WO1999042456A2 - Novel compounds and their use as positive ampa receptor modulators - Google Patents
Novel compounds and their use as positive ampa receptor modulators Download PDFInfo
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- WO1999042456A2 WO1999042456A2 PCT/DK1999/000070 DK9900070W WO9942456A2 WO 1999042456 A2 WO1999042456 A2 WO 1999042456A2 DK 9900070 W DK9900070 W DK 9900070W WO 9942456 A2 WO9942456 A2 WO 9942456A2
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- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
- C07D239/88—Oxygen atoms
- C07D239/90—Oxygen atoms with acyclic radicals attached in position 2 or 3
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- C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
- C07D285/15—Six-membered rings
- C07D285/16—Thiadiazines; Hydrogenated thiadiazines
- C07D285/18—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines
- C07D285/20—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines condensed with carbocyclic rings or ring systems
- C07D285/22—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D285/24—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring with oxygen atoms directly attached to the ring sulfur atom
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
- C07D285/15—Six-membered rings
- C07D285/16—Thiadiazines; Hydrogenated thiadiazines
- C07D285/18—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines
- C07D285/20—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines condensed with carbocyclic rings or ring systems
- C07D285/22—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D285/24—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring with oxygen atoms directly attached to the ring sulfur atom
- C07D285/26—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring with oxygen atoms directly attached to the ring sulfur atom substituted in position 6 or 7 by sulfamoyl or substituted sulfamoyl radicals
- C07D285/28—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring with oxygen atoms directly attached to the ring sulfur atom substituted in position 6 or 7 by sulfamoyl or substituted sulfamoyl radicals with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached in position 3
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
Definitions
- This invention relates to novel compounds useful as modulators of the AMPA sensitive glutamate receptors, pharmaceutical compositions comprising such compounds and their use in therapy.
- L-Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system which activates several subtypes of ionotropic and metabotropic receptors.
- the ionotropic receptors can be divided into three subtypes, NMDA, AMPA and kainate receptors, based on structural and pharmacological differences.
- Impairment of glutamatergic neurotransmission has been implicated in the learning and memory loss observed in numerous neurological disorders such as e.g. Alzheimer's decease, senile dementia, stroke (McEntee and Crook, Psycopharmacology 111 :391 -401 (1993)). It is widely accepted that learning and memory is related to the induction of long-term potentiation (LTP) which is a stable increase in the synaptic strength following repetitive high frequency stimulations.
- LTP long-term potentiation
- Experimental studies have shown that increasing the synaptic response mediated by AMPA receptors enhances the induction of LTP (Arai and Lynch, Brain Research, 598:173-184 (1992)). For the reasons stated above, compounds that stimulates AMPA receptor response in the brain, may induce improvements in the intellectual behavior and performance.
- AMPA receptors Activation of AMPA receptors with L-glutamate or the selective agonist AMPA leads to a rapid receptor desensitization; i.e. the receptor channel fails to open despite the continued presence of agonist. It is therefore possible to obtain an increase of the synaptic strength by attenuating the AMPA receptor desensitization normally elicited by the endogenous neurotransmitter L-glutamate.
- the benzothiadiazide cyclothiazide is a more potent and efficacious modulator of AMPA receptor current in -vitro than aniracetam (Johansen et al, Mol. Pharmacol. 48:946-955 (1995)).
- the effect of cyclothiazide on the kinetic properties of AMPA receptor currents appear to be by a different mechanism to that of aniracetam (Partin et al., J. Neuroscience 16:6634-6647 (1996)).
- cyclothiazide has no therapeutic potential for AMPA receptor modulation as it can not cross the blood-brain-barrier following peripheral administration.
- the low potency of know compounds also meets with higher demands for a high solubility due to the higher doses used for administration.
- DE 1470316 describes a method for producing some benzothiadiazides for use as additives in galvanizing baths.
- WO 9812185 describes benzothiadiazines of different structure as the compounds of the present invention.
- Another object of the present invention is to provide a method of treating disorders or diseases of a mammal, including a human, responsive to AMPA receptor modulators which comprises administering to a mammal in need thereof a compound of the invention.
- a third object of the present invention is to provide novel pharmaceutical compositions for the treatment of disorders or diseases of mammals, including a human, responsive to AMPA modulators.
- the invention then, inter alia, comprises the following, alone or in combination:
- the bond represented by the broken line may be a single, a double bond or absent; and if the bond is absent, then the nitrogen is substituted with a hydrogen and R 2 ;
- Y represents -CH(R 4 )-, -N(R 4 )- or -N(R 4 )-CH 2 -
- R 2 represents hydrogen, alkyl, cycloalkyl, aryl, benzyl; CO-R 9 wherein
- R 9 represents alkyl, cycloalkyl, benzyl, aryl; or R 2 together with R 3 and together with the atoms to which they are attached, forms a 4- to 7-membered ring optionally substituted one or more times with substituents selected from halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio and optionally containing one or more heteroatoms and optionally containing carbonyl groups;
- R represents hydrogen, cycloalkyl, alkyl, cycloalkylalkyl, haloalkyl, hydroxyalkyl, cyanoalkyl, alkoxyalkyl, alkoxy, haloalkoxy, acyl, alkyl-NR 13 R 14 , alkyl-S-R 13 wherein
- R 13 and R 14 independently represents hydrogen, alkyl, cycloalkyl; or R 13 and R 14 together with the nitrogen to which they are attached forms a 3- to 8 membered heterocyclic ring structure;
- a carbocyclic 7- to 12- membered ring optionally substituted with halogen, alkyl, hydroxy or alkoxy; or
- a heterocyclic 3- to 8 membered ring optionally substituted with halogen, alkyl, hydroxy or alkoxy; and optionally the heterocyclic ring is fused to an aryl;
- Benzyl which is optionally substituted one or more times with substituents selected from the group consisting of halogen, cycloalkyl, alkyl, hydroxy, alkoxy, amino or thio, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkylthio, alkylamino;
- Aryl which is optionally substituted one or more times with substituents selected from the group consisting of halogen, cycloalkyl, alkyl, hydroxy, alkoxy, amino or thio, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkylthio, alkylamino; or R 3 together with R 2 or R 4 and together with the atoms to which they are attached, forms a 4- to 7- membered ring optionally substituted one or more times with substituents selected from halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio and optionally containing one or more heteroatoms and optionally containing carbonyl groups.
- R 4 represents hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl,
- R 10 represents hydrogen, cycloalkyl, alkyl, aryl or benzyl; or
- R 4 together with R and together with the atoms to which they are attached, forms a 4- to 7- membered ring optionally substituted one or more times with substituents selected from halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio and optionally containing one or more heteroatoms and optionally containing carbonyl groups.
- R represents hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl,
- R 11 and R 12 independently represents hydrogen, alkyl, cycloalkyl, benzyl, aryl, or
- R 11 and R 12 together with the nitrogen to which they are attached forms a heterocyclic 3- to 8 membered ring structure optionally substituted with halogen, alkyl, hydroxy, alkoxy, amino or thio, aryl, benzyl, SO 2 -alkyl, SO 2 -aryl, SO 2 -benzyl; and optionally the heterocyclic ring is fused to an aryl;
- R represents hydrogen, halogen, alkyl, cyano, cyanoalkyl, nitro, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, cyclohaloalkyl,
- aryl is optionally substituted one or more times with substituents selected from halogen, alkyl, cycloalkyl, hydroxy, alkoxy, amino, thio, CF 3 , OCF 3 , NO 2 , aryl;
- Aryl optionally substituted one or more times with substituents selected from the group consisting of alkyl, cycloalkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, alkoxyalkyl or amino;
- HET optionally substituted one or more times with substituents selected from the group consisting of alkyl, cycloalkyl, alkoxy, halogen, haloalkyl, haloalkoxy;
- R' and R" independently represents hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, benzyl; and R 15 and R 16 independently represents hydrogen, alkyl, cycloalkyl, benzyl, aryl, or
- R 15 and R 16 together with the nitrogen to which they are attached forms a heterocyclic 3- to 8 membered ring structure optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio, aryl, benzyl, SO 2 -alkyl, SO 2 -aryl, SO 2 -benzyl; and optionally the heterocyclic ring is fused to an aryl;
- HET optionally substituted one or more times with substituents selected from halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, thio, aryl, -S-alkyl, -S-aryl,
- Aryl optionally substituted one or more times with substituents selected from the group consisting of alkyl, alkenyl, alkynyl, hydroxy, alkoxy, hydroxyalkyl, halogen, haloalkyl, amino,
- NHCO-alkyl, nitro, OCF3, -SO 2 -NR 17 R 18 wherein R 17 and R 18 independently represents hydrogen, alkyl, cycloalkyl, benzyl, aryl, or R 17 and R 18 together with the nitrogen to which they are attached forms a heterocyclic 3- to 8 membered ring structure optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio, aryl, benzyl, SO 2 -alkyl, SO 2 -aryl, SO 2 - benzyl; and optionally the heterocyclic ring is fused to an aryl; or R 7 together with R 6 or together with R 8 forms a 5- to 7-membered ring having the one of the following structures -O-(CH 2 )n-O-; wherein n is 1 , 2 or 3; -SO 2 -NR-(CH 2 )n- wherein n is 1 or 2 or
- R 8 represents hydrogen, alkyl, alkoxy, hydroxyalkyl, halogen, haloalkyl, CN, cyanoalkyl, nitro, nitroalkyl;
- Aryl optionally substituted one or more times with substituents selected from the group consisting of halogen, CF 3 , OCF 3 , NO 2 , alkyl, cycloalkyl, alkoxy;
- HET optionally substituted one or more times with substituents selected from the group consisting of halogen, CF 3 , OCF 3 , NO 2 , alkyl, cycloalkyl, alkoxy;
- (alkyl)m-CO 2 -R 19 and m is 0 or 1 ; and R' and R" independently represents hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, benzyl; and
- R 19 and R 20 independently represents hydrogen, alkyl, cycloalkyl, benzyl, aryl, or R 19 and R 20 together with the nitrogen to which they are attached forms a heterocyclic 3- to 8 membered ring structure optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio, aryl, benzyl, SO 2 -alkyl, SO 2 -aryl, SO 2 -benzyl; and optionally the heterocyclic ring is fused to an aryl; provided that when the broken line in formula I represents a double bond and X represents SO 2 and Y represent NH and the compound is monosubstituted then it is not monosubstituted with R 3 representing OCH 3 , methyl, pentyl, t-butyl, aminophenyl, 2- phenylethylene, phenethyl, cyclopentyl, cyclopentenyl, cyclohex
- a pharmaceutical composition comprising an therapeutically effective amount of a compound as above together with pharmaceutically acceptable carriers or exipients;
- the bond represented by the broken line may be a single, a double bond or absent; and if the bond is absent, then the nitrogen is substituted with a hydrogen and R 2 ;
- R represents hydrogen, alkyl, cycloalkyl, aryl, benzyl; CO-R 9 wherein
- R -.9 represents alkyl, cycloalkyl, benzyl, aryl; or R 2 together with R 3 and together with the atoms to which they are attached, forms a 4- to 7-membered ring optionally substituted one or more times with substituents selected from halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio and optionally containing one or more heteroatoms and optionally containing carbonyl groups;
- R 3 represents hydrogen, cycloalkyl, alkyl, cycloalkylalkyl, haloalkyl, hydroxyalkyl, cyanoalkyl, alkoxyalkyl, alkoxy, haloalkoxy, acyl, alkyl-NR 13 R 14 , alkyl-S-R 13 wherein R 13 and R 14 independently represents hydrogen, alkyl, cycloalkyl; or R 13 and
- R 14 together with the nitrogen to which they are attached forms a 3- to 8 membered heterocyclic ring structure
- a carbocyclic 7- to 12- membered ring optionally substituted with halogen, alkyl, hydroxy or alkoxy; or
- a heterocyclic 3- to 8 membered ring optionally substituted with halogen, alkyl, hydroxy or alkoxy; and optionally the heterocyclic ring is fused to an aryl;
- Benzyl which is optionally substituted one or more times with substituents selected from the group consisting of halogen, cycloalkyl, alkyl, hydroxy, alkoxy, amino or thio, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkylthio, alkylamino;
- Aryl which is optionally substituted one or more times with substituents selected from the group consisting of halogen, cycloalkyl, alkyl, hydroxy, alkoxy, amino or thio, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkylthio, alkylamino; or
- R 3 together with R 2 or R 4 and together with the atoms to which they are attached, forms a 4- to 7- membered ring optionally substituted one or more times with substituents selected from halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio and optionally containing one or more heteroatoms and optionally containing carbonyl groups.
- R 4 represents hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, -CO-R 10 , or CO 2 R 10 wherein R 10 represents hydrogen, cycloalkyl, alkyl, aryl or benzyl; or
- R 4 together with R 3 and together with the atoms to which they are attached, forms a 4- to 7- membered ring optionally substituted one or more times with substituents selected from halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio and optionally containing one or more heteroatoms and optionally containing carbonyl groups.
- R 5 represents hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl,
- R 11 and R 12 independently represents hydrogen, alkyl, cycloalkyl, benzyl, aryl, or
- R 11 and R 12 together with the nitrogen to which they are attached forms a heterocyclic 3- to 8 membered ring structure optionally substituted with halogen, alkyl, hydroxy, alkoxy, amino or thio, aryl, benzyl, SO 2 -alkyl, SO 2 -aryl, SO 2 -benzyl; and optionally the heterocyclic ring is fused to an aryl;
- R 6 represents hydrogen, halogen, alkyl, cyano, cyanoalkyl, nitro, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, cyclohaloalkyl,
- Aryl optionally substituted one or more times with substituents selected from the group consisting of alkyl, cycloalkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, alkoxyalkyl or amino;
- HET optionally substituted one or more times with substituents selected from the group consisting of alkyl, cycloalkyl, alkoxy, halogen, haloalkyl, haloalkoxy;
- R' and R" independently represents hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, benzyl; and R 15 and R 16 independently represents hydrogen, alkyl, cycloalkyl, benzyl, aryl, or
- R 15 and R 16 together with the nitrogen to which they are attached forms a heterocyclic 3- to 8 membered ring structure optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio, aryl, benzyl,
- R 17 and R 18 independently represents hydrogen, alkyl, cycloalkyl, benzyl, aryl, or R 17 and R 18 together with the nitrogen to which they are attached forms a heterocyclic 3- to 8 membered ring structure optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio, aryl, benzyl, SO 2 -alkyl, SO 2 -aryl, SO 2 -benzyl; and optionally the heterocyclic ring is fused to an aryl;
- HET optionally substituted one or more times with substituents selected from halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, thio, aryl, -S-alkyl, -S-aryl, SO-alkyl, SO-aryl, SO 2 -alkyl, SO 2 -aryl, SO 2 NR 17 R 18 ;
- Aryl optionally substituted one or more times with substituents selected from the group consisting of alkyl, alkenyl, alkynyl, hydroxy, alkoxy, hydroxyalkyl, halogen, haloalkyl, amino, NHCO-alkyl, nitro, OCF3, -SO 2 -NR 17 R 18 , wherein R 17 and R 18 independently represents hydrogen, alkyl, cycloalkyl, benzyl, aryl, or R 17 and R 18 together with the nitrogen to which they are attached forms a heterocyclic 3- to 8 membered ring structure optional
- R 8 represents hydrogen, alkyl, alkoxy, hydroxyalkyl, halogen, haloalkyl, CN, cyanoalkyl, nitro, nitroalkyl;
- Aryl optionally substituted one or more times with substituents selected from the group consisting of halogen, CF 3 , OCF 3 , NO 2 , alkyl, cycloalkyl, alkoxy;
- HET optionally substituted one or more times with substituents selected from the group consisting of halogen, CF 3 , OCF 3 , NO 2 , alkyl, cycloalkyl, alkoxy;
- heterocyclic 3- to 8 membered ring structure optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio, aryl, benzyl, SO 2 -alkyl, SO 2 -aryl, SO 2 -benzyl; and optionally the heterocyclic ring is fused to an aryl; for the manufacture of a medicament for the treatment of disorders or diseases responsive to modulation of the AMPA receptor complex.
- a method for the treatment of disorders or diseases responsive to the modulation of the AMPA receptor complex wherein a therapeutically efficient amount of a compound represented by the general formula
- the bond represented by the broken line may be a single, a double bond or absent; and if the bond is absent, then the nitrogen is substituted with a hydrogen and R 2 ;
- R represents hydrogen, alkyl, cycloalkyl, aryl, benzyl; CO-R 9 wherein
- R 9 represents alkyl, cycloalkyl, benzyl, aryl; or R 2 together with R 3 and together with the atoms to which they are attached, forms a 4- to 7-membered ring optionally substituted one or more times with substituents selected from halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio and optionally containing one or more heteroatoms and optionally containing carbonyl groups;
- R represents hydrogen, cycloalkyl, alkyl, cycloalkylalkyl, haloalkyl, hydroxyalkyl, cyanoalkyl, alkoxyalkyl, alkoxy, haloalkoxy, acyl, alkyl-NR 13 R 14 , alkyl-S-R 13 wherein R 13 and R 14 independently represents hydrogen, alkyl, cycloalkyl; or R 13 and R 14 together with the nitrogen to which they are attached forms a 3- to 8 membered heterocyclic ring structure;
- a carbocyclic 7- to 12- membered ring optionally substituted with halogen, alkyl, hydroxy or alkoxy; or
- a heterocyclic 3- to 8 membered ring optionally substituted with halogen, alkyl, hydroxy or alkoxy; and optionally the heterocyclic ring is fused to an aryl;
- Benzyl which is optionally substituted one or more times with substituents selected from the group consisting of halogen, cycloalkyl, alkyl, hydroxy, alkoxy, amino or thio, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkylthio, alkylamino;
- Aryl which is optionally substituted one or more times with substituents selected from the group consisting of halogen, cycloalkyl, alkyl, hydroxy, alkoxy, amino or thio, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkylthio, alkylamino; or
- R 3 together with R 2 or R 4 and together with the atoms to which they are attached, forms a 4- to 7- membered ring optionally substituted one or more times with substituents selected from halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio and optionally containing one or more heteroatoms and optionally containing carbonyl groups.
- R represents hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl,
- R 10 represents hydrogen, cycloalkyl, alkyl, aryl or benzyl; or
- R 4 together with R 3 and together with the atoms to which they are attached, forms a 4- to 7- membered ring optionally substituted one or more times with substituents selected from halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio and optionally containing one or more heteroatoms and optionally containing carbonyl groups.
- R 11 and R 12 independently represents hydrogen, alkyl, cycloalkyl, benzyl, aryl, or
- R 11 and R 12 together with the nitrogen to which they are attached forms a heterocyclic 3- to 8 membered ring structure optionally substituted with halogen, alkyl, hydroxy, alkoxy, amino or thio, aryl, benzyl, SO 2 -alkyl, SO 2 -aryl,
- Aryl optionally substituted one or more times with substituents selected from the group consisting of alkyl, cycloalkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, alkoxyalkyl or amino;
- HET optionally substituted one or more times with substituents selected from the group consisting of alkyl, cycloalkyl, alkoxy, halogen, haloalkyl, haloalkoxy;
- R' and R" independently represents hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, benzyl; and R 15 and R 16 independently represents hydrogen, alkyl, cycloalkyl, benzyl, aryl, or
- R 15 and R 16 together with the nitrogen to which they are attached forms a heterocyclic 3- to 8 membered ring structure optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio, aryl, benzyl, SO 2 -alkyl, SO 2 -aryl, SO 2 -benzyl; and optionally the heterocyclic ring is fused to an aryl;
- R 17 and R 18 independently represents hydrogen, alkyl, cycloalkyl, benzyl, aryl, or R 17 and R 18 together with the nitrogen to which they are attached forms a heterocyclic 3- to 8 membered ring structure optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio, aryl, benzyl, SO 2 -alkyl, SO 2 -aryl, SO 2 -benzyl; and optionally the heterocyclic ring is fused to an aryl;
- HET optionally substituted one or more times with substituents selected from halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, thio, aryl, -S-alkyl, -S-aryl, SO-alkyl, SO-aryl, SO 2 -alkyl, SO 2 -aryl, SO 2 NR 17 R 18 ;
- Aryl optionally substituted one or more times with substituents selected from the group consisting of alkyl, alkenyl, alkynyl, hydroxy, alkoxy, hydroxyalkyl, halogen, haloalkyl, amino, NHCO-alkyl, nitro, OCF3, -SO 2 -NR 17 R 18 , wherein R 17 and R 18 independently represents hydrogen, alkyl, cycloalkyl, benzyl, aryl, or R 17 and R 18 together with the nitrogen to which they are attached forms a heterocyclic 3- to 8 membered ring structure optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio, aryl, benzyl, SO 2 -alkyl, SO 2 -aryl, SO 2 - benzyl; and optionally the heterocyclic ring is fused to an aryl; or R 7 together with R 6 or together with R 8 forms a 5- to
- R 8 represents hydrogen, alkyl, alkoxy, hydroxyalkyl, halogen, haloalkyl, CN, cyanoalkyl, nitro, nitroalkyl;
- Aryl optionally substituted one or more times with substituents selected from the group consisting of halogen, CF 3 , OCF 3 , NO 2 , alkyl, cycloalkyl, alkoxy;
- HET optionally substituted one or more times with substituents selected from the group consisting of halogen, CF 3 , OCF 3 , NO 2 , alkyl, cycloalkyl, alkoxy;
- R 19 and R 20 independently represents hydrogen, alkyl, cycloalkyl, benzyl, aryl, or R 19 and R 20 together with the nitrogen to which they are attached forms a heterocyclic 3- to 8 membered ring structure optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio, aryl, benzyl, SO 2 -alkyl, SO 2 -aryl, SO 2 -benzyl; and optionally the heterocyclic ring is fused to an aryl, is administered.
- the invention provides novel compounds of formula I as shown above.
- Preferred embodiments of the invention are compounds of formula I as above wherein R 2 represents hydrogen, alkyl, cycloalkyl, phenyl, benzyl; or R 2 together with R 3 and together with the atoms to which they are attached forms a 5- to 6-membered ring optionally substituted one or more times with substituents selected from halogen, alkyl, hydroxy, alkoxy, amino or thio; and optionally containing one or more heteroatoms and optionally containing carbonyl groups;
- R 3 represents hydrogen, cycloalkyl, cycloalkylalkyl, alkyl, haloalkyl, alkoxy, a carbocyclic 7- to 10- membered ring; a heterocyclic 5- to 6 membered ring; benzyl; aryl;
- R represents hydrogen, alkyl, or R 4 together with R 3 and together with the atoms to which they are attached, forms a 5- to 6- membered ring; optionally substituted one or more times with substituents selected from halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio and optionally containing one or more heteroatoms and optionally containing carbonyl groups.
- R 5 represents hydrogen, halogen, alkyl, alkenyl, alkynyl, phenyl,
- R 11 and R 12 independently represents hydrogen, alkyl, cycloalkyl, benzyl, aryl, or R 11 and R 12 together with the nitrogen to which they are attached forms a heterocyclic 5- to 6- membered ring structure;
- R represents hydrogen, Br, F, I, cycloalkyl, alkyl, alkoxy, alkoxyalkyl,
- Phenyl optionally substituted one or more times with substituents selected from the group consisting of alkyl, alkoxy;
- R' and R" independently represents hydrogen, alkyl, cycloalkyl, phenyl, benzyl;
- R 15 and R 16 independently represents hydrogen, alkyl, cycloalkyl, benzyl, aryl, or R 15 and R 16 together with the nitrogen to which they are attached forms a heterocyclic 3- to 8 membered ring structure optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio, phenyl, benzyl, SO 2 -alkyl, SO 2 -aryl, SO 2 -benzyl; and optionally the heterocyclic ring is fused to an aryl; represents hydrogen, Br, F, I, alkyl, cyano, cyanoalkyl, nitro, nitroalkyl, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, cyclohaloalkyl, -(alkyl)m-NR 17 R 18 , NHSO 2 -R 17 , -S- R 17 ; -
- R 17 and R 18 independently represents hydrogen, alkyl, cycloalkyl, benzyl, aryl, or R 17 and R 18 together with the nitrogen to which they are attached forms a heterocyclic 3- to 8 membered ring structure optionally substituted with alkyl, SO 2 -alkyl, SO 2 -aryl, SO 2 -benzyl; and optionally the heterocyclic ring is fused to an aryl; HET optionally substituted one or more times with substituents selected from halogen, alkyl, phenyl, SO 2 NR 17 R 18 ;
- Phenyl optionally substituted one or more times with substituents selected from the group consisting of alkyl, hydroxy, alkoxy , halogen, haloalkyl, amino, NHCO-alkyl, nitro, OCF3, - SO 2 -NR 17 R 18 wherein R 17 and R 18 independently represents hydrogen, alkyl, cycloalkyl, benzyl, aryl, or R 17 and R 18 together with the nitrogen to which they are attached forms a heterocyclic 3- to 8 membered ring structure optionally substituted with halogen, alkyl, SO 2 -alkyl, SO 2 -aryl, SO 2 -benzyl; and optionally the heterocyclic ring is fused to an aryl; or R 7 together with R 6 or together with R 8 forms a 5- to 7-membered ring having the one of the following structures -O-(CH 2 )n-O-; wherein n is 1 , 2 or 3; -SO 2 -NR-(CH
- R 8 represents hydrogen, alkyl, alkoxy, hydroxyalkyl, halogen, haloalkyl, CN, cyanoalkyl, nitro, nitroalkyl;
- Phenyl optionally substituted one or more times with substituents selected from the group consisting of alkyl, cycloalkyl, alkoxy;
- R 19 and R 20 independently represents hydrogen, alkyl, cycloalkyl, benzyl, aryl, or R 19 and R 20 together with the nitrogen to which they are attached forms a heterocyclic 3- to 8 membered ring structure optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio, phenyl, benzyl,
- R 7 or R 6 are chloro when R 2 , R 4 , R 5 , R 8 and the remaining of R 6 and R 7 are all hydrogen; and provided that R 3 can represent CH 3 only when R 5 is hydrogen or R 7 is not sulfamoyl; and provided that when X represents SO 2 and Y represents N and the broken line represents a double bond then neither of R 7 or R 6 are chloro when R 2 , R 4 , R 5 , R 8 and the remaining of R 6 and R 7 are all hydrogen; and provided that R 2 , R 4 , R 5 , R 6 , R 7 and R 8 are not all hydrogen; and provided that the compound is not disubstituted with R 3 is being CH 3 when R 7 is fluoro, bromo, iodo, CF 3 , CH 3 , NO 2 , SO 2 N(CH 3 ) 2 , or R 6 is bromo, CF 3
- a more preferred embodiment of the invention is a compound of formula I as above , wherein
- R 2 represents hydrogen, alkyl, cycloalkyl; or R 2 together with R 3 forms a 5- to 6-membered ring; optionally substituted one or more times with substituents selected from halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio and optionally containing one or more heteroatoms and optionally containing carbonyl groups;
- R 3 represents hydrogen, cycloalkyl, alkyl, haloalkyl, alkoxy, a carbocyclic 7- to 10- membered ring; a heterocyclic 5- to 6 membered ring; benzyl; aryl; or
- R 3 together with R 2 or R 4 forms a 5- to 6- membered ring; optionally substituted one or more times with substituents selected from halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio and optionally containing one or more heteroatoms and optionally containing carbonyl groups.
- R 4 represents hydrogen, alkyl, or R 4 together with R 3 and together with the atoms to which they are attached, forms a 5- to 6- membered ring optionally substituted one or more times with substituents selected from halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio and optionally containing one or more heteroatoms and optionally containing carbonyl groups.
- R 5 represents hydrogen, halogen, alkyl, alkenyl, alkynyl, phenyl, -SO 2 -NR 11 R 12 wherein
- R 11 and R 12 independently represents hydrogen, alkyl, cycloalkyl, benzyl, aryl, or R 11 and R 12 together with the nitrogen to which they are attached forms a heterocyclic 3- to 8 membered ring structure;
- R 6 represents hydrogen, halogen, cycloalkyl, alkyl, alkoxy, alkoxyalkyl,
- Aryl optionally substituted one or more times with substituents selected from the group consisting of alkyl, alkoxy;
- R' and R" independently represents hydrogen, alkyl, cycloalkyl, phenyl, benzyl;
- R 15 and R 16 independently represents hydrogen, alkyl, cycloalkyl, benzyl, aryl, or R 15 and R 16 together with the nitrogen to which they are attached forms a heterocyclic 3- to 8 membered ring structure optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio, phenyl, benzyl, SO 2 -alkyl, SO 2 -aryl, SO 2 -benzyl; and optionally the heterocyclic ring is fused to an aryl;
- R 7 represents hydrogen, halogen, alkyl, cyano, cyanoalkyl, nitro, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, cyclohaloalkyl, -(alkyl)m-NR 17 R 18 , NHSO 2 -R 17 ,
- R' and R" independently represents hydrogen, alkyl, cycloalkyl, phenyl, benzyl; and R 17 and R 18 independently represents hydrogen, alkyl, cycloalkyl, benzyl, aryl, or R 17 and R 18 together with the nitrogen to which they are attached forms a heterocyclic 3- to 8 membered ring structure optionally substituted with alkyl, SO 2 -alkyl, SO 2 -aryl, SO 2 -benzyl; and optionally the heterocyclic ring is fused to an aryl;
- HET optionally substituted one or more times with substituents selected from halogen, alkyl, phenyl, SO 2 NR 17 R 18 ;
- Phenyl optionally substituted one or more times with substituents selected from the group consisting of alkyl, hydroxy, alkoxy , halogen, haloalkyl, amino, NHCO-alkyl, nitro, OCF3, - SO 2 -NR 17 R 18 wherein R 17 and R 18 independently represents hydrogen, alkyl, cycloalkyl, benzyl, aryl, or R 17 and R 18 together with the nitrogen to which they are attached forms a heterocyclic 3- to 8 membered ring structure optionally substituted with halogen, alkyl, SO 2 -alkyl, SO 2 -aryl, SO 2 -benzyl; and optionally the heterocyclic ring is fused to an aryl; or R 7 together with R 6 or together with R 8 forms a 5- to 7-membered ring having the one of the following structures
- R 8 represents hydrogen, alkyl, alkoxy, hydroxyalkyl, halogen, haloalkyl, CN, cyanoalkyl, nitro, nitroalkyl;
- Phenyl optionally substituted one or more times with substituents selected from the group consisting of alkyl, cycloalkyl, alkoxy;
- R' and R" independently represents hydrogen, alkyl, cycloalkyl, phenyl, benzyl;
- R 19 and R 20 independently represents hydrogen, alkyl, cycloalkyl, benzyl, aryl, or R 19 and R 20 together with the nitrogen to which they are attached forms a heterocyclic 3- to 8 membered ring structure optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio, phenyl, benzyl, SO 2 -alkyl, SO 2 -aryl, SO 2 -benzyl; and optionally the heterocyclic ring is fused to an aryl;
- An especially preferred embodiments is a compounds of formula I as above wherein
- R 2 represents H;
- R 3 represents cycloalkyl, a carbocyclic 7- to 10- membered ring; a heterocyclic 5- to 6 membered ring;
- R 4 represents H;
- R 5 represents H;
- R 6 represents hydrogen, alkyl or halogen
- R 7 represents cyanoalkyl, nitroalkyl, haloalkyl
- R 17 and R 18 independently represents hydrogen, alkyl, cycloalkyl, benzyl, aryl, or R 17 and R 18 together with the nitrogen to which they are attached forms a heterocyclic 3- to 8 membered ring structure optionally substituted with alkyl, SO 2 -alkyl, SO 2 -aryl, SO 2 -benzyl; and optionally the heterocyclic ring is fused to an aryl; or
- R 7 together with R 6 or together with R 8 forms a 5- to 7-membered ring having the one of the following structures
- R 8 represents alkyl, halogen, cyanoalkyl, nitroalkyl, haloalkyl,
- R' and R" independently represents hydrogen, alkyl, cycloalkyl, phenyl, benzyl;
- R 17 and R 18 independently represents hydrogen, alkyl, cycloalkyl, benzyl, aryl, or R 17 and R 18 together with the nitrogen to which they are attached forms a heterocyclic 3- to 8 membered ring structure optionally substituted with alkyl,
- R 3 represents hydrogen, cyclopropyl, cyclopentyl, cyclohexyl, methyl, ethyl, propyl, isopropyl, CF 3 , ethoxy, norbornene, norbornane, adamantane, benzyl; phenyl; or
- R 3 together with R 2 or R 4 and together with the atoms to which they are attached forms a
- R 4 represents hydrogen, methyl, ethyl; or R 4 together with R 3 and together with the atoms to which they are attached, forms a 5-membered ring;
- R 5 represents hydrogen, chloro, bromo, methyl, phenyl, -SO 2 NH 2 ;
- another embodiment of the invention is wherein
- R 6 represents hydrogen, 2-methoxyphenyl, 2-pyridyl, 3-pyridyl, methyl, methoxy, chloro or bromo;
- R 8 represents hydrogen, methyl, hydroxymethyl, 2-methoxyphenyl, 3-methoxyphenyl, 2-pyridyl, methoxy;
- R 8 represents hydrogen, methyl, hydroxymethyl, 2-methoxyphenyl, 3-methoxyphenyl, 2-pyridyl, methoxy;
- R 3 represents cyclohexyl, cyclopentyl, norbornene, norbomane, adamantane, phenyl, ethoxy; and R 4 represents hydrogen or CH 3 ; and
- R 5 represents hydrogen, CH 3 , phenyl, sulfamoyl, chloro, bromo, and
- R 6 represents hydrogen, CH 3 , 2-methoxyphenyl, methoxy, chloro, bromo, 2-pyridyl, 3- pyridyl; and
- R 7 represents hydrogen, chloro, bromo, methyl, 1 -hydroxyethyl, acetyl,
- Another especially preferred embodiment of the invention is a compounds of formula I as above wherein X is SO 2 and Y is N and the broken line represents a double bond and R 3 represents CH 3 or CF 3 or R 3 together with R 4 and together with the atoms to which and R 4 , R 6 and R 6 are all hydrogen; and R 5 is hydrogen or halogen; and R 7 is N-methylsulfamoyl, N,N-dimethylsulfamoyl, N-cyclohexylsulfamoyl, tetrahydropyridyl-sulfonyl; SO 2 OH, sulfamoyl;
- R 3 represents hydrogen, CH 3 , CF 3 , cyclohexyl, norbornene, phenyl, ethyl; and R 7 represents hydrogen, N,N-dimethylsulfamoyl, N-cyclohexylsulfamoyl, tetrahydropyridyl- sulfonyl, morphoiino-sulfonyl sulfamoyl, bromo; and R 5 represents hydrogen or bromo; and R 4 , R 6 and R 8 all represent hydrogen;
- Another especially preferred embodiment of the invention is a compounds of formula I as above wherein X represents CH 2 and Y is N; and R 3 represents cyclohexyl or norbornene; and R 5 represents hydrogen or bromo; and
- R 7 represents bromo or sulfamoyl; and R 2 , R 4 , R 6 and R 8 all represent hydrogen;
- Another especially preferred embodiment of the invention is a compounds of formula I as above wherein X represents SO 2 and Y represents NH; and the broken line is absent and R 2 ,
- R 4 , R 5 and R 8 all represent hydrogen
- R 3 represents cyclohexyl, methyl or hydrogen; and R 7 represents N,N-dimethylsulfamoyl, tetrahydropyridyl-sulfonyl, bromo; and R 6 represents bromo or hydrogen;
- Another especially preferred embodiment of the invention is a compounds of formula I as above wherein X is SO 2 and N is -NHCH 2 -; and R 3 represents 3-methylbut-2-yl, phenyl or cyclohexyl; and R 7 represents 1-piperidino-sulfonyl.
- the most preferred embodiment of the invention are compounds of formula I as above wherein the compounds are the following:
- the chemical compound of the invention may be provided in any form suitable for the intended administration. Suitable forms include pharmaceutically (i.e. physiologically) acceptable salts, and pre- or prodrug forms of the chemical compound of the invention.
- Examples of pharmaceutically acceptable addition salts include, without limitation, the non-toxic inorganic and organic acid addition salts such as the acetate derived from acetic acid, the aconate derived from aconitic acid, the ascorbate derived from ascorbic acid, the benzenesulfonate derived from benzensulfonic acid, the benzoate derived from benzoic acid, the cinnamate derived from cinnamic acid, the citrate derived from citric acid, the embonate derived from embonic acid, the enantate derived from enanthic acid, the formate derived from formic acid, the fumarate derived from fumaric acid, the glutamate derived from glutamic acid, the glycolate derived from glycolic acid, the hydrochloride derived from hydrochloric acid, the hydrobromide derived from hydrobromic acid, the lactate derived from lactic acid, the maleate derived from maleic acid, the malonate derived from mal
- Such salts may be formed by procedures well known and described in the art.
- Other acids such as oxalic acid, which may not be considered pharmaceutically acceptable, may be useful in the preparation of salts useful as intermediates in obtaining a chemical compound of the invention and its pharmaceutically acceptable acid addition salt.
- Metal salts of a chemical compound of the invention includes alkali metal salts, such as the sodium salt of a chemical compound of the invention containing a carboxy group.
- the chemical compound of the invention may be provided in dissoluble or indissoluble forms together with a pharmaceutically acceptable solvents such as water, ethanol, and the like.
- Dissoluble forms may also include hydrated forms such as the monohydrate, the dihydrate, the hemihydrate, the trihydrate, the tetrahydrate, and the like. In general, the dissoluble forms are considered equivalent to indissoluble forms for the purposes of this invention.
- Halogen is fluorine, chlorine, bromine, or iodine.
- Alkyl means a straight chain or branched chain of from one to six carbon atoms or cyclic alkyl of from three to seven carbon atoms, including but not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl; methyl, ethyl, propyl and isopropyl are preferred groups.
- Haloalkyl means alkyl as above substituted one or more times with halogen as defined above. Preferred embodiments are CF 3 , C 2 F 5 , CH 2 CI, CHCI 2 , -CHFCH 2 F, -CHCICH 2 CI;
- Cycloalkyl means cyclic alkyl of from three to seven carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl.
- Cycloalkylalkyl means cyclic alkyl as above and alkyl as above wherein the alkyl can be regarded as a substituent on the cycloalkyl and vice versa .
- Preferred groups are C 3-6 - cycloalkyl and C ⁇ . 4 -alkyl such as -(CH 2 )-cyclopropyl, -cyclopropyl-(C ⁇ .
- Halocycloalkyl means cyclic alkyl as above which is substituted with one or more halogen as above, including but not limited to chlorocyclopropyl, fluorocyclopropyl, iodocyclopropyl, dichlorocyclopropyl, difluorocyclopropyl, chlorocyclobutyl, fluorocyclobutyl, chlorocyclopentyl
- Preferred embodiments are mono- and di-substituted cycloalkyl of 3 to 6 carbons, such as dichlorocyclopropyl, difluorocyclopropyl, chlorocyclohexyl, fluorocyclohexyl, iodocyclohexyl, chlorocyclopentyl, fluorocyclopentyl.
- Alkenyl means a straight chain or branched chain of from two to six carbon atoms containing one double bond, including but not limited to ethenyl, 1 -propenyl, 2-propenyl, 1 -butenyl, 2- butenyl, and 3-butenyl.
- Alkynyl means a straight chain or branched chain of from two to six carbon atoms containing one triple bond, including but not limited to ethynyl, 1 -propynyl, 2-propynyl, 1 -butynyl, 2-butynyl, and 3-butynyl.
- Alkoxy is O-alkyl, wherein alkyl is as defined above.
- Alkoxyalkyl is -alkyl-O-alkyl, wherein alkyl is as defined above.
- Hydroxyalkyl is alkyl as defined above substituted with OH;
- Amino is NH 2 or NH-alkyl or N-(alkyl) 2 , wherein alkyl is as defined above.
- Alkylamino is alkyl as defined above which is substituted with amino as defined above.
- Preferred embodiments are -CH 2 -N(alkyl) 2 , -CH-N(alkyl) 2 CH 3 , -CH 2 CH 2 N(alkyl) 2 , -CH 2 -NH 2 , - CH-(NH 2 )-CH 3 , -CH 2 CH 2 NH 2 ;
- Cyano is CN
- Cyanoalkyl is alkyl as defined above substituted with CN;
- Nitro is -NO 2 ;
- Nitroalkyl is alkyl as defined above subsituted with nitro as defined above;
- Thio is SH or S-alkyl, wherein alkyl is as defined above;
- Alkylthio is alkyl as above substituted with a thio group which is as defined above.
- Acylamino is acyl-NH- wherein acyl is as defined above.
- Aryl is aromatic carbocycles such as phenyl or biphenyl and fused carbocycles such as naphtyl;
- HET is an 5- to 6-membered cyclic heteroaryl and includes for example, oxazol-2-yl, oxazol- 4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5- yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, 1 ,2,4-oxadiazol-3-yl, 1 ,2,4-oxadiazol-5-yl, 1 ,2,4-thiadiazol-3-yl, 1 ,2,4-thiadiazol-5-yl, 1 ,2,5-oxadiazol-3-yl, 1 ,2,5-oxadiazol-4-yl, 1 ,2,5-thiadiazol-3-yl, 1 ,2,5-thiadiazol-4-yl
- a carbocyclic 7- to 12- membered ring structure includes mono- bi- and tricyclic structures. Preferred embodiments are 7- to 10 membered ring structures such as
- a heterocyclic 3- to 8 membered ring structure includes a partly or completely saturated heterocyclic ringstructure such as aziridine, pyrrolidine, piperidine, piperazine, homopiperidine, homopiperazine, azacyclooctane, 1 ,3-diazacyclooctane, 1 ,4- diazacyclooctane, tetrahydrofuran, tetrahydrothiophene, morpholine, tetrahydropyridine, and compounds such as
- the preferred embodiments are 5- to 6-membered rings containing at least one nitrogen such as pyrrolidine, piperidine, piperazine, morpholine, tetrahydropyridine.
- the described 4- to 7-membered rings fused to the ring structure of formula I, formed between the substituents R 2 and R 3 or R 3 and R 4 or R 5 and R 6 or R 6 and R 7 or R 7 and R 8 are carbocyclic rings optionally containing a heteroatom and optionally containing a carbonyl group.
- Preferred rings are 5- and 6-membered carbocyclic rings;
- the compounds of this invention may exist in unsolvated as well as in solvated forms with pharmaceutically acceptable solvents such as water, ethanol and the like.
- pharmaceutically acceptable solvents such as water, ethanol and the like.
- the solvated forms are considered equivalent to the unsolvated forms for the purposes of this invention.
- the chemical compounds of the present invention may exist in (+) and (-) forms as well as in racemic forms.
- the racemates of these isomers and the individual isomers themselves are within the scope of the present invention.
- Racemic forms can be resolved into the optical antipodes by known methods and techniques.
- One way of separating the diastereomeric salts is by use of an optically active acid, and liberating the optically active amine compound by treatment with a base.
- Another method for resolving racemates into the optical antipodes is based upon chromatography on an optical active matrix.
- Racemic compounds of the present invention can thus be resolved into their optical antipodes, e.g., by fractional crystallisation of d- or I- (tartrates, mandelates, or camphorsulphonate) salts for example.
- the chemical compounds of the present invention may also be resolved by the formation of diastereomeric amides by reaction of the chemical compounds of the present invention with an optically active activated carboxylic acid such as that derived from (+) or (-) phenylalanine, (+) or (-) phenylglycine, (+) or (-) camphanic acid or by the formation of diastereomeric carbamates by reaction of the chemical compound of the present invention with an optically active chloroformate or the like. Additional methods for the resolving the optical isomers are known in the art.
- a chemical compound of the present invention may thus be the syn- or the anti-form (Z- and E-form), or it may be a mixture hereof.
- a compound of the invention includes endo- and exo-forms and tautomers where possible.
- An aspect of the invention provides novel pharmaceutical compositions comprising a therapeutically effective amount of the chemical compound of the invention and the use of compounds of the invention for the manufacture of a medicament for the treatment of specific diseases or disorders;
- a chemical compound of the invention for use in therapy may be administered in the form of the raw chemical compound, it is preferred to introduce the active ingredient, optionally in the form of a physiologically acceptable salt, in a pharmaceutical composition together with one or more adjuvants, excipients, carriers, buffers, diluents, and/or other customary pharmaceutical auxiliaries.
- the invention provides pharmaceutical compositions comprising the chemical compound of the invention, or a pharmaceutically acceptable salt or derivative thereof, together with one or more pharmaceutically acceptable carriers therefor, and, optionally, other therapeutic and/or prophylactic ingredients.
- the carrier(s) must be
- compositions of the invention may be those suitable for oral, rectal, bronchial, nasal, topical (including buccal and sub-lingual), transdermal, vaginal or parenteral (including cutaneous, subcutaneous, intramuscular, and intravenous injection) administration, or those in a form suitable for administration by inhalation or insufflation.
- compositions and unit dosages thereof may thus be placed into the form of pharmaceutical compositions and unit dosages thereof.
- forms include solids, and in particular tablets, filled capsules, powder and pellet forms, and liquids, in particular aqueous or non-aqueous solutions, suspensions, emulsions, elixirs, and capsules filled with the same, all for oral use, suppositories for rectal administration, and sterile injectable solutions for parenteral use.
- Such pharmaceutical compositions and unit dosage forms thereof may comprise conventional ingredients in conventional proportions, with or without additional active compounds or principles, and such unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed.
- the chemical compound of the present invention can be administered in a wide variety of oral and parenteral dosage forms. It will be obvious to those skilled in the art that the following dosage forms may comprise, as the active component, either a chemical compound of the invention or a pharmaceutically acceptable salt of a chemical compound of the invention.
- pharmaceutically acceptable carriers can be either solid or liquid.
- Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules.
- a solid carrier can be one or more substances which may also act as diluents, flavouring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
- the carrier is a finely divided solid which is in a mixture with the finely divided active component.
- the active component is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired.
- the powders and tablets preferably contain from five or ten to about seventy percent of the active compound.
- Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like.
- the term "preparation" is intended to include the formulation of the active compound with encapsulating material as carrier providing a capsule in which the active component, with or without carriers, is surrounded by a carrier, which is thus in association with it.
- cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid forms suitable for oral administration.
- a low melting wax such as a mixture of fatty acid glyceride or cocoa butter
- the active component is dispersed homogeneously therein, as by stirring.
- the molten homogenous mixture is then poured into convenient sized moulds, allowed to cool, and thereby to solidify.
- compositions suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
- Liquid preparations include solutions, suspensions, and emulsions, for example, water or water-propylene glycol solutions.
- parenteral injection liquid preparations can be formulated as solutions in aqueous polyethylene glycol solution.
- the chemical compound according to the present invention may thus be formulated for parenteral administration (e.g. by injection, for example bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion or in multi-dose containers with an added preservative.
- the compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulation agents such as suspending, stabilising and/or dispersing agents.
- the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization from solution, for constitution with a suitable vehicle, e.g. sterile, pyrogen-free water, before use.
- Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavours, stabilising and thickening agents, as desired.
- Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, or other well known suspending agents. Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active component, colorants, flavours, stabilisers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
- the chemical compound according to the invention may be formulated as ointments, creams or lotions, or as a transdermal patch.
- Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents.
- Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilising agents, dispersing agents, suspending agents, thickening agents, or colouring agents.
- compositions suitable for topical administration in the mouth include lozenges comprising the active agent in a flavoured base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerine or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
- Solutions or suspensions are applied directly to the nasal cavity by conventional means, for example with a dropper, pipette or spray.
- the compositions may be provided in single or multi-dose form. In the latter case of a dropper or pipette, this may be achieved by the patient administering an appropriate, predetermined volume of the solution or suspension.
- Administration to the respiratory tract may also be achieved by means of an aerosol formulation in which the active ingredient is provided in a pressurised pack with a suitable propellant such as a chlorofluorocarbon (CFC) for example dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, carbon dioxide, or other suitable gas.
- a suitable propellant such as a chlorofluorocarbon (CFC) for example dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, carbon dioxide, or other suitable gas.
- CFC chlorofluorocarbon
- the aerosol may conveniently also contain a surfactant such as lecithin.
- the dose of drug may be controlled by provision of a metered valve.
- the active ingredients may be provided in the form of a dry powder, for example a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP).
- a powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP).
- PVP polyvinylpyrrolidone
- the powder carrier will form a gel in the nasal cavity.
- the powder composition may be presented in unit dose form for example in capsules or cartridges of, e.g., gelatin, or blister packs from which the powder may be administered by means of an inhaler.
- the compound In compositions intended for administration to the respiratory tract, including intranasal compositions, the compound will generally have a small particle size for example of the order of 5 microns or less. Such a particle size may be obtained by means known in the art, for example by micronization.
- compositions adapted to give sustained release of the active ingredient may be employed.
- the pharmaceutical preparations are preferably in unit dosage forms.
- the preparation is subdivided into unit doses containing appropriate quantities of the active component.
- the unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packaged tablets, capsules, and powders in vials or ampoules.
- the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
- Tablets or capsules for oral administration and liquids for intravenous administration and continuous infusion are preferred compositions.
- the dose administered must of course be carefully adjusted to the age, weight and condition of the individual being treated, as well as the route of administration, dosage form and regimen, and the result desired.
- the active ingredient may be administered in one or several doses per day. A satisfactory result can, in certain instances, be obtained at a dosage as low as 0.1 ⁇ g/kg i.v. and 1 ⁇ g/kg p.o.
- the upper limit of the dosage range is presently considered to be about 10 mg/kg i.v. and 100 mg/kg p.o.
- Preferred ranges are from about 0.1 ⁇ g/kg to about 10 mg/kg/day i.v., and from about 1 ⁇ g/kg to about 100 mg/kg/day p.o.
- the compounds of the present invention are AMPA receptor stimulators and therefore useful for the treatment of a range of disorders or diseases responsive to AMPA receptor modulators.
- the disease are responsive to positive modulation of the AMPA receptor.
- the compounds may be used in the treatment, prevention, profylaxis or alleviation of a disease, disorder or condition of the central nervous system as for example: neurodegenerative disorders, cognitive or memory dysfunction, memory and learning disorders, attention disorder, learning and memory disorders resulting from ageing, trauma, stroke, epilepsy; Alzheimer's disease, depression, schizophrenia, memory loss, AIDS-dementia, senile dementia, learning deficit, cognition deficit, sexual dysfunctions, psychotic disorder, sexual dysfunction, intellectual impairment disorders, schizophrenia, depression or autism, attention deficit, or a disorder or disease resulting from neurotoxic agents, alcohol intoxication, substance abuse, cardiac bypass surgery or cerebral ischemia; Suitable dosage range are 0.1-500 milligrams daily, and especially 10-70 milligrams daily, administered once or twice a day, dependent as usual upon the exact mode
- I. p. means intraperetoneaily, which is a well known route of administration.
- P.o. means peroral, which is a well known route of administration.
- the invention then comprises the following alone or in combination:
- the disease is memory and learning disorders, psychotic disorder, sexual dysfunction, intellectual impairment disorders, schizophrenia, depression or autism; Alzheimer's disease, learning deficit, attention deficit, memory loss or senile dementia; or a disorder or disease resulting from trauma, stroke, epilepsy, Alzheimer's disease, neurotoxic agents, aging, neurodegenerative disorder, alcohol intoxication, substance abuse, cardiac bypass surgery or cerebral ischemia;
- GLU L-glutamate
- NMDA N-methyl-D-aspartate
- kainate receptors GLU receptor subtypes sensitive to quisqualate and kainate as a group are often referred to as non-NMDA receptors.
- AMPA ⁇ -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
- 3 H-kainate for kainate receptors
- AMPA has been known for several years to be a potent and selective agonist at the traditionally named quisqualate receptors. Activation of quisqualate receptors by AMPA is associated with Na + influx and K + efflux leading to depolarization.
- the non-NMDA receptors have recently been reclassified to include the quisqualate activated metabotropic receptor type, linked to the inositol triphosphate and diacylglycerate metabolism.
- AMPA does not interact with the metabotropic quisqualate receptor but only the ionotropic quisqualate receptor. Selective activation of the metabotropic type has been claimed for trans-ACPD.
- the potent and competitive non-NMDA receptor antagonists CNQX and NBQX have been described, and CNQX have been reported not to block the effect of quisqualate at the metabotropic receptor subtype.
- 3 H-AMPA is a selective radioligand for labelling the ionotropic quisqualate (AMPA) receptors.
- Cerebral cortex from male Wistar rats (150-200 g) is homogenized for 5-10 sec in 20 ml Tris-HCI (30 mM, pH 7.4) using an Ultra-Turrax homogenizer. The suspension is centrifuged at 27,000 x g for 15 min and the pellet is washed three times with buffer (centrifuged at 27,000 x g for 10 min). The washed pellet is homogenized in 20 ml of buffer and incubated on a water bath (37°C) for 30 min to remove endogenous glutamate and then centrifuged for 10 min at 27,000 x g. The pellet is then homogenized in buffer and centrifuged at for 10 min at 27,000 x g. The final pellet is resuspended in 30 ml buffer and the preparation is frozen and stored at -20°C.
- ASSAY ASSAY
- the membrane preparation is thawed and centrifuged at 2°C for 10 min at 27,000 x g for 10 min.
- the pellet is washed twice with 20 ml 30 mM Tris-HCI containing 2.5 mM CaCI 2 , pH 7.4 using an Ultra-Turrax homogenizer and centrifuged for 10 min at 27,000 x g.
- the final pellet is resuspended in 30 mM Tris-HCI containing 2.5 mM CaCI 2 and 100 mM KSCN, pH 7.4 (100 ml per g of original tissue) and used for binding assays.
- the test value will be given as the IC 50 (the concentration ( ⁇ M) of the test substance which inhibits the specific binding of 3 H-AMPA by 50%)
- Neurons which express receptors for excitatory amino acids can be depolarized by such compounds and this depolarization will ultimately lead to a release of transmitter substance from the neurons.
- Cultured neurons obtained from 16-day-old mouse embryo cortex are mainly GABAergic and express all types of excitatory amino acid receptors. This means that they can be stimulated by high potassium (55 mM) or by the excitatory amino acids NMDA (20 ⁇ M), AMPA (5 ⁇ M) and kainate (5 ⁇ M) to release their neurotransmitter GABA.
- 3 H-GABA may be used to label the GABA transmitter pool in the neurons and the release of 3 H-GABA from the neurons may be used as a simple functional model for studies of the effects of excitatory amino acid receptor agonists, antagonists, and modulators.
- Cerebral cortices of 15-16 day-old NMRI mouse embryos are chopped in 0.4 x 0.4 mm cubes and the tissue is dissociated by mild trypsinization (0.1% (wt/vol) trypsin, 37°C, 10 min). Subsequently the cell suspension (3 mill/ml) is inoculated into poly-L-lysine-coated 30 mm Petri dishes (3 ml/dish) containing a slightly modified DMEM (24.5 mM KCI) supplemented with p-aminobenzoate (7 ⁇ M), insulin (100 mU/L) and 10% (vol/vol) horse serum.
- DMEM slightly modified DMEM
- the preloading medium is removed and the Petri dishes are placed in a superfusion system consisting of a peristaltic pump continuously delivering thermostated 37°C superfusion medium (HEPES buffered saline (HBS): 10 mM HEPES, 135 mM NaCI, 5 mM KCI, 0.6 mM MgSO 4 , 1.0 mM CaCI 2 and 6 mM D-glucose; pH 7.4) from a reservoir to the top of the slightly tilted Petri dish.
- HBS thermostated 37°C superfusion medium
- the medium is continuously collected from the lower part of the dish and delivered to a fraction collector.
- the cells are superfused with HBS for 30 min (flow rate 2 ml/min). Then cells are stimulated for 30 sec every 4 min by changing the superfusion medium from HBS to a corresponding medium containing 5 ⁇ M AMPA in the absence or presence of modulators.
- Test substances are dissolved in 50% DMSO, 48% ethanol.
- the final DMSO and ethanol concentration in the assay must not exceed 0.1 %
- the potentiation of the AMPA response by a test substance is expressed relative to the potentiation of the AMPA response induced by cyclothiazide (30 ⁇ M).
- Mouse neocortical neurons were cultured essentially as described by Drejer et al. (1987). Briefly, the forebrains from embryonic (E17) NMRI mice were removed under sterile conditions. The tissue was chopped in 0.4 mm cubes and the triturated with trypsin (12.5 ⁇ g/ml) and DNAse (2.5 ⁇ g/ml), 15 min, 37 °C. The cells were suspended at a concentration of
- the cells were kept in culture for 7-14 days at 37 °C (5% CO 2 /95% O 2 ) before experiments were carried out.
- Electronics, programs and data acquisition The amplifier used was the EPC-9 (HEKA- electronics, Lambrect, Germany) run by a Power Macintosh G3 computer via an ITC-16 interface. Experimental conditions were set with the Pulse-software accompanying the amplifier. Data were low pass filtered and sampled directly to hard-disk at a rate of 3 times the cut-off frequency.
- Pipettes and electrodes Pipettes were pulled from borosilicate glass (Modulohm, Copenhagen, Denmark) using a horizontal electrode puller (Zeitz-lnstrumente, Augsburg, Germany).
- the pipette resistances were 1 .7 - 2.4 MW in the salt solutions used in these experiments.
- the pipette electrode was a chloridized silver wire, and the reference was a silverchloride pellet electrode (In Vivo Metric, Healdsburg, USA) fixed to the experimental chamber. The electrodes were zeroed with the open pipette in the bath just prior to sealing.
- Experimental procedure Coverslips were transferred to a 15 ml experimental chamber mounted on the stage of an inverted microscope (IMT-2, Olympus) supplied with Nomarski optics. The neurons were continuously superfused with extracellular saline at a rate of 2,5 ml/min. After giga-seal formation (1 -5 GW, success-rate « 90 %) the whole cell configuration was attained by suction.
- the cells were held at a holding voltage of -60 mV and at the start of each experiment the current was continuously measured for at least 30 sec to ensure a stable leak current.
- AMPA-containing solutions were delivered to the chamber through a custom-made gravity- driven flowpipe, the tip of which was placed approximately 50 ⁇ m from the cell. Application was triggered when the tubing connected to the flow pipe was compressed by a valve controlled by the Pulse-software. AMPA (30 ⁇ M) was applied for 1 sec every 45 sec. After obtainment of responses of a repeatable amplitude the compound to be tested was included in both the chamber and in the AMPA-containing solution. The compound was present until responses of a new repeatable was obtained.
- the sample interval in all experiments was 310 ⁇ sec.
- Horse serum, N2 supplement and culture media were purchased from Life Technologies
- AMPA (a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) was synthesized at NeuroSearch A/S. Tetrodotoxin was purchased from Alomone Labs, Jerusalem, Israel and
- the compounds 56 (Fig. 3), 63 (Fig. 4), 111(Fig. 6), 114(Fig. 7) and 115 (Fig. 5) all potentiated the current induced by application of 30 ⁇ M AMPA.
- An example for each compound is shown below. It is seen that the potentiation in every case is reversible, even though the effect of 56 and 63 persits for several minutes after wash out of the compounds.
- the time between AMPA stimulations was 45 sec. Scalebars: 63: 200 pA/2 sec; 56: 500 pA/5 sec; 115: 50 pA/2 sec; 111 : 400 pA/3 sec; 114: 40 pA/ 3 sec.
- concentration of the compounds was 3 ⁇ M (56, 63 and 114) or 10 ⁇ M (111 and 115)
- Hippocampal single neuron spike activity is strongly influenced by excitatory input, and iontophoretic application of AMPA induces spike activity in vivo in a dose-dependent manner (Mathiesen et al. 1998).
- the AMPA evoked spike activity is inhibited by intravenous (i.v.) administration of a wide range of AMPA receptor antagonists (Mathiesen et al. 1998), which indicated that the excitation is primarily mediated via AMPA receptors.
- PAMs potentate AMPA receptor activation in vitro, and if this mechanism also operates in vivo, the i.v. injection of an PAM should enhance AMPA evoked spike activity.
- the aim of this study was to test the in vivo effect of a group of in vitro active PAMs. This have been done by studying their ability to enhances AMPA evoked spike activity after i.v. administration.
- the trachea was cannulated and the rats were placed in a stereotaxic frame and ventilated by a rodent ventilator (Ugo Basile, Comerio-Varese, Italy). Core body temperature was maintained at 37.5°C by a DC heating pad. The left and dorsal part of the parietal bone was removed by craniotomy and the dura was withdrawn exposing the pia mater and underlying brain, covered with 0.9% NaCI.
- a rodent ventilator Ugo Basile, Comerio-Varese, Italy
- AMPA (Sigma, USA) was dissolved at 10 mM in 0.2 M NaCI.
- NMDA (Sigma, USA) was dissolved at 100 mM in 100 mM NaCI. Both solutions were adjusted to pH 7.5-8.0 with NaOH.
- COMPOUND 61 was dissolved in 200 mM CH 3 SO 3 " Na + at a contration of 10 mM for iontophoretic application (pH 5.7) and in isotonic glucose (278 mM) for i.v. administration.
- Cyclothiazide, COMPOUND 63, COMPOUND 56, COMPOUND 115 and COMPOUND 114 were all dissolved at in 5% chremophore solution at a concentration of 5 mg ml "1 .
- PARAMETERS Evoked neuronal spike activity was analyzed on-line by a computer, saving single spikes and time of event. Neuronal spike activity (number of action potentials s "1 ) was monitored on a pulse rate histogram together with indicators for AMPA, COMPOUND 61 and vehicle application.
- PROCEDURE Extracellular recordings of single hippocampal neuron spikes were made with five-barrel glass microelectrodes (5B120F-6, World Precision Instruments Inc., Sarasota, Florida, USA) with a tip diameter of 10-12 ⁇ m.
- the individual barrels were filled with 5 M NaCI (recording), 400 mM NaCI (current balancing), 10 mM COMPOUND 61 in 200 mM CH 3 SO 3 " Na + (pH 4.7), 200 mM CH 3 SO 3 " Na + (pH 4.7, Vehicle), and the last barrel was filled with the AMPA.
- AMPA was ejected into hippocampus in regular cycles of 100-105 s.
- neuronal responses were stable (when the AMPA responses did not vary more than 10%, measured over a 10 s time period) for at least Vz hour, then a single dose of either cyclothiazide, COMPOUND 63, COMPOUND 56, COMPOUND 115, COMPOUND 61 or COMPOUND 114 (10 mg kg "1 ) was injected into the femoral vein. Recording of neuronal spike activity was continued for at least 45 min after intravenous injection. The PAM reactivity was tested by microiontophoretic application of COMPOUND 61 (20 nA, Fig. ).
- Fig. 8 shows that iontophoretic application of COMPOUND 61 enhanced AMPA evoked spike activity, whereas the vehicle did not influence the evoked spike activity.
- Intravenous administration cyclothiazide (10 mg kg "1 ) did not enhance AMPA evoked spike activity (Fig. 10).
- COMPOUND 63 (10 mg kg-1 i.v.) enhanced the low intensity AMPA responses (12 nA), but had only marginal effect on high intensity AMPA responses (17 nA). 10 mg kg-1 COMPOUND 63 was given 1500 s after onset of recording. The time of injection is marked by a shaded box above the AMPA2 trace.
- COMPOUND 56 (10 mg kg "1 i.v.) enhanced AMPA evoked spike activity.
- the compound was injected 1250 s after onset of registration.
- the time of injection is marked with a shaded box above the AMPA trace.
- Fig. 13 shows an example of enhancement of AMPA spike activity after i.v. administration of COMPOUND 115 (10 mg kg "1 ). The effect started 2 min after i.v. administration and lasted for more than 2 hours.
- COMPOUND 61 (10 mg kg "1 ) also enhanced AMPA responses in hippocampus. The 3-fold increase in AMPA evoked spike activity induced by COMPOUND
- COMPOUND 114 (10 mg kg “1 ) induced a 10-fold increase of the AMPA responses, when control level of the AMPA responses were low (from 21 to 209 spikes response "1 , mean response, Fig. 15), while only smaller enhancement observed with larger control responses
- COMPOUND 115 (10 mg kg '1 i.v.) enhances AMPA evoked spike activity in hippocampus.
- the shaded box indicate the time in i.v. injection, 1900 s after onset of registration.
- the effect of COMPOUND 115 lasted for more than 2 hours.
- COMPOUND 61 enhanced AMPA responses in hippocampus. 10 mg kg "1 i.v. was given 1000 s after onset of registration (marked by a shaded box above the trace). The effect of COMPOUND 61 lasted for more than 2.5 hour.
- COMPOUND 114 (10 mg kg “1 i.v.) enhanced AMPA evoked spike activity. The compound was given 1730 s after onset of registration, which is marked by a shaded box above the AMPA trace. Fig. 16. COMPOUND 114 (10 mg kg "1 i.v.) approximately doubled the AMPA responses. The i.v. administration occurred at time 3900 s and is indicated by shaded box above the AMPA trace
- PAXINOS G. & WATSON, C. (1986). The rat brain in stereotaxic coordinates. Second Edition.
- PRINCIPLE A Mouse is placed in a light compartment with access to a dark compartment. If it enter the dark compartment it will receive a foot-shock (0.4 mA). After a delay (24 hours) the association to risk an unpleasant foot-shock by re-entering the dark compartment is tested.
- mice Female NMRI mice (Bomholdtgaard, DK) weighing 22-25 g were used. The mice were kept in Macrolon plastic cages with free access to food (Altromin, DK) and tap water. The mice were habituated to the laboratory for at least 3 days before testing (light on 7:00am/light off 7:00 pm).
- the passive avoidance apparatus consisted of a modular test chambers (ENV- 307, MED-Associates, US).
- the light and the dark compartment consisted of plexiglas boxes of equal size (15x17x13 cm; width x length x height) with metal grid floors.
- a sliding guillotine door was located at the aperture (4x4cm) connecting the two compartments.
- a manual grid scrambler (ENV-412, MED-Associates, US) was used to provide the 0.4 mA foot-shock.
- PARAMETERS Entry latency (sec) to re-enter the dark compartment was measured.
- Fig. 17 shows the memory enhancing effect of different concentrations of the compound 61 ;
- Fig. 1 and Fig. 2 shows the potentiation of AMPA induced [ 3 H]GABA release from cultured cortical neurons by compounds of the invention.
- Fig. 3-8 shows the voltage clamp experiments on compounds of the invention.
- the compounds 56 (Fig. 3), 63 (Fig. 4), 111(Fig. 6), 114(Fig. 7) and 115 (Fig. 5) all potentiated the current induced by application of 30 ⁇ M AMPA.
- Fig. 8 shows the concentration-dependent effect of a compound of the invention (114).
- Fig. 9 - Fig. 16 are experiments of iontophoresis.
- the compound (32.5 mmol) to be chlorosulfonated was dissolved in chlorosulfonic acid (75 ml) and heated in an oil bath at 110 °C, until TLC indicated that the reaction had gone to completion * .
- the reaction mixture was poured onto ice and the precipitate formed, was isolated by filtration.
- the isolated solid was washed with a small amount of water and dried on the filter.
- the solid was dissolved in dry THF (200 ml) and added an excess of the amine (230 mmol) and the reaction mixture was left over night with stirring at rt.
- the reaction mixture was evaporated to dryness, then stirred with water to afford a solid which was isolated by filtration and washed with EtOAc on the filter.
- Sonogashira coupling A mixture of an aryliodide or arylbromide (2 mmol); an acetylene (10 mmol); Pd(PPh 3 ) Cl2 (140 mg; 0.2 mmol); Cul (40 mg; 0.1 mmol) and triethylamine (10 ml) under N2 was stirred at rt. (in the case of arylbromides prolonged heating at 60 °C was necessary) over night. THF was added and the reaction mixture filtered through celite and the filtrate evaporated to dryness. Column chromatography gave the ethynylated arene. Yields ranged from 40-53% for arylbromides to 97% for aryliodides.
- reaction mixture was cooled to rt. and evaporated to nearly dryness (CAUTION ! Evaporation to dryness may lead to explosion due to the presence of some HN3) and added MeOH.
- the reaction mixture was stirred for 1 h (to remove the TMS-group in the TMS-triazole), then adsorbed onto silica, and purified by chromatography. Yields ranged from 20-72 %.
- 2-Aminobenzenesulfonamide was used as starting material for the following transformation sequence: Method E (using 4-chlorobutanoyl chloride. The reaction mixture was NOT subjected to NaOH catalyzed ring closure, but dissolved in H2SO4 and heated at 100 °C for 72 h and precipitated on ice). M.p. 149-154 °C.
- the product was purified by flash chromatography on SiO using EtOAc:n-hexane (1 :1 , v/v) as eluent, yielding 155 mg (100 %) of 2-amino-4-(2-methoxyphenyl)-benzenesulfonamide as colorless powder.
- the product was further transformed by Method G (using cyclohexanecarboxaldehyde). M.p. 219-221 °C.
- 2-Amino-5-(1 -hydroxyethyl)benzenesulfonamide 5-Acetyl-2-aminobenzenesulf onamide (see compound 13) (0.95 g, 4.4 mmol) was suspended in 96% EtOH (50 ml) and NaBH 4 (0.46 g, 12 mmol) was added in one portion. The mixture was stirred at 25°C for 4 h and filtered through Celite and the solvent was removed under reduced pressure. The residue was treated with sat. NaHCO 3 (50 ml) and extracted with EtOAc (2 x 50 ml), dried (Na 2 SO ) and evaporated to dryness.
- 2-Nitrophenylboronic acid A solution of phenylboronic acid (10 g; 82 mmol) in acetic acid anhydride (100 ml) at -15 °C was added fuming HNO3 (5 ml; 120 mmol) over 30 min such that reaction temperature was kept below -10 °C. The reaction mixture was allowed to warm up to rt. and left with stirring over night. The reaction mixture was poured onto ice and concentrated to 50 ml. The remanense was then re-evaporated 5 times from additional H2O (100 ml) and finally filtered to give 7.1 g crude product as a mixture of isomers.
- reaction temperature was kept below -60 °C.
- the cooling bath was removed and the reaction mixture allowed to slowly warm up to +20 °C.
- the reaction mixture was re- cooled to -70 °C and B(O/-Pr)3 (16.1 ml; 70 mmol) was added.
- the reaction mixture was left cold and allowed to warm up over night, 1 M HCI (100 ml) was added and stirring was continued at rt. for 1 h.
- the reaction mixture was then extracted with Et2 ⁇ (2x 50 ml) and the
- 3-hydroxyphenylboronic acid A stirred solution of 3-aminophenylboronic acid hemisulfate (6.2 g; 33.3 mmol) and 50% H SO 4 (3.7 ml; 33.3 mmol) in H 2 O (100 ml) at -2 °C was added a solution of NaNO2 (2.5 g; 36.3 mmol) in H2O (20 ml) over 1 h. The reaction mixture was slowly added to a stirred solution of cone. H2SO4 (25 ml) in H2O (20 ml) at reflux. After complete addition, the reaction mixture was refluxed for 30 min., cooled, added activated charcoal, heated to reflux, cooled and filtered through celite. The filtrate was saturated with NaCI (s), filtered and extracted with Et2 ⁇ (5x 100 ml). The combined organic fractions were dried (Na2SU4) and evaporated to dryness to give 4.3 g (94%) product.
- reaction mixture was then warmed to room temperature and hydrolysed with 0.5 M hydrochloric acid (50 ml) and extracted with EtOAc (3 x 80 ml), dried (Na 2 SO 4 ) and concentrated to ca. 40 ml.
- n-Hexane 120 ml was added slowly and the colorless crystalline product was filtered off and dried, yielding 1.26 g (95%).
- N-(4-(2-pyrimidinyl)phenyl)-2,2-dimethylpropanamide A mixture of 4-((2,2- dimethylpropanoyl)amino)phenylboronic acid (2.0 g, 9 mmol), 2-chloropyrimidine (0.8 g, 7 mmol), Pd(PPh 3 ) 2 CI 2 (100 mg, 2 mol %) 1 ,2-dimethoxyethane (40 ml) and Na 2 CO 3 (2M, 7 ml, 14 mmol) were refluxed under N 2 for 5 h. The mixture was diluted with 10 % Na 2 CO (20 ml) and extracted with EtOAc (3 x 50 ml).
- 5-Cyano-2-aminobenzenesulfonamide A mixture of 5-iodo-2-aminobenzene-sulfonamide (17.9 g; 60 mmol), Zn(CN) 2 (4.9 g; 41.9 mmol) and Pd(PPh 3 ) 4 (2.5 g; 2.2 mmol) in DMF (150 ml) under N2 was heated to 80 °C for 2 h. The reaction mixture was poured into NaHCO3
- 5-(N-hydroxyamidino)-2-aminobenzenesulfonamide A mixture of hydroxylamine hydrochloride (764 mg; 11 mmol) and NaOMe (616 mg; 11 .4 mmol) in MeOH (10 ml) was stirred at rt. for 1 h and then added 5-cyano-2-aminobenzenesulfonamide (1 g; 5 mmol). The reaction mixture was left with stirring for 48 h and poured into water and extracted with EtOAc (2x 50 ml). The combined organic fractions were dried (Na2SO4), evaporated to dryness and purified by column chromatography to give 200 mg (17%) of product.
- Method A using 25% NH3 (aq.) as amine
- Method G using cyclohexanecarboxaldehyde. M.p. 178-180 °C.
- 2-Aminobenzenesulfonamide was used as starting material for the following transformation sequence: Method E (using cyclohexanecarbonyl chloride), Method A (using diethyiamine as amine), Method F. M.p. 207-209 °C.
- 2-Aminobenzenesulfonamide was used as starting material for the following transformation sequence: Method E (using cyclohexanecarbonyl chloride), Method A (using pyrrolidine as amine), Method F. M.p. 244-246 °C.
- 2-Aminobenzenesulfonamide was used as starting material for the following transformation sequence: Method C, Method A (using piperidine as amine), Method D, Method G [using cyclopropancarboxaldehyde]. M.p. 228-231 °C.
- 2-Aminobenzenesulfonamide was used as starting material for the following transformation sequence: Method C, Method A (using piperidine as amine), Method D, Method G [using butyraldehyde]. M.p. 147.4-151.2 °C.
- Cyclopentanecarboxaldehyde A stirred solution of cyclopentanecarboxylic acid (2.16 ml; 20 mmol) in dry THF (50 ml) at rt. under N2 was added NaBH4 (2.28 g; 60 mmol) and left with stirring for 20 min. The reaction mixture was cooled to 0 °C and added BF3OEt2 (10 ml; 80 mmol) over 1 h, while the reaction temperature was kept below +3 °C. The reaction mixture was allowed to warm up to rt. and left with stirring over night. The reaction mixture was added
- 2-Aminobenzenesulfonamide was used as starting material for the following transformation sequence: Method E (using cyclohexanecarbonyl chloride), Method A (using piperidine as amine), Method F. M.p. 262-264 °C.
- 2-Aminobenzenesulfonamide was used as starting material for the following transformation sequence: Method C, Method A (using piperidine as amine), Method D, Method G [using a racemic endo/exo mixture of 2-norbornencarboxaldehyde]. Two separate diastereomeric mixtures were isolated with m.p. (A) 240-242 °C and m.p. (B) 234-238 °C.
- 2-Aminobenzenesulfonamide was used as starting material for the following transformation sequence: Method E (using cyclohexanecarbonyl chloride), Method A (using 1 ,2,3,6- tetrahydropyridine as amine), Method F. M.p. 237-239 °C.
- 2-Aminobenzenesulfonamide was used as starting material for the following transformation sequence: Method E (using cyclohexanecarbonyl chloride), Method A (using ⁇ /-methylaniiine as amine), Method F. M.p. 210-212 °C.
- 2-Aminobenzenesulfonamide was used as starting material for the following transformation sequence: Method C, Method A (using ⁇ /-methylpiperazine as amine), Method D, Method G (using cyclohexanecarboxaldehyde). M.p. 227-229 °C.
- 61 methane sulfonate salt 61 (0.6 g; 1.4 mmol) was dissolved in 99% EtOH (30 ml) and added a solution of 1 M CH3SO3H in 99% EtOH. The mixture was left for precipitation for 2 h and the salt isolated by filtration. The composition of the salt was checked by HPLC for stability compared to the free base. The salt was found to be stable towards hydrolysis under these conditions and had a water solubility of 10 mg/ml.
- N-Mesylpiperazinium chloride To a stirred solution of piperazine (4.3 g; 50 mmol) in CH2CI2
- 2-Aminobenzenesulfonamide was used as starting material for the following transformation sequence: Method E (using cyclohexanecarbonyl chloride), Method A (using morpholine as amine), Method F. M.p. 262-264 °C.
- 2-Methyl-4-oxo-3,4-dihydro-6-quinazoline-N, N-dimethylsulfonamide 2-Methyl-4-oxo-3,4- dihydroquinazoline was transformed by Method A (using dimethylamine as amine). M.p. 264- 266 °C.
- Antranilamide was used as starting material for the following transformation sequence:
- Method A Using 25% NH3 (aq.) as amine.
- the reaction mixture contained both the 5-mono and 5,7-disulfonamide, which were separated by chromatography), Method G (using cyclohexanecarboxaldehyde.
- the aminal auto oxidizes to the aromatic hydroxyquinazoline). M.p. 306-310 °C.
- 2-Aminobenzenesulfonamide was used as starting material for the following transformation sequence: Method C and Method A (using dimethylamine as amine). M.p. 240-242 °C.
- 2-Aminobenzenesulfonamide was used as starting material for the following transformation sequence: Method C and Method A (using NaOH instead of an amine). M.p. >330 °C.
- 5-Chloro-3-cyclohexyl-1 ,2-dihydro-1 ,2,4-benzothiadiazine-1 , 1 -dioxide-8-carboxylic acid To a solution of 5-chloro-3-cyclohexyl-1 ,2-dihydro-1 , 2, 4-benzothiadiazine-1 , 1 -dioxide (see compound 80) (0.30 g, 1.0 mmol) in dry THF (15 ml) at -78 °C was added s-Bu ⁇ in cyclohexane (1.3 M, 1.6 ml, 2.1 mmol) under N 2 . The yellow mixture was stirred for 15 min at -
- 5-Chloro-3-cyclohexyl-8-iodo-1 ,2-dihydro-1 ,2,4-benzothiadiazine-1 , 1-dioxide To a solution of 5-chloro-3-cyclohexyl-1 ,2-dihydro-1 ,2,4-benzothiadiazine-1 , 1 -dioxide (596 mg, 2 mmol) in dry THF (20 ml) at -78 °C was added s-BuLi in cyclohexane (1.3 M, 3.8 ml, 5 mmol) under N 2 .
- 5-Chloro-3-cyclohexyl-8-(2-methoxyphenyl)-1 ,2-dihydro-1 ,2,4-benzothiadiazine-1 , 1 -dioxide A mixture of 5-chloro-3-cyclohexyl-8-iodo-1 ,2-dihydro-1 ,2,4-benzothiadiazine-1 , 1 -dioxide (290 mg, 0.68 mmol), 2-methoxyphenylboronic acid (122 mg, 0.80 mmol), Pd(PPh 3 ) 2 CI 2 (10 mg, 2 mol %) in 1 ,2-dimethoxyethane (50 ml) and Na 2 CO 3 (2M, 2 ml, 4 mmol) were refluxed under N 2 for 2 h.
- reaction mixture was stirred over night at rt., evaporated to dryness, stirred with EtOAc and filtered.
- the isolated precipitate was stirred with CH2CI2 and filtered to leave the 2-methyl isomer in the filtrate and the 4-methyl isomer as the precipitate.
- the 4-methyl was purified by recrystalization from DMSO/H2O.
- the 2-methyl isomer was purified by column chromatography (EtOAc).
- 2-Aminobenzenesulfonamide was used as starting material for the following transformation sequence: Method E (using 4-chlorobutanoyl chloride), Method A (using methylamine as amine), Method F (using LiAIH and rt.). M.p. 244-245 °C.
- 2-Aminobenzenesulfonamide was used as starting material for the following transformation sequence: Method E (using 4-chlorobutanoyl chloride), Method A (using methylamine as amine). M.p. 244-247 °C.
- 2-Aminobenzenesulfonamide was used as starting material for the following transformation sequence: Method E (using 4-chlorobutanoyl chloride), Method A (using 1 ,2,3,6- tetrahydropyridine as amine). M.p. 204-206 °C.
- 2-Aminobenzenesulfonamide was transformed by Method A (using 25% NH3 (aq.) as amine) and Method G (using using a racemic endo/exo mixture of bicyclo[2.2.1]hept-5-ene-2- carboxaldehyde). M.p. 172-180 °C.
- 2-Amino-3-bromo-5-sulfamoylbenzenesulfonamide A stirred solution of 2-amino-5- sulfamoylbenzenesulfonamide (3.77 g; 15 mmol) in AcOH (50 ml) was added a solution of Br2 (0.78 ml; 15 mmol) in AcOH (10 ml). The reaction mixture was heated to 70 °C for 6 days, evaporated to dryness, resuspended in MeOH (85 ml) and added solid KOH (3.8 g; 68 mmol).
- 2-Amino-3,5-dibromobenzylamine A mixture of 2-aminobenzylamine (6.1 g; 50 mmol) in CHCI3 (100 ml) at 0 °C was added a solution Br 2 (5.1 ml; 100 mmol) in CHCI3 (45 ml) such that the reaction temperature was kept below +2 °C. Cooling was then removed and the reaction mixture was stirred at rt. over night. The reaction mixture was filtered and the precipitate washed with EtOAc and purified by column chromatography.
- Bicyclo[2.2.1]heptane-2-carboxaldehyde A stirred suspension of 2-norbornylmethanol (0.5 ml; 5.8 mmol) and PCC on AI2O3 * in CH CI 2 (25 ml) was stirred at 2-3 °C for 1 h and then allowed to slowly warm up to rt. The reaction mixture was filtered and the solid material washed with CH2CI2 (2x 25 ml). The combined organic fractions were adsorbed onto silica and chromatographed to give 300 mg (42%) product as an oil.
- reaction mixture was evaporated to dryness and subjected to column chromatography. M.p. 96-98 °C.
- 5-lodo-4-methyl-2-aminobenzenesulfonamide m-Toluidine was transformed by method B and the two isomers separated by column chromatography to give 4-methyl-2- aminobenzenesulfonamide.
- reaction mixture was stirred at 0 °C until H-NMR indicated full conversion of starting material.
- the reaction mixture was filtered and the isolated solid washed with small volumes of CHCI3, NaHCO3 (sat. aq.), H 2 O and air dried to give 640 mg (62 %) of product.
- Cyclopentanecarbonyl chloride Cyclopentanecarboxylic acid (0.55 ml; 5 mmol) was refluxed in thionylchloride (1 ml) for 3 h. The reaction mixture was cooled to rt., evaporated to dryness and used directly without any purification.
- reaction mixture was slowly warmed to rt. and left with stirring over night.
- the reaction mixture was filtered and the solid material was washed with THF.
- the combined organic fractions were evaporated to dryness and the remanense added H2O and extracted with EtOAc.
- the combined organic fractions were dried (Na2SO4) and evaporated to dryness to give 3 g (53%) product.
- 3-lsobutyl-8-piperidinosulfonyl-2,3,4,5-tetrahydro-1 ,2,5-benzothiadiazepine-1 , 1 -dioxide A solution of 3-isobutyl-4-oxo-2, 3, 4,5-tetrahydro-1 ,2,5-benzothiadiazepine-1 , 1 -dioxide (500 mg; 1.8 mmol) in dry THF (20 ml) under N at 0 °C was added a solution of 2M BH 3 »SMe 2 (9.2 ml; 18 mmol) in THF. After complete addition, the reaction mixture was warmed to rt. and then to reflux for 2h. The reaction mixture was cooled to rt.
- Compound 128 was synthesized by the method used for compound 127 (using DL- cyclohexylglycine as amino acid).
- Compound 129 3-Cyclohexyl-7-cyclopentylsulfinyl-1 ,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1 , 1-dioxide
- 2-Amino-5-cyclopentylthiobenzenesulfonamide A mixture of 5-iodo-2- aminobenzenesulfonamide (1.192 g; 4 mmol), triethylamine (750 ⁇ l; 10 mmol), Cul (76 mg; 0.4 mmol); cyclopentylmercaptane (590 ⁇ l; 6 mmol) and Pd(PP i3)4 (462 mg; 0.4 mmol) in dry dioxane (10 ml) under N2 was stirred in a screw cap ampule at 130 S C over night. The reaction mixture was cooled to rt., diluted with H2O, made alkaline (using 4 M NaOH) and filtered through celite. The filtrate was neutralized to pH 8.5 and evaporated to dryness. Column chromatography gave 327 mg (30 %) product.
Abstract
Description
Claims
Priority Applications (14)
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HU0101280A HUP0101280A3 (en) | 1998-02-18 | 1999-02-18 | Positive ampa receptor modulator compounds and their use |
AU25123/99A AU751384B2 (en) | 1998-02-18 | 1999-02-18 | Novel compounds and their use as positive AMPA receptor modulators |
EP99904730A EP1071426A2 (en) | 1998-02-18 | 1999-02-18 | Novel compounds and their use as positive ampa receptor modulators |
NZ506251A NZ506251A (en) | 1998-02-18 | 1999-02-18 | Benzothiadiazine and benzothiadiazepine derivatives and their use as positive AMPA receptor modulators |
CA002320354A CA2320354A1 (en) | 1998-02-18 | 1999-02-18 | Novel compounds and their use as positive ampa receptor modulators |
PL99342843A PL342843A1 (en) | 1998-02-18 | 1999-02-18 | Novel compounds and their use as positive ampa receptor modulators |
IL13772099A IL137720A0 (en) | 1998-02-18 | 1999-02-18 | Compounds and their use as positive ampa receptor modulators |
EEP200000468A EE200000468A (en) | 1998-02-18 | 1999-02-18 | The compounds, their use and the pharmaceutical composition |
SK1189-2000A SK11892000A3 (en) | 1998-02-18 | 1999-02-18 | Novel compounds and their use as positive ampa receptor modulators |
JP2000532408A JP2002504481A (en) | 1998-02-18 | 1999-02-18 | Novel compounds and methods of using them as positive AMPA receptor modulators |
IS5581A IS5581A (en) | 1998-02-18 | 2000-08-04 | New compounds and their use as positive direct AMPA receptors |
NO20004121A NO20004121L (en) | 1998-02-18 | 2000-08-17 | New compounds and their use as positive AMPA receptor modulators |
US09/641,814 US6943159B1 (en) | 1998-02-18 | 2000-08-18 | Compounds and their use as positive AMPA receptor modulators |
US10/642,224 US7235548B2 (en) | 1998-02-18 | 2003-08-18 | Compounds and their use as positive AMPA receptor modulators |
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DK0226/98 | 1998-02-18 | ||
DK22698 | 1998-02-18 |
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US09/641,814 Continuation US6943159B1 (en) | 1998-02-18 | 2000-08-18 | Compounds and their use as positive AMPA receptor modulators |
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EP (1) | EP1071426A2 (en) |
JP (1) | JP2002504481A (en) |
CN (1) | CN1293665A (en) |
AU (1) | AU751384B2 (en) |
CA (1) | CA2320354A1 (en) |
EE (1) | EE200000468A (en) |
HU (1) | HUP0101280A3 (en) |
IL (1) | IL137720A0 (en) |
IS (1) | IS5581A (en) |
NO (1) | NO20004121L (en) |
NZ (1) | NZ506251A (en) |
PL (1) | PL342843A1 (en) |
RU (1) | RU2214405C2 (en) |
SK (1) | SK11892000A3 (en) |
TR (1) | TR200002427T2 (en) |
WO (1) | WO1999042456A2 (en) |
ZA (1) | ZA991301B (en) |
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AU2512399A (en) | 1999-09-06 |
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