EP1435926A2 - 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 - Google Patents
Method for treatment and prevention of disturbances of the central nervous system associated with an alteration of glutamatergic neurotransmission by administration of 2-aminobenzenesulfonamide derivativesInfo
- Publication number
- EP1435926A2 EP1435926A2 EP02769353A EP02769353A EP1435926A2 EP 1435926 A2 EP1435926 A2 EP 1435926A2 EP 02769353 A EP02769353 A EP 02769353A EP 02769353 A EP02769353 A EP 02769353A EP 1435926 A2 EP1435926 A2 EP 1435926A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- treatment
- prevention
- formula
- compound
- alteration
- Prior art date
- Legal status (The legal status 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 status listed.)
- Withdrawn
Links
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Classifications
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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
- 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.
- 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 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.
- 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,
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Abstract
2-aminobenzenesulfonamide derivatives are used for the treatment or prevention of the disturbances of the central nervous system associated with a positive or negative modulation of glutamatergic neurotransmission, such as disturbances of memory and learning, schizophrenia, sexual disturbances, ischemic attacks, ictus, etc. For example, a compound according to formula (I): is administered to treat or prevent diseases of the central nervous system having a positive or negative modulation of AMPA/Kainate receptors and a negative modulation of NMDA receptors.
Description
TITLE OF THE INVENTION
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.
This application claims priority from Italian Patent Application No.
BO2001A000271 filed 8 May 2001, the entirety of which is hereby incorporated by reference.
TEXT OF THE DESCRIPTION
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.
State of the art 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.
The ionotropic glutamatergic receptors can be subdivided into three main classes: 1. N-methyl-D-aspartate (NMD A) receptors
2. (2-amino-3-(3-hydroxy-5-methylisoxazole-4-yl)propionic acid (AMP A) receptors
3. Kainic acid receptors
While, nowadays it has been established that excessive mediated excitation of glutamate receptors may cause neurotoxicity, a reduced functionality of such receptors seems to be implicated in memory and cognitive deficits. This involvement of the glutamatergic receptors in memory and cognitive processes is
suggested by the main role exercised by these receptors in the long-term potentiation (LTP) phenomenon and in long-term depression (LTD) of the post- synaptic electric responses which are currently thought to be the source of specific forms of memory. In addition, another experimental proof of the involvement of glutamatergic receptors in memory and cognitive processes is that the blockage of glutamatergic transmission by NMDA antagonistic isosteres or by AMPA receptors antagonistic isosteres leads to deep alterations in the processes of learning and memory both in humans and in experimental animals. Given the fact that it has been demonstrated experimentally that nootropic drugs (capable of enhancing memory and cognitive capacity) such as aniracetam, inhibit selectively the quick spontaneous desensitization of AMPA receptors, the potential therapeutic effect of compounds capable of activating such receptors has encouraged research for new AMPA receptor modulators.
It must be remembered that excessive activation of the AMPA receptor may cause excitotoxicity such as in the case of an ischemic attack, and therefore positive modulators of said receptor may promote neuronal damage under these conditions. Consequently, mediated excitotoxicity of the AMPA receptor may represent an undesirable side effect in the therapeutic utilization of the positive modulators of the AMPA receptor as nootropic drugs. Derivatives of pyrrolidinone, such as aniracetam (ITO et al 1990), derivatives of benzoylpiperidine such as BDP-12 (Arai et al 1996) and derivatives of benzothiadiazine (Yamada et al 1992; Yamada et al 1993; Bertolino et al 1993), inhibit the desensitization of the AMPA receptor. Among benzothiadiazine derivatives, 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
"performance" of the rats in the behavioral experiment of the "water maze" and "passive avoidance," when administered per os at low dose (μmol/Kg). The effect of Hydra21, increasing memory and cognitive capacity-which, in experimental animals, is 10-30 times more potent than aniracetam-suggests its therapeutic application in the treatment of learning, memory and attention disorders due to age,
trauma of the central nervous system, ictus and neuro-degenerative disturbances such as Alzheimer's disease (Uzunov et al 1995).
Objections have been raised concerning the therapeutic utilization of positive modulators of the AMPA receptor due to their potential neurotoxicity (Yamada et al 1999). Yamada et al have demonstrated that the enhancement of 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. In addition, recent studies have demonstrated that 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. Notwithstanding its high potency in vivo, the capacity of hydra21 to modulate the activity of the AMPA receptor in vitro is low with an EC50 close to 1 mM. As a minimum, two hypotheses may be made to explain the differences in the activity of hydra21 in vivo and in vitro.
Since 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. This hypothesis has been discredited by two recent articles (Cannazza et al 2000, Cannazza et al 2001) which demonstrate a quick interconversion of the two enantiomers of hydra21 in aqueous solutions. The second hypothesis consists of the possibility that hydra21 explains its nootropic action by a more active metabolite of hydra21(Impagnatiello et al 1997).
Summary of the invention
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:
In the above formula, R^ and R2 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 R2 together with the nitrogen to which they are bound forming a heterocyclic ring. R2 and R3 are independently chosen and are functional groups which include, without limitation thereto, the following: hydrogen, halogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl or R2 and R3 together with the nitrogen to which they are bound forming a heterocyclic ring.
R,, R5, R^, R7, Rg 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.
In particular, specific compounds under this invention are the compounds listed below (hereinafter Leuca compounds):
It has been discovered that the compounds with the above formula have a positive or negative modulating activity of AMPA/Kainate receptors and a negative modulating activity of NMDA receptors.
Brief description of the figures The purposes and characteristics of this invention will be better clarified by the following detailed descriptions of the invention taken together with the figures which are given simply as an illustration and do not limit this invention. Figure 1
General formula of the compounds constituting the object of this invention. Figure 2
Modulation of the synaptic currents induced by kainic acid and NMDA in cerebellar and hippocampal neurons of the rat by hydra21 and Leuca 1. Figure 3
Modulation of the synaptic currents produced by kainic acid on hippocampal neurons of the rat by certain 2-aminobenzenesulfonamide derivatives
(Leuca). Figure 4
Modulation of the synaptic currents induced by (S)-5-fluorowillardine on hippocampal neurons of the rat by certain 2-aminobenzenesulfonamide derivatives (Leuca).
Figure 5
Modulation of the synaptic currents induced by NMDA on hippocampal neurons of the rat by certain 2-aminobenzenesulfonamide derivatives (Leuca).
Definitions "cyano" refers to the group -CN.
"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 -SO2NH2.
"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. -CF3).
"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 term "independently" is used to indicate that two groups R' and R" may be identical or different.
Detailed description of the invention
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.
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. Among the 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 following examples illustrate the invention and do not limit it in any manner:
Example 1
Synthesis of 5-chloro-2-amino-N-methylbenzenesulfonamide (Leuca22)
- synthesis of 5-chloro-2-nitrobenzenesulfchloride
20 g of 5-chloro-2-nitroaniline (0.12 mol) are treated with 220 ml HC1 1 :1 and the mixture is brought to -5°, cooling it with ice and salt. Little by little, into the suspension obtained, we add by separatory funnel, a solution of 16g of NaNO2 (0.23 mol) in 70 ml of water, being careful to regulate the speed of addition of the reactant so that the temperature of the mixture in reaction is kept between 0° and - 5°. The solution of the chloride of 2-nitro-5-chlorophenyldiazone formed was then added to a solution of glacial acetic acid saturated with SO2 (250ml) and in the presence of an aqueous solution of CuCl2 (8.33g in 20 ml of water).
The product obtained was collected from the pump and washed with water. Yield 93%; melting point 67°- 68°
- synthesis of 5-chloro-2-nitrobenzenesulfonamide 17.5 g of 5-chloro-2-nitrobenzenesulfchloride (0.068 mol) have been added to an aqueous solution of methylamine 40% (61.8 ml, 0.68 mol). The solution was cooled and agitated for 2 hours at 35°. The crude yellow product was collected and solubilized in 1 liter of aqueous solution of NaOH 3%; filtered to eliminate impurities and with an addition of diluted HC1. The precipitate was collected and washed with water.
Yield 90.2%, melting point 157°- 158°
- synthesis of 2-amino-5-chloro-N-methylbenzenesulfonamide (Leuca22)
18.4 g of powdered iron are placed in a flask and caused to react with 70 ml of HCl diluted 1 :10 until hydrogen no longer forms, then added to an aqueous suspension of 5-chloro-2-nitro-N-methylbenzene sulfonamide (18.4 g in 50 ml). It is heated for three hours at 60° under mechanical agitation, and therefore it becomes alkaline by adding Na2CO3 until the substance transforms into phenolphthalein, and 50 ml of NaOH 15%. After agitation of the mixture for 30 minutes at ambient temperature, it is filtered in a pump and the filtrate is acidified with HCl until obtaining a slightly acid reaction with congo red; we obtain a white crystalline precipitate which, washed with water and dried under vacuum, has 74°-
75°.
Yield 73%.
Example 2 Synthesis of 5-chloro-2-methylaminobenzenesulfonamide (Leuca2)
2g of 2,5-dichlorobenzenesulfonamide (0.0088 mol) were added to 20 ml of an aqueous solution of methylamine 405 (0.258 mol) and placed in the reactor for
20 hours at 180°. The crude product obtained was concentrated under vacuum and crystallized by methanol/water. Dissolved in diluted NaOH and precipitated by adding diluted HCl.
Yield 50%, melting point 141°- 142°.
For the synthesis of the other compounds, we used, except for small modifications, the synthesis method of the reaction intermediates described in patent WO9812185. The experts in organic synthesis will easily understand that the protocols described above may be used, except for small modifications, for the other compounds under this invention.
Example 3
Study of the excitatory currents induced by kainic acid, (S)-5-fluorowillardine and NMDA in hippocampal and cerebellar neurons of the rat
Granular cells from the cerebellum or neurons from the hippocampus of Sprague-Dawley rats were dispersed with trypsin (0.24 mg/ml) and placed at a density of 106 cells/ml on a 35 mm Falcon dish, covered with poly-L-lysine (10 μg/ml). The cells were caused to grow in the Eagle basal medium, with addition of 10%) bovine fetal serum, 2 mM glutamine and 100 Ug/ml of gentamicin and incubated at 37° in atmosphere with 5% carbon anhydride. 10 μm of arabinofuranoside cytosine were added to the cultures 24 hours after their preparation to prevent astroglial proliferation.
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, MgCl2 3, EGTA 5,
HEPES 5, ATP-Na 2; pH=7.3 with KOH. The cells were continuously perfused with an external solution (mM9: NaCl 145, KCl 5, CaCl2 1, HEPES 5, glucose 5, sucrose 20, pH=7.4 with KOH).
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.
The data were analyzed with the pCLAMP 6.3 software. The results are expressed as average+standard error. The results of electrophysiological experiments are reported in figures 2-5
(note 1).
BIBLIOGRAPHY
1. Ito I., Tanabe S., Kohda A., Sugiyama H., J. Physiol. 424, 533-543 (1990).
2. Arai A., Guidotti A., Costa E., Lynch G., Neuroreport, 7, 2211- 2215 (1996).
3. Yamada K.A., Rothman S.M., J. Physiol., 458, 385-407 (1992).
4. Yamada K.A., Tang CM., J. Neurosc. 14, 325-331 (1993).
5. Bertolino M., Baraldi M., Parenti C, Braghiroli D., Di Bella M., Vicini S., Costa E., Receptors Channels, 1, 267-278 (1993). 6. Uzunov D.P., Zivkovich I., Pirkle W.H., Costa E., Guidotti A., J.
Pharm. Sci., 84, 937-942 (1995).
7. Yamada K.A., Neuroscience Report 249, 119-122 (1998).
8. Cannazza G., Braghiroli D., Baraldi M., Parenti C, J. Pharm. Biom. Anal., 23, 117-125 (2000). 9. Cannazza G., Braghiroli D., Tait A., Baraldi M., Parenti C, Lindner
W., Chiralty, 13, 94-101 (2001).
Claims
We claim:
1 ) A method for the treatment or prevention of disorders related to an alteration of glutamatergic neurotransmission which includes in its formulation a compound with the formula:
where, in the above formula R, and R2 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 R2 together with the nitrogen to which they are bound forming a heterocyclic ring. R2 and R3 are independently chosen and are functional groups which include, without limitation thereto, the following: hydrogen, halogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl or R2 and R3 together with the nitrogen to which they are bound forming a heterocyclic ring.
R4, R5, Rfi, R7, R8 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.
2) A method in accordance with point 1 , in which the compound in the formula is Rb R2, R3, R5, R^, R8 = H, R, = methyl or ethyl or propyl and R7 = Cl, I, Br, F, NO2, CF3 or CN.
3) A method in accordance with point 1, in which the compound in formula I is R' = methyl or ethyl or propyl R2, R3, R,, R5, R^, R8 = H and R7 = Cl, I, Br, F, NO2, CF3 or CN.
4) A method in accordance with point 1 , in which the compound in formula I is R5 = methyl or ethyl or propyl Rb R2, R3, R,, Rg, Rg = H and R7 = Cl, I,
Br, F, NO2, CF3 or CN.
5) A method in accordance with point 1 , in which the compound in formula I is R, and R5 = methyl or ethyl or propyl R,, R2, R3, Rj, R8 = H and R7 = Cl, I, Br, F, NO2, CF3 or CN.
6) A method for the treatment or prevention of disorders related to an alteration of glutamatergic neurotransmission which includes in its formulation a compound named leuca 1-22.
7) A method for the treatment of living animal subjects suffering from a condition which requires the treatment or prevention of diseases associated with an alteration of glutamatergic neurotransmission which includes the administration to the living subject of a certain quantity of the compounds reported in claims 1-6 or their salts with appropriate acids or bases, in an amount efficacious in alleviating the disorder or disease.
8) A pharmaceutical compound useful in the treatment or prevention of diseases associated with an alteration of glutamatergic neurotransmission which includes as a component an appropriate quantity of the compounds reported in claims 1-6 or their salts with appropriate acids or bases in association with one or several appropriate excipients or vehicles.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT2001BO000271A ITBO20010271A1 (en) | 2001-05-08 | 2001-05-08 | METHOD FOR THE TREATMENT AND PREVENTION OF DISORDERS OF THE CENTRAL NERVOUS SYSTEM ASSOCIATED WITH AN ALTERATION OF GL NEUROTRANSMISSION |
| ITBO20010271 | 2001-05-08 | ||
| PCT/US2002/014262 WO2002089734A2 (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 |
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| EP1435926A2 true EP1435926A2 (en) | 2004-07-14 |
| EP1435926A4 EP1435926A4 (en) | 2005-11-23 |
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| US20100048713A1 (en) * | 2006-01-06 | 2010-02-25 | Aarhus Universitet | Compounds acting on the serotonin transporter |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0815861A1 (en) * | 1996-06-28 | 1998-01-07 | F. Hoffmann-La Roche Ag | Sulphonamides and their use |
| WO2000012073A1 (en) * | 1998-08-28 | 2000-03-09 | Smithkline Beecham P.L.C. | Use of 5ht-6 antagonists |
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| FR2722502B1 (en) * | 1994-07-12 | 1996-08-23 | Adir | NOVEL BENZOTHIADIAZINE DERIVATIVE, ITS PREPARATION METHOD AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME |
| US6083947A (en) * | 1996-01-29 | 2000-07-04 | The Regents Of The University Of California | Method for treating sexual dysfunctions |
-
2001
- 2001-05-08 IT IT2001BO000271A patent/ITBO20010271A1/en unknown
-
2002
- 2002-05-07 WO PCT/US2002/014262 patent/WO2002089734A2/en not_active Application Discontinuation
- 2002-05-07 EP EP02769353A patent/EP1435926A4/en not_active Withdrawn
- 2002-05-07 AU AU2002308614A patent/AU2002308614A1/en not_active Abandoned
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0815861A1 (en) * | 1996-06-28 | 1998-01-07 | F. Hoffmann-La Roche Ag | Sulphonamides and their use |
| WO2000012073A1 (en) * | 1998-08-28 | 2000-03-09 | Smithkline Beecham P.L.C. | Use of 5ht-6 antagonists |
Non-Patent Citations (2)
| Title |
|---|
| D.J.HEALY ET ALL.: "Iontropic glutamate receptor modulation of 5-HT6 and 5-HT7 mRNA expression in rat brain" NEUROPSYCHOPHARMACOLOGY, vol. 21, no. 3, 1999, pages 341-351, XP002347588 * |
| See also references of WO02089734A2 * |
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| Publication number | Publication date |
|---|---|
| AU2002308614A1 (en) | 2002-11-18 |
| EP1435926A4 (en) | 2005-11-23 |
| ITBO20010271A1 (en) | 2002-11-08 |
| WO2002089734A3 (en) | 2003-03-06 |
| ITBO20010271A0 (en) | 2001-05-08 |
| WO2002089734A2 (en) | 2002-11-14 |
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