CA2137685A1 - N(hetero)-aryl-n-(hetero)-tetralin-alkyl-piperazine having serotoninergic, dopaminergic and adrenergic activity - Google Patents

N(hetero)-aryl-n-(hetero)-tetralin-alkyl-piperazine having serotoninergic, dopaminergic and adrenergic activity

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Publication number
CA2137685A1
CA2137685A1 CA002137685A CA2137685A CA2137685A1 CA 2137685 A1 CA2137685 A1 CA 2137685A1 CA 002137685 A CA002137685 A CA 002137685A CA 2137685 A CA2137685 A CA 2137685A CA 2137685 A1 CA2137685 A1 CA 2137685A1
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Prior art keywords
formula
piperazine
compound
methoxy
methoxyphenyl
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Abandoned
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CA002137685A
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French (fr)
Inventor
Roberto Perrone
Francesco Berardi
Francesco Fiorentini
Stefano Govoni
Vincenzo Olgiati
Ermes Vanotti
Mariano Gobetti
Giancarlo Tonon
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Pfizer Italia SRL
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Individual
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Publication of CA2137685A1 publication Critical patent/CA2137685A1/en
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P25/00—Drugs for disorders of the nervous system
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A—HUMAN NECESSITIES
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    • C07—ORGANIC CHEMISTRY
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
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    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/58—Radicals substituted by nitrogen atoms
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline

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Abstract

N(hetero)-aryl-N(hetero)-tetralinalkyl piperazine having serotoninergic, dopaminergic and adrenergic activity, the pro-cesses 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 disor-ders such as senile dementia, vigilance and memory disorders. Parkinson's and Alzheimer's diseases and for the treatment of ar-terial hypertension.

Description

~ W O 94/00441 ~13 7 ~ 8 5 PCT/EP93/01589 .~ ~5 ~

N(HETERO)-ARYL-N(HETERO)-TETRALIN-ALKYL-PIPERAZINE HAVING
SEROTONINERGIC, DOPAMINERGIC AND ADRENERGIC ACTIVITY .
FIELD OF THE lNV~llON
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 DIS~I.OSTJR~
The active drugs on 5-HTlA receptor resulted effective in the anxiety therapy. These drugs if compared to benzodiazepine are characterized by having a twofold advantage,they are able to produce anxiolythic activity, contemporaneously avoiding the onset of side effect as for example sedation and addiction [Drugs 41,11, (1991)-Trends Pharmacol. Sci. 8, 383, (1987)], and they can be utilized in some anxiety forms resistant to the treatment with benzodiazepins. In fact drugs having 5-HTlA
activity proved useful in the prevention of panic attacks [Psychopharmacology 10,3, (1990)] and for the treatment of obsessive-compulsive disorders [Journal of Psychiatry 147,798, (1990)].
The use of compounds showing 5-HTlA activity has been recently proposed for the treatment of depression [Psychopharmacology 10,77S, (1990) -Psichopharmacology 22, 27, (1989)], and for the W O 94/00441 ~131 68S P ~ /EP93/0 ~ ~

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 a receptors may represent a valid therapeutic approach to the treatment of schizophrenia. In fact the association of D-2 with ~ activity enhances the antipsychotic effect of the compound, whereas the presence of 5-HTlA seems able to reduce the hazard of side extrapi~
effects.[J. Med. Chem. 34 ,1860, (1991) - J. Neural. Transm. 57, 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, 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-Schmiedeberg' s Arch. Pharmacol. 336,597, (1987)]. The above finds also a confirmation in the recent reconsideration of the role of a-l blocking compounds in the treatment of arterial hypertension [JAMA 266, 394, (1991)].
In view of the foregoing it appears evident that compounds shcwing a sufficient selectivity toward 5-HTlA receptors or possessing a mixed activity on 5-HTlA/D-2/a/a-1 or 5-HTlA/~-l are ~ W O 94/00441 2~ 3 ~ 6 8 5 PC~r/EP93/01589 to be considered having a marked therapeutic potential in the aforementioned pathologies.
The N-alkyl-piperazine moiety is present in various structures of agents proposed and used as anxiolythic and antipsychotic compounds, since they are active on 5-HT1 type serotoninergic and/or on the D-2 type dopaminergic receptor system (see TFMPP, Buspirone, Gepirone, Ipsapirone, Tandospirone, (SM-3997), BMY -7378, NAN-19O, WY -47846, RK-153, RK-167, 1-NP, Quipazine, MK-212, m-CPP, oPC-4392, LY 165163 (PAPP), Eltoprazine, (DU-288553), Thiospirone, Revospirone, SM-9018, etc.
In all known N-alkyl-piperazine moieties from the prior art the affinity towards specific 5HT and DA type receptor subgroups resulted to depend on the substituent present on the second nitrogen atom of the piperazine ring, particularly when on this atom an alkyl group is present, being substituted on its turn with groups presenting a considerable structural complexity, the compounds show affinity towards both 5-HTlA- and D-2 receptors, but also towards ~-1 and ~ 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.
T~ ~Nl INVENTION
The present invention relates to N(hetero)-aryl-N(hetero)-~i376~5 tetralin-alkyl-piperazine and their pharmaceutically acceptable salts of general formula (I) R~ R2 )n ~ C ~ ~2 (I) wherein Ar2 is selected from phenyl; mono or di-substltuted aryl in which the substituent(s) is (are) selected on its (their) turn from linear or branched C1-C5 alkyl, halogen atoms, C1-C5 haloalkyl, methoxy; and heteroaryl containing one or more heteroatoms selected on their turn from N, O, S, said heteroaryl being optionally substituted with the above mentioned alkyl groups, said heteroaryl being a monocyc}ic group of from 5 to 6 atoms or condensed on an aryl group optionally substituted with the above mentioned groups, Ar1 is an aryl or a heteroaryl of from 5 to 6 carbon atoms cont~ining from 1 to 3 heteroatoms selected from N, O, or S; R1 and R2 equal or different from each other are selected from H, Cl-C5 alkoxy, OH, Cl-C5 alkyl, N02 and wherein X

is selected from:
AMENDED SHEET

~1~76~5 N~

ii) iii) ~ S~
iv) V) n = l or 2 and m = 2 or 3.
In the present invention the compounds (I) presenting an asimmetry center, may exist in racemic or in optically active form.
The compounds of the present invention are characterized by having a considerable affinity on 5-HTlA setoninergic receptors.
This activity is coupled to a good selectivity towards different serotonine receptor subtypes (as it results from the data reported in Table l).
The compounds of the present invention are active in a W O 94/00441 ~ ~ 3 7 6 8 ~; P ~ /EP93/0 ~ ~

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 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.
Therefore the compounds of the present invention result to act as pure antagonists on 5-HTlA 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, -1 and ~ adrenergic receptors (as it results from the data contained in Table 3 reported later on) to 5-HTlA activity, inducing to suggest that Z 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.
The considerable activity on 5-HTlA receptors induces to W O 94/00441 21 3 7 6 ~ S PC~r/EP93/01589 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 sti llAnt (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-HTlA 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, -l and a receptors, which can be associated or not to as a cnn~i~erable activity on 5-HTlA 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 -l receptor. This activity, associate to a good affinity towards 5-HTlA receptors and to a favourable selectivity ratio towards D-2 and ~ receptors, permits to propose some of the compounds of the present invention for the therapy of W O 94/00441 ~ ~ 3 ~6 8 5 P ~ /EP93/0 ) arterial hypertension.
Therefore the present invention further relates to therapeutic compositions cont~;ning 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 cont~ining the compounds of formula (I) having mainly 5-HTlA serotoninergic activity are suitable for the treatment of generalized anxiety, panic attacks, obsessive-compulsive syndromes, depression, opium like, psycho sti 1l~nt 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-HTlA or affinity on the receptors D-2, a and a-l, are in particular suitable for the treatment of schizophrenia and cerebral ischemia.
The therapeutic compGsitions cont~ining as the active principle the compounds of formula (I) having mainly affinity on 5-HTlA and a-l receptors are used for the treatment of arterial hypert~n~ion N(hetero3aryl-N(hetero)-tetr~lin~lkylpiperazine of formula (I) are prepared with different processes depending on the different X
I

~137C85 W O 94/00441 P ~ /EP93/01589 groups contained in the alicyclic group of formula (I).
For example for preparing the derivative of formula (I) wherein \ /
X

is:

i) ~r the process comprises the following steps:
a) reacting the compounds of formula (II) Rl R2 (~0 (II) (C)n wherein Arl, Rl, R2 and n have the above mentioned -~ning~ with an aminoalkylpiperazine of formula (III):

H2N~(CH2)m N ~ -Ar2 (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):

W O 94/00441 PCT/EP93/0 ~
21376~ lo Rl R2 CH2) -N~ N--Ar2 (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 \ /
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 R3-MgX, wherein R3 is selected from:
cyclopropyl and -(CH2)4Cl in an ethereal solvent thereby obt~ining the tertiary alcohol of formula (V) ii) ~137~g5 R~ R2 ~ R3 OH

~C)n (V) b') reac~ .S the tertiary alcohol (V), co~ing from the preceding step, wi~h HCl in acetic acid, therec: obt~inin~ tne chioride derivative cr formula (VI) or (VIa):
Rl R2 Rl R2 ~ (CH2) \ ~ (CHz)p~ Cl ~lch l C,~

(VI) (Y~LA) wherein p is = 1 or 2 and is =1 when in tr.e reactant (V) R3 is =
cycloprop~-_. or is = 2 in case R3 is = -(C~;2)4-Cl c') react_.5 the chloride intermediate (~.'') or (VIA) oD~ained in the preceiin~ step with N-arylpiperazine Or ~ormula (VII) N-~2 (VII) ~MENDED SHEET

W O 94/00441 P ~ /EP93/0 ~
~37~ 12 wherein Ar2 has the aforementioned meanings thereby obt~in;ng N(hetero)-aryl-N(hetero)-tetr~lin~lkylpiperazine of formula (I) wherein X is ii) ~ or v) ~

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 obt~ining the compounds of formula (I) wherein :

\ / ~
X is iii) The process for preparing the compounds of formula (I) wherein \ / ~S~
xl isiv~ T

comprises the following steps:
a") reacting the aforementioned keton (II) in the presence of a redu~;ng agent thereby obt~ining the corresponding alcohol (VIII) ~137~85 WO 94/00441 PCr/EP93/01589 R~2 QH

Arl ~
l--(C)n (VIII) b") successively treating the alcohol (VIII) obtained in the preceding step, with ethyl 2-mercapto-acetate and ZnI2, thus obt~in;ng the corresponding ester of formula (IX):

R~ R2 Et (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) Rl R2 ,~

Cl (X) d") reacting the acyl chloride (X) with the aforementioned N-aryl-piperazine (VII) thereby obt~ining the corresponding amide (XI): R~2 N N ~2 ~ (XI) e")treating the amide (XI) with LiAlH4 to obtain the desired W 0 94/00441 ~ 1 3 7 ~ ~ 5- PCT/EP93/0 ~

derivative of formula (I).

n~TATr.F.n DESCRIPTION OF THE lNV~llON
In the N(hetero)-aryl-N(hetero)-tetralinalkylpiperazine of formula (I) according to the present invention Arl is an aryl group, which is con~nced on the alicyclic ring so that it forms the derivatives of general formula (IA) ~2 X (C)mrN ~ N - k2 (IA) or the derivatives of general formula (IB):

~; IX (C)m~N ~N--k2 (IB) Rl is preferably, in the compounds of formula (I), OCH3, whereas R2 is preferably H.
Ar2 is preferably selected from : 2-methoxyphenyl, 3-W O 94/00441 1 3 7 6 8 5 ~ PC~r/EP93/01589 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 ~' ;n;stered 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 ~17he;mer's diseasesare those having the active principle selected among one or more of the 15 following derivatives:
- 1-(2-methoxyphenyl)-4-[N-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-2-aminoethyl]-piperazine (example 1 ) ;
- 4-[3-(6-methoxy-1,2-dihydronaphthalen-4-yl)n-propyl-1-(2-methoxyphenyl)piperazine (example 2);
- 1-phenyl-4-[3-(8-methoxy-1,2-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);
- 4-[3-(8-methoxy-1,2-dihydronaphthalen-4-yl)-n-propyl]-1-(2-pyridyl)-piperazine (example 12);

W O 94/00441 7 6~ ;. P ~ /EP93/0 - 4-[3-(1,2-dihydronaphthalen-4-yl)-n-propyl]-1-(2-methoxyphenyl)-piperazine (example 13);
- 1-(2-methoxyphenyl)-4-[3-(7-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-n-propyl]piperazine (example 14);
S - 1-phenyl-4-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-n-propyl]-piperazine (example 16);
- 1-(2-methoxyphenyl)-4-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-n-propyl]-piperazine (example 17);
- 4-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-n-propyl]-1-(2-pyridyl)-piperazine (example 18);
- 4-[3-(7-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-n-propyl]-1-(2-pyridyl)piperazine (example 19);
- 1-(2-methoxyphenyl)-4-[3-(4,5,6,7-tetrahydrobenzo[b]thien-4-yl-) n-propyl]piperazine (example 20);
- 1-(2-methoxyphenyl)-4-[3-(1,2,3,4-tetrahydronaphthalen-1-yl)-n-propyl]piperazine (example 21);
- 4-[4-(6-methoxy-1,2-dihydronaphthalen-4-yl)-n-butyl]-1-(2-methoxyphenyl)-piperazine (example 22);
- 1-(2-methoxyphenyl)-4-L4-(7-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-n-butyl]-piperazine (example 23);
- 1-(2-methoxyphenyl)-4-{2-[(7-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-thio]-ethyl}piperazine (example 24);
- 4-[1-(8-methoxy-1,2,3,4-tetrahydronaphthalen-4-yl)1-propylen-3-yl]-1-(2-methoxyphenyl)piperazine (example 25);

~ W 0 94/00441 ~13 7 6 8 ~ PCT/EP93/OlS89 17 - 4-[1-(8-methoxy-1,2,3,4-tetrahydronaphthalen-4-yl)-1-propylen-3-yl]-1-(2-pyridyl)piperazine (example 26);
- 1-(2-methoxyphenyl)-4-[(1,2,3,4-tetrahydronaphthalen-4-yl)-1-propylen-3-yl]piperazine (example 27);
- 1-(3-chlorophenyl)-4-t3-(8-methoxy-1,2,-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-1,2,3,4-tetrahydronaphthalen-1-yl)-n-propyl]-1-(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-(2-methoxyphenyl)-piperazine (example 9);
- 4-[3-(1,2-dihydronaphthalen-4-yl)-n-propyl]-1-(2-methoxyphenyl)-piperazine (example 13);
- 1-(2-methoxyphenyl)-4-[3-(7-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-n-propyl]piperazine (example 14);
- 1-phenyl-4-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-n-propyl]-piperazine (example 16);
- 1-(2-methoxyphenyl)-4-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-n-propyl]-piperazine (example 17);
- 4-[4-(6-methoxy-1,2-dihydronaphthalen-4-yl)-n-butyl]-1-(2-methoxyphenyl)-piperazine (example 22);

W O 94/00441 PC~r/EP93tO ~
21~7~85 18 - 1-(2-methoxyphenyl)-4-[4-(7-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-n-butyl]-piperazine (example 23);
- 1-(2-methoxyphenyl)-4[N-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-2-aminoethyl]-piperazine (example 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-(1,2,3,4-tetrahydronaphthalen-1-yl)-n-propyl]piperazine (example 21);
- 1-(2-methoxyphenyl)-4-{2-[(7-methoxy-1, 2, 3, 4 -tetrahydro-naphthalen-1-yl)-thio]-ethyl}piperazine (example 24);
-4-[1-(8-methoxy-1,2,3,4-tetrahydronaphthalen-4-yl)-1-propylen-3-yl]-1-(2-methoxyphenyl)piperazine (example 25);
- 1-(2-methoxyphenyl)-4-[(1,2,3,4-tetrahydronaphthalen-4-yl)-1-propylen-3-yl]piperazine (example 27);
Particularly suitable therapeutic compositions according to the present invention for the treatment of arterial hypertension are those having the active principle chosen among one or more of the following derivatives:
- 4-[3-(6-methoxy-1,2-dihydronaphthalen-4-yl)n-propyl-1-(2-methoxyphenyl)piperazine (example 2);
- 1-phenyl-4-[3-(8-methoxy-1,2-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);

2137~85 ~ W O 94/0044l PC~r/EP93/01589 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-1,2,3,4-tetrahydronaphthalen-1-yl)-n-propyl]piperazine (example 14);
1-(2-methoxyphenyl)-4-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-n-propyl]-piperazine (example 17);
4-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-n-propyl]-1-(2-pyridyl)-piperazine ~example 18);
4-[4-(6-methoxy-1,2-dihydronaphthalen-4-yl)-n-butyl]-1-(2-methoxyphenyl)-piperazine (example 22);
1-phenyl-4-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-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-(4,5,6,7-tetrahydrobenzo[b]thien-4-yl)-n-propyl]piperazine (example 20);
1-(2-methoxyphenyl)-4-[3-(1,2,3,4-tetrahydronaphthalen-1-yl)-n-propyl]piperazine (example 21);
1-(2-methoxyphenyl)-4-[4-(7-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-n-butyl]-piperazine (example 23);
1-(2-methoxyphenyl)-4-{2-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-1-yl)-thio]-ethyl}piperazine (example 24);
4-[1-(8-methoxy-1,2,3,4-tetrahydronaphthalen-4-yl)1-propylen-3-yl]-1-(2-methoxyphenyl)piperazine (example 25);

W O 94/00441 ~ ~ 3 ~ ~ ~ 5 PCT/EP93/0 - 4-[1-(8-methoxy-1,2,3,4-tetrahydronaphthalen-4-yl)-1-propylen-3-yl]-1-(2-pyridyl)piperazine (example 26);
-1-(2-methoxyphenyl)-4-[(1,2,3,4-tetrahydronaphthalen-4-yl)-1-propylen-3-yl]piperazine (example 27).
In particular as one can realize from what above stated, being in any case easily deducible from the data reported in tables 1-3 reported hereinbelow, some of these compounds may be advantageously utilized contemporaneously for the therapy of generalized anxiety, schizophrenia and arterial hyperten.qion.
lO 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-yl)-n-propyl]-1-(2-methoxyphenyl)-piperazine (example 13);
- 1-(2-methoxyphenyl)-4-[3-(7-methoxy-1,2,3,4-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-[4-(6-methoxy-1,2-dihydronaphthalen-4-yl)-n-butyl]-1-(2-methoxyphenyl)-piperazine (example Z2);
- l-phenyl-4-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-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);
- 1-(2-methoxyphenyl)-4-[3-(1,2,3,4-tetrahydronaphthalen-1-yl)-n-~137685 W O 94/00441 P ~ /EP93/01589 propyl]piperazine (example 21);
- l-(2-methoxyphenyl)-4-[4-(7-methoxy-l,2,3,4-tetrahydronaphthalen-l-yl)-n-butyl]-piperazine (example 23);
- l-(2-methoxyphenyl)-4-{2-[(7-methoxy-l,2,3,4-tetrahydronaphthalen- l-yl)-thio]-ethyl}piperazine (example 24);
- 4-[l-(8-methoxy-l,2,3,4-tetrahydronaphthalen-4-yl)-l-propylen-3-yl]-1-(2-methoxyphenyl)piperazine (example 25);
- l-(2-methoxyphenyl)-4-[(l,2,3,4-tetrahydronaphthalen-4-yl)-l-propylen-3-yl]piperazine (example 27).
N-aminoalkylpiperazine of formula (III) H2N (CH2)m N\ N-Ar2 (III) is prepared by reacting previously mentioned N-arylpiperazine (VII) with nitrile bromide of formula (XII) Nc-(cH2)m-l-Br in the presence of a polar solvent and of a weak base thereby obt~ining the intermediate (XIII) W O 94/00441 P ~ /EP93/01 ~37G~ 22 NC (CH2)m-1 N N-Ar2 ~ (XIII) which is on its turn treated with lithiumalllminllr~ydride 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.

1-(2-methoxyphenyl)-4-[N-(5-methoxy-1,2,3,4-tetrahydronaphtalen-1-yl)-2-aminoethyllpiperazine .
Brcmoacetonitrile (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, fiitered 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. LiAlH4 (10 mmoles) are added to the solution. The mixture is left under reflux for 1 hour, then it is cooled and the excess of hydride is destroyed by adding some drops of water. The mixture is then filtered, brought to dryness under reduced pressure and a colourless oil composed by N(aminoethyl)-N-arylpiperazine is obtained (yield 90%), which is purified by column chromatography.
The product coming from this purification (10 mmoles) is dissolved in anhydrous toluene and reacted with 5-methoxy-1-~137~8~
~ W O 94/00441 PC~r/EP93/01589 .. , ~

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 ; s~;~tely dissolved in anhydrous ethanol. NaBH4 (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 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).
lH-NMR (200 MHz,CDC13), o(ppm): 1,66-2,07 (m,4H,CH2CH2 endocyclic); 2,17 (broadened s ,lH,~x~h~nFes with D20,NH); 2,46-
2,93 [m,lOH,CH2 benzyl, NCH2CH2N(CH2)2]; 3,o8 [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.

4-[3-(6-methoxy-1,2-dihydronaphthalene-4-yl)-n-propyll-1-(2-methoxyphenyl)piperazine.
7-methoxy-1-tetralone (6 mmoles) solubilized in tetrahydrofuran (10 ml) are added to a solution of cyclopropyl ~ne~ium 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 r ,i W O 94/00441 P ~ /EP93tO ~
~1~768~4 washed with water, brought to dryness and a raw reaction product is obtained, composed mainly by 1-cyclopropyl-7-methoxy-1,2,3,4-tetrahydronaphthalen-1-ol, in the form of a dark oil.
The mixture is directly treated with a solution of HCl in diluted acetic acid and it is kept at room t ~ ture for about 2 hours, then is treated with alkali and extracted with CHCl3.
The solvent is evaporated and the dark oil obtained is purified by column chromatography; a product composed by 4-(3-chloropropyl)-6-methoxy-1,2-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 NaI (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 dimethylfol- de, it is diluted with H20 and extracted with CHC13. 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).
lH-NMR (200MHz,CDC13), ô(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. 180-182 C.

~13768~
W O 94/00441 25 P ~ /EP93/01589 l-phenyl-4-[3-(6-methoxy-1,2-dihydronaphthalen-4-yl)-n-propyl]-piperazine The same process described in Example 2 is followed with the only difference that in this case l-phenyl piperazine is used.
MS, m/z (rel. range): 364,25 (M++2; 3,3); 363,25 (M++l; 25,9);
362,25 (M+; 100,0); 175,10 (34,1); 173,10 (32,1); 132,10 (25,8).
lH-NMR (200MHz,CDCl3), o(ppm): 1,69-1,87(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~ 7 [
(CH2)2NAr]; 3,81(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.

1-(3-chlorophenyl)-4-r3-(6-methoxy-1,2-dihydronaphthalen-4-yl)-n-propyl]-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++l; 30,7); 396,15 (M+; 100,0);
209,10 (59,3); 207,00 (32,4); 166,00 (26,5).
lH-NMR (200MHz,CDCl3), o(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 [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 (m,7H,arom.).

W O 94/00441 ~13 7 ~ ~ S PC~r/EP93/0 ~

Hydrochlorate: m.p. 184-185 C.

4-[3-(6-methoxy-1,2-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-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);
200 00 (45,1); 172,10 (23,9).
lH-NMR (200MHz,CDCl3), ~(ppm): 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 [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 (m,7H,arom.).
Hydrochlorate: m.p. 189-190 C .
4-[3-(6-methoxy-1,2-dihydronaphthalen-4-yl)-n-propyl]-1-(2-pyridyl)piperazine The same process described in Example 2 is followed, with the only difference that in this case 1-pyridylpiperazine is used.
MS, m/z (rel. range): 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).
lH-NMR (200MHz,CDCl3), o(ppm): 1,70-1,90 (m,2H,CH2CH2CH2); 2,13-~37685 W O 94/00441 P ~ /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.).
Hydrochlorate: m.p. 225-226 C.

1-(2,5-dimethoxyphenyl)-4-[3-(6-methoxy-1,2-dihydronaphthalen-4-yl)-n-propyll-piperazine The same process described in Example 2 is followed, with the 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++l; 27,4);
422,25 (M+; 100,0).
lH-NMR (200MHz,CDCl3), o(ppm): 1,72-1,91 (m,2H,CH2CH2CH2), 2,14-2,28 (m~2H~cH2 endoc.); 2,39-2,83 [m,lOH,CH2 benz., _ 2CH2CH2N(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.

l-phenyl-4-~3-(8-methoxy-1.2-dihydronaphthalen-4-yl)-n-propyl]
piperazine The same process described in Example 2 is followed, with the only difference that in this case 5-methoxy-tetralone and 1-phenyl-piperazine are used.
MS, m/z (rel. range) : 364,25 (M++2; 3,4); 363,25 (M++l; 25,3);

~ f ~
W O 94/00441 PCT/EP93/0 ~

362,25 (M+; 100,0); 175,10 (36,8); 173,10 (30,3); 132,10 (26,5).
lH-NMR (200MHz,CDCl3) o(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,8H,arom.).
Hydrochlorate: m.p. 174-176 C.

4-[3-(8-methoxy-1.2-dihydronaphthalen-4-yl)-n-propyl]-1-(2-me-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++1; 27,0);
392,25 (M+; 100,0); 205,05 (25,6); 203,15 (24,6).
1H-NMR (200MHz, CDCl3), o (ppm): 1,71-1,88 (m,2H,CH2C_2CH2);
2,13-2,27 (m,2H,CH2 en~oc.); 2,42-2,58 (m,4H,C_2CH2C_2N); 2,62-2,84 [m,6H,CH2benz.,CH2N(C_2)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. 209-21~ C.

1-(3-chlorophenyl)-4-[3-(8-methoxy-1,2-dihydronaphthalen-4-yl)-n-propyl]piperazine The same process described in Example 8 is followed, with the ~137~5 W O 94/00441 P ~ /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+~l; 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).
lH-NMR (200MHz,CDCl3), ô(ppm): 1,66-1,85 (m,2H,CH2CH2CH2); 2,13-2,28 (m~2H~cH2 endoc.); 2,39-2,80 (m~loH~cH2 b Z ~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.

4-[3-(8-methoxy-1,2-dihydronaphthalen-4-yl)-n-propyl]-1-(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++l; 21,5);
430,25 (M+; 79,4); 256,10 (32,0); 243,00 (100,0); 241,00 (35,1);
200,00 (56,4); 172,00 (20,1).
lH-NMR (200MHz,CDCl3), ~(ppm): 1,73-1,91(m,2H,CH2CH2CH2); 2,14-2,28 (m,2H,CH2 endoc.); 2,42-2,82 (m,lOH,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

;i J ~

W O 94/00441 ~ ~ 3 7 S ~ ~ 30 PC~r/EP93/0 4-r3-(8-methoxy-l~2-dihydronaphthalen-4-yl)-n-propyll-l-(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;1,8); 364,Z5 (M++1;14,3);
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).
lH-NMR (200MHz, CDC13), o (ppm): 1,67-1.86 (m, 2H,CH2C_2CH2);
2,13-2,28 (m, 2H,CH2 endoc.); 2,40-2,63 [m,8H,C_2CH2 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. 218-220 C.

4-[3-(1,2-dihydronaphthalen-4-yl)-n-propyl]-1-(2-methoxyphenyl) piperazine The same process described in Example 8 is followed, with the only difference that 1-(2-methoxyphenyl)-piperazine is used.
MS, m/z (rel. range): 364,25 (M +2; 3,4); 363,25 (M++1;27,1);
362,25 (M ;100,0); 205,10 (31,3); 203,10 (30,4); 162,10 (22,9).
lH-NMR (200MHz,CDCl3), o (ppm): 1,72-1,83 (m,2H,CH2C_2CH2); 2,19-2,28 (m,2H,CH2endoc.); 2,43-2,55 (m,4H,C_2CH2CH2N); 2,62-2,78 [m,6H,CH2benz., CH2N(CH2)2]; 3,10 [broad.t, 4H, (CH2)2NAr]; 3,84 ~1~7~85 W 0 94/00441 31 P ~ /EP93/01589 (s,3H,CH3); 5,87 (t,lH, J=4,5 Hz, H vin.); 6,82-7,27 (m,8H, arom.).
Hydrochlorate: m.p. 185-187 C.

1-(2-methoxyphenyl)-4-[3-~7-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-n-propyl]piperazine 1-[3-(6-methoxy-1,2-dihydronaphthalen-4-yl)-n-propyl]-4-(2-metho-xyphenyl)piperazine hydrochlorate (2 mmoles) obtained as described in Example 2, is solubilized in MeOH (30 ml) and hydrogenated in the presence of a catalytic amount of 10X 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).
lH-NMR (200MIlz,CDC13), ~(ppm): 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 (m,7H, arom.).

4-[3-(7-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-n-propyl]-1-(3-trifluoromethylphenyl)piperazine The same process described in Example 14 is followed, starting ~3~ ~5 W O 94/00441 32 P ~ /EP93/0 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++l; 16,7), 432,25 (M+; 58,6); 243,10 (100,0); 230,10 (36,3).
lH-NMR (200MHz,CDC13), ô(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 Hz, (CH2)2NAr]; 3,77 (s,3H,CH3);
6,61-7,40 (m,7H,arom.).

l-phenyl-4-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-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); 365,30 (M++l; 21,4);
364,30 (M+; 80,5); 175,15 (100,0); 162,05 (35,0).
lH-NMR (200MHz,CDC13), o~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);
6,62-7,35 (m,8H,arom.).
Hydrochlorate: m.p. 206-207 C.

1-(2-methoxyphenyl)-4-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-l-yl)-n-propyl]piperazine The same process described in the Example 14 is followed, 2i3~&8~

starting from the hydrochlorate obtained in Example 9.

MS, m/z (rel. range): 396,30 (M++2; 3,3); 395,30 (M++l; 23,0);

394,30 (M+; 82,7); 205,10 (100,0); 192,10 (34,4); 150,10 (21,8).

lH-NMR (200MHz,CDCl3), o(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.

4-r3-(5-methoxy-l~2~3~4-tetrahydronaphthalen-l-yl)-n-pr (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++l; 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).
lH-NMR (200MHz,CDCl3), o(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.

4-r3-(7-methoxy-l~2~3~4-tetrahydronaphthalen-l-yl)-n-propyll-l-(2 pyridyl)piperazine The same process described in Example 14 is followed, starting W O 94/00441 P ~ /EP93/0 ~
~37~

from the hydrochlorate obtained in Example 12.
MS, m/z (rel.range): 367,25 (M++2;1,3); 366,25 (M++1;9,6); 365,25 (M+;39,7); 271,15 (21,7); 258,15 (60,1); 121,10 (31,7); 107,00 (100,00); 86,10 (24,6); 79,10 (20,7); 72,10 (48,0).
lH-NMR (200MHz, CDC13), o (ppm): 1,53-1,89 (m,8H,CH2CH2 endoc., CHC_2C_2CH2N); 2,50 [broad. t, 2H,CH2N(CH2)2]; 2,61-2,82 [m,7H,CH
and CH2 benz., CH2N(C_2)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. 143-145 C.

1-(2-methoxyphenyl)-4-[3-(4,5,6,7-tetrahydrobenzo[blthien-4-yl)-n-propyl]piperazine.
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;7,5j; 371,20 (M++1;25,0);
370,20 (M+; 100,0); 205,05(59,4); 192,15(25,0); 150,05 (25,4).
lH-NMR (200MHz, CDC13), o (ppm): 1,42-2,01 (m,8H,CH2 endoc., CHC_2C_2CH2N); 2,45 [t,2H, J=7,3Hz, C_2N(CH2)2]; 2,61-2,81 [m,7H,CH and CH2 benz., CH2N(C_2)2]; 3,12 [ broad. s, 4H, (C_2)2NAr]; 3,86 (s,3H,CH3); 6,82-7,05 (m,6H,arom.).
Hydrochlorate: m.p. 217-218 C.

1-(2-methoxyphenyl)-4-[3-(1,2,3,4-tetrahydronaphthalen-1-yl)-n-propyl]piperazine.
The same process described in Example 14 is followed, starting ~37685 W O 94/00441 35 PC~r/EP93/01589 from the hydrochlorate obtained in Example 9.
MS, m/z (rel. range): 366,25 (M++2;2,8): 365,25 (M++1;21,4);
364,25 (M+;77,7) 205,5 (100,0); 192,15 (30,7); 150,05 (24,5);
91,05 (21,3).
lH-NMR (200 MHz, CDCl3), o (ppm): 1,54-1,92 (m,8H,CH2CH2 endoc., CHC_2CH2CH2N); 2,45 [broad. t,2H,C_2N(CH2)2]; 2,62,-2,88 [m,7H,CH
and CH2 benz., CH2N(C_2)2]; 3,12 [broad.s, 4H,(C 2)2NAr]; 3,86 (s,3H,CH3); 6,82-7,21 (m, 8H, arom.).
Hydrochlorate: m.p. 223-224 C.

4-r4-(6-methoxy-l~2-dihydronaphthalen-4-yl)-n-butyl]-l-(2 methoxyphenyl)piperazine
7-methoxy-1-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++l; 29,2);
406,35 (M+; 99,9); 205,10 (22,9).
lH-NMR (200MHz,CDCl3), o(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
vin.); 6,64-7,09 (m, 7H, arom.).
Hydrochlorate: m.p. 205 C.

~37~85 1-(2-methoxyphenyl)-4-r4-(7-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-n-butyl]piperazine 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++1; 20,9);
408,25 (M+; 75,8); 205,10 (100,0).
lH-NMR (200MHz,CDCl3), o(ppm): 1,30-1,92 (m,lOH,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.

1-(2-methoxyphenyl)-4-{2-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-1-yl)-thiol-ethyl}piperazine.
Ethyl 2-mercapto-acetate (6 mmoles) and ZnI2 (3 mmoles) are added to a solution of 7-metnoxy-1-tetralol (6 mmoles) (prepared according to a known method from 7-methoxy-1-tetralone) in CH2Cl2 (12 ml). After two hours under stirring the reaction mixture is poured into water and extracted with CH2Cl2. The extracted solution is dried on Na2S04 and the solvent is evaporated, thereby obt~;n;ng a yellow oil composed by practically pure ethyl 2-[(7-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-thio]-acetate ~3~6~

W 0 94/00441 P ~ /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 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-1,2,3,4-tetrahydronaphthalen-1-yl)-thio]-acetic acid (5 mmoles) is treated with 5-6 ml SOCl2 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 oftrimethyl amine (10 mmoles). After 2 hours the reaction mixture is washed with H20 and with HCl 2N.
The organic phase, dried and evaporated, brings to an oily residue that is purified by chromatographic column.
The corresponding 4-(2-methoxyphenyl)piperazinamide of the above mentioned acid is thereby obtained as a yellow brown oil in a yield of 47~.
This amide (2 mmoles) dissolved in tetrahydrofuran (20 ml) is added drop by drop to a suspension of LiAlH4 (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 -W O 94/00441 ~13 7 6 8~ P ~ /EP93/0 4 of H20 are added, then the usual process is followed thereby obt~;ning a light yellow oil in a yield of 83%.
The product is then transformed into the corresponding hydrochlorate and crystallized from CHCl3/petroleum ether, m.p.
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).
lH-NMR (200 MHz,CDCl3), ~(ppm): 1,67-2,10 (m,4H,CH2CH2 endoc.);
2 56-2 85 [m,lOH,CH2 benz.,SCH2CH2NtCH2)2]; 3,10 [
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,o4 (m,7H,arom.).

4-[1-(8-methoxy-1,2,3,4-tetrahydronaphthalen-4-yl)-1-propylen-3-yl]-1-(2-methoxyphenyl)piperazine
8-methoxy-1-tetralone (6 mmoles) solubilized in tetrahydrofuran (10 ml) are added to a solution of cyclopropylm~gn~sium 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 1-cyclopropyl-8-methoxy-1, 2, 3, 4-tetrahydronaphthalen-1-ol, is obtained under the form of a dark oil.
The mixture is directly treated with a HCl solution in diluted ~ W O 94/00441 ~13 7 6 8 5 P ~ /EP93/01589 acetic acid. The mixture is thereby kept at room temperature for 1 hour, then it is treated with alkali and extracted with CHC13.
The solvent is evaporated and a dark oil is obtained, which is purified by column chromatography; the product recovered in a total yield of 64% is composed by 4-(3-chloro-1-propylen-1-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 NaI (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 CHCl3. After evaporating the solvent the obtained residue is purified by column chromatography thus obt~;ning the desired product in the form of a light yellow oil (yield 82 %).
MS, m/z (rel. range): 393,25 (M++1;2,0);392,25 (M+;7,1); 205,10 (100,0) -lH-NMR (200MHz, CDC13), o (ppm): 1,82 (m,2H,CH2endoc.); 2,42-2,65 (m,6H,CH2C=CHCH2CH2N); 2,67-2,85 [m,6H,CH2benz., CH2N(C_2)2];
3,15 (broad. s, 4H(C_2)2NAr]; 3,81 and 3,86 (2s,6H,2CH3); 6,oo (broad. s, lH, H vin.); 6,65-7,22 (m,7H,arom.).
Hydrochlorate: m.p. 202-203 C.

4-[1-(8-methoxy-1,2,3,4-tetrahydronaphthalen-4-yl)-1-propylen-3-~137~5 WO 94/00441 ~ r j i ~ r ~ PCT/EP93/01 yll-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); 147,10 (23,6); 121,10 (35,9).
H-NMR (200 MHz, CDC13), ~ (ppm): 1,82 (m,2H,CH2 endoc.); 2,37-2,66 [m~10H~C-2C=CHC_2C_2N(C_2)2]; 2,71 (t, 2H, J=6, 3Hz, CH2 benz.); 3,49-3,62 [m,4H,(C_2)2NAr]; 3,81 (s,3H,CH3,6,00 (broad.
t, lH, H vin.); 6,56-7,53 (m,6H,arom.); 8,14-8,25 (m,lH,N=CH
arom).
Hydrochlorate: m.p. 221-222 C.

1-(2-methoxyphenyl)-4-[1,2,3,4-tetrahydronaphthalen-4-yl)-1-propylen-3-yllpiperazine.
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++1;1,4); 362,20 (M+;5,5); 205,05 (100,00); 190,05 (21,6).
H-NMR (200 MHz, CDC13), o (ppm): 1,82 (m,2H,CH2 endoc.); 2,40 2,60 (m,6H,C_2C=CHC_2C_2N); 2,64-2,80 [m,6H, CH2 benz., CH2N(C_2)2]; 3,12 [broad.s,4H,(CH2)2NAr]; 3,85 (s,3H,CH3); 6,oo (broad.t, lH, H vin.); 6,83-7,62 (m,8H,arom.).
Hydrochlorate: m.p. 198-199 C.
BIOCHEMICAL AND p~ARMAcoLoGIcAL TRIALS
Preparation of rat cerebral tissue homogenate for receptorial W 0 94/00441 ~ i 3 i ~ 8 S P ~ /EP93/01589 41 h;n~i n g experiments.
Preparation 1, utilized for binding trial at the receptors:
5-HTlA, 5-HTlB, 5-HTlC, 5-HT2, D-2, D-l, ~
Cerebral tissue asported from male rats (Sprague Dawley) we;ghing 180-220 g is homogenized in Tris. HCl buffer, 50 mM, pH 7.4 with Ultra-Turrax (2 x 20 secs) and centrifugated at 50.000 g for 10 min.. The obtained pellet, resuspended in the same volume of buffer, incubated at 37 C for 10 minutes [Nelson, Mol.
Pharmacol. 14, 983, (1978)], is centrifugated again in the above mentioned conditions. The final pellet is dissolved in the appropriate incubation buffer just before the receptorial binding test.
Preparation 2, used for binding trial at the a receptor.
Cerebral tissue of male Hattly cavy (Charles River) weighing 300-600 g is homogenized in 0.32 M saccarose with Ultra-Turrax (2 x 20 sec.) and centrifugated at 900 g for 10 minutes. The surnatant is centrifugated at 22.000 g for 20 minutes. The obtained pellet, dissolved in Tris.HCl buffer pH = 7.4 is incubated at 37 C for 30 minutes and centrifugated at 22.000 g for 20 minutes.
The final pellet is dissolved in the appropriate incubation buffer just before the test.
2. Operating conditions for the receptorial binding trials.
5-HTlA Receptor. The methodology described by J.R. Schlegel, Biochem. Pharmacol. 35, 1943, (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 ,uM of W 0 94/00441 ~ ~ 3 7 6 ~ 5 P ~ /EP93/0 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-HTlB 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 cont~;ning 10 uM of pargyline, 4 mM CaC12, 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 ,uM) as the blocking agent of 5-HTlA receptors. The aspecific bond is evaluated by the use of 5-HT (10 ~M).
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. HCl 50 mM, pH = 7.7 cont~;n;ng 10 ,uM
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 ,uM) and RU-24960 (lOnM) as the blocking agents respectively of 5-HTlA and 5-HTlB receptors. The aspecific bond is evaluated by the use of 5-HT (10 ,uM).
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 ~1~768~
W O 94/00441 ' P ~ /EP93/01589 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 ,uM).
D-1 Receptor. The methodology described by W.B. Billard, Life Science, 35, 1885, (1984) is essentially used.
In short, rat cauda striati homogenate is dissolved in the incubation buffer (Tris. HC1 50 mM, pH = 7.4 cont~ining 120 mM of NaCl, 5 mM of KCl, 2mM of CaCl2, lmM of MgCl2) and incubated in the final volume of 1 ml at 37 C, for 15 minutes in the presence of 3H-SCH-23390 (0.3 nM). The aspecific bond is evaluated by the use of SCH-23390 (1 ~M).
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.HC1 50 mM, pH = 7.4 cont~in;ng 120 mM
NaCl, 5 mM KCl, 2 mM CaCl2, 1 mM MgC12) and incubated in the final volume of 1 ml, at 37 C for 15 minutes in the presence of 3H-Spiroperidole (0.25 mM) and Ketanserine (40 nM) as blocking agent of 5-HT2 receptors. The aspecific bond is evaluated by the use of Butaclamol (10 ,uM).
~-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.HC1 50 mM, pH = 7.7 cont~;ning 10 ,uM

pargyline, 0.1% ascorbic acid) and incubated in the final volume W O 94/00441 ~ P ~ /EP93/0 ~
~a5 44 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).
a 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 uM).
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 ~r;nistered 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 ~ in;Stration 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.

~ W O 94/00441 213 7 6 8 5 PC~r/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 ~m;ni~tration.
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 ~m;n;~ctration of the products under question starting from 3 minutes after the ~ ;n;~tration of 80H-DPAT.
The results of the above mentioned trials are reported in the following Tables 1,2 and 3.

2~37~5 W O 94/00441 PC~r/EP93/01 -_______________________________________________________________ IC 50 (nM) __________________________________________ EXAMPLES 5-HTlA 5-HTlB 5-HTlC 5-HT2 _______________________________________________________________ EXAMPLE 1 7.013084.00 >10000.003336.70 EXAMPLE 2 2.001134.00 1022.45 221.00 EXAMPLE 3147.103550.00 1699.36 390.80 EXAMPLE 4131.105118.00 7400.40 132.50 EXAMPLE 5138.106102.10 5224.74 1173-80 EXAMPLE 663.60 5373-53 1960.11 146.20 EXAMPLE 7160.705793.13 2556.85 932.30 EXAMPLE 818.306108.00 5449.00 204.00 EXAMPLE 9 8.82>10000.00>10000.00 770.00 EXAMPLE 1031.509643.42 3928.07 1337-9 EXAMPLE 1155-89>10000.00 2767.602366.00 EXAMPLE 121.427067.54 7911.43 204.60 EXAMPLE 1315.728511.88 6884.38 103.80 EXAMPLE 141.50 1512-52 1005.31 219.60 EXAMPLE 1588.401789.71 1783.98 '390.60 EXAMPLE 160.366968.90 1888.62 170.30 EXAMPLE 170.321007.80 1011.29 357.90 EXAMPLE 180.581642.70 2021.37 330.5 EXAMPLE 193.382872.62 2472.86 287.90 EXAMPLE 201.132943.57 3941.84 146.80 EXAMPLE 210.821504.89 2728.72 155.20 EXAMPLE 221.53 992-37 888.70 208.60 21~7685 W O 94/00441 P ~ /EP93/01589 EXAMPLE 23 0.89 1570.30 1970.60 400.30 EXAMPLE 24 5.942740.41>10000.00 110.80 EXAMPLE 25 0.52913.72 2054.58 667.30 EXAMPLE 26 0.351742.601950.70 416.50 EXAMPLE 27 1.84980.00 800.06 147.20 Buspirone 12.78>10000.00>10000.00 _______________________________________________________________ W O 94/00441. PCT/EP93/0 ~
2137~85 DE50 (mg/kg s.c.) EXAMPLE 12.13 EXAMPLE 20.76 EXAMPLE 11 24.19 EXAMPLE 14 o.87 EXAMPLE 17 < 0.10 EXAMPLE 26 < 0.10 W O 94/00441 PCT~EP93/01589 ~1 397685 _______________________________________________________________ __________________________________________ EXAMPLES Dl D-2 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. o 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 13369.21327.5 >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 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 W O 94/00441 ~13 7 ~ 8 5 P ~ /EP93/ ~ ~

EXAMPLE 22 2090.3 10.7 80.7 15.3 EXAMPLE 23 4070.1 20.7 96.7 90.3 EXAMPLE 24 2789.8 50.2 270.2110.2 EXAMPLE 25 1753-8 11.3 52.1 5.6 EXAMPLE 26 1603.2 150.3 99.1 72.2 EXAMPLE 27 5820.4012.7 82.7 3.6 Buspirone >10000.0 275-2 262.8 _____________________ __________________________________________

Claims (13)

AMENDED CLAIMS
1. A compound of formula (I) (I) wherein Ar2 is selected from phenyl; mono or di-substituted aryl in which the substituent(s) is (are) selected on its (their) turn from linear or branched C1-C5 alkyl, halogen atoms, C1-C5 haloalkyl, methoxy; and heteroaryl containing one or more heteroatoms selected on their turn from N, O, 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;
Ar1 is an aryl or a heteroaryl of from 5 to 6 carbon atoms containing from 1 to 3 heteroatoms selected from N, O, or S;
R1 and R2 equal or different from each other are selected from H, C1-C5 alkoxy, OH, C1-C5 alkyl and NO2;
the group 17 is selected from:

18 i) 18 ii) 19 iii) 20 iv) and 21 v) ;

22 n is 1 or 2; m is 2 or 3, and the pharmaceutically acceptable 23 salts thereof.
2. A compound of formula (I) according to claim 1 wherein Ar1 is a phenyl group condensed on the alicyclic ring to form a compound of formula (IB) (IB) wherein Ar2 is selected from pyridyl, phenyl, mono or di-substituted phenyl in which the substituent(s) is (are) selected on its (their) turn from linear or branched C1-C5 alkyl, halogen atoms, C1-C5 haloalkyl and methoxy;
R1 and R2 equal or different from each other are selected from H, C1-C5 alkoxy, OH, C1-C5 alkyl and NO2;
the group is selected from:

i) ii) iii) iv) and V) ;

n is 2, m is 2 or 3; and the pharmaceutically acceptable salts thereof.
3. A compound of formula (I) according to claim 1 or 2 wherein R1 is OCH3, and R2 is H.
4. A compound of formula (I) according to any one of the preceding claims wherein Ar2 is selected from: 2-methoxyphenyl, 3-chlorophenyl, 3-trifluoromethylphenyl, 2-pyridyl and 2,5-dimethyoxyphenyl.
5. Compounds according to claim 2 (general formula IB) wherein the moiety:

is represented by a dihydronaphthalene group and Ar2 is a phenyl (or substituted phenyl) group, selected from:
4-[3-(6-methoxy-1,2-dihydronaphthalen-4-yl)n-propyl]-1-(2-methoxyphenyl)-piperazine;
1-phenyl-4-[3-(8-methoxy-1,2-dihydronaphthalen-4-yl)-n-propyl]-piperazine;
4-[3-(8-methoxy-1,2-dihydronaphthalen-4-yl)-n-propyl]-1-(2-methoxyphenyl)-piperazine;
4-[3-(1,2-dihydronaphthalen-4-yl)-n-propyl]-1-(2-methoxyphenyl)-piperazine;
4-t4-(6-methoxy-1,2-dihydronaphthalen-4-yl)-n-butyl]-1-(2-methoxyphenyl)-piperazine;
1-(3-chlorophenyl)-4-[3-(8-methoxy-1,2-dihydronaphthalen-4-yl)-n-propyl]-piperazine;

4-[3-(8-methoxy-1,2-dihydronaphthalen-4-yl)n-propyl]-1-(3-trifluoromethylphenyl)-piperazine;
and the pharmaceutically acceptable salts thereof.
6. Compounds according to claim 2 (general formula IB) wherein the moiety:

is represented by a tetrahydronaphthalen group and Ar2 is a phenyl (or substituted phenyl) group, selected from:
1-(2-methoxyphenyl)-4[N-(5-methoxy-1,2,3,4-tetrahydro -naphthalen-1-yl)-2-aminoethyl]-piperazine;
1-(2-methoxyphenyl)-4-[3-(7-methoxy-1,2,3,4-tetrahydro-naphthalen-1-yl)-n-propyl]-piperazine;
1-phenyl-4-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-n-propyl]-piperazine;
1-(2-methoxyphenyl)-4-[3-(5-methoxy-1,2,3,4-tetrahydro naphthalen-1-yl)n-propyl]-piperazine;
1-(2-methoxyphenyl)-4-[3-(4,5,6,7-tetrahydronaphthalen-1-yl)-n-propyl]-piperazine;
1-(2-methoxyphenyl)-4-[4-(7-methoxy-1,2,3,4-tetrahydro naphthalen-1-yl)-n--butyl]-piperazine;
1-(2-methoxyphenyl)-4-{2[(7-methopxy-1,2,3,4-tetrahydro naphthalen-1-yl)thio]-ethyl}-piperazine;

4-[1-(8-methoxy-1,2,3,4-tetrahydronaphthalen-4-yl)-1-propylen-3-yl]-1-(2-methoxyphenyl)-piperazine;
1-(2-methoxyphenyl)-4-[(1,2,3,4-tetrahydronaphthalen-4-yl)-1-propylen-3-yl]-piperazine;
4-[3-(7-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)n-propyl]-1-(3-trifluoromethylphenyl)-piperazine;
and the pharmaceutically acceptable salts thereof.
7. Compounds according to claim 2 (general formula IB) wherein Ar2 is a pyridyl group, selected from:
4-[3-(8-methoxy-1,2-dihydronaphthalen-4-yl)-n-propyl]-1-(2-pyridyl)-piperazine;
4-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-n-propyl]-1-(2-pyridyl)-piperazine;
4-[3-(7-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-n-propyl]-1-(2-pyridyl)-piperazine;
4-[1-(8-methoxy-1,2,3,4-tetrahydronaphthalen-4-yl)-1-propylen-3-yl]-1-(2-pyridyl)-piperazine;
and the pharmaceutically acceptable salts thereof.
8. A process for preparing a compound of formula (I) as defined in claim 1, wherein the group is:
i) and wherein Ar1, R1, R2, m, n and Ar2 are as defined in claim 1, comprising the following steps:
a) reacting a ketone of formula (II) (II) wherein Ar1, R1, R2 and n are as defined above, with a compound of formula (III) (III) wherein m and Ar2 are as defined above, in an apolar solvent under reflux and in the presence of catalytic amounts of an acid, thereby obtaining a compound of formula (IV) (IV) wherein Ar1, R1, R2, n, m and Ar2 are as defined above: and b) reducing a compound of formula (IV) obtained in the preceding step a) with sodium borohydride in a polar solvent at room temperature.
9. A process for preparing a compound of formula (I) as defined in claim 1 wherein the group is selected from:

ii) iii) and v) and wherein Ar1, R1, R2, m, n and Ar2 are as defined in claim 1, comprising the following steps:

a') reacting a ketone of formula (II) as defined in claim 8, with a Grignard reagent R3-MgX, wherein R3 is cyclopropyl or (CH2)4Cl and X is a halogen atom, in an etheral solvent thereby obtaining a compound of formula (V) (V) wherein Ar1, R1 , R2 , R3 and n are as defined above;

b') reacting the compound of formula (V) obtained in the preceding step a') with HCl in acetic acid thereby obtaining a compound of formula (VI) or (VIA) (VI) (VIA) wherein Ar1, R1, R2 and n are as defined above and wherein either p is 1 when in the compound of formula (V) R3 is cyclopropyl, or p is 2 when R3 is -(CH2)4-Cl;

c') reacting the compound of formula (VI) or (VIA) obtained in the preceding step b') with a compound of formula (VII) (VII) wherein Ar2 is as defined above, thereby obtaining a compound of formula (I) wherein is ii) or v) and, if desired, d') reacting a compound of formula (I) obtained in the preceding step c') with hydrogen in the presence of catalysts consisting of noble metals in a polar solvent thereby obtaining another compound of formula (I) wherein is iii)
10. A process for preparing a compound of formula (I) as defined in claim 1 and the pharmaceutically acceptable salts thereof wherein the group is: iv) and wherein Ar1, R1, R2, n, m, and Ar2 are as defined in claim 1, comprising the following steps:

a'') 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) (VIII) wherein Ar1, R1, R2 and n are as defined above, b'') treating a compound of formula (VIII) obtained in the preceding step a'') with ethyl 2-mercapto-acetate and ZnI2, thus obtaining a compound of formula (IX) (IX) wherein Ar1, R1, 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) (X) wherein Ar1, R1, R2 and n are as defined above;

d'') reacting a compound of formula (X) with a compound of formula (VII) as defined in claim 9 thereby obtaining a compound of formula (XI) (XI) wherein Ar1, R1, R2, n and Ar2 are as defined above, and e'') treating the compound of formula (XI) with LiAlH4.
11. A therapeutic composition containing as the active principle one or more compounds of formula (I), or pharmaceutically acceptable salt thereof, as defined in claim 1 in combination with suitable excipients and/or diluents.
12. Use of a compound of formula (I), or pharmaceutically acceptable salt thereof, as defined in claim 1 in the treatment of generalized anxiety, panic attacks, obsessive-compulsive syndromes, depression, opium-like psycho stimulant substances and alcohol abuse syndromes, cognitive disorders such as senile dementia, vigilance and memory disorders, Parkinson's and Alzheimer's diseases, schizophrenia or cerebral ischemia.
13. Use of a compound of formula (I), or pharmaceutically acceptable salt thereof, as defined in claim 1 in the treatment of cognitive disorders such as as senile dementia, vigilance and memory disorders, Parkinson's and Alzheimer's diseases.
CA002137685A 1992-06-26 1993-06-22 N(hetero)-aryl-n-(hetero)-tetralin-alkyl-piperazine having serotoninergic, dopaminergic and adrenergic activity Abandoned CA2137685A1 (en)

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