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WO1996006846A1 - New arylpiperazine derivatives - Google Patents

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Publication number
WO1996006846A1
WO1996006846A1 PCT/ES1995/000094 ES9500094W WO9606846A1 WO 1996006846 A1 WO1996006846 A1 WO 1996006846A1 ES 9500094 W ES9500094 W ES 9500094W WO 9606846 A1 WO9606846 A1 WO 9606846A1
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cyano
trifluoromethyl
amino
bromo
compound according
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Spanish (es)
French (fr)
Inventor
Maria Luz Lopez Rodriguez
Maria Luisa Rosado Samitier
Bellinda Benahmu Salama
Esther Fernandez Velando
Maria Jose Morcillo Ortega
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Universidad Complutense de Madrid
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Universidad Complutense de Madrid
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Priority claimed from ES9401895A external-priority patent/ES2082727B1/en
Application filed by Universidad Complutense de Madrid filed Critical Universidad Complutense de Madrid
Priority to AU30792/95A priority Critical patent/AU3079295A/en
Priority claimed from ES9501534A external-priority patent/ES2095811B1/en
Publication of WO1996006846A1 publication Critical patent/WO1996006846A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention concerns new compounds of general formula JL where X is - (CH 2 ) 3 - or - (CH 2 ) 4 -; m is equal to 0 or 1; n is equal to 1, 2, 3 or 4; Ar is 1-naphthyl, 7-benzofuranyl, 2,3-dihydro-l, 4-benzodioxan-5-yl, 3,4-dihydro-2i-l, 5-benzodioxepin-6-yl, phenyl or alkyl substituted phenyl , halogen, trifluoromethyl, nitro, cyano, alkoxy, amino, alkylcarbamoyl, alkylsulfonamido or alkoxycarbonyl.
  • 5-HT 1A receptor agonists play in controlling anxiety and depression (M. Hamon, Trends Pharmacol. Sci. 1994, 15, 36; P. Blier and C. Montigny, Trends Pharmacol. Sci. 1994, 15, 220). So far, the only 5-HT agonist, A marketed is buspirone. However, this drug lacks specificity on said receptor, since it is capable of binding to other types of receptors (dopaminergic, ⁇ -yo adrenergic, ⁇ -aminobutyric acid (GABA) -benzodiazepines and muscarinic).
  • GABA ⁇ -aminobutyric acid
  • the present invention relates to new arylpiperazine derivatives, which have shown a high affinity for the 5-HT, A receptor.
  • the new arylpiperazine derivatives are represented by the general formula I:
  • X is - (CH 2 ) 3 - or - (CH 2 ) 4 -; m is equal to 0 or 1; n is equal to 1, 2, 3 or 4
  • R 1 , R 2 and R 3 is hydrogen, alkyl, halogen tri-fluoromethyl, nitro, cyano, alkoxy, amino, alkylcarbamoyl, alkylsulfonamido or alkoxycarbonyl
  • Non-commercial 1-arylpiperazines have been obtained according to the methods described in the literature: J. A. Chem. Soc, 76, 1853 (1954); J. Med. Chem., 32, 1052 (1989); JP61, 152,655; J. Med. Chem., 31, 1934 (1988).
  • the starting products of formula m are obtained by treating the L-proline or ethyl pipecolinate with 2-chloroethyl isocyanate.
  • affinities of some of the compounds of general structure I by the serotonergic 5-HT 1A receptor in rat cerebral cortex membranes were determined by radioligand techniques using 3 H-8-OH-DPAT [8-hydroxy-2- (di -n-propylamino) tetralin] with selective ligand.
  • mice Male albino rats (Rattus norvegicus albimts), Sprague-Dawley breed, weighing approximately 200 g, are sacrificed by decapitation. Brains are quickly removed and frozen in liquid nitrogen. The tissue is stored at -40 ° C until it is used.
  • the cerebral cortex is homogenized in 10 volumes of 50 mM Tris-HCl buffer, pH 7, at 25 ° C and centrifuged at 28000 x g for 15 min, at 4 ° C. The supernatant is neglected and sediment is washed twice by resuspension and centrifugation under the conditions described.
  • the resuspended sediment is incubated at 37 ° C for 10 min.
  • the membranes are centrifuged again and the pellet is resuspended in 10 volumes of Tris-HCl buffer with 5 mM MgSO 4 and 0.5 mM NajEDTA (pH 7.4 at 25 ° C).
  • Fractions of 100 ⁇ l of the final suspension of the membranes (5 mg / ml protein) are incubated for 10 min at 37 ° C with 3 H 8-OH-DPAT 0.6 nM in the presence or absence of the compound under study in an end volume of 1.1 ml of 50 mM Tris-HCl buffer, pH 7.4.
  • Non-specific binding is determined with 10 ⁇ M serotonin.
  • the bound radioactive ligands are separated from the free ones by vacuum filtration on Whatman GF / B filter washed twice with 4 ml of 50 M Tris-HCl buffer, pH 7.4 at 4 ° C. After sec the filters for one hour at 60 ° C, 4 ml of scintillation liquid (Aquasol) are added and the radioactivity bound to the membranes is measured by liquid scintillation spectrometry.
  • Whatman GF / B filter washed twice with 4 ml of 50 M Tris-HCl buffer, pH 7.4 at 4 ° C. After sec the filters for one hour at 60 ° C, 4 ml of scintillation liquid (Aquasol) are added and the radioactivity bound to the membranes is measured by liquid scintillation spectrometry.
  • Aquasol scintillation liquid

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to new compounds having general formula (I), wherein X is -(CH2)3-O-(CH2)4-; m equals 0 or 1, n equals 1, 2, 3 or 4; Ar is 1-naphthyl, 7-benzofuranyl, 2,3-dihydro-1,4-benzodioxane-5-yl, 3,4-dihydro-2H-1,5-benzodioxepin-6-yl, phenyl or phenyl substituted by alkyl, halogen, trifluoromethyl, nitro, cyano, alkoxy, amino, alkylcarbamyl, alkylsulfonamido or alkoxycarbonylo. The invention also relates to various alternative methods for the preparation of said compounds which present an affinity for the serotoninergic receptor 5-HT1A, which indicates their utility from the therapeutical point of view in the treatment of the CNS disorders such as anxiety and depression.

Description

NUEVOS DERIVADOS DE ARILPIPERAZINASNEW DERIVATIVES OF ARILPIPERAZINAS

La presente invención trata de nuevos compuestos de fórmula general JL donde X es -(CH2)3- o -(CH2)4-; m es igual a 0 ó 1; n es igual a 1, 2, 3 ó 4; Ar es 1-naftilo, 7-benzofuranilo, 2,3-dihidro-l,4-benzodioxan-5-ilo, 3,4-dihidro-2i -l,5-benzodioxepin-6-ilo, fenilo o fenilo sustituido por alquilo, halógeno, trifluorometilo, nitro, ciano, alcoxi, amino, alquilcarbamoilo, alquilsulfonamido o alcoxicarbonilo.The present invention concerns new compounds of general formula JL where X is - (CH 2 ) 3 - or - (CH 2 ) 4 -; m is equal to 0 or 1; n is equal to 1, 2, 3 or 4; Ar is 1-naphthyl, 7-benzofuranyl, 2,3-dihydro-l, 4-benzodioxan-5-yl, 3,4-dihydro-2i-l, 5-benzodioxepin-6-yl, phenyl or alkyl substituted phenyl , halogen, trifluoromethyl, nitro, cyano, alkoxy, amino, alkylcarbamoyl, alkylsulfonamido or alkoxycarbonyl.

Se describen los diferentes métodos alternativos de preparación de dichos compuestos, los cuales presentan afinidad por el receptor serotoninérgico 5-HT1A, lo que indica su utilidad desde el punto de vista terapéutico en el tratamiento de trastornos en el SNC, tales como la ansiedad y depresión.The different alternative methods of preparing said compounds are described, which have an affinity for the 5-HT 1A serotonergic receptor, indicating their usefulness from the therapeutic point of view in the treatment of CNS disorders, such as anxiety and depression.

ANTECEDENTESBACKGROUND

Existen antecedentes sobre el importante papel que los agonistas del receptor 5-HT1A juegan en el control de la ansiedad y de la depresión (M. Hamon, Trends Pharmacol. Sci. 1994, 15, 36; P. Blier y C. Montigny, Trends Pharmacol. Sci. 1994, 15, 220). Hasta el momento, el único agonista 5-HT, A comercializado es la buspirona. Sin embargo, este fármaco carece de especificidad sobre dicho receptor, ya que es capaz de unirse a otro tipo de receptores (dopaminérgicos, adrenérgicos α, y o j, del ácido γ-aminobutírico (GABA)-benzodiazepinas y muscarinicos). Por otra parte, sus propiedades farmacocinéticas no son óptimas y su duración de acción es corta (D. P. Taylor y S. L. Moon, Neuropeptides 1991, 19, 15; A. D. Levy y L. D. Van der Ker, Life Sci. 1992, 51, 83; K. V. Kastenhoz y M. L. Crismon, Clin. Pharm. 1984, 3, 600). Por consiguiente, la búsqueda de agentes más selectivos, con mejores propiedades farmacocinéticas y que estén exentos de los efectos colaterales de las benzodiazepinas, constituye un importante objetivo en el tratamiento de la ansiedad y de la depresión.There is background on the important role that 5-HT 1A receptor agonists play in controlling anxiety and depression (M. Hamon, Trends Pharmacol. Sci. 1994, 15, 36; P. Blier and C. Montigny, Trends Pharmacol. Sci. 1994, 15, 220). So far, the only 5-HT agonist, A marketed is buspirone. However, this drug lacks specificity on said receptor, since it is capable of binding to other types of receptors (dopaminergic, α-yo adrenergic, γ-aminobutyric acid (GABA) -benzodiazepines and muscarinic). On the other hand, its pharmacokinetic properties are not optimal and its duration of action is short (DP Taylor and SL Moon, Neuropeptides 1991, 19, 15; AD Levy and LD Van der Ker, Life Sci. 1992, 51, 83; KV Kastenhoz and ML Crismon, Clin. Pharm. 1984, 3, 600). Therefore, the search for more selective agents, with better pharmacokinetic properties and that are exempt from the side effects of benzodiazepines, is an important objective in the treatment of anxiety and depression.

DESCRIPCIÓNDESCRIPTION

La presente invención se refiere a nuevos derivados de arilpiperazinas, los cuales han mostrado una elevada afinidad por el receptor 5-HT,A. Los nuevos derivados de arilpiperazinas se representan mediante la fórmula general I:The present invention relates to new arylpiperazine derivatives, which have shown a high affinity for the 5-HT, A receptor. The new arylpiperazine derivatives are represented by the general formula I:

Figure imgf000003_0001
donde X es -(CH2)3- o -(CH2)4-; m es igual a 0 ó 1; n es igual a 1, 2, 3 ó 4
Figure imgf000003_0001
where X is - (CH 2 ) 3 - or - (CH 2 ) 4 -; m is equal to 0 or 1; n is equal to 1, 2, 3 or 4

, 1-naftilo, 7-benzofuranilo, 2,3-dihidro-l,4-benzodioxan-5-ilo, 2,4-, 1-naphthyl, 7-benzofuranyl, 2,3-dihydro-l, 4-benzodioxan-5-yl, 2,4-

Figure imgf000004_0001
dihidro-2H-l,5-benzodioxepin-6-ilo; en donde R1, R2 y R3 es hidrógeno, alquilo, halógeno triíluorometilo, nitro, ciano, alcoxi, amino, alquilcarbamoilo, alquilsulfonamido o alcoxicarbonilo
Figure imgf000004_0001
dihydro-2H-l, 5-benzodioxepin-6-yl; wherein R 1 , R 2 and R 3 is hydrogen, alkyl, halogen tri-fluoromethyl, nitro, cyano, alkoxy, amino, alkylcarbamoyl, alkylsulfonamido or alkoxycarbonyl

Los compuestos de estructura general I se han obtenido siguiendo las rutas sintética representadas en el Esquema.Compounds of general structure I have been obtained following the synthetic routes represented in the Scheme.

Método AMethod A

Figure imgf000004_0002
π Método B
Figure imgf000004_0002
π Method B

Figure imgf000004_0003
m
Figure imgf000004_0003
m

Método CMethod C

Figure imgf000004_0004
Figure imgf000004_0004

IVIV

Método DMethod D

Figure imgf000004_0005
π Los productos de fórmula II (X= -(CH2)3-, -(CH2)4- y m=0) se han sintetizado por tratamiento de la L-prolina o del ácido D,L-pipecolínico con cianato potásico y posterior calefacción con ácido clorhídrico según los métodos descritos por H. D. Dakin, J. Biol. Chem., 44, 499 (1920) y M. E. Freed y A. R. Day, J. Org. Chem., 25, 2108 (1960). Los productos de fórmula II (X= -(CH2)3-, -(CH2)4- y m= 1) se han preparado de acuerdo con el procedimiento sintético descrito por T. Ueda y col, Bull. Chem. Soc. Jpn., 56, 568 (1983).
Figure imgf000004_0005
π Products of formula II (X = - (CH 2 ) 3 -, - (CH 2 ) 4 - and m = 0) have been synthesized by treatment of L-proline or D, L-pipecolinic acid with potassium cyanate and subsequent heating with hydrochloric acid according to the methods described by HD Dakin, J. Biol. Chem., 44, 499 (1920) and ME Freed and AR Day, J. Org. Chem., 25, 2108 (1960). Products of formula II (X = - (CH 2 ) 3 -, - (CH 2 ) 4 - ym = 1) have been prepared according to the synthetic procedure described by T. Ueda et al, Bull. Chem. Soc. Jpn., 56, 568 (1983).

Las 1 -arilpiperazinas no comerciales se han obtenido según los métodos que se describen en la literatura: J. A . Chem. Soc, 76, 1853 (1954); J. Med. Chem., 32, 1052 (1989); patente JP61, 152,655; J. Med. Chem., 31, 1934 (1988). Por reacción de Mannich de π con formaldehído y 1 -arilpiperazinas (Método A), se han obtenido los compuestos de estructura general I (1) (n= 1).Non-commercial 1-arylpiperazines have been obtained according to the methods described in the literature: J. A. Chem. Soc, 76, 1853 (1954); J. Med. Chem., 32, 1052 (1989); JP61, 152,655; J. Med. Chem., 31, 1934 (1988). By reaction of Mannich of π with formaldehyde and 1-arylpiperazines (Method A), the compounds of general structure I (1) (n = 1) have been obtained.

Por tratamiento de la L-prolina o del pipecolinato de etilo con isocianato de 2-cloroetilo se obtienen los productos de partida de fórmula m. La reacción de sustitución de m con 1- arilpiperazinas en proporción molar 1 : 1, utilizando acetonitrilo como disolvente en presencia de carbonato sódico conduce a los compuestos de estructura general I (2) (n= 2) (Método B).The starting products of formula m are obtained by treating the L-proline or ethyl pipecolinate with 2-chloroethyl isocyanate. The substitution reaction of m with 1-arylpiperazines in 1: 1 molar ratio, using acetonitrile as solvent in the presence of sodium carbonate leads to compounds of general structure I (2) (n = 2) (Method B).

Los compuestos de fórmula I (3) (n= 3) (Método C) se sintetizaron por reacción de II con las 4-(3-cloropropil)-l -arilpiperazinas (IV), las cuales se obtienen a partir de l-bromo-3- cloropropano y de la 1-arilpiperazina correspondiente de acuerdo con el método descrito por J. Bourdais, Bull. Soc. Chim. Fr., 3246 (1968). Por tratamiento de π con l-bromo-4-clorobutano en presencia de hidruro sódico en atmósfera de nitrógeno y posterior tratamiento del derivado halogenado V con la 1-arilpiperazina correspondiente se han sintetizado los compuestos de fórmula I (4) (n= 4) (Método D).Compounds of formula I (3) (n = 3) (Method C) were synthesized by reaction of II with 4- (3-chloropropyl) -l-arylpiperazines (IV), which are obtained from l-bromine -3- chloropropane and the corresponding 1-arylpiperazine according to the method described by J. Bourdais, Bull. Soc. Chim. Fr., 3246 (1968). By treating π with l-bromo-4-chlorobutane in the presence of sodium hydride in a nitrogen atmosphere and subsequent treatment of the halogenated derivative V with the corresponding 1-arylpiperazine, the compounds of formula I (4) have been synthesized (n = 4) (Method D).

MODO DE REALIZACIÓN DE LA INVENCIÓNEMBODIMENT OF THE INVENTION

EJEMPLO 1 Método AEXAMPLE 1 Method A

2-(4-Fenil-l-piperazinilmetil)-l,3-dioxoperhidroimidazo[l,5- ]piridina, la2- (4-Phenyl-l-piperazinylmethyl) -l, 3-dioxoperhydroimidazo [l, 5-] pyridine, the

A una suspensión de l,3-dioxoperhidroimidazo[l,5-íi]piridina (1,5 g) y 1 mi de formaldehído al 35% en 20 mi de etanol, se le adicionan 1,57 g de 1-fenilpiperazina. La suspensión resultante se calienta en baño de agua durante 1 hora. Una vez enfriada la mezcla de reacción se precipita con 30 mi de agua, obteniéndose 3,1 g de la que se aisla en forma de diclorhidrato. P.f. 178-180 °C.To a suspension of 1, 3-dioxoperhydroimidazo [1,5-yl] pyridine (1.5 g) and 1 ml of 35% formaldehyde in 20 ml of ethanol, 1.57 g of 1-phenylpiperazine are added. The resulting suspension is heated in a water bath for 1 hour. Once the reaction mixture has cooled, it is precipitated with 30 ml of water, obtaining 3.1 g from which it is isolated as a dihydrochloride. P.f. 178-180 ° C.

De forma análoga se prepararon los siguientes compuestos: 2-[4-(o-Metoxifenil)- 1 -piperazinilmetil]- l,3-dioxoperhidroimidazo[ 1 ,5-α]piridina.2HCl.H2O. P.f. 160-162 °C, Ib 2-[4-(OT-Clorofeml)-l-piperazinilmetil]-l,3-dioxoperhidroimidazo[l,5-α]piridina.2HC1.3H2O. P.f. 176-178 °C, icSimilarly, the following compounds were prepared: 2- [4- (o-Methoxyphenyl) -1 -piperazinylmethyl] -l, 3-dioxoperhydroimidazo [1,5-α] pyridine. 2 HCl. H 2 OPf 160-162 ° C, Ib 2- [4- (OT-Chlorofeml) -l-piperazinylmethyl] -l, 3-dioxoperhydroimidazo [l, 5-α] pyridine. 2HC1.3H 2 OPf 176-178 ° C, ic

2-[4-(/w-Trifluorometilfenil)- 1 -pipeπizbiilmetil]- 1 ,3 -dioxoperhidroimidazo [ 1 , 5- ]piridina.2HC1. P.f. 165-167 °C, id 2-[4-(p-Fluorofenil)- 1 -piperazinilmetil]- 1 , 3 -dioxoperhidroimidazo[ 1 , 5-α]piridina.2HCl.H2O. P.f. 170-172 °C, le2- [4 - (/ w-Trifluoromethylphenyl) -1-pipeπizbiylmethyl] -1,3-dioxoperhydroimidazo [1, 5-] pyridine. 2HC1. Mp 165-167 ° C, id 2- [4- (p-Fluorophenyl) -1 -piperazinylmethyl] -1,3-diioxoperhydroimidazo [1,5-α] pyridine. 2HCl.H 2 OPf 170-172 ° C, le

2-[4-(p-Nitrofenil)- 1 -piperazinilmetil]- 1 , 3-dioxoperhidroimidazo[ 1 , 5-α]piridina.2HC1.1 /2H2O . P.f. 176-178 °C, lf 2^4-Feιτü-l-ρiρeraziιιJJmetü l,3-dioxoperhidropirrolo[l,2-c]imidazol.2HC1.3/2H2O. P.f. 178-18 °c, ig2- [4- (p-Nitrophenyl) -1 -piperazinylmethyl] -1,3-dioxoperhydroimidazo [1,5-α] pyridine. 2HC1.1 / 2H 2 O. Mp 176-178 ° C, lf 2 ^ 4-Feιτü-l-ρiρeraziιιJJmetü l, 3-dioxoperhydropyrrolo [l, 2-c] imidazole. 2HC1.3 / 2H 2 OPf 178-18 ° c, ig

2-[4-(o-Metoxiferύl)-l-piperazirülmetil]-l,3-dioxopertódropirrolo[l,2-c]imidazol.2HCl. P.f. 168-2- [4- (o-Methoxiferύl) -l-piperazirülmethyl] -l, 3-dioxopertodropyrrolo [1, 2-c] imidazole. 2HCl. P.f. 168-

170 °C, Uι170 ° C, Uι

2-[4-(/í7-Clorofeny)-l-piperazιralmetU]-l,3-dioxoperhidropirrolo[l,2-c]imidazol.2HCl.l/2H2O P.f.2- [4 - (/ í7-Chloropheny) -l-piperazιralmetU] -l, 3-dioxoperhydropyrrolo [l, 2-c] imidazole. 2HCl.l / 2H 2 O Pf

146-148 °C, ü 2-[4-(m-Trifluorometitfeml)-l-piperaziiιi^146-148 ° C, ü 2- [4- (m-Trifluorometitfeml) -l-piperaziiιi ^

P.f. 158-159 °C, ÜP.f. 158-159 ° C, Ü

2-[4-(p-Fluorofenil)- 1 -piperazinilmetil]- 1 ,3-dioxoperhidropirrolo[ 1 ,2-c]imidazol.2HCl.H2O. P.f.2- [4- (p-Fluorophenyl) - 1 -piperazinylmethyl] -1,3-dioxoperhydropyrrolo [1,2-c] imidazole. 2HCl.H 2 OPf

180-182 °C, lk180-182 ° C, lk

2-[4-(p-Nitrofenil)- 1 -piperazinilmetil]- 1 ,3-dioxoperhidropirrolo[ 1 ,2-c]imidazol.HCl.H2O. P.f. 150- 152 °C, H2- [4- (p-Nitrophenyl) - 1 -piperazinylmethyl] -1,3-dioxoperhydropyrrolo [1,2-c] imidazole.HCl.H 2 OPf 150-152 ° C, H

2-[4-( 1 -Naftil)- 1 -piperazinilmetil]- 1 ,4-dioxoperhidropirrolo[ 1 ,2- ]pirazina.HC1.3/2H2O. P.f. 2562- [4- (1-Naphthyl) - 1 -piperazinylmethyl] -1,4-dioxoperhydropyrrolo [1, 2-] pyrazine.HC1.3 / 2H 2 OPf 256

259 °C, lm259 ° C, lm

EJEMPLO 2 Método BEXAMPLE 2 Method B

2-(2-Cloroetil)-l,3-dioxoperhidropirrolo[l,2-c]imidazol, Ifla2- (2-Chloroethyl) -l, 3-dioxoperhydropyrrolo [l, 2-c] imidazole, Ifla

A una suspensión de 5 g de L-prolina en 50 mi de acetona anhidra, se le agregan 4 mi d isocianato de 2-cloroetilo y se calienta a reflujo durante 2 horas en atmósfera de nitrógeno. El sólid resultante se filtra y se cristaliza en dioxano/cloroformo, obteniéndose 8,1 g del ácido l-(2 cloroetilcarbamoil)-2-pirrolidinacarboxílico. P.f. 154-156 °C. A 5 g de dicho ácido se le adiciona 30 mi de ácido clorhídrico al 25 % y la solución resultante se calienta a reflujo durante 35 minutos. Se elimina el disolvente a presión reducida, obteniéndose un aceite que se disuelve en aceton anhidra y se seca sobre MgSO4 , aislándose 4,3 g de IHa. P e. 80-82 °C (0,01 mm Hg).To a suspension of 5 g of L-proline in 50 ml of anhydrous acetone, 4 ml of 2-chloroethyl isocyanate is added and heated at reflux for 2 hours under a nitrogen atmosphere. The resulting solid is filtered and crystallized from dioxane / chloroform, yielding 8.1 g of l- (2 chloroethylcarbamoyl) -2-pyrrolidinecarboxylic acid. Mp 154-156 ° C. To 5 g of said acid is added 30 ml of 25% hydrochloric acid and the resulting solution is heated at reflux for 35 minutes. The solvent is removed under reduced pressure, obtaining an oil that is dissolved in anhydrous aceton and dried over MgSO 4 , isolating 4.3 g of IHa. P e. 80-82 ° C (0.01 mm Hg).

2-(2-Cloroetil)- 1 ,3 -dioxoperhidroimidazo [ 1 ,5-α]piridina, UJ A una suspensión de 4 g de pipecolinato de etilo en 25 mi de acetona anhidra, se le agregan gota a gota 2,2 mi de isocianato de 2-cloroetilo y se calienta ligeramente durante 2 horas en atmósfera de nitrógeno. El disolvente se elimina a presión reducida, obteniéndose 6,3 g de 2-(2- cloroetilcarbamoil)pipecolinato de etilo. P.e. 150-152 °C (0,7 mm Hg). A 6 g de dicho ester se le adiciona una solución de hidróxido potásico en etanol al 10 % hasta pH básico. La solución resultante se calienta a reflujo en 25 mi de etanol durante 45 minutos. El disolvente se elimina a presión reducida, obteniéndose un aceite que se disuelve en éter etílico y se seca sobre MgSO4> aislándose 5,2 g de mb. P.e. 125 °C (0,4 mm Hg).2- (2-Chloroethyl) - 1, 3-dioxoperhydroimidazo [1,5-α] pyridine, UJ To a suspension of 4 g of ethyl pipecolinate in 25 ml of anhydrous acetone, 2.2 ml of 2-chloroethyl isocyanate is added dropwise and heated slightly for 2 hours under a nitrogen atmosphere. The solvent is removed under reduced pressure, obtaining 6.3 g of ethyl 2- (2- chloroethylcarbamoyl) pipecolinate. Pe 150-152 ° C (0.7 mm Hg). A solution of potassium hydroxide in 10% ethanol is added to 6 g of said ester to basic pH. The resulting solution is heated at reflux in 25 ml of ethanol for 45 minutes. The solvent is removed under reduced pressure, obtaining an oil that is dissolved in ethyl ether and dried over MgSO 4> isolating 5.2 g of mb. Pe 125 ° C (0.4 mm Hg).

2-[2-(4-Fenil- 1 -piperazinil)etil]- 1 ,3-dioxoperhidroimidazo[ 1 ,5-úr]piridina, 2a2- [2- (4-Phenyl-1 -piperazinyl) ethyl] -1,3-dioxoperhydroimidazo [1,5-ur] pyridine, 2nd

A una suspensión de 3,25 g de Dlb y 2,93 g de carbonato sódico en 50 mi de acetonitrilo, se le adicionan 2,27 g de 1-fenilpiperazina. La suspensión resultante se calienta a reflujo durante 5 días. La mezcla de reacción se filtra en caliente y se elimina el disolvente a presión reducida, obteniéndose un aceite que se cromatografia en columna de gel de sílice (acetato de etilo-etanolTo a suspension of 3.25 g of Dlb and 2.93 g of sodium carbonate in 50 ml of acetonitrile, 2.27 g of 1-phenylpiperazine are added. The resulting suspension is heated at reflux for 5 days. The reaction mixture is filtered hot and the solvent is removed under reduced pressure, obtaining an oil which is chromatographed on a silica gel column (ethyl acetate-ethanol

9: 1), aislándose 2,52 g de un aceite que se transforma en el diclorhidrato; el sólido así aislado se cristaliza en cloroformo/acetato de etilo. P.f. 193-195 °C. De forma análoga se prepararon los compuestos:9: 1), 2.52 g of an oil being transformed into the dihydrochloride being isolated; The solid thus isolated is crystallized from chloroform / ethyl acetate. P.f. 193-195 ° C. In a similar way the compounds were prepared:

2-[2-[4-(o-Metoxi enU)-l-piperaziM]etil]-l,3-dioxoperhidroimidazo[l,5-α]piridina.2HCl.H2O. P.f. 178-180 °C, 2b2- [2- [4- (o-Methoxy in U) -l-piperaziM] ethyl] -l, 3-dioxoperhydroimidazo [l, 5-α] pyridine. 2HCl.H 2 OPf 178-180 ° C, 2b

2-[2-[4-(w-Clorofeml)-l-piperaziιτil]etil]-l,3-dioxoperhidroimidazo[l,5-α]piridina.HCl. P.f. 224-2- [2- [4- (w-Chlorofeml) -l-piperaziιτil] ethyl] -l, 3-dioxoperhydroimidazo [1, 5-α] pyridine.HCl. P.f. 224-

226 °C, 2Í 226 ° C, 2 Í

2-[2-[4-(/M-Trifluorometilfenil)- 1 -piperazinil]etil]- 1 ,3-dioxoperhidroimidazo[ 1 , 5-α]piridina.HCl . P.f.2- [2- [4 - (/ M-Trifluoromethylphenyl) -1 -piperazinyl] ethyl] -1,3-dioxoperhydroimidazo [1,5-α] pyridine.HCl. P.f.

208-210 °C, 2JÍ 2-[2-[4-(p-Fluorofeml)-l-piperazinil]etil]-l,3-dioxoperhidro¡riτidazo[l,5-fl]piridina.HCl. P.f. 222-208-210 ° C, 2JÍ 2- [2- [4- (p-Fluorofeml) -l-piperazinyl] ethyl] -l, 3-dioxoperhydro¡riτidazo [1,5-fl] pyridine.HCl. P.f. 222-

224 °C, 2fi224 ° C, 2fi

2-[2-[4-(^ ιtroferal l-piperazinü]etU]-l,3-dioxoperhidroimidazo[l,5-α]piridin^ 252-2542- [2- [4 - (^ ιtroferal l-piperazinü] etU] -l, 3-dioxoperhydroimidazo [l, 5-α] pyridin ^ 252-254

°C, 2f° C, 2f

2-[2-(4-Ferιil-l-piperazinil)et¡l]-l,3-dioxoperhidropirrolo[l,2-c]imidazol. P.f. 116-118 °C, 2fi 2-[2-[4-(o-Metoxi erιil l-piperaziM]etil]-l,3-dioxoperhidropirrolo[l,2-c]imidazol.2HCl. P.f. 186-2- [2- (4-Ferιil-l-piperazinyl) etl] -l, 3-dioxoperhydropyrrolo [1,2-c] imidazole. P.f. 116-118 ° C, 2fi 2- [2- [4- (o-Methoxy erιil l-piperaziM] ethyl] -l, 3-dioxoperhydropyrrolo [l, 2-c] imidazole. 2HCl. P.f. 186-

188 °C, 21l 2-[2-[4-(m-Clorofer l)-l-piperazirύl]etil]-l,3-dioxoperlιidropiπ-olo[l,2-c]imidazol.2HCl. P.f. 174-188 ° C, 21l 2- [2- [4- (m-Chlorofer l) -l-piperazirύl] ethyl] -l, 3-dioxoperlιidropiπ-olo [l, 2-c] imidazole. 2HCl. P.f. 174-

176 °C, 2j176 ° C, 2j

2-[2-[4-(w-Trifluorometilfenil)-l -piperazinil]etil]- 1 ,3-dioxoperhidropirrolo[ 1 ,2-c]imidazol.2HCl. P.f. 206-208 °C, 2j2- [2- [4- (w-Trifluoromethylphenyl) -l -piperazinyl] ethyl] -1,3-dioxoperhydropyrrolo [1,2-c] imidazole. 2HCl. P.f. 206-208 ° C, 2j

2-[2-[4-( -Fluorofenil)- 1 -piperazinil]etil]- 1 ,3-dioxoperhidropirrolo[ 1 ,2-c]imidazol.2HCl. P.f. 196- 198 °C, 2Jí2- [2- [4- (-Fluorophenyl) -1 -piperazinyl] ethyl] -1,3-dioxoperhydropyrrolo [1,2-c] imidazole. 2HCl. P.f. 196-198 ° C, 2Jí

2-[2-[4-(p-Nitrofenil)- 1 -piperazinil]etil]- 1 ,3-dioxoperhidropirrolo[ 1 ,2-c]imidazol.2HCl. P.f. 130- 132 °C, 2J EJEMPLO 3 Método C2- [2- [4- (p-Nitrophenyl) -1 -piperazinyl] ethyl] -1,3-dioxoperhydropyrrolo [1,2-c] imidazole. 2HCl. Mp 130-132 ° C, 2J EXAMPLE 3 Method C

2-[3-(4-Fenil- 1 -piperazinil)propil]- 1 ,4-dioxoperhidropirrolo[ 1 ,2-α]pirazina, 212- [3- (4-Phenyl-1 -piperazinyl) propyl] -1,4-dioxoperhydropyrrolo [1,2-α] pyrazine, 21

A una suspensión de 3 g de 1-fenilpiperazina y 3,07 g de carbonato potásico anhidro en 1 mi de DMF anhidra, se le adicionan, en atmósfera inerte, 2,2 mi de l-bromo-3-cloropropano. L suspensión resultante se deja a temperatura ambiente durante 24 horas. La mezcla de reacción s filtra y se elimina el disolvente a presión reducida, obteniéndose un aceite que se cromatografia e columna de gel de sílice (acetato de etilo-hexano 1 : 1), aislándose 3,48 g de IV (aceite).To a suspension of 3 g of 1-phenylpiperazine and 3.07 g of anhydrous potassium carbonate in 1 ml of anhydrous DMF, 2.2 ml of l-bromo-3-chloropropane is added in an inert atmosphere. The resulting suspension is left at room temperature for 24 hours. The reaction mixture is filtered and the solvent is removed under reduced pressure, obtaining an oil that is chromatographed on a silica gel column (ethyl acetate-hexane 1: 1), 3.48 g of IV (oil) being isolated.

A una solución de 2 g de l,4-dioxoperhidropirrolo[l,2-¿ι]piraz_na en 14,2 mi de DM anhidra, en atmósfera inerte, se le adicionan, en pequeñas porciones, 0,52 g de hidruro sódico 60% en aceite mineral. La mezcla de reacción se agita a 60 °C durante 1 hora. A esta solución s le añaden, gota a gota, 3,48 g de TV en 14,2 mi de DMF anhidra, y la mezcla se calienta a 110 ° durante 2 horas. Una vez enfriada la mezcla, se elimina el disolvente a presión reducida, el residu se añade sobre agua y se extrae con CH2C12. La fase orgánica se seca sobre MgSO4, el disolvent se elimina a presión reducida y el aceite resultante se cromatografía en columna de gel de sílic (cloruro de metileno-metanol 9,5:0,5), obteniéndose 4,02 g de 3t que se aisla en forma d clorhidrato. P.f. 244-246 °C. De forma análoga se prepararon los siguientes compuestos:To a solution of 2 g of l, 4-dioxoperhydropyrrolo [l, 2-¿ι] pyrazine in 14.2 ml of anhydrous DM, in an inert atmosphere, 0.52 g of sodium hydride is added in small portions % in mineral oil. The reaction mixture is stirred at 60 ° C for 1 hour. To this solution, 3.48 g of TV in 14.2 ml of anhydrous DMF is added dropwise, and the mixture is heated at 110 ° for 2 hours. Once the mixture has cooled, the solvent is removed under reduced pressure, the residue is added to water and extracted with CH 2 C1 2 . The organic phase is dried over MgSO 4 , the solvent is removed under reduced pressure and the resulting oil is column chromatographed on silica gel (methylene chloride-methanol 9.5: 0.5), yielding 4.02 g of 3t which is isolated in d form hydrochloride. Mp 244-246 ° C. The following compounds were prepared analogously:

2-[3-(4-Fenil- 1 -piperazύιil)propil]- 1 ,3-dioxoperhidroimidazo[ 1 ,5-α]piridina.2HCl.H2O. P .f. 213 -212- [3- (4-Phenyl-1-piperazύιil) propyl] -1,3-dioxoperhydroimidazo [1,5-α] pyridine. 2 HCl. H 2 O. P .f. 213-21

°C, 2a° C, 2nd

2-[3-[4-(r MetoxtfenU)-l-piperazinü]propil]-^2- [3- [4- (r MetoxtfenU) -l-piperazinü] propyl] - ^

P.f. 208-210 °C, 2b 2-[3-[4-(j7i-Clorofenil)-l-piperazinil]propil]-l,3-dioxoperhidroimidazo[l,5-α]piridina.2HCl. P.P.f. 208-210 ° C, 2b 2- [3- [4- (j7i-Chlorophenyl) -l-piperazinyl] propyl] -l, 3-dioxoperhydroimidazo [1,5-α] pyridine. 2HCl. P.

173-175 °C, 3_£173-175 ° C, £ 3

2-[3-[4-(/w-Trifluorometilfenil)- 1 -piperazinil]propil]- 1 ,3-dioxoperhidroimidazo[ 1 ,5 α]piridina.2HC1.4H2O. P.f. 206-208 °C, 3_d_2- [3- [4 - (/ w-Trifluoromethylphenyl) - 1 -piperazinyl] propyl] -1,3-dioxoperhydroimidazo [1,5 α] pyridine. 2HC1.4H 2 OPf 206-208 ° C, 3_d_

2-[3-[4-(p-Fluorofenil)-l-piperaziml]propil]-l,3-dioxoperhidroimidazo[l,5-t7]piridina.2HCl. P. 205-207 °C, 3_£2- [3- [4- (p-Fluorophenyl) -l-piperaziml] propyl] -l, 3-dioxoperhydroimidazo [1, 5-t7] pyridine. 2HCl. P. 205-207 ° C, £ 3

2-[3-[4-(p- ιtrofeíτU)-l-pipera2ÍnU]propü]-l,3-dioxoperhidroimidazo[l,5-α]piridina.2H^ P.f. 1182- [3- [4- (p- ιtrofeíτU) -l-pipera2ÍnU] propü] -l, 3-dioxoperhydroimidazo [l, 5-α] pyridine. 2H ^ P.f. 118

120 °C, 31120 ° C, 31

2-[3-[4-(f Tolil l-piperaz U]propU]-l,3-dioxoperi idroirrudazo[l,5-α]piridina.2HCl. P.f. 180-182- [3- [4- (f Tolyl l-piperaz U] propU] -l, 3-dioxoperi idroirrudazo [l, 5-α] pyridine. 2 HCl. P.f. 180-18

°C, 2g 2-[3-[4-(o-Propoxicarbonilfenil)-l-piperazinil]propil]-l ,3-dioxoperhidroimidazo[ l,5 ]piridina.HCl.H2O. P.f. 185-186 °C, 3_h° C, 2g 2- [3- [4- (o-Propoxycarbonylphenyl) -l-piperazinyl] propyl] -l, 3-dioxoperhydroimidazo [1, 5] pyridine.HCl.H 2 OPf 185-186 ° C, 3_h

2-[3-[4-( -Etilsulfonamidofenil)- l -piperazinil]propil]-l,3-dioxoperhidroimidazo[l,5 α]piridina.2HC1.2H2O. P.f. 164-166 °C, 3j 2-[3-(4-Ferül-l-piperazirιil)propU]-l,3-dioxoper¡nidropirrolo[l,2-c]imidazol.2HCl. P.f. 210-212 °C,2- [3- [4- (-Ethylsulfonamidophenyl) - l -piperazinyl] propyl] -l, 3-dioxoperhydroimidazo [l, 5 α] pyridine. 2HC1.2H 2 OPf 164-166 ° C, 3j 2- [3- (4-Ferül-l-piperazirιil) propU] -l, 3-dioxoperimidropyrrolo [l, 2-c] imidazole. 2HCl. Mp 210-212 ° C,

2i2i

2-[3-[4-(o-Metoxifenil)- l-piperazinil]propil]- 1 ,3-dioxoperhidropirrolo[ 1 ,2-c]imidazol.2HCl.H2O.2- [3- [4- (o-Methoxyphenyl) -l-piperazinyl] propyl] -1,3-dioxoperhydropyrrolo [1,2-c] imidazole. 2HCl.H 2 O.

P.f. 212-214 °C, 3Js 2-[3-[4-(w-Clorofenil)-l-piperazinil]propil]-l,3-dioxoperι idropirrolo[l,2-c]imidazol.2HCl. P.f.P.f. 212-214 ° C, 3Js 2- [3- [4- (w-Chlorophenyl) -l-piperazinyl] propyl] -l, 3-dioxoperι idropirrolo [1, 2-c] imidazole. 2HCl. P.f.

164-166 °C, 3J164-166 ° C, 3J

2-[3-[4-(OT-Trifluorometilfenil)- 1 -piperazinil]propil]- 1 , 3 -dioxoperhidropirrolo[ 1 ,2-c]imidazol.2HC1.

Figure imgf000009_0001
2- [3- [4- (OT-Trifluoromethylphenyl) -1 -piperazinyl] propyl] -1,3-diioxoperhydropyrrolo [1,2-c] imidazole. 2HC1.
Figure imgf000009_0001

2-[3-[4-(p-Fluorofenil)-l-piperazM]propil]-l,3-dioxoperhidropirrolo[l,2-c]imidazol.HCl. P.f. 230- 232 °C, 2n2- [3- [4- (p-Fluorophenyl) -l-piperazM] propyl] -l, 3-dioxoperhydropyrrolo [1,2-c] imidazole.HCl. P.f. 230-232 ° C, 2n

2-[3-[4-(^Nitrofer l)-l-piperazinil]propil]-l,3-dioxoperhidropirrolo[l,2-c]irnidazol.HCl. P.f. 244-2- [3- [4 - (^ Nitrofer l) -l-piperazinyl] propyl] -l, 3-dioxoperhydropyrrolo [l, 2-c] irnidazole.HCl. P.f. 244-

246 °C, 2ffi246 ° C, 2ffi

2-[3-[4-(o-Propilcarbamoilfenil)-l -piperazinil]propil]- l ,3-dioxoperhidropirrolo[ l ,2 - c]imidazol.2HCl. P.f. 181-183 °C, 3jι 2-[3-[4-(/w-Bromofenil)-l -piperazinil]propil]-l ,3-dioxoperhidropirrolo[ 1 ,2-c]imidazol.2HCl. P.f.2- [3- [4- (o-Propylcarbamoylphenyl) -l -piperazinyl] propyl] -l, 3-dioxoperhydropyrrolo [1,2-c] imidazole. 2HCl. P.f. 181-183 ° C, 3jι 2- [3- [4 - (/ w-Bromophenyl) -l -piperazinyl] propyl] -l, 3-dioxoperhydropyrrolo [1,2-c] imidazole. 2HCl. P.f.

205-207 °C, 2205-207 ° C, 2

2-[3 -[4-(/«-Amhofeml)- 1 -piperaaml] propia2- [3 - [4 - (/ «- Amhofeml) - 1 -piperaaml] own

P.f. 151-153 °C, 3 :P.f. 151-153 ° C, 3:

2-[3-[4-(o-Butoxiferύl)-l-piperazinil]propil]-l,3-dioxoperhidropirrolo[l,2-c]imidazol.2HCl. P.f. 187-190 0C, 3_s2- [3- [4- (o-Butoxiferύl) -l-piperazinyl] propyl] -l, 3-dioxoperhydropyrrolo [1,2-c] imidazole. 2HCl. Mp 187-190 0 C, 3_s

2-[3-[4-(o-Cianofenil)- 1 -piperazinil]propil]- 1 ,4-dioxoperhidropirrolo [ 1 , 2-£.]pirazina.2HC1. P . f. 214-

Figure imgf000009_0002
2- [3- [4- (o-Cyanophenyl) - 1 -piperazinyl] propyl] -1,4-dioxoperhydropyrrolo [1, 2- £.] Pyrazine. 2HC1. P. F. 214-
Figure imgf000009_0002

2-[3-[4-(o-Tolil)-l-piperazinil]propil]-l,4-dioxoperhidropirrolo[l,2-α]pirazina.2HCl. P.f. 259-2612- [3- [4- (o-Tolyl) -l-piperazinyl] propyl] -l, 4-dioxoperhydropyrrolo [1, 2-α] pyrazine. 2HCl. P.f. 259-261

°C, 2ϊ 2-[3-[4-(o-Propoxicarbonilfenil)- 1 -piperazinil]propil]- 1 ,4-dioxoperhidropirrolo[ 1 ,2 - α]pirazina.HCl.H2O. P.f. 69-70 °C, 2ff° C, 2ϊ 2- [3- [4- (o-Propoxycarbonylphenyl) -1 -piperazinyl] propyl] -1,4-dioxoperhydropyrrolo [1,2-α] pyrazine.HCl.H 2 OPf 69-70 ° C, 2ff

2-[3-[4-(o-Metoxifenil)-l -piperazinil]propil]- 1 ,4-dioxoperhidropirrolo[ 1 ,2-α]pirazina.2HCl.H2O.2- [3- [4- (o-Methoxyphenyl) -l -piperazinyl] propyl] -1,4-dioxoperhydropyrrolo [1,2-α] pyrazine. 2HCl.H 2 O.

P.f. 142-144 °C, 3_χP.f. 142-144 ° C, 3_χ

2-[3-[4-(o-Butoχjferúl)-l-piperazύrιy]propü]-l,4-dioxoperhidropirido[l,2-α]pirazina.2HCl.H2O. P.f. 187-188 °C, 3_y. 2- [3- [4- (o-Butoχjferúl) -l-piperazύrιy] propü] -l, 4-dioxoperhydropyrido [l, 2-α] pyrazine . 2HCl.H 2 OPf 187-188 ° C, 3_y .

2-[3-[4-(/w-Trifluorometilfenil)-l -piperazinil]propil]-l ,4-dioxoperhidropirido[ l ,2 - α]pirazina.2HCl.H2O. P.f. 276-278 °C, 2z2- [3- [4 - (/ w-Trifluoromethylphenyl) -l -piperazinyl] propyl] -l, 4-dioxoperhydropyrid [l, 2 - α] pyrazine. 2HCl.H 2 OPf 276-278 ° C, 2z

EJEMPLO 4 Método DEXAMPLE 4 Method D

2-[4-[4-(o-Metoxifenil)- 1 -piperazinil]butil]- 1 ,4-dioxoperhidropirrolo[ 1 ,2-α]pirazina, 41 A una solución de 1,5 g de l,4-dioxoperhidropirrolo[l,2-α]pirazina en 10,1 mi de D anhidra, en atmósfera inerte, se le adicionan, en pequeñas porciones, 0,39 g de hidruro sódico 60% en aceite mineral. La mezcla de reacción se agita a 60 °C durante 1 hora. A esta solución le añaden, gota a gota, 2,24 mi de l-bromo-4-cloropropano en 4 mi de DMF anhidra, y la mezc se calienta a 110 °C durante 1 ,5 horas. Una vez enfriada la mezcla, se elimina el disolvente a presi reducida, el residuo se añade sobre agua y se extrae con CH2C12. La fase orgánica se seca sob MgSO4 y el disolvente se elimina a presión reducida, obteniéndose 2 g de V como un aceite amaril pálido. Este aceite se disuelve junto con 2,37 g de l-(o-metoxifenil)piperazina en 16,5 mi acetonitrilo y a la mezcla resultante se le adicionan 1,71 mi de trietilamina y se calienta a reflu durante 18 horas. Después de enfriar la mezcla de reacción, se elimina el disolvente a presi reducida, se añade agua y se extrae con CH2C12. La fase orgánica se seca sobre MgSO4, disolvente se elimina a presión reducida y el aceite resultante se cromatografía en columna de g de sílice (cloruro de metileno-metanol 9,5:0,5), obteniéndose 1,44 g de 4t que se aisla en forma diclorhidrato. P.f. 204-206 °C. De forma análoga se obtuvieron los siguientes compuestos:2- [4- [4- (o-Methoxyphenyl) -1-piperazinyl] butyl] -1,4-dioxoperhydropyrrolo [1,2-α] pyrazine, 41 To a solution of 1.5 g of l, 4-dioxoperhydropyrrolo [l, 2-α] pyrazine in 10.1 ml of anhydrous D, in an inert atmosphere, 0.39 g of sodium hydride is added in small portions 60% in mineral oil. The reaction mixture is stirred at 60 ° C for 1 hour. To this solution is added, dropwise, 2.24 ml of l-bromo-4-chloropropane in 4 ml of anhydrous DMF, and the mixture is heated at 110 ° C for 1.5 hours. Once the mixture has cooled, the solvent is removed under reduced pressure, the residue is added to water and extracted with CH 2 C1 2 . The organic phase is dried over MgSO 4 and the solvent is removed under reduced pressure, obtaining 2 g of V as a pale yellow oil. This oil is dissolved together with 2.37 g of l- (o-methoxyphenyl) piperazine in 16.5 ml acetonitrile and 1.71 ml of triethylamine is added to the resulting mixture and heated at reflux for 18 hours. After cooling the reaction mixture, the solvent is removed under reduced pressure, water is added and extracted with CH 2 C1 2 . The organic phase is dried over MgSO 4 , solvent is removed under reduced pressure and the resulting oil is column chromatographed on silica g (methylene chloride-methanol 9.5: 0.5), obtaining 1.44 g of 4t which dihydrochloride is isolated. Mp 204-206 ° C. The following compounds were obtained analogously:

2-[4-(4-Ferιil-l-piperazinil)butil]-l,3-dioxoperhidroimidazo[l,5- ]piridina.2HCl.H2O. P.f. 198-22- [4- (4-Ferιil-l-piperazinyl) butyl] -l, 3-dioxoperhydroimidazo [l, 5-] pyridine. 2HCl.H 2 OPf 198-2

°C, áa° C, year

2-[4-[4-(c^Metox¡fenU)-l-piperazinU]butU]-l,3-d¡oxop P2- [4- [4- (c ^ Metox¡fenU) -l-piperazinU] butU] -l, 3-d¡oxop P

199-201 °C, áb 2-[4-[4-(m-Clorofenil)-l-piperazjjιU]butU]-l,3-dioxoperι idroinιidazo[l,5-σ]piridina.2HCl. P.f. 19199-201 ° C, bb 2- [4- [4- (m-Chlorophenyl) -l-piperazjjιU] butU] -l, 3-dioxoperι idroinιidazo [l, 5-σ] pyridine. 2HCl. P.f. 19

192 °C, 4£192 ° C, £ 4

2-[4-[4-(m-Trifluorometilfenil)- 1 -piperaziniljbutil]- 1 ,3-dioxoperhidroimidazo[ 1 ,5 α]piridina.2HCl. l/2H2O. P.f. 140-142 °C, ú2- [4- [4- (m-Trifluoromethylphenyl) -1 -piperazinyljbutyl] -1,3-dioxoperhydroimidazo [1,5 α] pyridine. 2HCl. l / 2H 2 OPf 140-142 ° C, ú

2-[4-[4-(p-Fluoroferύl)-l-piperazinil]butil]-l,3-dioxoperhidroimidazo[l,5- ]piridina.2HC1.2H2 P.f. 168-170 °C, 4*2- [4- [4- (p-Fluoroferύl) -l-piperazinyl] butyl] -l, 3-dioxoperhydroimidazo [l, 5-] pyridine. 2HC1.2H 2 Mp 168-170 ° C, 4 *

2-[4-[4-(^>Tιtroferal)-l-piperazinil]butil]- 1 ,3-dioxoperhidroimidazo[ 1 ,5- ]piridina.2HCl. P.f. 202- [4- [4 - (^> Tιtroferal) -l-piperazinyl] butyl] -1,3-dioxoperhydroimidazo [1, 5-] pyridine. 2HCl. P.f. twenty

202 °C, 41202 ° C, 41

2-[4-[4-(/w- Aminofenil)- 1 -piperazinil]butil]- 1 ,3 -dioxoperhidroimidazo[ 1 , 5-α]piridina.3 HC1. P.f. 162- [4- [4 - (/ w- Aminophenyl) -1 -piperazinyl] butyl] -1,3-diioxoperhydroimidazo [1,5-α] pyridine. 3 HC1. P.f. 16

169 °C, 4g 2-[4-[4-(f ButoxifenU l-piperazirιil]buty]-l,3-dioxoperhidroiιrιidazo[l,5-^ P.f. 21169 ° C, 4g 2- [4- [4- (f ButoxifenU l-piperazirιil] buty] -l, 3-dioxoperhydroiιrιidazo [l, 5- ^ P.f. 21

216 °C, 4Jι216 ° C, 4Jι

2-[4-[4-(o-PropUcarbamoi^enil)-l-piperazirιil]butil]-l,3-dioxoperhidroiιτιidazo[l,5- ]piridina.H2- [4- [4- (o-PropUcarbamoi ^ enyl) -l-piperazirιil] butyl] -l, 3-dioxoperhydroiιτιidazo [l, 5-] pyridine.H

3/2H2O. P.f. 85-87 °C, 4j3 / 2H 2 OPf 85-87 ° C, 4j

2-[4-(4-Fenil-l-piperazirύl)butil]-l,3-dioxoperludropirrolo[l,2-c]irnidazol.2HCl. P.f. 210-212 ° ái2- [4- (4-Phenyl-l-piperazirύl) butyl] -l, 3-dioxoperludropyrrolo [1, 2-c] irnidazole. 2HCl. P.f. 210-212 ° ai

2-[4-[4-(r Metoxtfenil)-l-piperazinU]butU]-l,3-diox P.f. 172- [4- [4- (r Methoxtphenyl) -l-piperazinU] butU] -l, 3-diox P.f. 17

180 °C, 4k180 ° C, 4k

2-[4-[4-(/w-Clorofenü)-l-piperazM]butU]-l,3-dioxoperhidropirrolo[l,2-c]irnidazol.^ 192- [4- [4 - (/ w-Chlorophenü) -l-piperazM] butU] -l, 3-dioxoperhydropyrrolo [l, 2-c] irnidazole. ^ 19

194 °C, 41 2-[4-[4-(/w-Trifluorometüfenil)- 1 -piperaziniljbutil]- 1 ,3-dioxoperhidropirrolo[ 1 ,2-c]imidazol.2HCl.

Figure imgf000011_0001
194 ° C, 41 2- [4- [4 - (/ w-Trifluorometüphenyl) -1 -piperazinyljbutyl] -1,3-dioxoperhydropyrrolo [1,2-c] imidazole. 2HCl.
Figure imgf000011_0001

2 - [4- [4-(/7-Fluorofenil)- 1 -piperazinil]butil] -1,3 -dioxoperhidropirrolo [ 1 , 2-c]imidazol .2HC 1.2H2O .2 - [4- [4 - (/ 7-Fluorophenyl) -1 -piperazinyl] butyl] -1,3-dioxoperhydropyrrolo [1,2-c] imidazole .2HC 1.2H 2 O.

P.f. 194-196 °C, 4JI 2-[4-[4-(^ ιtrofer)il)-l-piperazina]butU]-l,3-dioxopertódropirrolo[l,2-c]irm P.f. 86-88P.f. 194-196 ° C, 4JI 2- [4- [4 - (^ ιtrofer) il) -l-piperazine] butU] -l, 3-dioxopertodropyrrolo [l, 2-c] irm P.f. 86-88

°C, áo.° C, year.

2-[4-[4-(o-Cianofenil)- 1 -piperaziniljbutil]- 1 , 3 -dioxoperhidropirrolo [ 1 , 2-c]imidazol . HC1. P.f. 185-2- [4- [4- (o-Cyanophenyl) -1 -piperazinyljbutyl] -1,3-diioxoperhydropyrrolo [1,2-c] imidazole. HC1. P.f. 185-

186 °C, 4e186 ° C, 4e

2-[4-[4-(/w-Etilsulfonamidofenil)-l -piperazinil]butil]-l ,3-dioxoperhidropirrolo[ l ,2 - c]imidazol.2HCl. l/2H2O. P.f. 187-190 °C, 4α2- [4- [4 - (/ w-Ethylsulfonamidophenyl) -l -piperazinyl] butyl] -l, 3-dioxoperhydropyrrolo [1, 2-c] imidazole. 2HCl. l / 2H 2 OPf 187-190 ° C, 4α

2-[4-[4-(f TolU)-l-pipera2dnU]b^^ P.f. 231-2- [4- [4- (f TolU) -l-pipera2dnU] b ^^ P.f. 231-

233 °C, ∑233 ° C, ∑

2-[4-[4-(o-Propoxicarbonilfenil)-l-piperazinil]butil]-l ,3-dioxoperhidropirrolo[ l ,2 - c]imidazol.2HC1.3/2H2O. P.f. 69-70 °C, 4s 2-[4-[4-(o-Butoxifenil)- 1 -piperazinil]butil]-l ,4-dioxoperhidropirrolo[ 1 ,2-α]pirazina.2HC1.2H2O.2- [4- [4- (o-Propoxycarbonylphenyl) -l-piperazinyl] butyl] -l, 3-dioxoperhydropyrrolo [1, 2-c] imidazole. 2HC1.3 / 2H 2 OPf 69-70 ° C, 4s 2 - [4- [4- (o-Butoxyphenyl) - 1 -piperazinyl] butyl] -l, 4-dioxoperhydropyrrolo [1,2-α] pyrazine. 2HC1.2H 2 O.

P.f. 188-190 °C, 4JIP.f. 188-190 ° C, 4JI

2-[4-[4-(í7j-Trifluorometilfenil)- l -piperazinil]but¡l]-l ,4-dioxoperhidropirrolo[l ,2 7]pirazina.HCl.H2O. P.f. 182-183 °C, 4y.2- [4- [4- (í7j-Trifluoromethylphenyl) -l -piperazinyl] butyl] -l, 4-dioxoperhydropyrrolo [l, 2 7] pyrazine.HCl.H 2 OPf 182-183 ° C, 4y.

2-[4-[4-(c>-Cianoferal)-l-piperazύώ]butU]-l,4-dioxoperhidropirido[l,2-α]pirazina.HCl.H2O. P.f. 98- 100 °C, 4JΪ2- [4- [4- (c> -Cyanoferal) -l-piperazύώ] butU] -l, 4-dioxoperhydropyrid [l, 2-α] pyrazine.HCl.H 2 OPf 98-100 ° C, 4JΪ

2-[4-[4-(o-Propoxicarbonilfenil)- 1 -piperazinil]butil]- 1 ,4-dioxoperhidropirido[ 1 ,2 - α]pirazina.2HC1.2H2O. P.f. 77-78 °C, 4i 2-[4-[4-(f^Tolil)-l-piperazinil]butil]-l,4-d¡oxoperhidropirido[l,2-í7]pirazina.HCl. P.f. 266-267 °C, éx 2-[4-[4-(/w-Etilsulfonamidofenil)- 1 -piperazinil]butil]- 1 ,4-dioxoperhidropirido[ 1 , 2-α]pirazina.2HC1. P.f. 219-220 °C, 4z 2- [4- [4- (o-Propoxycarbonylphenyl) - 1 -piperazinyl] butyl] -1,4-dioxoperhydropyrid [1,2-α] pyrazine. 2HC1.2H 2 OPf 77-78 ° C, 4i 2- [ 4- [4- (f ^ Tolyl) -l-piperazinyl] butyl] -l, 4-dxoxoperhydropyrid [1,2-7] pyrazine.HCl. Mp 266-267 ° C, success 2- [4- [4 - (/ w-Ethylsulfonamidophenyl) -1 -piperazinyl] butyl] -1,4-dioxoperhydropyrid [1,2-α] pyrazine. 2HC1. Mp 219-220 ° C, 4z

EJEMPLO 5EXAMPLE 5

INHIBICIÓN DE LA UNION ESPECIFICA DE Η-8-OH-DPAT AL RECEPTOINHIBITION OF THE SPECIFIC UNION OF Η-8-OH-DPAT TO THE RECEPT

SEROTONINERGICO 5-HT1A EN CEREBRO DE RATA IN VITROSEROTONINERGICO 5-HT 1A IN RAT IN VITRO BRAIN

Las afinidades de algunos de los compuestos de estructura general I por el recepto serotoninérgico 5-HT1A en membranas de corteza cerebral de rata se determinaron mediant técnicas de radioligandos utilizando 3H-8-OH-DPAT [8-hidroxi-2-(di-n-propilamino)tetralina] com ligando selectivo.The affinities of some of the compounds of general structure I by the serotonergic 5-HT 1A receptor in rat cerebral cortex membranes were determined by radioligand techniques using 3 H-8-OH-DPAT [8-hydroxy-2- (di -n-propylamino) tetralin] with selective ligand.

ProcedimientoProcess

Ratas albinas machos (Rattus norvegicus albimts), raza Sprague-Dawley, con un pes aproximado de 200 g, son sacrificadas por decapitación. Los cerebros se extirpan rápidamente y s congelan en nitrógeno líquido. El tejido se guarda a -40 °C hasta el momento de su utilización.Male albino rats (Rattus norvegicus albimts), Sprague-Dawley breed, weighing approximately 200 g, are sacrificed by decapitation. Brains are quickly removed and frozen in liquid nitrogen. The tissue is stored at -40 ° C until it is used.

La corteza cerebral se homogeniza en 10 volúmenes de tampón Tris-HCl 50 mM, pH 7, a 25 °C y se centrifuga a 28000 x g durante 15 min, a 4 °C. El sobrenadante se desprecia y sedimento se lava dos veces mediante resuspensión y centrifugación en las condiciones descritaThe cerebral cortex is homogenized in 10 volumes of 50 mM Tris-HCl buffer, pH 7, at 25 ° C and centrifuged at 28000 x g for 15 min, at 4 ° C. The supernatant is neglected and sediment is washed twice by resuspension and centrifugation under the conditions described.

Después del tercer lavado el sedimento resuspendido se incuba a 37 °C durante 10 min. La membranas se centrifugan nuevamente y el sedimento se resuspende en 10 volúmenes de tampó Tris-HCl con MgSO4 5 mM y NajEDTA 0,5 mM (pH 7,4 a 25 °C). Fracciones de 100 μl de l suspensión final de las membranas (5 mg/ml de proteina) se incuban durante 10 min a 37°C con 3H 8-OH-DPAT 0,6 nM en presencia o ausencia del compuesto objeto de estudio en un volumen fin de 1,1 mi de tampón Tris-HCl 50 mM, pH 7,4. La unión no específica se determina con serotonin 10 μM. Los ligandos radiactivos unidos se separan de los libres por filtración a vacio sobre filtro Whatman GF/B lavados dos veces con 4 mi de tampón Tris-HCl 50 M, pH 7,4 a 4 °C. Tras sec los filtros durante una hora a 60 °C se adicionan 4 mi de líquido de centelleo (Aquasol) y se mid la radiactividad unida a las membranas mediante espectrometría de centelleo líquido.After the third wash the resuspended sediment is incubated at 37 ° C for 10 min. The membranes are centrifuged again and the pellet is resuspended in 10 volumes of Tris-HCl buffer with 5 mM MgSO 4 and 0.5 mM NajEDTA (pH 7.4 at 25 ° C). Fractions of 100 μl of the final suspension of the membranes (5 mg / ml protein) are incubated for 10 min at 37 ° C with 3 H 8-OH-DPAT 0.6 nM in the presence or absence of the compound under study in an end volume of 1.1 ml of 50 mM Tris-HCl buffer, pH 7.4. Non-specific binding is determined with 10 μM serotonin. The bound radioactive ligands are separated from the free ones by vacuum filtration on Whatman GF / B filter washed twice with 4 ml of 50 M Tris-HCl buffer, pH 7.4 at 4 ° C. After sec the filters for one hour at 60 ° C, 4 ml of scintillation liquid (Aquasol) are added and the radioactivity bound to the membranes is measured by liquid scintillation spectrometry.

Para la determinación de la inhibición de la unión de radioligando se utilizan sei concentraciones diferentes del fármaco. Los valores de unión específica obtenidos se representa directamente en función del logaritmo de la concentración del inhibidor. El cálculo de la CI]0 se h realizado mediante regresión no lineal de la curva de desplazamiento, obtenida utilizando l ecuación %UE = 100(1 - C*)/(CI50 b + C*). La conversión de la CI50 a K, se ha llevado a cabo co la ecuación K, = CI^l + LVKD), donde L es la concentración de radioligando y KD su constante d disociación.For the determination of the radioligand binding inhibition, different concentrations of the drug are used. The specific binding values obtained are directly represented as a function of the logarithm of the inhibitor concentration. The calculation of the CI ] 0 was performed by non-linear regression of the displacement curve, obtained using the equation% EU = 100 (1 - C *) / (IC 50 b + C *). The conversion of the IC 50 to K has been carried out with the equation K, = CI ^ 1 + LVK D ), where L is the concentration of radioligand and K D its constant d dissociation.

3H-8-OH-DPAT de New England Nuclear. Actividad específica aproximadamente 14 Ci/mmol. 3 H-8-OH-DPAT from New England Nuclear. Specific activity approximately 14 Ci / mmol.

Los resultados obtenidos se facilitan en la Tabla 1, junto con el valor de K, de la buspiron como referencia. Tabla 1. Datos de Afinidad por el Receptor 5-HT1A.The results obtained are given in Table 1, together with the value of K, of the buspiron as a reference. Table 1. Affinity Data for the 5-HT 1A Receiver.

Figure imgf000013_0001
Los términos en que se ha descrito esta memoria deberán ser tomados siempre con caráct amplio y no limitativo.
Figure imgf000013_0001
The terms in which this report has been described should always be taken with broad and non-limiting character.

Claims

REIVINDICACIONES 1- Compuestos de fórmula general I1- Compounds of general formula I
Figure imgf000015_0001
Figure imgf000015_0001
 en la que :in which : X es -(CH2)3- o -(CH2)4-; m es igual a 0 ó 1; n es igual a 1, 2, 3 ó 4X is - (CH 2 ) 3 - or - (CH 2 ) 4 -; m is equal to 0 or 1; n is equal to 1, 2, 3 or 4 Ar es , 1-naftilo, 7-benzofuranilo, 2,3-dihidro-l,4-benzodioxan-5-ilo, 3,4-
Figure imgf000015_0002
Ar is, 1-naphthyl, 7-benzofuranyl, 2,3-dihydro-l, 4-benzodioxan-5-yl, 3,4-
Figure imgf000015_0002
 dihidro-2/ ,5-benzodioxepin-6-ilo; en donde R1, R2 y R3 es hidrógeno, alquilo, halógeno, trifluorometilo, nitro, ciano, alcoxi, amino, alquilcarbamoilo, alquilsulfonamido o alcoxicarbonilo. 2- Un compuesto según la reivindicación 1, donde X es -(CH^-, m es cero, n es 1 y Ar es un fenilo opcionalmente sustituido por metilo, fluoro, cloro, bromo, trifluorometilo, ciano, metoxi o amino. 3- Un compuesto según la reivindicación 1, donde X es -(CH2)4-, m es cero, n es 1 y Ar es un fenilo opcionalmente sustituido por metilo, fluoro, cloro, bromo, trifluorometilo, ciano, metoxi o amino.dihydro-2 /, 5-benzodioxepin-6-yl; wherein R 1 , R 2 and R 3 is hydrogen, alkyl, halogen, trifluoromethyl, nitro, cyano, alkoxy, amino, alkylcarbamoyl, alkylsulfonamido or alkoxycarbonyl. 2- A compound according to claim 1, wherein X is - (CH ^ -, m is zero, n is 1 and Ar is a phenyl optionally substituted by methyl, fluoro, chloro, bromo, trifluoromethyl, cyano, methoxy or amino. - A compound according to claim 1, wherein X is - (CH 2 ) 4 -, m is zero, n is 1 and Ar is a phenyl optionally substituted by methyl, fluoro, chloro, bromo, trifluoromethyl, cyano, methoxy or amino. 4- Un compuesto según la reivindicación 1, donde X es -(CH2)3-, m es 1, n es 1 y Ar es 1- naftilo. 5- Un compuesto según la reivindicación 1, donde X es -(CH2)3-, m es cero, n es 2 y Ar es un fenilo opcionalmente sustituido por metilo, fluoro, cloro, bromo, trifluorometilo, ciano, metoxi o amino.4- A compound according to claim 1, wherein X is - (CH 2 ) 3 -, m is 1, n is 1 and Ar is 1- naphthyl. 5- A compound according to claim 1, wherein X is - (CH 2 ) 3 -, m is zero, n is 2 and Ar is a phenyl optionally substituted by methyl, fluoro, chloro, bromo, trifluoromethyl, cyano, methoxy or amino . 6- Un compuesto según la reivindicación 1 , donde X es -(CH2)4-, m es cero, n es 2 y Ar es un fenilo opcionalmente sustituido por metilo, fluoro, cloro, bromo, trifluorometilo, ciano, metoxi o amino.6- A compound according to claim 1, wherein X is - (CH 2 ) 4 -, m is zero, n is 2 and Ar is a phenyl optionally substituted by methyl, fluoro, chloro, bromo, trifluoromethyl, cyano, methoxy or amino . 7- Un compuesto según la reivindicación 1, donde X es -(CH2)3-, m es 0 ó 1, n es 3 y Ar es un fenilo opcionalmente sustituido por metilo, fluoro, cloro, bromo, trifluorometilo, nitro, ciano, metoxi, butoxi, amino, propilcarbamoilo, etilsulfonamido o propoxicarbonilo. 8- Un compuesto según la reivindicación 1, donde X es -(CH2)4-, m es 0 ó 1, n es 3 y Ar es un fenilo opcionalmente sustituido por metilo, fluoro, cloro, bromo, trifluorometilo, nitro, ciano, metoxi, butoxi, amino, propilcarbamoilo, etilsulfonamido o propoxicarbonilo.7- A compound according to claim 1, wherein X is - (CH 2 ) 3 -, m is 0 or 1, n is 3 and Ar is a phenyl optionally substituted by methyl, fluoro, chloro, bromo, trifluoromethyl, nitro, cyano , methoxy, butoxy, amino, propylcarbamoyl, ethylsulfonamido or propoxycarbonyl. 8- A compound according to claim 1, wherein X is - (CH 2 ) 4 -, m is 0 or 1, n is 3 and Ar is a phenyl optionally substituted by methyl, fluoro, chloro, bromo, trifluoromethyl, nitro, cyano , methoxy, butoxy, amino, propylcarbamoyl, ethylsulfonamido or propoxycarbonyl. 9- Un compuesto según la reivindicación 1, donde X es -(CH2)3-, m es 0 ó 1, n es 4 y Ar es 1-naftilo, 7-benzofuranilo, 2,3-dihidro-l,4-benzodioxan-5-ilo, 3,4-dihidro-2/ -l,5-benzodioxepin-6- ilo o un fenilo opcionalmente sustituido por metilo, fluoro, cloro, bromo, trifluorometilo, nitro, ciano, metoxi, butoxi, amino, propilcarbamoilo, etilsulfonamido o propoxicarbonilo.9- A compound according to claim 1, wherein X is - (CH 2 ) 3 -, m is 0 or 1, n is 4 and Ar is 1-naphthyl, 7-benzofuranyl, 2,3-dihydro-l, 4- benzodioxan-5-yl, 3,4-dihydro-2 / -l, 5-benzodioxepin-6- yl or a phenyl optionally substituted by methyl, fluoro, chloro, bromo, trifluoromethyl, nitro, cyano, methoxy, butoxy, amino, propylcarbamoyl, ethylsulfonamido or propoxycarbonyl. 9- Un compuesto según la reivindicación 1, donde X es -(CH2)4-, m es 0 ó 1, n es 4 y Ar es 1-naftilo, 7-benzofuranilo, 2,3-dihidro-l,4-benzodioxan-5-ilo, 3,4-dihidro-2H-l,5-benzodioxepin-6- ilo o un fenilo opcionalmente sustituido por metilo, fluoro, cloro, bromo, trifluorometilo, nitro, ciano, metoxi, butoxi, amino, propilcarbamoilo, etilsulfonamido o propoxicarbonilo.9- A compound according to claim 1, wherein X is - (CH 2 ) 4 -, m is 0 or 1, n is 4 and Ar is 1-naphthyl, 7-benzofuranyl, 2,3-dihydro-l, 4- benzodioxan-5-yl, 3,4-dihydro-2H-l, 5-benzodioxepin-6- yl or a phenyl optionally substituted by methyl, fluoro, chloro, bromo, trifluoromethyl, nitro, cyano, methoxy, butoxy, amino, propylcarbamoyl , ethylsulfonamido or propoxycarbonyl. 10- Un procedimiento para la obtención de compuestos de fórmula general I en donde n es igual a 1, caracterizado por la reacción de II con formaldehído y 1 -arilpiperazinas.10- A process for obtaining compounds of general formula I wherein n is equal to 1, characterized by the reaction of II with formaldehyde and 1-arylpiperazines. 11- Un procedimiento para la obtención de compuestos de fórmula general I en donde n es igual a 2, caracterizado por la reacción de la L-prolina o del pipecolinato de etilo con isocianato de 2-cloroetilo y posterior reacción de sustitución del intermedio DI con 1 -arilpiperazinas.11- A process for obtaining compounds of general formula I wherein n is equal to 2, characterized by the reaction of L-proline or ethyl pipecolinate with 2-chloroethyl isocyanate and subsequent replacement reaction of intermediate DI with 1-arylpiperazines. 12- Un procedimiento para la obtención de compuestos de fórmula general I en donde n es igual a 3, caracterizado por la reacción de II con las correspondientes 4-(3-cloropropil)-l- arilpiperazinas. 13- Un procedimiento para la obtención de compuestos de fórmula general I en donde n es igual a 4, caracterizado por la reacción de II con l-bromo-4-clorobutano y posterior tratamiento del derivado halogenado con 1 -arilpiperazinas.12- A process for obtaining compounds of general formula I wherein n is equal to 3, characterized by the reaction of II with the corresponding 4- (3-chloropropyl) -l-arylpiperazines. 13- A process for obtaining compounds of general formula I wherein n is equal to 4, characterized by the reaction of II with l-bromo-4-chlorobutane and subsequent treatment of the halogenated derivative with 1-arylpiperazines. 14- Compuestos de fórmula general I para su utilización como medicamentos.14- Compounds of general formula I for use as medicines. 15- Utilización de los compuestos de fórmula general I para la preparación de un medicamento destinado al tratamiento de trastornos en el SNC, tales como la ansiedad y depresión. 15- Use of the compounds of general formula I for the preparation of a medicament for the treatment of CNS disorders, such as anxiety and depression.
PCT/ES1995/000094 1994-09-01 1995-07-28 New arylpiperazine derivatives Ceased WO1996006846A1 (en)

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ES2154605A1 (en) * 1999-09-14 2001-04-01 Univ Madrid Complutense NEW MIXED DERIVATIVES OF BENCIMIDAZOL-ARILPIPERAZINA AFFINED BY SEROTONINERGIC RECEPTORS 5-HT1A AND 5-HT3
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