WO1996006846A1 - Nouveaux derives d'aryle piperazines - Google Patents

Nouveaux derives d'aryle piperazines Download PDF

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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
Authority
WO
WIPO (PCT)
Prior art keywords
cyano
trifluoromethyl
amino
bromo
compound according
Prior art date
Application number
PCT/ES1995/000094
Other languages
English (en)
Spanish (es)
Inventor
Maria Luz Lopez Rodriguez
Maria Luisa Rosado Samitier
Bellinda Benahmu Salama
Esther Fernandez Velando
Maria Jose Morcillo Ortega
Original Assignee
Universidad Complutense De Madrid
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from ES9401895A external-priority patent/ES2082727B1/es
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/es
Publication of WO1996006846A1 publication Critical patent/WO1996006846A1/fr

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Classifications

    • 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

L'invention concerne de nouveaux composés de formule générale (I), dans laquelle X représente -(CH2)3-O-(CH2)4-; m est égal à 0 ou 1; n est égal à 1, 2, 3 ou 4; Ar représente 1-naphthyle, 7-benzofuranyle, 2,3-dihidro-1,4-benzodioxane-5-yle, 3,4-dihydro-2H-1,5-benzodioxépine-6-yle, phényle ou phényle substitué par alkyle, halogène, trifluorométhyle, nitro, cyano, alcoxy, amino, alkylcarbamyle, alkylsulfonamido ou alcoxy carbonylo. L'invention concerne également les différents procédés de préparation de ces composés, lesquels présentent une affinité pour le récepteur sérotoninergique 5-HT1A, mettant en évidence son utilité du point de vue thérapeutique dans le traitement des troubles du SNC, tels que l'anxiété et la dépression.
PCT/ES1995/000094 1994-09-01 1995-07-28 Nouveaux derives d'aryle piperazines WO1996006846A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU30792/95A AU3079295A (en) 1994-09-01 1995-07-28 New arylpiperazine derivatives

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
ESP9401895 1994-09-01
ES9401895A ES2082727B1 (es) 1994-09-01 1994-09-01 Nuevos derivados de arilpiperazinas.
ES9501534A ES2095811B1 (es) 1995-07-28 1995-07-28 Nuevos derivados de arilpiperazinas.
ESP9501534 1995-07-28

Publications (1)

Publication Number Publication Date
WO1996006846A1 true WO1996006846A1 (fr) 1996-03-07

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/ES1995/000094 WO1996006846A1 (fr) 1994-09-01 1995-07-28 Nouveaux derives d'aryle piperazines

Country Status (2)

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AU (1) AU3079295A (fr)
WO (1) WO1996006846A1 (fr)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999015527A1 (fr) * 1997-09-23 1999-04-01 Universidad Complutense De Madrid PROCEDE D'OBTENTION DU 2-[4-[4-(m- ETHYLSULFONAMIDOPHENYL) PIPERAZINE-1-YL] BUTYL]-1,3- DIOXOPERHYDROPYRROLO [1,2-c]IMIDAZOL
ES2154605A1 (es) * 1999-09-14 2001-04-01 Univ Madrid Complutense Nuevos derivados mixtos de bencimidazol-arilpiperazina con afinidad por los receptores serotoninergicos 5-ht1a y 5-ht3
US6417189B1 (en) 1999-11-12 2002-07-09 Gpi Nil Holdings, Inc. AZA compounds, pharmaceutical compositions and methods of use
EP1674103A1 (fr) * 2004-12-27 2006-06-28 Cepa Schwarz Pharma s.l. Dérivés d'arylpiperazines et leurs utilisations en tant que ligands du récepteur 5-HT1A
US7253169B2 (en) 1999-11-12 2007-08-07 Gliamed, Inc. Aza compounds, pharmaceutical compositions and methods of use
US7351732B2 (en) 2002-07-31 2008-04-01 Schwarz Pharma S.L. Cycloalkanedione derivatives, method for the production thereof and their pharmacological applications
US7459473B2 (en) 1998-06-03 2008-12-02 Glia Med, Inc. N-linked sulfonamides of N-heterocyclic carboxylic acids or carboxylic acid isosteres
WO2023135528A1 (fr) 2022-01-11 2023-07-20 Suven Life Sciences Limited Dérivés hétéroalicycliques et leur utilisation dans le traitement de troubles du snc

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2092785A1 (en) * 1970-06-18 1972-01-28 Hokuriku Pharmaceutical 2-azaquinolizidine derivs and salts neurotropic and anti - -histamine agents synthesis
US3717634A (en) * 1969-11-24 1973-02-20 Mead Johnson & Co N-(heteroarcyclic)piperazinylalkyl-azaspiroalkanediones
EP0256936A1 (fr) * 1986-08-12 1988-02-24 Rhone-Poulenc Sante Nouveaux dérivés de la benzyl-4 pipérazine, leur préparation et les compositions pharmaceutiques qui les contiennent
EP0296048A1 (fr) * 1987-06-15 1988-12-21 Adir Et Compagnie Nouveaux dérivés de la pipérazinyl alkyl piperazine dione, leurs procédés de préparation et les compositions pharmaceutiques qui les contiennent
EP0362555A1 (fr) * 1988-09-03 1990-04-11 Hoechst Aktiengesellschaft Pipérazinediones à activité psychotrope

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3717634A (en) * 1969-11-24 1973-02-20 Mead Johnson & Co N-(heteroarcyclic)piperazinylalkyl-azaspiroalkanediones
FR2092785A1 (en) * 1970-06-18 1972-01-28 Hokuriku Pharmaceutical 2-azaquinolizidine derivs and salts neurotropic and anti - -histamine agents synthesis
EP0256936A1 (fr) * 1986-08-12 1988-02-24 Rhone-Poulenc Sante Nouveaux dérivés de la benzyl-4 pipérazine, leur préparation et les compositions pharmaceutiques qui les contiennent
EP0296048A1 (fr) * 1987-06-15 1988-12-21 Adir Et Compagnie Nouveaux dérivés de la pipérazinyl alkyl piperazine dione, leurs procédés de préparation et les compositions pharmaceutiques qui les contiennent
EP0362555A1 (fr) * 1988-09-03 1990-04-11 Hoechst Aktiengesellschaft Pipérazinediones à activité psychotrope

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
R. PERRONE ET AL.: "Mixed 5-HT1A/D-2 activity of a new model of arylpiperazines: 1-aryl-4-[3-(1,2-dihydronaphtalen-4-yl)-n-propyl]piperazines. 1. Synthesis and structure-activity relationships", JOURNAL OF MEDICINAL CHEMISTRY, vol. 37, no. 1, WASHINGTON US, pages 99 - 104 *

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999015527A1 (fr) * 1997-09-23 1999-04-01 Universidad Complutense De Madrid PROCEDE D'OBTENTION DU 2-[4-[4-(m- ETHYLSULFONAMIDOPHENYL) PIPERAZINE-1-YL] BUTYL]-1,3- DIOXOPERHYDROPYRROLO [1,2-c]IMIDAZOL
ES2129370A1 (es) * 1997-09-23 1999-06-01 Univ Madrid Complutense Procedimiento para la obtencion del 2-(4-(4-(m-etilsulfonamidofenil)p iperazin-1-il(butil)-1,3-dioxoperhidropirrolo)1,2-c(imidazol
US7459473B2 (en) 1998-06-03 2008-12-02 Glia Med, Inc. N-linked sulfonamides of N-heterocyclic carboxylic acids or carboxylic acid isosteres
ES2154605A1 (es) * 1999-09-14 2001-04-01 Univ Madrid Complutense Nuevos derivados mixtos de bencimidazol-arilpiperazina con afinidad por los receptores serotoninergicos 5-ht1a y 5-ht3
US6417189B1 (en) 1999-11-12 2002-07-09 Gpi Nil Holdings, Inc. AZA compounds, pharmaceutical compositions and methods of use
US7253169B2 (en) 1999-11-12 2007-08-07 Gliamed, Inc. Aza compounds, pharmaceutical compositions and methods of use
US7351732B2 (en) 2002-07-31 2008-04-01 Schwarz Pharma S.L. Cycloalkanedione derivatives, method for the production thereof and their pharmacological applications
EP1674103A1 (fr) * 2004-12-27 2006-06-28 Cepa Schwarz Pharma s.l. Dérivés d'arylpiperazines et leurs utilisations en tant que ligands du récepteur 5-HT1A
WO2006069993A1 (fr) * 2004-12-27 2006-07-06 Schwarz Pharma S.L. Derives d’arylpiperazine et leur utilisation comme ligands du recepteur as 5-ht1a
WO2023135528A1 (fr) 2022-01-11 2023-07-20 Suven Life Sciences Limited Dérivés hétéroalicycliques et leur utilisation dans le traitement de troubles du snc

Also Published As

Publication number Publication date
AU3079295A (en) 1996-03-22

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