WO2005013977A1 - Indol-5-yl sulfonamide derivatives, their preparation and their use 5-ht-6 as modulators - Google Patents
Indol-5-yl sulfonamide derivatives, their preparation and their use 5-ht-6 as modulators Download PDFInfo
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- WO2005013977A1 WO2005013977A1 PCT/EP2004/008511 EP2004008511W WO2005013977A1 WO 2005013977 A1 WO2005013977 A1 WO 2005013977A1 EP 2004008511 W EP2004008511 W EP 2004008511W WO 2005013977 A1 WO2005013977 A1 WO 2005013977A1
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- SOEGWNPZRRIYRM-UHFFFAOYSA-N c1ccc(C=[I]C=C2)c2c1 Chemical compound c1ccc(C=[I]C=C2)c2c1 SOEGWNPZRRIYRM-UHFFFAOYSA-N 0.000 description 1
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- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
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- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
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- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D417/12—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 linked by a chain containing hetero atoms as chain links
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- 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
- the present invention refers to new sulfonamide derivatives, of general formula (la, lb, lc),
- the new compounds of the present invention may be used in the pharmaceutical industry as intermediates and for preparing medicaments.
- the superfamily of serotonin receptors (5-HT) comprises 7 classes (5- HTr5-HT ), which cover 14 human subclasses [D. Hoyer, et al., Neuropharmacology, 1997, 36, 419].
- the 5-HT 6 receptor has been the last serotonin receptor identified by molecular cloning in rats [F.J. Monsma, et al., 25 Mol. Pharmacol., 1993, 43, 320; M. Ruat, et al., Biochem. Biophys. Res. Commun., 1993, 193, 268] as well as in humans [R. Kohen, et al., J.
- the compounds with an affinity for the ⁇ -HT ⁇ receptor are useful in treating different disorders of the Central Nervous System and of the Gastrointestinal system, as well as the irritable bowel syndrome.
- the compounds with an affinity for the 5-HT 6 receptor are useful for treating anxiety, depression and cognitive memory disorders [M. Yoshioka, et al., Ann. NY Acad. Sci., 1998, 861 , 244; A. Bourson, et al., Br. J. Pharmacol., 1998, 125, 1562; D.C. Rogers, et al., Br. J. Pharmacol. Suppl., 1999, 127, 22P; A. Bourson, et al., J. Pharmacol. Exp.
- the compounds with an affinity for the 5-HT 6 receptor are useful for treating infantile hyperkinesia (ADHD, attention deficit / hyperactivity disorder) [W.D. Hirst, et al., Br. J. Pharmacol., 2000, 130, 1597; C. Gerard, et al., Brain Research, 1997, 746, 207; M.R. Pranzatelli, Drugs of Today, 1997, 33, 379].
- ADHD attention deficit / hyperactivity disorder
- Patent application WO 01/32646 discloses sulfonamides derived from bicycles, whereby each of the rings is 6-membered, aromatic or heteroaromatic rings with 5-HT ⁇ receptor antagonist activity.
- Patent application EP 0 733 628 discloses sulfonamides derived from indole with 5-HT-IF receptor antagonist activity, useful for the treatment of migraines.
- Eating disorders are a serious and increasingly frequent threat for the health of persons from all age groups, since they increase the risk of developing other serious and even mortal diseases, preferably diabetes and coronary artery diseases. Therefore, an object of the present invention was to provide new compounds, particularly suitable as active substances in medicaments, preferably in medicaments for 5-HT ⁇ receptor regulation, for the prophylaxis and/or treatment of a disorder or disease related to food intake, preferably for the regulation of appetite, for the maintenance, increase or reduction of body weight, for the prophylaxis and/or treatment of obesity, bulimia, anorexia, cachexia or type II diabetes (non insulin dependent diabetes mellitus), preferably type II diabetes caused by obesity, for the prophylaxis and/or treatment of gastrointestinal tract disorders, preferably irritable bowel syndrome, for cognitive enhancement, for the prophylaxis and/or treatment of disorders of the central nervous system, anxiety, panic disorders, depression, bipolar disorders, cognitive memory disorders, senile dementia processes, preferably Alzheimer's disease, Parkinson'
- indol-5-yl sulfonamide compounds of general formulas (la, lb, lc) described below show an affinity for the 5-HTe receptor.
- These compounds are therefore suitable for the manufacture of a medicament for the prophylaxis and/or treatment of a disorder or disease related to food intake, preferably for the regulation of appetite, for the maintenance, increase or reduction of body weight, for the prophylaxis and/or treatment of obesity, bulimia, anorexia, cachexia or type II diabetes (non insulin dependent diabetes mellitus), preferably type II diabetes caused by obesity, for the prophylaxis and/or treatment of gastrointestinal tract disorders, preferably irritable bowel syndrome, for cognitive enhancement, for the prophylaxis and/or treatment of disorders of the central nervous system, anxiety, panic disorders, depression, bipolar disorders, cognitive memory disorders, senile dementia processes, neurodegenerative disorders, preferably Alzheimer's disease, Parkinson's disease, Huntington's disease and Multiple Sclerosis, schizophrenia, psychosis or
- R represents a -NR 8 R 9 radical or a saturated or unsaturated, optionally at least mono-substituted cycloaliphatic radical, which may optionally contain at least one heteroatom as a ring member and/or which may be condensed with a saturated or unsaturated, optionally at least mono-substituted mono- or bicyclic cycloaliphatic ring system, which may optionally contain at least one heteroatom as a ring member,
- R 2 , R 3 , R 4 , R 6 and R 7 identical or different, each represent hydrogen, halogen, nitro, alkoxy, cyano, a saturated or unsaturated, linear or branched, optionally at least mono-substituted aliphatic radical or an optionally at least mono- substituted phenyl or an optionally at least mono-substituted heteroaryl radical,
- R 5 represents hydrogen or a saturated or unsaturated, linear or branched, optionally at least mono-substituted aliphatic radical
- R 8 and R 9 identical or different, each represent hydrogen or a saturated or unsaturated, linear or branched, optionally at least mono-substituted aliphatic radical
- R 8 and R 9 are not hydrogen at the same time, and if one of them, R 8 and R 9 , represents a saturated or unsaturated, linear or branched, optionally at least mono-substituted C 1 -C 4 aliphatic radical, the other one represents a saturated or unsaturated, linear or branched, optionally at least mono-substituted aliphatic radical with at least five carbon atoms, or
- R 8 and R 9 together with the bridging nitrogen atom form a saturated or unsaturated, optionally at least mono-substituted heterocyclic ring, which may contain at least one additional heteroatom as a ring member and/or which may be condensed with a saturated or unsaturated, optionally at least mono- substituted, mono- or bicyclic cycloaliphatic ring system which may optionally contain at least one heteroatom as a ring member,
- A represents an optionally at least mono-substituted mono- or polycyclic aromatic ring system, which may be bonded via an optionally at least mono- substituted alkylene, alkenylene or alkynylene group and/or which may contain at least one heteroatom as a ring member in one or more of its rings
- n O, 1 , 2, 3 or 4;
- R 1 represents a -NR 8 R 9 radical
- R 2 , R 3 , R 4 , R 6 and R 7 identical or different, each represent hydrogen, halogen, nitro, alkoxy, cyano, a saturated or unsaturated, optionally at least mono- substituted, linear or branched aliphatic radical, or an optionally at least mono- substituted phenyl radical or an optionally at least mono-substituted heteroaryl radical,
- R 5 represents hydrogen or a saturated or unsaturated, linear or branched, optionally at least mono-substituted aliphatic radical
- R 8 and R 9 identical or different, each represent hydrogen or a saturated or unsaturated, linear or branched, optionally at least mono-substituted, C 1 -C 4 aliphatic radical,
- A represents an optionally at least mono-substituted mono- or polycyclic aromatic ring system, which may be bonded via an optionally at least mono- substituted alkylene, alkenylene or alkynylene group and/or which may contain at least one heteroatom as a ring member in one or more of its rings, and n is 0, 1 , 2, 3 or 4;
- R 1 represents a -NR 8 R 9 radical or a saturated or unsaturated, optionally at least mono-substituted, cycloaliphatic radical, which may optionally contain at least one heteroatom as a ring member and/or which may be condensed with a saturated or unsaturated, optionally at least mono-substituted mono- or bicyclic cycloaliphatic ring system, which may optionally contain at least one heteroatom as a ring member,
- R 2 , R 3 , R 4 , R 6 and R 7 identical or different, each represent hydrogen, halogen, nitro, alkoxy, cyano, a saturated or unsaturated, linear or branched, optionally at least mono-substituted aliphatic radical or an optionally at least mono- substituted phenyl or an optionally at least mono-substituted heteroaryl radical, R 5 represents hydrogen or a saturated or unsaturated, linear or branched, optionally at least mono-substituted aliphatic radical,
- R 8 and R 9 identical or different, each represent hydrogen or a saturated or unsaturated, linear or branched, optionally at least mono-substituted aliphatic radical,
- R 8 and R 9 together with the bridging nitrogen atom form a saturated or unsaturated, optionally at least mono-substituted heterocyclic ring, which may contain at least one additional heteroatom as a ring member and/or which may be condensed with a saturated or unsaturated, optionally at least mono- substituted, mono- or bicyclic cycloaliphatic ring system which may optionally contain at least one heteroatom as a ring member,
- A represents an optionally at least mono-substituted mono- or polycyclic aromatic ring system, which may be bonded via an optionally at least mono- substituted alkylene, alkenylene or alkynylene group and/or which may contain at least one heteroatom as a ring member in one or more of its rings
- n 0, 1 , 2, 3 or 4;
- moieties R 2 -R 9 represent a saturated or unsaturated aliphatic radical, that is, an alkyl, alkenyl or alkynyl radical which is substituted by one or more substituents
- each one of these substituents may preferably be chosen, unless otherwise defined, from the group consisting of hydroxy, fluorine, chlorine, bromine and trifluoromethyl.
- R 1 is a saturated or unsaturated, optionally at least one heteroatom as a ring member containing cycloaliphatic radical, which is substituted by one or more substituents and/or is condensed with a saturated or unsaturated, optionally at least one heteroatom as a ring member containing mono- or bicyclic cycloaliphatic ring system, which is substituted by one or more substituents, each one of these substituents may preferably be chosen, unless otherwise defined, from the group consisting of hydroxy, fluorine, chlorine, bromine, linear or branched C-i-C ⁇ alkyl, linear or branched C ⁇ -C6 alkoxy, linear or branched d- C ⁇ perfluoroalkyl, linear or branched C C ⁇ perfluoroalkoxy and benzyl, preferably from the group consisting of linear or branched C-i-C ⁇ alkyl and benzyl.
- heteroatoms of said cycloaliphatic radical and/or of said mono- or bicyclic cycloaliphatic ring may, independently from one another, preferably be chosen from the group consisting of nitrogen, sulphur and oxygen, more preferably nitrogen is chosen as a heteroatom.
- Said cycloaliphatic radical may contain 0, 1 , 2 or 3 heteroatoms chosen from the above mentioned group, preferably it contains 0, 1 or 2 heteroatoms chosen from the above mentioned group.
- R 8 and R 9 together with the bridging nitrogen atom form a saturated or unsaturated, optionally at least mono-substituted heterocyclic ring, which may contain at least one further heteroatom as a ring member and/or which is condensed with a saturated or unsaturated mono- or bicyclic cycloaliphatic ring system, which may contain at least one heteroatom as a ring member and/or which is substituted by one or more substituents
- each one of these substituents may preferably be chosen, unless otherwise defined, from the group consisting of hydroxy, fluorine, chlorine, bromine, linear or branched C C ⁇ alkyl, linear or branched C- ⁇ -C- 6 alkoxy, linear or branched C C 6 perfluoroalkyl, linear or branched C C ⁇ perfluoroalkoxy and benzyl, preferably from the group consisting of linear or branched CrC 6 alkyl and benzyl.
- heterocyclic ring contains one or more additional heteroatoms, and/or if one or both rings of the mono- or bicyclic ring system contain one or more heteroatoms, these heteroatoms may, independently from one another, preferably be chosen from the group consisting of nitrogen, sulphur and oxygen, more preferably nitrogen is chosen as a heteroatom.
- Said heterocyclic ring may contain 0, 1 , 2 or 3 additional heteroatoms chosen from the above mentioned group, preferably it contains 0 or 1 heteroatoms chosen from the above mentioned group.
- A is a mono- or polycyclic aromatic ring system which may be bonded via an alkylene, alkenylene or alkynylene group and/or which may contain at least one heteroatom as a ring member and/or which may be substituted by one or more substituents
- heteroatoms - like the heteroatoms of a previously mentioned 5- or 6-membered heteroaryl radical - may preferably be chosen from the group consisting of nitrogen, sulphur and oxygen.
- each one of these substituents may preferably be chosen from the group consisting of fluorine, chlorine, bromine, linear or branched C C 6 alkyl, linear or branched C- ⁇ -C 6 alkoxy, linear or branched C C 6 alkylthio, trifluoromethyl radical, cyano radical and a -NR 12 R 13 radical, wherein R 2 and R 13 , identical or different, represent hydrogen or a linear or branched CrC 6 alkyl.
- each of these substituents may preferably be chosen from the group consisting of hydroxy, halogen, linear or branched Ci-C ⁇ alkyl, linear or branched C ⁇ -C 6 alkoxy, linear or branched Ci-C ⁇ perfluoroalkyl, linear or branched C C 6 perfluoroalkoxy or an optionally at least mono-substituted phenyl radical.
- each one of these substituents may preferably be chosen from the group consisting of fluorine, chlorine, bromine, linear or branched C-i-C ⁇ alkyl, linear or branched d-C ⁇ alkoxy, linear or branched C- ⁇ -C- 6 alkylthio, trifluoromethyl radical, cyano radical and a -NR 12 R 13 radical, wherein R 12 and R 13 , identical or different, represent hydrogen or a linear or branched C ⁇ C 6 alkyl.
- substituents R 2 , R 3 , R 4 , R 6 and R 7 may have 1 to 6, preferably 1 to 3 carbon atoms.
- condensed indicates that the condensed rings share more than one atom.
- fused may also be used for this type of bonding.
- R 1 represents an -NR 8 R 9 radical or a saturated or unsaturated, optionally at least mono-substituted 5- or 6-membered cycloaliphatic radical which may optionally contain at least one heteroatom as a ring member and/or which may be condensed with a saturated or unsaturated, optionally at least mono-substituted mono- or bicyclic cycloaliphatic ring system, which may optionally contain at least one heteroatom as a ring member, whereby the rings of the ring system are 5- or 6-membered,
- R 1 represents an -NR 8 R 9 radical or a radical chosen from the group consisting of
- R 10 represents hydrogen, a linear or branched G C 6 alkyl radical or a benzyl radical, preferably hydrogen or a C C 2 alkyl radical and R 2 to R 9 , A and n are defined as above.
- Sulfonamide derivatives of general formula (la) are also preferred, wherein R 2 , R 3 , R 4 , R 6 and R 7 , identical or different, each represent hydrogen, a linear or branched, optionally at least mono-substituted C ⁇ -C 6 alkyl radical, a linear or branched, optionally at least mono-substituted C2-C 6 alkenyl radical or a linear or branched, optionally at least mono-substituted C 2 -C 6 alkynyl radical,
- R 2 , R 3 , R 4 , R 6 and R 7 identical or different, each represent hydrogen or a linear or branched, optionally at least mono-substituted C- ⁇ -C 6 alkyl radical,
- R 2 , R 3 , R 4 , R 6 and R 7 each represent hydrogen or a C 1 - 2 alkyl radical and R 1 , R 5 , R 8 , R 9 , A and n are defined as above.
- R 5 represents hydrogen, a linear or branched, optionally at least mono- substituted C- ⁇ -C 6 alkyl radical, a linear or branched, optionally at least mono- substituted C 2 -C 6 alkenyl radical, a linear or branched, optionally at least mono- substituted C 2 -C 6 alkynyl radical,
- R 5 represents hydrogen or a linear or branched, optionally at least mono-substituted C- ⁇ -C- 6 alkyl radical
- R 5 represents hydrogen or a CrC 2 alkyl radical and R 1 -
- R 4 , R 6 -R 9 , A and n are defined as above.
- sulfonamide derivatives of general formula (la) are also preferred, wherein R 8 and R 9 , identical or different, each represent a linear or branched, optionally at least mono-substituted C 1 -C 10 alkyl radical, a linear or branched, optionally at least mono-substituted C 2 _C ⁇ o alkenyl radical, a linear or branched, optionally at least mono-substituted C 2 -C 10 alkynyl radical, with the proviso that R 8 and R 9 do not represent hydrogen at the same time, and if one of them, R 8 and R 9 , represents a saturated or unsaturated, linear or branched, optionally at least mono-substituted C 1 -C 4 aliphatic radical, the other one represents a saturated or unsaturated, linear or branched, optionally at least mono-substituted aliphatic radical, with at least five carbon atoms, or
- R 8 and R 9 together with the bridging nitrogen atom form a saturated or unsaturated, optionally at least mono-substituted 5- or 6-membered heterocyclic ring which may contain at least one additional heteroatom as a ring member and/or which may be condensed with a saturated or unsaturated, optionally at least mono-substituted mono- or bicyclic cycloaliphatic ring system, which may optionally contain at least one heteroatom as a ring member, whereby the rings of the ring system are 5- 6- or 7-membered and R 1 -R 7 , A and n are defined as above.
- R 8 and R 9 are hydrogen or a linear or branched C 1 -C1 0 alkyl radical, with the proviso that R 8 and R 9 do not represent hydrogen at the same time, and if one of them, R 8 and R 9 , represents a saturated or unsaturated, linear or branched, optionally at least mono-substituted C1-C 4 aliphatic radical, the other one represents a saturated or unsaturated, linear or branched, optionally at least mono-substituted aliphatic radical, with at least five carbon atoms, or
- R 8 and R 9 together with the nitrogen atom bridge form a radical chosen from the group consisting of
- R 11 represents hydrogen, a linear or branched C C ⁇ alkyl radical or a benzyl radical, preferably hydrogen or a C ⁇ -C 2 alkyl radical, and R 1 - R 9 , A and n are defined as above.
- sulfonamide derivatives of general formula (la) are preferred, wherein A represents an optionally at least mono-substituted mono- or polycyclic aromatic ring system, wherein the ring(s) is/are 5- or 6-membered, which may be bonded via an optionally at least mono-substituted C-i—C ⁇ alkylene group, an optionally at least mono-substituted C2— C ⁇ alkenylene group or an optionally at least mono-substituted C 2 — C ⁇ alkynylene group and/or wherein the ring(s) may contain at least one heteroatom as a ring member,
- A represents an optionally at least mono-substituted mono- or polycyclic aromatic ring system, wherein the ring(s) is/are 5- or 6-membered and wherein one or more of the rings contain at least one heteroatom,
- X, Y, Z independently from one another, each represent a radical selected from the group consisting of hydrogen, fluorine, chlorine, bromine, nitro, acetyl, linear or branched C C ⁇ alkyl, linear or branched CrC ⁇ alkoxy, linear or branched CrC 6 alkylthio, a trifluoromethyl radical, a cyano radical and a -NR 12 R 13 radical,
- R 12 and R 13 identical or different, each represent hydrogen or linear or branched CrC ⁇ alkyl
- W represents a single chemical bond between the two rings, a CH 2 , O, S group or a NR 14 radical,
- R 14 is hydrogen or a linear or branched d-C ⁇ alkyl
- n 0, 1 , 2, 3 or 4 and
- sulfonamide derivatives of general formula (la) are preferred, wherein A represents an optionally at least mono-substituted mono- or polycyclic aromatic ring system, wherein the ring(s) is/are 5- or 6-membered, which may be bonded via an optionally at least mono-substituted C ⁇ _C 6 alkylene group, an optionally at least mono-substituted C 2 — C ⁇ alkenylene group or an optionally at least mono-substituted C 2 — C ⁇ alkynylene group, and/or wherein the ring(s) may contain at least one heteroatom as a ring member,
- A represents an optionally at least mono-substituted mono- or polycyclic aromatic ring system, wherein the ring(s) is/are 5- or 6-membered and wherein one or more of the rings contain at least one heteroatom, or a radical chosen from the group consisting of
- X, Y, Z independently from one another, each represent a radical selected from the group consisting of hydrogen, fluorine, chlorine, bromine, linear or branched d-C ⁇ alkyl, linear or branched CrC ⁇ alkoxy, linear or branched d-C 6 alkylthio, a trifluoromethyl radical, a cyano radical and a - NR 12 R 13 radical,
- R 12 and R 13 identical or different, each represent hydrogen or linear or branched CrC ⁇ alkyl
- W represents a single chemical bond between the two rings, a CH 2 , O, S group or a NR 14 radical,
- R _14 is hydrogen or a linear or branched d-C- 6 alkyl
- n O, 1 , 2, 3 or 4.
- R -R and n are defined as above.
- X, Y, Z independently from one another, each represent a radical selected from the group consisting of hydrogen, fluorine, chlorine, bromine, nitro, acetyl, linear or branched -C ⁇ alkyl, linear or branched CrC 6 alkoxy, linear or branched CrCe alkylthio, a trifluoromethyl radical, a cyano radical and a -NR 12 R 13 radical,
- R >12 and R j13 identical or different, each represent hydrogen or linear or branched CrC 6 alkyl
- W represents a single chemical bond between the two rings, a CH 2 , O, S group or a NR 14 radical,
- R -14 is hydrogen or a linear or branched d-C 6 alkyl
- n O, 1 , 2, 3 or 4 and
- n 1 or 2 or 2, preferably 2, and R 1 -R 9 and n are defined as above.
- sulfonamide derivatives of general formula (la) are preferred, wherein n is 0, 1 , 2, 3 or 4; preferably n is 1 , 2 or 3; more preferably n is 2 or 3 and R 1 to R 9 and A are defined as above.
- Those most preferred compounds of general formula (la) are selected from the group consisting of
- sulfonamide derivatives of general formula (lb) are also preferred, wherein R 2 , R 3 , R 4 , R 6 and R 7 , identical or different, each represent hydrogen, a linear or branched, optionally at least mono-substituted C ⁇ .C 6 alkyl radical, a linear or branched, optionally at least mono-substituted C 2 -C 6 alkenyl radical, or a linear or branched, optionally at least mono-substituted C 2 -C 6 alkynyl radical,
- R 2 , R 3 , R 4 , R 6 and R 7 identical or different, each represent hydrogen or a linear or branched, optionally at least mono-substituted Ci-C ⁇ alkyl radical,
- R 2 , R 3 , R 4 , R 6 and R 7 each represent hydrogen or an C 1 - 2 alkyl radical and R 1 , R 5 , R 8 , R 9 , A and n are defined as above.
- Sulfonamide derivatives of general formula (lb) are also preferred, wherein R 5 hydrogen, a linear or branched, optionally at least mono-substituted CrC 6 alkyl radical, a linear or branched, optionally at least mono-substituted C 2 -C 6 alkenyl radical or a linear or branched, optionally at least mono-substituted C 2 -C ⁇ alkynyl radical, preferably that R 5 represents hydrogen or a linear or branched, optionally at least mono-substituted d-C ⁇ alkyl radical,
- R 5 represents hydrogen or a C 1 -C2 alkyl radical and R 1 - R 4 , R 6 -R 9 , A and n are defined as above.
- sulfonamide derivatives of general formula (lb) are also preferred, wherein R 8 and R 9 , identical or different, each represent hydrogen or a linear or branched, optionally at least mono-substituted C1-C 4 alkyl radical,
- R 8 and R 9 are not hydrogen at the same time and R 1 -R 7 , A and n are defined as above.
- R 8 and R 9 are not hydrogen at the same time, and R 1 -R 7 , A and n are defined as above.
- sulfonamide derivatives of general formula (lb) are preferred, wherein A represents an optionally at least mono-substituted mono- or polycyclic aromatic ring system, wherein the ring(s) is/are 5- or 6-membered, which may be bonded via an optionally at least mono-substituted C ⁇ _C ⁇ alkylene group, an optionally at least mono-substituted C2— C ⁇ alkenylene group or an optionally at least mono-substituted C 2 — C ⁇ alkynylene group and/or wherein the ring(s) may contain at least one heteroatom as a ring member,
- A represents an optionally at least mono-substituted mono- or polycyclic aromatic ring system, wherein the ring(s) is/are 5- or 6-membered and wherein one or more of the rings contain at least one heteroatom, or a radical chosen from the group consisting of
- X, Y, Z independently from one another, each represent a radical selected from the group consisting of hydrogen, fluorine, chlorine, bromine, nitro, acetyl, linear or branched d-C ⁇ alkyl, linear or branched d-C ⁇ alkoxy, linear or branched C Ce alkylthio, a trifluoromethyl radical, a cyano radical and a -NR 12 R 13 radical,
- R 12 and R 13 identical or different, each represent hydrogen or linear or branched d-C ⁇ alkyl
- W represents a single chemical bond between the two rings, a CH 2 , O, S group or a NR 14 radical,
- R ⁇ 14 is hydrogen or a linear or branched d-C- 6 alkyl
- m is 0, 1 , 2, 3 or 4 and ____ __ . . J u U i- -24-
- n1 is 1 or 2, preferably 2, and R 1 -R 9 and n are defined as above.
- sulfonamide derivatives of general formula (lb) are preferred, wherein A represents an optionally at least mono-substituted mono- or polycyclic aromatic ring system, wherein the ring(s) is/are 5- or 6-membered, which may be bonded via an optionally at least mono-substituted —C ⁇ alkylene group, an optionally at least mono-substituted C 2 — C 6 alkenylene group or an optionally at least mono-substituted C 2 — C 6 alkynylene group, and/or wherein the ring(s) may contain at least one heteroatom as a ring member,
- A represents an optionally at least mono-substituted mono- or polycyclic aromatic ring system, wherein the ring(s) is/are 5- or 6-membered and wherein one or more of the rings contain at least one heteroatom, or a radical chosen from the group consisting of
- X, Y, Z independently from one another, each represent a radical selected from the group consisting of hydrogen, fluorine, chlorine, bromine, linear or branched CrCe alkyl, linear or branched d-C- 6 alkoxy, linear or branched d-C 6 alkylthio, a trifluoromethyl radical, a cyano radical and a - NR 12 R 13 radical,
- R 12 and R 13 identical or different, each represent hydrogen or linear or branched d-C 6 alkyl, W represents a single chemical bond between the two rings, a CH 2 , O, S group or a NR 14 radical,
- R J4 is hydrogen or a linear or branched d-C 6 alkyl
- n O, 1 , 2, 3 or 4.
- R 1 -R 9 and n are defined as above.
- X, Y, Z independently from one another, each represent a radical selected from the group consisting of hydrogen, fluorine, chlorine, bromine, nitro, acetyl, linear or branched d-C ⁇ alkyl, linear or branched d-Ce alkoxy, linear or branched CrC ⁇ alkylthio, a trifluoromethyl radical, a cyano radical and a -NR 12 R 13 radical,
- R 12 and R 13 identical or different, each represent hydrogen or linear or branched CrCe alkyl
- W represents a single chemical bond between the two rings, a CH 2 , O, S group or a NR 14 radical,
- R is hydrogen or a linear or branched CrC ⁇ alkyl
- n 0, 1 , 2, 3 or 4 and
- nl 1 or 2, preferably 2,
- R ⁇ 1 - DR9 and n are defined as above.
- sulfonamide derivatives of general formula (lb) are preferred, wherein n is 0, 1 , 2, 3 or 4; preferably n is 1 , 2 or 3; more preferably n is 2 or 3 and R 1 to R 9 and A are defined as above.
- Those most preferred compounds of general formula (lb) are selected from the group consisting of
- R 1 represents an -NR 8 R 9 radical or a saturated or unsaturated, optionally at least mono-substituted 5- or 6-membered cycloaliphatic radical which may optionally contain at least one heteroatom as a ring member and/or which may be condensed with a saturated or unsaturated, optionally at least mono-substituted mono- or bicyclic cycloaliphatic ring system, which may optionally contain at least one heteroatom as a ring member, whereby the rings of the ring system are 5- or 6-membered,
- R 1 represents an -NR 8 R 9 radical or a radical chosen from the group consisting of
- R 10 represents hydrogen, a linear or branched CrC ⁇ alkyl radical or a benzyl radical, preferably hydrogen or a d-C- 2 alkyl radical and R 2 to R 9 , A and n are defined as above.
- R 2 , R 3 , R 4 , R 6 and R 7 are also preferred, wherein R 2 , R 3 , R 4 , R 6 and R 7 , identical or different, each represent hydrogen, a linear or branched, optionally at least mono-substituted C ⁇ -C 6 alkyl radical, a linear or branched, optionally at least mono-substituted C 2 .Ce alkenyl radical or a linear or branched, optionally at least mono-substituted C 2 -C 6 alkynyl radical,
- R 2 , R 3 , R 4 , R 6 and R 7 identical or different, each represent hydrogen or a linear or branched, optionally at least mono-substituted d-C ⁇ alkyl radical,
- R 2 , R 3 , R 4 , R 6 and R 7 each represent hydrogen or a C1-2 alkyl radical and R 1 , R 5 , R 8 , R 9 , A and n are defined as above.
- Sulfonamide derivatives of general formula (lc) are also preferred, wherein R 5 represents hydrogen, a linear or branched, optionally at least mono-substituted CrC 6 alkyl radical, a linear or branched, optionally at least mono-substituted C - C 6 alkenyl radical, a linear or branched, optionally at least mono-substituted C 2 - C ⁇ alkynyl radical,
- R 5 represents hydrogen or a linear or branched, optionally at least mono-substituted CrC ⁇ alkyl radical
- R 5 represents hydrogen or a C 1 -C2 alkyl radical and R 1 - R 4 , R 6 -R 9 , A and n are defined as above.
- sulfonamide derivatives of general formula (lc) are also preferred, wherein R 8 and R 9 , identical or different, each represent a linear or branched, optionally at least mono-substituted C 1 -C 10 alkyl radical, a linear or branched, optionally at least mono-substituted C — C 10 alkenyl radical, a linear or branched, optionally at least mono-substituted C2-C 10 alkynyl radical, or R 8 and R 9 together with the bridging nitrogen atom form a saturated or unsaturated, optionally at least mono-substituted 5- or 6-membered heterocyclic ring which may contain at least one additional heteroatom as a ring member and/or which may be condensed with a saturated or unsaturated, optionally at least mono-substituted mono- or bicyclic cycloaliphatic ring system, which may optionally contain at least one heteroatom as a ring member, whereby the rings of the
- R 11 represents hydrogen, a linear or branched CrC ⁇ alkyl radical or a benzyl radical, preferably hydrogen or a C 1 -C 2 alkyl radical, and R 1 - R 9 , A and n are defined as above.
- sulfonamide derivatives of general formula (lc) are preferred, wherein A represents an optionally at least mono-substituted mono- or polycyclic aromatic ring system, wherein the ring(s) is/are 5- or 6-membered, which may be bonded via an optionally at least mono-substituted Ci—C ⁇ alkylene group, an optionally at least mono-substituted C2— C ⁇ alkenylene group or an optionally at least mono-substituted C2— C ⁇ alkynylene group and/or wherein the ring(s) may contain at least one heteroatom as a ring member,
- A represents an optionally at least mono-substituted mono- or polycyclic aromatic ring system, wherein the ring(s) is/are 5- or 6-membered and wherein one or more of the rings contain at least one heteroatom,
- X, Y, Z independently from one another, each represent a radical selected from the group consisting of hydrogen, fluorine, chlorine, bromine, nitro, acetyl, linear or branched CrC 6 alkyl, linear or branched CrC ⁇ alkoxy, linear or branched CrC ⁇ alkylthio, a trifluoromethyl radical, a cyano radical and a -NR 12 R 13 radical,
- R 12 and R 13 identical or different, each represent hydrogen or linear or branched CrC ⁇ alkyl
- W represents a single chemical bond between the two rings, a CH 2) O, S group or a NR 14 radical,
- R >14 is hydrogen or a linear or branched CrCe alkyl
- n 0, 1 , 2, 3 or 4 and
- sulfonamide derivatives of general formula (lc) are preferred, wherein A represents an optionally at least mono-substituted mono- or polycyclic aromatic ring system, wherein the ring(s) is/are 5- or 6-membered, which may be bonded via an optionally at least mono-substituted C ⁇ _C ⁇ alkylene group, an optionally at least mono-substituted C2— C ⁇ alkenylene group or an optionally at least mono-substituted C 2 _C ⁇ alkynylene group, and/or wherein the ring(s) may contain at least one heteroatom as a ring member,
- A represents an optionally at least mono-substituted mono- or polycyclic aromatic ring system, wherein the ring(s) is/are 5- or 6-membered and wherein one or more of the rings contain at least one heteroatom, or a radical chosen from the group consisting of
- X, Y, Z independently from one another, each represent a radical selected from the group consisting of hydrogen, fluorine, chlorine, bromine, linear or branched CrC ⁇ alkyl, linear or branched CrC 6 alkoxy, linear or branched d-C ⁇ alkylthio, a trifluoromethyl radical, a cyano radical and a - NR 12 R 13 radical,
- R 12 and R 13 identical or different, each represent hydrogen or linear or branched CrC 6 alkyl
- W represents a single chemical bond between the two rings, a CH 2 , O, S group or a NR 14 radical,
- R >14 is hydrogen or a linear or branched CrC ⁇ alkyl
- n O, 1 , 2, 3 or 4.
- R )1 - DR9 and n are defined as above.
- X, Y, Z independently from one another, each represent a radical selected from the group consisting of hydrogen, fluorine, chlorine, bromine, nitro, acetyl, linear or branched CrC 6 alkyl, linear or branched d-C ⁇ alkoxy, linear or branched C C ⁇ alkylthio, a trifluoromethyl radical, a cyano radical and a -NR 12 R 13 radical,
- R 12 and R 13 identical or different, each represent hydrogen or linear or branched CrC ⁇ alkyl
- W represents a single chemical bond between the two rings, a CH 2 , O, S group or a NR >14 radical,
- R >14 is hydrogen or a linear or branched CrC ⁇ alkyl
- n 0, 1 , 2, 3 or 4 and
- n 1 or 2 or 2, preferably 2, and R 1 -R 9 and n are defined as above.
- sulfonamide derivatives of general formula (lc) are preferred, wherein n is 0, 1 , 2, 3 or 4; preferably n is 1 , 2 or 3; more preferably n is 2 or 3 and R 1 to R 9 and A are defined as above.
- Another aspect of the present invention are compounds of general formula (lc),
- R 1 represents a -NR 8 R 9 radical
- R 2 represents hydrogen or an alkyl radical selected from the group consisting of methyl, ethyl, n-propyl and iso-propyl, more preferably hydrogen or methyl,
- R 3 , R 4 , R 6 and R 7 each represent hydrogen
- R 5 represents hydrogen
- R 8 and R 9 identical or different, each represent methyl, ethyl, n-propyl or iso- propyl, more preferably methyl or ethyl,
- R 8 and R 9 together with the bridging nitrogen form a 5- or 6-membered heterocyclic ring, more preferably form pyrrolidine or piperidine
- n 2 or 3
- the present invention likewise refers to the salts, preferably the physiologically acceptable salts of the compounds of general formula (la) and/or (lb) and/or of general formula (lc), preferably the addition salts of mineral acids, more preferably of hydrochloric acid, hydrobromic acid acid, phosphoric acid, sulphuric acid, nitric acid, and the salts of organic acids, more preferably of citric acid, maleic acid acid, fumaric acid, tartaric acid or their derivatives, p- toluenesulphonic acid, methanesulphonic acid, camphorsulphonic acid, etc.
- the salts preferably the physiologically acceptable salts of the compounds of general formula (la) and/or (lb) and/or of general formula (lc), preferably the addition salts of mineral acids, more preferably of hydrochloric acid, hydrobromic acid acid, phosphoric acid, sulphuric acid, nitric acid, and the salts of organic acids, more preferably of citric acid,
- sulfonamide derivatives of the general formula (I) refers to one or more compounds of general formula (la) and/or to one or more compounds of general formula (lb) and/or to one or more compounds of general formula (lc), respectively, and optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemate, or in form of a mixture of at least two of their stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or a salt thereof, preferably a corresponding physiologically acceptable salt thereof, or a corresponding solvate thereof.
- Another aspect of the present invention consists of a process for preparing the new derivatives of general formula (I), wherein R 1 -R 9 , n and A have the previously indicated meaning, according to which at least one compound of general formula (II),
- the reaction between the compounds of general formula (II) and (III) is usually carried out in the presence of an organic reaction medium, preferably in the presence of dialkyl ether, more preferably diethyl ether or a cyclic ether, more preferably tetrahydrofuran or dioxane, an halogenated organic hydrocarbon, more preferably methylene chloride or chloroform, an alcohol, more preferably methanol or ethanol, a dipolar aprotic solvent, more preferably acetonitrile, pyridine or dimethylformamide, or any other suitable reaction medium.
- dialkyl ether more preferably diethyl ether or a cyclic ether, more preferably tetrahydrofuran or dioxane
- an halogenated organic hydrocarbon more preferably methylene chloride or chloroform
- an alcohol more preferably methanol or ethanol
- a dipolar aprotic solvent more preferably acetonitrile, pyridine or dimethylformamide
- the reaction is preferably carried out in the presence of a suitable base, for example, an inorganic base, more preferably alkaline metal hydroxides and alkaline metal carbonates, or in the presence of an organic base, more preferably triethylamine, N-ethyldiisopropylamine or pyridine.
- a suitable base for example, an inorganic base, more preferably alkaline metal hydroxides and alkaline metal carbonates, or in the presence of an organic base, more preferably triethylamine, N-ethyldiisopropylamine or pyridine.
- the most suitable reaction temperatures range from 0°C to room temperature, that is, approximately 25°C, and the reaction time preferably comprises from 5 minutes to 24 hours.
- the resulting sulfonamide derivative of general formula (I) may be purified and/or isolated according to conventional methods known in the prior art.
- the sulfonamide derivatives of general formula (I) may be isolated by evaporating the reaction medium, adding water and, if necessary, adjusting the pH so that a solid which may be isolated by filtration is obtained; or the sulfonamide derivative may be extracted with a water immiscible solvent, preferably chloroform, and be purified by chromatography or recrystallization in a suitable solvent.
- the compounds of general formula (II) are commercially available, or they may be prepared according to standard methods known in the prior art, for example by methods similar to those described in the literature [E.E.Gilbert, Synthesis, 1969, 1 , 3].
- the compounds of general formula (III) may also be prepared according to standard methods known in the prior art, for example by methods similar to those described in the literature: Pigerol, Charles; De Cointet de Fillain, Paul; Eymard, Pierre; Manynec, Jean Pierre; Broil, Madeleine. (Labaz S. A., Fr.). Ger. Often. (1977). DE 2727047 19771229. Schwink, Lothar; Stengelin, Siegfried; Gossel, Dr.
- R 1 -R 7 and n have the previously indicated meaning, or one of their suitably protected derivatives, and, if necessary, the protective groups are removed in order to obtain the corresponding amine of general formula (III), which may be purified and/or isolated by means of conventional methods known in the prior art.
- the compounds of general formula (IV) may also be prepared according to standard methods known in the prior art, for example by methods similar to those described in the literature: Journal of Heterocyclic Chemistry, 37(5), 1103- 1108; 2000; Schwink, Lothar; Stengelin, Siegfried; Gossel, Matthias.
- R 2 -R 7 and n have the previously mentioned meaning, or one of their suitably protected derivatives, and, if necessary, the protective groups are removed in order to obtain the corresponding amine of general formula (III), which may be purified and/or isolated by means of conventional methods known in the prior art.
- the compounds of general formula (V) are commercially available or may also be prepared according to standard methods known in the prior art, as for example YAMASHKIN, S. A.; YUROVSKAYA, M. A.; Chem Heterocycl Compd (N Y) 1999, 35 (12), 1426-1432. OTTONI, O.; CRUZ, R.; KRAMMER, N.
- Another aspect of the present invention consists of a process for preparing the new sulfonamide derivatives of general formula (I), wherein R 1 -R 4 , R 6 -R 9 , A, n and A have the previously indicated meaning and R 5 is an alkyl radical, preferably a linear or branched, optionally at least mono-substituted d- C ⁇ alkyl radical, by alkylation of a sulfonamide derivative of general formula (I), wherein R 1 -R 4 , R 6 -R 9 , n and A have the previously indicated meaning, and R 5 is a hydrogen atom, with an alkyl halogenide or dialkyl sulfate.
- the alkylation reaction is carried out preferably in the presence of a suitable base, more preferably in the presence of alkaline metal hydroxides and alkaline metal carbonates, metal hydrides, metal alkoxides, even more preferably sodium methoxide or potassium tert-butoxide, organometallic compounds, even more preferably butyllithium or tert-butyllithium, in the presence of an organic reaction medium, more preferably dialkyl ether, even more preferably diethyl ether, or a cyclic ether, even more preferably tetrahydrofuran or dioxane, an hydrocarbon, even more preferably toluene, an alcohol, even more preferably methanol or ethanol, a dipolar aprotic solvent, even more preferably acetonitrile, pyridine or dimethylformamide, or any other suitable reaction medium.
- a suitable base more preferably in the presence of alkaline metal hydroxides and alkaline metal carbonates, metal hydrides, metal
- reaction temperatures range from 0°C to the boiling temperature of the reaction medium, and the reaction times preferably comprise from 1 to 24 hours.
- the resulting sulfonamide derivative of general formula (I) may be isolated by filtration, concentrating the filtrate under reduced pressure, adding water and, if necessary, adjusting the pH so that a solid which may be isolated by filtration is obtained; or the sulfonamide derivative may be extracted with a water immiscible solvent, preferably chloroform, and be purified by chromatography or recrystallization of a suitable solvent.
- a water immiscible solvent preferably chloroform
- the salts may be prepared by means of conventional methods known in the prior art, preferably by reaction with a mineral acid, more preferably by reaction with hydrochloric acid, hydrobromic acid, phosphoric acid acid, sulphuric acid or nitric acid, or by reaction with organic acids, more preferably by reaction with citric acid, maleic acid, fumaric acid acid, tartaric acid, or their derivatives, p-toluenesulphonic acid, methanesulphonic acid, camphorsulphonic acid, etc., in a suitable solvent, preferably methanol, ethanol, diethyl ether, ethyl acetate, acetonitrile or acetone, and obtaining the resulting salts by using the usual techniques for the precipitation or crystallization of the corresponding salts.
- a suitable solvent preferably methanol, ethanol, diethyl ether, ethyl acetate, acetonitrile or acetone
- the preferred physiologically acceptable salts of the sulfonamide derivatives of general formula (I) are the addition salts of mineral acids, more preferably of hydrochloric acid, hydrobromic acid, phosphoric acid, sulphuric acid acid or nitric acid, and the addition salts of organic acids, more preferably citric acid, maleic acid, fumaric acid, tartaric acid, or their derivatives, p- toluenesulphonic acid, methanesulphonic acid, camphorsulphonic acid, etc.
- the solvates preferably the physiologically acceptable solvates, more preferably hydrates, of the sulfonamide derivatives of general formula (I) or of the corresponding physiologically acceptable salts, may be prepared by methods known in the prior art.
- the sulfonamide derivatives of general formula (I) are obtained in form of a mixture of stereoisomers, preferably enantiomers or diastereomers, said mixtures may be separated by means of standard processes known in the prior art, for example chromatographic methods or crystallization with chiral agents.
- Another aspect of the present invention is a medicament comprising at least one indol-5-yl sulfonamide derivative of general formula (I), optionally in form of one of its stereoisomers, preferably enantiomers or diastereomers, its racemate, or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or a corresponding physiologically acceptable salt thereof or a corresponding solvate thereof, and optionally one or more pharmaceutically acceptable adjuvants.
- indol-5-yl sulfonamide derivative of general formula (I) optionally in form of one of its stereoisomers, preferably enantiomers or diastereomers, its racemate, or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or a corresponding physiologically acceptable salt thereof or a corresponding solvate thereof, and optionally one or
- This medicament is suitable for 5-HT 6 receptor regulation, for the prophylaxis and/or treatment of a disorder or disease related to food intake, preferably for the regulation of appetite, for the maintenance, increase or reduction of body weight, for the prophylaxis and/or treatment of obesity, bulimia, anorexia, cachexia or type II diabetes (non insulin dependent diabetes mellitus), preferably type II diabetes caused by obesity, for the prophylaxis and/or treatment of gastrointestinal tract disorders, preferably irritable bowel syndrome, for cognitive enhancement, for the prophylaxis and/or treatment of disorders of the central nervous system, anxiety, panic disorders, depression, bipolar disorders, cognitive memory disorders, senile dementia processes, neurodegenerative disorders, preferably Alzheimer's disease, Parkinson's disease, Huntington's disease and Multiple Sclerosis, schizophrenia, psychosis or infantile hyperkinesia (ADHD, attention deficit / hyperactivity disorder), and other disorders mediated by the 5-HT ⁇ serotonin receptor in humans and/or in animals, preferably in mammals, more
- Another aspect of the present invention is a medicament comprising at least one indol-5-yl sulfonamide derivative of general formula (la), optionally in form of one of its stereoisomers, preferably enantiomers or diastereomers, its racemate, or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or a corresponding physiologically acceptable salt thereof or a corresponding solvate thereof, and optionally one or more pharmaceutically acceptable adjuvants.
- la indol-5-yl sulfonamide derivative of general formula (la)
- This medicament is suitable for 5-HT 6 receptor regulation, for the prophylaxis and/or treatment of a disorder or disease related to food intake, preferably for the regulation of appetite, for the maintenance, increase or reduction of body weight, for the prophylaxis and/or treatment of obesity, bulimia, anorexia, cachexia or type II diabetes (non insulin dependent diabetes mellitus), preferably type II diabetes caused by obesity, for the prophylaxis and/or treatment of gastrointestinal tract disorders, preferably irritable bowel syndrome, for cognitive enhancement, for the prophylaxis and/or treatment of disorders of the central nervous system, anxiety, panic disorders, depression, bipolar disorders, cognitive memory disorders, senile dementia processes, neurodegenerative disorders, preferably Alzheimer's disease, Parkinson's disease, Huntington's disease and Multiple Sclerosis, schizophrenia, psychosis or infantile hyperkinesia (ADHD, attention deficit / hyperactivity disorder) and other disorders mediated by the 5-HT 6 serotonin receptor in humans and/or in animals, preferably in mammals, more
- Another aspect of the present invention is a medicament comprising at least one indol-5-yl sulfonamide derivative of general formula (lb), optionally in form of one of its stereoisomers, preferably enantiomers or diastereomers, its racemate, or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or a corresponding physiologically acceptable salt thereof or a corresponding solvate thereof, and optionally one or more pharmaceutically acceptable adjuvants.
- indol-5-yl sulfonamide derivative of general formula (lb) optionally in form of one of its stereoisomers, preferably enantiomers or diastereomers, its racemate, or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or a corresponding physiologically acceptable salt thereof or a corresponding solvate thereof, and optionally
- This medicament is suitable for 5-HT 6 receptor regulation, for the prophylaxis and/or treatment of a disorder or disease related to food intake, preferably for the regulation of appetite, for the maintenance, increase or reduction of body weight, for the prophylaxis and/or treatment of obesity, bulimia, anorexia, cachexia or type II diabetes (non insulin dependent diabetes mellitus), preferably type II diabetes caused by obesity, for the prophylaxis and/or treatment of gastrointestinal tract disorders, preferably irritable bowel syndrome, for cognitive enhancement, for the prophylaxis and/or treatment of disorders of the central nervous system, anxiety, panic disorders, depression, bipolar disorders, cognitive memory disorders, senile dementia processes, neurodegenerative disorders, preferably Alzheimer's disease, Parkinson's disease, Huntington's disease and Multiple Sclerosis, schizophrenia, psychosis or infantile hyperkinesia (ADHD, attention deficit / hyperactivity disorder) and other disorders mediated by the 5-HT 6 serotonin receptor in humans and/or in animals, preferably in mammals, more
- Another aspect of the present invention is a medicament composed of at least one indol-5-yl sulfonamide derivative of general formula (lc), optionally in form of one of its stereoisomers, preferably enantiomers or diastereomers, its racemate, or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or a corresponding physiologically acceptable salt thereof or a corresponding solvate thereof, and optionally one or more pharmaceutically acceptable adjuvants.
- indol-5-yl sulfonamide derivative of general formula (lc) optionally in form of one of its stereoisomers, preferably enantiomers or diastereomers, its racemate, or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or a corresponding physiologically acceptable salt thereof or a corresponding solvate thereof, and optionally
- This medicament is suitable for 5-HT 6 receptor regulation, for the prophylaxis and/or treatment of a disorder or disease related to food intake, preferably for the regulation of appetite, for the maintenance, increase or reduction of body weight, for the prophylaxis and/or treatment of obesity, bulimia, anorexia, cachexia or type II diabetes (non insulin dependent diabetes mellitus), preferably type II diabetes caused by obesity, for the prophylaxis and/or treatment of gastrointestinal tract disorders, preferably irritable bowel syndrome, for cognitive enhancement, for the prophylaxis and/or treatment of disorders of the central nervous system, anxiety, panic disorders, depression, bipolar disorders, cognitive memory disorders, senile dementia processes, neurodegenerative disorders, preferably Alzheimer's disease, Parkinson's disease, Huntington's disease and Multiple Sclerosis, schizophrenia, psychosis or infantile hyperkinesia (ADHD, attention deficit / hyperactivity disorder) and other disorders mediated by the 5-HT 6 serotonin receptor in humans and/or in animals, preferably in mammals, more
- the medicament obtained according to the present invention is particularly suitable for the administration to mammals, including man.
- the medicament may preferably be administered to all age groups, namely, children, adolescents and adults.
- Another aspect of the present invention is the use of at least one sulfonamide derivative of general formula (I), optionally in form of one of its stereoisomers, preferably enantiomers or diastereomers, its racemate, or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or a corresponding physiologically acceptable salt thereof or a corresponding solvate thereof, for the manufacture of a medicament for 5-HT ⁇ receptor regulation, for the prophylaxis and/or treatment of a disorder or disease related to food intake, preferably for the regulation of appetite, for the maintenance, increase or reduction of body weight, for the prophylaxis and/or treatment of obesity, bulimia, anorexia, cachexia or type II diabetes (non insulin dependent diabetes mellitus), preferably type II diabetes caused by obesity, for the prophylaxis and/or treatment of gastrointestinal tract disorders, preferably irritable bowel syndrome, for cognitive enhancement, for the prophyl
- Another aspect of the present invention is the use of at least one sulfonamide derivative of the previous general formula (la), optionally in form of one of its stereoisomers, preferably enantiomers or diastereomers, its racemate, or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or a corresponding physiologically acceptable salt thereof or a corresponding solvate thereof, for the manufacture of a medicament for 5-HT 6 receptor regulation, for the prophylaxis and/or treatment of a disorder or disease related to food intake, preferably for the regulation of appetite, for the maintenance, increase or reduction of body weight, for the prophylaxis and/or treatment of obesity, bulimia, anorexia, cachexia or type II diabetes (non insulin dependent diabetes mellitus), preferably type II diabetes caused by obesity, for the prophylaxis and/or treatment of gastrointestinal tract disorders, preferably irritable bowel syndrome, for cognitive enhancement, for the pro
- Another aspect of the present invention is the use of at least one sulfonamide derivative of the previous general formula (lb), optionally in form of one of its stereoisomers, preferably enantiomers or diastereomers, its racemate, or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or a corresponding physiologically acceptable salt thereof or a corresponding solvate thereof, for the manufacture of a medicament for 5-HT 6 receptor regulation, for the prophylaxis and/or treatment of a disorder or disease related to food intake, preferably for the regulation of appetite, for the maintenance, increase or reduction of body weight, for the prophylaxis and/or treatment of obesity, bulimia, anorexia, cachexia or type II diabetes (non insulin dependent diabetes mellitus), preferably type II diabetes caused by obesity, for the prophylaxis and/or treatment of gastrointestinal tract disorders, preferably irritable bowel syndrome, for cognitive enhancement, for the
- Another aspect of the present invention is the use of at least one sulfonamide derivative of the previous general formula (lc), optionally in form of one of its stereoisomers, preferably enantiomers or diastereomers, its racemate, or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or a corresponding physiologically acceptable salt thereof or a corresponding solvate thereof, for the manufacture of a medicament for 5-HT 6 receptor regulation, for the prophylaxis and/or treatment of a disorder or disease related to food intake, preferably for the regulation of appetite, for the maintenance, increase or reduction of body weight, for the prophylaxis and/or treatment of obesity, bulimia, anorexia, cachexia or type II diabetes (non insulin dependent diabetes mellitus), preferably type II diabetes caused by obesity, for the prophylaxis and/or treatment of gastrointestinal tract disorders, preferably irritable bowel syndrome, for cognitive enhancement, for the
- compositions may, in addition to at least one sulfonamide derivative of general formula (I), optionally in form of one of its stereoisomers, preferably enantiomers or diastereomers, its racemate, or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or a corresponding physiologically acceptable salt thereof or a corresponding solvate thereof, as excipients, fillers, solvents, diluents, dyes, coating agents, matrix forming agents and/or binders.
- sulfonamide derivative of general formula (I) optionally in form of one of its stereoisomers, preferably enantiomers or diastereomers, its racemate, or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or a corresponding physiologically acceptable salt thereof or a corresponding solvate thereof, as excipient
- Medicaments suitable for oral administration are, for example, tablets, coated tablets, capsules or multiparticulates, preferably granules or pellets, optionally subjected to compression in tablets, filled in capsules or suspended in solutions, suspensions or suitable liquids.
- Medicaments suitable for parenteral, topical or inhalatory administration may preferably be chosen from the group consisting of solutions, suspensions, quickly reconstitutable dry preparations and also sprays.
- Medicaments suitable for oral or percutaneous use may release the sulfonamide compounds of general formula (I) in a sustained manner, the preparation of these sustained release medicaments generally being known in the prior art.
- Suitable sustained release forms are known in the art, for example from the indices of "Modified-Release Drug Delivery Technology", Rathbone, J.JI, Hadgraft, J. and Roberts, M.S. (Eds.), Marcel Dekker, Inc., New York (2002); "Handbook of Pharmaceutical Controlled Release Technology”, Wise, D.L. (Ed.), Marcel Dekker, Inc. New York (2000); "Controlled Drug Delivery", Vol. I, Basic Concepts, Bruck, S.D. (Ed.), CRD Press, Inc., Boca Raton (1983), and by
- the medicament of the present invention may also have at least one enteric coating, which dissolves according to the pH. As a result of this coating, the medicament may pass through the stomach without dissolving, and the compounds of general formula I are only released in the intestinal tract.
- the enteric coating preferably dissolves at a pH of between 5 and 7.5.
- the materials and methods suitable for preparing enteric coatings are also known in the prior art.
- the pharmaceutical compositions and the medicaments comprise from 1 to 60% by weight of one or more sulfonamide derivatives of general formula (I), and from 40 to 99% by weight of one or more excipients.
- the active substance amount to be administered to the patient varies according to the patient's weight, the administration route, the indication and the severity of the disorder. Usually from 1 mg to 2 g of at least one sulfonamide derivative of general formula (I) are administered per patient per day. The total daily dose may be administered to the patient in one or more doses.
- the commercial membrane is diluted (1 :40 dilution) with the binding buffer: 50 mM Tris-HCI, 10 mM MgCI 2 , 0.5 mM EDTA (pH 7.4).
- the radioligand used is [ 3 H]-LSD at a concentration of 2.7 nM, the final volume being 200 ⁇ l. Incubation begins by adding 100 ⁇ l of the membrane suspension ( « 22.9 ⁇ g of membrane protein), and is prolonged for 60 minutes at a temperature of 37°C.
- mice Male W rats (200-270 g) from Harlan, S.A. are used. The animals are acclimatized to the housings during at least 5 days prior to being subjected to any treatment. During this period, the animals are housed (in groups of five) in translucent cages and have free access to water and food. The animals are housed in individual cages at least 24 hours prior to starting the treatment.
- the acute effect of the sulfonamide derivatives of formula (I) used inventively on food ingestion in rats in fasting conditions is then determined as follows: The rats are kept in fasting conditions for 23 hours in their individual cages.
- the rats are orally or intraperitoneally treated with a dose of a composition containing a sulfonamide derivative of general formula (I) or a corresponding composition (vehicle) without said sulfonamide derivative.
- a composition containing a sulfonamide derivative of general formula (I) or a corresponding composition (vehicle) without said sulfonamide derivative is administered a dose of a composition containing a sulfonamide derivative of general formula (I) or a corresponding composition (vehicle) without said sulfonamide derivative.
- the rat is left with pre-weighed food and the accumulated food intake is measured after 1 , 2, 4 and 6 hours.
- This food ingestion measuring method is also described in publications of Kask et al., European Journal of Pharmacology 414 (2001 ), 215-224, and Turnbull et al., Diabetes, Vol. 51 , August, 2002.
- the respective bibliographic descriptions are incorporated as a reference and they form
- Example 50 Preparation of 3,5-dichloro-N-(1-(3-(piperidin-1-yl)propyl)-1 H-indol- 5-yl)benzenesulfonylamide
- the melting point and spectroscopic data for identifying some of the compounds of the present invention are indicated in the following table.
- T of the present invention are indic
- T ised between 1 milligram and 2 gr istered in one or several doses.
- T t are compatible with the administ ti t d f bl t bl t t d t blets, capsules, suppositories, solutions or suspensions.
- These compositions are prepared by means of known methods and comprise from 1 to 60% by weight of the active
Abstract
Description
Claims
Priority Applications (11)
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MXPA06001159A MXPA06001159A (en) | 2003-07-30 | 2004-07-29 | Indol-5-yl sulfonamide derivatives, their preparation and their use 5-ht-6 as modulators. |
AT04763610T ATE432699T1 (en) | 2003-07-30 | 2004-07-29 | INDOL-5 SULFONAMIDE DERIVATIVES, THEIR PREPARATION AND USE AS 5-HT-6 MODULATORS |
AU2004262485A AU2004262485A1 (en) | 2003-07-30 | 2004-07-29 | Indol-5-yl sulfonamide derivatives, their preparation and their use 5-HT-6 as modulators |
JP2006521529A JP2007500165A (en) | 2003-07-30 | 2004-07-29 | Indole-5 sulfonamide derivatives, their preparation and their use as 5-HT-6 modulators |
CA002533976A CA2533976A1 (en) | 2003-07-30 | 2004-07-29 | Indol-5-yl sulfonamide derivatives, their preparation and their use 5-ht-6 as modulators |
DE602004021384T DE602004021384D1 (en) | 2003-07-30 | 2004-07-29 | INDOL-5-SULFONAMIDE DERIVATIVES, THEIR PREPARATION AND USE AS 5-HT-6 MODULATORS |
US10/566,094 US20070032520A1 (en) | 2003-07-30 | 2004-07-29 | Indol-5-yl sulfonamide derivatives, their preparation and their use 5-ht-6 as modulators |
BRPI0413110-0A BRPI0413110A (en) | 2003-07-30 | 2004-07-29 | Indo-5-yl sulfonamide derivatives, their preparation and use of 5-ht-6 as modulators |
EP04763610A EP1648445B1 (en) | 2003-07-30 | 2004-07-29 | Indol-5-yl sulfonamide derivatives, their preparation and their use 5-ht-6 as modulators |
IL172891A IL172891A0 (en) | 2003-07-30 | 2005-12-29 | Indol-5-yl-sulfonamide derivatives, their preparation and their use 5-ht-6 as modulators |
NO20060865A NO20060865L (en) | 2003-07-30 | 2006-02-22 | Indol-5-YL sulfonamide derivatives, their preparation and their use 5-HT-6 as modulators |
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ES200301805A ES2222827B1 (en) | 2003-07-30 | 2003-07-30 | DERIVATIVES OF 5-INDOLILSULFONAMIDS, ITS PREPARATION AND ITS APPLICATION AS MEDICINES. |
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US (1) | US20070032520A1 (en) |
EP (1) | EP1648445B1 (en) |
JP (1) | JP2007500165A (en) |
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CN (1) | CN100558355C (en) |
AR (1) | AR045156A1 (en) |
AT (1) | ATE432699T1 (en) |
AU (1) | AU2004262485A1 (en) |
BR (1) | BRPI0413110A (en) |
CA (1) | CA2533976A1 (en) |
DE (1) | DE602004021384D1 (en) |
EC (1) | ECSP066325A (en) |
ES (2) | ES2222827B1 (en) |
IL (1) | IL172891A0 (en) |
MX (1) | MXPA06001159A (en) |
NO (1) | NO20060865L (en) |
PE (1) | PE20050725A1 (en) |
PT (1) | PT1648445E (en) |
RU (1) | RU2006105779A (en) |
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Cited By (11)
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WO2008099000A2 (en) * | 2007-02-16 | 2008-08-21 | Boehringer Ingelheim International Gmbh | Substituted arylsulphonylglycines, the preparation thereof and the use thereof as pharmaceutical compositions |
WO2008113760A3 (en) * | 2007-03-16 | 2008-11-13 | Boehringer Ingelheim Int | Arylsulphonyglycine derivatives as suppressors of the interaction of glycogen phosphorylase a with the gl subunit of glycogen-associated protein phosphatase 1 (ppl) for the treatment of metabolic disorders, particulary diabetes |
EP2018861A1 (en) * | 2007-07-26 | 2009-01-28 | Laboratorios del Dr. Esteve S.A. | 5HT6-Ligands such as sulfonamide derivatives in drug-induced weight-gain |
EP2020230A1 (en) | 2007-08-01 | 2009-02-04 | Laboratorios del Dr. Esteve S.A. | Combination of at least two 5-HT6-Ligands |
EP2053052A1 (en) | 2007-10-23 | 2009-04-29 | Laboratorios del Dr. Esteve S.A. | Process for the preparation of 6-substituted imidazo[2,1-b]thiazole-5-sulfonyl halide |
US7968538B2 (en) | 2005-01-25 | 2011-06-28 | Galenea Corp. | Substituted arylamine compounds and methods of treatment |
US7973069B2 (en) | 2004-07-14 | 2011-07-05 | Ptc Therapeutics, Inc. | Methods for treating hepatitis C |
US8013006B2 (en) | 2004-07-14 | 2011-09-06 | Ptc Therapeutics, Inc. | Methods for treating hepatitis C |
US8163911B2 (en) | 2007-09-05 | 2012-04-24 | Boehringer Ingelheim International Gmbh | Arylsulfonylaminomethylphosphonic acid derivatives, the preparation thereof and the use thereof as pharmaceutical compositions |
US8211923B2 (en) | 2007-07-27 | 2012-07-03 | Boehringer Ingelheim International Gmbh | Substituted arylsulfonylaminomethylphosphonic acid derivatives, their preparation and their use in the treatment of type I and II diabetes mellitus |
US8357689B2 (en) | 2007-07-27 | 2013-01-22 | Boehringer Ingelheim International Gmbh | Substituted arylsulfonylaminomethylphosphonic acid derivatives, their preparation and their use in the treatment of type I and II diabetes mellitus |
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EP1953153A1 (en) * | 2007-01-31 | 2008-08-06 | Laboratorios del Dr. Esteve S.A. | Heterocyclyl-substituted sulfonamides for the treatment of cognitive or food ingestion related disorders |
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US20190336585A1 (en) * | 2018-05-03 | 2019-11-07 | John Lawrence Mee | Method for sustainable human cognitive enhancement |
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2003
- 2003-07-30 ES ES200301805A patent/ES2222827B1/en not_active Expired - Fee Related
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2004
- 2004-07-29 ES ES04763610T patent/ES2327847T3/en active Active
- 2004-07-29 AT AT04763610T patent/ATE432699T1/en not_active IP Right Cessation
- 2004-07-29 DE DE602004021384T patent/DE602004021384D1/en active Active
- 2004-07-29 BR BRPI0413110-0A patent/BRPI0413110A/en not_active Application Discontinuation
- 2004-07-29 EP EP04763610A patent/EP1648445B1/en active Active
- 2004-07-29 WO PCT/EP2004/008511 patent/WO2005013977A1/en active Application Filing
- 2004-07-29 CA CA002533976A patent/CA2533976A1/en not_active Abandoned
- 2004-07-29 CN CNB2004800224721A patent/CN100558355C/en not_active Expired - Fee Related
- 2004-07-29 KR KR1020067001392A patent/KR20060066710A/en not_active Application Discontinuation
- 2004-07-29 AU AU2004262485A patent/AU2004262485A1/en not_active Abandoned
- 2004-07-29 AR ARP040102698A patent/AR045156A1/en unknown
- 2004-07-29 TW TW093122669A patent/TW200504014A/en unknown
- 2004-07-29 US US10/566,094 patent/US20070032520A1/en not_active Abandoned
- 2004-07-29 RU RU2006105779/04A patent/RU2006105779A/en unknown
- 2004-07-29 MX MXPA06001159A patent/MXPA06001159A/en active IP Right Grant
- 2004-07-29 ZA ZA200600422A patent/ZA200600422B/en unknown
- 2004-07-29 JP JP2006521529A patent/JP2007500165A/en active Pending
- 2004-07-29 PT PT04763610T patent/PT1648445E/en unknown
- 2004-08-02 PE PE2004000736A patent/PE20050725A1/en not_active Application Discontinuation
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2005
- 2005-12-29 IL IL172891A patent/IL172891A0/en unknown
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US8013006B2 (en) | 2004-07-14 | 2011-09-06 | Ptc Therapeutics, Inc. | Methods for treating hepatitis C |
US7973069B2 (en) | 2004-07-14 | 2011-07-05 | Ptc Therapeutics, Inc. | Methods for treating hepatitis C |
US7968538B2 (en) | 2005-01-25 | 2011-06-28 | Galenea Corp. | Substituted arylamine compounds and methods of treatment |
US8604021B2 (en) | 2005-01-25 | 2013-12-10 | Oren Becker | Substituted arylamine compounds and methods of treatment |
JP2010518149A (en) * | 2007-02-16 | 2010-05-27 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | Substituted arylsulfonylglycines, their preparation and their use as pharmaceutical compositions |
WO2008099000A3 (en) * | 2007-02-16 | 2009-06-18 | Boehringer Ingelheim Int | Substituted arylsulphonylglycines, the preparation thereof and the use thereof as pharmaceutical compositions |
WO2008099000A2 (en) * | 2007-02-16 | 2008-08-21 | Boehringer Ingelheim International Gmbh | Substituted arylsulphonylglycines, the preparation thereof and the use thereof as pharmaceutical compositions |
US8232312B2 (en) | 2007-03-16 | 2012-07-31 | Boehringer Ingelheim International Gmbh | Substituted arylsulphonylglycines, the preparation thereof and the use thereof as pharmaceutical compositions |
WO2008113760A3 (en) * | 2007-03-16 | 2008-11-13 | Boehringer Ingelheim Int | Arylsulphonyglycine derivatives as suppressors of the interaction of glycogen phosphorylase a with the gl subunit of glycogen-associated protein phosphatase 1 (ppl) for the treatment of metabolic disorders, particulary diabetes |
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EP2018861A1 (en) * | 2007-07-26 | 2009-01-28 | Laboratorios del Dr. Esteve S.A. | 5HT6-Ligands such as sulfonamide derivatives in drug-induced weight-gain |
ES2360164A1 (en) * | 2007-07-26 | 2011-06-01 | Laboratorios Del Dr. Esteve, S.A. | 5ht6-ligands in drug-induced weight-gain |
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US8211923B2 (en) | 2007-07-27 | 2012-07-03 | Boehringer Ingelheim International Gmbh | Substituted arylsulfonylaminomethylphosphonic acid derivatives, their preparation and their use in the treatment of type I and II diabetes mellitus |
US8357689B2 (en) | 2007-07-27 | 2013-01-22 | Boehringer Ingelheim International Gmbh | Substituted arylsulfonylaminomethylphosphonic acid derivatives, their preparation and their use in the treatment of type I and II diabetes mellitus |
EP2020230A1 (en) | 2007-08-01 | 2009-02-04 | Laboratorios del Dr. Esteve S.A. | Combination of at least two 5-HT6-Ligands |
US8163911B2 (en) | 2007-09-05 | 2012-04-24 | Boehringer Ingelheim International Gmbh | Arylsulfonylaminomethylphosphonic acid derivatives, the preparation thereof and the use thereof as pharmaceutical compositions |
EP2053052A1 (en) | 2007-10-23 | 2009-04-29 | Laboratorios del Dr. Esteve S.A. | Process for the preparation of 6-substituted imidazo[2,1-b]thiazole-5-sulfonyl halide |
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AU2004262485A1 (en) | 2005-02-17 |
MXPA06001159A (en) | 2006-04-24 |
NO20060865L (en) | 2006-02-22 |
US20070032520A1 (en) | 2007-02-08 |
TW200504014A (en) | 2005-02-01 |
EP1648445A1 (en) | 2006-04-26 |
PT1648445E (en) | 2009-09-03 |
CN1832740A (en) | 2006-09-13 |
CA2533976A1 (en) | 2005-02-17 |
CN100558355C (en) | 2009-11-11 |
DE602004021384D1 (en) | 2009-07-16 |
JP2007500165A (en) | 2007-01-11 |
ATE432699T1 (en) | 2009-06-15 |
PE20050725A1 (en) | 2005-11-16 |
KR20060066710A (en) | 2006-06-16 |
ECSP066325A (en) | 2006-08-30 |
RU2006105779A (en) | 2007-09-20 |
ES2222827B1 (en) | 2006-03-01 |
ES2327847T3 (en) | 2009-11-04 |
BRPI0413110A (en) | 2006-10-03 |
ZA200600422B (en) | 2007-03-28 |
IL172891A0 (en) | 2006-06-11 |
AR045156A1 (en) | 2005-10-19 |
ES2222827A1 (en) | 2005-02-01 |
EP1648445B1 (en) | 2009-06-03 |
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