NZ253689A

NZ253689A - N-(hetero)aryl-n'(hetero)-tetralinalkyl piperazine derivatives and pharmaceutical compositions

Info

Publication number: NZ253689A
Application number: NZ253689A
Authority: NZ
Inventors: Roberto Perrone; Francesco Berardi; Francesco Fiorentini; Stefano Govoni; Vincenzo Olgiati; Ermes Vanotti; Marino Gobetti; Giancarlo Tonon
Original assignee: Erba Carlo Spa
Priority date: 1992-06-26
Filing date: 1993-06-22
Publication date: 1996-11-26
Also published as: KR950702195A; ITMI921569A0; RU94046220A; HUT71405A; HU9403768D0; ITMI921569A1; IT1255178B; WO1994000441A1; AU670444B2; FI945997A; RU2115651C1; CA2137685A1; AU4419593A; EP0647222A1; JPH07508514A; ZA934472B; FI945997A0; IL106124A

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number £53689 » Zealand No. 253689 tfernational No. PCT/EP93/01589 Complete Specification Frfed: .Jttr&l&lSS Class: (6) Publication Date: _..?...?...N.9.!!LJ9B& P.O. Journal No: I.Hr.lQ.i NO DRAWINGS "The inventors of this invention in the sense of being the actual devisers thereof within the meaning of section 23 of the Patents Act 1953 are: ROBERTO PERRONE an Italian citizen of Via Postiglione, 12A-70126 Bari, Italy; FRANCESCO BERARDI an Italian citizen of Via Incoronata, 10870016 Noicattaro, Bari, Italy: FRANCESCO FIORENTINI an Italian citizen of Via de Sanctis, 52-20141 Milano, Italy; STEFANO GOVONI an Italian citizen of Via Carlo Alberto Dalla Chiesa 18/20-20083 aggiano, Italy; VINCENZO OLGIATI an Italian citizen of Via Settembrini, 16-20010 Casorezzo, Milan, Italy; ERMES VANOTTI an Italian citizen of Via G. Cimabue, 4-20148 Milano, Italy; MARINO GOBETTI an Italian citizen of Via YolctoJ"0. - 2°'52 lo«o<7f i+aKi • Q To Hot* livi Italian CI-H26V1 of \l;m £. Bexvw/do,35/fe - ioiaq ttiUaMo, NEW ZEALAND PATENTS ACT 1953 COMPLETE SPECIFICATION Title of Invention: N(hetero)-aryl-N(hetero)-tetralin-alkyl-piperazine having serotoninergic, dopaminergic and adrenergic activity Name, address and nationality of applicant(s) as in international application form: FARMITALIA CARLO ERBA S.R.L., an Italian company of Milan, Via Carlo Imbonati 24, 20159 Milano, Italy (FOLLOWED BY PAGE 1A) WO 94/00441 PCT/EP93/01589 25368® N(IIETERO) -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 5 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 10 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 15 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, 20 (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 WO 94/00441 2 PCT/EP93/01580 control of the alcohol abuse [ Proc. Natl. Acad. Sci. USA 85. 5274 (1988) - Psychopharmacology 22, 49. (1989)]-Compounds able to combine activity on 5-HT1A receptor and the capacity of interaction with D-2 and a receptors may represent a 5 valid therapeutic approach to the treatment of schizophrenia. In fact the association of D-2 with a 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. 10 255, (1983)]. Moreover the activity on a 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. 15 255. (1991)]- Finally the use of active compounds on 5"HTIA receptor, or compounds having mixed activity on 5-HTlA/a-l receptors has been recently suggested for the treatment of arterial hypertension [Naunyn-Schmiedeberg1 s Arch. Pharmacol. 336,597. (1987)]. The 20 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 shewing a sufficient selectivity toward 5~HT1A receptors "»r 25 possessing a mixed activity on 5-HTlA/D-2/o/a-l or 5-HTlA/a-l are WO 94/00441 3 PCT/EP93/0I589 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 5 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 -W<6, RK-153, RK-I67. 1-NP, Quipazine, MK-212, m-CPP, OPC-4392, LY 165163 (PAPP), Eltoprazine, (DU-288553). 10 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 15 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-HT1A- and D-2 receptors, but also towards a-1 and o receptors . Presently a great need is felt to find compounds acting 20 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. 25 THE PRESENT INVENTION The present invention relates to N(hetero)-aryl-N(hetero)- 25368 4 tetralin-alkyl-piperazine and their phannaceutically acceptable salts of general formula (I) wherein is selected from phenyl; mono or di-substituted aryl in which the substituent(s) is (are) selected on its (their) turn 5 from linear or branched C^-C^ alkyl, halogen atoms, C^-C^ haloalkyl. methoxy; and heteroaryl containing one or more heteroatoms selected on their turn from N, 0, S, said heteroaryl being optionally substituted with the above mentioned C,-Cj alkyl groups, saxd heteroaryl being a monocyclic group of from 5 to 6 10 atoms or condensed on an aryl group optionally substituted with the above mentioned C,-Cs alkyl groups, Ar, is an aryl or a heteroaryl of from 5 to 6 carbon atoms containing from 1 to 3 heteroatons selected from N, 0, or S; and equal or different from each other are selected from H, C1"C^ alkoxy, OH, alkyl, NO2 15 and wherein R1 f?2 (I) r is selected from: AMENDED SHEET 5 2 5 3 68 9 i) ii) iii) iv) Y"- Y , and v) n = 1 or 2; and m = 2 or 3. In the present invention the compounds (I) presenting an asymmetry 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 Taule 1) v * t o; 10 The compounds of the present invention are actf^v in a^ jf o" V f*l ' >■ T. r r • \?J WO 94/00441 PCT/EP93/01589 6 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. 10 Therefore the compounds of the present invention result to act as pure antagonists on 5-HT1A receptor. 1he "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 o adrenergic receptors (as it results from the data contained in Table 3 reported later on) to 5-HT1A 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-HTIA receptors induces to WO 94/00441 PCT/EP93/01589 7 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 5 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 10 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 a receptors, which can be associated or 15 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 20 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~HT1A receptors and to a favourable 25 selectivity ratio towards D-2 and o receptors, permits to propose some of the compounds of the present invention for the therapy of WO 94/00441 8 PCT/EP93/01589 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 5 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-10 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,a and 5-HT1A or affinity on the receptors D-2, o and a-1, are in particular 15 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 20 hypertension. N(hetero)aryl-N(hetero)-tetralinalkylpiperazine of formula (I) are prepared with different processes depending on the different Y - \ / X 2 5 3 68 9 9 groups contained in the alicyclic group of formula (I). For example for preparing the derivative of formula (I) wherein Y - \ / X is: i) Y H » the process comprises the following steps: 5 a) reacting the compounds of formula (II) wherein Ar^, R^, R2 and n have the above mentioned meanings with an aminoalkylpiperazine of formula (III): H2N-(CH2)b ./"V \_y 10 (III) wherein m and A^ 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 o \ ' ■* . v. r- < 2 5 3 6 8 9 10 «1 i<2 —^ (CHa). N-Ar. (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: ii) iii) and v) comprises the following steps: a') reacting the above mentioned keton of general formula (II) with Grignard reactant R^-MgX, wherein R^ is selected from: cyclopropyl and -(C^J^Cl in an ethereal solvent thereby obtaining the tertiary alcohol of formula (V) ii) 1 25 3 68 9 11 (V) b1) reacting the tertiary alcohol (V). cssasig from the preceding step, with HC1 in acetic acid, thereby obtaining the chloride derivative cf fornula (VI) or (Via): (VI) (VIA) wherein p is = 1 or 2 and is =1 when in the reactant (V) is = cydopropyl. or is » 2 in case is = -(CKjJti-Cl c') reacting the chloride interaediate (YD or (VIA) obtained in the preceding: step with N-arylpiperazine cf formula (VII) AMENDED SHEET 2 5 3 68 9 12 wherein Ar£ has the aforementioned meanings thereby obtaining N(hetero)-aryl-N(hetero)-tetralinalkylpiperazine of formula (I) wherein Y- \ / X I is ii T" or v) y\ 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 : \ / X is iii) Hie process for preparing Y - \ / X is iv) the compounds of formula (I) wherein .s. 10 comprises the following steps: a") reacting the aforementioned keton (II) in the presence of a reducing agent thereby obtaining the corresponding alcohol (VIII) V i 2 5 3 * 3 9 13 b") successively treating the alcohol (VIII) obtained in the preceding step, with ethyl 2-mercapto-acetate and Zn^, thus obtaining the corresponding ester of formula (IX): *1 t<2 (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): /~\ N N—Aro \ / 2 <XD e")treating the amide (XI) with LiAlH^ to obtain the desiri 1 2 5 3 6 8 9 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) V / \ h I, \_y (CHj) N—Aro (IA) or the derivatives of general formula (IB) /~\ * (CHJZ\ /—^2 (CHj). (IB) is preferably, in the compounds of formula (I), OCH^, whereas R2 is preferably H. Ar2 is preferably selected from : 2-methoxypherv WO 94/00441 15 PCT/EP93/01589 chlorophenyl, 3~trifluoromethylphenyl, 2-pyridyl, 2,5~ dimethoxyphenyl. Particularly preferred derivatives of formula (I) are those having n =2. 5 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 10 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 15 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-(2-20 methoxyphenyl)piperazine (example 2); - l-phenyl-4-[3-(8-methoxy-l,2-dihydronaphthalen-4-yl)-n-propyl]piperazine (example 8); - 4-[3-8-methoxy-1,2-dihydronaphthalen-4-yl)-n-propyl]-1-(2-methoxyphenyl)piperazine (example 9) ; 25 - 4-[3~(8-methoxy-l,2-dihydronaphthalen-4-yl)-n-propyl]-l-(7-pyridyl)-piperazine (example 12); WO 94/00441 16 PCT/EP93/01589 - 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); 5 - l-phenyl-4-[3-(5~methoxy-l,2,3,4-tetrahydronaphthalen-l-yl)-n-propyl]-piperazine (example 16); - 1-(2-methoxyphenyl)-4-[3-(5~Eethoxy-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- 10 (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-(4,5,6,7-tetrahydrobenzo[b]thien-4-yl-) n-propyl]piperazine (example 20); 15 - l-(2-me thoxypheny1)-4-[3-(1,2,3.4-tetrahydronaphthalen-1-yl)-n-propyl]piperazine (example 21); - 4-[4-(6-methoxy-1,2-dihydronaphthalen-4-yl)-n-butyl]—1—(2-methoxyphenyl)-piperazine (example 22); - 1-(2-methoxyphenyl)-4-[4-(7-methoxy-l,2,3.4- 20 tetrahydronaphthalen-l-yl)-n-butyl]-piperazine (example 23); - 1-(2-methoxypheny1)—4—{2-[(7~methoxy-1,2,3.4-tetrahydronaphthalen-l-yl)-thio]-ethyl}piperazine (example 24); - 4-[1-(8-methoxy-l,2,3,4-tetrahydronaphthalen-^-yl)l-propylen-3-yl]-l-(2-methoxyphenyl)piperazine (example 25); WO 94/00441 17 PCT/EP93/01589 - 4-[l- (8-methoxy-l ,2,3,4-tetrahydronaphthalen-4-yl)-l-propylen-3-yl]-l-(2-pyridyl)piperazine (example 26); - l-(2-methoxyphenyl)-4-[ (1,2,3.4-tetrahydronaphthalen-4-yl) -1 -propylen-3-yljpiperazine (example 27); 5 - 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~ trifluoromethylphenylJpiperazine (example 11); - 4 - [ 3- (7 -me thoxy-1,2,3.4- te trahydronaphthalen-1 -yl) -n-propyl ] -1 -10 (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: 15 - 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-methoxyphen-j 1) -piperazine (example 13): 1-(2-methoxypheny1)-4-[3-(7-me thoxy-1,2,3,4-20 tetrahydronaphthalen-l-yl)-n-propyl]piperazine (example 14); - 1-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); 25 - 4-[4-(6-methoxy-l ,2-dihydronaphthalen-4-yl)-n-butyl]-l-(2-methoxyphenyl)-piperazine (example 22); WO 94/00441 PCT/EP93/01589 18 1-(2-methoxyphenyl)-4-[4-(7-methoxy-l,2,3.4-tetrahydronaphthalen-l-yl)-n-butyl]-piperazine (example 23); - 1-(2-methoxyphenyl)-4[N-(5-methoxy-l,2,3.4-tetrahydronaphthalen-l-yl)-2-aminoethyl]-piperazine (example 5 1); - 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-l-yl)-n-propyl]piperazine (example 21); 10 - 1-(2-methoxyphenyl)-4-{2-[(7-methoxy-l, 2, 3. 4 -tetrahydro-naphthalen-l-yl)-thio]-ethyl}piperazine (example 24); -4-[1-(8-methoxy-l,2,3,4-tetrahydronaphthalen-4-yl)-1-propylen-3-yl]-l-(2-methoxyphenyl)piperazine (example 25); - 1-(2-methoxyphenyl)-4-[(1,2,3.4-tetrahydronaphthalen-4-yl)-1-15 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: 20 - 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-(2-25 methoxypheny1)-piperazine (example 9)5 94/00441 19 PCT/EP93/01589 - 4-[3~ (8-methoxy-l, 2-dihydronaphthalen-4-yl)-n-propyl]-l-(2-pyridyl)-piperazine (example 12); - 4-[3-(l,2-dihydronaphthalen-4-yl)-n-propyl]-l-(2-methoxyphenyl)-piperazine (example 13); 5 - l-(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-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]-1- 10 (2-pyridyl)-piperazine (example 18); - 4-[4-(6-me thoxy-1,2-dihydronaphthalen-4-y1)-n-butyl]-1-(2-methoxypheny1)-piperazine (example 22); - 1-phenyl-4-[3-(5~methoxy-1,2,3.4-tetrahydronaphthalen-1-y1)-n-propyl]-piperazine (example 16); 15 - 4-[3- (7-methoxy-l ,2,3,4-tetrahydronaphthalen-l-yl-) -n-propyl ] -1-(2-pyridyl)piperazine (example 19); - 1-(2-methoxyphenyl)-4-[3~(4,5.6,7-tetrahydrobenzo[b]thien-4-yl)-n-propyl]piperazine (example 20); 1-(2-methoxyphenyl)—4—[3~(1,2,3,4-tetrahydronaphthalen-l-yl)-n- 20 propyl]piperazine (example 21); 1-(2-methoxyphenyl)-4-[4-(7-methoxy-l,2,3,4-tetrahydronaphthalen-l-yl)-n-butyl]-piperazine (example 23); - 1-(2-methoxyphenyl)-4-{2-[(7-oethoxy-l,2,3,4-tetrahydro-naphthalen-l-yl)-thio]-ethyl}piperazine (example 24); 25 - 4 - [ 1 - (8-methoxy-l, 2,3,4- te trahydronaphthalen-4 -y 1) 1 -propylen-3-yl]-l-(2-methoxyphenyl)piperazine (example 25); WO 94/00441 20 PCT/EP93/01589 - 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). 5 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. 10 These compounds are in particular : - 4-[3-8-methoxy-1,2-dihydronaphthalen-4-yl)-n-propyl]-1-(2-methoxyphenyl)-piperazine (example 9); - 4-[3-(1,2-dihydronaphthalen-4-y1)-n-propyl]-1-(2-methoxyphenyl)-piperazine (example 13); 15 - l-(2-methoxyphenyl)-4-[3-(7-niethoxy-l,2,3,4- tetrahydronaphthalen-l-yl)-n-propyl]piperazine (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-1,2-dihydronaphthalen-4-yl)-n-butyl]-1-(2- 20 methoxyphenyl)-piperazine (example 22); - 1-phenyl-4-[3-(5-methoxy-l,2,3,4-te trahydronaphthalen-1-yl)-n-propyl]-piperazine (example 16); - 1-(2-methoxyphenyl)-4-[3(4,5.6,7-tetrahydrobenzo[b]thien-4-yl)-n-propyl]piperazine (example 20); 25 - 1- (2-methoxyphenyl)-4-[3-(1,2,3,4-tetrahydronaphthalen-l-yl)-n- WO 94/00441 PCT/EP93/01589 21 propyl]piperaz±ne (example 21); 1-(2-methoxyphenyl)-4-[4-(7-nethoxy-l,2,3,4- tetrahydronaphthalen-l-yl) -n-butyl] -piperazine (example 23); - 1-(2-methoxyphenyl)-4-{2-[(7-nethoxy-1,2,3,4- 5 tetrahydronaphthalen- l-yl)-thio]-ethyl}piperazine (example 24); - 4-[1-(8-methoxy-l,2,3,4-tetrahydronaphthalen-4-yl)-1-propylen-3- yl]-l-(2-methoxyphenyl)piperazine (example 25); 1-(2-methoxyphenyl)-4-[(1,2,3,4-tetrahydronaphthalen-4-yl)-1--O propylen-3-yl]piperazine (example 27). N-aminoalkylpiperazine of formula (III) H2N- (CH2) m-/ \-Ar2 (III) is prepared by reacting previously mentioned N-arylpiperazine (VII) with nitrile bromide of formula (XII) NC-tCI^^-Br 15 in the presence of a polar solvent and of a weak base thereby obtaining the intermediate (XIII) WO 94/00441 22 PCT/EP93/01589 NC-fCI^.j-N N-Ar2 N / (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. 5 EXAMPLE 1 1-(2-methoxyphenyl)-4-fN-(5-methoxy-l.2.3.^-tetrahydronaphtalen-1-yl) -2-aminoethyl"[piperazine . Brcmoacetonitrile (10 mmoles) and sodium bicarbonate (10 mmoles) were added to 1-(2-methoxyphenyl)piperazine (10 mmoles) 10 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 15 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 20 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~nethoxy-l- WO 94/00441 PCT/EP93/01589 23 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 5 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$%). 10 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,CDC13), 6(ppm): 1,66-2,07 (m,4H,CH2CH2 endocyclic); 2,17 (broadened s ,1H,exchanges with D20.NH); 2,46-15 2,93 [m,10H,CH2 benzyl, NCH2CH2N(CH2)2]S 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 20 4-f3~(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 aided to a solution of cyclopropylmagnesium bromide (9 mmoles) dissolved in tetrahydrofuran. The mixture is left 25 under reflux for about 1 hour. Then it is cooled and a solution saturated by ammonium chloride is added. The organic phase is WO 94/00441 PCT/EP93/01589 24 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-l-ol, in the form of a dark oil. The mixture is directly treated with a solution of HCl in diluted 5 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) 10 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 15 is cooled and, after evaporating the dimethylformamide, it is diluted with H2O 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); 20 392,25 (M+, 100,0); 205,10 (20,9); 203,10 (24,9) .k 1H-NMR (200MHz,GDCI3), 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.H [broad, s ,4H, (CH2)2NAr]; 3.80 (s,3H), 3.85 (s,3H), (2 CH3); 5.90 (t,lH, J=4,5 25 Hz, H vinilic); 6,63-7.10 (m,7H,arom.). Hydrochlorate : m.p. 180-182 °C. WO 94/00441 25 PCT/EP93/01589 EXAMPLE 3 1 -phenyl-4-f 3-(6-methoxy-1.2-dihydronaphthalen-4-yl)-n-propyl1-piperazine The same process described in Example 2 is followed with the only 5 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,CDC13), <5(ppm): 1,69"1,87(m,2H.CH2CH2CH2); 2,16-2,30 (m,2H,CH2 endocycl.); 2,47 (t,4H, J=7.7Hz, CH2CH2CH2N); 10 2.57-2.74 [m.6H.CH2 benz., CH2N(CH2)2]; 3.18-3.27 C 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 15 1- (3-chlorophenyl) -4-f 3- (6-me thox.v-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 l-(3-chlorophenyl)-piperazine is used. 20 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); 2,16-2.30 (m.2H.CH2 endoc.); 2.38-2.53 (m,4H,CH2CH2CH2N) ; 2,54-2,74 25 [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 Hz.H vin.); 6.65-7.20 (in,7H,arom.). WO 94/00441 26 PCT/EP93/01589 Hydrochlorate: m.p. 184-185 °C. EXAMPLE 5 4-f3-(6-methoxy-l.2-dihydronaphthalen-4-vl)-n-propyl "1-1-(3-trifluoromethylphenyl)piperazine 5 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): 432,25 (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): 10 200.00 (45,1); 172,10 (23,9). 1H-NMR (200MHz,CDCl^), 6(ppm): 1,69-1,87 (m,2H,CH2CH2CH2); 2,l6-2,30 (m,2H,CH2 endoc.); 2,41-2,54 (m,4H,CH2CH2CH2N); 2,57-2,73 [m,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 15 (m,7H,arom.). Hydrochlorate: m.p. 189-190 °C . EXAMPLE 6 4-f 3-(6-methoxy-1,2-dihydronaphthalen-4-yl)-n-propyll-1-(2-pyridyl)piperazine 20 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): 365.25 (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)-25 1H-NMR (200MHz,CDC13), 6(ppm): 1,70-1,90 (m,2H,CH2gi2CH2); 2,13- WO 94/00441 27 PCT/EP93/01589 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=5.1 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,lH,N=CH arom.). 5 Hydrochlorate: o.p. 225-226 °C. EXAMPLE 7 1-(2.5-dimethoxyphenyl)-4-f 3-(6-methoxy-l.2-dihydronaphthalen-4-yl) -n-propyl "|-piperazine The same process described in Example 2 is followed, with the 10 only difference that in this case 1-(2,5-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,CDClj), 6(ppm): 1.72-1.91 (m,2H.CH2gi2CH2). 2,14-15 2,28 (m,:>H,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.); 6,43-7.12 (m,6H, arom.). Hydrochlorate: m.p. 192-193 °C. 20 EXAMPLE 8 l-phenyl-4-f 3-(8-methoxv-l.2-dihvdronaphthalen-4-yl)-n-propyll piperazine The same process described in Example 2 is followed, with the only difference that in this case 5-methoxy-tetralone and 1-25 phenyl-piperazine are used. MS, m/z (rel. range) : 364,25 (M++2; 3.4); 363.25 (M++1; 25,3); WO 94/00441 28 PCT/EP93/01589 362,25 (M+; 100,0); 175,10 (36,8); 173.10 (30,3); 132,10 (26,5). 1H-NMR (200MHz,CDC13) <5(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(Oi2)2]; 3.15"3.29 [m,4H, (CH2)2NAr]; 5 3.83 (s,3H,CH3); 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 — f 3—(8-methoxy-l,2-dihydronaphthalen-4-yl)-n-propyll-1-(2-me-10 thoxyphenyl)piperazine The same process described in Example 8 is followed, with the only difference that in this case 1 — (2 methoxyphenyl) -piperazine is used. MS, m/z (rel. range): 394.25 (M++2; 4,2) 393.25 (M++l; 27.0); 15 392,25 (M+; 100,0); 205.05 (25.6); 203.15 (24.6). 1H-NMR (200MHz, CDC13), 6 (ppm): 1,71-1,88 (m, 2H, CH2CH2CH2); 2,13-2,27 (m,2H,CH2 endpc.); 2,42-2,58 (m,4H,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.); 20 6,75-7.20 (m,7H,arom.). Hydrochlorate: m.p. 209"2r0°C. EXAMPLE 10 1-(3-chlorophenyl)-4-f3~(8-methoxy-l,2-dihydronaphthalen-4-yl)-n- 25 propylIpiperazine The same process described in Example 8 is followed, with the WO 94/00441 29 PCT/EP93/01589 only difference that in this case l-(3-chlorophenyl)-piperazine is used. MS, m/z (rel. range):400,15 (M++4;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); 5 222,00 (23,6); 211,10 (21,2); 209.00 (76,2); 207.00 (30,4); 166,00 (33.6). 1H-NMR (200MHz,CDCl^), 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 10 (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-T3~(8-methoxy-l.2-dihydronaphthalen-4-yl)-n-propyll-1-(3-15 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); 20 430,25 (M+; 79.4); 256,10 (32,0); 243,00 (100,0); 24l,00 (35.1); 200,00 (56,4); 172,00 (20,1). 1H-NMR (200MHz,CDC13), 6(ppm): 1,73-1,91(m,2H,CH2CH2CH2); 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) ; 25 5.89 (t,lH, J=4,5 Hz.H vin.); 6,75~7,42 (m,7H,arom.). Hydrochlorate: m.p. 145-147 °C WO 94/00441 30 PCT/EP93/01589 EXAMPLE 12 4-f 3-f8-methoxy-l,2-dihydronaphthalen-4-yl)-n-propyl1-1-(2-pyridyl )piperazine The same process described in Example 8 is followed, with the 5 only difference that in this case l-{2-pyridyl)piperazine is used. MS. m/z (rel. range): 365.25 (M++2;1.8); 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). 10 1H-NMR (200MHz. CDC13). 6 (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,1H,N=CH arom.). 15 Hydrochlorate: m.p. 2l8-220°C. EXAMPLE 13 4-T3-(1.2-dihydronaphthalen-4-yl)-n-propyl1-1-(2-methoxyphenyl) piperazine The same process described in Example 8 is followed, with the 20 only difference that 1-(2-methoxyphenyl)-piperazine is used. MS, m/z (rel. range): 364.25 (M++2; 3.4); 363.25 (M++l;27,l); 362.25 (M+;100,0); 205,10 (31.3); 203.10 (30.4); 162.10 (22.9). 1H-NMR (200MHz.CDC13), 6 (ppra): 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 25 [m,6H,CH2benz.. CH2N(CH2)2]; 3,10 [broad.t. 4H, (CH2)2NAr]; 3.84 WO 94/00441 31 PCT/EP93/01589 (s.3H.CH3); 5.87 (t,1H, J=4,5 Hz, H vin.); 6.82-7.27 (m,8H, arom.). Hydrochlorate: m.p. l85~l87°C. EXAMPLE 14 5 1-(2-methoxyphenyl) -4-f 3-(7-methoxy-l.2.3.4-tetrahydronaphthalen-1-yl)-n-propyl1piperazine 1 - [ 3~ (6-methoxy-1,2-dihydronaphthalen-4 -yl) -n-propyl ] -4- (2-methoxyphenyl )piperazine hydrochlorate (2 mmoles) obtained as described in Example 2, is solubilized in MeOH (30 ml) and 10 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%). I5 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.CDCl^), 6(ppm): 1.54-1.90 (m,8H,CH2CH2 endoc.,CHCH2CH2CH2N); 2,46 [broad. t,2H,CH2N(CH2)2]; 2,62-2,84 20 [rn.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 (m,7H. arom.). EXAMPLE 15 4-f3-(7-methoxy-l.2.3.4-tetrahydronaphthalen-l-yl)-n-propyl1-1- 25 (3-trifluoromethylpheny1)piperazine The same process described in Example 14 is followed, starting WO 94/00441 32 PCT/EP93/01589 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). 5 1H-NMR (200MHz,CDC13) , 6(ppm): 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 Hi. (CH2)2NAr]; 3.77 (s.3H.CH3); 6,61-7,40 (m,7H,arom.). EXAMPLE 16 10 1-phenyl-4-f 3-(5-methoxy-1.2.3.4-tetrahydronaphthalen-l-yl)-n-propylIpiperazine 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); 15 364,30 (M+; 80,5); 175.15 (100.0); 162,05 (35.0). 1H-NMR (200MHz.CDCI3), 6(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]; 3.81 (s,3H,CH3); 20 6,62-7,35 (m,8H,arom.). Hydrochlorate: m.p. 206-207 °C. EXAMPLE 17 1-(2-methoxyphenyl)-4-f 3-(5-methoxy-l.2.3,4-tetrahydronaphthalen-l-yl )-n-propylIpiperazine 25 The same process described in the Example 14 is followed, WO 94/00441 33 PCT/EP93/01589 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); 394.30 (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 5 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,bk-7,17 (m,7H. arom.). Hydrochlorate: m.p. 206-207 #C. EXAMPLE 18 10 4 - f 3- (5-me thoxy-1,2.3.4- tetrahydronaphthalen-l-yl) -n-propyl 1-1-(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.range ): 367.20 (M++2; 1,9): 366,20 (M++1; 13,8); 15 365.20 (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 (ra,9H.CH and CH2 benz., 20 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.1H.N=CH arora.). Hydrochlorate: m.p. 169-171 °C. EXAMPLE 19 4-f3-(7-methoxy-l.2.3.4-tetrahydronaphthalen-l-yl)-n-propyl1-1-(2- m 25 pyridyl)piperazine The same process described in Example 14 is followed, starting WO 94/00441 34 PCT/EP93/01580 from the hydrochlorate obtained in Example 12. MS, m/z (rel.range): 367.25 (M++2;l,3); 366,25 (M++l;9.6); 365.25 (M+;39,7); 271,15 (21,7); 258,15 (60,l); 121,10 (31.7); 107.00 (100,00); 86,10 (24,6); 79.10 (20,7); 72,10 (48,0). 5 1H-NMR (200MHz, CDC13), 6 (ppm): 1,53-1.89 (m,8H,CH2CH2 endoc., CHCH2CH2CH2N); 2,50 [bi-oad. t, 2H,CH2N(CH2)2]; 2,61-2,82 [m,7H,CH and CH2 benz., CH2N(CH2)2]; 3.63 [broad. t,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: m.p. l43-l45°C. 10 ESEMPI0 20 1-(2-methoxyphenyl)-4-f 3-(4.5.6.7-tetrahydrobenzofblthien-4-yl)-n-propylIpiperazine. The same process described in Example 14 is followed, starting from the hydrochlorate obtained in Example 9-15 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). 1H-NMR (200MHz, CDCl^), 6 (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, 20 (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-f 3-(1.2.3.4-tetrahydronaphthalen-l-yl)-n-propyllpiperazine. 25 The same process described in Example 14 is followed, starting WO 94/00441 35 PCT/EP93/01589 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). 5 ^-NMR (200 MHz, CDCl^), 6 (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, (CH2)2NAr-]; 3.86 (s,3H,CH3); 6,82-7.21 (m, 8H, arom.). Hydrochlorate: m.p. 223-224°C. 10 EXAMPLE 22 4-f4 - (6-methoxy-l. 2-dihydronaphthalen-4-yl) -n-butyl "1 -1- (2-methoxyphenyl)piperazine 7-methoxy-l-tetralone (6 mmoles) solubilized in tetrahydrofuran (10 ml) is added to a solution of 4-chloro-n-butylmagnesium 15 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); 20 406,35 (M+; 99.9); 205.10 (22,9). 1H-NMR (200MHz.CDCl^). 6(ppm): 1.50-1.73 (m,4H,CH2CH2CH2CH2N); 2,14-2,19 (m,2H,CH2 endoc.); 2,38-2,54 (m,4H, CH2CH2CH2CH2N); 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); 5.87 (t.lH. J= 5 Hz, H 25 vin.); 6,64-7,09 (m, 7H, arom.). Hydrochlorate: m.p. 205 °C. WO 94/0044J 36 PCT/EP93/01589 EXAMPLE 23 1-(2-methoxyphenyl)-4-T4-(7-methoxy-l.2.3.4-tetrahydronaphthalen-l-yl) -n-butyl Ipiperazine Following the process described in Example 14 starting from the 5 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++1; 20,9); 408,25 (M+; 75.8); 205,10 (100,0). 10 1H-NMR (200MHz,CDCl^), 6(ppm): 1,30-1,92 (m,10H,CH2CH2 endoc., CH2CH2CH2CH2N); 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. 15 EXAMPLE 24 1-(2-methoxyphenyl)-4-{2-f(7-methoxy-1.2,3,4-te trahydro-naphthalen-l-yl)-thiol-ethylIpiperazine. Ethyl 2-mercapto-acetate (6 mmoles) and Znl2 (3 mmoles) are added to a solution of 7-metnoxy-l-tetralol (6 mmoles) (prepared 20 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 Na2S0i| and the solvent is evaporated, thereby obtaining a yellow oil composed by practically pure ethyl 25 2-[(7-methoxy-l,2,3,4-tetrahydronaphthalen-l-yl)-thio]-acetate WO 94/00441 PCT/EP93/01589 (yield 98%). 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 5 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-l-yl)-thio]-acetic 10 acid (5 mmoles) is treated with 5-6 ml SOCI2 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)-15 piperazine (8 mmoles) in toluene (30 ml) in the presence of trimethyl amine (10 mmoles). After 2 hours the reaction mixture is washed with H2O and with HCl 2N. The organic phase, dried and evaporated, brings to an oily residue that is purified by chromatographic column. 20 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 25 tetrahydrofuran under stirring. The mixture is kept at the boiling temperature for 6 hours, then it is cooled and few drops WO 94/00441 PCT/EP93/01589 38 of H2O 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. 5 200-201 °C. The following analyses are carried out on the free base: MS, m/z (rel. range): 414,25 (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^), 6(ppm): 1,67-2.10 (m,4H,CH2CH2 endoc.); 10 2,56-2,85 [m,10H,CH2 benz.,SCH2CH2N(CH2)2]; 3.10 [broad t.4H,(CH2)2NAr]; 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-[1-(8-methoxy-1,2.3.4-tetrahydronaphthalen-4-yl)-1-propylen-3-15 yl1-1-(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. 20 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. 25 The mixture is directly treated with a HCl solution in diluted WO 94/00441 39 PCT/EP93/01589 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 5 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 10 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 15 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,l); 205.10 (100,0). 20 1H-NMR (200MHz, CDC13), 6 (ppm): 1,82 (m,2H,CH2endoc.); 2,42-2,65 (m,6H,CH2C=CHCH2CH2N); 2,67-2,85 [m,6H.C' anz., CH2N(CH2)2]; 3.15 (broad, s, 4H(CH2)2NAr]; 3.81 and 3,86 (2s,6H,2CH3); 6,00 (broad, s, 1H, H vin.); 6,65-7,22 (m,7H,arom.). Hydrochlorate: m.p. 202-203°C. 25 EXAMPLE 26 4-U~(8-methoxy-l .2.3.4-tetrahydronaphthalen-4-yl)-l-propylen-3- WO 94/00441 PCT/EP93/01589 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): 363.25 (M+:3.6); 176.10 (100,0); 147.10 5 (23.6); 121,10 (35,9). 1H-NMR (200 MHz, CDClj), 6 (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.); 3.49-3.62 [m,4H,(CH2)2NAr]; 3.8l . (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 10 arom). Hydrochlorate: m.p. 221-222*C. EXAMPLE 27 1-(2-methoxyphenyl)-4-f1.2.3,4-tetrahydronaphthalen-4-yl)-1-propylen- 3 ~.y 11 piperazine. 15 The same process described in Example 25 is followed starting from the hydrochlorate obtained in Example 3. MS. m/z (rel. range): 363.20 (M++l;l,4); 362,20 (M+;5.5); 205.05 (100,00); 190,05 (21,6). 1H-NMR (200 MHz, CDC13), 6 (ppm): 1,82 (m,2H,CH2 endoc.); 2,40-20 2,60 (m,6H,CH2C=CHCH2CH2N); 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. ig8-199<'C. BIOCHEMICAL AND PHARMACOLOGICAL TRIALS 25 Preparation of rat cerebral tissue homogenate for receptorial WO 94/00441 41 PCT/EP93/01589 binding experiments. Preparation 1. utilized for binding trial at the receptors: 5-HT1A, 5-HT1B, 5-HT1C, 5~HT2, D-2, D-l, a-1. Cerebral tissue asported from male rats (Sprague Dawley) weighing 5 180-220 g is homogenized in Tris. HCl buffer, 50 mM, pH 7 A 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 10 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 a receptor. 15 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 20 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, 25 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 pM of WO 94/00441 42 PCT/EP93/01589 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 pM). 5 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 pM of pargyline, 4 mM CaCl2, 0.1% of ascorbic acid) and incubated in 10 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 pM) as the blocking agent of 5-HT1A receptors. The aspecific bond is evaluated by the use of 5-HT (10 pM). 5-HT1C Receptor. The methodology described by S.J. Peroutka, J. 15 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 pM 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 20 3H-5HT (2.0 nM) and 80H-DPAT (0.1 pM) 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 pM). 5-HT2 Receptor. The methodology described by A.K.Mir, Eur. J. Pharmacol. 149, 107. (1988) is essentially used. 25 In short, rat frontal cortex homogenate is dissolved in the WO 94/00441 PCT/EP93/01589 43 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 pM). 5 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. HCl 50 mM, pH = 7-^ containing 120 mM of NaCl, 5 mM of KC1, 2mM of CaC^, lmM of MgC^) and incubated in 10 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-23390 (1 pM). D-2 Receptor. The methodology described by I. Creese, Eur. J. Pharmacol. 49, 201, (1978) is essentially used. 15 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 CaC^, 1 mM MgC^) 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 20 agent of 5-HT2 receptors. The aspecific bond is evaluated by the use of Butaclamol (10 pM). a-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 25 incubation buffer (Tris.HCl 50 mM, pH = 7-7 containing 10 pM pargyline, 0.1% ascorbic acid) and incubated in the final volume WO 94/00441 44 PCT/EP93/01589 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 UM). ct 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 10 evaluated by the use of Haloperidol (1 pM). 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)]-15 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 20 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. 25 1: presence of ambiguous behaviouristic signs. WO 94/00441 45 PCT/EP93/01589 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 5 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. 10 The results of the above mentioned trials are reported in the following Tables 1,2 and 3' WO 94/00441 PCI7EP93/01589 46 TABLE 1 IC 50 (nM) EXAMPLES 5-HT1A 5-HT1B 5-HT1C 5-HT2 EXAMPLE 1 7.01 3084.00 >10000.00 3336.70 EXAMPLE 2 2.00 1134.00 1022.45 221.00 EXAMPLE 3 147.10 3550.00 1699.36 390.80 EXAMPLE 4 131.10 5118.00 7400.40 132.50 EXAMPLE 5 138.10 6102.10 5224.74 1173.80 EXAMPLE 6 63.60 5373-53 1960.11 146.20 EXAMPLE 7 160.70 5793.13 2556.85 932.30 EXAMPLE 8 18.30 6108.00 5449.00 204.00 EXAMPLE 9 8.82 >10000.00 >10000.00 770.00 EXAMPLE 10 31.50 9643.42 3928.07 1337.90 EXAMPLE 11 55-89 >10000.00 2767.60 2366.00 EXAMPLE 12 1.42 7067.54 7911.43 204.60 EXAMPLE 13 ' 15.72 8511.88 6884.38 103.80 EXAMPLE 14 1.50 1512.52 1005.31 219.60 EXAMPLE 15 88.40 1789.71 1783.98 390.60 EXAMPLE 16 0.36 6968.90 1888.62 170.30 EXAMPLE 17 0.32 1007.80 1011.29 357.90 EXAMPLE 18 O.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 2728.72 155.20 EXAMPLE 22 1.53 992.37 888.70 208.60 WO 94/00441 47 PCT/EP93/01589 EXAMPLE 23 0.89 1570.30 1970.60 400.30 EXAMPLE 24 5-94 2740.41 >10000.00 110.80 EXAMPLE 25 0.52 913.72 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 WO 94/00441 PCT/EP93/01580 48 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 0.87 EXAMPLE 17 <0.10 EXAMPLE 26 <0.10 WO 94/00441 PCT/EP93/01589 49 TABLE 3 IC 50 (nM) EXAMPLES D1 D-2 a a-1 EXAMPLE 1 1092.3 17.8 152.7 149.4 EXAMPLE 2 1531.0 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 17.4 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 1692.8 20.0 59.9 1.9 EXAMPLE 18 1168.0 176.7 407.6 31.4 EXAMPLE 15 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 </div>

Claims

<div class="application article clearfix printTableText" id="claims"> WO 94/00441 PCT /EP93/0158® EXAMPLE 22 2090.3 10.7 80.7 15.3 EXAMPLE 23 4070.1 20.7 96.7 90.3 EXAMPLE 24 2789.8 50.2 « 270.2 110.2 EXAMPLE 25 1753.8 11-3 52.1 5-6 EXAMPLE 26 1603.2 150.3 99-1 12.2 EXAMPLE 27 5820.40 12.7 82.7 3.6 Buspirone >10000.0 275.2 262.8 1 2 3 4 5 6 7 8 9 10 11 12 13 1. 51. CLAIMS A compound of formula (I) 253689 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^-Cg alkyl, halogen atoms , Ci-C5 haloalkyl and methoxy; and heteroaryl containing one or more heteroatoms selected on their turn from N, 0 snd s, said heteroaryl being optionally substituted with a CfCj alkyl group, said heteroaryl being a monocyclic group of from 5 to 6 atoms or condensed on an aryl group optionally substituted with the aforementioned C,-Cs alkyl groups; Ari is an aryl of from 5 to 6 carbon atoms or a heteroaryl of from 5 to 6 member ring containing from 1 to 3 heteroatoms, selected from N, O and S condensed with a CrCs ring; R, and Rj equal or different from each other are selected from H, C]_—C5 alkoxy, OH, Ci-Cs alkyl and NQ2; the group Y- \ / X 1 amended sheet 17 is seiec-ced from: 25 3 68 52 18 n « nA 18 ii 11) 19 iiil 20 iv) and 21 V) ' 4 22 n is l or 2; and m is 2 or 3; and the pharmaceutically acceptable 23 salts thereof. 12. A compound of formula (I) according to claim 1 wherein Ar^, 2 is a phenyl group condensed on the alicyclic ring to form a 3 compound of formula (IB) r~\ * <cv»-* /- (CHj). Ar2 (IB) amended sheet 2 5 3 68 9 53 4 wherein 5 Ar2 is selected from pyridyl, phenyl, mono or di—substituted phenyl in 6 which the substituent(s) is (are) selected on its (their) turn 7 from linear or branched Ci-Cs alkyl, halogen atoms, Ci-Cj 8 haloalkyl and methoxy; * 9 Ri and R2 equal or different from each other are selected from 10 H, C1-C5 alkoxy, OH, C1-C5 alkyl and NO2; 11 the group \ /" x I 12 is selected from: 13 i) 4 14 ii) 15 iii) 16 iv) 17 V) I 18 n is 2; and m is 2 or 3; and the pharmaceutically acceptable salts 19 thereof. H V" • T • * 25 3 68 9 54 1 3. A compound of formula (I) according to claim 1 or 2 wherein 2 R^ is OCH3, and R2 is H. 14. A compound of formula (I) according to any one r.f the 2 preceding claims wherein At2 is selected from: 2-methoxyphenyl, 3 3-chlorophenyl, 3-trifluoromethylphenyl, 2-pyridyl and 2,5- 4 dimethyloxyphenyl. 1 5. A compound according to claim 2 (general formula IB) wherein 2 the moiety: 3 is represented by a dihydronaphthalene group and Ar2 is a phenyl 4 (or substituted phenyl) group, selected from: 5 4-[3—(6-methoxy-l,2-dihydronaphthalen-4-yl)n-propyl]-l-(2- 6 methoxyphenyl)-piperazine; 7 l-phenyl-4-[3-(8-methoxy-l,2-dihyaronaphthalen-4-yl)-n-propyl] - 8 piperazine; 9 4—[3—(8-methoxy-l,2-dihydronaphthalen-4-yl)-n-propyl]-l-(2- 10 methoxyphenyl)-piperazine; 11 4-[3-(1,2-dihydronaphthalen-4-yl)-n-propyl]-1-(2-methoxyphenyl )- 12 piperazine; 13 4-[4-(6-methoxy-l,2-dihydronaphthalen-4-yl)-n-butyl]-1^23^^ 14 methoxyphenyl)-piperazine; c\. 15 i-( 3-chlorophenyl )-4-[3-( 8-methoxy-l, 2-dlhydronapl|thalen-4-yW-| I'/- ^ f 16 n-propyl]-piperazine; and \ ? ' ,_Q,/ AMENDED SHEET 25 3 68 9 55 17 4-[3-(3-methoxy-l,2-dihydronaphthalen-4-yl)n-propyl]-l-(3- 18 trifluoromerhylphenyl)-piperazine; 19 and the pharmaceutically acceptable salts thereof. 16. A compound according ro claim 2 (general formula IB) wherein 2 the moie"cy: 3 is represented by a tetrahydronaphthalen.yl group and Ar2 is a 4 phenyl (or substituted phenyl) group, selected from: 5 l-(2-methoxyphenyl)-4[N-(5-raethoxy-l,2,3,4-tetrahydro - 6 naphthalen"1 -yl)-2-aminoethyl ] -piperazine; 7 1-(2-methoxyphenyl)- 4- [3 -( 7-methoxy-l, 2,3,4-tetrahydro- 8 naphthalen-1 -yl) -n-propyl ] -piperazine; 9 l-phenyl-4-[3-( 5-methoxy-l, 2,3,4-tetrahydronaphthalen-l-yl )-n-propyl]-piperazine; 11 l-( 2-methoxyphenyl) —4— [3— ( 5-methoxy-l,2,3,4-tetrahydro 12 naphthalen-1-yl)n-propyl] -piperazine; 13 i_ (2-methoxyphenyl )-4-[3-(4,5,6,7-terrahydronaphthalen-l-yl) -n- 14 propyl]-piper.?.:: 15 1-( 2-methoxyphenyl )-4-[4-( 7-methoxy-l, 2,3,4-tetrahydro 16 naphthalen-1-yl )-n—butyl] -piperazine; R (CHA 17 l-( 2-methoxyphenyl )-4-{2[ ( 7-methopxy-l, 2,3,4-tetrah 18 naphthalen-1-yl )thio]-ethyl}-piperazine; 2 5 3 6 8 9 56 19 4-[l-(8-methoxy-l,2,3,4-tetrahydronaphthalen-4-yl)-l-propylen-3- 20 yl]-l-( 2-methoxyphenyl)-piperazine; % ^^21 l-(2-methoxyphenyl)-4-[(1,2,3,4-tetrahydronaphthalen-4-yl)-l- 22 propylen-3-yl]-piperazine;and 23 4-[3-(7-methoxy-l,2,3,4-tetrahydronaphthalen-l-yl)n-propyl]-1- 24 (3-trifluoromethylphenyl)-piperazine; 25 and the pharmaceutically acceptable salts thereof. a 17. A compound according to claim 2 (general formula IB) wherein 2 At2 is a pyridyl group, selected frcm: 3 4-[3-(8-methoxy-l,2-dihydronaphthalen-4-yl)-n-propyl]-l-(2- 4 pyridyl)-piperazine; 5 4—[3—(5-methoxy-l,2,3,4-tetrahydronaphthalen-l-yl)-n-propyl]-1- 6 (2-pyridyl) -pipierazine; ^^7 4-[3-(7-methoxy-l,2,3,4-tetrahydronaphthalen-l-yl)-n-propyl]-1- 8 (2-pyridyl)-piperazine; and 9 4-[1-(8-methoxy-l,2,3,4-tetrahydronaphthalen-4-yl)-l-propylen- 10 3-yl]-l-( 2-pyridyl)-piperazine; 9 11 and the pharmaceutically acceptable salts thereof. 1 8. A process for preparing a compound of formula (I) as defined 2 in claim 1, wherein the group Y \ / X 3 is: 4 i) H 2 5 3 68 9 57 5 and vnerein Ari, Ri, ' -• n and are as defined in 6 comprising the following snaps: 7 a) reaching a ketone cf fsraula (ZZ) c-a: R| R* rrnL (CH^ a wherein Ar:, Ri, R2 and n are as defined above, 9 cf fsrsala (III) (II) i»"ith a cczcound 10 11 12 \ H2N-(CH2)B-^ y*-Ar2 (III) wherein a and Ar2 are as defined above, in an apolar solvent under reflux and in the presence of catalytic amounts cf an acii. thereay obtaining a ccapouna cf formula (IV) 13 (Vyy -(cHA-t. (CKJ, wherein Ar*, , R2/ n, m ana Ar? are as defined above: ana 14 15 16 reaucir.g a conpour.a reding s~ep a> with sc:: : r.snnerature. fcrsula (IV) obtained ir. tr.e u- ccronyciride in a polar sriver.r = ■ AMENDED SHEET 1 2 3 4 5 6 7 8 9 10 11 12 2 5 3 6 8 9 58 9. A process for preparing a compound of formula (I) as defined in claim 1 wherein the group Y- \ / X is selected from: ii) iii) and v) and wherein Ari, Rj., R2, m, n and Ar2 are as defined in claim 1, comprising the following seeps: a') reacting a ketone of formula (II) as defined in claim 8, with a Grignard reagent R3-MgX, wherein R3 is cyclopropyl or (CH2) 4CI and X is a halogen atom, in an etheral solvent thereby obtaining a compound of formula (V) amended sheet •17 18 19 20 £ 21 22 23 2 5 368 9 59 wherein Ar^, Rlf R2/ R3 anci n ara as defined above; b1) reacting the compound of foraula (V) obtained in the preceding seep a') with HCl in acetic acid thereby obtaining a compound of formula (VI) or (VIA) (VI) (VIA) wherein Ari, R1# R2 and n are as defined above and wherein either d is l whe-i in the compound of formula (V) R3 is cycicpropyl, or p is 2 when R3 is -(CH2)4-C1; c') reacting the compound of fcrsuia (VI) or (VIA) obtained ir. the preceding step b') with a compound of f oraula (VII) wherein Ar2 is as defined above;thereby obtaining a compound c: formula (I) wherein amended SHEO 60 2 5 3 68 9 Y- \ / X I 24 and, if desired, 25 d') reacting a compound of formula (I) obtained in the 26 preceding step c1) with, hydrogen in the presence of one or more catalysts 27 consisting of one or more noble metals in a polar solvent thereby obtaining 28 another compound of formula (I) wherein or v) is iii) 1 io A process for preparing a compound of formula (I) as 2 defined in claim 1 and the pharmaceutically acceptable salts 3 thereof wherein 4 the group Y- is: iv) 6 7 and wherein Ar^ , R,, R2, n, m, and Ar2 1, comprising the following steps: are ^ed in clain ED SHEET 15 16 17 18 25 3 68 9 61 a1') reacting a ketone of formula (II) as defined in claim 8, in the presence of a reducing agent thereby obtaining a compound of formula (VIII) Ri Rj <3? ^—a (CH OH (VIII) (CH,). wherein Atx, Ri, R2 and n are as defined above, b'*) treating a compound of formula (VIII) obtained in the preceding step a11) with ethyl 2-mercapto—acetate and Znl2, thus obtaining a compound of formula (IX) (IX) wherein Ari, Rlf R2 and n are as defined above; c'') hydrolyzing a compound of formula (IX) to the corresponding acid and successively treating this acid with thionyl chloride to obtain a compound of formula (X) 62 2 5 3 68 9 19 wherein Arj., Ri, R2 and n are as defined above; 20 d'') reacting a compound of formula (X) with a compound of 21 formula (VII) as defined in claim 9 thereby obtaining a 22 compound of formula (XI) (XI) 23 wherein Arlf Ri, R2, n and Ar2 are as defined above, and 24 e'') treating the compound of formula (XI) with LiAlH4. 1 11. A therapeutic composition containing as the active 2 principle one or more compounds of formula (I) , or 3 pharmaceutically acceptable salt thereof, as defined in claim 1 4 4 in combination with one or more suitable excipients and/or diluents. 1 12. Use of a compound of formula (I), or pharmaceutically 2 acceptable salt thereof, as defined in claim 1 for die manufacture of a medicament for the 3 treatment of generalized anxiety, j^nic attacks, obsessive-compulsive 4 syndromes, depression, opium-like psycho stimulant substances 5 and alcohol abuse syndromes, cognitive disorders, senile 6 dementia, vigilance and memory disorders, Parkinson's and 7 Alzheimer's diseases, schizophrenia or cerebral ischemia. 1 13- Use of a crwpc'und of formula (I) , or pharmaceutically 2 acceptable salt thereof, as defined in claim 1 for the manufacture of a medicament for the 3 1 treatment of cognitive disorders, senile dementia, vigilance 4 and memory disorders, Parkinson's and Alzheimer's diseases. | amended S.-'-p- </div>