trifluoromethyl group, or yet R _? and R-, together represent an alkylenedioxy group in which the alkyl group is C ₁ -C ₆ ,  characterized in that a compound of formula (XXII) is submitted:

in which R ₁ and Z are as defined above, to an N-phenylation using triphenylbismuth diacetate in the presence of copper in a chlorinated solvent.  14. Process for the preparation of the compounds of formula (Ie):

 in which  - n is an integer from 0 to 3, - Z represents a methyl group, a phthalimide group or a group in which A is an oxygen atom, a function

 ketone, a CHOH group, or a vinyl group unsubstituted or substituted by a phenyl group, - R ₁ , R ₂ and R ₃ , identical or different, represent a hydrogen or halogen atom, a C ₁ -C ₆ alkyl, a C ₁ -C ₆ alkoxy or a trifluoromethyl group, or alternatively R ₂ and R ₃ together represent an alkylenedioxy group in which the alkyl group is C ₁ -C ₆ ,  characterized in that a compound of formula (XXII) is condensed:

with 2-chloro-5-nit ropyridine in a ketone solvent in the presence of potassium or sodium carbonate and a catalytic amount of sodium or potassium iodide.  15. Process for the preparation of the compounds of formula (If):

in which  - X represents an oxygen or sulfur atom, a methylene group, or an amino group unsubstituted or substituted by a phenyl, paratoluenesulfonyl or nit ropyridine group,  - n is an integer from 0 to 3, - R ₁ , R ₂ and R ₃ , identical or different, represent a hydrogen atom, a halogen atom, a C ₁ -C ₆ alkyl, a C ₁ -C ₆ alkoxy or a trifluoromethyl group, or alternatively R ₂ and R ₃ together represent an aky lenedioxy group in which the alkyl group is C ₁ -C ₆ , characterized in that the corresponding ketone of formula is reduced

in which X, n, R ₁ , R ₂ and R ₃ are as defined above, by a reducing agent such as sodium borohydride in an alcoholic solvent.  16. Intermediaries of synthesis of formula (XVIII)

in which  - X represents a group

n is an integer from 0 to 3, - R ₁ is a hydrogen atom, a halogen atom, a lower alkoxy group or a trifluoromethyl group, Zb represents a methyl group, a phthalimide group or a group in which A is an oxygen atom, a

CHOH group or a vinyl group unsubstituted or substituted by a phenyl group,  17. Pharmaceutical compositions containing, as active principle, a derivative according to any one of claims 1 to 9 in association with a pharmaceutically acceptable vehicle or in the form of an inclusion complex.