AU692594B2

AU692594B2 - New compounds having a 1-(arylalkenyl)-4-(arylmethyl) piperazine structure, process for preparing them and pharmaceutical compositions containing them

Info

Publication number: AU692594B2
Application number: AU33114/95A
Authority: AU
Inventors: Genevieve Baziard-Mouysset; Daniel-Henri Caignard; Youssef Labssita; Marc Payard; Pierre Renard; Marie-Claire Rettori; Sallouma Younes
Original assignee: ADIR SARL
Current assignee: ADIR SARL
Priority date: 1994-10-10
Filing date: 1995-10-06
Publication date: 1998-06-11
Anticipated expiration: 2015-10-06
Also published as: FI954719A0; ZA958532B; FR2725445B1; FR2725445A1; JPH08176129A; CN1133288A; EP0707004A1; NO305699B1; CN1053441C; CA2160214A1; NO954010D0; FI954719A; JP3035475B2; AU3311495A; NZ280192A; NO954010L

Description

I"

RIg'/ulan1 2/a3.

Rogulallon 3,2(2) r

AUSTRALIA

Patents Act 1990

ORIGINAL

COMPLETE SPECIFICATION STANDARD PATENT r r ai

D

Application Number: Lodged: Invention Title: NEW COMPOUNDS HAVING A 1-(ARYLALKENYL)-4- (ARYLMETHYL)PIPERAZINE STRUCTURE, PROCESS FOR PREPARING THEM AND PHARAMCEUTICAL COMPOSITIONS CONTAINING THEM The following statement is a full description of this invention, including the best method of performing it known to us

I

I The present invention relates to new compounds having a 1-(arylalkenyl)-4- (arylmethyl)piperazine structure, to processes for preparing them and also to pharmaceutical compositions containing them.

The Applicant has now discovered that such compounds are potent ligands for 5 sigma receptors, lacking affinity for the other central receptors. Accordingly, they may be used in a number of disorders of the central nervous system such as anxiety, psychosis or depression without the major drawbacks which accompany the traditional therapies for these central disorders. Among these side effects which are lacking in the compounds of the invention, drowsiness, sedation, or buccolingual spasms and oculogyric crises may be mentioned, these side effects being very uncomfortable for the patient.

The very high affinity for sigma receptors also makes the compounds of the invention valuable in the prevention and treatment of cerebral circulatory diseases, memory disorders and Alzheimer's disease, immune type inflammatory diseases such as arthritis and disorders of intestinal peristalsis.

More especially, the present invention relates to a compound of formula

RA

Ar2y N N-CH-Ar,

(I)

where Arl and Ar2, which may be identical or different, represent, independently of one another, a phenyl or naphthyl or substituted phenyl or substituted naphthyl group, X and Y each represent two hydrogen atoms or, together, form an oxo group, RA represents an alkyl group, its optical isomers, in pure form or in the form of a mixture, and its addition salts with a

L--I

I~ s~ l~--~111111111-r pharmaceutically acceptable acid or base, on the understanding that: the term substituted applied to the phenyl and naphthyl substituents means that these substituents may be substituted with one to three groups chosen from hydroxyl, alkyl, alkoxy, halogen and alkyl substituted with one or more halogens, the terms "alkyl" and "alkoxy" denote linear or branched groups containing from 1 to 6 carbon atoms.

Preferentially, the invention relates to a compound of formula for which:.

SRA represents a methyl group and Ar2 represents an unsubstituted phenyl group, of formula (IA): 3 o* N /N-CH -Ar (IA) -I C "I 2 where X, Y and Arl have the same definition as in the formula its optical isomers in pure form or in the form of a mixture and its addition salts with a pharmaceutically acceptable acid or base, f a 1-(3-phenyl-2-methyl-2-propenoyl)-4-benzylpiperazine of formula: "o H 3 I 0 and its addition salts with a pharmaceutically acceptable acid, 1 -(3-phenyl-2-methyl-2-propenyl)-4-benzylpiperazine of formula: i

CH

3 NN and its addition salts with a pharmaceutically acceptable acid, 1 -(3-phenyl-2-methyl-2-propenoyl)-4-(4-methoxybenzyl)piperazine of formula: r -3- CH H3

OCH

N N 0 and its addition salts with a pharmaceutically acceptable acid, 1-(3-phenyl-2-methyl-2-propenyl)-4-(4-methoxybenzyl)piperazine of formula:

COH

3 0 F O CH 3 N N OC N and its addition salts with a pharmaceutically acceptable acid, Among pharmaceutically acceptable acids which may be used to salify the compounds of the invention, hydrochloric, hydrobromic, sulfuric, nitric, oxalic, malic, maleic, succinic, tartaric, methanesulfonic, camphoric and camphorsulfonic acids may be mentioned by way of example and without implied limitation.

O*.0 Among pharmaceutically acceptable bases which may be used to form an addition salt with the compounds of the invention, sodium, potassium, calcium or aluminum hydroxide, triethylamine, benzylamine, diethanolamine, tert-butylamine, dicyclohexylamine and arginine S may be mentioned by way of examples and without implied limitation.

The invention also encompasses the process for preparing the compounds of formula wherein a compound of formula (II): H-N N-CH--Ar,

(II)

in which Arl is as defined in the formula is reacted either with a compound of formula (II):

RA

A

2 (liI) Ar COZ in which RA and Ar2 are as defined in the formula and Z represents a hydroxyl group or a halogen atom, to obtain a compound of formula (la); ~brsn~RI~ ~Wg3~" -4-

RA

Ar 2 "A "C-N N-CH-Ar, (la)

II

0 in which RA, Arl and Ar2 are as defined above, which compound (la) is subjected to a reduction to give a compound of formula (Ib):

RA

Ar 2 CH,-N N-CH,-Ar, (Ib) where RA, Arl and Ar2 have the same definition as above, or with a compound of formula (IV):

RA

CA (IV)

CH,-X

in which RA and Ar 2 are as defined above and X represents a halogen atom, in the S presence of an alkaline agent, to obtain a compound of formula (Ib) as defined above, the compounds of formula (la) and (Ib) collectively forming the compounds of the invention, which may, if so desired, be separated into their different optical isomers, salified with a pharmaceutically acceptable acid or base.

The starting materials used in the process described above are either commercially available or readily accessible to a person skilled in the art according to processes which are well known in the literature.

The acid chlorides, if they are not commercially available, are obtained by treating the corresponding acids with a chlorinating agent such as thionyl chloride.

The compounds of formula possess advantageous pharmacological properties.

The very high affinity of the compounds of the invention for a (sigma) receptors means that they can be used in the treatment of disorders associated with sigma receptors, central nervous system disorders, motor disorders such as dystonia (Walker JM. Pharmacol.

Biochem. Behav. 1990, 36 151), tardive dyskinesia (Lindstrom L.H. Acta Psychiatr. Scand.

1988, 77: 1122), psychotic disorders (Chouinard Annable L. Psychopharmacology 1984, 84: 282), and disorders such as damage associated with ischemia, cerebral circulatory insufficiency, memory disorders and Alzheimer's disease, and shock states (Pontecorvo M.J.

DsQIIDBPII~ f Brain Res. Bull. 1991, 26: 461), the regulation of immune phenomena (Carroll F.I. Med.

Chem. Re. 1992, 2 the treatment of cocaine addiction (Abou Gharbia Academic.

Press. Inc. Bristol. J. Ed. Publisher. 1993, 28: tumor diagnosis and localization (Hudzick T.J. Psychopharmacology. 1992, 108: 115; Abou Gharbia Academic Press. Inc. Bristol.

J. Ed. Publisher 1993, 28: the treatment of vomiting (Hudzick T.J. Eur. J. Pharmacol.

1993, 236 279); inflammatory diseases of immune origin such as arthritis, bronchopulmonary inflammation and psoriasis, allergic pathologies, eczema, septic shock and also disorders of intestinal motor function. As regards the treatment of central nervous system disorders, the compounds of the invention lack affinity for central receptors other than the sigma receptor, and hence lack the side effects traditionally encountered in this type of activity.

The subject of the present invention is also pharmaceutical compositions containing the compounds of formula or one of their addition salts with a pharmaceutically acceptable acid or base in combination with one or more excipients.

15 Among the pharmaceutical compositions according to the invention, those which are suitable for oral, parenteral, nasal, per- or transcutaneous, rectal, perlingual, ocular or respiratory administration may be mentioned more especially, and in particular simple or sugar-coated tablets, sublingual tablets, sachets, packets, hard gelatin capsules, sublingual preparations, S troches, suppositories, creams, ointments, skin gels and ampoules for use orally or by injection.

*too The dosage varies according to the patient's age, sex and weight, the administration route and the nature of the therapeutic indication or of any associated treatments, and ranges between 0.1 mg and 1 g per 24 hours taken in 1 or 2 doses, more especially 1 to 100 mg, for example 1 to 10 mg.

The examples which follow illustrate the invention but in no way limit it.

H nuclear magnetic resonance spectra were recorded using TMS (tetramethylsilane) as internal reference. Chemical shifts are expressed in parts per million (ppm). Infrared spectra were run in the form of a potassium bromide disk containing approximately 1% of the product to be analyzed.

EXAMPLE 1: 1-(3-PHENYL-2-METHYL-2-PROPENOYL)-4-BENZYLPIPERAZINE I I Bysl~l~"u~i~a~laarrP r~l i~ar~ -6- To 0.05 mol of (E)-a-methylcinnamoyl chloride (obtained by halogenation of the corresponding acid with thionyl chloride) dissolved in 100 ml of methylene chloride, 0.05 mol of benzyl piperazine, also dissolved in 100 ml of methylene chloride, is added. The mixture is left stirring for three hours.

The precipitate is obtained, filtered off and dried and recrystallized in ethanol.

Physicochemical properties (hydrochloride): Yield: C21H25CIN20 :"10 Molecular weight: 356.90 Melting point: 2020C S Spectral characteristics Infrared: 2990 3100 cm 1 (v CH) 1625 cm-1 (v CON) 1H Nuclear Magnetic Resonance (DMSO-dG) 2.13 ppm (singlet 3CH CH3) *4 EXAMPLE 2: 1-(3-PHENYL-2-METHYL-2-PROPENOYL)-4-(4-METHOXYBENZYL)PIPERAZINE 3 7 0 C H, N N OCH, 0 Using the procedure described in Example 1, but replacing 1-benzylpiperazine by 1-(4methoxybenzyl)piperazine, the product of the title is obtained.

Physicochemical properties (hydrochloride): Yield: 89%

C

2 2H27CIN202 Molecular weight: 386.93 -7- I I Melting point: 238°C Spectral characteristics Infrared 3000 3100 cm" 1 (v CH) 1620 cm- 1 (v CON) 'H Nuclear Magnetic Resonance (DMSO-d6) 2.13 ppm (singlet 3H CH3; =C-CH3) 3.89 ppm (singlet 3H OCH3) EXAMPLE 3: 1-(3-PHENYL-2-METHYL-2-PROPENYL)-4-BENZYLPIPERAZINE N To 0.02 mol of 1-(3-phenyl-2-methyl-2-propenoyl)-4-benzylpiperazine obtained in Example 1, dissolved in 100 ml of tetrahydrofuran (THF), 1 g of lithium aluminum hydride is added. The S operation is repeated 3 hours later.

After the end of the reaction, followed by thin-layer chromatography, the excess hydride is destroyed with 20 ml of methanol.

After evaporation to dryness, the residue is taken up with 5 ml of water and with 100 ml of S. ethyl acetate. The organic phase is filtered, evaporated and purified by chromatography on a column of silica gel 60, using methylene chloride and then ethyl acetate as eluents. The product is thereby obtained in base form.

Yield: 56% C21H26N2 Molecular weight: 306 Spectral characteristics Infrared 1605 cm- 1 (v C=C) 1H Nuclear Magnetic Resonance (CDCI3) 1.89 ppm (singlet 3H 0CH3) Obtaining the dihydrochioride The product obtained above is dissolved in 10 ml of hot isopropanol. After dissolution, 5 m! of a solution of hydrogen chloride in isopropanol are introduced. After cooling, the product is filtered off and dried.

Molecular weight: 379.38 Melting point: 24600 EXAMPLE 4: 1 -(3-PHENYL-2-METHYL-2-PROPENYL)-4-(4-METHOXYBENZYL)PIPERAZINE

OH

3 0:0N N OCH 3 *1 0 Using the procedure described in Example 3, but replacing 1-(3-phenyl-2-methyl-2- S propenoyl)-4-benzylpiperazine by 1 -(3-phenyl-2-methyl-2-p rope noyl)-4-(4methoxybenzyl)piperazine obtained in Example 3, the product of the title is obtained.

Yield: 41 C22H28N20 Molecular. weiojht: 336 Melting point: 46-C Spectral characteristics Infrared 1610 cm- (v 0=0) -H Nuclear Magnetic Resonance (DMVSO-d6) 1.89 ppm (singlet 3H js 3.79 ppm (singlet 3H OCH-3) Using the same procedure, the following compounds of Examples 5 to 18 are obtained: 1 -(3-phenyl-2-methyl-2-propenoyl)-4-(1 -naphthyl)methyl]piperazine 6) 1 -(3-ph enyl-2-m ethyl-2-p rope noyl) -4-(4-chlo robenzyl) pipe razi ne 7) 1 -(3-phenyl-2-methyl-2-propenoyl)-4-(4-hydroxybenzyl)piperazine 8) 1 -(3-phenyl-2-methyl-2-propenoyl)-4-(2-phenylethyl)piperazine 9) 1 -(3-phenyl-2-ethyl-2-propenoyl)-4-benzylpiperazine I I 1-[3-(1-naphthyl)-2-methyl-2-propenoyl]-4-benzylpiperazine 11) 1 -[3-(3-methoxyphenyl)-2-methyl-2-propenoyl]4-benzylpiperazine 12) 1 -(3-phenyl-2-methyl-2-propenyl)-4-[(1 -naphthyl)methyl]piperazine 13) 1 -(3-phenyl-2-methyl-2-propenyl)-4-(4-chlorobenzyl)piperazine 14) 1 -(3-phenyl-2-methyl-2-propenyl)-4-(4-hydroxybenzyl)piperazine 1-(3-phenyl-2-methyl-2-propenyl)-4-(2-phenylethyl)piperazine 16) 1 -(3-phenyl-2-ethyl-2-propenyl)-4-benzylpiperazine 17) -naphthyl)-2-methyl-2-propenyl]-4-benz;,lpiperazine 18) 1 -[3-(3-methQxyphenyl)-2-methyl-2-propenyl]-4-benzylpiperazine and also their additiorn salts with a pharmaceutically acceptable acid.

PHARMACOLOGICAL STUDY OF THE COMPOUNDS OF THE INVENTION 6 EXAMPLE A: STUDY OF ACUTE TOXICITY 1 4 4- The acute toxicity was assessed after oral administration of a dose of 100 mg.kg- 1 of the 4.04 compounds of the invention to groups ci 8 mice (26 2 grams). The animals were observed at regular intervals during the first day and daily over the two weeks following treatment.

It is apparent that the compounds of the invention are completely nontoxic. They do not give S rise to any mortality after administration at a dose of 100 mg.kg- and no disorders are observed after administration of this dose.

44 EXAMPLE B: EVALUATION OF IN VITRO RECEPTOR AFFINITY The products are tested on each receptor at 5 different concentrations (10-5M, 106 M, -7 -8 10-7M, 10- 8 M, 10-9M) in triplicate. When the binding coefficient IC50 is below a concentration of 10-6M, Ki is measured using 12 concentrations of the product.

The receptors for which the affinity of the compounds of the invention was determined, the tissue chosen, the concentration adopted for determining the nonspecific fraction and the radio ligand used to label the receptor are recorded in the table below.

The results of the tests showed that the compounds of the invention are potent and selective ligands for o receptors. (Affinity of the order of 10-1 0 M for C receptors, see Table B).

Table A:-Evaluadon of in vitro receptor affinity e 9 9. 9 9 9 5 9 Receptor or Radioligand Nonspecific fraction Tissue Al 6 8-OH-DPAT 1 0- 5 M Hippocampus buspirone 5-HT1 B 3 H]-cyanopindolol 10 5 M Rat brain se roton in 5-HT1 C N-Methyl- 0& 5 M Frontal cortex mesulergine mianserin hippocampus 5-HT2 3 10- 5 M Frontal cortex ketanserin spiperone 5-HT 3 f HI- 10- 5 M Rat ileum guipazine zacopride 13H]- 10- 5 M Rat brain p razosin p hentolamine X23H]-rauwolscine 10- 5 M Rat brain yohimbine D1 10- 6 M Rat striatumn SCH 23390 butaclamol D2 3i H]-raclopride 10- 6 M Rat striatumn haloperidol Mi 3 H]-telenzepine 10- 5 M Cortex atropine Hi 3I 10- 6 M Calf cortex pyrilamine chlorpheniramine

I

-11 Table A (continued): Receptor or site Radioligand Nonspecific fraction Tissue a 3 H]DTG 10 6 M Calf or H]3-PPP 3-PPPhippocampus 1 3 H]-pentazocine 5x10 6M Guinea pig brain _haloperidol 02 3 H]DTG 5x10 6 M Guinea pig brain haloperidol Table B: Results of the tests of binding to s receptors: Compound Receptor Radio ligand IC50 (M) Example 3 a [3H] DTG 6.9x10 1 0 Example 4 o H] DTG 7.9x10- 1 0 r *S S 4 4 5C 4 4*

S

EXAMPLE C: ANTAGONISM OF AMPHETAMINE-INDUCED HYPERMOTILITY This test was developed by COSTALL B. et al. (Brain Research 1977, 123: 89-111).

-1 Groups of 10 NMRI-CERJ mice are injected intraperitoneally (IP) with 4 mg.kgl of Damphetamine immediately after the test compound (also injected IP), and the mice are placed in an activity cage for 30 minutes.

The number of interruptions of the beam of photoelectric cells is counted, as is stereotyped behavior.

The activity of the compounds tested is expressed as a percentage of the antagonism of amphetamine-induced hyperactivity.

The results of the test show that the compounds of the invention are potent antagonists of amphetamine-induced hypermobility. This enables the conclusion to be drawn that the -12compounds of the invention are good candidates for the treatment of central nervous system disorders.

EXAMPLE D: ANTAGONISM OF N-ALLYLNORMETAZOCINE-INDUCED HYPERACTIVITY This test was developed by SNYDER S.H. et al. Neuropsychiatry, 1989, 1: 7-15). N- Allylnormetazocine SKF 10047) induces psychotic behavior in man and is the prototype a receptor agonist.

Measurement of the hyperactivity induced by this product is hence used as an alternative model for detecting the antipsychotic activity of compounds acting on a receptors.

A group of 12 rats is treated with the test compound before the subcutaneous administration of 50 mg/kg of N-allylnormetazocine. 30 minutes later, the animals are placed in an activity cage for 30 minutes.

0 0 Haloperidol is used as reference compound.

4 The results of the test show that the compounds of the invention are potent antagonists of Nallylnormetazocine-induced hyperactivity. Thus, for example, the compound of Example 9 at a dose of 32 mg.kg" antagonizes N-allylnormetazocine-induced hypermotility by 42%.

This test hence confirms the value of the products of the invention for the treatment of central nervous system disorders.

4 4 EXAMPLE E: TESTING FOR A CATALEPTOGENIC EFFECT This test was developed by CHERMAT R. et al. Pharmacol. 1975, 6: 493-496).

The cataleptogenic effect is tested for in rats using the intraperitoneal route. 6 groups of Wistar rats receive an injection of the compounds of the invention and are then tested for the cataleptogenic activity of the latter at 30-minute intervals. Prochlorperazine is used as reference.

The results of this test demonstrate that the compounds of the invention display a negligible cataleptogenic effect in comparison with prochlorperazine under the same test conditions.

-13- This result confirms the absence of extrapyramidal type side effects of the products of the invention, which could be expected on the basis of the binding results (Example B).

EXAMPLE F: STUDY OF THE ANTI-DEPRESSANT ACTIVITY OF THE COMPOUNDS OF THE INVENTION

PRINCIPLE:

Study of the products is carried out on the model of "learned helplessness", which consists in inducing in the animal, by a series of uncontrollable aversive events, a defect during the subsequent avoidance tasks.

PROTOCOL:

This test was developed by Sherman Sacquitne J.L. and Petty F. (Pharmacol.

Biochem. Behav. 1982, 16: 449-454). We use male Wistar rats weighing between 180 and 200 grams. The animals are kept in the animal house for one week before the test, in plastic so* boxes, in groups of 10, at an ambient temperature of 21 C 1 0 C, with free access to water o and feed.

0 4 The animals are then isolated in small boxes and are subjected to 60 unavoidable electric shocks (0.8 mA every minute 15 seconds). A group of control rats does not receive electric shocks.

The animals' capacity to carry out an avoidance learning (passage from one compartment to the other in order to avoid the electric shocks) is assessed 48 hours later and over 3 °*20 consecutive days.

During the learning sessions, the animals undergo 2 tests per minute over 15 minutes. The number of escape failures is noted for each rat. The animals are treated 0.5 cm 3 /100 g) in the fasted state 6 hours after the unavoidable shocks and on 4 consecutive days, in the morning 30 minutes before the learning session and at night between 6 p.m. and 7 p.m.

The products under study are dissolved in distilled water.

The products under study are administered at doses of 0.05 mg.kgl 1 /day.

RESULTS:

The test demonstrates that the products of the invention significantly decrease the number of escape failures, thereby reflecting a strong activity of the anti-depressant type.

I 4> S, -14- EXAMPLE G: STUDY OF ANXIOLYTIC ACTIVITY SO-CALLED LIGHT/DARK CAGES TEST IN MICE

PROTOCOL:

This test was developed by CRAWLEY et al. (1981, Pharmacol. Biochem. Behav. 1981, 695-699), then modified and validated behaviorally.

The test involves two PVC cages of equal size (20 x 20 x 14 cm). One is strongly illuminated by a 100 W lamp ("cold" light), the other is darkened. The two cages are separated from one another by means of a small opaque tunnel (5 x 7 cm). The mice are introduced individually into the dark cage, and the time spent by the animals in the illuminated cage, and also the number of transits between the dark cage and the illuminated cage, are recorded over minutes by means of keyboards connected to a computer. Each experimental group comprises at least 15 animals.

#*see:

RESULTS:

The intraperitoneal administration of some products of the invention leads to an increase in C5 the time spent by the mice in the illuminated cage, and in the number of transits between the 4 4 S° dark cage and the illuminated cage.

44 This significant increase in the two parameters under study shows the exceptional anxiolytic activity of the compounds of the invention.

EXAMPLE H: TESTING FOR AN ANTIARTHRITIC ACTIVITY IN RATS

PROTOCOL:

Groups of 5 male or female Lewis rats weighing from 130 to 150 g are used. A suspension of 0.3 mg of killed Mycobacterium tuberculosis in 0.1 ml of mineral oil (Freund's complete adjuvant, FCA) is administered in the region of the hind foot on Day 1. The volumes of the hind feet are measured by displacement of water on days 0, 1, 5, 14 and 18. The test products are suspended in carboxymethylcellulose and administered orally over consecutive days from Days 1 to

RESULTS:

After administration of the products of the invention, a significant decrease is observed in the volume of the hind feet in the early phase and in the late phase of the inflammation (after D 14), thereby demonstrating a potential therapeutic activity in arthritis.

EXAMPLE 1: PHARMACEUTICAL COMPOSITION Tablets containing a 0.1 mg dose of 1-(3-phenyl-2-methyl-2-propenyl)-4-benzylpiperazine which can be used in the treatment of central nervous system disorders.

Formula for 10,000 tablets: 1 g Wheat starch 75 g Maize 75 g Lactose 325 g Magnesium stearate 1 lg g lg 0:00 Tablets containing a 50 mg dose of 1-(3-phenyl-2-methyl-2-propenyl)-4-(4- *methoxybenzyl)piperazine which can be used in the treatment of chronic arthritis.

0 00 to Formula for 1,000 taolets 0 15 1 Phenyl-2-methyl-2-p rope nyl)-4-(4-m ethoxybenzyl) pipe razi ne 50 g Wheatstarch 150g Maize 150 g 450 g Magnesium stearate log g to Hydroxyp ropylcel lu lose 1 lg

Claims

1. A compound of formula RA RAr /N N-CH-(Ar, (I) X Y where Arl and Ar2, which may be identical or different, represent, independently of one another, a phenyl or naphthyl or substituted phenyl or substituted naphthyl group, X and Y each represent two hydrogen atoms or, together, form an oxo group, RA represents an alkyl group, its optical isomers, in pure form or in the form of a mixture, and its addition salts with a pharmaceutically acceptable acid or base, on the understanding that: the term substituted applied to the phenyl and naphthyl substituents means that these substituents may be substituted with one to three groups chosen from hydroxyl, alkyl, alkoxy, halogen and alkyl substituted with one or more halogens, the terms "alkyl" and "alkoxy" denote linear or branched groups containing from 1 to 6 carbon atoms.

2. A compound of formula as claimed in claim 1, for which RA represents a methyl group and Ar2 represents an unsubstituted phenyl group, of formula (IA): 3 CH 3 -N N-CH-Ar, (IA) X Y where X, Y and Arl have the same definition as in claim 1, its optical isomers in pure form or in the form of a mixture and its addition salts with a pharmaceutically acceptable acid or base.

3. A compound as claimed in claim 1, which is 1-(3-phenyl-2-methyl-2-propenoyl)-4- benzylpiperazine of formula: i CH 3 N N 0 S. -17 and its addition salts with a pharmaceutically acceptable acid.

4. A compound as claimed in claim 1, which is 1-(3-phenyl-2-methyl-2-propenyl)-4- benzylpiperazine of formula: CH 3 N N and its addition salts with a pharmaceutically acceptable acid.

A compound as claimed in claim 1, which is 1-(3-phenyl-2-methyl-2-propenoyl)-4-(4- methoxybenzyl)piperazine of formula: 3 OCH 3 N N N N C o and its addition salts with a pharmaceutically acceptable acid. "10

6. A compound as claimed in claim 1, which is 1-(3-phenyl-2-methyl-2-propenyl)-4-(4- S: methoxybenzyl)piperazine of formula: CH 3 0 C H 3 N N\N N and its addition salts with a pharmaceutically acceptable acid.

7. A process for preparing a compound of formula as claimed in claim 1, wherein a compound of formula (II): H-N N-CH,-Ar, (II) in which Arl is as defined in claim 1, is reacted either with a compound of formula (ll): RA Ar 2 (Il) v COZ r -18- in which RA and Ar2 are as defined in claim 1 and Z represents a hydroxyl group or a halogen atom, to obtain a compound of formula (la): RA C-N N-CH--Ar, (Ia) O in which RA, Arl and Ar2 are as defined above, which compound (la) is subjected to a reduction to give a compound of formula (Ib): RA ACH-- N N-CH--Ar, (Ib) where RA, Arl and Ar2 have the same definition as above, 0 or with a compound of formula (IV): RA Ar 2 °CH-X (IV) 00* in which RA and Ar2 are as defined above and X represents a halogen atom, in the 00 0 presence of an alkaline agent, to obtain a compound of formula (Ib) as defined above, the compounds of formulae (la) and (Ib) collectively forming the compounds of the invention, which may, if so desired, be separated into their different optical isomers, salified with a pharmaceutically acceptable acid or base.

8. A pharmaceutical composition containing a compound of formula as claimed in claim 1 or one of its addition salts with a pharmaceutically acceptable acid or base in combination with one or more excipients.

9. A pharmaceutical composition as claimed in claim 8, which is useful for the treatment of central nervous system disorders.

10. The pharmaceutical composition as claimed in claim 8, which is useful for the treatment of inflammatory diseases of immune origin. DATED this 6th day of October 1995. ADIR ET COMPAGNIE WATERMARK PATENT TRADEMARK ATTORNEYS 290 BURWOOD ROAD HAWTHORN. VIC. 3122. ABSTRACT NEW COMPOUNDS HAVING A 1-(ARYLALKENYL)-4- (ARYLMETHYL)PIPERAZINE STRUCTURE, PROCESS FOR PREPARING THEM AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM ADIR ET COMPAGNIE 1, RUE CARLE HEBERT F-92415 COURBEVOIE CEDEX Compounds of formula (1) 0* *040 000000 *000 A2 RA Ar 2 N N-CHi-Ar 1 10 where RA, An Ar2, X and Y are defined in the description. Medicinal products.