IL106124A - N (hetero)-aryl-n (hetero)- tetralin-alkyl-piperazines having serotoninergic, dopaminergic and adrenergic activity - Google Patents

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. [WO9400441A1]

Description

t REF : 2782/93 1 ·> TNIS ·> D-b ·> ti- 1 ·>¾ioo- ( 1 io ) n-b·> IN- ( 1 ion ) N r AimiNi n*Aii»n«Di ,n»^ii¾iioiio nit>¾3)D ys N ( HETERO ) -ARYL- ( HETERO ) -TETRALIN-ALKYL-PIPERAZINE HAVING SEROTONINERGIC, DOPAMINERGIC AND ADRENERGIC ACTIVITY ( HETERO ) -ARYL-N ( HETERO ) -TETRALIN-ALKYL-PIPERAZINE HAVING SEROTONINERGIC , DOPAMINERGIC AND ADRENERGIC ACTIVITY .

FIELD OF THE IIWENTION 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, ( 199D -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 , 7 8. ( 1990 ) ] .

The use of compounds showing 5"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 5-HTlA 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 extrapiramidal effects. [J. Med. Chem. 34 .i860, (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/ot-l receptors has been recently suggested for the treatment of arterial hypertension [Naunyn-Schmiedeberg1 s Arch. Pharmacol. 336,597, (I987)]. The above finds also a confirmation in the recent reconsideration of the role of a-1 blocking compounds in the treatment of arterial hypertension [JAMA 266, 394, (1991)].

In view of the foregoing it appears evident that compounds showing a sufficient selectivity toward 5"HT1A receptors or possessing a mixed activity on 5-HTlA/D-2/o/a-l or 5-HTlA/a-l are 3 106124/2 to be considered having a marked therapeutic potential in the aforementioned pathologies.

Chemical Abstracts 103:123437a discloses a number of piperazine derivatives with serotoninolytic properties. DE 2,235,597 discloses N- [3- ( tetrahydronaphth-l-yloxy) -propyl] piperazine derivatives, although no serotonergic, dopaminergic or adrenergic activity is for these compounds is mentioned.

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. l-NP, Quipazine. M - 212. m-CPP. OPC-43 2 , LY 16 163 (PAPP) . Eltoprazine, (DU-288553 ) .

Thiospirone, Revospirone, S -9018. etc.

In all known N-alkyl-piperazine moieties from the prior art the affinity towards specific 5H 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 a-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 ( he tero ) -aryl- ( hetero ) - 106124/2 4 tetralin-alkyl-piperazine and their pharmaceutically acceptable salts of general formula (I) (I) wherein A 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 Cj_-C^ alkyl, halogen atoms, C^-C^ 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 5 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; and equal or different from each other are selected from H, C^-Ce alkoxy. OH, C1-Cc alkyl, N02 and wherein is selected from: 106124/2 5 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-HTlA setoninergic receptors.

This activity is coupled to a good selectivity towards different serotonine receptor subtypes (as it results rom 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-HTlA activity "in vivo" and permitting to understand if the compounds in question act as agonists or antagonists. The Applicant has found that all the analyzed compounds , selected on the base of receptor screening, are able to inhibit, at low dosages, stereotypy induced by 8OH-DPAT (as it results from the data contained in Table 2 reported later on) , without producing the behaviouristic effects ascribable to a serotoninergic activation.

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 Nervous System.

Some compounds of the present invention associate a considerable effectiveness on D-2 dopaminergic, a-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 the same can be used as antipsychotic and, in some cases, as antihypertensive and antiischeraic 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.

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, a-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 a-1 receptor. This activity, associate to a good affinity towards 5-HTlA 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 106124/2 8 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 Ώ-2,σ and 5-HTIA or affinity on the receptors D-2, σ and a-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 a-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 106124/2 9 groups contained in the alicyclic group of formula (I).

For example for preparing the derivative of formula (I) wherein process comprises the following steps reacting the compounds of formula (II) wherein A ^ , R^, R and n have the above mentioned meanings 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): 106124/2 10 (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 is selected from 5 comprises the following steps: a') reacting the above mentioned keton of general formula (II) with Grignard reactant R^- gX, wherein is selected from: cyclopropyl and -(CH2)iCl in an ethereal solvent thereby obtaining the tertiary alcohol of formula (V) ii) 106124/2 11 (V) b') reacting the tertiary alcohol (V), coming from the preceding step, with HC1 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-^ i cyclopropyl, or is = 2 in case is = -(CH^^-Cl c') reacting the chloride intermediate (VI) or (VIA) obtained the preceding step with N-arylpiperazine of formula (VII) (VII) 106124/2 12 wherein has the aforementioned meanings the obtaining N (hetero ) -aryl-N ( hetero ) - tetralinalkyl iperazine 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) 106124/2 13 b") successively creating the alcohol (VIII) obtained in the preceding step, with ethyl 2-mercapto-acetate and Zn^. 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) (X) d") reacting the acyl chloride (X) with the aforementioned N-aryl-piperazine (VII) thereby obtaining the corresponding amide (XI): e") reating the amide (XI) with LiAlH^ to obtain the desired 106124/2 14 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) is preferably, in the compounds of formula (I), OCH^, whereas i¾2 is preferably H. 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-l-yl) -2-aminoethyl]-piperazine (example i); - 4-[3- (6-methoxy-l ,2-dihydronaphthalen-4-yl)n-propyl-l-(2- methoxyphenyl)piperazine (example 2); - 1-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- -yl) -n-propyl]-l-( - 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- 1,2,3,4-tetrahydronaphthalen-l-yl)-n-propyl]piperazine (example 14); l-phenyl-4-[ 3- (5-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-[3- (5-methoxy-l .2, 3, 4- tetrahydronaphthalen-l-yl )-n-propyl]-l- (2-pyridyl) -piperazine (example 18) ; 4-[3-(7-methoxy-l, 2, 3, 4-tetrahydronaphthalen-l-yl )-n-propyl] -1-(2-pyridyl) piperazine (example 19); 1 - ( 2-methoxyphenyl )-4-[3-(4, ,6,7-tetrahydrobenzo[b] thien-4-yl-) n-propyl]piperazine (example 20); 1 - ( 2-methoxyphenyl )-4-[3-(l,2,3, 4- tetrahydronaphthalen- 1-yl ) -n-propyl]piperazine (example 21); 4-[ - ( 6-methoxy- 1 , 2-dihydronaphthalen-4-yl ) -n-butyl ] - 1 - ( 2-methoxyphenyl) -piperazine (example 22); 1 - ( 2-methoxyphenyl ) - -[ 4- (7-methoxy- 1.2,3.4-tetrahydronaphthalen-l-yl)-n-butyl]-piperazine (example 23); 1- ( 2-methoxyphenyl ) -4- {2-[ (7-methoxy-l , 2,3,4-tetrahydronaphthalen-1 -yl ) - thio ] -ethyl }piperazine ( example 24); 4-[ 1- ( 8-methoxy-l ,2, , - etrahydronaphthalen-4-yl ) l-propylen-3-yl]-l-(2-methoxyphenyl)piperazine (example 25); - 4-[l- (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 , - 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-1 , 2-dihydronaphthalen-4-yl ) -n-propyl ]-1- ( 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-1 , 2-dihydronaphthalen-4-yl ) -n-propyl ] -1- ( - methoxyphenyl) -piperazine (example 9); - 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 jpiperazine (example 14); - l-phenyl-4-[3- (5-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); 1- ( 2-methoxyphenyl ) -4[N- ( ~methoxy-l ,2,3,4- tetrahydronaphthalen-l-yl) -2-aminoethyl]-piperazine (example i); - 1- (2-methoxyphenyl) -4-[3- (4 , 5,6, 7-tetrahydrobenzo[b] thien-4-yl- n-propyl]piperazine (example 20) ; - 1- ( 2-methoxyphenyl )-4-[3-(l,2,3, 4-tetrahydronaphthalen-1-yl ) -n- propyl]piperazine (example 21) ; l-( 2-methoxyphenyl) -4-{2-[ (7-methoxy-l , 2, 3, 4 -tetrahydronaphthalen-1-yl)-thio] -ethyl Jpiperazine (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 , -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 ollowing 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- propyljpiperazine (example 8) ; - 4-[3-8-methoxy-l ,2-dihydronaphthalen-4-yl) -n-propyl]-l- (2- methoxyphenyl) -piperaz ne (example 9); 4- [ 3- ( 8-methoxy- 1 , 2-dihydronaphthalen-4-yl ) -n-propyl] - 1- ( 2-pyridyl) -piperazine (example 12); 4- [ 3- ( 1 , 2-dihydronaphthalen-4-yl ) -n-propyl ] - 1 - ( 2-methoxyphenyl ) -piperazine (example 13) ; 1- ( 2-methoxyphenyl ) -4-[3~ (7-methoxy-l ,2,3.4-tetrahydronaphthalen-l-yl) -n-propyl ]piperazine (example 14); 1 - ( 2-methoxyphenyl ) -4 - [ 3~ (5-methoxy- 1,2,3.4-tetrahydronaphthalen-l-yl) -n-propyl] -piperazine (example 17); 4- [ 3- (5-methoxy-l , 2,3,4-tetrahydronaphthalen-l-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-methoxy-l ,2,3, 4-tetrahydronaphthalen-l-yl ) -n-propyl] -piperazine (example 16) ; 4- [ 3 - ( 7-methoxy- 1,2,3,4-tetrahydronaphthalen- 1-yl ) -n-propyl ] - 1 -(2-pyridyl) piperazine (example 19); 1- ( 2-methoxyphenyl ) -4-[ 3" (4,5.6,J-tetrahydrobenzo[b] thien-4-yl) -n-propyl ]piperazine (example 20); 1- ( 2-methoxyphenyl ) -4- [ 3- ( 1 , 2 , 3.4- etrahydronaphthalen- 1-yl ) -n-propyl]piperazine (example 21); 1- ( 2-methoxyphenyl ) -4- [4- ( 7-methoxy- 1,2,3,4-tetrahydronaphthalen-l-yl) -n-butyl]-piperazine (example 23); 1- (2-methoxyphenyl) -4- {2- [ (7_methoxy-l ,2,3 , 4-tetrahydronaphthalen-l-yl) -thio]-ethyl}piperazine (example 24); 4- [1- (8-methoxy- 1 ,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) -1-propylen- 3~yl]-l- (2-pyridyl)piperazine (example 26); -1- (2-methoxypheny1 ) - -[(1,2, 3, -tetrahydronaphthaien-4-y1 ) -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); - 1- ( 2-methoxyphenyl ) -4-[3- (7-methoxy-1,2,3,4- tetrahydronaphthalen-l-yl) -n-propyl]piperazine (example 14); - l-(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, -tetrahydronaphthalen-l-yl) -n- propyl] -piperazine (example 16) ; - 1- (2-methoxyphenyl) -4-[3 ( , 5 , 6 , 7_ etrahydrobenzo[b] thien-4-yl ) - n-propyl]piperazine (example 20); - 1- ( 2-methoxyphenyl ) -4-[3- ( 1 , 2 , 3 , -tetrahydronaphthalen-l-yl ) -n- propyl Jpiperazine (example 21); - 1- ( 2-me hoxypheny1 ) -4-[4- (7-methoxy-1 , 2 , 3.4- tetrahydronaphthalen-l-yl) -n-butyl]-piperazine (example 23); - 1- (2-methoxyphenyl ) -4-{2-[ (7-methoxy-l ,2,3,4- tetrahydronaphthalen- 1-yl) -thio] -ethyl Jpiperazine (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-[(l,2,3, 4- tetrahydronaphthalen-4-yl ) -1- propylen-3-yl Jpiperazine (example 27).

N-aminoalkylpiperazine of formula (III) (III) is prepared by reacting previously mentioned N-arylpiperazine (VII) with nitrile bromide of formula (XII) NC-iCH^^-Br in the presence of a polar solvent and of a weak base thereby obtaining the intermediate (XIII) 106124/2 22 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. Passages of the description which are not within the scope of the claims do not constitute a part of the invention.

EXAMPLE 1 l-(2-methoxyphenyl) ( -methoxy-l .2,3. ^-tetrahydronaphtalen-1-yl ) -2-aniinoethyllpiperazine .

Bromoacetonitrile (10 mmoles) and sodium bicarbonate (10 mmoles) were added to 1- (2-methoxyphenyl ) piperazine (10 mmoles) solubilized in 50 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. LiAlffy (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 rom this purification (10 mmoles) is dissolved in anhydrous toluene and reacted with 5~methoxy-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^ (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 orm of a dark yellow oil (yield 65%) · 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,CDCl3), 6(ppm) : 1,66-2,07 (m,4H,CH2CH2 endocyclic) ; 2,17 (broadened s , 1H , exchanges with D20. H); 2,46-2.93 [m,10H,CH2 benzyl, NCH2CH2 ( CH2 ) 2 ] ; 3.08 [s broad..4H, (CH2)2NAr]; 3.75-3.83 (m+s,4H,CHN,CH3) ; 3.85 (s,3H CH3) ; 6,65" 7,18 (m,7H, aromatic).

Hydrochlorate: m.p. 223-224 °C.

EXAMPLE 2 4-f 3~ (6-methoxy-l , 2-dihydronaphthalene-4-yl) -n-propyl (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,2,3i4-tetrahydronaphthalen-l-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#) . 1- ( 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 and extracted with CHCl^. 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, CDC13 ) , 6(ppm) : 1,70-1,88 (m,2H,CH2CH2CH2) ; 2,15" 2,29 (m,2H,CH2 endocyclic); 2,40-2,55 (m,4H, CH2CH2CH2N) ; 2,66 [broadened t,6H,CH2 benzilic,CH2N(CH2)2] ; 3,11 [broad, s ,4H, (CH2)2NAr]; 3.80 (s,3H). 3,85 (s,3H), (2 CH3) ; 5,90 (t.lH. J=4,5 Hz, H vinilic) ; 6,63-7,10 (m,7H,arom. ) .

Hydrochlorate : m.p. l80-l82 °C.

EXAMPLE 3 l-phenyl-4-[3-(6-methoxy-l ,2-dihydronaphthalen-4-yl)-n-propyl"l-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 ( ++1; 25.9); 362,25 (M+; 100.0); 175.10 (34.1); 173.10 (32.1); 132.10 (25.8). 1H-NMR ( 200MHz, CDC13 ) . 6(ppm): 1.69-I , 87 (m .2H . CH2CH2CH2) ; 2,16-2,30 (m,2H,CH2 endocycl.) ; 2,47 (t,4H, J=7,7Hz. CH2CH2CH2N) 2,57-2,74 [m,6H,CH2 benz., CH2N(CH2)2]; 3.18-3,27 [ dt.4H, (CH2)2NAr]; 3,8l(s,3H,CH3) ; 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- ( -chlorophenyl ) -4-f 3~ ( 6-methoxy-l .2-dihydronaphthalen-4-yl ) -n-propyll-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 (M++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, CDC13 ) . 6(ppm) : 1,67-1,86 (m,2H.CH2CH2CH2) ; 2,l6-2,30 (m,2H,CH2 endoc); 2,38-2,53 (m,4H.CH2CH2CH2N) ; 2,54-2.74 [m.6H,CH2 benz . , CH2N(CH2) 2] ; 3,14-3,26 [m,4H, (CH2)2NAr]; 3,80 (s,3H,CH3); 5,90 (t.lH, J=4,5 Ηζ,Η vin.); 6.65-7-20 (m,7H,arom. ) .

Hydrochlorate: m.p. 184-185 °C.

EXAMPLE 5 4-Γ - (6-methoxy-l , 2-dihydronaphthalen-4-yl ) -n-propyll-1- ( 3" trifluoromethylphenyl ) piperazine The same process described in Example 2 is followed with the only difference that in this case 1- ( 3- rifluoromethylphenyl ) -piperazine is used.

MS, m/z (rel. range): 432,25 (M++2; 3,9); 431,25 (M++1; 26,3); 430,25 (M+; 100,0); 256,10 (20,0); 243,10 (69.0); 241,10 (33,9); 200,00 (45.1); 172,10 (23,9). 1H-NMR ( 200MHz, CDC13 ) . δ(ρριπ): 1,69-1,87 (m,2H,CH2CH2CH2) ; 2,16-2,30 (m,2H,CH2 endoc); 2,41-2,54 (m,4H,CH2CH2CH2N) ; 2,57-2,73 0,6H,CH2 benz. ,CH2N(CH2)2]; 3.28 [t,4H, J=5,0 Hz, (CH2)2NAr]; 3,80 (s,3H,CH3); 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]-l- (2-pyridyl ) piperazine The same process described in Example 2 is followed, with the only difference that in this case l-pyridylpiperazine is used. MS, m/z (rel. range): 36 .25 (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 , CDCl ) , 6(ppm): 1,70-1,90 ( m , 2H , CH2CH2CH2 ) ; 2,13- 2,28 (m,2H,CH2 endoc); 2,38-2.54 (m,4H,CH2CH2CH2N) ; 2,54-2,74 [m,6H,CH2 benz. ,CH2N(CH2)2]; 3,58 [t,4H, J=5,l Hz, (CH2)2NAr]; 3,78 (s,3H,CH3); 5,88 (t.lH. J= 4,5 Hz.H vin.); 6.55-7.52 (m,6H,arom. ) ; 8,12-8,21 (m, 1H,N=CH arom. ) .

Hydrochlorate: m.p. 225-226 °C.

EXAMPLE 7 1- ( 2 , 5~dimethoxyphenyl ) -4-Γ ~ ( 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 , 5 -dime thoxyphenyl ) -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, CDC13 ) . δ(ρριπ) : 1,72-1,91 (m,2H,CH2CH2CH2) . 2,l4-2.28 (m,2H.CH2 endoc); 2.39-2,83 [m,10H.CH2 benz., CH2CH2CH2N(CH2)2]; 3,12 [ broad, s , 4H, (CH2)2NAr] ; 3.75. 3,79. 3.80 (3s,9H,3 CH3); 5,89 (t.lH, J =4,6 Hz.H vin.); 6, 3-7,1 (m , 6Η , arom . ) .

Hydrochlorate: m.p. 192-193 °C.

EXAMPLE 8 l-phenyl-4-f3- (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) : 36 ,2 (M++2; 3,4); 363,2 (M++1; 25,3); 362,25 (M+; 100,0); 175.10 (36,8); 173.10 (30.3); 132,10 (26,5). 1H-NMR ( 200MHz, CDC13) 0(ppm): 1,68-1, 87 (m,2H,CH2CH2CH2) ; 2,15-2,29 (m,2H,CH2 endoc); 2,48 (t,4H, J=7.6 Hz , CH2CH2CH2N) ; 2,58- 2.81 [m,6H,CH2 benz. ,CH2N(CH2)2]; 3,15-3.29 [m,4H, (CH2)2NAr]; 3.83 (s,3H,CH3); 5.89 (t.lH, J=4,5 Hz.H vin.); 6,75-7.35 (m, 8Η , arom . ) .

Hydrochlorate : m.p. 174-176 °C.

EXAMPLE 9 4-f3-(8-methoxy-l , 2-dihydronaphthalen-4-yl ) -n-propyl~|-l-(2-me-thoxyphenyl ) iperazine 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).

½-NMR (200MHz. CDCl^) . δ (ppm) : 1,71-1,88 (m,2H,CH2CH2CH2) ; 2,13-2,27 (m,2H,CH2 end,oc); 2,42-2,58 (m, H,CH2CH2CH2N) ; 2,62- 2.84 [m,6H,CH2benz. ,CH2N(CH2)2]; 3.12[broad. t,4H, (CH2)2NAr] ; 3.82 (s.3H). 3.85 (s,3H). (2CH3); 5.88 (t.lH. J=4,5Hz, H vin.); 6.75-7.20 (m,7H,arom. ) .

Hydrochlorate: m.p. 209-21O°C.

EXAMPLE 10 1- (3-chlorophenyl ) -4- f 3~ (8-methoxy-1 , 2-dihydronaphthalen-4-yl) -n-propyl Ipiperazine 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, CDC13 ) . 6(ppm) : 1.66-1.85 (m,2H,CH2CH2CH2) ; 2,13-2,28 (m,2H,CH2 endoc . ) ; 2.39-2,80 (m,10H,CH2 benz. ,CH2CH2CH2N(CH2)2]; 3.21 [broad. t ,4H, (CH2)2NAr] ; 3,83 (s,3H, CH3); 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-Γ3- (8-methoxy-l , 2-dihydronaphthalen-4-yl ) -n-propyll-l- (3~ trifluoromethylphenyl ) piperazine The same process described in Example 8 is followed with the only difference that in this case 1- ( 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: 200.00 (56,4) ; 172,00 (20,1) . 1H-NMR ( 200MHz, CDC13 ) , 6(ppm) : 1 ,73-1 ,91 (m,2HfCH2CH2CH2) ; 2,14-2,28 (m,2H,CH2 endoc); 2,42-2.82 (m,10H,CH2 benz. CH2CH2CH2N(CH2)2]; 3.20-3.37 [m,4H, (CH2)2NAr] ; 3.83 (s.3H. CH3) ; 5,89 (t.lH, J=4,5 Hz.H vin. ) ; 6,75-7.42 (m,7H,arom. ) .

Hydrochlorate: m.p. 145-147 °C EXAMPLE 12 4-Γ3- (8-methoxy-l , 2-dihydronaphthalen-4-yl ) -n-propyl "]-!-( 2-pyri-dyl)piperazine The same process described in Example 8 is followed, with the only difference that in this case 1- (2-pyridyl)piperazine is used.

MS, m/z (rel. range): 365.25 (M++2;l,8); 364.25 (M++l;l4,3); 363,25 ( +;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).

½-NMR (200MHz. CDClj) , δ (ppm) : 1,67-1.86 (m, 2H.CH2CH2CH2) ; 2,13-2,28 (m. 2H.CH2 endoc); 2,40-2,63 [m,8H.CH2CH2 CH2N(CH2)2]; 2,73 (t,2H, J=8Hz,CH2benz. ) ; 3.50-3.62 [m,4H, (CH2)2NAr] ; 3,82 (s,3H,CH3); 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. 2l8-220°C.

EXAMPLE 13 4~Γ3~ ( 1 , 2-dihydronaphthalen-4-yl ) -n-propyl ]-l- (2-methoxyphenyl) piperazine The same process described in Example 8 is followed, with the only difference that 1- ( 2-methoxyphenyl ) -piperazine is used.

MS, m/z (rel. range): 364,25 (M++2; 3.4); 363. 5 (M+ + 1;27,D; 362,25 (M+;100.0); 205.10 (31.3); 203,10 (30,4); 162,10 (22.9).

½-NMR ( 200MHz, CDC13 ) , δ (ppm): 1,72-1.83 (m,2H.CH2CH2CH2) ; 2,19" 2,28 (m,2H,CH2endoc. ) ; 2.43-2,55 (m,4H,CH2CH2CH2N) ; 2,62-2,78 [m,6H,CH2benz. , CH2N(CH2)2]; 3.10 [broad. t, 4H, (CH2)2NAr]; 3.84 (s,3H,CH3); 5.87 (t.lH, J=4,5 Hz, H vin.); 6,82-7,27 (m,8H, arom . ) .

Hydrochlorate: m.p. l85-l87°C.

EXAMPLE 14 1- (2-methoxyphenyl ) -4-Γ3- (7-methoxy-l ,2,3 , 4-tetrahydronaphthalen-1-yl ) -n-propyl Tpiperazine l-[3~ (6-methoxy-l ,2-dihydronaphthalen-4-yl) -n-propyl] 2-methoxyphenyl ) 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/Et20 (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 ,CDC13) , δ(ρριη): 1,54-1,90 (m.8H,CH2CH2 endoc. ,CHCH2CH2CH2N) ; 2,46 [broad. t.2H,CH2N(CH2)2] ; 2,62-2,84 [m,7H,CH and CH2 benz . , CH2N ( CH2 ) 2 ] ; 3,12 [broad. S,4H, (CH2)2NAr]; 3.78 (s.3H). 3.86 (s,3H). (2CH3) ; 6,63-7.07 (ra,7H. arom . ) .

EXAMPLE 1 4-[3~ (7-methoxy-l .2, . -tetrahydronaphthalen-l-yl ) -n-propyl"]-!-( ~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): 34,25 (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, CDC13) , δ(ρριη): 1,53-1.92 (m,8H,CH2CH2 endoc. ,CHCH2CH2CH2N) ; 2,36-2,83 [m,9H,CH and CH2 benz . , CH2N(CH2)2]; 3.25 [t,4H, J=4,9 Hz, (CH2)2NAr]; 3.77 (s,3H,CH3); 6,61-7.40 (m,7H,arom. ) .

EXAMPLE 16 l-phenyl-4-Γ 3- ( -methoxy- 1,2, , - etrahydronaphthalen-1-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); 36 .30 (M++1; 21,4); 364,30 (M+; 80,5); 175.15 (100,0); 162,05 (35.0). 1H-NMR (200MHz, CDC13) , <5(ppm): 1,54-1,90 (m.8H,CH2CH2 endoc. ,CHCH2CH2CH2N) ; 2,38-2,85 [m,9H,CH and CH2 benz., CH2N(CH2)2]; 3.24 [ broad t .,4H, (CH2)2NAr]; 3.8l (s,3H,CH3); 6,62-7,35 (m,8H,arom. ) .

Hydrochlorate: m.p. 206-207 °C.

EXAMPLE 17 1- (2-methoxyphenyl ) -4-f3~ ( -methoxy- 1 ,2. ■ -tetrahydronaphthalen-l-yl) -n-propyl]piperazine The same process described in the Example 14 is followed, starting from the hydrochlorate obtained in Example 9· MS, m/z (rel. range): 396,30 (M++2; 3.3); 395.30 (M++1; 23,0); 3 ^,30 (M+; 82,7); 205.10 (100,0); 192,10 (34.4); 150.10 (21,8). 1H-NMR (200MHz, CDC13) , 6(ppm): 1,53-1,89 (m,8H,CH2CH2 endoc. ,CHCH2CH2CH2N) ; 2,38-2,87 [m,9H,CH and CH2 benz . , CH2N(CH2)2]; 3.13 [broad. S,4H, (CH2)2NAr]; 3,81 (s,3H), 3,86 (s,3H), (2 CH3); 6,62-7.17 (m.7H, arom.).

Hydrochlorate: m.p. 206-207 °C.

EXAMPLE 18 4-[3~ ( -methoxy-l ,2,3.4-tetrahydronaphthalen-l-yl ) -n-propyll-l-(2-pyridyl ) piperazine The same process described in the Example 14 is followed, starting from the hydrochlorate obtained in Example 12.

MS, m/z (rel. ange ): 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, CDC13 ) , 6(ppm): 1,52-1,88 (m,8H,CH2CH2 endoc. ,CHCH2CH2CH2N' ; 2,38-2,85 (m,9H,CH and CH2 benz., CH2N(CH2)2]; 3.59 [broad. t,4H, (CH2)2NAr]; 3.80 (s,3H,CH3); 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-propyll -1- (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. 5 (M++2;l,3); 366,25 (M++l;9,6); 36 .2 (M+;39.7); 271.15 (21,7); 258,15 (60. l); 121.10 (3L7); 107,00 (100,00); 86,10 (24,6); 79.10 (20,7); 72.10 (48,0).

½-NMR (200MHz, CDClj) , <5 (ppm) : 1,53-1,89 (m,8H.CH2CH2 endoc, CHCH2CH2CH2N) ; 2,50 [broad, t, 2H,CH2N(CH2)2] ; 2,61-2,82 [m,7H,CH and CH2 benz., CH2N(CH2)2]; 3.63 [broad, , 4H, (CH2) 2NAr] ; 3,76 (s,3H,CH3; 6,58-7.52 (m,6H,arom. ) ; 8.15-8,21 (m,lN,N=CH arom.). Hydrochlorate: ra.p. l43-l45°C.

ESEMPIO 20 1- ( 2-methoxyphenyl ) -4- [ 3- ( 4 , 5.6 , 7- etrahydrobenzo[b ] thien-4-yl ) -n-propyll iperazine.

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).

½-NMR (200MHz, CDCl^) . δ (ppm): 1,42-2,01 (m,8H,CH2 endoc, CHCH2CH2CH2N) ; 2,45 [t,2H, J=7.3Hz , CH2N(CH2)2]; 2.61-2,81 [m,7H,CH and CH2 benz., CH2N(CH2)2]; 3.12 [ broad, s. 4H, (CH2)2NAr]; 3,86 (s,3H,CH3); 6.82-7.05 (m, 6H, arom. ) .

Hydrochlorate: m.p. 217-2l8°C.

EXAMPLE 21 1- (2-methoxyphenyl) -4-[3-(1.2.3 , -tetrahydronaphthalen-l-yl ) -n-propyl Ipiperazine .

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): 365,25 (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).

½-NMR (200 MHz , CDC13), δ (ppm) : 1,54-1,92 (m,8H,CH2CH2 endoc, CHCH2CH2CH2N) ; 2,45 [broad. t,2H,CH2N(CH2)2] ; 2,62,-2,88 [m,7H,CH and CH2 benz., CH2N(CH2)2]; 3,12 [broad. s, 4H, (CH_2)2NAr] ; 3,86 (s,3H,CH3); 6,82-7,21 (m, 8H, arora.).

Hydrochlorate: m.p. 223-22 °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, CDC13 ) , 6(ppm): 1,50-1,73 (m,4H,CH2CH2CH2CH2N) ; 2,14-2,19 (m,2H,CH2 endoc); 2,38-2,54 (m,4H, CJ2CH2CH2CH_2N) ; 2,61-2.80 [m,6H.CH2 benz .. CH2N(CH2 ) 2] ; 3,12 [broad. t. 4H,(CH2)2 NAr]; 3.79 (s,3H), 3.86 (s,3H). (2 CH3); .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 ) - -fU- (7-methoxy-l ,2,3.4-tetrahydronaphthalen-1-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 87#· The following analyses are carried out on the free base: MS, m/z (rel. range): 410,35 (M++2; 2,9); 409,25 (M*+l; 20,9); 408,25 (M+; 75.8); 205.10 (100.0). 1H-NMR ( 200MHz, CDC13 ) , δ(ρρηι) : 1,30-1,92 (m, 10H,CH2CH2 endoc, CH2CH2CH2CH2N) ; 2,44 [t,2H, J=7,6 Hz , CH2N ( CH2 ) 2 ] ; 2,62-2,83 [m,7H,CH and CH2 benz. ,CH2N(CH2)2] ; 3,18 [broad s . ,4H, (CH2)2NAr] ; 3,78 (s,3H). 3.86 (s.3H). (2 CH3); 6,63-7.02 (m, 7H, arom.). Hydrochlorate: m.p. 192-193 °C.

EXAMPLE 24 1- ( 2-methoxyphenyl) -4-{2-f (7-methoxy-l ,2,3,4-tetrahydro-naphthalen-l-yl ) - thio] -ethyl }piperazine.

Ethyl 2-mercapto-acetate (6 mmoles) and Znl2 (3 mmoles) are added to a solution of 7-methoxy-l- tetralol (6 mmoles) (prepared according to a known method from 7_methoxy-l-tetralone) in CH2C12 (12 ml). After two hours under stirring the reaction mixture is poured into water and extracted with CH2C12> The extracted solution is dried on a2S0^ 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 HC1 and extracted with Et20. 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-methoxy-l ,2, 3,4- tetrahydronaphthalen-1-yl) -thio] -acetic acid (5 mmoles) is treated with 5-6 ml S0C12 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 H20 and with HC1 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 LiAlHjj (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 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-j), δ(ρρπι): 1,67-2,10 (m,4H,CH2CH2 endoc); 2,56-2,85 [m,10H,CH2 benz . , SCH2CH2N ( CH2 ) 2 ] ; 3.10 [broad t, 4H . (CH2)2NArJ; 3.78 (s,3H). 3.86 (s,3H). (2 CH3); 4, 12 (t.lH, J=4 Hz, CHS); 6,67-7.04 (m,7H,arom. ) .

EXAMPLE 25 4-f1- (8-methoxy-l ,2. , -tetrahydronaphthalen-4-yl) -l-propylen-3~ yl~|-l- (2-methoxyphenyl ) 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 HC1 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 CHCl^. The solvent is evaporated and a dark oil is obtained, which is purified by column chromatography; the product recovered in a total yield of 6 % is composed by 4- ( 3-chloro-l-propylen-l-yl) -8-methoxy-1 ,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 CHCl^. 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.D; 205.10 (100,0) .

½-NMR (200MHz, CDCl^) . δ (ppm) : 1,82 (m,2H,CH2endoc. ) ; 2,42-2,65 (m,6H,CH2C=CHCH2CH2N) ; 2,67-2,85 [m , 6H , CH2benz . , CH2N(CH2)2]; 3,15 (broad, s, 4H(CH2)2NAr] ; 3.8l and 3,86 ( 2s , 6H , 2CH3 ) ; 6,00 (broad, s, 1H, H vin.); 6.65-7,22 (rn.7H.arom.).

Hydrochlorate: m.p. 202-203 °C.

EXAMPLE 26 4-[l- (8-methoxy-1 ,2.3 , 4- tetrahydronaphthalen-4-yl ) -l-propylen-3- yl1-1- (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): 363,25 (M+:3,6); 176,10 (100,0); 1^7,10 (23,6); 121,10 (35.9)· ½-NMR (200 MHz , CDClg) , δ (ppm) : 1,82 (m,2H,CH2 endoc); 2,37-2,66 [m,10H,CH2C=CHCH2CH2N(CH2)2]; 2,71 (t, 2H, J=6, 3Hz, CH2 benz.); 3.49-3. 2 [m,4H, (CH2)2NAr] ; 3,81 (s,3H.CH3 , 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 l-(2-methoxyphenyl) - -[l ,2, 3. -tetrahydronaphthalen- -yl ) -1-propylen-3~yl1piperazine.

The same process described in Example 25 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).

½-NMR (200 MHz, CDClj) , <5 (ppm): 1,82 (m,2H,CH2 endoc); 2,40-2,60 ; 2,64-2,80 [m,6H, CH2 benz., CH2N(CH2)2]; 3.12 [broad. s , 4H, (CH2) 2NAr] ; 3.85 (s,3H,CH3); 6,00 (broad. t, 1H, H vin.); 6,83-7.62 (m,8H,arom. ) .

Hydrochlorate: m.p. 198-199°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-HTlC, 5"HT2, D-2 , D-l, a-1.

Cerebral tissue asported from male rats (Sprague Dawley) weighing 180-220 g is homogenized in Tris. HC1 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 , 83 , ( 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 3OO-6OO 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-HTlA Receptor. The methodology described by J.R. Schlegel. Biochem. Pharmacol. 35 , 1 43 , ( 1986 ) is essentially used.

In short, rat cerebral cortex horaogenate is dissolved in the incubation buffer (Tris.HCl 50 mM, pH = 7 .7 containing 10 μΜ of pargyline, 4 mM CaCl2, 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 uM). 5-HTIB 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 μΜ of pargyline, 4 mM CaC^. 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 μΜ) as the blocking agent of 5-HTIA receptors. The aspecific bond is evaluated by the use of 5-HT (10 μΜ) . 5-HTlC 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. HC1 50 mM, pH = 7 .7 containing 10 μΜ pargyline, 4mM CaCl2, 0. 1% ascorbic acid) and incubated in the final volume of 1 ml, at 25 °C, for 15 minutes in the presence of 3H-5HT (2.0 nM) and 80H-DPAT (0.1 μΜ) and RU-24960 (ΙΟηΜ) as the blocking agents respectively of 5-HTIA and 5-HTIB receptors. The aspecific bond is evaluated by the use of 5-HT (10 μΜ) . 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 μΜ) .

D-l 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. HC1 50 mM, pH = 7 . 4 containing 120 mM of NaCl, 5 mM of C1, 2mM of CaCl2, ImM of MgCl2) and incubated in the final volume of 1 ml at 37 °C, for 1 minutes in the presence of 3H-SCH-23390 (O.3 nM). The aspecific bond is evaluated by the use of SCH-2339O (1 μΜ) .

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 KC1, 2 mM CaCl2, 1 mM MgCl2) and incubated in the final volume of 1 ml, at 37 °C for 1 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 uM). ot- 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 μΜ 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 μ ). σ Receptor. The methodology described by E.Weber, Proc. Natl.

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 μΜ) . 3. Behaviouristic experiments. 5-HTlA activity evaluation "in vivo".

The compounds under question are analyzed by using the method described by Tricklebank [Eur. J. Pharmacol., 106, 271 (1985)]· The compounds under question are administered subcutaneously to male rats (S.D.) treated with reserpine (1 mg/ g) l8 hours before the test.

The evaluation of the behaviour starts 3 minutes after the administration of the compounds under question and continue for 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. 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 1 IC 50 (nM) EXAMPLES 5-HT1A 5-HT1B 5-HTlC 5-HT2 EXAMPLE 1 7.01 3084.00 >10000.00 3336.70 EXAMPLE 2 2.00 II34.OO 1022.45 221.00 EXAMPLE 3 147.10 3550.00 I69 .36 390.80 EXAMPLE 4 131.10 5II8.OO 7400.40 132.50 EXAMPLE 5 138.10 6102.10 5224.74 II73.8O EXAMPLE 6 63.60 5373-53 196O.II 146.20 EXAMPLE 7 160.70 5793.13 2556.85 932.30 EXAMPLE 8 I8.3O 6108.00 4 9.ΟΟ 204.00 EXAMPLE 9 8.82 >10000.00 > 10000.00 770.00 EXAMPLE 10 31.50 9643.42 3928.Ο7 I337.9O EXAMPLE 11 55.89 > 10000.00 2767 - 60 2366.ΟΟ EXAMPLE 12 1.42 7Ο67.54 7 II.43 204.60 EXAMPLE 13 15.72 85II.88 6884.38 IO3.8O EXAMPLE 14 I.50 1512.52 IOO5.31 219.6O EXAMPLE 15 88.40 I78 .7I 1783.98 390.60 EXAMPLE 16 Ο.36 6968.9Ο 1888.62 170.30 EXAMPLE 17 0.32 IOO7.8O 1011.29 357.90 EXAMPLE 18 Ο.58 1642.70 2021.37 330.50 EXAMPLE 19 3-38 2872.62 2472.86 287.90 EXAMPLE 20 1.13 2943.57 3941.84 146.80 EXAMPLE 21 0.82 1504.89 2728.72 155. 0 EXAMPLE 22 I.53 992.37 888.70 208.60 EXAMPLE 23 Ο.89 157O.3O I97O.6O 400.30 EXAMPLE 24 5.94 27^0.41 > 10000.00 110.80 EXAMPLE 25 Ο.52 913.72 2054.58 667.30 EXAMPLE 26 0.35 1742.60 1950.70 416.50 EXAMPLE 27 1.84 980.00 800.06 147.20 Buspirone 12.78 > 10000.00 > 10000.00 TABLE 2 EXAMPLES INHIBITION OF THE STEREOTYPY FROM 80H-DPAT DE50 (mg/kg s.c. ) EXAMPLE 1 2.13 EXAMPLE 2 Ο.76 EXAMPLE 11 24.19 EXAMPLE 14 Ο.87 EXAMPLE 17 < 0.10 EXAMPLE 26 < 0.10 TABLE 3 IC 50 (nM) EXAMPLES Dl D-2 σ α-1 EXAMPLE 1 1092.3 17.8 152.7 149.4 EXAMPLE 2 I53I.O 90.6 227.8 24.5 EXAMPLE 3 2763.2 776.9 847.6 528.6 EXAMPLE 4 1484.0 768.3 642.5 590.4 EXAMPLE 5 9058.3 1291.8 9276.8 3070.2 EXAMPLE 6 2659.2 777.8 1242.6 152.4 EXAMPLE 7 4475.3 200.5 874.5 237-4 EXAMPLE 8 3876.2 302.9 372.6 49.0 EXAMPLE 9 4972.3 17. 60.2 95.0 EXAMPLE 10 5780.3 484.3 463-7 364.9 EXAMPLE 11 6870.6 644.0 > 10000.0 277.5 EXAMPLE 12 5832.7 119.3 104.9 6929.8 EXAMPLE 13 6432.1 14.7 90.7 31.1 EXAMPLE 14 4370.7 51.5 64.1 43.2 EXAMPLE 15 13369.2 1327.5 > 10000.0 2928.5 EXAMPLE 16 10820.6 96.7 92.2 78.8 EXAMPLE 17 I692.8 20.0 59-9 1.9 EXAMPLE 18 1168.0 176.7 407.6 31.4 EXAMPLE 19 3962.7 327.9 1441.7 147.8 EXAMPLE 20 2475-6 24.1 121.7 172.6 EXAMPLE 21 2011.9 24.7 28.6 85-7 EXAMPLE 22 2090.3 10.7 80.7 15-3 EXAMPLE 23 4070.1 20.7 6-7 90.3 EXAMPLE 24 2789.8 50.2 270.2 110.2 EXAMPLE 25 I753.8 II.3 5 .I 5-6 EXAMPLE 26 I6O3.2 150.3 99.I 72.2 EXAMPLE 27 5820.40 12.7 82.7 3-6 Buspirone > 10000.0 275.2 262.8 106124/2 51

Claims (1)

1. CLAIMS l.N(hetero) -aryl-N(hecero) -tetralin-alkyl-piperazine and pharmaceutically acceptable salts of general formula (I) (I) wherein Ai'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^-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; and R2 equal or different from each other are selected from H, C1-C^ alkoxy, OH, Cj_-C^ alkyl. N02 and wherein 52 106124/2 is selected from: and m = 2 or 3 ; 2. N(hetero) -aryl-N(hetero) - etralin-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) 106124/2 53 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) . . N(hetero) -aryl-N(hetero) -tetralin-alkyl-piperazine according to claim 1, wherein is OCH^, and R is H. 5. N(hetero) -aryl-N(hetero) -tetralin-alkyl-piperazine according to claim 1 wherein Ar is selected from : 2-methoxyphenyl, 3" chlorophenyl , 3-trif luoromethylphenyl , 2-pyridyl, 2,5-dimethoxyphenyl. 6. N(hetero) -aryl-iV(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) 106124/2 54 wherein 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^-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; and E¾2 equal or different from each other are selected from H, C1-C^ alkoxy, OH, C^-C^ alkyl, N02 and wherein comprising the following steps: a) reacting the keton of formula (II) 106124/2 55 wherein Ar^ , R^, R2 and n have the aforementioned meanings an aminoalkylpiperazine of formula (III): (III) wherein m and Ar2 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) 106124/2 56 4 wherein Ar? 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-^-C- alkyl , halogen atoms, Cj_-C- 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 10 being a monocyclic group of f om 5 to 6 atoms or condensed on an 11 aryl group optionally substituted with the aforementioned groups, 12 Ar^ is an aryl or a heteroaryl of om 5 to 6 carbon atoms 13 containing f om 1 to 3 heteroatoms selected from N, 0, or S; 14 and equal or different from each other are selected from H, 15 C1-C^ alkoxy, OH, Cj^-C^ alkyl, 02 and wherein 16 selected from 17 comprising the following steps: 18 a') reacting the keton of general formula (II! 106124/2 57 wherein ΑΓ·|_ , , and n have Che aforementioned meanings with the Grignard reactant R^-MgX, wherein R^ is selected from: cyclopropyl and -(Ch^l^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 = -(C^^-Cl c') reacting the chloride intermediate (VI) or (VIA) obtained in the preceding step with N-arylpiperazine of formula (VII) 106124/2 58 (VII) 30 wherein ΑΓ has the aforementioned meanings thereby 31 obtaining N(hetero)aryl-N(hetero) -tetralinalkylpiperazine of 32 formula (I) wherein 33 d') reacting the derivative of formula (I) obtained in the 34 preceding step with hydrogen in the presence of catalysts 35 consisting of noble metals in a polar solvent thereby obtaining 36 the compounds of formula (I) wherein : 9· Process for preparing N(hetero) -aryl-N(hetero) -tetralin alkyl-piperazine and their pharmaceutically acceptable salts general formula (I) 106124/2 59 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^-C^ alkyl, halogen atoms, C^-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 Co 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; and f¾2 equal or different from each other are selected from H, Cj^-C^ alkoxy, OH, Cj_-C^ alkyl, N02 and wherein in the presence of a reducing agent thereby obtaining the corresponding alcohol (VIII) 106124/2 60 (VIII) b") successively creating the alcohol (VIII) obtained in the preceding step with ethyl 2-mercapto-acetate and Zn^, 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 a orementioned N-aryl-piperazine (VII) thereby obtaining the corresponding amide (XI): 106124/2 61 (XI) e") treating the amide (XI) with LiAlH^ 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) (I) wherein A^ 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-^-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 Co 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 106124/2 62 14 containing from 1 to 3 heteroatoras selected from N, 0, or S; 15 and F¾2 equal or different from each other are selected from H, 16 C^-C^ alkoxy, OH, C^-C^ alkyl, 02 and wherein 17 is selected from: H I i) 18 and m = 2 or 3, 19 in combination with suitable excipients and or diluents. 1 11. The therapeutic composition according to claim 10 2 containing the active principle in amounts ranging from 1 to 200 106124/2 68 ~ (S-mechoxy-i .2,3 , 4- tecrahydronaphthalen- -yl) -1-propyien- 3~yl]"i" ( 2-pyricyI) piperazine ; - 1- (2-mechoxyphenyl) -*-[ (1,2,3.4-tetrahydronaph alen-4-yl ) -l- propylen-3-yl jpiperazine . 18. A compound according to any one of claims 1 to 6 for use as a medicament. 19. Use of a compound according to any one of claims 1 to 6 in the preparation of a medicament, substantially as described in the specification. TO