N(HETERO)-ARYL-N(HETERO)-TETRALIN-ALKYL-PIPERAZINE HAVING SEROTONINERGIC, DOPAMINERGIC AND ADRENERGIC ACTIVITY

Abstract: N(hetero)-aryl-N(hetero)-tetralinalkyl piperazine having serotoninergic, dopaminergic and adrenergic activity, the processes for their preparation and relative therapeutic compositions for the treatment of anxiety generated by depression, for the treatment of schizophrenia, cerebral ischemia, opium like and psycho stimulant substances abuse syndromes consciousness disorders such as senile dementia, vigilance and memory disorders. Parkinson's and Alzheimer's diseases and for the treatment of arterial hypertension.

Description: N(HETERO)-ARYL-N(HETERO)-TETRALIN-ALKYL-PIPERAZINE HAVING SEROTONINERGIC, DOPAMINERGIC AND ADRENERGIC ACTIVITY . FIELD OF THE INVENTION The present invention relates to N(hetero) -aryl-N(hetero)- tetralin-alkyl-piperazine having serotoninergic, dopaminergic and adrenergic activity, the processes for their preparation and relative therapeutic compositions for the treatment of generalized anxiety, depression, schizophrenia, cerebral ischemia, opium like, psycho stimulant substances and alcohol abuse syndromes, and for the therapy of arterial hypertension. PRIOR ART DISCLOSURE The active drugs on 5~HT1A receptor resulted effective in the anxiety therapy. These drugs if compared to benzodiazepine are characterized by having a twofold advantage,they are able to produce anxiolythic activity, contemporaneously avoiding the onset of side effect as for example sedation and addiction [Drugs 41,11. (1991)-Trends Pharmacol. Sci. 8, 383. (1987)], and they can be utilized in some anxiety forms resistant to the treatment with benzodiazepins. In fact drugs having 5-HT1A activity proved useful in the prevention of panic attacks [Psychopharmacology 10,3. (1990)] and for the treatment of obsessive-compulsive disorders [Journal of Psychiatry 147,798, (1990)]. The use of compounds showing -HT1A activity has been recently proposed for the treatment of depression [Psychopharmacology 10.77S, (1990) -Psichopharmacology 22, 27, (1989)], and for the control of the alcohol abuse [ Proc. Natl. Acad. Sci. USA 85, 5274 (1988) - Psychopharmacology 22, 49, (1989)]. Compounds able to combine activity on -HT1A receptor and the capacity of interaction with D-2 and σ receptors may represent a valid therapeutic approach to the treatment of schizophrenia. In fact the association of D-2 with σ activity enhances the antipsychotic effect of the compound, whereas the presence of 5~ HT1A seems able to reduce the hazard of side extr.apiramidal effects.[J. Med. Chem. 34 ,1860, (1991) - J- Neural. Transm. 57, 255, (1983)]. Moreover the activity on σ receptors is considered very important in pathologies such as cerebral ischemia in which a massive activation of glutamatergic system is present [J. Med. Chem.35. 1526, ( 1992) ; Med. Chem. Res . 1 , 425 , (1992) ; Drug of Today 27 , 255. (1991 ) ] . Finally the use of active compounds on 5-HTIA receptor, or compounds having mixed activity on 5-HTlA/α-l receptors has been recently suggested for the treatment of arterial hypertension [Naunyn-Schmiedeberg' s Arch. Pharmacol. 336,597, (I987)]. The above finds also a confirmation in the recent reconsideration of the role of α-1 blocking compounds in the treatment of arterial hypertension [JAMA 266, 394, (1991)]. In view of the foregoing it appears evident that compounds shewing a sufficient selectivity toward 5-HTlA receptors or possessing a mixed activity on 5-HTlA/D-2/σ/α-l or 5-HTlA/α-l are to be considered having a marked therapeutic potential in the aforementioned pathologies. The N-alkyl-piperazine moiety is present in various structures of agents proposed and used as anxiolythic and antipsychotic compounds, since they are active on 5-HT1 type serotoninergic and/or on the D-2 type dopaminergic receptor system (see TFMPP, Buspirone, Gepirone, Ipsapirone, Tandospirone, (SM-3997) . BMY - 7378, NAN-190, WY -47846, RK-153, RK-I67. 1-NP, Quipazine, MK- 212, m-CPP, OPC-4392, LY I65I63 (PAPP) , Eltoprazine, (DU-288553) , Thiospirone, Revospirone, SM-9018, etc. In all known N-alkyl-piperazine moieties from the prior art the affinity towards specific 5HT and DA type receptor subgroups resulted to depend on the substituent present on the second nitrogen atom of the piperazine ring, particularly when on this atom an alkyl group is present, being substituted on its turn with groups presenting a considerable structural complexity, the compounds show affinity towards both 5-HTIA- and D-2 receptors, but also towards α-1 and σ receptors . Presently a great need is felt to find compounds acting selectively on a type of receptor group, so that they can be utilized for the treatment of pathologies such as anxiety and depression, or compounds possessing activity on more than one receptor, among those above identified for the treatment of pathologies such as schizophrenia and arterial hypertension. THE PRESENT INVENTION The present invention relates to N(hetero)-aryl-N(hetero) - tetralin-alkyl-piperazine and their pharmaceutically acceptable salts of general formula ( I) (I) wherein Ar2 is selected from phenyl; mono or di-substituted aryl in which the substituent(s) is (are) selected on its (their) turn from linear or branched C^-Cc alkyl, halogen atoms, C^-Cc haloalkyl; heteroaryl containing one or more heteroatoms selected on their turn from N, 0, S, said heteroaryl being optionally substituted with the above mentioned alkyl groups, said heteroaryl being a monocyclic group of from to 6 atoms or condensed on an aryl group optionally substituted with the above mentioned groups, Ar-^ is an aryl or a heteroaryl of from 5 to 6 carbon atoms containing from 1 to 3 heteroatoms selected from N, 0, or S; R^ and R 2 equal or different from each other are selected from H, C-^-Cc alkoxy, OH, C^-C alkyl, N0 2 and wherein Y - \ / X I is selected from: n = 1 or 2 and m = 2 or 3 - In the present invention the compounds ( I ) presenting an asimmetry center, may exist in racemic or in optically active form. The compounds of the present invention are characterized by having a considerable affinity on 5-HT1A setoninergic receptors . This activity is coupled to a good selectivity towards different serotonine receptor subtypes ( as it results from the data reported in Table 1 ) . The compounds of the present invention are active in a sperimental model [Tricklebank, Eur. J. Pharmacol. 106,271.(1985)] evaluating 5-HT1A activity "in vivo" and permitting to understand if the compounds in question act as agonists or antagonists. The Applicant has found that all the 5 analyzed compounds , selected on the base of receptor screening, are able to inhibit, at low dosages, stereotypy induced by 80H- DPAT (as it results from the data contained in Table 2 reported later on) , without producing the behaviouristic effects ascribable to a serotoninergic activation. 1° Therefore the compounds of the present invention result to act as pure antagonists on 5-HT1A receptor. The "in vivo" activity of the analyzed compounds can be very well correlated to receptor affinity, thereby indicating that the analyzed compounds are able to well penetrate inside the Central I 5 Nervous System. Some compounds of the present invention associate a considerable effectiveness on D-2 dopaminergic, α-1 and σ adrenergic receptors (as it results from the data contained in Table 3 reported later on) to 5-HTlA activity, inducing to suggest that 20 the same can be used as antipsychotic and, in some cases, as antihypertensive and antiischemic principles. The compounds of the present invention are characterized by having a marked activity on receptors involved in several pathologies both of Central and Peripheral Nervous System. 25 The considerable activity on 5-HT1A receptors induces to hypothesize a use of the compounds of the present invention in pathologies such as generalized anxiety, depression, panic attacks, obsessive-compulsive syndromes, opium like and psycho stimulant (amphetamine, cocaine, caffeine) substances and alcohol abuse syndromes, consciousness disorders such as senile dementia, vigilance and memory disorders, Parkinson's and Alzheimer's diseases. In addition it is to be underlined how some compounds according to the present invention exhibit a marked activity and a selectivity towards 5"HT1A receptors, the above feature being common to few anxiolythic drugs commercially available or in phase of advanced clinical experimentation. Some compounds of the present invention exhibit a considerable activity on D-2, α-1 and σ receptors, which can be associated or not to as a considerable activity on 5-HT1A receptor. The general pattern of activities of the compounds of the present invention allow to foresee their very promising use in the therapy of schizophrenia and cerebral ischemia. That,because of the interesting activity demonstrated by some compounds of the present invention , common to few antipsychotic drugs now in use. An other important and interesting aspect characterizing the compounds of the present invention is the marked affinity of some of them on α-1 receptor. This activity, associate to a good affinity towards 5-HT1A receptors and to a favourable selectivity ratio towards D-2 and σ receptors, permits to propose some of the compounds of the present invention for the therapy of arterial hypertension. Therefore the present invention further relates to therapeutic compositions containing as the active principle one or more derivatives of general formula (I) in combination with suitable excipients and/or diluents . In particular the therapeutic compositions according to the present invention containing the compounds of formula (I) having mainly 5-HT1A serotoninergic activity are suitable for the treatment of generalized anxiety , panic attacks , obsessive- compulsive syndromes , depression, opium like, psycho stimulant substances and alcohol abuse syndromes . - The therapeutic compositions containing the compounds of formula (I) having mainly affinity on the receptors D-2, σ and 5-HT1A or affinity on the receptors D-2 , σ and α-1 , are in particular suitable for the treatment of schizophrenia and cerebral ischemia. The therapeutic compositions containing as the active principle the compounds of formula (I) having mainly affinity on 5-HT1A and α-1 receptors are used for the treatment of arterial hypertension. N(hetero) aryl-N(hetero) -tetralinalkylpiperazine of formula (I) are prepared with different processes depending on the different Y - \ / X groups contained in the alicyclic group of formula (I) . For example for preparing the derivative of formula (I) wherein Y - \ / X the process comprises the following steps: a) reacting the compounds of formula (II) wherein Ar-^, R-^, R 2 and n have the above mentioned meanings with an a inoalkylpiperazine of formula (III): (III) wherein m and Ar 2 have the above mentioned meanings, in an apolar solvent under reflux and in the presence of catalytic amounts of an acid, thereby obtaining the derivative of formula (IV): (IV) b) reducing the product obtained in the preceding step with sodium borohydride in a polar solvent at room temperature. The process for preparing the derivatives of formula (I) wherein Y - \ / X is selected from: comprises the following steps: a') reacting the above mentioned keton of general formula (II) with Grignard reactant Ro-MgX, wherein Ro is selected from: cyclopropyl and -(CH 2 ) / ,C1 in an ethereal solvent thereby obtaining the tertiary alcohol of formula (V) ϋ) (V) b') reacting the tertiary alcohol (V), coming from the preceding step, with HCl in acetic acid, thereby obtaining the chloride derivative of formula (VI) or (Via) : (VI) (VIA) wherein p is = 1 or 2 and is =1 when in the reactant (V) Ro is = cyclopropyl, or is = 2 in case R is = -{CH )/ j -Cl c') reacting the chloride intermediate (VI) or (VIA) obtained in the preceding step with N-arylpiperazine of formula (VII) (VII) wherein Ar 2 has the aforementioned meanings thereby obtaining N(hetero) -aryl-N(hetero) -tetralinalkylpiperazine of formula ( I ) wherein d ' ) reacting the derivative of formula ( I ) obtained in the preceding step with hydrogen in the presence of catalysts consisting of noble metals in a polar solvent thereby obtaining the compounds of formula (I) wherein : The process for preparing the compounds of formula (I) wherein comprises the following steps: a") reacting the aforementioned keton (II) in the presence of a reducing agent thereby obtaining the corresponding alcohol (VIII) b") successively treating the alcohol (VIII) obtained in the preceding step, with ethyl 2-mercapto-acetate and Znl , thus obtaining the corresponding ester of formula (IX): (IX) c") hydrolyzing the obtained ester to the corresponding acid and successively treating this acid with thionyl chloride in order to obtain the acyl chloride (X) d") reacting the acyl chloride (X) with the aforementioned N- aryl-piperazine (VII) thereby obtaining the corresponding amide e")treating the amide (XI) with LiAlH/ to obtain the desired derivative of formula (I). DETAILED DESCRIPTION OF THE INVENTION In the N(hetero)-aryl-N(hetero)-tetralinalkylpiperazine of formula (I) according to the present invention Ar-^ is an aryl group, which is condensed on the alicyclic ring so that it forms the derivatives of general formula (IA) (IA) or the derivatives of general formula (IB) (IB) R^ is preferably, in the compounds of formula ( I ) , OCHo , whereas R 2 is preferably H. Ar 2 is preferably selected from : 2-methoxyphenyl , 3- chlorophenyl, 3-trifluoromethylphenyl, 2-pyridyl, 2,5~ dimethoxyphenyl. Particularly preferred derivatives of formula (I) are those having n = 2. The therapeutic compositions of the present invention preferably contain the active principle at dosages of from 1 to 200 mg and are generally administered 2-3 times daily. Particularly preferred therapeutic compositions according to the present invention for the treatment of generalized anxiety, panic attacks, obsessive-compulsive syndromes, depression, opium like, psycho-stimulant substances and alcohol abuse syndromes, consciousness disorders such as senile dementia, vigilance and memory disorders, Parkinson's and Alzheimer's diseasesare those having the active principle selected among one or more of the following derivatives: - 1-(2-methoxyphenyl)-4-[N-(5-methoxy-l,2,3,4- tetrahydronaphthalen-1-yl)-2-aminoethyl]-piperazine (example i); - 4-[3-(6-methoxy-l,2-dihydronaphthalen-4-yl)n-propyl-l-(2- methoxyphenyl)piperazine (example 2) ; l-phenyl-4-[3 _ (8-methoxy-l,2-dihydronaphthalen-4-yl)-n- propyl]piperazine (example 8); - 4-[3-8-methoxy-l,2-dihydronaphthalen-4-yl)-n-propyl]-l-(2- methoxyphenyl)piperazine (example 9) - - 4-[3-(8-methoxy-l,2-dihydronaphthalen-4-yl)-n-propyl]-l-(2- pyridyl)-piperazine (example 12); - 4-[3-(1,2-dihydronaphthalen-4-yl)-n-propyl]-l-(2-methoxyphenyl) • piperazine (example 13) ; - 1-(2-methoxyphenyl)-4-[3~(7-methoxy-l,2,3,4- tetrahydronaphthalen-l-yl)-n-propyl]piperazine (example 14); - l-phenyl-4-[3-(5-methoxy-l,2,3.4-tetrahydronaphthalen-1-yl)-n- propyl]-piperazine (example 16) ; - 1-(2-methoxyphenyl)-4-[3~(5-methoxy-l,2,3,4- tetrahydronaphthalen-l-yl)-n-propyl]-piperazine (example 17); - 4-[3-(5 -m ethoxy-l,2,3,4-tetrahydronaphthalen-l-yl)-n-propyl]-l- (2-pyridyl)-piperazine (example 18) ; - 4-[3-(7-ωethoxy-l,2,3.4-tetrahydronaphthalen-l-yl)-n-propyl]-l- (2-pyridyl)piperazine (example 19) ; - 1-(2-methoxyphenyl)-4-[3 _ (4,5.6,7-tetrahydrobenzo[b]thien-4- yl-) n-propyl]piperazine (example 20); - 1-(2-methoxyphenyl)-4-[3~(1, ,3,4-tetrahydronaphthalen-1-yl)-n- propyl]piperazine (example 21); - 4-[4-(6-methoxy-l,2-dihydronaphthalen-4-yl)-n-butyl]-l-(2- methoxyphenyl)-piperazine (example 22); - 1-(2-methoxyphenyl)-4-[4-(7-methoxy-l,2,3,4- tetrahydronaphthalen-l-yl)-n-butyl]-piperazine (example 23); - l-(2-methoxyphenyl)-4-{2-[(7-methoxy-l,2,3,4- tetrahydronaphthalen-1-yl)-thio]-ethyl}piperazine (example 24); - 4-[l-(8-methoxy-l,2,3.4-tetrahydronaphthalen-4-yl)l-propylen-3~ yl]-l-(2-methoxyphenyl)piperazine (example 25); - 4-[l-(8-methoxy-l,2,3,4-tetrahydronaphthalen-4-yl)-l-propylen- 3-yl]-l-(2-pyridyl)piperazine (example 26); - 1-(2-methoxyphenyl)-4-[(1,2,3,4-tetrahydronaphthalen-4-yl)-1- propylen-3-yl]piperazine (example 27) ; - 1-(3-chlorophenyl)-4-[3~(8-methoxy-l,2,-dihydronaphthalen-4- yl)-n-propyl]piperazine (example 10); - 4-[3-(8-methoxy-l,2-dihydronaphthalen-4-yl)-n-propyl]-l-(3 _ trifluoromethylphenyl)piperazine (example 11); " 4-[3-(7-methoxy-l,2,3.4-tetrahydronaphthalen-l-yl)-n-propyl]-l- (3-trifluoromethylphenyl)piperazine (example 15). Particularly preferred therapeutic compositions according to the present invention for the treatment of schizophrenia are those wherein the active principle is selected among one or more of the following derivatives: - 4-[3-(8-methoxy-l,2-dihydronaρhthalen-4-yl)-n-propyl]-l-(2- methoxyphenyl)-piperazine (example 9); - 4-[3-(l,2-dihydronaphthalen-4-yl)-n-propyl]-l-(2- methoxyphenyl)-piperazine (example 13); 1-(2-methoxyphenyl)-4-[3-(7-methoxy-l,2,3,4- tetrahydronaphthalen-l-yl)-n-propyl]piperazine (example 14) ; l-phenyl-4-[3~( -methoxy-l,2,3.4-tetrahydronaphthalen-l-yl)-n- propyl]-piperazine (example 16) ; - 1-(2-methoxyphenyl)-4-[3-(5-methoxy-l,2,3,4- tetrahydronaphthalen-l-yl)-n-propyl]-piperazine (example 17); _ 4-[4-(6-methoxy-l,2-dihydronaphthalen-4-yl)-n-butyl]-l-(2- methoxyphenyl)-piperazine (example 22) ; - 1-(2-methoxyphenyl)-4-[4-(7-methoxy-l,2,3,4- tetrahydronaphthalen-l-yl)-n-butyl]-piperazine (example 23); - l-(2-methoxyphenyl)-4[N-(5-methoxy-l,2,3,4- tetrahydronaphthalen-1-yl)-2-aminoethyl]-piperazine (example 1); - l-(2-methoxyphenyl)-4-[3-(4,5,6,7 _ tetrahydrobenzo[b]thien-4-yl- n-propyl]piperazine (example 20) ; - 1-(2-methoxyphenyl)-4-[3~(1,2,3,4-tetrahydronaphthalen-1-yl)-n- propyl]piρerazine (example 21); - l-(2-methoxyphenyl)-4-{2-[(7-methoxy-l, 2, 3, 4 -tetrahydro- naphthalen-l-yl)-thio]-ethyl}piperazine (example 24); -4-[l-(8-methoxy-l,2,3.4-tetrahydronaphthalen-4-yl)-l-propylen- 3-yl]-l-(2-methoxyphenyl)piperazine (example 25); - 1-(2-methoxyphenyl)-4-[(1,2,3,4-tetrahydronaphthalen-4-yl)-1- propylen-3 _ yl]piperazine (example 27) ; Particularly suitable therapeutic compositions according to the present invention for the treatment of arterial hypertension are those having the active principle chosen among one or more of the following derivatives: - 4-[3-(6-methoxy-l,2-dihydronaphthalen-4-yl)n-propyl-l-(2- methoxyphenyl)piperazine (example 2) ; l-phenyl-4-[3-(8-methoxy-l,2-dihydronaphthalen-4-yl)-n- propyl]piperazine (example 8) ; - 4-[3-8-methoxy-l,2-dihydronaphthalen-4-yl)-n-propyl]-l-(2- methoxyphenyl)-piperazine (example 9); - 4-[3-(8-methoxy-l,2-dihydronaphthalen-4-yl)-n-propyl]-l-(2- pyridyl)-piperazine (example 12); - 4-[3~(1,2-dihydronaphthalen-4-yl)-n-propyl]-l-(2-methoxyphenyl)- piperazine (example 13); - l-(2-methoxyphenyl)-4-[3-(7-methoxy-l,2,3,4- tetrahydronaphthalen-1-yl)-n-propyl]piperazine (example 14) ; 1-(2-methoxyphenyl)-4-[3-(5-methoxy-l,2,3,4- tetrahydronaphthalen-1-yl)-n-propyl]-piperazine (example 17) ; - 4-[3-(5-methoxy-l,2,3,4-tetrahydronaphthalen-1-yl)-n-propyl]-l- (2-pyridyl)-piperazine (example 18) ; - 4-[4-(6-methoxy-l,2-dihydronaphthalen-4-yl)-n-butyl]-l-(2- methoxyphenyl)-piperazine (example 22) ; - l-phenyl-4-[3-(5-πιethoxy-l,2,3,4-tetrahydronaphthalen-l-yl)-n- propyl]-piperazine (example 16); - 4-[3-(7-methoxy-l,2,3,4-tetrahydronaphthalen-1-yl)-n-propyl]-1- (2-pyridyl)piperazine (example 19); - l-(2-methoxyphenyl)-4-[3-(4,5.6,7 _ tetrahydrobenzo[b]thien-4- yl)-n-propyl]piperazine (example 20); - l-(2-methoxyphenyl)-4-[3-(1,2,3.4-tetrahydronaphthalen-l-yl)-n- propyl]piperazine (example 21); - 1-(2-methoxyphenyl)-4-[4-(7-methoxy-l,2,3,4- tetrahydronaphthalen-l-yl)-n-butyl]-piperazine (example 23); - l-(2-methoxyphenyl)-4-{2-[(7-methoxy-l,2,3,4-tetrahydro- naphthalen-l-yl)-thio]-ethyl}piperazine (example 24); _ 4-[l-(8-methoxy-l,2,3,4-tetrahydronaphthalen-4-yl)l-propylen-3- yl]-l-(2-methoxyphenyl)piperazine (example 25); - 4-[1-(8-methoxy-l,2,3,4-tetrahydronaphthalen-4-yl)-1-propylen- 3-yl]-l-(2-pyridyl)piperazine (example 26); -1-(2-methoxyphenyl)-4-[(1,2,3,4-tetrahydronaphthalen-4-yl)-1- propylen-3~yl]piperazine (example 27) . In particular as one can realize from what above stated, being in any case easily deducible from the data reported in tables 1-3 reported hereinbelow, some of these compounds may be advantageously utilized contemporaneously for the therapy of generalized anxiety, schizophrenia and arterial hypertension. These compounds are in particular : - 4-[3-8-methoxy-l,2-dihydronaphthalen-4-yl)-n-propyl]-l-(2- methoxyphenyl)-piperazine (example 9); - 4-[3~(1,2-dihydronaphthalen-4-yl)-n-propyl]-l-(2-methoxyphenyl) ■ piperazine (example 13) ; - l-(2-methoxyphenyl)-4-[3-(7-methoxy-l,2,3.4- tetrahydronaphthalen-l-yl)-n-propyl]piρerazine (example 14); - 1-(2-methoxyphenyl)-4-[3-(5-methoxy-l,2,3.4- tetrahydronaphthalen-l-yl)-n-propyl]-piperazine (example 17); - 4-[4-(6-methoxy-l,2-dihydronaphthalen-4-yl)-n-butyl]-l-(2- methoxyphenyl)-piperazine (example 22); - l-phenyl-4-[3-(5-methoxy-l,2,3,4-tetrahydronaphthalen-l-yl)-n- propyl]-piperazine (example 16) ; - l-(2-methoxyphenyl)-4-[3(4,5.6,7 _ tetrahydrobenzo[b]thien-4-yl)- n-propyl]piperazine (example 20) ; - 1-(2-methoxypheny1)-4-[3-(l,2,3,4-tetrahydronaphthalen-1-yl)-n- propyl]piperazine (example 21); - 1-(2-methoxyphenyl)-4-[4-(7-methoxy-l,2,3,4- tetrahydronaphthalen-l-yl)-n-butyl]-piperazine (example 23); - l-(2-methoxyphenyl)-4-{2-[(7-methoxy-l,2,3,4- tetrahydronaphthalen- l-yl)-thio]-ethyl}piperazine (example 24); - 4-[1-(8-methoxy-l,2,3,4-tetrahydronaphthalen-4-yl)-l-propylen-3- yl]-l-(2-methoxyphenyl)piperazine (example 25); - 1-(2-methoxyphenyl)-4-[ (1,2,3,4-tetrahydronaphthalen-4-yl)-1- propylen-3~yl]piperazine (example 27) . N-aminoalkylpiperazine of formula (III) (III) is prepared by reacting previously mentioned N-arylpiperazine (VII) with nitrile bromide of formula (XII) NC-fCH^-^-Br in the presence of a polar solvent and of a weak base thereby obtaining the intermediate (XIII) which is on its turn treated with lithiumaluminumhydride in an ethereal solvent to obtain finally the desired intermediate (III) . The following examples are reported for illustrative, but not limitative purposes of the present invention. EXAMPLE 1 1-(2-methoxyphenyl)-4-fN-(5~π-βthoxy-l,2,3,4-tetrahydronaphtalen- l-yl)-2-aminoethyl]piperazine . Brcmoacetonitrile (10 mmoles) and sodium bicarbonate (10 mmoles) were added to l-(2-methoxyphenyl)piperazine (10 mmoles) solubilized in 0 ml benzene. The mixture is kept under reflux for about 1 hour. Then it is cooled, filtered and washed with ether and the organic phase is brought to dryness at reduced pressure. A dark yellow oil is obtained (yield 80% ) composed by N-cyanomethyl-N-aryl-piperazine that, without purification is dissolved in anhydrous diethyl ether. LiAlH /j (10 mmoles) are added to the solution. The mixture is left under reflux for 1 hour, then it is cooled and the excess of hydride is destroyed by adding some drops of water. The mixture is then filtered, brought to dryness under reduced pressure and a colourless oil composed by N(aminoethyl)-N-arylpiperazine is obtained (yield 90?-), which is purified by column chromatography. The product coming from this purification (10 mmoles) is dissolved in anhydrous toluene and reacted with 5 _ ∞ethoxy-l- tetralone (11 mmoles) in the presence of a catalytic amount of p- toluensulfonic acid. The mixture is kept under reflux for about one hour, then it is cooled, the solvent is evaporated under reduced pressure and the residue is immediately dissolved in anhydrous ethanol. NaBH/ j (20 mmoles) is added to the solution that is then left under stirring for about 2 hours. The solvent is evaporated under reduced pressure and the residue is purified by column chromatography. The desired compound is obtained in the form of a dark yellow oil (yield 6 ?-). MS, m/z (rel. range): 395,20 (M+; 1,7); 206,20 (45,6); 205,10 (100,0); 190,10 (37.8); 177.10 (21,4); 175,10 (23,1); 162,10 (25,7); 161,10 (47,5). 1H-NMR (200 MHz.CDCl^), ό(ppm): 1,66-2,07 (m,4H,CH 2 CH 2 endocyclic) ; 2,17 (broadened s ,1H,exchanges with D 2 0,NH) ; 2,46- 2,93 [m,10H,CH 2 benzyl, NCH 2 CH 2 N(CH 2 ) 2 ] ; 3,08 [s broad.,4H, (CH 2 ) 2 NAr]; 3,75-3.83 (m+s,4H,CHN,CH 3 ) ; 3,85 (s,3H CHg); 6,65- 7,18 (m,7H, aromatic). Hydrochlorate: m.p. 223-224 °C. EXAMPLE 2 4-[3~(6-methoxy-l,2-dihydronaphthalene-4-yl)-n-propyl1-1-(2- methoxyphenyl)piperazine. 7-methoxy-l-tetralone (6 mmoles) solubilized in tetrahydrofuran (10 ml) are added to a solution of cyclopropylmagnesium bromide (9 mmoles) dissolved in tetrahydrofuran. The mixture is left under reflux for about 1 hour. Then it is cooled and a solution saturated by ammonium chloride is added. The organic phase is washed with water, brought to dryness and a raw reaction product is obtained, composed mainly by l-cyclopropyl-7-methoxy-l,2,3,4- tetrahydronaphthalen-1-ol, in the form of a dark oil. The mixture is directly treated with a solution of HCl in diluted acetic acid and it is kept at room temperature for about 2 hours, then is treated with alkali and extracted with CHCl . The solvent is evaporated and the dark oil obtained is purified by column chromatography; a product composed by 4-(3~ chloropropyl)-6-methoxy-l,2-dihydronaphthalene intermediate (VI) with p = 1 is obtained (total yield 64?-). l-(2-methoxyphenyl)piperazine (3-5 mmoles) is added to the compound (VI) (3-5 mmoles) dissolved in dimethylformamide (10 ml) in the presence of Nal (catalytic amount) and sodium carbonate (3-5 mmoles). The mixture is left under reflux for 1 hour then it is cooled and, after evaporating the dimethylformamide, it is diluted with H 2 0 and extracted with CHClo. By solvent evaporation a residue is obtained, which after chromatography on column provides the product in the form of a yellow oil in a 80$ yield. MS, m/z (rel. range): 394,25 (M++2; 4,0); 393,25 (M++1; 27,1); 392,25 (M+, 100,0); 205,10 (20,9); 203,10 (24,9). 1H-NMR (200MHz,CDC1 3 ), δ(ppm): 1,70-1,88 (m,2H,CH 2 CH 2 CH 2 ) ; 2,15- 2,29 (m,2H,CH 2 endocyclic) ; 2,40-2,55 (m,4H, CH 2 CH 2 CH 2 N) ; 2,66 [broadened t,6H,CH 2 benzilic,CH 2 N(CH 2 ) 2 ]; 3,11 [broad, s ,4H, (CH 2 ) 2 NAr]; 3.80 (s,3H), 3.85 (s,3H), (2 CH 3 ); 5,90 (t.lH, J=4,5 Hz, H vinilic); 6,63-7,10 (m,7H,arom. ) . Hydrochlorate : m.p. 180-182 °C. EXAMPLE 3 l-phenyl-4-[3~(6-methoxy-l,2-dihydronaphthalen-4-yl)-n-propyl]- piperazine The same process described in Example 2 is followed with the only difference that in this case 1-phenyl piperazine is used. MS, m/z (rel. range): 364,25 (M++2; 3,3); 363,25 (M++1; 25,9); 362,25 (M + ; 100,0); 175,10 (34,1); 173,10 (32,1); 132,10 (25,8). 1H-NMR (200MHz,CDClj), δ(ppm): 1,69-1,87(m,2H,CH 2 CH 2 CH 2 ) ; 2,l6- 2,30 (m,2H,CH 2 endocycl.); 2,47 (t,4H, J=7,7Hz, C 2 CH 2 CH 2 N) ; 2,57-2,74 [m,6H,CH 2 benz., CH 2 N(CH 2 ) 2 ]; 3,18-3,27 [ dt,4H, (CH 2 ) 2 NAr]; 3,81(s,3H,CH 3 ) ; 5,90 (t.lH, J=4,5 Hz.H vin.); 6,65- 7,33 (m,8H,arom.). Hydrochlorate: m.p. 175-177 °C. EXAMPLE 4 1-(3-chlorophenyl)-4-[3~(6-methoxy-l,2-dihydronaphthalen-4-yl)-n- propyl1-piperazine The same process described in Example 2 is followed with the only difference that in this case l-(3 _ chlorophenyl)-piperazine is used. MS, m/z (rel. range): 400,15 (M++4; 1,0); 399,15 ( ++3; 8,2); 398,15 (M++2; 35.2); 397,15 (M++1; 30,7); 396,15 (M+; 100,0); 209,10 (59,3); 207,00 (32,4); 166,00 (26,5). 1H-NMR (200MHz,CDC1 3 ), δ(ppm) : 1,67-1,86 (m,2H,CH 2 CH 2 CH 2 ) ; 2,16- 2,30 (m,2H,CH 2 endoc); 2,38-2,53 (m,4H,CH 2 CH 2 CH 2 N) ; 2,54-2,74 [m,6H,CH 2 benz. ,CH 2 N(CH 2 ) 2 ]; 3,14-3,26 [m,4H, (CH 2 ) 2 NAr]; 3.80 (s,3H,CH 3 ); 5,90 (t.lH, J=4,5 Hz,H vin.); 6.65-7-20 (m,7H,arom. ) . Hydrochlorate: m.p. 184-185 ° C. EXAMPLE 4-[3-(6-methoxy-l,2-dihydronaphthalen-4-yl)-n-propyl1-1-(3- trifluoromethylphenyl)piperazine The same process described in Example 2 is followed with the only difference that in this case 1-(3~trifluoromethylphenyl)- piperazine is used. MS, m/z (rel. range): 432,2 (M++2; 3,9); 431,25 (M++1; 26,3); 430,25 (M+; 100,0); 256,10 (20,0); 243,10 (69,0); 24l,10 (33,9); 200.00 (45,1); 172,10 (23,9). 1H-NMR (200MHz,CDC1 3 ), δ(ppm) : 1,69-1,87 (m,2H,CH 2 CH 2 CH 2 ) ; 2,16- 2,30 (m,2H,CH 2 endoc); 2,41-2,54 (m,4H,CH 2 CH 2 CH 2 N) ; 2,57-2,73 [m,6H,CH 2 benz.,CH 2 N(CH 2 ) 2 ]; 3,28 [t,4H, J=5,0 Hz, (CH 2 ) 2 NAr]; 3,80 (s,3H,CH 3 ); 5,90 (t.lH, J=4,5 Hz.H vin.); 6,64-7,40 (m,7H,arom. ) . Hydrochlorate: m.p. 189-190 °C . EXAMPLE 6 4-f3-(6-methoxy-l,2-dihydronaphthalen-4-yl)-n-propyl]-1-(2- pyridyl)piperazine The same process described in Example 2 is followed, with the only difference that in this case 1-pyridylpiperazine is used. MS, m/z (rel. range): 36 , 5 (M++2; 2,0); 364,25 (M++1; 16,0); 363,25 (M+; 62,5); 256,10 (38,6); 244,10 (47,3); 121,10 (36,4); 107,10 (100,0); 72,05 (39.7). 1H-NMR (200MHz,CDC1 3 ), δ(ppm) : 1,70-1,90 (m,2H,CH 2 CH 2 CH 2 ) ; 2,13- 2,28 (m,2H,CH 2 endoc); 2,38-2,54 (m,4H,CH 2 CH 2 CH 2 N) ; 2,54-2,74 [m,6H,CH 2 benz.,CH 2 N(CH 2 ) 2 ]; 3,58 [t,4H, J=5,l Hz, (CH 2 ) 2 NAr]; 3,78 (s,3H,CH 3 ); 5.88 (t.lH, J=4,5 Hz.H vin.); 6,55"7,52 (m,6H,arom.); 8,12-8,21 (m,lH,N=CH arom. ) . Hydrochlorate: m.p. 225-226 °C. EXAMPLE 7 1-(2,5-dimethoxyphenyl)-4-[3~(6-methoxy-1,2-dihydronaphthalen-4- yl)-n-propyl1-piperazine The same process described in Example 2 is followed, with the only difference that in this case 1-(2, -dimethoxyphenyl) - piperazine is used. MS, m/z (rel. range): 424,25 (M++2; 4,1); 423,25 (M++1; 27,4); 422,25 (M+; 100,0). 1H-NMR (200MHz,CDC1 3 ), δ(ppm): 1,72-1,91 (m,2H,CH 2 CH 2 CH 2 ) , 2,l4- 2,28 (m,2H,CH 2 endoc); 2,39-2,83 [m,10H,CH 2 benz., CH 2 CH 2 CH 2 N(CH 2 ) 2 ]; 3,12 [ broad, s ,4H, (CH 2 ) 2 NAr] ; 3,75. 3.79. 3.80 (3S.9H.3 CH 3 ); 5.89 (t.lH, J=4,6 Hz.H vin.); 6,43-7.12 (m,6H, arom. ) . Hydrochlorate: m.p. 192-193 °C. EXAMPLE 8 l-phenyl-4-[3-(8-methoxy-l,2-dihydronaphthalen-4-yl)-n-propyl] piperazine The same process described in Example 2 is followed, with the only difference that in this case 5-methoxy-tetralone and 1- phenyl-piperazine are used. MS, m/z (rel. range) : 364,25 (M++2; 3.4); 363. 5 (M++1; 25,3); 362,25 (M+; 100,0); 175,10 (36,8); 173,10 (30,3); 132,10 (26,5). 1H-NMR (200MHz,CDC1 3 ) δ(ppm): 1,68-1,87(m,2H,CH 2 CH 2 CH 2 ) ; 2,15- 2,29 (m,2H,CH 2 endoc); 2,48 (t,4H, J=7,6 Hz,CH 2 CH 2 CH 2 N) ; 2,58- 2.81 [m,6H,CH 2 benz.,CH 2 N(CH 2 ) 2 ]; 3,15-3,29 [m,4H, (CH 2 ) 2 NAr]; 3.83 (s,3H,CH 3 ); 5.89 (t.lH, J=4,5 Hz.H vin.); 6,75"7.35 (m,8H,arom. ) . Hydrochlorate: m.p. 174-176 °C. EXAMPLE 9 4-[3-(8-methoxy-l,2-dihydronaphthalen-4-yl)-n-ρropyll-l-(2-me- thoxyphenyl)piperazine The same process described in Example 8 is followed, with the only difference that in this case l-(2 methoxyphenyl)-piperazine is used. MS, m/z (rel. range): 394,25 (M + +2; 4,2) 393.25 (M + +l; 27.0); 392.25 (M + ; 100,0); 205,05 (25,6); 203,15 (24,6). 1 H-NMR (200MHz, CDClj), δ (ppm) : 1,71-1,88 (m,2H,CH 2 CH 2 CH 2 ) ; 2,13-2,27 (m,2H,CH 2 endpc); 2,42-2,58 (m,4H,CH 2 CH 2 CH 2 N) ; 2,62- 2,84 [m,6H,CH 2 benz.,CH 2 N(CH 2 ) 2 ]; 3,12[broad.t,4H, (CH 2 ) 2 NAr]; 3.82 (s.3H), 3.85 (s.3H). (2CH 3 ); 5,88 (t.lH, J=4,5Hz, H vin.); 6,75-7,20 (m,7H,arom.). Hydrochlorate: m.p. 209"21O°C. EXAMPLE 10 l-(3-chlorophenyl)-4-[3-(8-methoxy-l,2-dihydronaphthalen-4-yl)-n- propylIpiperazine The same process described in Example 8 is followed, with the only difference that in this case l-(3~chlorophenyl)-piperazine is used. MS, m/z (rel. range) : 400, 15 (M++ ; 1 , 1 ) ; 399,15 (M++3; 8,3) 398,15 (M++2; 34,2); 397,15 (M++1; 30,4); 396,15 (M÷; 100,0) 222,00 (23,6); 211,10 (21,2); 209,00 (76,2); 207,00 (30,4) 166,00 (33,6). 1H-NMR (200MHz,CDC1 3 ), δ(ppm) : 1,66-1,85 (m,2H,CH 2 CH 2 CH 2 ) ; 2,13- 2,28 (m,2H,CH 2 endoc); 2,39-2,80 (m,10H,CH 2 benz.,CH 2 CH 2 CH 2 N(CH 2 ) 2 ]; 3,21 [broad.t ,4H, (CH 2 ) 2 NAr]; 3,83 (s,3H, CH 3 ); 5,87 (t.lH, J=5,0 Hz, H vin.); 6,71-7,21 (m,7H,arom. ) . Hydrochlorate: m.p. 190-192 °C. EXAMPLE 11 4-[3-(8-methoxy-l,2-dihydronaphthalen-4-yl)-n-propyl]-l-(3- trifluoromethylphenyl)piperazine The same process described in Example 8 is followed with the only difference that in this case l-(3-trifluoromethylpiperazine) is used. MS, m/z (rel. range): 432,25 (M++2; 2,9); 431,25 (M++1; 21,5); 430,25 (M+; 79,4); 256,10 (32.0); 243.00 (100,0); 241,00 (35.D 5 200,00 (56,4); 172,00 (20,1). 1H-NMR ( 200MHz, CDC1 3 ) , δ(ppm) : 1 ,73-1 ,91(m,2H,CH 2 CH 2 CH 2 ) ; 2,14- 2,28 (m,2H,CH 2 endoc); 2,42-2,82 (m,10H,CH 2 benz. CH 2 CH 2 CH 2 N(CH 2 ) 2 ]; 3.20-3,37 [m,4H, (CH 2 ) 2 NAr]; 3.83 (s,3H, CH 3 ) ; 5,89 (t.lH, J=4,5 Hz.H vin.); 6,75~7,42 (m,7H,arom. ) . Hydrochlorate: m.p. 1 -1 7 °C EXAMPLE 12 4-[3~(8-methoxy-l,2-dihydronaphthalen-4-yl)-n-propyl1-1-(2-pyri- dyl)piperazine The same process described in Example 8 is followed, with the only difference that in this case l-(2-pyridyl)piperazine is used. MS, m/z (rel. range): 365, 5 (M + +2;l,8); 364,25 (M + +l;l4,3); 363,25 (M + ;53,3); 256,25 (39,0); 244,25 (46,1); 121,10 (34,0); 107.10 (100,0); 79.10 (23,0); 78,10 (20,6); 72,10 (35.9). 1 H-NMR (200MHz, CDClg), δ (ppm) : 1,67-1.86 (m, 2H,CH 2 CH 2 CH 2 ) ; 2,13-2,28 (m, 2H,CH 2 endoc); 2,40-2,63 [m,8H,CH 2 CH 2 CH 2 N(CH 2 ) 2 ]; 2,73 (t,2H, J=8Hz,CH 2 benz.); 3,50-3,62 [m,4H, (CH 2 ) 2 NAr]; 3,82 (s,3H,CH 3 ); 5.87 (t.lH, J=4,5Hz, H vin.); 6,58-7,52 (m, 6H arom); 8,16-8,23 (m,lH,N=CH arom.). Hydrochlorate: m.p. 218-220 ° C. EXAMPLE 13 4-[3~(1,2-dihydronaphthalen-4-yl)-n-propyl]-1-(2-methoxyphenyl) piperazine The same process described in Example 8 is followed, with the only difference that l-(2-methoxyphenyl)-piperazine is used. MS, m/z (rel. range): 364,25 (M + +2; 3,4); 363,2 (M + +1;27,D; 362,25 (M + ;100,0); 205,10 (3L3); 203,10 (30,4); 162,10 (22,9). ^-NMR (200MHz,CDC1 3 ), δ (ppm): 1,72-1,83 (m,2H,CH 2 CH 2 CH 2 ) ; 2,19- 2,28 (m,2H,CH 2 endoc); 2,43-2,55 (m,4H,CH 2 CH 2 CH 2 N) ; 2,62-2,78 [m,6H,CH 2 benz., CH 2 N(CH 2 ) 2 ]; 3,10 [broad.t, 4H, (CH 2 ) 2 NAr]; 3,84 (s,3H,CH 3 ); 5,87 (t.lH, J=4,5 Hz, H vin.); 6,82-7,27 (m,8H, arom . ) . Hydrochlorate: m.p. l85-lδ7°C. EXAMPLE 14 1-(2-methoxyphenyl)-4-f -(7~methoxy-l,2,3,4-tetrahydronaphthalen- l-yl)-n-propyl]piperazine l-[3"(6-methoxy-l,2-dihydronaphthalen-4-yl)-n-propyl]-4-(2-metho¬ xyphenyl)piperazine hydrochlorate (2 mmoles) obtained as described in Example 2, is solubilized in MeOH (30 ml) and hydrogenated in the presence of a catalytic amount of 10% Pd/C . After about 2 hours the mixture is filtered on Celite, the solvent is evaporated and the hydrochlorate salt of the desired product is obtained as a light yellow solid, that is crystallized from MeOH/Et 2 0 (yield 90%). Hydrochlorate: m.p. 203-205 °C, MS, m/z (rel. range): 396,35 (M++2; 3.3); 395.35 (M++1; 23,4); 394,35 (M+; 83,8); 205,10 (100,0); 192,10 (33,4); 150,10 (22,8). 1H-NMR (200MHz,CDC1 3 ) , δ(ppm): 1,54-1,90 (m,8H,CH 2 CH 2 endoc,CHCH 2 CH 2 CH 2 N); 2,46 [broad. t,2H,CH 2 N(CH 2 ) 2 ]; 2,62-2,84 [m,7H,CH and CH 2 benz. ,CH 2 N(CH 2 ) 2 ] ; 3,12 [broad. s,4H, (CH 2 ) 2 NAr]; 3.78 (s,3H), 3.86 (s,3H), (2CH 3 ); 6,63"7,07 (m,7H, arom. ) . EXAMPLE 15 4-[3-(7-methoxy-l,2,3,4-tetrahydronaphthalen-l-yl)-n-propyll-l- (3~trifluoromethylphenyl)piperazine The same process described in Example 14 is followed, starting from the hydrochlorate obtained in Example 5- Hydrochlorate: m.p. 150-152 C. MS, m/z (rel. range): 434,25 (M++2;2,4); 433.25 (M++1; 16,7), 432,25 (M+; 58,6); 243,10 (100.0); 230,10 (36,3). 1H-NMR (200MHz,CDC1 3 ) , δ(ppm): 1,53-1,92 (m,8H,CH 2 CH 2 endoc. ,CHCH 2 CH 2 CH 2 N) ; 2,36-2,83 [m,9H,CH and CH 2 benz., CH 2 N(CH 2 ) 2 ]; 3.25 [t,4H, J=4,9 Hz, (CH 2 ) 2 NAr]; 3.77 (s,3H,CH 3 ); 6,61-7,40 (m,7H,arom.) . EXAMPLE 16 l-phenyl-4-f3-(5-'nβthoxy-l,2,3,4-tetrahydronaphthalen-l-yl)-n- propyllpiperazine The same process described in Example 14 is followed, starting from the hydrochlorate obtained in Example 8. MS, m/z (rel. range): 366.30 (M++2; 2,8); 365.30 (M++1; 21,4); 364,30 (M+; 80,5); 175.15 (100,0); 162,05 (35.0). 1H-NMR (200MHz,CDC1 3 ) , δ(pρm): 1,54-1,90 (m,8H,CH 2 CH 2 endoc. ,CHCH 2 CH 2 CH 2 N) ; 2,38-2,85 [m,9H,CH and CH 2 benz., CH 2 N(CH 2 ) 2 ]; 3,24 [ broad t . ,4H, (CH 2 ) 2 NAr]; 3,81 (s,3H,CH 3 ); 6,62-7,35 (m,8H,arom.). Hydrochlorate: m.p. 206-207 ° C. EXAMPLE 17 l-(2-methoxyphenyl)-4-r3-(5~πιethoxy-l,2,3,4-tetrahydronaphthalen- l-yl)-n-propyllpiperazine The same process described in the Example 14 is followed, starting from the hydrochlorate obtained in Example ' . MS, m/z (rel. range): 396,30 (M++2; 3,3); 395.30 (M++1; 23,0); 394,30 (M+; 82,7); 205.10 (100,0); 192,10 (34,4); 150,10 (21,8). 1H-NMR (200MHz,CDC1 3 ) , δ(ppm): 1,53-1.89 (m,8H,CH 2 CH 2 endoc. ,CHCH 2 CH 2 CH 2 N) ; 2,38-2,87 [m,9H,CH and CH 2 benz., CH 2 N(CH 2 ) 2 ]; 3.13 [broad. s,4H, (CH 2 ) 2 NAr]; 3.8l (s,3H), 3.86 (s,3H), (2 CH 3 ); 6,62-7,17 (m,7H, arom.). Hydrochlorate: m.p. 206-207 ° C EXAMPLE 18 4 - f ~ ( 5 -me thoxy- 1,2,3.4- tetrahydronaphthalen- 1 -yl ) -n-propyl ] - 1 - ( 2-ρyridyl ) piperazine The same process described in the Example 14 is followed, starting from the hydrochlorate obtained in Example 12. MS, m/z (rel. range ): 367,20 (M++2; 1,9); 366,20 (M++1; 13,8); 365,20 (M+; 50,8); 271,20 (29,5); 258,20 (87.0); 121,05 (32,6); 107,05 (100,0); 86,15 (22,4); 79.05 (25.6); 78,00 (22,4); 72,00 (37,6). 1H-NMR ( 200MHz, CDC1 3 ) , δ(ppm): 1,52-1,88 (m,8H,CH 2 CH 2 endoc ,CHCH 2 CH 2 CH 2 N) ; 2,38-2,85 (m,9H.CH and CH 2 benz., CH 2 N(CH 2 ) 2 ]; 3,59 [broad. t,4H, (CH 2 ) 2 NAr]; 3,80 (s,3H,CH 3 ); 6,58-7,52 (m,6H,arom.); 8,14-8,23 (m,lH,N=CH arom. ) . Hydrochlorate: m.p. 169- 171 °C. EXAMPLE 19 4-[3-(7-methoxy-l,2,3,4-tetrahydronaphthalen-l-yl)-n-propyl]-l-(2- pyridyl)piperazine The same process described in Example 14 is followed, starting from the hydrochlorate obtained in Example 12. MS, m/z (rel.range): 367.25 (M + +2;l,3); 366,25 (M + +l;9,6); 365. ( + ;39.7); 271.15 (21,7); 258,15 (60,1); 121,10 (31.7); 107,00 ( 100 , 00) ; 86 , 10 (24 , 6) ; 79.10 (20 , 7 ) ; 72 , 10 (48 , 0) . ^-NMR (200MHz , CDClj ) , δ (ppm) : 1 , 53-1 , 89 ( m , 8H , CH 2 CH 2 endoc , CHCH 2 CH 2 CH 2 N) ; 2,50 [broad, t, 2H,CH 2 N(CH 2 ) 2 ] ; 2,61-2,82 [m,7H,CH and CH 2 benz., CH 2 N(CH 2 ) 2 ]; 3.63 [broad. t,4H. (CH 2 ) 2 NAr]; 3,76 (s,3H,CH 3 ; 6,58-7,52 (m,6H,arom.); 8,15-8,21 (m,1N,N=CH arom. ) . Hydrochlorate: m.p. l43-l45°C. ESEMPIO 20 1-(2-methoxyphenyl)-4-[3-(4, , ,7~tetrahydrobenzo[b]thien-4-yl)- n-propyllpiperazine. The same process described in Example 14 is followed, starting from the hydrochlorate obtained in Example 9- MS, m/z (rel. range): 372,20 (M + +2;7,5); 371.20 (M + +l;25,0); 370,20 (M + ; 100,0); 205,05(59.4); 192,15(25.0); 150,05 (25,4). 1 H-NMR (200MHz, CDClj), δ (ppm): 1,42-2,01 (m,8H,CH 2 endoc, CHCH 2 CH 2 CH 2 N) ; 2,45 [t,2H, J=7,3Hz, CH 2 N(CH 2 ) 2 ] ; 2,61-2,81 [m,7H,CH and CH 2 benz., CH 2 N(CH 2 ) 2 ]; 3,12 [ broad, s, 4H, (CH 2 ) 2 NAr]; 3,86 (s,3H,CH 3 ); 6,82-7,05 (m,6H,arom. ) . Hydrochlorate: m.p. 217-218°C. EXAMPLE 21 1-(2-methoxyphenyl)-4-[3~(1,2, ,4-tetrahydronaphthalen-1-yl)-n- propyllpiperazine. The same process described in Example 14 is followed, starting from the hydrochlorate obtained in Example 9- MS, m/z (rel. range): 366,25 (M + +2;2,8): 365, 5 (M + +l;21,4); 364,25 (M + ;77,7) 205,5 (100,0); 192,15 (30,7); 150,05 (24,5); 91,05 (21,3). X H-NMR (200 MHz, CDClg) , δ (ppm): 1,54-1,92 (m,8H,CH 2 CH 2 endoc, CHCH 2 CH 2 CH 2 N) ; 2,45 [broad. t,2H,CH 2 N(CH 2 ) 2 ]; 2,62,-2,88 [m,7H,CH and CH 2 benz., CH 2 N(CH 2 ) 2 ]; 3,12 [broad.s, 4H, (CH 2 ) 2 NAr]; 3,86 (s,3H,CH 3 ); 6,82-7,21 (m, 8H, arom.). Hydrochlorate: m.p. 223-224 ° C. EXAMPLE 22 4-[4-(6-methoxy-l,2-dihydronaphthalen-4-yl)-n-butyl]-l-(2- methoxyphenyl)piperazine 7-methoxy-l-tetralone (6 mmoles) solubilized in tetrahydrofuran (10 ml) is added to a solution of 4-chloro-n-butylmagnesium bromide (9 mmoles) in tetrahydrofuran. The process is the same as that described in Example 2. Through the corresponding raw intermediate product (VI) wherein p = 2 the desired product is obtained, as an oil, in a total yield of 60 . MS, m/z (rel. range): 408,25 (M++2; 4,7); 407,25 (M++1; 29,2); 406,35 (M+; 99,9); 205,10 (22,9). 1H-NMR (200MHz,CDC1 3 ), δ(ppm): 1,50-1,73 (m,4H,CH 2 CH 2 CH 2 CH 2 N) ; 2,14-2,19 (m,2H,CH 2 endoc); 2,38-2,54 (m,4H, CH 2 CH 2 CH 2 CH 2 N) ; 2,61-2,80 [m,6H,CH 2 benz.,CH 2 N(CH 2 ) 2 ]; 3,12 [broad.t, 4H,(CH 2 ) 2 NAr]; 3,79 (s,3H), 3,86 (s,3H). (2 CH 3 ) ; 5,87 (t.lH, J= 5 Hz, H vin.); 6,64-7,09 (m, 7H, arom.). Hydrochlorate: m.p. 205 "C. EXAMPLE 23 1-(2-methoxyphenyl)-4-[4-(7-methoxy-l,2,3,4-tetrahydronaphthalen- l-yl)-n-butyllpiperazine Following the process described in Example 14 starting from the corresponding product described in previous Example 22, the desired product is obtained in a yield of ~ % . The following analyses are carried out on the free base: MS, m/z (rel. range): 410,35 ( ++2; 2,9.); 409,25 (M++1; 20,9); 408,25 (M+; 75,8); 205,10 (100,0). 1H-NMR (200MHz,CDC1 3 ), δ(ppm): 1,30-1,92 (m,10H,CH 2 CH 2 endoc, CH 2 CH 2 CH 2 CH 2 N) ; 2,44 [t,2H, J=7 , 6 Hz ,CH 2 N(CH 2 ) 2 ] ; 2,62-2,83 [m,7H,CH and CH 2 benz. ,CH 2 N(CH 2 ) 2 ]; 3,18 [broad s. ,4H, (CH 2 ) 2 NAr]; 3.78 (s,3H), 3,86 (s,3H), (2 CH 3 ); 6,63~7,02 (m, 7H, arom.). Hydrochlorate: m.p. 192-193 °C. EXAMPLE 24 l-(2-methoxyphenyl)-4-{2-[ (7-methoxy-l,2,3.4-tetrahydro- naphthalen-l-yl)-thio]-ethyl}piperazine. Ethyl 2-mercapto-acetate (6 mmoles) and ZnI- > (3 mmoles) are added to a solution of 7-metnoxy-l-tetralol (6 mmoles) (prepared according to a known method from 7-methoxy-l-tetralone) in CH 2 C1 2 (12 ml). After two hours under stirring the reaction mixture is poured into water and extracted with CH 2 C1 2 . The extracted solution is dried on Na 2 S0i and the solvent is evaporated, thereby obtaining a yellow oil composed by practically pure ethyl 2-[(7-methoxy-l,2,3,4-tetrahydronaphthalen-l-yl)-thio]-acetate (yield 38% ) . This product is directly hydrolyzed with KOH in a hydroalcoholic solution at the boiling temperature. After cooling, a minimum amount of water is added and the mixture is concentrated. The mixture is thereby acidified with HCl and extracted with Et 2 0. After solvent evaporation a light yellow solid is obtained that is crystallized from cyclohexane. The corresponding product belonging to type F is prepared in this way in a yield of 89-. 2-[(7-ωethoxy-l,2,3,4-tetrahydronaphthalen-l-yl)-thio]-acetic acid (5 mmoles) is treated with - ml S0C1 2 and heated under vacuum in a rotavapor and brought to dryness. The obtained raw oil, composed by the chloride of the corresponding acid is dissolved in toluene (20 ml) and left to react under reflux with a solution of 1- (2-methoxyphenyl)- piperazine (8 mmoles) in toluene (30 ml) in the presence of trimethyl amine (10 mmoles). After 2 hours the reaction mixture is washed with H 0 and with HCl 2N. The organic phase, dried and evaporated, brings to an oily residue that is purified by chromatographic column. The corresponding 4-(2-methoxyphenyl)piperazinamide of the above mentioned acid is thereby obtained as a yellow brown oil in a yield of 47%. This amide (2 mmoles) dissolved in tetrahydrofuran (20 ml) is added drop by drop to a suspension of LiAlH^ (100 mg) in 30 ml tetrahydrofuran under stirring. The mixture is kept at the boiling temperature for 6 hours, then it is cooled and few drops of H 2 0 are added, then the usual process is followed thereby obtaining a light yellow oil in a yield of 83%. The product is then transformed into the corresponding hydrochlorate and crystallized from CHCl /petroleum ether, m.p. 200-201 °C. The following analyses are carried out on the free base: MS, m/z (rel. range): 4l4,25 (M++2; 1,4); 413,25 (M++1; 4,7); 412,35 (M+; 17,4); 219,20 (24,0); 205,10 (100,0); 190,10 (29,5). 1H-NMR (200 MHz,CDCl 3 ), δ(ppm) : 1,67-2,10 (m,4H,CH 2 CH 2 endoc); 2,56-2,85 [m,10H,CH 2 benz. ,SCH 2 CH 2 N(CH 2 ) - W ' 3,10 [broad t,4H,(CH 2 ) 2 NAr]; 3,78 (s,3H), 3.86 (s,3H), (2 CH 3 ); 4,12 (t.lH, J=4 Hz, CHS); 6,67-7,04 (m,7H,arom.). EXAMPLE 2 4-T1-(8-methoxy-l,2,3,4-tetrahydronaphthalen-4-yl)-l-propylen-3~ yl]-1-(2-me hoxyphenyl)piperazine 8-methoxy-l-tetralone (6 mmoles) solubilized in tetrahydrofuran (10 ml) are added to a solution of cyclopropylmagnesium bromide (9 mmoles) dissolved in tetrahydrofuran (10 ml), and left under reflux for about 1 hour. The mixture is cooled and a solution saturated by ammonium chloride is added. The organic phase is washed with water, brought to dryness and a raw reaction product mainly composed by l-cyclopropyl-8-methoxy-l, 2, 3, 4-tetrahydronaphthalen-l-ol, is obtained under the form of a dark oil. The mixture is directly treated with a HCl solution in diluted acetic acid. The mixture is thereby kept at room temperature for 1 hour, then it is treated with alkali and extracted with CHClo. The solvent is evaporated and a dark oil is obtained, which is purified by column chromatography; the product recovered in a total yield of 64% is composed by 4-(3 _ chloro-l-propylen-l-yl)-8- methoxy-l,2,3,4-tetrahydronaphthalene intermediate (VI a) with P=l. 1- (2-methoxyphenyl ) piperazine ( 3 « 5 mmoles ) are added to a dimethylformamide solution ( 10 ml) of the compound (VI A) (3-5 mmoles ) in the presence of Nal ( catalytic amount ) of Sodium Carbonate (3 - 5 mmoles ) . The mixture is kept under reflux for 1 hour, then it is cooled and after evaporating dimethylformamide, the residue is added with water and extracted with CHClo . After evaporating the solvent the obtained residue is purified by column chromatography thus obtaining the desired product in the form of a light yellow oil (yield 82 %) . MS, m/z (rel. range): 393.25 (M + +l;2,0) ;392,25 (M + ;7.1); 205,10 (100,0). 1 H-NMR (200MHz, CDClg), δ (ppm): 1,82 (m,2H,CH 2 endoc ) ; 2,42-2,65 (m,6H,CH 2 C=CHCH 2 CH 2 N); 2,67-2,85 [m,6H,CH 2 benz. , CH 2 N(CH ) 2 ]; 3,15 (broad, s, 4H(CH 2 ) 2 NAr]; 3,81 and 3.86 (2s,6H,2CH 3 ) ; 6,00 (broad, s, 1H, H vin.); 6,65~7,22 (m,7H,arom. ) . Hydrochlorate: m.p. 202-203°C. EXAMPLE 26 4-[l-(8-methoxy-l,2,3.4-tetrahydronaphthalen-4-yl)-l-propylen-3- yll-l-(2-pyridyl)piperazine. The same process described in Example 25 is followed starting from the hydrochlorate obtained in Example 12. MS, m/z (rel. range): 3 3, (M + :3,6); 176,10 (100,0); 147,10 (23,6); 121,10 (35,9). ^ ■ H-NMR (200 MHz, CDClj), δ (ppm): 1,82 (m,2H,CH 2 endoc); 2,37- 2,66 [m,10H,CH 2 C=CHCH 2 CH 2 N(CH 2 ) 2 ]; 2,71 (t, 2H, J=6, 3Hz, CH 2 benz.); 3,49~3,62 [m,4H, (CH 2 ) 2 NAr]; 3,81 (s,3H,CH 3 ,6,00 (broad. t, 1H, H vin.); 6,56-7.53 (m,6H,arom. ) ; 8,14-8,25 (m,lH,N=CH arom) . Hydrochlorate: m.p. 221-222°C. EXAMPLE 27 1-(2-methoxyphenyl)-4-[1,2,3,4-tetrahydronaphthalen-4-yl)-1- propylen-3~yl]piperazine. The same process described in Example 2 is followed starting from the hydrochlorate obtained in Example 9- MS, m/z (rel. range): 363,20 (M + +l;l,4) ; 362,20 (M + ;5,5); 205,05 (100,00); 190,05 (21,6). ^ ■ H-NMR (200 MHz, CDClg) , δ (ppm): 1,82 (m,2H,CH 2 endoc); 2,40- 2,60 (m,6H,CH 2 C=CHCH 2 CH 2 N) ; 2,64-2,80 [m,6H, CH 2 benz., CH 2 N(CH 2 ) 2 ]; 3,12 [broad.s,4H, (CH 2 ) 2 NAr]; 3,85 (s,3H,CH 3 ); 6,00 (broad.t, 1H, H vin.); 6,83-7,62 (m.δH.arom. ) . Hydrochlorate: m.p. 19δ-199°C. BIOCHEMICAL AND PHARMACOLOGICAL TRIALS Preparation of rat cerebral tissue homogenate for receptorial binding experiments. Preparation 1, utilized for binding trial at the receptors: 5-HT1A, 5-HT1B, 5-HT1C, 5-HT2, D-2, D-l, α-1. Cerebral tissue asported from male rats (Sprague Dawley) weighing 180-220 g is homogenized in Tris. HCl buffer, 50 mM, pH 7.4 with Ultra-Turrax (2 x 20 sees) and centrifugated at 50.000 g for 10 min.. The obtained pellet, resuspended in the same volume of buffer, incubated at 37 °C for 10 minutes [Nelson, Mol . Pharmacol. 14, 983, (1978)], is centrifugated again in the above mentioned conditions. The final pellet is dissolved in the appropriate incubation buffer just before the receptorial binding test. Preparation 2, used for binding trial at the σ receptor. Cerebral tissue of male Hattly cavy (Charles River) weighing 300- 600 g is homogenized in 0.32 M saccarose with Ultra-Turrax (2 x 20 sec.) and centrifugated at 900 g for 10 minutes. The surnatant is centrifugated at 22.000 g for 20 minutes. The obtained pellet, dissolved in Tris.HCl buffer pH = 7.4 is incubated at 37 °C for 30 minutes and centrifugated at 22.000 g for 20 minutes. The final pellet is dissolved in the appropriate incubation buffer just before the test. 2. Operating conditions for the receptorial binding trials. 5-HT1A Receptor. The methodology described by J.R. Schlegel, Biochem. Pharmacol. 35, 19 3, (1986) is essentially used. In short, rat cerebral cortex homogenate is dissolved in the incubation buffer (Tris.HCl 50 mM, pH = 7.7 containing 10 μM of pargyline, 4 mM CaCl 2 , 0.1% ascorbic acid) and incubated in the final volume of 1 ml, at 25 °C, for 30 minutes in the presence of 3H-80H-DPAT (0.1 nM). The aspecific bond is evaluated by the use of 5-HT (10 μM). 5-HT1B Receptor. The methodology described by S.J. Peroutka, J. Neurochem. 47, 529, (1986) is essentially used. In short, rat cauda striati homogenate is dissolved in the incubation buffer (Tris.HCl 50 mM, pH = 7.7 containing 10 μM of pargyline, 4 mM CaCl 2 , 0.1% of ascorbic acid) and incubated in the final volume of 1 ml at 25 °C for 30 minutes in the presence of 3H-5HT (2.0 nM) and 80H-DPAT (0.1 μM) as the blocking agent of 5-HT1A receptors. The aspecific bond is evaluated by the use of 5-HT (10 μM). 5-HT1C Receptor. The methodology described by S.J. Peroutka, J. Neurochem. 47, 529. (1986) is essentially used. In short, rat cerebral cortex homogenate is dissolved in the incubation buffer (Tris. HCl 50 mM, pH = 7.7 containing 10 μM pargyline, 4mM CaCl 2 , 0.1% ascorbic acid) and incubated in the final volume of 1 ml, at 2 °C, for 1 minutes in the presence of 3H-5HT (2.0 nM) and 80H-DPAT (0.1 μM) and RU-24960 (lOnM) as the blocking agents respectively of 5-HT1A and 5-HT1B receptors. The aspecific bond is evaluated by the use of 5-HT (10 μM) . 5-HT2 Receptor. The methodology described by A.K.Mir, Eur. J. Pharmacol. 149, 107, (1988) is essentially used. In short, rat frontal cortex homogenate is dissolved in the incubation buffer (Tris.HCl 50 mM, pH = 7.7) and incubated in the final volume of 1 ml, at 37 °C, for 15 minutes in the presence of 3H-Ketanserine (0.35 nM ) • The aspecific bond is evaluated by the use of methysergide (1 μM) . D-1 Receptor. The methodology described by W.B. Billard, Life Science, 35. 1885, (1984) is essentially used. In short, rat cauda striati homogenate is dissolved in the incubation buffer (Tris. HCl 50 mM, pH = 7.4 containing 120 mM of NaCl, 5 mM of KCl, 2mM of Ca ' Cl 2 , ImM of MgCl 2 ) and incubated in the final volume of 1 ml at 37 °C, for 15 minutes in the presence of 3H-SCH-23390 (0.3 nM) . The aspecific bond is evaluated by the use of SCH-2339O (1 μM). D-2 Receptor. The methodology described by I. Creese, Eur. J. Pharmacol. 49, 201, (1978) is essentially used. In short, rat cauda striati homogenate is dissolved in the incubation buffer (Tris.HCl 50 mM, pH = 7.4 containing 120 mM NaCl, 5 mM KCl, 2 mM CaCl 2 , 1 M MgCl 2 ) and incubated in the final volume of 1 ml, at 37 °C for 15 minutes in the presence of 3H-Spiroperidole (0.25 mM) and Ketanserine (40 nM) as blocking agent of 5"HT2 receptors. The aspecific bond is evaluated by the use of Butaclamol (10 μM) . α-1 Receptor. The methodology described by A.K.Mir, Eur. J. Pharmacol. 149, 107, (1988) is essentially used. In short, rat cerebral cortex homogenate is dissolved in the incubation buffer (Tris.HCl 50 mM, pH = 7.7 containing 10 μM pargyline, 0.1% ascorbic acid) and incubated in the final volume of 1 ml at 25 °C for 30 minutes in the presence of 3H-Prazosin (0.2 nM) . The aspecific bond is evaluated by the use of Prazosin (3 μM). σ Receptor. The methodology described by E.Weber, Proc Natl. 5 Acad. SCI. USA 83, 8784, (1986) is essentially used. In short, rat brain deprived of the cerebellum is homogenized and then dissolved in the incubation buffer (Tris.HCl 50 mM, pH = 7.4) and incubated in the final volume of 1 ml, at 25 °C, for 90 minutes in the presence of 3H-DTG (0.9 nM) . The aspecific bond is ° evaluated by the use of Haloperidol (1 μM) . 3. Behaviouristic experiments. 5-HT1A activity evaluation "in vivo". The compounds under question are analyzed by using the method described by Tricklebank [Eur. J. Pharmacol., 106, 271 (1985)]. 5 The compounds under question are administered subcutaneously to male rats (S.D.) treated with reserpine (1 mg/Kg) 18 hours before the test. The evaluation of the behaviour starts 3 minutes after the administration of the compounds under question and continue for 0 the following 30 minutes. The behaviour intensity is evaluated every 3 minutes by the use of a scale that assign the following scores to the two specific behaviours named "Flat body posture" and "Forepaw Treading": 0: absence of behaviouristic effects. 5 1: presence of ambiguous behaviouristic signs. 2: presence of evident behaviouristic effects. 3: presence of intense behavioural effects. The possible agonistic activity of the products under question is evaluated every 3 minutes for 30 minutes after their administration. The antagonist activity on the stereotypy induced by 80H-DPAT (0.125 mg/Kg, s.c) is evaluated every 3 minutes from 30 to 60 minutes after the administration of the products under question starting from 3 minutes after the administration of 80H-DPAT. The results of the above mentioned trials are reported in the following Tables 1,2 and 3> TABLE 2 EXAMPLES INHIBITION OF THE STEREOTYPY FROM 80H-DPAT DE50 (mg/kg s.c.) EXAMPLE 1 2.13 EXAMPLE 2 0.76 EXAMPLE 11 24.19 EXAMPLE 14 O.87 EXAMPLE 17 < 0.10 EXAMPLE 26 < 0.10 TABLE 3

Claims: CLAIMS l.N(hetero)-aryl-N(hetero)-tetralin-alkyl-piperazine and their pharmaceutically acceptable salts of general formula (I) (I) wherein Ar is selected from phenyl; mono or di-substituted aryl in which the substituent(s) is (are) selected on its (their) turn from linear or branched -^-C- alkyl, halogen atoms, C-^-Cc haloalkyl; heteroaryl containing one or more heteroatoms selected on their turn from N, 0, S, said heteroaryl being optionally substituted with the aforementioned alkyl groups, said heteroaryl being a monocyclic group of from 5 to 6 atoms or condensed on an aryl group optionally substituted with the aforementioned groups, Ar^ is an aryl or a heteroaryl of from 5 tά 6 carbon atoms containing from 1 to 3 heteroatoms selected from N, 0, or S; R-^ and R 2 equal or different from each other are selected from H, ^1~^ alkoxy, OH, C^-Cr alkyl, N0 2 and wherein Y- \ / X is selected from : iϋ) Y ^ n 1 or 2 and m = 2 or 3 - 2. N(hetero)-aryl-N(hetero)-tetralin-alkyl-piperazine of general formula (I) according to claim 1 wherein Ar^ is an aryl group which is condensed on the alicyclic ring so that it forms the derivatives of general formula (IA) (IA) 3- N(hetero)-aryl-N(hetero)-tetralin-alkyl-piperazine of general formula (I) according to claim 1 wherein Ar-^ is an aryl group which is condensed on the alicyclic ring so that it forms the derivatives of general formula (IB). 4. N(hetero)-aryl-N(hetero)-tetralin-alkyl-piperazine according to claim 1, wherein R^ is OCHo, and R 2 is H. 5. N(hetero)-aryl-N(hetero)-tetralin-alkyl-piperazine according to claim 1 wherein Ar 2 is selected from : 2-methoxyphenyl, 3~ chlorophenyl, 3~trifluoromethylphenyl, 2-pyridyl, 2,5- dimethoxyphenyl. 6. N(hetero)-aryl-N(hetero)-tetralin-alkyl-piperazine according to claim 1, wherein n is 2. 7- Process for preparing N(hetero)-aryl-N(hetero)-tetralin- alkyl-piperazine and their pharmaceutically acceptable salts of general formula (I) (I) wherein Ar 2 is selected from phenyl; mono or di-substituted aryl in which the substituent(s) is (are) selected on its (their) turn from linear or branched C^- -C- alkyl, halogen atoms, C^-Cc haloalkyl; heteroaryl containing one or more heteroatoms selected on their turn from N, 0, S, said heteroaryl being optionally substituted with the aforementioned alkyl groups, said heteroaryl being a monocyclic group of from 5 to 6 atoms or condensed on an aryl group optionally substituted with the aforementioned groups, Ar^ is an aryl or a heteroaryl of from to 6 carbon atoms containing from 1 to 3 heteroatoms selected from N, 0, or S; R-^ and R 2 equal or different from each other are selected from H, ^-Cr alkoxy, OH, C^-C r - alkyl, N0 2 and wherein Y- \ / X I is : comprising the following steps: a) reacting the keton of formula (II) (II) wherein Ar^, R^, R 2 and n have the aforementioned meanings with an aminoalkylpiperazine of formula (III): (III) wherein m and Ar have the above mentioned meanings, in an apolar solvent under reflux and in the presence of catalytic amounts of an acid, thereby obtaining the derivative of formula (IV) : (IV) b) reducing the product obtained in the preceding step with sodium borohydride in a polar solvent at room temperature . 8. Process for preparing N(hetero)-aryl-N(hetero)-tetralin- alkyl-piperazine and their pharmaceutically acceptable salts of general formula (I) (I) wherein Ar 2 is selected from phenyl; mono or di-substituted aryl in which the substituent(s) is (are) selected on (its) their turn from linear or branched C^-Cc alkyl, halogen atoms, 0^-0-- haloalkyl; heteroaryl containing one or more heteroatoms selected on their turn from N, 0, S, said heteroaryl being optionally substituted with the aforementioned alkyl groups, said heteroaryl being a monocyclic group of from 5 to 6 atoms or condensed on an aryl group optionally substituted with the aforementioned groups, Ar^ is an aryl or a heteroaryl of from 5 to 6 carbon atoms containing from 1 to 3 heteroatoms selected from N, 0, or S; R-^ and R 2 equal or different from each other are selected from H, C 1" C 5 alkoχ y. 0H ' c l" c 5 alkyl, N0 2 and wherein comprising the following steps: a') reacting the keton of general formula (II) R l 1*2 wherein Ar^, R^, R 2 and n have the aforementioned meanings with the Grignard reactant Ro-MgX, wherein R is selected from: cyclopropyl and -(CH 2 )/ j Cl in an ethereal solvent thereby obtaining the tertiary alcohol of formula (V) (V) b' ) reacting the tertiary alcohol (V) coming from the preceding step with HCl in acetic acid thereby obtaining the chloride derivative of formula (VI) or (Via) : (VI) (VIA) wherein p is = 1 or 2 and is =1 when in the reactant (V) R is = cyclopropyl, or is = 2 in case R is = -(CH 2 )^-C1 c') reacting the chloride intermediate (VI) or (VIA) obtained in the preceding step with N-arylpiperazine of formula (VII) (VII ) wherein Ar 2 has the aforementioned meanings thereby obtaining N(hetero) aryl-N (hetero) - tetralinalkylpiperazine of formula (I ) wherein d ' ) reacting the derivative of formula ( I ) obtained in the preceding step with hydrogen in the presence of catalysts consisting of noble metals in a polar solvent thereby obtaining the compounds of formula (I) wherein : 9- Process for preparing N(hetero)-aryl-N(hetero)-tetralin- alkyl-piperazine and their pharmaceutically acceptable salts of general formula (I) 4 wherein Ar 2 is selected from phenyl; mono or di-substituted aryl 5 in which the substituent(s) is (are) selected on its (their) turn 6 from linear or branched C^-Cr alkyl, halogen atoms, C^-Cc 7 haloalkyl; heteroaryl containing one or more heteroatoms selected 8 on their turn from N, 0, S, said heteroaryl being optionally 9 substituted with the aforementioned alkyl groups, said heteroaryl 1° being a monocyclic group of from 5 to 6 atoms or condensed on an H aryl group optionally substituted with the aforementioned groups, 12 Ar^ is an aryl or a heteroaryl of from 5 to 6 carbon atoms 13 containing from 1 to 3 heteroatoms selected from N, 0, or S; R-^ 14 and R 2 equal or different from each other are selected from H, 5 c ι~Cc alkoxy, OH, C^C,- alkyl, N0 2 and wherein Y- \ / X I 7 comprising the following steps: 8 a") reacting the keton (II) 9 in the presence of a reducing agent thereby obtaining the 0 corresponding alcohol (VIII ) (VIII ) b" ) successively treating the alcohol (VIII ) obtained in the preceding step with ethyl 2-mercapto-acetate and Znl 2 , thus obtaining the corresponding ester of formula (IX) : ( IX) c") hydrolyzing the obtained ester to the corresponding acid and successively treating this acid with thionyl chloride in order to obtain the acyl chloride (X) d") reacting the acyl chloride (X) with the aforementioned N- aryl-piperazine (VII) thereby obtaining the corresponding amide (XI): (XI) e") treating the amide (XI) with LiAlH /j to obtain the desired derivative of formula (I) . 10.A therapeutic composition containing as the active principle one or more N(hetero)-aryl-N(hetero)-tetralin-alkyl-piperazine and their pharmaceutically acceptable salts of general formula (I) wherein Ar 2 is selected from phenyl; mono or di-substituted aryl in which the substituent(s) is (are) selected on its (their ) turn from linear or branched C^-Cc alkyl, halogen atoms, Cι~ c haloalkyl; heteroaryl containing one or more heteroatoms selected on their turn from N, 0, S, said heteroaryl being optionally substituted with the aforementioned alkyl groups, said heteroaryl being a monocyclic group of from 5 to 6 atoms or condensed on an aryl group optionally substituted with the aforementioned groups, Ar^ is an aryl or a heteroaryl of from 5 to 6 carbon atoms containing from 1 to 3 heteroatoms selected from N, 0, or S; R^ and R 2 equal or different from each other are selected from H, c i" c 5 alkoxy, OH, C-^-C,- alkyl, N0 2 and wherein Y- \ / is selected from: iv) Y n = 1 or 2 and m = 2 or 3, in combination with suitable excipients and or diluents. 11. The therapeutic composition according to claim 10 containing the active principle in amounts ranging from 1 to 200 mg. 12. The therapeutic composition according to claim 10 containing the compounds of formula (I) having mainly 5-HT1A serotoninergic activity for the treatment of generalized anxiety, panic attacks, obsessive-compulsive syndromes, depression, opium like, psycho stimulant substances and alcohol abuse syndromes, consciousness disorders such as senile dementia, vigilance and memory disorders, Parkinson's and Alzheimer's diseases. 13. The therapeutic compositions according to claim 12 wherein the active principle is selected among one or more of the following derivatives: - l-(2-methoxyphenyl)-4[N-(5-methoxy-l,2,3,4- tetrahydronaphthalen-l-yl)-2-aminoethyl]-piperazine; -4 -[3-(6-methoxy-l,2-dihydronaphthalen-4-yl)n-propyl-l-(2- methoxyphenyl)-piperazine; - l-phenyl-4-[3-(8-methoxy-l,2-dihydronaphthalen-4-yl)-n- propyl]piperazine; - 4-[3-8-methoxy-l,2-dihydronaphthalen-4-yl)-n-propyl]-l-(2- methoxyphenyl)-piperazine; - 4-[3-(8-methoxy-l,2-dihydronaphthalen-4-yl)-n-propyl]-l-(2- pyridyl)-piperazine; - 4-[3-(1,2-dihydronaphthalen-4-yl)-n-propyl]-l-(2-methoxyphenyl) ■ piperazine; - l-(2-methoxyphenyl)-4-[3-(7-methoxy-l,2,3,4- tetrahydronaphthalen-l-yl)-n-propyl]piperazine; " l-phenyl-4-[3-(5-methoxy-l,2,3,4-tetrahydronaρhthalen-l-yl)-n- propyl]-piperazine; - l-(2-methoxyphenyl)-4-[3-(5-methoxy-l,2,3,4- tetrahydronaphthalen-1-yl)-n-propyl]-piperazine; - 4-[3-(5-methoxy-l,2,3,4-tetrahydronaphthalen-1-yl)-n-propyl]-l- (2-pyridyl)-piperazine; - 4-[3-(7-methoxy-l,2,3,4-tetrahydronaphthalen-l-yl)-n-propyl]-l- (2-pyridyl)piperazine; - l-(2-methoxyphenyl)-4-[3-(4,5,6,7-tetrahydrobenzo[b]thien-4-yl)- n-propyl]piperazine; - 1-(2-methoxyphenyl)-4-[3~(1.2,3,4-tetrahydronaphthalen-l-yl)-n- propyl]piperazine; - 4-[4-(6-methoxy-l,2-dihydronaphthalen-4-yl)-n-butyl]-l-(2- methoxyphenyl)-piperazine; - l-(2-methoxyphenyl)-4-[4-(7-methoxy-l,2,3,4- tetrahydronaphthalen-1-yl)-n-butyl]-piperazine; - l-(2-methoxyphenyl)-4-{2[(7-methoxy-l,2,3,4- tetrahydronaphthalen-l-yl)-thio]-ethyl}piperazine; - 4-[1-(8-methoxy-l,2,3,4-tetrahydronaphthalen-4-yl)l-propylen-3- yl]-1-(2-methoxyphenyl)piperazine; " 4-[l-(8-methoxy-l,2,3,4-tetrahydronaphthalen-4-yl)-l-propylen- 3~y1]-1~(2-pyridyl)piperazine; - l-(2-methoxyphenyl)-4-[(1,2,3, -tetrahydronaphthalen-4-yl)-l- propylen-3~yl]piperazine; ~ l-(3 _ chlorophenyl)-4-[3-(8-methoxy-l,2,-dihydronaphthalen-4- yl)-n-propyl]piperazine; - 4-[3-(8-methoxy-l,2-dihydronaphthalen-4-yl)-n-propyl]-l-(3- trifluoromethylphenyl)piperazine; - 4-[3~(7-methoxy-l,2,3,4-tetrahydronaphthalen-1-yl)-n-propyl]-l- (3"trifluoromethylphenyl)piperazine. 14. The therapeutic composition according to claim 10 containing the compounds of formula (I) having mainly affinity on D-2, σ and 5- HTIA receptors or on D-2, σ and α-1 receptors for the therapy of schizophrenia or cerebral ischemia. 15. The therapeutic composition according to claim 14 wherein the active principle is selected among one or more of the following derivatives: - 4-[3-(8-methoxy-l,2-dihydronaphthalen-4-yl)-n-propyl]-l-(2- methoxyphenyl)-piperazine; - 4-[3"(l,2-dihydronaphthalen-4-yl)-n-propyl]-l-(2- methoxyphenyl)-piperazine; - l-(2-methoxyphenyl)-4-[3-(7-methoxy-l,2,3,4- tetrahydronaphthalen-1-yl)-n-propyl]piperazine; " l-phenyl-4-[3-(5-ωethoxy-l,2,3,4-tetrahydronaphthalen-l-yl)-n- propyl]-piperazine; - l-(2-methoxyphenyl)-4-[3-(5-methoxy-l,2,3,4- tetrahydronaphthalen-1-yl)-n-propyl]-piperazine; " 4-[4-(6-methoxy-l,2-dihydronaphthalen-4-yl)-n-butyl]-l-(2- methoxyphenyl)-piperazine; - l-(2-methoxyρhenyl)-4-[4-(7-methoxy-l,2,3,4- tetrahydronaphthalen-1-yl)-n-butyl]-piperazine; - l- (2-methoxyphenyl) -4[N- (5-methoxy-l , 2, 3 ,4- tetrahydronaphthalen-1-yl)-2-aminoethyl]-piperazine; -l-(2-methoxyphenyl)-4-[3-(4,5,6,7-tetrahydrobenzo[b]thien-4-yl)- n-propyl]piperazine; _ 1-(2-methoxyphenyl)-4-[3-(1,2,3,4-tetrahydronaphthalen-l-yl)-n- propyl]piperazine; - l-(2-methoxyphenyl)-4-{2[(7- ethoxy-l,2,3,4- tetrahydrσnaphthalen-1-yl)-thio]-ethyl}piperazine; - 4-[l-(8-methoxy-l,2,3,4-tetrahydronaphthalen-4-yl)l-propylen-3- yl]-1-( -methoxyphenyl)piperazine; - 1-(2-methoxyphenyl)-4-[(1,2,3,4-tetrahydronaphthalen-4-yl)-1- propylen-3 _ yl]piperazine. 16. The therapeutic composition according to claim 10 containing as the active principle the compounds of formula (I) having mainly affinity on 5"HT1A, α-1 receptors for the treatment of arterial hypertension. 17. The therapeutic compositions according to claim 16 wherein the active principle is selected among one or more of the following derivatives: - 4-[3-(6-methoxy-l,2-dihydronaphthalen-4-yl)n-propyl-l-(2- methoxyphenyl)piperazine; - l-phenyl-4-[3-(8-methoxy-l,2-dihydronaphthalen-4-yl)-n- propyl]piperazine; " 4-[3 _ (8-methoxy-l,2-dihydronaphthalen-4-yl)-n-propyl]-l-(2- methoxyphenyl)piperazine; - 4-[3 _ (8-methoxy-l,2-dihydronaphthalen-4-yl)-n-propyl]-l-(2- pyridyl)-piperazine; - 4-[3~(1,2-dihydronaphthalen-4-yl)-n-propyl]-l-(2-methoxyphenyl)- piperazine; - l-(2-methoxyphenyl)-4-[3-(7-methoxy-l,2,3,4- tetrahydronaphthalen-1-yl)-n-propyl]piperazine; - l-(2-methoxyphenyl)-4-[3-(5-methoxy-l,2,3,4- tetrahydronaphthalen-1-yl)-n-propyl]-piperazine; " 4-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-n-propyl]-1- (2-pyridyl)-piperazine; " 4-[4-(6-methoxy-l,2-duhydronaphthalen-4-yl)-n-butyl]-l-(2- methoxyphenyl)-piperazine; - l-phenyl-4-[3-(5-methoxy-l,2,3,4-tetrahydronaphthalen-l-yl)-n- propyl]-piperazine; - 4-[3~(7-methoxy-l,2,3,4-tetrahydronaphthalen-1-yl)-n-propyl]-l- (2-pyridyl)piperazine; - 1-(2-me hoxyphenyl)-4-[3~(4, .6,7~tetrahydrobenzo[b]thien-4- yl)-n-propyl]piperazine; - 1-(2-methoxyphenyl)-4-[3-(1,2,3,4-tetrahydronaphthalen-l-yl)-n- propyl]piperazine; - l-(2-methoxyphenyl)-4-[4-(7-methoxy-l,2,3,4- tetrahydronaphthalen-1-yl)-n-butyl]-piperazine; - l-(2-methoxyphenyl)-4-{2[(7-methoxy-l,2,3,4- tetrahydronaphthalen-l-yl)-thio]-ethyl}piperazine; - 4-[l-(8-methoxy-1,2,3,4-tetrahydronaphthalen-4-yl)l-propylen-3- yl]-1-(2-methoxyphenyl)piperazine; " 4-[1-(8-methoxy-l,2,3,4-tetrahydronaphthalen-4-yl)-1-propylen- 3-yl]-1-(2-pyridyl)piperazine; - 1-(2-methoxyphenyl)-4-[(l,2,3,4-tetrahydronaphthalen- -y1)-1- propylen-3 _ yl]piperazine.

Inventors: BERARDI FRANCESCO, FIORENTINI FRANCESCO, GOBETTI MARINO, GOVONI STEFANO, OLGIATI VINCENZO, PERRONE ROBERTO, TONON GIANCARLO, VANOTTI ERMES, BERARDI, FRANCESCO, FIORENTINI, FRANCESCO, GOBETTI, MARINO, GOVONI, STEFANO, OLGIATI, VINCENZO, PERRONE, ROBERTO, TONON, GIANCARLO, VANOTTI, ERMES
Applicants: BERARDI FRANCESCO, FIORENTINI FRANCESCO, GOBETTI MARINO, GOVONI STEFANO, OLGIATI VINCENZO, PERRONE ROBERTO, PIERREL SPA, TONON GIANCARLO, VANOTTI ERMES, PIERREL S.P.A.
Application year: 1993
Main classification: C07D295
IPC codes: A61K31, A61P9, A61P25, C07D213, C07D295, C07D333