CA2140229A1

CA2140229A1 - N-cycloalkylpiperazine derivatives, methods of obtaining them and pharmaceutical compositions containing them

Info

Publication number: CA2140229A1
Application number: CA002140229A
Authority: CA
Inventors: Gilles Tran; Youssef El Ahmad; Roland Ollivier; Elisabeth Laurent; Akram Talab
Original assignee: Individual
Current assignee: Cooperation Pharmaceutique Francaise SAS
Priority date: 1992-07-16
Filing date: 1993-07-15
Publication date: 1994-02-03
Also published as: JPH08501285A; WO1994002473A1; FR2693722B1; EP0649419A1; AU4573793A; FR2693722A1

Description

N-CYCLOALKYLPIPERAZINE DERIVATIVES, METHODS OF OBTAIN-ING THEM AND PHARMAC~u~l~ICAL COMPOSITIONS CONTAINING
THEM

05 The present invention relates to N-cycloalkyl-piperazine derivatives, to their methods of preparation and to the pharmaceutical compositions in which they are present. The invention further relates to their use as pharmacological reagents.
The invention further relates to the levo-rotatory and dextrorotatory derivatives of the N-cyclo-alkylpiperazine compounds, to their preparation and to their use as pharmacological reagents.
The derivatives of the invention have valuable pharmacological properties, particularly neuroleptic properties, on the central nervous system.
The compounds of the invention are also good ligands for the 5-HTlA serotoninergic receptors and therefore possess antidepressant, antihypertensive, aggressolytic, analgesic and anxiolytic properties.
Compounds which act on the 5-HTlA receptors have already been described. In this connection, there may be mentioned patent application EP-A-0 434 561, which describes naphth-1-ylpiperazine derivatives, and patent application EP-A-0 466 585, which relates to piperidine derivatives having this type of activity.
It has also been demonstrated that 5-HTlA ago-nists reduce alcohol consumption in strains of alcohol-craving rats (Drug Dev. Res. 26, 319-341, 1992; Alcohol 6, 17-21, 1989; Alcohol 9, 283-6, 1992; Pharmacol.
Biochem. Behav. 34, 381-6, 1989; Alcohol 5, 147-152, 1988; Jpn. Psychiatr. Neurol. 46, 197-203, 1992), in monkeys (Alcohol 4, 49-56, 1987) and in man (Psycho-pathology 22 (suppl. 1), 49-59, 1989; J. Clin. Psycho-pharmacol. 9, 379-380, 1989).

~1~0229 The invention therefore relates to a novel family of compounds which have general formula (I) below:

(~c~ >~N N (C~ )A - A~ (I) E~

in which:
O O
- A is an amide group, -NH - C- or -C NH - , - R1, R2, R3, R4 and R5, which are identical or dif-ferent, are a hydrogen atom, a halogen atom, a C1_CG_ alkyl group, a C1-CG-alkoxy group, a trifluoromethyl group or a phenyl group, - m is an integer between 1 and 3, - n is an integer equal to 2 or 3.
In the present description:
- C1-C~-alkoxy denotes a hydroxyl group substituted by a C1-CG-alkyl; and - C1-CG-alkyl denotes straight-chain or branched-chain saturated aliphatic hydrocarbon radicals containing 1 to 6 carbon atoms. The preferred alkyl group is the methyl group.
The term "halogen" denotes the four halogens, F, Cl, Br and I. Preferably, if they are a halogen, R1, R2, R3, R4 and R5 are F or Cl.
Advantageous compounds of formula (I) are those in which at least one of the following conditions is fulfilled:

- A is an amide group -NH C- , 214022~
-- R3 is a hydrogen atom or a halogen atom, preferably fluorine or chlorine, - m = 2 or 3, - n = 2.
05 The preferred derivatives for the purposes of the invention are the racemic and levorotatory com-pounds which correspond to the above description and in which m is equal to 2.
The compounds of formula (I) can be obtained by condensing the substituted piperazines of formula (II) with the chlorinated derivatives of formula (III) below, in the presence of sodium or potassium carbonate and a catalytic amount of sodium or potassium iodide, in a ketone solvent such as methyl ethyl ketone (butan-2-one) or diethyl ketone.

Z ) C--A~ S

III II

In this reaction scheme, m, n, A, R1, R2, R3, R4 and R5 are as defined above.
The derivatives of the invention can also be prepared by condensing the monosubstituted N-cyclo-alkylpiperazines of formula (XV) with the halogenated amides of formula (VIII), in which X is a halogen atom, preferably chlorine or bromine, in an aromatic solvent such as benzene or toluene, or in dimethylformamide, in the presence of triethylamine or pyridine.

21~û229 ~ N~_~NH ~ .

XV VIII
The levorotatory and dextrorotatory derivatives of formula (I) are obtained in accordance with the above scheme from the resolved N-cycloalkylpiperazines of formula (XV). The resolution is effected by forming the diastereoisomeric salts with L-(+)-aspartic acid if it is desired to obtain the levorotatory compounds, or with L-(+)-tartaric acid if it is desired to obtain the dextrorotatory compounds.
The levorotatory or dextrorotatory derivatives of formula (I) in optically pure form are novel com-pounds forming part of the invention.
The compounds of formula (XV), in which m is as defined abov.e, are prepared by saponification and decarboxylation of the N-carboxylated piperazines of formula (XVI) with potassium hydroxide in an alcoholic medium in accordance with the following scheme:

~ KOH
m(H2C) ~_~N~ ~ m(H2C) N~--~

The compounds of formula (XVI) are easily obtained by condensing commercially available carbeth-oxypiperazine of formula (XVII) with the chlorinated derivatives of formula (III) in a mixture of methyl -ethyl ketone and DMF, in the presence of potassium carbonate and sodium iodide, in accordance with the following scheme:

~ + ~ O ~ XVI
m(H2C) Cl CH3 III XVII

The chlorinated derivatives of formula (III) can easily be obtained by chlorinating the correspon-ding alcohol of formula (IV), in which m is as definedabove, with thionyl chloride in an aromatic solvent such as benzene or toluene (BOGESO K.P. et al., J. Med.

Chem., 1983, 26(7), 944), or in a chlorinated solvent such as methylene chloride or chloroform:

N-~H ~ ~) 80Cl ~ ~

( N 2 C ) \~o ROH ~ ~ N 2 C ) \~ JlrH 2 Cl V IV III

The alcohols of formula (IV) are prepared by reducing the corresponding ketones of formula (V), which are commercially available, with sodium boro-hydride in an alcohol having from 1 to 6 carbon atoms, such as methanol or ethanol.
The piperazines of formula (II) are obtained by hydrogenolysis of the corresponding benzylated deriva-tives of formula (VI), in which n, A, Rl, R2, R3, R4 21~0229 and R5 are as defined above, in the presence of palla-dium-on-charcoal, in an alcohol such as methanol or ethanol, in accordance with the following scheme:

3~$A--(CH2~n N~JN 2~ H2 Pd/C ~$A--(CHz~n--N NH
R~, R5 R~ R5 Vl I~
The benzylated compounds of formula (VI) are prepared in conventional manner by reacting two equi-valents of 4-benzylpiperazine of formula (VII) with the halogenated amides of formula (VIII), in which X is as defined above, in dimethylformamide, in the presence of sodium or potassium iodide.

l~<R2 DMr \ ~
N NH ~ X--(CH2~n-A~R N N--(CH2~ A~R3 R5 R~ ~) R5 R~
V~l VIII

The derivatives of formula (VI) in which:
- n, Rl, R2, R3, R4 and Rs are as defined above, 1l - A is an amide group -NH C--~
can also be prepared by condensing the 4-benzyl-1~
aminoalkyl)piperazine of formula (IX) with the corres-ponding acid chlorides of formula (X). The reaction is carried out in an aromatic solvent such as benzene or toluene, in the presence of triethylamine.

~1~0229 /~~~ ArH
Cl ~ ~ N ~CH2)n~NH2 --------~ N N (CH2) The 4-benzyl-1-(~-aminoalkyl)piperazine of formula (IX) is obtained by reducing the 4-benzyl-1-(~-cyanoalkyl)piperazine of formula (XII) with lithium aluminum hydride (AlLiH4) in a solvent such as tetra-hydrofuran, in accordance with the following scheme:

~ AlLlH4 ~

/ = <--N N--(CH2)n-1--CN~ ~ = <--N N (CH2)n--NN2 ~ ~II ~ IX

The compound of formula (XII) is prepared in conventional manner by condensing the corresponding halogenonitrile of formula (XIII) with 4-benzylpipera-zine of formula (VII) in the presence of potassium or sodium carbonate, in dimethylformamide, X and n being as defined above.

2s ~ ~ NA2CO3 /--\
N NH ~ X (CH2)n-1-CN ~ ~ N N -(CH2)n-1-CN

VII XIII ~ XII

The halogenated amides of formula (VIII) below in which:
- n, R1, R2, R3, R4 and R5 are as defined above for the compounds of formula (I), Il .
- A is an amide group -C NH - , , - X is as defined above are obtained by reacting the anilines of formula (X) with the acid chlorides of formula (XI), in which X is a halogen atom, preferably a bromine or chlorine atom, 05 in an aromatic solvent such as benzene or toluene, in the presence of triethylamine, in accordance with the following reaction scheme:

x--( 0117 ) n ~ X~

~C ~CI VIII

The halogenated amides of formula (VIII) in which:
- n~ R1, R2, R3, R4 and R5 are as defined above for the compounds of formula (I), - A is an amide group -M~--C--, - X is as defined above can also be prepared by a conventional method of condensing the corresponding benzoyl chloride of formula (XIII) with the hydrohalides, especially the hydrochlorides, of the commercially available ~-halo-geno-l-alkylamines in a chlorinated solvent such as dichloromethane or chloroform, in the presence of one equivalent of sodium or potassium carbonate, in accor-dance with the following scheme:

~l~n.2~s 3~ 3 (CH23n X, X - 2C03 ~ R3 R" R5 R5 R~
XIII ~CIV VIII

The compounds (I~) of the invention, and more particularly the (-) levorotatory derivatives, in which:
- m and n are equal to 2, - A is an amide group -M~--C- , - R1, R2, R4 and R5 are a hydrogen atom, - R3 is a hydrogen atom or halogen atom, namely fluo-rine or chlorine, can be prepared with good yields by condensing the corresponding acid chlorides (XIII~) with racemic or levorotatory 1-[2-amino-1-ethyl]-4-[1,2,3,4-tetra-hydronaphth-l-yl]piperazine (XVIII) in a chlorinated solvent such as methylene chloride or chloroform, or in an aromatic solvent such as toluene or xylene, in the presence of triethylamine or pyridine.

~Cl 8-- --/ ~NN2 NN R3 N N

XIII- XVIII

The compound of formula (XVIII) is easily obtained by treating the corresponding phthalimide (XIX) with hydrazine in solution in an alcohol having from 1 to 6 carbon atoms, such as methanol or ethanol.

_f' 8--U N~ ~ N2N-IIN 2 ~---- ~ ~IIN~

XIX XVI I I
The phthalimide (XIX) results from condensing racemic or resolved l-(1,2,3,4-tetrahydronaphth-1-yl)-piperazine (XV~) with 2-chloro- or 2-bromo-ethylphtha-limide in a solvent such as DMF, acetonitrile or butan-2-one.

5 8~ ~n~ 8 N~ ~3 XIX
XV~

The acid addition salts of the derivatives of formula (I) according to the invention can be obtained by conventional methods with acids commonly used for obtaining pharmaceutically acceptable salts, such as hydrochloric, hydrobromic, maleic and fumaric acids.
Hydrochloric acid will preferably be used.
As indicated above, the derivatives of formula (I) possess valuable pharmacological properties on the central nervous system. They have an atypical neuro-leptic profile in animal pharmacology. Their affinity for the 5-HTlA serotoninergic receptors gives the derivatives according to the invention properties of the non-benzodiazepinic anxiolytic, antidepressant, antihypertensive, analgesic, aggressolytic and anti-alcoholic type.
The invention further relates to the pharma-21~0229 ceutical compositions in which a derivative of formula (I) is present as the active principle, in association with a pharmaceutically acceptable vehicle, and to the inclusion complexes such as those described especially 05 in Chem. Pharm. Bull., 1975, 23, 6, 1205; 1975, 23, 12, 3062; 1978, 26, 10, 2952. It will be advantageous to use the inclusion complexes of the compounds of the invention in ~-cyclodextrin.
The compositions according to the invention can be compositions capable of oral, sublingual, subcutane-ous, intramuscular, intravenous, transdermal, local or rectal administration.
The appropriate forms of administration include especially forms for oral administration, such as tablets, gelatin capsules, powders, granules and solutions or suspensions to be taken orally, forms for sublingual and buccal administration, forms for sub-cutaneous, intramuscular, intravenous, intranasal or intraocular administration and forms for rectal admini-stration.
According to another of its features, theinvention relates to the use of the derivatives of formula (I) as pharmacological reagents, either as such or labeled with radioactive or non-radioactive iso-topes, especially tritium or 1~C.
The invention will now be described in greaterdetail by means of the illustrative Examples below. In the Examples, the derivatives prepared were identified and characterized by studying their NMR and infrared spectra and by their elemental analysis.
Example 1 describes the preparation of a derivative of formula (I) in which n = 2, m = 2, A = - ~I C--, Rl, Rz, R~ and R5 = H, and R3 = Cl.
Example 2 describes the preparation of the (+) 21~0229 dextrorotatory derivative of this same compound. Exam-ple 3 describes a general method of preparing the racemic or optically pure (levorotatory or dextro-rotatory) derivatives of general formula (Ia) in which n = 2, m = 2, A = - ~I C-- , R1, R2, R4, R5 = H, and R3 = H, F, Cl.
Examples 4 to 16 relate to the preparation of intermediates which can be used for obtaining the derivatives of formula (I).

Preparation of 1-[2-(4-chlorobenzamido)-1-ethyll-4-(1,2,3,4-tetrahydronaphth-1-yl)piperazine dihydrochlo-ride ll (derivative I: n = 2, m = 2, A =-~I C-- Rl, R2, R~, R5 = H, R3 = Cl) A mixture of 1-[4-chlorobenzamido-2-ethyl]-piperazine (5 g - 0.018 M), 2-chlorotetralin (3.1 g -0.018 M), potassium carbonate (6.5 g - 0.047 M) and sodium iodide (2.8 g - 0.018 M) in 150 ml of methyl ethyl ketone is refluxed for 24 h.
The solvent is evaporated off to dryness, the residue is taken up with water and extracted with ethyl acetate and the extract is washed with acid and base to give 6.4 g of the crude base. Crude yield = 90%.
The product is purified on a silica column using AcOEt:Et3N 0.5% as the eluent to give 4.5 g of a white solid. Yield = 63%. M.p. = 130 C.
Preparation of the dihydrochloride The base is dissolved in alcohol, a solution of hydrogen chloride in alcohol is added and the salt crystallizes out. M.p. = 228 C.

. . , Preparation of (+)-1-~2-(4-chlorobenzamido)-1-ethyll-4-(1,2,3,4-tetrahydronaphth-1-yl)piperazine dihydro-chloride (derivative I: n = 2, m = 2, A = ~ ,Rl, R2, R
R5 = H, R3 = Cl) A mixture of (+)-1-(1,2,3,4-tetrahydronaphth-1-yl)piperazine (5.4 g - 0.025 M), N-(2-chloroethyl)-4-ll chlorobenzamide (VIII, n = 2, X = Cl, A =-~I C--, R1, R2, R4, R5 = H, R3 = Cl) (7 g - 0.032 M) and 8 ml of triethylamine in solution in 150 ml of DMF is heated at 60 C for 48 h, with stirring. After cooling the 15 reaction mixture is poured all at once into 200 ml of water and then extracted with ethyl acetate. The organic phase is dried over MgSO4, filtered and then evaporated under vacuum. The residual oil is chromato-graphed on silica using AcOEt/cyclohexane/Et3N 85/15/
0.4 as the eluent to give 3 g of a pure product.
Yield = 30%.
Preparation of the dihydrochloride The base is dissolved in alcohol, a solution of hydrogen chloride in alcohol is added and the salt 25 crystallizes out. M.p. = 232 C.

Preparation of levorotatory, dextrorotatory and racemic 1-[2-(benzamido)-1-ethyll-4-(1 2 3 4-tetrahydronaphth-1-yl)piperazine dihydrochloride In a 250 ml three-necked flask, a mixture of levorotatory, dextrorotatory or racemic 1-(2-amino-l-ethyl)-4-(1,2,3,4-tetrahydronaphth-1-yl)piperazine (0.01 M), triethylamine (2 ml) and 50 ml of chloroform is cooled to 5 C. Benzoyl chloride which is unsubsti-2l~a22s -tuted or substituted in the para position by a halogen atom (0.01 M) in 70 ml of chloroform is added dropwise to this mixture, the temperature being kept at or below 10 C.
05 When the addition is complete, the reaction mixture is stirred magnetically at room temperature for 4 hours. The solvent is evaporated off under vacuum, the residue is taken up with water and extracted with dichloromethane and the organic phase is washed with 2 N NaOH.
The product is purified on a silica column using AcOEt:Et3N 0.35% as the eluent.

(Stereochemistry), R3 (Levorotatory), Cl (Dextrorotatory), Cl (Racemic), Cl Yield87% 85% 85%
M.p.145 C 145 c 134 c (Levorotatory), H (Dextrorotatory), H (Racemic), H
Yield83% 82% 83%
M.p.147 C 147 C 94 C
(Levorotatory), F (Dextrorotatory), F (Racemic), F
Yield84% 86% 83%
M.p.142 C 142 C 145 C

Preparation of the dihydrochloride The base is dissolved in ethanol, a solution of hydrogen chloride in alcohol is added and the salt crystallizes out.

Compound (Stereochemistry) 8 (Levorotatory) 8 (Dextrorotatory) 8 (Racemic) M.p. 232 C 232 C 225 C
34 (Levorotatory) 34 (Dextrorotatory) 34 (Racemic) M.p. 215 C 215 C 232 C
2 (Levorotatory) 9 (Dextrorotatory) 9 (Racemic) M.p. 223 C 223 c 220 C

Preparation of 1-~2-(4-chlorobenzamido)-1-ethyl]piper-azine 05 (derivative II: n = 2, A = -NH - ~--,Rl, R2, R4, R5 =
H, R3 = Cl) l-Benzyl-4-[2-(4-chlorobenzamido)-1-ethyl]pipe-razine dihydrochloride (25 g - 0.06 M) is dissolved in a mixture of 100 ml of water + 100 ml of ethanol. 3 g of palladium-on-charcoal are added. Hydrogenolysis is carried out at room temperature.
The reaction mixture is filtered and the fil-trate is neutralized with 2 N sodium hydroxide and eva-porated to dryness. The product is taken up with dichloromethane, dried over magnesium sulfate and con-centrated under vacuum.
This gives 13 g of a pasty product. Yield =
81%.

Preparation of 4-benzyl-1-[2-(4-fluorobenzamido)-1-ethyl]piperazine dihydrochloride ll (derivative VI: n = 2, A =-NH ~-- Rl, R2, R~, R5 =
H, R3 = F) A mixture of benzylpiperazine (35.2 g - 0.2 M), sodium iodide (15 g - 0.1 M) and 150 ml of dimethyl-formamide is placed in a three-necked flask and a mixture of l-(2-chloroethyl)-4-fluorobenzamide (20.15 g - 0.1 M) and 50 ml of dimethylformamide is then added dropwise; the medium is stirred for 4 hours at room temperature and then for 2 hours at 60-70C.
After cooling, water is added and the mixture is extracted with ethyl acetate. The organic phase is washed several times with water, dried and then con-- 21 iO229 --centrated under vacuum to give 29 g of the crude base (yield = 85%). This base is dissolved in ethanol, a solution of hydrogen chloride in alcohol is then added and the dihydrochloride crystallizes out. 27.5 g of 05 dihydrochloride are obtained. Yield = 77.5%. M.p. =
201 C.

Preparation of N-~2-[(4-fluorophenylamino)carbonyl]-ethyl~-N'-~benzyl~piperazine dihydrochloride (derivative VI: n = 2, A = -C NH ,Rl, R2, R4, R5 H, R3 = F) A solution of 1-bromo-2-(4-fluorophenylamino)-carbonylethane (12.3 g - 0.05 M) in 30 ml of anhydrous dimethylformamide is added dropwise to a suspension of 4-benzylpiperazine (17.6 g - 0.1 M) and sodium iodide (7.5 g - 0.05 M) in 100 ml of anhydrous dimethylfor-mamide. The medium is stirred for 4 hours at room temperature and then for 2 hours at 60-70 C. After cooling, water is added and the mixture is extracted with ethyl acetate. The organic phase is washed several times with water, dried and then concentrated under vacuum to give 15 g of the crude base (yield =
87.9%). This base is dissolved in ethanol, a solution of hydrogen chloride in alcohol is then added and the dihydrochloride crystallizes out. 14 g of dihydro-chloride are obtained. Yield = 76.8%. M.p. = 226 C.

Preparation of 4-(benzyl)-1-(2-(4-chlorobenzamido)-1-ethyl)piperazine dihydrochloride ll (derivative VIa: n = 2, A =-NH C - ,Rl, R2, R~, R5 =
H, R3 = Cl) 21~02~9 .
A mixture of 4-chlorobenzoyl chloride (17.5 g -0.1 M) and 250 ml of benzene is placed in a three-necked flask. It is cooled to 5 C, 1-(benzyl)-4-[2-amino-l-ethyl]piperazine (20.5 g - 0.1 M) + 14 ml of 05 triethylamine + 50 ml of benzene are added dropwise at a temperature of 10 C or below and the mixture is then left to stand for 2 hours at room temperature. It is washed with water and then with a 10% solution of sodium hydroxide and the organic phase is dried over magnesium sulfate and then concentrated under vacuum to give 29.5 g of the crude base. Yield = 86%.
This base is dissolved in ethanol, a solution of hydrogen chloride in alcohol is then added and the dihydrochloride crystallizes out. 32 g of dihydro-chloride are obtained. Yield = 76.8%. M.p. = 209C.

Preparation of 4-(benzyl)-1-~2-amino-1-ethyl]piperazine (derivative IX, n = 2) In a three-necked flask, l-benzyl-4-(cyano-methyl)piperazine (10.5 g - 1.05 M) in solution in 100 ml of tetrahydrofuran is added dropwise, at a tempera-ture of 10 C or below, to a suspension of lithium aluminum hydride (2.6 g - 0.068 M) in tetrahydrofuran;
the mixture is then refluxed for 6 hours. It is cooled to 0 C and hydrolyzed by the dropwise addition of 3 ml of water and then 3 ml of 15% NaOH, still at a tempera-ture of 10 C or below; the solid is filtered off and washed with 2 times 100 ml of ethyl ether.
The filtrate is concentrated under vacuum and the oil obtained is taken up with 200 ml of ether; the ether solution is dried over MgSO4 and then concen-trated under vacuum.
This gives 8.6 g of product in the form of an oil. Yield = 80%.

21~0229 Preparation of 1-(benzyl)-4-(cyanomethyl)piperazine (derivative XII, n = 2) Potassium carbonate (17.6 g - 0.127 M), 100 ml 05 of dimethylformamide and 4-benzylpiperazine (17.6 g, 0.1 M) are placed in a three-necked flask and chloro-acetonitrile (9.06 g, 0.12 M) in 10 ml of dimethyl-formamide is then added dropwise; the temperature rises to 35 C.
After the addition, the mixture is stirred for 24 hours at room temperature.
100 ml of water are added and the mixture is extracted twice with 150 ml of ethyl acetate; the organic phase is washed twice with 150 ml of water and lS then once with 150 ml of a saturated solution of sodium chloride, dried over magnesium sulfate and then con-centrated under vacuum.
This gives 17.1 g of a thick oil. Yield: 85%.

Preparation of ~-bromo-N-(4-fluorophenyl)propionamide ll (derivative VIII, n = 2, X = Br, A = C NH ~ R
R2, R4, R5 = H, R3 = F) A mixture of 4-fluoroaniline (22.2 g - 0.2 M), 20 ml of triethylamine and 50 ml of benzene is placed in a three-necked flask and cooled to 5 C. 3-Bromo-propionyl chloride (34.3 g - 0.2 M) dissolved in 150 ml of benzene is then added dropwise. When the addition is complete, the reaction medium is left to stand at room temperature for 4 hours.
The benzene is evaporated off under vacuum.
The solid is taken up with dichloromethane and then washed with iced water. The organic phase is dried and then concentrated under vacuum to give 39 g of a solid.

21~û229 -. . .
Yield = 79%. M.p. = 115 C.

Preparation of 1-(2-chloroethyl)-4-fluorobenzamide (derivative VIII, n = 2, X = Cl, A = - ~I C - , Rl, Rz, R~, R5 = H, R3 = F) In a three-necked flask, 4-fluorobenzoyl chlo-ride (33.05 g - 0.21 M) dissolved in 50 ml of dichloro-methane is added dropwise to an aqueous solution ofchloroethylamine hydrochloride (26.60 g - 0.23 M) and potassium carbonate (37.4 g - 0.27 M). After stirring for 24 hours, the medium is extracted with dichloro-methane and the organic phase is dried and then concen-15 trated under vacuum to give 40 g of a solid. Yield =83.5%. M.p. = 108 C.

Preparation of 1-carbethoxy-4-(1,2,3,4-tetrahydro-20 naphth-1-yl)piperazine (derivative XVI: m = 2) Carbethoxypiperazine (317 g - 2 M), potassium carbonate (552 g - 4 M) and sodium iodide (100 g - 0.66 M) in solution in 1 l of methyl ethyl ketone (butan-2-25 one) and 400 ml of DMF are placed in a reactor. Chlo-rotetralin (302 g - 1.82 M) in solution in 400 ml of methyl ethyl ketone is added slowly. The mixture is refluxed for 24 hours.
After cooling, the mixture is filtered and the solvents are evaporated off. The residual oil is poured all at once into water and the product is extracted 3 times with ethyl acetate. The organic phase is concentrated and the residual oil is taken up with ethyl ether. A solution of hydrogen chloride in alcohol is then added. The hydrochloride formed is `_ -.
filtered off. The base is freed with sodium carbonate in a methylene chloride/water mixture. After decanta-tion, the organic phase is dried over MgSO4 and the solvent is evaporated off.
05 This gives 330 g of an oil. Yield = 63%.

Preparation of 1-(1,2,3,4-tetrahydronaphth-1-yl)-piperazine 1-Carbethoxy-4-(1,2,3,4-tetrahydronaphth-1-yl)-piperazine (330 g - 1.14 M) in solution in 1.2 1 of methanol and 300 ml of water is placed in a reactor.
Potassium hydroxide (840 g - 15 M) is added slowly.
The mixture is brought to the reflux point. The reac-tion is monitored by thin layer chromatography.
After the starting material has disappeared, the mixture is cooled, filtered and then extracted with dichloromethane. The solvent is evaporated off and the residual oil is taken up with ethanol. Oxalic acid is then added. The oxalate formed is filtered off and then freed with sodium carbonate in a methylene chlo-ride/water mixture. After decantation, the organic phase is dried over MgSO4 and the solvent is evaporated off under vacuum.
210 g of a pure oil are collected. Yield =
84%.

Resolution of 1-(1.2,3,4-tetrahydronaphth-1-yl)piper-azine 1. Treatment of the racemic amine with L-(+)-aspartic acid L-(+)-Aspartic acid (3.6 g - 0.027 M) is added to a solution of racemic amine (7.315 g - 0.0339 M) in 70 ml of 95% ethanol. The mixture is brought to the reflux point, stirred for a few minutes and then left to stand at room temperature for 3 to 4 hours. The precipitate formed is filtered off and dried in air to give 4.67 g of aspartate (39% based on the amine). The 05 filtrate is retained and treated as described below.
The solid obtained is decomposed with 150 ml of a 3 M
aqueous solution of sodium hydroxide. The aqueous phase is extracted with 3 times 150 ml of ethyl ether.
The organic phase is dried over MgSO4, filtered and evaporated under vacuum to give 1.915 g of impure (-)-amine in the form of an oil (26% of the initial amine).
[~]D25 = -114 (c = 1.64; 95% EtOH); enantiomeric excess (ee) 41%.
The mother liquors of the salt are evaporated to dryness to give 7.14 g of a product, which is treated with 240 ml of a 3 M aqueous solution of NaOH.
The aqueous phase is extracted with 3 times 200 ml of ethyl ether; the ether phase is dried over MgSO4, fil-tered and evaporated to dryness to give 5.02 g (69%) of impure (+)-amine in the form of an oil. [~]D25 = +50 (c = 1.38; 95% EtOH); ee 41%.
2. Purification of the levorotatory (-)-amine A solution of the impure (-)-amine (2.03 g -9.4 mM) in 80 ml of 95% ethanol is treated with oxalic acid dihydrate (1.2 g - 9.5 mM). A copious precipitate of oxalate forms very rapidly. The mixture is left to stand at room temperature for 1 to 2 hours and then filtered and the product is dried in air to give 2.2 g of (-)-oxalate. Yield = 76%; [~]D25 = -32 (c = 1.64;
H2O); melting point = 202-3 C; ee 100%.
The free amine is obtained by decomposing the oxalate with 3 M sodium hydroxide.
3. Preparation of the tartrate of the dextrorotatory (+)-amine A solution of impure (+)-amine (5 g - 0.023 M) 21~0229 , in 200 ml of 95% ethanol is treated with (+)-tartaric acid (3.47 g - 0.023 M). The mixture is heated to the reflux point and then left to stand at room temperature for about 3 hours. The precipitated tartrate is fil-05 tered off (5.5 g, 65%).
The tartrate thus obtained is decomposed with220 ml of 3 M sodium hydroxide. The aqueous phase is extracted with 3 times 200 ml of ethyl ether; the organic phase is dried over MgSO~, filtered and eva-porated to dryness to give 3.05 g of (+)-amine in the form of an oil. [~]D25 = +99 (c = 1.62; 95% EtOH); ee 81%.
4. Purification of the dextrorotatory (+)-amine The procedure is the same as for the levoro-tatory enantiomer, the oxalate of the (+)-amine being prepared by the addition of one equivalent of oxalic acid in 95% ethanol. The oxalate obtained is filtered off and then dried in air. Yield = 76%; [~]Dzs = +29 (c = 1.52; H2O); ee 97%.
The free amine is obtained by decomposing the oxalate with 3 M sodium hydroxide.

Preparation of levorotatory, dextrorotatory and racemic 1-(2-phthalimido-1-ethyl)-4-(1,2,3,4-tetrahydronaphth-1-yl)piperazine A mixture of levorotatory, dextrorotatory or racemic l-(1,2,3,4-tetrahydronaphth-1-yl)piperazine (10.8 g - 0.05 M), 2-bromoethylphthalimide (16.51 g -0.065 M), potassium carbonate (17.25 g - 0.125 M) and sodium iodide (1 g - 0.006 M) in 200 ml of acetonitrile is refluxed for 24 hours.
The solvent is evaporated off to dryness and the residue is taken up with water, extracted with ethyl acetate and washed with acid and base.

2I ~ 0229 --. . , The product is purified on a silica column using AcOEt/cyclohexane 35/65 as the eluent.

Levorotatory Dextrorotatory Racemic Yield 72% 73% 72%
05 M.p. 103 C 103 C 77 C

EX~I~PLE 16 Preparation of levorotatory, dextrorotatory and racemic 1-(2-amino-1-ethyl)-4-(1,2,3,4-tetrahydronaphth-1-yl)-piperazine A mixture of levorotatory, dextrorotatoryor racemic 1-(2-phthalimido-1-ethyl)-4-(1,2,3,4-tetra-hydronaphth-l-yl)piperazine (11.5 g - 0.029 M) and hydrazine hydrate (3.4 g - 0.068 M) in 200 ml of metha-nol is stirred magnetically at room temperature for 24hours.
The solvent is evaporated off under vacuum, 150 ml of 2 M HCl are added and the mixture is stirred magnetically for two hours. The solid formed is fil-tered off, the filtrate is neutralized with Na2CO3 andthe product is extracted with ethyl acetate to give a thick oil.

Levorotatory Dextrorotatory Racemic Yield 83% 79% 81%

The derivatives of formula (I) obtained from intermediates analogous to those of Examples 4 to 16, and containing the desired substituents, are collated in Table I below. Their yields and their melting points in the form of the base or a salt are reported in Table II below and their spectral data in Table III.

Derivatives of formula I

N l~(CH2 )n A~E~ (I) TABLE I

N- A n m R1 R2 R3 R4 Rs Empiricalformula NH-C0 2 1 H H Cl H HC22H26ClN3o NH-C0 2 1 H H ~ H HC2gH31N30 6 NH-C0 2 1 Cl H Cl H HCæH25Cl2N30 7 NH-C0 2 1 H0-CH3 0-CH3 0-CH3 HC2sH33N304 8 NH-C0 2 2 H H Cl H HC23H28ClN3 9 NH-C0 2 2 H H F H HC23H2gFN30 12 NH-C0 2 2 H H ~> H HC2gH33N30 13 NH-C0 2 2 Cl H Cl H HC23H27Cl2N3o NH-C0 2 3 H H Cl H HC24H30ClN30 17 NH-C0 2 3 H H aH3 H HC25H33N3 18 NH-C0 2 3 H H 0-CH3 H HC2sH33N302 19 NH-C0 2 3 H H <~ H HC30H35N30 NH-C0 2 3 Cl H Cl H HC24H29c12N3o 21 NH-C0 2 3 H0-CH3 0-CH3 0-CH3 HC~7H37N304 214022~

TABLE I ( continuation ) 24 NH-CO 3 3 H H F H HC2sH32FN3O
25 CO-NH 2 1 H H F H HCæH26FN3O

32 CO-NH 3 2 H H CF3 H HC2sH30F3N3 34 NH-CO 2 2 H H H H H C~H?gN3O

TABLE II

N- Yld 9~0 Mp~ C Mps C

S 75 153 2æ

9 54 145 æo Sl 134 210 11 56 149 l9S

lS 38 pasty 194 -.

TABLE II (continuation) 2152 pasty 214 24S5 oily 180 2954 oily 204 3053 pasty 236 3356,4oily 217 Mp" C: melting point of the base MPS C: melting point of the salt 2I~229 TABLE I I I
SPECTRAL DATA

IR ~cm~l) N- IH NMR (ppm) C= O NH

1 2,1(q,2H); 2,4-2,9(m,12H); 3,5(q,2H) 1633,5 3295 4,35(t,1H); 6,8 (NH); 7,1-7,9(DL8H) 2 2,1(q,2H); 2,4-3~mL12H);3,5(q,2H) 1634 3290,5 4,35(t,1H); 6,8~NH);7-7,9~mL8H) 3 2,1(q,2H); 2,37(s,3H); 2,5-3(~L12H); 3,5(q,2H) 1629,5 3299 4,35(t,1H); 6,8~NH); 7,1-7,8~mL8H) 4 2,1(q,2H); 2,4-3(m,12H); 3,5(q,2H); 3,8(s,3H) 1627 3320,7 4,3(t,1H); 6,8~NH); 6,8-7,8(m,8H) 2,1(q,2H); 2,4-3~mL12H); 3,5(q,2H); 1629 3295 4,35(t,1H); 6,8(NH); 7,2-8~mL13H) 6 2,1(q,2H); 2,45-3~mL12H); 3,5(q,2H) 1646,9 3280 4,3(t,1H); 6,9~NH); 7,1-7,7(nL7H) 7 2,1(q,2H); 2,4-3(m,12H); 3,5(q,2H) 1634 3283 3,85(s,qH); 4,3(t,1H); 6,8~NH); 7-7,4(m,6H) 8 1,85~L4H); 2,4-3~mL12H); 3,5(q,2H) 1633 3300 3,8(t,1H); 6,9(NH); 7-7,8(m,8H) 9 1,85~EL4H); 2,4-2,8(m,12H); 3,5(q,2H); 1634 3304 3,8(t,1H); 6,8~NH); 6,9-7,8(nl8H) 1,85(m,4H); 2,4(s,3H); 2,45-2,8(m,12H); 1632 3293 3,5(q,2H); 3,8(t,1H); 6,8(NH); 7-7,8(m,8H) 11 1,85(m,4H); 2,4-2,8(m,12H); 3,5(q,2H); 1627 3318 3,85(t,4H); 6,75(NH); 6,8-7,85(m,8H) 21~0229 -TABLE I I I ( continuation ) IR (cm~l) N- 'H NMR (ppm) C= O NH

12 1,85~EL4H);2,4-2,8~aL12H); 3,5(q,2H); 1635 3298 3,8(t,1H); 6,8(NH); 6,9-7,85(m,13H) 13 1,85(m,4H); 2,4-2,8~mL12H); 3,5(q,2H); 1635 3290 3,8(t,1H); 6,7~H); 6,9-7,8~EL7H) 14 1,85~EL4H~; 2,4-2,8~mL12H); 3,5(q,2H); 1634 3291 3.9(m,10H); 6,8(NH); 7-7,75 (m,6H) 1,5-2,2~CL6H~; 2,3-2,75(nL12H); 3,2(t,1H); 1639 3372 3,5(q,2H); 6,8(NH); 6,95-7,8(m,8H) 16 1,5-2,2(m,6H); 2,3-2,75(m,12H); 3,2(t,1H); 1643 3375 3,5(q,2H); 6,8(NH); 6,9-7,9(m,8H) 17 1,5-2,2~mL6H); 2,9(s,3H); 2,45-2,7~mL12H~; 1633 3312 3,2(t,1H); 3,5(q,2H~; 6,8(NH); 7-7,7~mL8H) 18 1,5-2,2~L6H); 2,4-2,75~mL12H); 3,2(t,1H); 1634 3341 3,5(q,2H); 3,85(s,3H); 6,6(NH); 6,8-7,85~EL8H) 19 1,5-2,2(m,6H); 2,4-2,8(m,12H); 3,2(t,1H); 1638 3350 3,5(q,2H); 6,8(NH); 6,9-7,9~mL13H) 1,5-2,2(m,6H); 2,4-2,8(m,12H); 3,2(t,1H); 1648 3443 3,5(q,2H); 6,9~NH); 7-7,75(m,7H) 21 1,5-2,2(m,6H); 2,4-2,75(m,12H); 3,2(t,1H); 1639 3363 3,5(q,2H); 3,9(s,9H); 6,9-7,25(m,7H~
22 1,65-2,2(m,4H); 2,4-3(EL12H); 3,5(q,2H); 1631 3344 4,3(t,1H); 6,85-7,95(m,8H); 8,4(NH~
23 1,65-2,15(m,6H); 2,4-2,95(m,12H); 1633 3321 3,4-4(m,3H); 6~9-8(m~8H); 8,45(NH) 21~02~9 TABLE III (continuation) IR (cm~l) N- 'H NMR (ppm) C= O NH
24 1,5-2,2~mL8H); 2,4-2,9(nL12H~; 1646 3334 3,1(t,1H); 3,5(q,2H); 6,95-7,95~mL8H); 8,4~NH) 2,1(q,2H); 2,4-3(m,14H); 4,4(t,1H); 1651 3285 6,8-7,6(nL8H); ll,OS~NH) 26 1,7-2,1(m,4H); 2,4-2,9(~L14H); 1654 3291 3,9(t,1H); 6,8-7,7(m,8H); ll,l~NH) 27 1,5-2,2~CL6H); 2,4-2,9~EL14H); 1683 3278 3,2(t,1H); 6,85-7,6(~L8H); ll,OS(NH) 28 1,7-2,15~m~4H); 2,35-3~14H); 4,3(t,1H); 1650 3277 6,85-7,6~mL8H); 9 (NH) 29 1,5-2,1~mL6H); 2,35-2,85~mL14H); 1646 3271 3,8(t,1H); 6,85-7,75(m,8H); 9,l~YH) 1,5-2,1~,8H); 2,3-2,8(m,14H); 1661 3261 3,2(t,1H); 6,85-7,7(m,8H); 9~NH) 31 1,6-2,15~mL4H); 2,4-2,9(~14H); 1686 3225 3,9(t,1H); 7-7,8(m8H); 11,45(NH) 32 1,5-2,15(~6H); 2,3-2,9~mL14H); 1667 3304 3,85(t,1H~; 7-7,8(m8H); 9,25(NH) 33 1,6-2,15(m,6H); 2,3(s,3H); 2,4-2,9(m,14H); 1655 3285 3,85(t,1H); 7-7,8(m,8H); 8,8(NH) 34 1,85(m,4H); 2,4-2,8(m,12H); 3,5(q,2H); 1636 3310 3,8(t,1H); 6,85(NH); 7-7,8(m,8H) 21~02~

PEIARMACOLOGICAL TESTS
The neuroleptic activity of the derivatives of formula (I) was evaluated by the following tests:
- Antagonism towards the effects induced by the injec-05 tion of 1 mg/kg of apomorphine (hypothermia, stereo-typies, redressments) - Increase in the immobility time in the tail suspen-sion test (TST) - Affinity (in vitro) for the D2 dopaminergic recep-tors.
As neuroleptics generally have a sedative and hypothermic character, the results obtained from the study of toxicity/Irwin symptoms will also be indicated in the Summary Table.
As correlations had been demonstrated between the anxiolytic activity of novel "non-benzodiazepinic"
derivatives, such as buspirone or ipsapirone, and their affinity for the 5-HTlA serotoninergic receptors, the compounds of the invention were evaluated on this basis. The values found on the other receptors are givenby way of indication and reflect the selectivity of the compounds of the invention.
1 - Interactions with apomorphine (1 mg/kg, administered subcutaneously) The test product is administered intraperi-toneally 60 min before the injection of apomorphine.
The apomorphine is injected subcutaneously at a rate of 1 mg/kg. The mice are then isolated in separate cages.
The redressments, the stereotypies (20 min after the injection of apomorphine) and the rectal tem-perature of the animals ( 30 min after the injection of apomorphine) are noted.
Conventional neuroleptics antagonize the symp-toms induced by apomorphine. Atypical neuroleptics can be ineffective on one or other of the three parameters, 21~022g or even on all three.
The results are expressed as follows:
- as the percentage change relative to the control for the redressments and the stereotypies, 05 - as the absolute change relative to the controls for the hypothermia.
The significance is indicated as follows: ns =
not significant; * = p < 0.05; ** = p < 0.01; *** = p <
0.001 according to the value of the Student test.
2 - Tail suspension test (TST) The tail suspension test described by STERU et al. (Prog. Neuropsycho. Pharmacol. Biol. Psychiat.
1987, 11, 659-671; Arch. Int. Pharmacodyn. Ther. 1987, 288 (1), 11-30) was prepared in order to detect psycho-tropic activities.
A rodent placed in an unpleasant situation withno obvious escape (suspended by the tail) rapidly reduces its evasive activity and then becomes immobile.
The test product is administered intraperi-toneally 60 min before the mouse is suspended.
Two parameters are measured:
- the period of immobility over 6 min - the power of the movements; this parameter, based on the energy expended by the animals, is independent of the duration of the activity.
10 animals are studied per dose. Antidepres-sants conventionally reduce the immobility time. Neu-roleptics tend to increase it.
The results are expressed as the percentage change relative to the untreated control.
The significance is indicated as follows: ns =
not significant; * = p < 0.05; ** = p < 0.01; *** = p <
O . 001 .
The results are reported in Table IV below:

21~02~9 -:
o C C~
c.~ E C * C C C C C c * * c * c * c O ~O ~ O ~ ~ o ~ ~ cr ~ cr~ ~ ~ ~O ~
+ + + + + + + + + +
~.
D C * C C C C C * C C * C * * *
a ~ ~ O ~ O ~
a ~+ ~+ ' ~+ ' ' ~+ ~+ + + ' ~+ + O+~ ~+

~ ~ ~ o o ~ ~ ~ `o ~ ~ ~t ~ l v~

~o ~ o o o o o o o o t` ~` o o t` l` o CL ~

~ -*c*****cc*c*c _ ~ ~ o o ~ ~; o o E- I I I + I + + I I + I I I I +
a .~
,_ C~ /
U~ ~
~ /

/ -Z

1'ABLE IV (continl~q~i!n.) TestsSedationHypothermia Dosetested Apomorphine TST
N- \ (i) (i) (ii) Hypoth.Redress.Stereotypy Immobility Power of movements 19 64 0 128 -1,4-C** 0% 13% +45% ns +10% ns 22 16 16 32 -2,5-C** 0% 6% +85%*~* -23% ns 23 64 16 32 -1,6-C ns 0% 0% +50%* +15% ns 24 16 32 32 -0,2-C ns 0% -6% +81%* -29% ,"
26 64 32 64 -2-C* * * 0% -13% +124%* * -12%
27 32 64 128 -0,1-C ns 0% 0% +51% ns +40%
29 32 32 64 -2,3-C*** -20% -13% +54% ns -44% ns 32 64 128 -1,0-C* 0% -41% +114%*** -46~o*
8 8 16 -0,3-C ns 0% -13% -8% ns +68%*
(i): dose in mg/kg at which activity appears in the Irwin test (ii): dosc tested in mg/kg (IP) in thc apomorphine and TST tests.

21~0229 -. . , 3 - Receptology The synaptic membranes are prepared by the method of JONES and MATUS (1980). The rats are decapi-tated and the brains (without the cerebellum) are 05 quickly removed.
The synaptic membranes are purified on a dis-continuous gradient of sucrose from a mitochondrial fraction lyzed by hypotonic shock, and are stored at The rat striatum membranes are prepared from different striata under the same conditions.
The membranes (100 ~g of proteins) are incu-bated in the presence of radioligands under the fol-lowing conditions reported in Table V below:

TABLE V

Receptor Labeled ligand Concentration Incubation (conditions) ~1 (3H) Prazozine0.25 nM 30 min/25 C

D2 (3H) Haloperidol 1 nM 45 min/25 C

5-HTlA (3H) 8-OH-DPAT 0.25 nM 60 min/25 C

5-HTz (3H) Ketanserine 0.5 nM 40 min/25 C

The measurements are made in the absence and presence of the derivatives to be studied. Each mole-cule is used at concentrations of 10-5, 10-7 and 10-9 M.
The results obtained with the various products are expressed as a percentage relative to the control without product.
All the derivatives of the invention exhibited - a 50% greater inhibition at a concentration of 10-5 M.
The effect of the products on the various 35 receptors, reported in Table VI below, is coded as 21~229 -follows:
+ : inhibition of between 30 and 50% at 10-7 M
++: inhibition greater than 50% at IO-7 M

\ Receptor ~1 Dz 5-HTz 5-HT,A

Derivative \

9 ++
+
17 +
+ ++
16 +
11 ++
2 + ++
4 +
13 +
18 ++

The pKi (-log Ki) values of some derivatives according to the invention, compared with buspirone and 8-hydroxy-di-n-propylaminotetralin (8-OH DPAT) taken as reference compounds, are given in Table VII below:

TABLE VII

\ Receptor C~lD2 5-HTz5-HTlA

Derivative \
(-) 8 6.35 6.32 5.568.40 (+) 8 5.08 6.16 5.426.68 9 7.10 7.17 5.938.82 (-) 9 6.90 7.17 5.869.30 (+) 9 6.15 6.12 5.887.30 34 6.82 6.96 6.158.96 (-) 34 6.72 6.88 9.40 8-oH DPAT 5.02 5.62 5.569.26 buspirone 5.87 7.35 5.908.13

Claims

WHAT IS CLAIMED IS:

1. N-Cycloalkylpiperazine derivatives of formula (I) (I) in which:
- A is an amide group, or - R1, R2, R3, R4 and R5, which are identical or dif-ferent, are a hydrogen atom, a halogen atom, a C1-C6-alkyl group, a C1-C6-alkoxy group, a trifluoromethyl group or a phenyl group, - m is an integer between 1 and 3, - n is an integer equal to 2 or 3, and their pharmaceutically acceptable acid addition salts.

2. Derivatives according to claim 1 of formula (I) in which R1, R2, R3, R4 and R5 are H, F or Cl.

3. Derivatives according to claim 1 or 2 of for-mula (I) in which at least one of the following con-ditions is fulfilled:
- A is an amide group , - R3 is a hydrogen atom or a halogen atom, preferably fluorine or chlorine, - m = 2 or 3, - n = 2.

4. Derivatives according to any one of claims 1 to 3 which are levorotatory.

5. A method of preparing the derivatives of formula (I) according to claim 1, and their pharmaceu-tically acceptable acid addition salts, wherein a piperazine of formula (II):

(II) in which A, n, R1, R2, R3, R4 and R5 are as defined for (I) in claim 1, is condensed with a chlorinated derivative of formula (III):

(III) in which m is as defined for (I) in claim 1, in the presence of sodium or potassium carbonate and a catalytic amount of sodium or potassium iodide, in a ketone solvent, and the resulting compounds are converted to their pharmaceutically acceptable salts if appropriate.

6. A method of preparing the dextrorotatory or levorotatory derivatives of formula (I) according to claim 1 in optically pure form, and their pharmaceuti-cally acceptable acid addition salts, wherein the amines of formula (XV):

(XV) in which m is as defined for (I) in claim 1, are resolved by forming the diastereoisomeric salts with L-(+)-aspartic acid if it is desired to obtain levo-rotatory compound, and with L-(+)-tartaric acid if it is desired to obtain dextrorotatory compounds, the amines resolved in this way are reacted with a haloge-nated amide of formula (VIII):

(VIII) in which n, A, R1, R2, R3, R4 and R5 are as defined for (I) in claim 1 and X is a halogen atom, in an aromatic solvent, in the presence of triethylamine, and the resulting compounds are converted to their pharmaceutically acceptable salts if appropriate.

7. A method of preparing the derivatives according to claim 1 of formula (I) in which m and n are equal to 2, R1, R2, R4 and R5 are a hydrogen, R3 is a hydrogen atom or halogen atom, preferably fluorine or chlorine, and A = , in racemic or optically pure form, and their pharmaceutically acceptable acid addition salts, wherein the racemic or enantiomerically pure aminoethylpiperazine (XVIII):

(XVIII) is condensed with the benzoyl chlorides (XIIIa):

( XIIIa) in which R3 is as defined above, and the resulting compounds are converted to their pharmaceutically acceptable salts if appropriate.

8. Derivatives according to any one of claims 1 to 4 for their use as agents active on the central nervous system.

9. Derivatives according to claim 8 for their use as neuroleptics.

10. Derivatives according to any one of claims 1 to 4 for their use as 5-HT1A agonists.

11. Pharmaceutical compositions in which a deriva-tive according to any one of claims 1 to 4, or one of its pharmaceutically acceptable acid addition salts, is present as the active principle, in association with a pharmaceutically acceptable vehicle.

12. Use of a derivative of formula (I) according to any one of claims 1 to 4, or one of its pharmaceuti-cally acceptable acid addition salts, for the prepara-tion of drugs active on the central nervous system.

13 . Use of a derivative of formula (I) according to any one of claims 1 to 4 as a pharmacological reagent.