WO2002089734A2 - Methode de traitement et de prevention de troubles du systeme nerveux central associes a une alteration de la neurotransmission glutamatergique par administration de derives de 2-aminobenzenesulfonamide - Google Patents

Methode de traitement et de prevention de troubles du systeme nerveux central associes a une alteration de la neurotransmission glutamatergique par administration de derives de 2-aminobenzenesulfonamide Download PDF

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Publication number
WO2002089734A2
WO2002089734A2 PCT/US2002/014262 US0214262W WO02089734A2 WO 2002089734 A2 WO2002089734 A2 WO 2002089734A2 US 0214262 W US0214262 W US 0214262W WO 02089734 A2 WO02089734 A2 WO 02089734A2
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WO
WIPO (PCT)
Prior art keywords
treatment
prevention
formula
compound
alteration
Prior art date
Application number
PCT/US2002/014262
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English (en)
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WO2002089734A3 (fr
Inventor
Giuseppe Cannazza
Carlo Parenti
Wolfgang Lindner
Giulia Puia
Mario Baraldi
Daniela Braghiroli
Annalisa Tait
Original Assignee
Rett Corporation
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
Application filed by Rett Corporation filed Critical Rett Corporation
Priority to AU2002308614A priority Critical patent/AU2002308614A1/en
Priority to EP02769353A priority patent/EP1435926A4/fr
Publication of WO2002089734A2 publication Critical patent/WO2002089734A2/fr
Publication of WO2002089734A3 publication Critical patent/WO2002089734A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/136—Amines having aromatic rings, e.g. ketamine, nortriptyline having the amino group directly attached to the aromatic ring, e.g. benzeneamine

Definitions

  • This invention relates to the use of 2-aminobenzenesulfonamide derivatives for the treatment or prevention of the disturbances of the central nervous system associated with an alteration of glutamatergic neurotransmission, such as disturbances of memory and learning, schizophrenia, sexual disturbances, ischemic attacks, ictus, etc.
  • L-glutamate is the main neurotransmitter of the central nervous system in mammals and is capable of activating specific ionotropic and metabotropic receptors of neuronal and glial cells.
  • N-methyl-D-aspartate (NMD A) receptors The ionotropic glutamatergic receptors can be subdivided into three main classes: 1. N-methyl-D-aspartate (NMD A) receptors
  • Hydra21(7-chloro-3-methyl-3,4-dihydro-2H-l,2,4-benzothiadiazine 1,1 -dioxide) has drawn particular interest by their ability to improve the
  • AMPAergic synaptic currents due to the activation of the AMPA receptors of cyclothiazide, diazoxide, Hydra21 and 1-BCP is toxic for hippocampal neurons in culture.
  • the fact that no side effect of hydra21 has been found in numerous experiments in vivo conducted on experimental animals indicates that the concentrations reached in the brain by this substance in order to exercise its nootropic effect are not sufficient for the excitotoxic effect observed in experiments in cell cultures.
  • hydra21 acts as a non-competitive antagonist of the NMDA receptor with neuro- protective properties in vitro, reducing in excitotoxicity experiments the cellular death induced by NMDA.
  • hydra21 has a chiral carbon atom, it is possible that only one enantiomer is active, while the other may be inactive or have properties of competitive antagonism with said receptor, so as to compete with the active enantiomer in the same site on the receptor (Uznov et al 1995).
  • Uznov et al described how a saline solution of the (+) enantiomer of hydra21 administered per os is more active than a solution with the same concentration of hydra21 in racemic form, in increasing memory and cognitive capacity in experimental animals.
  • the object of this invention is a method for the treatment or prevention of all the disturbances of the central nervous system sensitive to a positive or negative modulation of glutamatergic neurotransmission.
  • the purpose of the invention is to supply a method for the treatment or prevention of all the disturbances of the central nervous system sensitive to a positive or negative modulation of glutamatergic neurotransmission and, in particular, to a positive or negative modulation of AMPA/Kainate receptors and to a negative modulation of NMDA receptors, through the administration of a compound with the formula:
  • R ⁇ and R 2 are independently chosen and are functional groups which include, without limitation thereto, the following: hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl or R, and R 2 together with the nitrogen to which they are bound forming a heterocyclic ring.
  • R 2 and R 3 are independently chosen and are functional groups which include, without limitation thereto, the following: hydrogen, halogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl or R 2 and R 3 together with the nitrogen to which they are bound forming a heterocyclic ring.
  • R,, R 5 , R ⁇ , R 7 , R g are independently chosen and are functional groups which include, without limitation thereto, the following: hydrogen, halogen, cyano, hydroxide, thiol, sulfamoyl, alkoxyl, nitro, haloalkyl, alkyl, substituted alkyl, aryl, substituted aryl, acyl or carboxyl.
  • specific compounds under this invention are the compounds listed below (hereinafter Leuca compounds):
  • halogen refers to fluoro, bromo, chloro, iodo atoms
  • hydroxy refers to the group -OH.
  • thiol refers to the group -SH.
  • sulfamoyl refers to the group -SO 2 NH 2 .
  • alkyl refers to linear or branched alkyl groups with one to eight carbon atoms.
  • substituted alkyl refers to the alkyls described above, made up of one or several functional groups such as aryl, acyl, halogen, hydroxyl, amido, amino, acyloxy, alkoxy, cyano, nitro, thioalkyl and others.
  • haloalkyl refers to the groups described above when some or all hydrogens are replaced by halogen atoms (e.g. -CF 3 ).
  • aryl refers to aromatic substitutes which may have a single or multiple condensate ring, covalently bound.
  • the aromatic rings may contain an ether atom.
  • substituted aryl refers to the aryls described above containing one or several functional groups such as acyl, halogen, hydroxyl, amido, amino, acyloxy, alkoxy, cyano, nitro, thioalkyl and others.
  • alkoxy refers to the group -OR in which R may be an alkyl, a substituted alkyl, an aryl, a substituted aryl.
  • acyl indicates -C(O)R groups in which R is an alkyl or a substituted alkyl or an aryl or an amine group.
  • amino indicates an -NRR' group in which R and R' can be independently a hydrogen, alkyl, substituted alkyl, aryl or acyl.
  • the purpose of the invention is to supply a method for the treatment or prevention of all disturbances of the central nervous system sensitive to a positive or negative modulation of glutamatergic neurotransmission and, in particular, to a positive or negative modulation of AMPA/Kainate receptors and a negative modulation of NMDA receptors, obtained by administration of a formula I compound.
  • the synthesis of the formula I compounds may be carried out by conventional methods known to the specialist in organic synthesis, except for small modifications and already described in the literature (for example patents WO9812185, US6083947, US5488049, WO9942456, etc.). It has been discovered that formula I compounds, as well as their salts with the appropriate acids or bases, have the capacity to positively modulate glutamatergic neurotransmission.
  • the object of this invention also includes the methods for administration of formula I compounds salified with the appropriate acids, such as hydrochloric, hydrobromic, sulfuric, phosphoric, acetic, trifluoroacetic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, tartaric, maleic, citric, ascorbic, methanesulfonic, oxalic and similar acids which may be mentioned among those pharmaceutically acceptable.
  • the object of this invention also includes the methods for administration of the formula I compounds salified with appropriate bases such as sodium hydroxide, potassium hydroxide, sodium bicarbonate and others which may be mentioned among those pharmaceutically acceptable.
  • the compounds under this invention have advantageous pharmacological properties because they enhance the electrophysiological responses in hippocampal or cerebellar neurons induced by kainic acid or by (S)-5-fluorowillardine and/or reduce the electrophysiological responses in hippocampal or cerebellar neurons induced by NMDA. As can be deduced from the results of electrophysiological studies, the compounds under this invention have the pharmacological and therapeutic potential to be used in the treatment of disturbances of glutamatergic neurotransmission.
  • the compounds under this invention can therefore be used as agents for the activation or inhibition induced by glutamic acid on the AMPA/kainate receptor and NMDA receptor, respectively, and constitute by their activity therapeutic agents for the treatment or prevention of diseases associated with alterations of the glutamatergic system such as: memory, cognitive and sexual disorders due to age, depressive syndromes, anxiety, memory deficit in neuro-degenerative diseases such as Alzheimer's disease, Huntington's chorea and schizophrenia, consequences of acute neuro-degenerative diseases such as ischemia, epilepsy, etc.
  • diseases associated with alterations of the glutamatergic system such as: memory, cognitive and sexual disorders due to age, depressive syndromes, anxiety, memory deficit in neuro-degenerative diseases such as Alzheimer's disease, Huntington's chorea and schizophrenia, consequences of acute neuro-degenerative diseases such as ischemia, epilepsy, etc.
  • Another object of this invention is a pharmaceutical composition containing one of the formula I compounds in combination with one or several excipients or appropriate vehicles for a pharmaceutical form.
  • appropriate pharmaceutical forms included in the invention which may contain the formula I compounds, we can mention, as an example only and without limitation thereto, those appropriate for oral, rectal, nasal, parenteral or sublingual administration, especially tablets, coated tablets, gel capsules, granules, pills, suppositories, aerosols and injectable or drinkable solutions.
  • the dose varies from individual to individual, depending on the age, weight and sex of the patient, on the route of administration and of the nature and intensity of the disease.
  • the doses used vary between 0.1 mg and 500 mg for a treatment that may be divided into 1-3 doses taken within 24 hours.
  • the electrophysiological records were made by "voltage clamp” in the “whole cell” configuration on individual neurons in culture after 7 days.
  • the electrodes were harvested from the borosilicate glass with vertical puller and had a resistance of 5-7 Mohm when refilled with an internal solution of KCl.
  • the currents were amplified with an Axopatch ID amplifier, filtered at 5 KHz and digitalized at 10 KHz.
  • a pCLAMP software was used for analysis.
  • the intracellular solution consisted of (mM): KCl 140, MgCl 2 3, EGTA 5,
  • the compounds tested were dissolved in dimethylsulfoxide and diluted to a final concentration of ImM with extracellular medium (final concentration of dimethylsulfoxide lower than 0.1%). All compounds were applied directly by gravity through a Y tube.

Abstract

L'invention porte sur des dérivés de 2-aminobenzènesulfonamide utilisés pour le traitement ou la prévention de troubles du système nerveux central associés à une modulation positive ou négative de la neurotransmission glutamatergique, notamment des troubles de la mémoire et de l'apprentissage, de la schizophrénie, des dysfonctionnements sexuels, d'attaques ischémiques, d'ictus, etc. A titre d'exemple, un composé de formule I est administré afin de traiter ou de prévenir des maladies du système nerveux central présentant une modulation positive ou négative des récepteurs AMPA-Kainate et une modulation négative des récepteurs NMDA.
PCT/US2002/014262 2001-05-08 2002-05-07 Methode de traitement et de prevention de troubles du systeme nerveux central associes a une alteration de la neurotransmission glutamatergique par administration de derives de 2-aminobenzenesulfonamide WO2002089734A2 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
AU2002308614A AU2002308614A1 (en) 2001-05-08 2002-05-07 Method for treatment and prevention of disturbances of the central nervous system associated with an alteration of glutamatergic neurotransmission by administration of 2-aminobenzenesulfonamide derivatives
EP02769353A EP1435926A4 (fr) 2001-05-08 2002-05-07 Methode de traitement et de prevention de troubles du systeme nerveux central associes a une alteration de la neurotransmission glutamatergique par administration de derives de 2-aminobenzenesulfonamide

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ITBO2001A000271 2001-05-08
IT2001BO000271A ITBO20010271A1 (it) 2001-05-08 2001-05-08 Metodo per il trattamento e la prevenzione dei disturbi del sistema nervoso centrale associati ad una alterazione della neurotrasmissione gl

Publications (2)

Publication Number Publication Date
WO2002089734A2 true WO2002089734A2 (fr) 2002-11-14
WO2002089734A3 WO2002089734A3 (fr) 2003-03-06

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PCT/US2002/014262 WO2002089734A2 (fr) 2001-05-08 2002-05-07 Methode de traitement et de prevention de troubles du systeme nerveux central associes a une alteration de la neurotransmission glutamatergique par administration de derives de 2-aminobenzenesulfonamide

Country Status (4)

Country Link
EP (1) EP1435926A4 (fr)
AU (1) AU2002308614A1 (fr)
IT (1) ITBO20010271A1 (fr)
WO (1) WO2002089734A2 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007076875A2 (fr) * 2006-01-06 2007-07-12 Aarhus Universitet Composes agissant sur le transporteur de la serotonine
US7297713B2 (en) 2005-07-29 2007-11-20 Wyeth Cyanopyrrole-phenyl amide progesterone receptor modulators and uses thereof
EP3311842A1 (fr) 2013-06-13 2018-04-25 VeroScience LLC Compositions et procédés de traitement des troubles métaboliques

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5536719A (en) * 1994-07-12 1996-07-16 Adir Et Compagnie Benzothiadiazine compound
US6083947A (en) * 1996-01-29 2000-07-04 The Regents Of The University Of California Method for treating sexual dysfunctions

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5939451A (en) * 1996-06-28 1999-08-17 Hoffmann-La Roche Inc. Use of sulfonamides
GB9818916D0 (en) * 1998-08-28 1998-10-21 Smithkline Beecham Plc Use

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5536719A (en) * 1994-07-12 1996-07-16 Adir Et Compagnie Benzothiadiazine compound
US6083947A (en) * 1996-01-29 2000-07-04 The Regents Of The University Of California Method for treating sexual dysfunctions

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP1435926A2 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7297713B2 (en) 2005-07-29 2007-11-20 Wyeth Cyanopyrrole-phenyl amide progesterone receptor modulators and uses thereof
US7652062B2 (en) 2005-07-29 2010-01-26 Wyeth Llc Cyanopyrrole-phenyl amide progesterone receptor modulators and uses thereof
WO2007076875A2 (fr) * 2006-01-06 2007-07-12 Aarhus Universitet Composes agissant sur le transporteur de la serotonine
WO2007076875A3 (fr) * 2006-01-06 2007-11-15 Univ Aarhus Composes agissant sur le transporteur de la serotonine
EP3311842A1 (fr) 2013-06-13 2018-04-25 VeroScience LLC Compositions et procédés de traitement des troubles métaboliques

Also Published As

Publication number Publication date
AU2002308614A1 (en) 2002-11-18
EP1435926A4 (fr) 2005-11-23
ITBO20010271A1 (it) 2002-11-08
EP1435926A2 (fr) 2004-07-14
WO2002089734A3 (fr) 2003-03-06
ITBO20010271A0 (it) 2001-05-08

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