WO1994000441A1 - 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 Download PDF

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Publication number
WO1994000441A1
WO1994000441A1 PCT/EP1993/001589 EP9301589W WO9400441A1 WO 1994000441 A1 WO1994000441 A1 WO 1994000441A1 EP 9301589 W EP9301589 W EP 9301589W WO 9400441 A1 WO9400441 A1 WO 9400441A1
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piperazine
methoxy
methoxyphenyl
propyl
tetrahydronaphthalen
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PCT/EP1993/001589
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French (fr)
Inventor
Roberto Perrone
Francesco Berardi
Francesco Fiorentini
Stefano Govoni
Vincenzo Olgiati
Ermes Vanotti
Marino Gobetti
Giancarlo Tonon
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Farmitalia Carlo Erba S.R.L.
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Application filed by Farmitalia Carlo Erba S.R.L. filed Critical Farmitalia Carlo Erba S.R.L.
Priority to AU44195/93A priority Critical patent/AU670444B2/en
Priority to JP6502035A priority patent/JPH07508514A/en
Priority to EP93914690A priority patent/EP0647222A1/en
Publication of WO1994000441A1 publication Critical patent/WO1994000441A1/en
Priority to FI945997A priority patent/FI945997A0/en
Priority to KR1019940704767A priority patent/KR950702195A/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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
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    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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
    • C07D295/12—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C—CHEMISTRY; METALLURGY
    • 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

Definitions

  • the present invention relates to N(hetero) -aryl-N(hetero)- tetralin-alkyl-piperazine having serotoninergic, dopaminergic and adrenergic activity, the processes for their preparation and relative therapeutic compositions for the treatment of generalized anxiety, depression, schizophrenia, cerebral ischemia, opium like, psycho stimulant substances and alcohol abuse syndromes, and for the therapy of arterial hypertension.
  • PRIOR ART DISCLOSURE The active drugs on 5 ⁇ HT1A receptor resulted effective in the anxiety therapy.
  • 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.
  • drugs having 5-HT1A activity proved useful in the prevention of panic attacks [Psychopharmacology 10,3. (1990)] and for the treatment of obsessive-compulsive disorders [Journal of Psychiatry 147,798, (1990)].
  • 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) .
  • TFMPP Buspirone
  • Gepirone Gepirone
  • Ipsapirone Tandospirone
  • SM-3997 D-2 type dopaminergic receptor system
  • the present invention relates to N(hetero)-aryl-N(hetero) - tetralin-alkyl-piperazine and their pharmaceutically acceptable salts of general formula ( I)
  • Ar2 is selected from phenyl; mono or di-substituted aryl in which the substituent(s) is (are) selected on its (their) turn from linear or branched C ⁇ -Cc alkyl, halogen atoms, C ⁇ -Cc haloalkyl; heteroaryl containing one or more heteroatoms selected on their turn from N, 0, S, said heteroaryl being optionally substituted with the above mentioned alkyl groups, said heteroaryl being a monocyclic group of from to 6 atoms or condensed on an aryl group optionally substituted with the above mentioned groups, Ar- ⁇ is an aryl or a heteroaryl of from 5 to 6 carbon atoms containing from 1 to 3 heteroatoms selected from N, 0, or S; R ⁇ and R 2 equal or different from each other are selected from H, C- ⁇ -Cc alkoxy, OH, C ⁇ -C alkyl, N0 2 and wherein
  • the compounds ( I ) presenting an asimmetry center may exist in racemic or in optically active form.
  • the compounds of the present invention are characterized by having a considerable affinity on 5-HT1A setoninergic receptors .
  • the compounds of the present invention are active in a sperimental model [Tricklebank, Eur. J. Pharmacol. 106,271.(1985)] evaluating 5-HT1A activity "in vivo" and permitting to understand if the compounds in question act as agonists or antagonists.
  • the Applicant has found that all the 5 analyzed compounds , selected on the base of receptor screening, are able to inhibit, at low dosages, stereotypy induced by 80H- DPAT (as it results from the data contained in Table 2 reported later on) , without producing the behaviouristic effects ascribable to a serotoninergic activation.
  • 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
  • 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
  • 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.
  • 5-HT1A receptors The considerable activity on 5-HT1A receptors induces to hypothesize a use of the compounds of the present invention in pathologies such as generalized anxiety, depression, panic attacks, obsessive-compulsive syndromes, opium like and psycho stimulant (amphetamine, cocaine, caffeine) substances and alcohol abuse syndromes, consciousness disorders such as senile dementia, vigilance and memory disorders, Parkinson's and Alzheimer's diseases.
  • Some compounds of the present invention exhibit a considerable activity on D-2, ⁇ -1 and ⁇ receptors, which can be associated or not to as a considerable activity on 5-HT1A receptor.
  • the general pattern of activities of the compounds of the present invention allow to foresee their very promising use in the therapy of schizophrenia and cerebral ischemia. That,because of the interesting activity demonstrated by some compounds of the present invention , common to few antipsychotic drugs now in use.
  • An other important and interesting aspect characterizing the compounds of the present invention is the marked affinity of some of them on ⁇ -1 receptor. This activity, associate to a good affinity towards 5-HT1A 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 arterial hypertension.
  • the present invention further relates to therapeutic compositions containing as the active principle one or more derivatives of general formula (I) in combination with suitable excipients and/or diluents .
  • compositions according to the present invention containing the compounds of formula (I) having mainly 5-HT1A serotoninergic activity are suitable for the treatment of generalized anxiety , panic attacks , obsessive- compulsive syndromes , depression, opium like, psycho stimulant substances and alcohol abuse syndromes . -
  • compositions containing the compounds of formula (I) having mainly affinity on the receptors D-2, ⁇ and 5-HT1A or affinity on the receptors D-2 , ⁇ and ⁇ -1 are in particular suitable for the treatment of schizophrenia and cerebral ischemia.
  • compositions containing as the active principle the compounds of formula (I) having mainly affinity on 5-HT1A and ⁇ -1 receptors are used for the treatment of arterial hypertension.
  • N(hetero) aryl-N(hetero) -tetralinalkylpiperazine of formula (I) are prepared with different processes depending on the different
  • the process comprises the following steps: a) reacting the compounds of formula (II)
  • Ar- ⁇ is an aryl group, which is condensed on the alicyclic ring so that it forms the derivatives of general formula (IA)
  • R ⁇ is preferably, in the compounds of formula ( I ) , OCHo , whereas
  • R 2 is preferably H.
  • Ar 2 is preferably selected from : 2-methoxyphenyl , 3- chlorophenyl, 3-trifluoromethylphenyl, 2-pyridyl, 2,5 ⁇ dimethoxyphenyl.
  • 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.
  • compositions according to the present invention for the treatment of generalized anxiety, panic attacks, obsessive-compulsive syndromes, depression, opium like, psycho-stimulant substances and alcohol abuse syndromes, consciousness disorders such as senile dementia, vigilance and memory disorders, Parkinson's and Alzheimer's diseasesare those having the active principle selected among one or more of the following derivatives:
  • compositions according to the present invention for the treatment of schizophrenia are those wherein the active principle is selected among one or more of the following derivatives: - 4-[3-(8-methoxy-l,2-dihydrona ⁇ hthalen-4-yl)-n-propyl]-l-(2- methoxyphenyl)-piperazine (example 9);
  • compositions according to the present invention for the treatment of arterial hypertension are those having the active principle chosen among one or more of the following derivatives: - 4-[3-(6-methoxy-l,2-dihydronaphthalen-4-yl)n-propyl-l-(2- methoxyphenyl)piperazine (example 2) ; l-phenyl-4-[3-(8-methoxy-l,2-dihydronaphthalen-4-yl)-n- propyl]piperazine (example 8) ;
  • Example 2 The same process described in Example 2 is followed, with the only difference that in this case 1-(2, -dimethoxyphenyl) - piperazine is used.
  • Example 2 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.
  • Example 8 The same process described in Example 8 is followed, with the only difference that in this case l-(2 methoxyphenyl)-piperazine is used.
  • Example 8 The same process described in Example 8 is followed with the only difference that in this case l-(3-trifluoromethylpiperazine) is used.
  • Example 8 The same process described in Example 8 is followed, with the only difference that in this case l-(2-pyridyl)piperazine is used.
  • Example 8 The same process described in Example 8 is followed, with the only difference that l-(2-methoxyphenyl)-piperazine is used.
  • Example 14 The same process described in Example 14 is followed, starting from the hydrochlorate obtained in Example 5-
  • Example 14 The same process described in Example 14 is followed, starting from the hydrochlorate obtained in Example 8.
  • Example 14 The same process described in the Example 14 is followed, starting from the hydrochlorate obtained in Example 12.
  • MS, m/z (rel. range ): 367,20 (M++2; 1,9); 366,20 (M++1; 13,8); 365,20 (M+; 50,8); 271,20 (29,5); 258,20 (87.0); 121,05 (32,6);
  • Example 14 The same process described in Example 14 is followed, starting from the hydrochlorate obtained in Example 12.
  • Example 14 The same process described in Example 14 is followed, starting from the hydrochlorate obtained in Example 9- MS, m/z (rel. range): 372,20 (M + +2;7,5); 371.20 (M + +l;25,0);
  • MS, m/z (rel. range): 408,25 (M++2; 4,7); 407,25 (M++1; 29,2); 406,35 (M+; 99,9); 205,10 (22,9).
  • Example 14 Following the process described in Example 14 starting from the corresponding product described in previous Example 22, the desired product is obtained in a yield of ⁇ % .
  • the obtained raw oil composed by the chloride of the corresponding acid is dissolved in toluene (20 ml) and left to react under reflux with a solution of 1- (2-methoxyphenyl)- piperazine (8 mmoles) in toluene (30 ml) in the presence of trimethyl amine (10 mmoles). After 2 hours the reaction mixture is washed with H 0 and with HCl 2N.
  • Example 25 The same process described in Example 25 is followed starting from the hydrochlorate obtained in Example 12.
  • BIOCHEMICAL AND PHARMACOLOGICAL TRIALS Preparation of rat cerebral tissue homogenate for receptorial binding experiments.
  • Cerebral tissue asported from male rats (Sprague Dawley) weighing 180-220 g is homogenized in Tris. HCl buffer, 50 mM, pH 7.4 with
  • the final pellet is dissolved in the appropriate incubation buffer just before the test.
  • the aspecific bond is evaluated by the use of 5-HT (10 ⁇ M).
  • 5-HT1B Receptor The methodology described by S.J. Peroutka, J. Neurochem. 47, 529, (1986) is essentially used.
  • the aspecific bond is evaluated by the use of 5-HT (10 ⁇ M).
  • 5-HT1C Receptor The methodology described by S.J. Peroutka, J. Neurochem. 47, 529. (1986) is essentially used.
  • the aspecific bond is evaluated by the use of 5-HT (10 ⁇ M) . 5-HT2 Receptor.
  • 5-HT 5-HT10 ⁇ M
  • 5-HT2 Receptor The methodology described by A.K.Mir, Eur. J. Pharmacol.
  • the aspecific bond is evaluated by the use of methysergide (1 ⁇ M) .
  • D-1 Receptor The methodology described by W.B. Billard, Life Science, 35. 1885, (1984) is essentially used.
  • the aspecific bond is evaluated by the use of SCH-2339O (1 ⁇ M).
  • D-2 Receptor The methodology described by I. Creese, Eur. J. Pharmacol. 49, 201, (1978) is essentially used.
  • the aspecific bond is evaluated by the use of Butaclamol (10 ⁇ M) .
  • ⁇ -1 Receptor The methodology described by A.K.Mir, Eur. J. Pharmacol. 149, 107, (1988) is essentially used.
  • Prazosin 3 ⁇ M
  • ⁇ Receptor The methodology described by E.Weber, Proc Natl. 5 Acad. SCI. USA 83, 8784, (1986) is essentially used.
  • the aspecific bond is ° evaluated by the use of Haloperidol (1 ⁇ M) .
  • the compounds under question are analyzed by using the method described by Tricklebank [Eur. J. Pharmacol., 106, 271 (1985)]. 5 The compounds under question are administered subcutaneously to male rats (S.D.) treated with reserpine (1 mg/Kg) 18 hours before the test.
  • the evaluation of the behaviour starts 3 minutes after the administration of the compounds under question and continue for 0 the following 30 minutes.
  • the behaviour intensity is evaluated every 3 minutes by the use of a scale that assign the following scores to the two specific behaviours named "Flat body posture” and "Forepaw Treading”:
  • the antagonist activity on the stereotypy induced by 80H-DPAT (0.125 mg/Kg, s.c) is evaluated every 3 minutes from 30 to 60 minutes after the administration of the products under question starting from 3 minutes after the administration of 80H-DPAT.
  • the results of the above mentioned trials are reported in the following Tables 1,2 and 3>

Abstract

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

Description

N(HETERO)-ARYL-N(HETERO)-TETRALIN-ALKYL-PIPERAZINE HAVING SEROTONINERGIC, DOPAMINERGIC AND ADRENERGIC ACTIVITY . FIELD OF THE INVENTION
The present invention relates to N(hetero) -aryl-N(hetero)- tetralin-alkyl-piperazine having serotoninergic, dopaminergic and adrenergic activity, the processes for their preparation and relative therapeutic compositions for the treatment of generalized anxiety, depression, schizophrenia, cerebral ischemia, opium like, psycho stimulant substances and alcohol abuse syndromes, and for the therapy of arterial hypertension. PRIOR ART DISCLOSURE The active drugs on 5~HT1A receptor resulted effective in the anxiety therapy. These drugs if compared to benzodiazepine are characterized by having a twofold advantage,they are able to produce anxiolythic activity, contemporaneously avoiding the onset of side effect as for example sedation and addiction [Drugs 41,11. (1991)-Trends Pharmacol. Sci. 8, 383. (1987)], and they can be utilized in some anxiety forms resistant to the treatment with benzodiazepins. In fact drugs having 5-HT1A activity proved useful in the prevention of panic attacks [Psychopharmacology 10,3. (1990)] and for the treatment of obsessive-compulsive disorders [Journal of Psychiatry 147,798, (1990)].
The use of compounds showing -HT1A activity has been recently proposed for the treatment of depression [Psychopharmacology 10.77S, (1990) -Psichopharmacology 22, 27, (1989)], and for the control of the alcohol abuse [ Proc. Natl. Acad. Sci. USA 85, 5274 (1988) - Psychopharmacology 22, 49, (1989)]. Compounds able to combine activity on -HT1A receptor and the capacity of interaction with D-2 and σ receptors may represent a valid therapeutic approach to the treatment of schizophrenia. In fact the association of D-2 with σ activity enhances the antipsychotic effect of the compound, whereas the presence of 5~ HT1A seems able to reduce the hazard of side extr.apiramidal effects.[J. Med. Chem. 34 ,1860, (1991) - J- Neural. Transm. 57, 255, (1983)].
Moreover the activity on σ receptors is considered very important in pathologies such as cerebral ischemia in which a massive activation of glutamatergic system is present [J. Med. Chem.35. 1526, ( 1992) ; Med. Chem. Res . 1 , 425 , (1992) ; Drug of Today 27 , 255. (1991 ) ] .
Finally the use of active compounds on 5-HTIA receptor, or compounds having mixed activity on 5-HTlA/α-l receptors has been recently suggested for the treatment of arterial hypertension [Naunyn-Schmiedeberg' s Arch. Pharmacol. 336,597, (I987)]. The above finds also a confirmation in the recent reconsideration of the role of α-1 blocking compounds in the treatment of arterial hypertension [JAMA 266, 394, (1991)].
In view of the foregoing it appears evident that compounds shewing a sufficient selectivity toward 5-HTlA receptors or possessing a mixed activity on 5-HTlA/D-2/σ/α-l or 5-HTlA/α-l are to be considered having a marked therapeutic potential in the aforementioned pathologies.
The N-alkyl-piperazine moiety is present in various structures of agents proposed and used as anxiolythic and antipsychotic compounds, since they are active on 5-HT1 type serotoninergic and/or on the D-2 type dopaminergic receptor system (see TFMPP, Buspirone, Gepirone, Ipsapirone, Tandospirone, (SM-3997) . BMY - 7378, NAN-190, WY -47846, RK-153, RK-I67. 1-NP, Quipazine, MK- 212, m-CPP, OPC-4392, LY I65I63 (PAPP) , Eltoprazine, (DU-288553) , Thiospirone, Revospirone, SM-9018, etc.
In all known N-alkyl-piperazine moieties from the prior art the affinity towards specific 5HT and DA type receptor subgroups resulted to depend on the substituent present on the second nitrogen atom of the piperazine ring, particularly when on this atom an alkyl group is present, being substituted on its turn with groups presenting a considerable structural complexity, the compounds show affinity towards both 5-HTIA- and D-2 receptors, but also towards α-1 and σ receptors . Presently a great need is felt to find compounds acting selectively on a type of receptor group, so that they can be utilized for the treatment of pathologies such as anxiety and depression, or compounds possessing activity on more than one receptor, among those above identified for the treatment of pathologies such as schizophrenia and arterial hypertension. THE PRESENT INVENTION
The present invention relates to N(hetero)-aryl-N(hetero) - tetralin-alkyl-piperazine and their pharmaceutically acceptable salts of general formula ( I)
Figure imgf000006_0001
(I) wherein Ar2 is selected from phenyl; mono or di-substituted aryl in which the substituent(s) is (are) selected on its (their) turn from linear or branched C^-Cc alkyl, halogen atoms, C^-Cc haloalkyl; heteroaryl containing one or more heteroatoms selected on their turn from N, 0, S, said heteroaryl being optionally substituted with the above mentioned alkyl groups, said heteroaryl being a monocyclic group of from to 6 atoms or condensed on an aryl group optionally substituted with the above mentioned groups, Ar-^ is an aryl or a heteroaryl of from 5 to 6 carbon atoms containing from 1 to 3 heteroatoms selected from N, 0, or S; R^ and R2 equal or different from each other are selected from H, C-^-Cc alkoxy, OH, C^-C alkyl, N02 and wherein
Y -
\ / X
I
is selected from:
Figure imgf000007_0001
n = 1 or 2 and m = 2 or 3 -
In the present invention the compounds ( I ) presenting an asimmetry center, may exist in racemic or in optically active form.
The compounds of the present invention are characterized by having a considerable affinity on 5-HT1A setoninergic receptors .
This activity is coupled to a good selectivity towards different serotonine receptor subtypes ( as it results from the data reported in Table 1 ) .
The compounds of the present invention are active in a sperimental model [Tricklebank, Eur. J. Pharmacol. 106,271.(1985)] evaluating 5-HT1A activity "in vivo" and permitting to understand if the compounds in question act as agonists or antagonists. The Applicant has found that all the 5 analyzed compounds , selected on the base of receptor screening, are able to inhibit, at low dosages, stereotypy induced by 80H- DPAT (as it results from the data contained in Table 2 reported later on) , without producing the behaviouristic effects ascribable to a serotoninergic activation.
1° Therefore the compounds of the present invention result to act as pure antagonists on 5-HT1A receptor.
The "in vivo" activity of the analyzed compounds can be very well correlated to receptor affinity, thereby indicating that the analyzed compounds are able to well penetrate inside the Central
I5 Nervous System.
Some compounds of the present invention associate a considerable effectiveness on D-2 dopaminergic, α-1 and σ adrenergic receptors (as it results from the data contained in Table 3 reported later on) to 5-HTlA activity, inducing to suggest that
20 the same can be used as antipsychotic and, in some cases, as antihypertensive and antiischemic principles.
The compounds of the present invention are characterized by having a marked activity on receptors involved in several pathologies both of Central and Peripheral Nervous System.
25 The considerable activity on 5-HT1A receptors induces to hypothesize a use of the compounds of the present invention in pathologies such as generalized anxiety, depression, panic attacks, obsessive-compulsive syndromes, opium like and psycho stimulant (amphetamine, cocaine, caffeine) substances and alcohol abuse syndromes, consciousness disorders such as senile dementia, vigilance and memory disorders, Parkinson's and Alzheimer's diseases.
In addition it is to be underlined how some compounds according to the present invention exhibit a marked activity and a selectivity towards 5"HT1A receptors, the above feature being common to few anxiolythic drugs commercially available or in phase of advanced clinical experimentation.
Some compounds of the present invention exhibit a considerable activity on D-2, α-1 and σ receptors, which can be associated or not to as a considerable activity on 5-HT1A receptor. The general pattern of activities of the compounds of the present invention allow to foresee their very promising use in the therapy of schizophrenia and cerebral ischemia. That,because of the interesting activity demonstrated by some compounds of the present invention , common to few antipsychotic drugs now in use. An other important and interesting aspect characterizing the compounds of the present invention is the marked affinity of some of them on α-1 receptor. This activity, associate to a good affinity towards 5-HT1A receptors and to a favourable selectivity ratio towards D-2 and σ receptors, permits to propose some of the compounds of the present invention for the therapy of arterial hypertension.
Therefore the present invention further relates to therapeutic compositions containing as the active principle one or more derivatives of general formula (I) in combination with suitable excipients and/or diluents .
In particular the therapeutic compositions according to the present invention containing the compounds of formula (I) having mainly 5-HT1A serotoninergic activity are suitable for the treatment of generalized anxiety , panic attacks , obsessive- compulsive syndromes , depression, opium like, psycho stimulant substances and alcohol abuse syndromes . -
The therapeutic compositions containing the compounds of formula (I) having mainly affinity on the receptors D-2, σ and 5-HT1A or affinity on the receptors D-2 , σ and α-1 , are in particular suitable for the treatment of schizophrenia and cerebral ischemia.
The therapeutic compositions containing as the active principle the compounds of formula (I) having mainly affinity on 5-HT1A and α-1 receptors are used for the treatment of arterial hypertension.
N(hetero) aryl-N(hetero) -tetralinalkylpiperazine of formula (I) are prepared with different processes depending on the different
Y -
\ / X groups contained in the alicyclic group of formula (I) .
For example for preparing the derivative of formula (I) wherein
Y -
\ / X
Figure imgf000011_0001
the process comprises the following steps: a) reacting the compounds of formula (II)
Figure imgf000011_0002
wherein Ar-^, R-^, R2 and n have the above mentioned meanings with an a inoalkylpiperazine of formula (III):
Figure imgf000011_0003
(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):
Figure imgf000012_0001
(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:
Figure imgf000012_0002
comprises the following steps: a') reacting the above mentioned keton of general formula (II) with Grignard reactant Ro-MgX, wherein Ro is selected from: cyclopropyl and -(CH2)/,C1 in an ethereal solvent thereby obtaining the tertiary alcohol of formula (V) ϋ)
Figure imgf000012_0003
Figure imgf000013_0001
(V) b') reacting the tertiary alcohol (V), coming from the preceding step, with HCl in acetic acid, thereby obtaining the chloride derivative of formula (VI) or (Via) :
Figure imgf000013_0002
(VI) (VIA)
wherein p is = 1 or 2 and is =1 when in the reactant (V) Ro is = cyclopropyl, or is = 2 in case R is = -{CH )/j-Cl
c') reacting the chloride intermediate (VI) or (VIA) obtained in the preceding step with N-arylpiperazine of formula (VII)
Figure imgf000013_0003
(VII) wherein Ar2 has the aforementioned meanings thereby obtaining N(hetero) -aryl-N(hetero) -tetralinalkylpiperazine of formula ( I ) wherein
Figure imgf000014_0001
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 :
Figure imgf000014_0002
The process for preparing the compounds of formula (I) wherein
Figure imgf000014_0003
comprises the following steps: a") reacting the aforementioned keton (II) in the presence of a reducing agent thereby obtaining the corresponding alcohol (VIII)
Figure imgf000015_0001
b") successively treating the alcohol (VIII) obtained in the preceding step, with ethyl 2-mercapto-acetate and Znl , thus obtaining the corresponding ester of formula (IX):
Figure imgf000015_0002
(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)
Figure imgf000015_0003
d") reacting the acyl chloride (X) with the aforementioned N- aryl-piperazine (VII) thereby obtaining the corresponding amide
Figure imgf000015_0004
e")treating the amide (XI) with LiAlH/ to obtain the desired derivative of formula (I).
DETAILED DESCRIPTION OF THE INVENTION
In the N(hetero)-aryl-N(hetero)-tetralinalkylpiperazine of formula (I) according to the present invention Ar-^ is an aryl group, which is condensed on the alicyclic ring so that it forms the derivatives of general formula (IA)
Figure imgf000016_0001
(IA)
or the derivatives of general formula (IB)
Figure imgf000016_0002
(IB)
R^ is preferably, in the compounds of formula ( I ) , OCHo , whereas
R2 is preferably H.
Ar2 is preferably selected from : 2-methoxyphenyl , 3- chlorophenyl, 3-trifluoromethylphenyl, 2-pyridyl, 2,5~ dimethoxyphenyl.
Particularly preferred derivatives of formula (I) are those having n = 2. The therapeutic compositions of the present invention preferably contain the active principle at dosages of from 1 to 200 mg and are generally administered 2-3 times daily.
Particularly preferred therapeutic compositions according to the present invention for the treatment of generalized anxiety, panic attacks, obsessive-compulsive syndromes, depression, opium like, psycho-stimulant substances and alcohol abuse syndromes, consciousness disorders such as senile dementia, vigilance and memory disorders, Parkinson's and Alzheimer's diseasesare those having the active principle selected among one or more of the following derivatives:
- 1-(2-methoxyphenyl)-4-[N-(5-methoxy-l,2,3,4- tetrahydronaphthalen-1-yl)-2-aminoethyl]-piperazine (example i);
- 4-[3-(6-methoxy-l,2-dihydronaphthalen-4-yl)n-propyl-l-(2- methoxyphenyl)piperazine (example 2) ; l-phenyl-4-[3_(8-methoxy-l,2-dihydronaphthalen-4-yl)-n- propyl]piperazine (example 8);
- 4-[3-8-methoxy-l,2-dihydronaphthalen-4-yl)-n-propyl]-l-(2- methoxyphenyl)piperazine (example 9) - - 4-[3-(8-methoxy-l,2-dihydronaphthalen-4-yl)-n-propyl]-l-(2- pyridyl)-piperazine (example 12); - 4-[3-(1,2-dihydronaphthalen-4-yl)-n-propyl]-l-(2-methoxyphenyl)• piperazine (example 13) ;
- 1-(2-methoxyphenyl)-4-[3~(7-methoxy-l,2,3,4- tetrahydronaphthalen-l-yl)-n-propyl]piperazine (example 14); - l-phenyl-4-[3-(5-methoxy-l,2,3.4-tetrahydronaphthalen-1-yl)-n- propyl]-piperazine (example 16) ;
- 1-(2-methoxyphenyl)-4-[3~(5-methoxy-l,2,3,4- tetrahydronaphthalen-l-yl)-n-propyl]-piperazine (example 17);
- 4-[3-(5-methoxy-l,2,3,4-tetrahydronaphthalen-l-yl)-n-propyl]-l- (2-pyridyl)-piperazine (example 18) ;
- 4-[3-(7-ωethoxy-l,2,3.4-tetrahydronaphthalen-l-yl)-n-propyl]-l- (2-pyridyl)piperazine (example 19) ;
- 1-(2-methoxyphenyl)-4-[3_(4,5.6,7-tetrahydrobenzo[b]thien-4- yl-) n-propyl]piperazine (example 20); - 1-(2-methoxyphenyl)-4-[3~(1, ,3,4-tetrahydronaphthalen-1-yl)-n- propyl]piperazine (example 21);
- 4-[4-(6-methoxy-l,2-dihydronaphthalen-4-yl)-n-butyl]-l-(2- methoxyphenyl)-piperazine (example 22);
- 1-(2-methoxyphenyl)-4-[4-(7-methoxy-l,2,3,4- tetrahydronaphthalen-l-yl)-n-butyl]-piperazine (example 23);
- l-(2-methoxyphenyl)-4-{2-[(7-methoxy-l,2,3,4- tetrahydronaphthalen-1-yl)-thio]-ethyl}piperazine (example 24);
- 4-[l-(8-methoxy-l,2,3.4-tetrahydronaphthalen-4-yl)l-propylen-3~ yl]-l-(2-methoxyphenyl)piperazine (example 25); - 4-[l-(8-methoxy-l,2,3,4-tetrahydronaphthalen-4-yl)-l-propylen- 3-yl]-l-(2-pyridyl)piperazine (example 26);
- 1-(2-methoxyphenyl)-4-[(1,2,3,4-tetrahydronaphthalen-4-yl)-1- propylen-3-yl]piperazine (example 27) ; - 1-(3-chlorophenyl)-4-[3~(8-methoxy-l,2,-dihydronaphthalen-4- yl)-n-propyl]piperazine (example 10);
- 4-[3-(8-methoxy-l,2-dihydronaphthalen-4-yl)-n-propyl]-l-(3_ trifluoromethylphenyl)piperazine (example 11);
" 4-[3-(7-methoxy-l,2,3.4-tetrahydronaphthalen-l-yl)-n-propyl]-l- (3-trifluoromethylphenyl)piperazine (example 15).
Particularly preferred therapeutic compositions according to the present invention for the treatment of schizophrenia are those wherein the active principle is selected among one or more of the following derivatives: - 4-[3-(8-methoxy-l,2-dihydronaρhthalen-4-yl)-n-propyl]-l-(2- methoxyphenyl)-piperazine (example 9);
- 4-[3-(l,2-dihydronaphthalen-4-yl)-n-propyl]-l-(2- methoxyphenyl)-piperazine (example 13);
1-(2-methoxyphenyl)-4-[3-(7-methoxy-l,2,3,4- tetrahydronaphthalen-l-yl)-n-propyl]piperazine (example 14) ; l-phenyl-4-[3~( -methoxy-l,2,3.4-tetrahydronaphthalen-l-yl)-n- propyl]-piperazine (example 16) ;
- 1-(2-methoxyphenyl)-4-[3-(5-methoxy-l,2,3,4- tetrahydronaphthalen-l-yl)-n-propyl]-piperazine (example 17); _ 4-[4-(6-methoxy-l,2-dihydronaphthalen-4-yl)-n-butyl]-l-(2- methoxyphenyl)-piperazine (example 22) ; - 1-(2-methoxyphenyl)-4-[4-(7-methoxy-l,2,3,4- tetrahydronaphthalen-l-yl)-n-butyl]-piperazine (example 23);
- l-(2-methoxyphenyl)-4[N-(5-methoxy-l,2,3,4- tetrahydronaphthalen-1-yl)-2-aminoethyl]-piperazine (example 1);
- l-(2-methoxyphenyl)-4-[3-(4,5,6,7_tetrahydrobenzo[b]thien-4-yl- n-propyl]piperazine (example 20) ;
- 1-(2-methoxyphenyl)-4-[3~(1,2,3,4-tetrahydronaphthalen-1-yl)-n- propyl]piρerazine (example 21); - l-(2-methoxyphenyl)-4-{2-[(7-methoxy-l, 2, 3, 4 -tetrahydro- naphthalen-l-yl)-thio]-ethyl}piperazine (example 24); -4-[l-(8-methoxy-l,2,3.4-tetrahydronaphthalen-4-yl)-l-propylen- 3-yl]-l-(2-methoxyphenyl)piperazine (example 25);
- 1-(2-methoxyphenyl)-4-[(1,2,3,4-tetrahydronaphthalen-4-yl)-1- propylen-3_yl]piperazine (example 27) ;
Particularly suitable therapeutic compositions according to the present invention for the treatment of arterial hypertension are those having the active principle chosen among one or more of the following derivatives: - 4-[3-(6-methoxy-l,2-dihydronaphthalen-4-yl)n-propyl-l-(2- methoxyphenyl)piperazine (example 2) ; l-phenyl-4-[3-(8-methoxy-l,2-dihydronaphthalen-4-yl)-n- propyl]piperazine (example 8) ;
- 4-[3-8-methoxy-l,2-dihydronaphthalen-4-yl)-n-propyl]-l-(2- methoxyphenyl)-piperazine (example 9); - 4-[3-(8-methoxy-l,2-dihydronaphthalen-4-yl)-n-propyl]-l-(2- pyridyl)-piperazine (example 12);
- 4-[3~(1,2-dihydronaphthalen-4-yl)-n-propyl]-l-(2-methoxyphenyl)- piperazine (example 13); - l-(2-methoxyphenyl)-4-[3-(7-methoxy-l,2,3,4- tetrahydronaphthalen-1-yl)-n-propyl]piperazine (example 14) ; 1-(2-methoxyphenyl)-4-[3-(5-methoxy-l,2,3,4- tetrahydronaphthalen-1-yl)-n-propyl]-piperazine (example 17) ;
- 4-[3-(5-methoxy-l,2,3,4-tetrahydronaphthalen-1-yl)-n-propyl]-l- (2-pyridyl)-piperazine (example 18) ;
- 4-[4-(6-methoxy-l,2-dihydronaphthalen-4-yl)-n-butyl]-l-(2- methoxyphenyl)-piperazine (example 22) ;
- l-phenyl-4-[3-(5-πιethoxy-l,2,3,4-tetrahydronaphthalen-l-yl)-n- propyl]-piperazine (example 16); - 4-[3-(7-methoxy-l,2,3,4-tetrahydronaphthalen-1-yl)-n-propyl]-1- (2-pyridyl)piperazine (example 19);
- l-(2-methoxyphenyl)-4-[3-(4,5.6,7_tetrahydrobenzo[b]thien-4- yl)-n-propyl]piperazine (example 20);
- l-(2-methoxyphenyl)-4-[3-(1,2,3.4-tetrahydronaphthalen-l-yl)-n- propyl]piperazine (example 21);
- 1-(2-methoxyphenyl)-4-[4-(7-methoxy-l,2,3,4- tetrahydronaphthalen-l-yl)-n-butyl]-piperazine (example 23);
- l-(2-methoxyphenyl)-4-{2-[(7-methoxy-l,2,3,4-tetrahydro- naphthalen-l-yl)-thio]-ethyl}piperazine (example 24); _ 4-[l-(8-methoxy-l,2,3,4-tetrahydronaphthalen-4-yl)l-propylen-3- yl]-l-(2-methoxyphenyl)piperazine (example 25); - 4-[1-(8-methoxy-l,2,3,4-tetrahydronaphthalen-4-yl)-1-propylen- 3-yl]-l-(2-pyridyl)piperazine (example 26);
-1-(2-methoxyphenyl)-4-[(1,2,3,4-tetrahydronaphthalen-4-yl)-1- propylen-3~yl]piperazine (example 27) . In particular as one can realize from what above stated, being in any case easily deducible from the data reported in tables 1-3 reported hereinbelow, some of these compounds may be advantageously utilized contemporaneously for the therapy of generalized anxiety, schizophrenia and arterial hypertension. These compounds are in particular :
- 4-[3-8-methoxy-l,2-dihydronaphthalen-4-yl)-n-propyl]-l-(2- methoxyphenyl)-piperazine (example 9);
- 4-[3~(1,2-dihydronaphthalen-4-yl)-n-propyl]-l-(2-methoxyphenyl)■ piperazine (example 13) ; - l-(2-methoxyphenyl)-4-[3-(7-methoxy-l,2,3.4- tetrahydronaphthalen-l-yl)-n-propyl]piρerazine (example 14);
- 1-(2-methoxyphenyl)-4-[3-(5-methoxy-l,2,3.4- tetrahydronaphthalen-l-yl)-n-propyl]-piperazine (example 17);
- 4-[4-(6-methoxy-l,2-dihydronaphthalen-4-yl)-n-butyl]-l-(2- methoxyphenyl)-piperazine (example 22);
- l-phenyl-4-[3-(5-methoxy-l,2,3,4-tetrahydronaphthalen-l-yl)-n- propyl]-piperazine (example 16) ;
- l-(2-methoxyphenyl)-4-[3(4,5.6,7_tetrahydrobenzo[b]thien-4-yl)- n-propyl]piperazine (example 20) ; - 1-(2-methoxypheny1)-4-[3-(l,2,3,4-tetrahydronaphthalen-1-yl)-n- propyl]piperazine (example 21);
- 1-(2-methoxyphenyl)-4-[4-(7-methoxy-l,2,3,4- tetrahydronaphthalen-l-yl)-n-butyl]-piperazine (example 23);
- l-(2-methoxyphenyl)-4-{2-[(7-methoxy-l,2,3,4- tetrahydronaphthalen- l-yl)-thio]-ethyl}piperazine (example 24);
- 4-[1-(8-methoxy-l,2,3,4-tetrahydronaphthalen-4-yl)-l-propylen-3- yl]-l-(2-methoxyphenyl)piperazine (example 25);
- 1-(2-methoxyphenyl)-4-[ (1,2,3,4-tetrahydronaphthalen-4-yl)-1- propylen-3~yl]piperazine (example 27) .
N-aminoalkylpiperazine of formula (III)
Figure imgf000023_0001
(III) is prepared by reacting previously mentioned N-arylpiperazine (VII) with nitrile bromide of formula (XII)
NC-fCH^-^-Br
in the presence of a polar solvent and of a weak base thereby obtaining the intermediate (XIII)
Figure imgf000024_0001
which is on its turn treated with lithiumaluminumhydride in an ethereal solvent to obtain finally the desired intermediate (III) . The following examples are reported for illustrative, but not limitative purposes of the present invention. EXAMPLE 1
1-(2-methoxyphenyl)-4-fN-(5~π-βthoxy-l,2,3,4-tetrahydronaphtalen- l-yl)-2-aminoethyl]piperazine .
Brcmoacetonitrile (10 mmoles) and sodium bicarbonate (10 mmoles) were added to l-(2-methoxyphenyl)piperazine (10 mmoles) solubilized in 0 ml benzene. The mixture is kept under reflux for about 1 hour. Then it is cooled, filtered and washed with ether and the organic phase is brought to dryness at reduced pressure. A dark yellow oil is obtained (yield 80% ) composed by N-cyanomethyl-N-aryl-piperazine that, without purification is dissolved in anhydrous diethyl ether. LiAlH/j (10 mmoles) are added to the solution. The mixture is left under reflux for 1 hour, then it is cooled and the excess of hydride is destroyed by adding some drops of water. The mixture is then filtered, brought to dryness under reduced pressure and a colourless oil composed by N(aminoethyl)-N-arylpiperazine is obtained (yield 90?-), which is purified by column chromatography.
The product coming from this purification (10 mmoles) is dissolved in anhydrous toluene and reacted with 5_∞ethoxy-l- tetralone (11 mmoles) in the presence of a catalytic amount of p- toluensulfonic acid. The mixture is kept under reflux for about one hour, then it is cooled, the solvent is evaporated under reduced pressure and the residue is immediately dissolved in anhydrous ethanol. NaBH/j (20 mmoles) is added to the solution that is then left under stirring for about 2 hours. The solvent is evaporated under reduced pressure and the residue is purified by column chromatography. The desired compound is obtained in the form of a dark yellow oil (yield 6 ?-). MS, m/z (rel. range): 395,20 (M+; 1,7); 206,20 (45,6); 205,10 (100,0); 190,10 (37.8); 177.10 (21,4); 175,10 (23,1); 162,10 (25,7); 161,10 (47,5).
1H-NMR (200 MHz.CDCl^), ό(ppm): 1,66-2,07 (m,4H,CH2CH2 endocyclic) ; 2,17 (broadened s ,1H,exchanges with D20,NH) ; 2,46- 2,93 [m,10H,CH2 benzyl, NCH2CH2N(CH2)2] ; 3,08 [s broad.,4H, (CH2)2NAr]; 3,75-3.83 (m+s,4H,CHN,CH3) ; 3,85 (s,3H CHg); 6,65- 7,18 (m,7H, aromatic). Hydrochlorate: m.p. 223-224 °C. EXAMPLE 2 4-[3~(6-methoxy-l,2-dihydronaphthalene-4-yl)-n-propyl1-1-(2- methoxyphenyl)piperazine.
7-methoxy-l-tetralone (6 mmoles) solubilized in tetrahydrofuran (10 ml) are added to a solution of cyclopropylmagnesium bromide (9 mmoles) dissolved in tetrahydrofuran. The mixture is left under reflux for about 1 hour. Then it is cooled and a solution saturated by ammonium chloride is added. The organic phase is washed with water, brought to dryness and a raw reaction product is obtained, composed mainly by l-cyclopropyl-7-methoxy-l,2,3,4- tetrahydronaphthalen-1-ol, in the form of a dark oil. The mixture is directly treated with a solution of HCl in diluted acetic acid and it is kept at room temperature for about 2 hours, then is treated with alkali and extracted with CHCl . The solvent is evaporated and the dark oil obtained is purified by column chromatography; a product composed by 4-(3~ chloropropyl)-6-methoxy-l,2-dihydronaphthalene intermediate (VI) with p = 1 is obtained (total yield 64?-). l-(2-methoxyphenyl)piperazine (3-5 mmoles) is added to the compound (VI) (3-5 mmoles) dissolved in dimethylformamide (10 ml) in the presence of Nal (catalytic amount) and sodium carbonate (3-5 mmoles). The mixture is left under reflux for 1 hour then it is cooled and, after evaporating the dimethylformamide, it is diluted with H20 and extracted with CHClo. By solvent evaporation a residue is obtained, which after chromatography on column provides the product in the form of a yellow oil in a 80$ yield. MS, m/z (rel. range): 394,25 (M++2; 4,0); 393,25 (M++1; 27,1); 392,25 (M+, 100,0); 205,10 (20,9); 203,10 (24,9).
1H-NMR (200MHz,CDC13), δ(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. EXAMPLE 3 l-phenyl-4-[3~(6-methoxy-l,2-dihydronaphthalen-4-yl)-n-propyl]- piperazine
The same process described in Example 2 is followed with the only difference that in this case 1-phenyl piperazine is used.
MS, m/z (rel. range): 364,25 (M++2; 3,3); 363,25 (M++1; 25,9);
362,25 (M+; 100,0); 175,10 (34,1); 173,10 (32,1); 132,10 (25,8).
1H-NMR (200MHz,CDClj), δ(ppm): 1,69-1,87(m,2H,CH2CH2CH2) ; 2,l6-
2,30 (m,2H,CH2 endocycl.); 2,47 (t,4H, J=7,7Hz, C 2CH2CH2N) ; 2,57-2,74 [m,6H,CH2 benz., CH2N(CH2)2]; 3,18-3,27 [ dt,4H,
(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.
EXAMPLE 4 1-(3-chlorophenyl)-4-[3~(6-methoxy-l,2-dihydronaphthalen-4-yl)-n- propyl1-piperazine
The same process described in Example 2 is followed with the only difference that in this case l-(3_chlorophenyl)-piperazine is used. MS, m/z (rel. range): 400,15 (M++4; 1,0); 399,15 ( ++3; 8,2);
398,15 (M++2; 35.2); 397,15 (M++1; 30,7); 396,15 (M+; 100,0);
209,10 (59,3); 207,00 (32,4); 166,00 (26,5).
1H-NMR (200MHz,CDC13), δ(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. ) . Hydrochlorate: m.p. 184-185 °C.
EXAMPLE
4-[3-(6-methoxy-l,2-dihydronaphthalen-4-yl)-n-propyl1-1-(3- trifluoromethylphenyl)piperazine The same process described in Example 2 is followed with the only difference that in this case 1-(3~trifluoromethylphenyl)- piperazine is used.
MS, m/z (rel. range): 432,2 (M++2; 3,9); 431,25 (M++1; 26,3);
430,25 (M+; 100,0); 256,10 (20,0); 243,10 (69,0); 24l,10 (33,9); 200.00 (45,1); 172,10 (23,9).
1H-NMR (200MHz,CDC13), δ(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 .
EXAMPLE 6
4-f3-(6-methoxy-l,2-dihydronaphthalen-4-yl)-n-propyl]-1-(2- pyridyl)piperazine The same process described in Example 2 is followed, with the only difference that in this case 1-pyridylpiperazine is used.
MS, m/z (rel. range): 36 , 5 (M++2; 2,0); 364,25 (M++1; 16,0);
363,25 (M+; 62,5); 256,10 (38,6); 244,10 (47,3); 121,10 (36,4);
107,10 (100,0); 72,05 (39.7). 1H-NMR (200MHz,CDC13), δ(ppm) : 1,70-1,90 (m,2H,CH2CH2CH2) ; 2,13- 2,28 (m,2H,CH2 endoc); 2,38-2,54 (m,4H,CH2CH2CH2N) ; 2,54-2,74
[m,6H,CH2 benz.,CH2N(CH2)2]; 3,58 [t,4H, J=5,l Hz, (CH2)2NAr];
3,78 (s,3H,CH3); 5.88 (t.lH, J=4,5 Hz.H vin.); 6,55"7,52
(m,6H,arom.); 8,12-8,21 (m,lH,N=CH arom. ) . Hydrochlorate: m.p. 225-226 °C.
EXAMPLE 7
1-(2,5-dimethoxyphenyl)-4-[3~(6-methoxy-1,2-dihydronaphthalen-4- yl)-n-propyl1-piperazine
The same process described in Example 2 is followed, with the only difference that in this case 1-(2, -dimethoxyphenyl) - piperazine is used.
MS, m/z (rel. range): 424,25 (M++2; 4,1); 423,25 (M++1; 27,4);
422,25 (M+; 100,0).
1H-NMR (200MHz,CDC13), δ(ppm): 1,72-1,91 (m,2H,CH2CH2CH2) , 2,l4- 2,28 (m,2H,CH2 endoc); 2,39-2,83 [m,10H,CH2 benz.,
CH2CH2CH2N(CH2)2]; 3,12 [ broad, s ,4H, (CH2)2NAr] ; 3,75. 3.79.
3.80 (3S.9H.3 CH3); 5.89 (t.lH, J=4,6 Hz.H vin.); 6,43-7.12
(m,6H, arom. ) .
Hydrochlorate: m.p. 192-193 °C. EXAMPLE 8 l-phenyl-4-[3-(8-methoxy-l,2-dihydronaphthalen-4-yl)-n-propyl] piperazine
The same process described in Example 2 is followed, with the only difference that in this case 5-methoxy-tetralone and 1- phenyl-piperazine are used.
MS, m/z (rel. range) : 364,25 (M++2; 3.4); 363. 5 (M++1; 25,3); 362,25 (M+; 100,0); 175,10 (36,8); 173,10 (30,3); 132,10 (26,5). 1H-NMR (200MHz,CDC13) δ(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.
EXAMPLE 9
4-[3-(8-methoxy-l,2-dihydronaphthalen-4-yl)-n-ρropyll-l-(2-me- thoxyphenyl)piperazine
The same process described in Example 8 is followed, with the only difference that in this case l-(2 methoxyphenyl)-piperazine is used.
MS, m/z (rel. range): 394,25 (M++2; 4,2) 393.25 (M++l; 27.0); 392.25 (M+; 100,0); 205,05 (25,6); 203,15 (24,6).
1H-NMR (200MHz, CDClj), δ (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.); 6,75-7,20 (m,7H,arom.).
Hydrochlorate: m.p. 209"21O°C. EXAMPLE 10 l-(3-chlorophenyl)-4-[3-(8-methoxy-l,2-dihydronaphthalen-4-yl)-n- propylIpiperazine The same process described in Example 8 is followed, with the only difference that in this case l-(3~chlorophenyl)-piperazine is used.
MS, m/z (rel. range) : 400, 15 (M++ ; 1 , 1 ) ; 399,15 (M++3; 8,3)
398,15 (M++2; 34,2); 397,15 (M++1; 30,4); 396,15 (M÷; 100,0) 222,00 (23,6); 211,10 (21,2); 209,00 (76,2); 207,00 (30,4)
166,00 (33,6).
1H-NMR (200MHz,CDC13), δ(ppm) : 1,66-1,85 (m,2H,CH2CH2CH2) ; 2,13-
2,28 (m,2H,CH2 endoc); 2,39-2,80 (m,10H,CH2 benz.,CH2CH2CH2N(CH2)2]; 3,21 [broad.t ,4H, (CH2)2NAr]; 3,83 (s,3H, CH3); 5,87 (t.lH, J=5,0 Hz, H vin.); 6,71-7,21
(m,7H,arom. ) .
Hydrochlorate: m.p. 190-192 °C.
EXAMPLE 11
4-[3-(8-methoxy-l,2-dihydronaphthalen-4-yl)-n-propyl]-l-(3- trifluoromethylphenyl)piperazine
The same process described in Example 8 is followed with the only difference that in this case l-(3-trifluoromethylpiperazine) is used.
MS, m/z (rel. range): 432,25 (M++2; 2,9); 431,25 (M++1; 21,5); 430,25 (M+; 79,4); 256,10 (32.0); 243.00 (100,0); 241,00 (35.D 5
200,00 (56,4); 172,00 (20,1).
1H-NMR ( 200MHz, CDC13 ) , δ(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) ; 5,89 (t.lH, J=4,5 Hz.H vin.); 6,75~7,42 (m,7H,arom. ) .
Hydrochlorate: m.p. 1 -1 7 °C EXAMPLE 12
4-[3~(8-methoxy-l,2-dihydronaphthalen-4-yl)-n-propyl1-1-(2-pyri- dyl)piperazine
The same process described in Example 8 is followed, with the only difference that in this case l-(2-pyridyl)piperazine is used.
MS, m/z (rel. range): 365, 5 (M++2;l,8); 364,25 (M++l;l4,3);
363,25 (M+;53,3); 256,25 (39,0); 244,25 (46,1); 121,10 (34,0);
107.10 (100,0); 79.10 (23,0); 78,10 (20,6); 72,10 (35.9). 1H-NMR (200MHz, CDClg), δ (ppm) : 1,67-1.86 (m, 2H,CH2CH2CH2) ;
2,13-2,28 (m, 2H,CH2 endoc); 2,40-2,63 [m,8H,CH2CH2 CH2N(CH2)2];
2,73 (t,2H, J=8Hz,CH2benz.); 3,50-3,62 [m,4H, (CH2)2NAr]; 3,82
(s,3H,CH3); 5.87 (t.lH, J=4,5Hz, H vin.); 6,58-7,52 (m, 6H arom);
8,16-8,23 (m,lH,N=CH arom.). Hydrochlorate: m.p. 218-220°C.
EXAMPLE 13
4-[3~(1,2-dihydronaphthalen-4-yl)-n-propyl]-1-(2-methoxyphenyl) piperazine
The same process described in Example 8 is followed, with the only difference that l-(2-methoxyphenyl)-piperazine is used.
MS, m/z (rel. range): 364,25 (M++2; 3,4); 363,2 (M++1;27,D;
362,25 (M+;100,0); 205,10 (3L3); 203,10 (30,4); 162,10 (22,9).
^-NMR (200MHz,CDC13), δ (ppm): 1,72-1,83 (m,2H,CH2CH2CH2) ; 2,19-
2,28 (m,2H,CH2endoc); 2,43-2,55 (m,4H,CH2CH2CH2N) ; 2,62-2,78 [m,6H,CH2benz., CH2N(CH2)2]; 3,10 [broad.t, 4H, (CH2)2NAr]; 3,84 (s,3H,CH3); 5,87 (t.lH, J=4,5 Hz, H vin.); 6,82-7,27 (m,8H, arom . ) .
Hydrochlorate: m.p. l85-lδ7°C. EXAMPLE 14 1-(2-methoxyphenyl)-4-f -(7~methoxy-l,2,3,4-tetrahydronaphthalen- l-yl)-n-propyl]piperazine l-[3"(6-methoxy-l,2-dihydronaphthalen-4-yl)-n-propyl]-4-(2-metho¬ xyphenyl)piperazine hydrochlorate (2 mmoles) obtained as described in Example 2, is solubilized in MeOH (30 ml) and hydrogenated in the presence of a catalytic amount of 10% Pd/C . After about 2 hours the mixture is filtered on Celite, the solvent is evaporated and the hydrochlorate salt of the desired product is obtained as a light yellow solid, that is crystallized from MeOH/Et20 (yield 90%). Hydrochlorate: m.p. 203-205 °C,
MS, m/z (rel. range): 396,35 (M++2; 3.3); 395.35 (M++1; 23,4); 394,35 (M+; 83,8); 205,10 (100,0); 192,10 (33,4); 150,10 (22,8). 1H-NMR (200MHz,CDC13) , δ(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. ) . EXAMPLE 15 4-[3-(7-methoxy-l,2,3,4-tetrahydronaphthalen-l-yl)-n-propyll-l- (3~trifluoromethylphenyl)piperazine
The same process described in Example 14 is followed, starting from the hydrochlorate obtained in Example 5-
Hydrochlorate: m.p. 150-152 C.
MS, m/z (rel. range): 434,25 (M++2;2,4); 433.25 (M++1; 16,7),
432,25 (M+; 58,6); 243,10 (100.0); 230,10 (36,3). 1H-NMR (200MHz,CDC13) , δ(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.) .
EXAMPLE 16 l-phenyl-4-f3-(5-'nβthoxy-l,2,3,4-tetrahydronaphthalen-l-yl)-n- propyllpiperazine
The same process described in Example 14 is followed, starting from the hydrochlorate obtained in Example 8.
MS, m/z (rel. range): 366.30 (M++2; 2,8); 365.30 (M++1; 21,4); 364,30
(M+; 80,5); 175.15 (100,0); 162,05 (35.0).
1H-NMR (200MHz,CDC13) , δ(pρm): 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.
EXAMPLE 17 l-(2-methoxyphenyl)-4-r3-(5~πιethoxy-l,2,3,4-tetrahydronaphthalen- l-yl)-n-propyllpiperazine The same process described in the Example 14 is followed, starting from the hydrochlorate obtained in Example '.
MS, m/z (rel. range): 396,30 (M++2; 3,3); 395.30 (M++1; 23,0);
394,30 (M+; 82,7); 205.10 (100,0); 192,10 (34,4); 150,10 (21,8).
1H-NMR (200MHz,CDC13) , δ(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]; 3.8l (s,3H), 3.86
(s,3H), (2 CH3); 6,62-7,17 (m,7H, arom.).
Hydrochlorate: m.p. 206-207 °C
EXAMPLE 18 4 - f ~ ( 5 -me thoxy- 1,2,3.4- tetrahydronaphthalen- 1 -yl ) -n-propyl ] - 1 -
( 2-ρyridyl ) piperazine
The same process described in the Example 14 is followed, starting from the hydrochlorate obtained in Example 12.
MS, m/z (rel. range ): 367,20 (M++2; 1,9); 366,20 (M++1; 13,8); 365,20 (M+; 50,8); 271,20 (29,5); 258,20 (87.0); 121,05 (32,6);
107,05 (100,0); 86,15 (22,4); 79.05 (25.6); 78,00 (22,4); 72,00
(37,6).
1H-NMR ( 200MHz, CDC13 ) , δ(ppm): 1,52-1,88 (m,8H,CH2CH2 endoc ,CHCH2CH2CH2N) ; 2,38-2,85 (m,9H.CH and CH2 benz., CH2N(CH2)2]; 3,59 [broad. t,4H, (CH2)2NAr]; 3,80 (s,3H,CH3);
6,58-7,52 (m,6H,arom.); 8,14-8,23 (m,lH,N=CH arom. ) .
Hydrochlorate: m.p. 169- 171 °C.
EXAMPLE 19
4-[3-(7-methoxy-l,2,3,4-tetrahydronaphthalen-l-yl)-n-propyl]-l-(2- pyridyl)piperazine
The same process described in Example 14 is followed, starting from the hydrochlorate obtained in Example 12.
MS, m/z (rel.range): 367.25 (M++2;l,3); 366,25 (M++l;9,6); 365.
( +;39.7); 271.15 (21,7); 258,15 (60,1); 121,10 (31.7); 107,00
( 100 , 00) ; 86 , 10 (24 , 6) ; 79.10 (20 , 7 ) ; 72 , 10 (48 , 0) . ^-NMR (200MHz , CDClj ) , δ (ppm) : 1 , 53-1 , 89 ( m , 8H , CH2CH2 endoc ,
CHCH2CH2CH2N) ; 2,50 [broad, t, 2H,CH2N(CH2)2] ; 2,61-2,82 [m,7H,CH and CH2 benz., CH2N(CH2)2]; 3.63 [broad. t,4H. (CH2)2NAr]; 3,76
(s,3H,CH3; 6,58-7,52 (m,6H,arom.); 8,15-8,21 (m,1N,N=CH arom. ) .
Hydrochlorate: m.p. l43-l45°C. ESEMPIO 20
1-(2-methoxyphenyl)-4-[3-(4, , ,7~tetrahydrobenzo[b]thien-4-yl)- n-propyllpiperazine.
The same process described in Example 14 is followed, starting from the hydrochlorate obtained in Example 9- MS, m/z (rel. range): 372,20 (M++2;7,5); 371.20 (M++l;25,0);
370,20 (M+; 100,0); 205,05(59.4); 192,15(25.0); 150,05 (25,4).
1H-NMR (200MHz, CDClj), δ (ppm): 1,42-2,01 (m,8H,CH2 endoc,
CHCH2CH2CH2N) ; 2,45 [t,2H, J=7,3Hz, CH2N(CH2)2] ; 2,61-2,81
[m,7H,CH and CH2 benz., CH2N(CH2)2]; 3,12 [ broad, s, 4H, (CH2)2NAr]; 3,86 (s,3H,CH3); 6,82-7,05 (m,6H,arom. ) .
Hydrochlorate: m.p. 217-218°C.
EXAMPLE 21
1-(2-methoxyphenyl)-4-[3~(1,2, ,4-tetrahydronaphthalen-1-yl)-n- propyllpiperazine. The same process described in Example 14 is followed, starting from the hydrochlorate obtained in Example 9-
MS, m/z (rel. range): 366,25 (M++2;2,8): 365, 5 (M++l;21,4);
364,25 (M+;77,7) 205,5 (100,0); 192,15 (30,7); 150,05 (24,5);
91,05 (21,3). XH-NMR (200 MHz, CDClg) , δ (ppm): 1,54-1,92 (m,8H,CH2CH2 endoc,
CHCH2CH2CH2N) ; 2,45 [broad. t,2H,CH2N(CH2)2]; 2,62,-2,88 [m,7H,CH and CH2 benz., CH2N(CH2)2]; 3,12 [broad.s, 4H, (CH2)2NAr]; 3,86
(s,3H,CH3); 6,82-7,21 (m, 8H, arom.).
Hydrochlorate: m.p. 223-224°C. EXAMPLE 22
4-[4-(6-methoxy-l,2-dihydronaphthalen-4-yl)-n-butyl]-l-(2- methoxyphenyl)piperazine
7-methoxy-l-tetralone (6 mmoles) solubilized in tetrahydrofuran
(10 ml) is added to a solution of 4-chloro-n-butylmagnesium bromide (9 mmoles) in tetrahydrofuran. The process is the same as that described in Example 2. Through the corresponding raw intermediate product (VI) wherein p = 2 the desired product is obtained, as an oil, in a total yield of 60 .
MS, m/z (rel. range): 408,25 (M++2; 4,7); 407,25 (M++1; 29,2); 406,35 (M+; 99,9); 205,10 (22,9).
1H-NMR (200MHz,CDC13), δ(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. EXAMPLE 23
1-(2-methoxyphenyl)-4-[4-(7-methoxy-l,2,3,4-tetrahydronaphthalen- l-yl)-n-butyllpiperazine
Following the process described in Example 14 starting from the corresponding product described in previous Example 22, the desired product is obtained in a yield of ~ % .
The following analyses are carried out on the free base:
MS, m/z (rel. range): 410,35 ( ++2; 2,9.); 409,25 (M++1; 20,9);
408,25 (M+; 75,8); 205,10 (100,0). 1H-NMR (200MHz,CDC13), δ(ppm): 1,30-1,92 (m,10H,CH2CH2 endoc,
CH2CH2CH2CH2N) ; 2,44 [t,2H, J=7 , 6 Hz ,CH2N(CH2)2] ; 2,62-2,83
[m,7H,CH and CH2 benz. ,CH2N(CH2)2]; 3,18 [broad s. ,4H, (CH2)2NAr];
3.78 (s,3H), 3,86 (s,3H), (2 CH3); 6,63~7,02 (m, 7H, arom.).
Hydrochlorate: m.p. 192-193 °C. EXAMPLE 24 l-(2-methoxyphenyl)-4-{2-[ (7-methoxy-l,2,3.4-tetrahydro- naphthalen-l-yl)-thio]-ethyl}piperazine.
Ethyl 2-mercapto-acetate (6 mmoles) and ZnI-> (3 mmoles) are added to a solution of 7-metnoxy-l-tetralol (6 mmoles) (prepared according to a known method from 7-methoxy-l-tetralone) in 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 2-[(7-methoxy-l,2,3,4-tetrahydronaphthalen-l-yl)-thio]-acetate (yield 38% ) . This product is directly hydrolyzed with KOH in a hydroalcoholic solution at the boiling temperature.
After cooling, a minimum amount of water is added and the mixture is concentrated. The mixture is thereby acidified with HCl and extracted with 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-ωethoxy-l,2,3,4-tetrahydronaphthalen-l-yl)-thio]-acetic acid (5 mmoles) is treated with - ml S0C12 and heated under vacuum in a rotavapor and brought to dryness.
The obtained raw oil, composed by the chloride of the corresponding acid is dissolved in toluene (20 ml) and left to react under reflux with a solution of 1- (2-methoxyphenyl)- piperazine (8 mmoles) in toluene (30 ml) in the presence of trimethyl amine (10 mmoles). After 2 hours the reaction mixture is washed with H 0 and with HCl 2N.
The organic phase, dried and evaporated, brings to an oily residue that is purified by chromatographic column. The corresponding 4-(2-methoxyphenyl)piperazinamide of the above mentioned acid is thereby obtained as a yellow brown oil in a yield of 47%.
This amide (2 mmoles) dissolved in tetrahydrofuran (20 ml) is added drop by drop to a suspension of LiAlH^ (100 mg) in 30 ml tetrahydrofuran under stirring. The mixture is kept at the boiling temperature for 6 hours, then it is cooled and few drops of H20 are added, then the usual process is followed thereby obtaining a light yellow oil in a yield of 83%.
The product is then transformed into the corresponding hydrochlorate and crystallized from CHCl /petroleum ether, m.p. 200-201 °C.
The following analyses are carried out on the free base:
MS, m/z (rel. range): 4l4,25 (M++2; 1,4); 413,25 (M++1; 4,7);
412,35 (M+; 17,4); 219,20 (24,0); 205,10 (100,0); 190,10 (29,5).
1H-NMR (200 MHz,CDCl3), δ(ppm) : 1,67-2,10 (m,4H,CH2CH2 endoc); 2,56-2,85 [m,10H,CH2 benz. ,SCH2CH2N(CH2) - W ' 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 2
4-T1-(8-methoxy-l,2,3,4-tetrahydronaphthalen-4-yl)-l-propylen-3~ yl]-1-(2-me hoxyphenyl)piperazine
8-methoxy-l-tetralone (6 mmoles) solubilized in tetrahydrofuran
(10 ml) are added to a solution of cyclopropylmagnesium bromide
(9 mmoles) dissolved in tetrahydrofuran (10 ml), and left under reflux for about 1 hour. The mixture is cooled and a solution saturated by ammonium chloride is added. The organic phase is washed with water, brought to dryness and a raw reaction product mainly composed by l-cyclopropyl-8-methoxy-l, 2, 3, 4-tetrahydronaphthalen-l-ol, is obtained under the form of a dark oil. The mixture is directly treated with a HCl solution in diluted acetic acid. The mixture is thereby kept at room temperature for 1 hour, then it is treated with alkali and extracted with CHClo. The solvent is evaporated and a dark oil is obtained, which is purified by column chromatography; the product recovered in a total yield of 64% is composed by 4-(3_chloro-l-propylen-l-yl)-8- methoxy-l,2,3,4-tetrahydronaphthalene intermediate (VI a) with
P=l.
1- (2-methoxyphenyl ) piperazine ( 3 « 5 mmoles ) are added to a dimethylformamide solution ( 10 ml) of the compound (VI A) (3-5 mmoles ) in the presence of Nal ( catalytic amount ) of Sodium
Carbonate (3 - 5 mmoles ) .
The mixture is kept under reflux for 1 hour, then it is cooled and after evaporating dimethylformamide, the residue is added with water and extracted with CHClo . After evaporating the solvent the obtained residue is purified by column chromatography thus obtaining the desired product in the form of a light yellow oil (yield 82 %) .
MS, m/z (rel. range): 393.25 (M++l;2,0) ;392,25 (M+;7.1); 205,10
(100,0). 1H-NMR (200MHz, CDClg), δ (ppm): 1,82 (m,2H,CH2endoc ) ; 2,42-2,65
(m,6H,CH2C=CHCH2CH2N); 2,67-2,85 [m,6H,CH2benz. , CH2N(CH )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. EXAMPLE 26
4-[l-(8-methoxy-l,2,3.4-tetrahydronaphthalen-4-yl)-l-propylen-3- yll-l-(2-pyridyl)piperazine.
The same process described in Example 25 is followed starting from the hydrochlorate obtained in Example 12.
MS, m/z (rel. range): 3 3, (M+:3,6); 176,10 (100,0); 147,10 (23,6); 121,10 (35,9).
^■H-NMR (200 MHz, CDClj), δ (ppm): 1,82 (m,2H,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]; 3,81 (s,3H,CH3,6,00 (broad. t, 1H, H vin.); 6,56-7.53 (m,6H,arom. ) ; 8,14-8,25 (m,lH,N=CH arom) .
Hydrochlorate: m.p. 221-222°C.
EXAMPLE 27
1-(2-methoxyphenyl)-4-[1,2,3,4-tetrahydronaphthalen-4-yl)-1- propylen-3~yl]piperazine. The same process described in Example 2 is followed starting from the hydrochlorate obtained in Example 9-
MS, m/z (rel. range): 363,20 (M++l;l,4) ; 362,20 (M+;5,5); 205,05
(100,00); 190,05 (21,6).
^■H-NMR (200 MHz, CDClg) , δ (ppm): 1,82 (m,2H,CH2 endoc); 2,40- 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.δH.arom. ) .
Hydrochlorate: m.p. 19δ-199°C.
BIOCHEMICAL AND PHARMACOLOGICAL TRIALS Preparation of rat cerebral tissue homogenate for receptorial binding experiments.
Preparation 1, utilized for binding trial at the receptors:
5-HT1A, 5-HT1B, 5-HT1C, 5-HT2, D-2, D-l, α-1.
Cerebral tissue asported from male rats (Sprague Dawley) weighing 180-220 g is homogenized in Tris. HCl buffer, 50 mM, pH 7.4 with
Ultra-Turrax (2 x 20 sees) and centrifugated at 50.000 g for 10 min.. The obtained pellet, resuspended in the same volume of buffer, incubated at 37 °C for 10 minutes [Nelson, Mol .
Pharmacol. 14, 983, (1978)], is centrifugated again in the above mentioned conditions. The final pellet is dissolved in the appropriate incubation buffer just before the receptorial binding test.
Preparation 2, used for binding trial at the σ receptor. Cerebral tissue of male Hattly cavy (Charles River) weighing 300-
600 g is homogenized in 0.32 M saccarose with Ultra-Turrax (2 x
20 sec.) and centrifugated at 900 g for 10 minutes. The surnatant is centrifugated at 22.000 g for 20 minutes. The obtained pellet, dissolved in Tris.HCl buffer pH = 7.4 is incubated at 37 °C for 30 minutes and centrifugated at 22.000 g for 20 minutes.
The final pellet is dissolved in the appropriate incubation buffer just before the test.
2. Operating conditions for the receptorial binding trials.
5-HT1A Receptor. The methodology described by J.R. Schlegel, Biochem. Pharmacol. 35, 19 3, (1986) is essentially used.
In short, rat cerebral cortex homogenate is dissolved in the incubation buffer (Tris.HCl 50 mM, pH = 7.7 containing 10 μM of pargyline, 4 mM 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 μM). 5-HT1B Receptor. The methodology described by S.J. Peroutka, J. Neurochem. 47, 529, (1986) is essentially used.
In short, rat cauda striati homogenate is dissolved in the incubation buffer (Tris.HCl 50 mM, pH = 7.7 containing 10 μM of pargyline, 4 mM CaCl2, 0.1% of ascorbic acid) and incubated in the final volume of 1 ml at 25 °C for 30 minutes in the presence of 3H-5HT (2.0 nM) and 80H-DPAT (0.1 μM) as the blocking agent of 5-HT1A receptors. The aspecific bond is evaluated by the use of 5-HT (10 μM). 5-HT1C Receptor. The methodology described by S.J. Peroutka, J. Neurochem. 47, 529. (1986) is essentially used.
In short, rat cerebral cortex homogenate is dissolved in the incubation buffer (Tris. HCl 50 mM, pH = 7.7 containing 10 μM pargyline, 4mM CaCl2, 0.1% ascorbic acid) and incubated in the final volume of 1 ml, at 2 °C, for 1 minutes in the presence of 3H-5HT (2.0 nM) and 80H-DPAT (0.1 μM) and RU-24960 (lOnM) as the blocking agents respectively of 5-HT1A and 5-HT1B receptors. The aspecific bond is evaluated by the use of 5-HT (10 μM) . 5-HT2 Receptor. The methodology described by A.K.Mir, Eur. J. Pharmacol. 149, 107, (1988) is essentially used. In short, rat frontal cortex homogenate is dissolved in the incubation buffer (Tris.HCl 50 mM, pH = 7.7) and incubated in the final volume of 1 ml, at 37 °C, for 15 minutes in the presence of 3H-Ketanserine (0.35 nM) • The aspecific bond is evaluated by the use of methysergide (1 μM) . D-1 Receptor. The methodology described by W.B. Billard, Life Science, 35. 1885, (1984) is essentially used.
In short, rat cauda striati homogenate is dissolved in the incubation buffer (Tris. HCl 50 mM, pH = 7.4 containing 120 mM of NaCl, 5 mM of KCl, 2mM of Ca'Cl2, ImM 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-2339O (1 μM).
D-2 Receptor. The methodology described by I. Creese, Eur. J. Pharmacol. 49, 201, (1978) is essentially used. In short, rat cauda striati homogenate is dissolved in the incubation buffer (Tris.HCl 50 mM, pH = 7.4 containing 120 mM NaCl, 5 mM KCl, 2 mM CaCl2, 1 M MgCl2) and incubated in the final volume of 1 ml, at 37 °C for 15 minutes in the presence of 3H-Spiroperidole (0.25 mM) and Ketanserine (40 nM) as blocking agent of 5"HT2 receptors. The aspecific bond is evaluated by the use of Butaclamol (10 μM) . α-1 Receptor. The methodology described by A.K.Mir, Eur. J. Pharmacol. 149, 107, (1988) is essentially used. In short, rat cerebral cortex homogenate is dissolved in the incubation buffer (Tris.HCl 50 mM, pH = 7.7 containing 10 μM pargyline, 0.1% ascorbic acid) and incubated in the final volume of 1 ml at 25 °C for 30 minutes in the presence of 3H-Prazosin (0.2 nM) . The aspecific bond is evaluated by the use of Prazosin (3 μM). σ Receptor. The methodology described by E.Weber, Proc Natl. 5 Acad. SCI. USA 83, 8784, (1986) is essentially used.
In short, rat brain deprived of the cerebellum is homogenized and then dissolved in the incubation buffer (Tris.HCl 50 mM, pH = 7.4) and incubated in the final volume of 1 ml, at 25 °C, for 90 minutes in the presence of 3H-DTG (0.9 nM) . The aspecific bond is ° evaluated by the use of Haloperidol (1 μM) . 3. Behaviouristic experiments. 5-HT1A activity evaluation "in vivo".
The compounds under question are analyzed by using the method described by Tricklebank [Eur. J. Pharmacol., 106, 271 (1985)]. 5 The compounds under question are administered subcutaneously to male rats (S.D.) treated with reserpine (1 mg/Kg) 18 hours before the test.
The evaluation of the behaviour starts 3 minutes after the administration of the compounds under question and continue for 0 the following 30 minutes. The behaviour intensity is evaluated every 3 minutes by the use of a scale that assign the following scores to the two specific behaviours named "Flat body posture" and "Forepaw Treading":
0: absence of behaviouristic effects. 5 1: presence of ambiguous behaviouristic signs. 2: presence of evident behaviouristic effects.
3: presence of intense behavioural effects. The possible agonistic activity of the products under question is evaluated every 3 minutes for 30 minutes after their administration.
The antagonist activity on the stereotypy induced by 80H-DPAT (0.125 mg/Kg, s.c) is evaluated every 3 minutes from 30 to 60 minutes after the administration of the products under question starting from 3 minutes after the administration of 80H-DPAT. The results of the above mentioned trials are reported in the following Tables 1,2 and 3>
Figure imgf000048_0001
Figure imgf000049_0001
TABLE 2
EXAMPLES INHIBITION OF THE STEREOTYPY FROM 80H-DPAT DE50 (mg/kg s.c.)
EXAMPLE 1 2.13 EXAMPLE 2 0.76 EXAMPLE 11 24.19 EXAMPLE 14 O.87 EXAMPLE 17 < 0.10 EXAMPLE 26 < 0.10
TABLE 3
Figure imgf000051_0001
Figure imgf000052_0001

Claims

CLAIMS l.N(hetero)-aryl-N(hetero)-tetralin-alkyl-piperazine and their pharmaceutically acceptable salts of general formula (I)
Figure imgf000053_0001
(I) wherein Ar is selected from phenyl; mono or di-substituted aryl in which the substituent(s) is (are) selected on its (their) turn from linear or branched -^-C- alkyl, halogen atoms, C-^-Cc haloalkyl; heteroaryl containing one or more heteroatoms selected on their turn from N, 0, S, said heteroaryl being optionally substituted with the aforementioned alkyl groups, said heteroaryl being a monocyclic group of from 5 to 6 atoms or condensed on an aryl group optionally substituted with the aforementioned groups, Ar^ is an aryl or a heteroaryl of from 5 tά 6 carbon atoms containing from 1 to 3 heteroatoms selected from N, 0, or S; R-^ and R2 equal or different from each other are selected from H, ^1~^ alkoxy, OH, C^-Cr alkyl, N02 and wherein
Y-
\ / X is selected from :
Figure imgf000054_0001
Figure imgf000054_0002
iϋ) Y^
Figure imgf000054_0003
n 1 or 2 and m = 2 or 3 -
2. N(hetero)-aryl-N(hetero)-tetralin-alkyl-piperazine of general formula (I) according to claim 1 wherein Ar^ is an aryl group which is condensed on the alicyclic ring so that it forms the derivatives of general formula (IA)
Figure imgf000054_0004
(IA)
3- N(hetero)-aryl-N(hetero)-tetralin-alkyl-piperazine of general formula (I) according to claim 1 wherein Ar-^ is an aryl group which is condensed on the alicyclic ring so that it forms the derivatives of general formula (IB).
Figure imgf000055_0001
4. N(hetero)-aryl-N(hetero)-tetralin-alkyl-piperazine according to claim 1, wherein R^ is OCHo, and R2 is H.
5. N(hetero)-aryl-N(hetero)-tetralin-alkyl-piperazine according to claim 1 wherein Ar2 is selected from : 2-methoxyphenyl, 3~ chlorophenyl, 3~trifluoromethylphenyl, 2-pyridyl, 2,5- dimethoxyphenyl.
6. N(hetero)-aryl-N(hetero)-tetralin-alkyl-piperazine according to claim 1, wherein n is 2. 7- Process for preparing N(hetero)-aryl-N(hetero)-tetralin- alkyl-piperazine and their pharmaceutically acceptable salts of general formula (I)
Figure imgf000055_0002
(I) wherein Ar2 is selected from phenyl; mono or di-substituted aryl in which the substituent(s) is (are) selected on its (their) turn from linear or branched C^- -C- alkyl, halogen atoms, C^-Cc haloalkyl; heteroaryl containing one or more heteroatoms selected on their turn from N, 0, S, said heteroaryl being optionally substituted with the aforementioned alkyl groups, said heteroaryl being a monocyclic group of from 5 to 6 atoms or condensed on an aryl group optionally substituted with the aforementioned groups, Ar^ is an aryl or a heteroaryl of from to 6 carbon atoms containing from 1 to 3 heteroatoms selected from N, 0, or S; R-^ and R2 equal or different from each other are selected from H, ^-Cr alkoxy, OH, C^-Cr- alkyl, N02 and wherein
Y-
\ / X
I
is :
Figure imgf000056_0001
comprising the following steps: a) reacting the keton of formula (II)
(II)
Figure imgf000056_0002
wherein Ar^, R^, R2 and n have the aforementioned meanings with an aminoalkylpiperazine of formula (III):
Figure imgf000057_0001
(III) wherein m and Ar have the above mentioned meanings, in an apolar solvent under reflux and in the presence of catalytic amounts of an acid, thereby obtaining the derivative of formula (IV) :
Figure imgf000057_0002
(IV) b) reducing the product obtained in the preceding step with sodium borohydride in a polar solvent at room temperature . 8. Process for preparing N(hetero)-aryl-N(hetero)-tetralin- alkyl-piperazine and their pharmaceutically acceptable salts of general formula (I)
Figure imgf000057_0003
(I) wherein Ar2 is selected from phenyl; mono or di-substituted aryl in which the substituent(s) is (are) selected on (its) their turn from linear or branched C^-Cc alkyl, halogen atoms, 0^-0-- haloalkyl; heteroaryl containing one or more heteroatoms selected on their turn from N, 0, S, said heteroaryl being optionally substituted with the aforementioned alkyl groups, said heteroaryl being a monocyclic group of from 5 to 6 atoms or condensed on an aryl group optionally substituted with the aforementioned groups, Ar^ is an aryl or a heteroaryl of from 5 to 6 carbon atoms containing from 1 to 3 heteroatoms selected from N, 0, or S; R-^ and R2 equal or different from each other are selected from H, C1"C5 alkoχy. 0H' cl"c5 alkyl, N02 and wherein
Figure imgf000058_0002
Figure imgf000058_0001
comprising the following steps: a') reacting the keton of general formula (II)
Rl 1*2 wherein Ar^, R^, R2 and n have the aforementioned meanings with the Grignard reactant Ro-MgX, wherein R is selected from: cyclopropyl and -(CH2)/jCl in an ethereal solvent thereby obtaining the tertiary alcohol of formula (V)
Figure imgf000059_0001
(V) b' ) reacting the tertiary alcohol (V) coming from the preceding step with HCl in acetic acid thereby obtaining the chloride derivative of formula (VI) or (Via) :
Figure imgf000059_0002
(VI) (VIA)
wherein p is = 1 or 2 and is =1 when in the reactant (V) R is = cyclopropyl, or is = 2 in case R is = -(CH2)^-C1 c') reacting the chloride intermediate (VI) or (VIA) obtained in the preceding step with N-arylpiperazine of formula (VII)
Figure imgf000060_0001
(VII )
wherein Ar2 has the aforementioned meanings thereby obtaining N(hetero) aryl-N (hetero) - tetralinalkylpiperazine of formula (I ) wherein
Figure imgf000060_0002
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 :
Figure imgf000060_0003
9- Process for preparing N(hetero)-aryl-N(hetero)-tetralin- alkyl-piperazine and their pharmaceutically acceptable salts of general formula (I)
Figure imgf000060_0004
4 wherein Ar2 is selected from phenyl; mono or di-substituted aryl
5 in which the substituent(s) is (are) selected on its (their) turn
6 from linear or branched C^-Cr alkyl, halogen atoms, C^-Cc
7 haloalkyl; heteroaryl containing one or more heteroatoms selected
8 on their turn from N, 0, S, said heteroaryl being optionally
9 substituted with the aforementioned alkyl groups, said heteroaryl 1° being a monocyclic group of from 5 to 6 atoms or condensed on an H aryl group optionally substituted with the aforementioned groups,
12 Ar^ is an aryl or a heteroaryl of from 5 to 6 carbon atoms
13 containing from 1 to 3 heteroatoms selected from N, 0, or S; R-^
14 and R2 equal or different from each other are selected from H, 5 cι~Cc alkoxy, OH, C^C,- alkyl, N02 and wherein
Y-
\ / X
I
Figure imgf000061_0001
7 comprising the following steps: 8 a") reacting the keton (II)
Figure imgf000061_0002
9 in the presence of a reducing agent thereby obtaining the 0 corresponding alcohol (VIII )
Figure imgf000062_0001
(VIII ) b" ) successively treating the alcohol (VIII ) obtained in the preceding step with ethyl 2-mercapto-acetate and Znl2 , thus obtaining the corresponding ester of formula (IX) :
Figure imgf000062_0002
( 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)
Figure imgf000062_0003
d") reacting the acyl chloride (X) with the aforementioned N- aryl-piperazine (VII) thereby obtaining the corresponding amide (XI):
Figure imgf000063_0001
(XI) e") treating the amide (XI) with LiAlH/j to obtain the desired derivative of formula (I) . 10.A therapeutic composition containing as the active principle one or more N(hetero)-aryl-N(hetero)-tetralin-alkyl-piperazine and their pharmaceutically acceptable salts of general formula
Figure imgf000063_0002
(I) wherein Ar2 is selected from phenyl; mono or di-substituted aryl in which the substituent(s) is (are) selected on its (their ) turn from linear or branched C^-Cc alkyl, halogen atoms, Cι~ c haloalkyl; heteroaryl containing one or more heteroatoms selected on their turn from N, 0, S, said heteroaryl being optionally substituted with the aforementioned alkyl groups, said heteroaryl being a monocyclic group of from 5 to 6 atoms or condensed on an aryl group optionally substituted with the aforementioned groups, Ar^ is an aryl or a heteroaryl of from 5 to 6 carbon atoms containing from 1 to 3 heteroatoms selected from N, 0, or S; R^ and R2 equal or different from each other are selected from H, ci"c5 alkoxy, OH, C-^-C,- alkyl, N02 and wherein
Y-
\ /
is selected from:
Figure imgf000064_0001
Figure imgf000064_0002
Figure imgf000064_0003
iv) Y
Figure imgf000064_0004
n = 1 or 2 and m = 2 or 3, in combination with suitable excipients and or diluents. 11. The therapeutic composition according to claim 10 containing the active principle in amounts ranging from 1 to 200 mg. 12. The therapeutic composition according to claim 10 containing the compounds of formula (I) having mainly 5-HT1A serotoninergic activity for the treatment of generalized anxiety, panic attacks, obsessive-compulsive syndromes, depression, opium like, psycho stimulant substances and alcohol abuse syndromes, consciousness disorders such as senile dementia, vigilance and memory disorders, Parkinson's and Alzheimer's diseases. 13. The therapeutic compositions according to claim 12 wherein the active principle is selected among one or more of the following derivatives: - l-(2-methoxyphenyl)-4[N-(5-methoxy-l,2,3,4- tetrahydronaphthalen-l-yl)-2-aminoethyl]-piperazine; -4 -[3-(6-methoxy-l,2-dihydronaphthalen-4-yl)n-propyl-l-(2- methoxyphenyl)-piperazine; - l-phenyl-4-[3-(8-methoxy-l,2-dihydronaphthalen-4-yl)-n- propyl]piperazine; - 4-[3-8-methoxy-l,2-dihydronaphthalen-4-yl)-n-propyl]-l-(2- methoxyphenyl)-piperazine; - 4-[3-(8-methoxy-l,2-dihydronaphthalen-4-yl)-n-propyl]-l-(2- pyridyl)-piperazine; - 4-[3-(1,2-dihydronaphthalen-4-yl)-n-propyl]-l-(2-methoxyphenyl)■ piperazine; - l-(2-methoxyphenyl)-4-[3-(7-methoxy-l,2,3,4- tetrahydronaphthalen-l-yl)-n-propyl]piperazine; " l-phenyl-4-[3-(5-methoxy-l,2,3,4-tetrahydronaρhthalen-l-yl)-n- propyl]-piperazine; - l-(2-methoxyphenyl)-4-[3-(5-methoxy-l,2,3,4- tetrahydronaphthalen-1-yl)-n-propyl]-piperazine; - 4-[3-(5-methoxy-l,2,3,4-tetrahydronaphthalen-1-yl)-n-propyl]-l- (2-pyridyl)-piperazine; - 4-[3-(7-methoxy-l,2,3,4-tetrahydronaphthalen-l-yl)-n-propyl]-l- (2-pyridyl)piperazine; - l-(2-methoxyphenyl)-4-[3-(4,5,6,7-tetrahydrobenzo[b]thien-4-yl)- n-propyl]piperazine; - 1-(2-methoxyphenyl)-4-[3~(1.2,3,4-tetrahydronaphthalen-l-yl)-n- propyl]piperazine; - 4-[4-(6-methoxy-l,2-dihydronaphthalen-4-yl)-n-butyl]-l-(2- methoxyphenyl)-piperazine; - l-(2-methoxyphenyl)-4-[4-(7-methoxy-l,2,3,4- tetrahydronaphthalen-1-yl)-n-butyl]-piperazine; - l-(2-methoxyphenyl)-4-{2[(7-methoxy-l,2,3,4- tetrahydronaphthalen-l-yl)-thio]-ethyl}piperazine; - 4-[1-(8-methoxy-l,2,3,4-tetrahydronaphthalen-4-yl)l-propylen-3- yl]-1-(2-methoxyphenyl)piperazine; " 4-[l-(8-methoxy-l,2,3,4-tetrahydronaphthalen-4-yl)-l-propylen- 3~y1]-1~(2-pyridyl)piperazine; - l-(2-methoxyphenyl)-4-[(1,2,3, -tetrahydronaphthalen-4-yl)-l- propylen-3~yl]piperazine; ~ l-(3_chlorophenyl)-4-[3-(8-methoxy-l,2,-dihydronaphthalen-4- yl)-n-propyl]piperazine; - 4-[3-(8-methoxy-l,2-dihydronaphthalen-4-yl)-n-propyl]-l-(3- trifluoromethylphenyl)piperazine; - 4-[3~(7-methoxy-l,2,3,4-tetrahydronaphthalen-1-yl)-n-propyl]-l- (3"trifluoromethylphenyl)piperazine. 14. The therapeutic composition according to claim 10 containing the compounds of formula (I) having mainly affinity on D-2, σ and 5- HTIA receptors or on D-2, σ and α-1 receptors for the therapy of schizophrenia or cerebral ischemia. 15. The therapeutic composition according to claim 14 wherein the active principle is selected among one or more of the following derivatives: - 4-[3-(8-methoxy-l,2-dihydronaphthalen-4-yl)-n-propyl]-l-(2- methoxyphenyl)-piperazine; - 4-[3"(l,2-dihydronaphthalen-4-yl)-n-propyl]-l-(2- methoxyphenyl)-piperazine; - l-(2-methoxyphenyl)-4-[3-(7-methoxy-l,2,3,4- tetrahydronaphthalen-1-yl)-n-propyl]piperazine; " l-phenyl-4-[3-(5-ωethoxy-l,2,3,4-tetrahydronaphthalen-l-yl)-n- propyl]-piperazine; - l-(2-methoxyphenyl)-4-[3-(5-methoxy-l,2,3,4- tetrahydronaphthalen-1-yl)-n-propyl]-piperazine; " 4-[4-(6-methoxy-l,2-dihydronaphthalen-4-yl)-n-butyl]-l-(2- methoxyphenyl)-piperazine; - l-(2-methoxyρhenyl)-4-[4-(7-methoxy-l,2,3,4- tetrahydronaphthalen-1-yl)-n-butyl]-piperazine; - l- (2-methoxyphenyl) -4[N- (5-methoxy-l , 2, 3 ,4- tetrahydronaphthalen-1-yl)-2-aminoethyl]-piperazine; -l-(2-methoxyphenyl)-4-[3-(4,5,6,7-tetrahydrobenzo[b]thien-4-yl)- n-propyl]piperazine; _ 1-(2-methoxyphenyl)-4-[3-(1,2,3,4-tetrahydronaphthalen-l-yl)-n- propyl]piperazine; - l-(2-methoxyphenyl)-4-{2[(7- ethoxy-l,2,3,4- tetrahydrσnaphthalen-1-yl)-thio]-ethyl}piperazine; - 4-[l-(8-methoxy-l,2,3,4-tetrahydronaphthalen-4-yl)l-propylen-3- yl]-1-( -methoxyphenyl)piperazine; - 1-(2-methoxyphenyl)-4-[(1,2,3,4-tetrahydronaphthalen-4-yl)-1- propylen-3_yl]piperazine. 16. The therapeutic composition according to claim 10 containing as the active principle the compounds of formula (I) having mainly affinity on 5"HT1A, α-1 receptors for the treatment of arterial hypertension. 17. The therapeutic compositions according to claim 16 wherein the active principle is selected among one or more of the following derivatives: - 4-[3-(6-methoxy-l,2-dihydronaphthalen-4-yl)n-propyl-l-(2- methoxyphenyl)piperazine; - l-phenyl-4-[3-(8-methoxy-l,2-dihydronaphthalen-4-yl)-n- propyl]piperazine; " 4-[3_(8-methoxy-l,2-dihydronaphthalen-4-yl)-n-propyl]-l-(2- methoxyphenyl)piperazine; - 4-[3_(8-methoxy-l,2-dihydronaphthalen-4-yl)-n-propyl]-l-(2- pyridyl)-piperazine; - 4-[3~(1,2-dihydronaphthalen-4-yl)-n-propyl]-l-(2-methoxyphenyl)- piperazine; - l-(2-methoxyphenyl)-4-[3-(7-methoxy-l,2,3,4- tetrahydronaphthalen-1-yl)-n-propyl]piperazine; - l-(2-methoxyphenyl)-4-[3-(5-methoxy-l,2,3,4- tetrahydronaphthalen-1-yl)-n-propyl]-piperazine; " 4-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-n-propyl]-1- (2-pyridyl)-piperazine; " 4-[4-(6-methoxy-l,2-duhydronaphthalen-4-yl)-n-butyl]-l-(2- methoxyphenyl)-piperazine; - l-phenyl-4-[3-(5-methoxy-l,2,3,4-tetrahydronaphthalen-l-yl)-n- propyl]-piperazine; - 4-[3~(7-methoxy-l,2,3,4-tetrahydronaphthalen-1-yl)-n-propyl]-l- (2-pyridyl)piperazine; - 1-(2-me hoxyphenyl)-4-[3~(4, .6,7~tetrahydrobenzo[b]thien-4- yl)-n-propyl]piperazine; - 1-(2-methoxyphenyl)-4-[3-(1,2,3,4-tetrahydronaphthalen-l-yl)-n- propyl]piperazine; - l-(2-methoxyphenyl)-4-[4-(7-methoxy-l,2,3,4- tetrahydronaphthalen-1-yl)-n-butyl]-piperazine; - l-(2-methoxyphenyl)-4-{2[(7-methoxy-l,2,3,4- tetrahydronaphthalen-l-yl)-thio]-ethyl}piperazine; - 4-[l-(8-methoxy-1,2,3,4-tetrahydronaphthalen-4-yl)l-propylen-3- yl]-1-(2-methoxyphenyl)piperazine; " 4-[1-(8-methoxy-l,2,3,4-tetrahydronaphthalen-4-yl)-1-propylen- 3-yl]-1-(2-pyridyl)piperazine; - 1-(2-methoxyphenyl)-4-[(l,2,3,4-tetrahydronaphthalen- -y1)-1- propylen-3_yl]piperazine.
PCT/EP1993/001589 1992-06-26 1993-06-22 N(hetero)-aryl-n(hetero)-tetralin-alkyl-piperazine having serotoninergic, dopaminergic and adrenergic activity WO1994000441A1 (en)

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AU44195/93A AU670444B2 (en) 1992-06-26 1993-06-22 N(hetero)-aryl-N(hetero)-tetralin-alkyl-piperazine having serotoninergic, dopaminergic and adrenergic activity
JP6502035A JPH07508514A (en) 1992-06-26 1993-06-22 N(hetero)-aryl-N(hetero)-tetralin-alkyl-piperazine with serotoninic, dopaminergic and adrenergic activity
EP93914690A EP0647222A1 (en) 1992-06-26 1993-06-22 N(hetero)-aryl-n(hetero)-tetralin-alkyl-piperazine having serotoninergic, dopaminergic and adrenergic activity
FI945997A FI945997A0 (en) 1992-06-26 1994-12-21 N (hetero) -aryl-N (hetero) -tetralinalkylpiperazine with serotonergic, dopaminergic and adrenergic activity
KR1019940704767A KR950702195A (en) 1992-06-26 1994-12-26 [N (hetero) -ary-N (hetero) -tetralin-alkyl-piperazine having serotoninergic, dopaminergic and adrenergic activity] with serotonin, dopamine and adrenaline activity

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WO1995018118A1 (en) * 1993-12-28 1995-07-06 The Upjohn Company Heterocyclic compounds for the treatment of cns and cardiovascular disorders
FR2716193A1 (en) * 1994-02-16 1995-08-18 Synthelabo Derivatives of 1 [2- (1H-inden-3-yl) ethyl] -4- (naphthalen-1-yl) piperazine, their preparation and their therapeutic application.
US5472966A (en) * 1995-03-29 1995-12-05 Bristol-Myers Squibb Company Antidepressant heteroarylaminoalkyl derivatives of naphthyl-monazines
FR2737723A1 (en) * 1995-08-09 1997-02-14 Synthelabo New 1-(2-(1H-inden-3-yl) ethyl) 4-(naphthalen-1-yl) piperazine derivs - have affinity for serotoninergic receptors and are used to treat anxiety, depression, phobia(s), migraine, hypertension, and to regulate appetite
KR100496874B1 (en) * 2003-07-03 2005-06-22 주식회사 엘지화학 Method for Preparing Polymethylmethacrylate Using Supercritical Carbon Dioxide
EP1829869A1 (en) * 2006-03-02 2007-09-05 Laboratorios Del Dr. Esteve, S.A. 4,5,6,7-Tetrahydrobenzo[b]thiophene derivatives and their use as sigma receptor ligands
US7423176B2 (en) 2004-04-13 2008-09-09 Cephalon, Inc. Bicyclic aromatic sulfinyl derivatives
US9351954B2 (en) 2009-12-04 2016-05-31 Sunovion Pharmaceuticals Inc. Multicyclic compounds and methods of use thereof
US10196403B2 (en) 2016-07-29 2019-02-05 Sunovion Pharmaceuticals Inc. Compounds and compositions and uses thereof
US10780074B2 (en) 2017-08-02 2020-09-22 Sunovion Pharmaceuticals Inc. Compounds and uses thereof
US10815249B2 (en) 2018-02-16 2020-10-27 Sunovion Pharmaceuticals Inc. Salts, crystal forms, and production methods thereof
US11077090B2 (en) 2016-07-29 2021-08-03 Sunovion Pharmaceuticals Inc. Compounds and compositions and uses thereof
US11129807B2 (en) 2017-02-16 2021-09-28 Sunovion Pharmaceuticals Inc. Methods of treating schizophrenia
US11136304B2 (en) 2019-03-14 2021-10-05 Sunovion Pharmaceuticals Inc. Salts of a heterocyclic compound and crystalline forms, processes for preparing, therapeutic uses, and pharmaceutical compositions thereof
US11738002B2 (en) 2020-04-14 2023-08-29 Sunovion Pharmaceuticals Inc. Methods of treating neurological and psychiatric disorders

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CA2395869C (en) * 1999-12-30 2006-07-25 H. Lundbeck A/S 4-phenyl-1-piperazinyl, -piperidinyl and -tetrahydropyridyl derivatives

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Cited By (30)

* Cited by examiner, † Cited by third party
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WO1995018118A1 (en) * 1993-12-28 1995-07-06 The Upjohn Company Heterocyclic compounds for the treatment of cns and cardiovascular disorders
US5877317A (en) * 1993-12-28 1999-03-02 Pharmacia & Upjohn Company Heterocyclic compounds for the treatment of CNS and cardiovascular disorders
US6133446A (en) * 1993-12-28 2000-10-17 Pharmacia & Upjohn Company Heterocyclic compounds for the treatment of CNS and cardiovascular disorders
FR2716193A1 (en) * 1994-02-16 1995-08-18 Synthelabo Derivatives of 1 [2- (1H-inden-3-yl) ethyl] -4- (naphthalen-1-yl) piperazine, their preparation and their therapeutic application.
EP0668273A1 (en) * 1994-02-16 1995-08-23 Synthelabo Derivatives of 1-2-(1H-inden-3-yl)ethyl-4-(naphtalen-1-yl)-piperazin, their preparation and their therapeutical use
US5530002A (en) * 1994-02-16 1996-06-25 Synthelabo 1-[2-(1H-inden-3-yl)ethyl]-4-(naphth-1-yl)piperazine derivatives, their preparation and their application in therapeutics
AU680327B2 (en) * 1994-02-16 1997-07-24 Synthelabo 1-(2-(1H-inden-3-yl)ethyl)-4-(naphth-1-yl)piperazine derivatives, their preparation and their application in therapeutics
US5472966A (en) * 1995-03-29 1995-12-05 Bristol-Myers Squibb Company Antidepressant heteroarylaminoalkyl derivatives of naphthyl-monazines
FR2737723A1 (en) * 1995-08-09 1997-02-14 Synthelabo New 1-(2-(1H-inden-3-yl) ethyl) 4-(naphthalen-1-yl) piperazine derivs - have affinity for serotoninergic receptors and are used to treat anxiety, depression, phobia(s), migraine, hypertension, and to regulate appetite
KR100496874B1 (en) * 2003-07-03 2005-06-22 주식회사 엘지화학 Method for Preparing Polymethylmethacrylate Using Supercritical Carbon Dioxide
US8314155B2 (en) 2004-04-13 2012-11-20 Cephalon, Inc Bicyclic aromatic sulfinyl derivatives
US7423176B2 (en) 2004-04-13 2008-09-09 Cephalon, Inc. Bicyclic aromatic sulfinyl derivatives
US8227625B2 (en) 2006-03-02 2012-07-24 Laboratorios Del Dr. Esteve, S.A. 4,5,6,7-tetrahydrobenzo[b]thiophene derivatives and their use as sigma receptor ligands
EP1829869A1 (en) * 2006-03-02 2007-09-05 Laboratorios Del Dr. Esteve, S.A. 4,5,6,7-Tetrahydrobenzo[b]thiophene derivatives and their use as sigma receptor ligands
US8492563B2 (en) 2006-03-02 2013-07-23 Laboratorios Del Dr. Esteve, S.A. 4,5,6,7-tetrahydrobenzo[B]thiophene derivatives and their use as sigma receptor ligands
WO2007098961A1 (en) * 2006-03-02 2007-09-07 Laboratorios Del Dr. Esteve, S.A. 4, 5, 6,7-tetrahydrobenzo[b]thiophene derivatives and their use as sigma receptor ligands
US10894033B2 (en) 2009-12-04 2021-01-19 Sunovion Pharmaceuticals Inc. Multicyclic compounds and methods of use thereof
US9351954B2 (en) 2009-12-04 2016-05-31 Sunovion Pharmaceuticals Inc. Multicyclic compounds and methods of use thereof
US10085968B2 (en) 2009-12-04 2018-10-02 Sunovion Pharmaceuticals Inc. Multicyclic compounds and methods of use thereof
US11077090B2 (en) 2016-07-29 2021-08-03 Sunovion Pharmaceuticals Inc. Compounds and compositions and uses thereof
US10927124B2 (en) 2016-07-29 2021-02-23 Sunovion Pharmaceuticals Inc. Compounds and compositions and uses thereof
US10196403B2 (en) 2016-07-29 2019-02-05 Sunovion Pharmaceuticals Inc. Compounds and compositions and uses thereof
US11958862B2 (en) 2016-07-29 2024-04-16 Sumitomo Pharma America, Inc. Compounds and compositions and uses thereof
US11129807B2 (en) 2017-02-16 2021-09-28 Sunovion Pharmaceuticals Inc. Methods of treating schizophrenia
US10780074B2 (en) 2017-08-02 2020-09-22 Sunovion Pharmaceuticals Inc. Compounds and uses thereof
US11491133B2 (en) 2017-08-02 2022-11-08 Sunovion Pharmaceuticals Inc. Heteroaryl-isochroman compounds and uses thereof
US10815249B2 (en) 2018-02-16 2020-10-27 Sunovion Pharmaceuticals Inc. Salts, crystal forms, and production methods thereof
US11440921B2 (en) 2018-02-16 2022-09-13 Sunovion Pharmaceuticals Inc. Salts, crystal forms, and production methods thereof
US11136304B2 (en) 2019-03-14 2021-10-05 Sunovion Pharmaceuticals Inc. Salts of a heterocyclic compound and crystalline forms, processes for preparing, therapeutic uses, and pharmaceutical compositions thereof
US11738002B2 (en) 2020-04-14 2023-08-29 Sunovion Pharmaceuticals Inc. Methods of treating neurological and psychiatric disorders

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IL106124A (en) 1998-02-22
EP0647222A1 (en) 1995-04-12
ZA934472B (en) 1994-01-18
IT1255178B (en) 1995-10-20
CA2137685A1 (en) 1994-01-06
AU670444B2 (en) 1996-07-18
AU4419593A (en) 1994-01-24
HU9403768D0 (en) 1995-02-28
KR950702195A (en) 1995-06-19
ITMI921569A1 (en) 1993-12-26
RU94046220A (en) 1996-09-27
FI945997A (en) 1994-12-21
HUT71405A (en) 1995-11-28
RU2115651C1 (en) 1998-07-20
JPH07508514A (en) 1995-09-21
NZ253689A (en) 1996-11-26
ITMI921569A0 (en) 1992-06-26
FI945997A0 (en) 1994-12-21

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