English
Tiếng Việt
(en)The present invention refers to new sulfonamide derivatives, of general formula (1a, 1b, 1c) 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 their salts, preferably the corresponding, physiologically acceptable salts, or corresponding solvates; to the processes for their preparation, to their application as medicaments in human and/or veterinary therapeutics, and to the pharmaceutical compositions containing them.
1.ApplicationNumber: US-56609404-A
1.PublishNumber: US-2007032520-A1
2.Date Publish: 20070208
3.Inventor: MERCE VIDAL RAMON
CODONY SOLER XAVIER
DORDAL ZUERAS ALBERTO
4.Inventor Harmonized: MERCE VIDAL RAMON(ES)
CODONY SOLER XAVIER(ES)
DORDAL ZUERAS ALBERTO(ES)
5.Country: US
6.Claims:
(en)The present invention refers to new sulfonamide derivatives, of general formula (1a, 1b, 1c) 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 their salts, preferably the corresponding, physiologically acceptable salts, or corresponding solvates; to the processes for their preparation, to their application as medicaments in human and/or veterinary therapeutics, and to the pharmaceutical compositions containing them.
7.Description:
(en)The present invention refers to new sulfonamide derivatives, of general formula (Ia, Ib, Ic),
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 their salts, preferably the corresponding, physiologically acceptable salts thereof, or corresponding solvates thereof; to the processes for their preparation, to their application in medicaments in human and/or veterinary therapeutics, and to the pharmaceutical compositions containing them.
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-HT 1 -5-HT 7 ), 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., 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. Neurochem., 1996, 66, 47]. The compounds with an affinity for the 5-HT 6 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. Ther., 1995, 274,173; A. J. Sleight, et al., Behav. Brain Res., 1996, 73, 245; T. A. Branchek, et al., Annu. Rev. Pharmacol. Toxicol., 2000, 40, 319; C. Routledge, et al., Br. J. Pharmacol., 2000,130,1606]. It has been shown that the typical and atypical antipsychotics for treating schizophrenia have a high affinity for the 5-HT 6 receptors [B. L. Roth, et al., J. Pharmacol. Exp. Ther., 1994, 268, 1403; C. E. Glatt, et al., Mol. Med., 1995, 1, 398; F. J. Mosma, et al., Mol. Pharmacol., 1993, 43, 320; T. Shinkai, et al, Am. J. Med. Genet, 1999, 88, 120]. 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. Gérard, et al., Brain Research, 1997, 746, 207; M. R. Pranzatelli, Drugs of Today, 1997, 33, 379].
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 6 receptor antagonist activity.
Patent application EP 0 733 628 discloses sulfonamides derived from indole with 5-HT 1F receptor antagonist activity, useful for the treatment of migraines.
Furthermore, it has been shown that the 5-HT 6 receptor plays a role in the ingestion of food [Neuropharmacology, 41, 2001, 210-219].
Eating disorders, particularly obesity, 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 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, preferably Alzheimers 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 preferably in humans.
It has been found that the indol-5-yl sulfonamide compounds of general formulas (Ia, Ib, Ic) described below show an affinity for the 5-HT 6 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 infantile hyperkinesia (ADHD, attention deficit/hyperactivity disorder) and other disorders mediated by the 5-HT 6 serotonin receptor in mammals, including humans. These compounds are also suitable for the preparation of a medicament for cognitive enhancement.
Thus, one aspect of the present invention are compounds of general formula (Ia),
wherein
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,
with the proviso that 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
and
n is 0, 1, 2, 3 or 4;
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 salt thereof, preferably a corresponding, physiologically acceptable salt thereof, or a corresponding solvate thereof.
Another aspect of the present invention are compounds of the general formula (Ib)
wherein
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;
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 salt thereof, preferably a corresponding, physiologically acceptable salt thereof, or a corresponding solvate thereof.
Yet, another aspect of the present invention are compounds of general formula (Ic),
wherein
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,
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
and
n is 0, 1, 2, 3or4;
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 salt thereof, preferably a corresponding, physiologically acceptable salt thereof, or a corresponding solvate thereof.
If one or more of the 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.
If 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 1 -C 6 alkyl, linear or branched C 1 -C 6 alkoxy, linear or branched C 1 -C 6 perfluoroalkyl, linear or branched C 1 -C 6 perfluoroalkoxy and benzyl, preferably from the group consisting of linear or branched C 1 -C 6 alkyl and benzyl.
The 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.
If 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 1 -C 6 alkyl, linear or branched C 1 -C 6 alkoxy, linear or branched C 1 -C 6 perfluoroalkyl, linear or branched C 1 -C 6 perfluoroalkoxy and benzyl, preferably from the group consisting of linear or branched C 1 -C 6 alkyl and benzyl.
If the 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 lo 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.
If 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, each one of these substituents may preferably be chosen from the group consisting of nitro, —O-phenyl, —O—C 1-6 alkyl, —C(═O)—C 1-6 alkyl, hydroxy, halogen, linear or branched C 1 -C 6 alkyl, linear or branched C 1 -C 6 alkoxy, linear or branched C 1 -C 6 perfluoroalkyl, linear or branched C 1 -C 6 perfluoroalkoxy, an optionally at least mono-substituted phenyl radical and 5- or 6-membered heteroaryl, more preferably from the group consisting of nitro, —O-phenyl, —C(═O)-C 1-6 alkyl, linear or branched C 1 -C 6 alkoxy, halogen, linear or branched C 1 -C 6 alkyl, an optionally at least mono-substituted phenyl radical and 5- or 6-membered heteroaryl, even more preferably from the group consisting of nitro, —O-phenyl, —O—CH 3 , —C(═O)—CH 3 , fluorine, chlorine, bromine, linear or branched C 1 -C 6 alkyl, an optionally at least mono-substituted phenyl radical and 5- or 6-membered heteroaryl.
If one or more of the rings of the mono- or polycyclic aromatic ring system contain one or more heteroatoms, these 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.
If the previously mentioned phenyl radical is itself substituted by one or more substituents, each one of these substituents may preferably be chosen from the group consisting of fluorine, chlorine, bromine, linear or branched C 1 -C 6 alkyl, linear or branched C 1 -C 6 alkoxy, linear or branched C 1 -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 1 -C 6 alkyl.
If the previously mentioned alkylene, alkenylene or alkynylene group is substituted by one or more substituents, each of these substituents may preferably be chosen from the group consisting of hydroxy, halogen, linear or branched C 1 -C 6 alkyl, linear or branched C 1 -C 6 alkoxy, linear or branched C 1 -C 6 perfluoroalkyl, linear or branched C 1 -C 6 perfluoroalkoxy or an optionally at least mono-substituted phenyl radical.
If said phenyl radical is itself substituted by one or more substituents, each one of these substituents may preferably be chosen from the group consisting of fluorine, chlorine, bromine, linear or branched C 1 -C 6 alkyl, linear or branched C 1 -C 6 alkoxy, linear or branched C 1 -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 1 -C 6 alkyl.
If one or more of the substituents R 2 , R 3 , R 4 , R 6 and R 7 represents an alcoxy radical, said radical may have 1 to 6, preferably 1 to 3 carbon atoms.
Those skilled in the art understand that the term “condensed” indicates that the condensed rings share more than one atom. The terms “annulated” or “fused” may also be used for this type of bonding.
Sulfonamide derivatives of general formula (la) are preferred, wherein 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,
more preferably R 1 represents an —NR 8 R 9 radical or a radical chosen from the group consisting of
wherein, if present, the dotted line is an optional chemical bond, and R 10 represents hydrogen, a linear or branched C 1 -C 6 alkyl radical or a benzyl radical, preferably hydrogen or a C 1 -C 2 alkyl radical and R 2 to R 9 , A and n are defined as above.
Sulfonamide derivatives of general formula (Ia) 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 1 -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,
more preferably 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 1 -C 6 alkyl radical,
even more preferably 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.
The use of sulfonamide derivatives of general formula (Ia) is also preferred, wherein R 5 represents hydrogen, a linear or branched, optionally at least mono-substituted C 1 -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,
more preferably R 5 represents hydrogen or a linear or branched, optionally at least mono-substituted C 1 -C 6 alkyl radical,
even more preferably R 5 represents hydrogen or a C 1 -C 2 alkyl radical and R 1 —R 4 , R 6 -R 9 , A and n are defined as above.
Furthermore, sulfonamide derivatives of general formula (Ia) 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 10 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.
Particularly preferred is the use of sulfonamide derivatives of general formula (la), wherein R 8 and R 9 , identical or different, each represent hydrogen or a linear or branched C 1 -C 10 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 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 nitrogen atom bridge form a radical chosen from the group consisting of
wherein R 11 , if present, represents hydrogen, a linear or branched C 1 -C 6 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.
Furthermore, sulfonamide derivatives of general formula (Ia) 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 1 -C 6 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,
preferably 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
wherein 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 1 -C 6 alkyl, linear or branched C 1 -C 6 alkoxy, linear or branched C 1 -C 6 alkylthio, a trifluoromethyl radical, a cyano radical and a —NR 12 R 13 radical,
wherein R 12 and R 13 , identical or different, each represent hydrogen or linear or branched C 1 -C 6 alkyl,
W represents a single chemical bond between the two rings, a CH 2 , O, S group or a NR 14 radical,
wherein R 14 is hydrogen or a linear or branched C 1 -C 6 alkyl,
m is 0, 1, 2, 3 or 4 and
m1 is 1 or 2, preferably 2, and R 1 —R 9 and n are defined as above.
Furthermore, sulfonamide derivatives of general formula (Ia) 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 1 -C 6 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,
more preferably 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
wherein X, Y, Z, independently from one another, each represent a radical selected from the group consisting of hydrogen, fluorine, chlorine, bromine, linear or branched C 1 -C 6 alkyl, linear or branched C 1 -C 6 alkoxy, linear or branched C 1 -C 6 alkylthio, a trifluoromethyl radical, a cyano radical and a —NR 12 R 13 radical,
wherein R 12 and R 13 , identical or different, each represent hydrogen or linear or branched C 1 -C 6 alkyl,
W represents a single chemical bond between the two rings, a CH 2 , O, S group or a NR 14 radical,
wherein R 14 is hydrogen or a linear or branched C 1 -C 6 alkyl,
and
m is 0, 1, 2, 3 or 4.
and R 1 —R 9 and n are defined as above.
Furthermore, sulfonamide derivatives of general formula (Ia) are preferred, wherein A represents a heteroaryl radical selected from the group consisting of quinolinyl, benzo[b]thiophenyl, benzo[1,2,5]thiadiazolyl, thiophenyl and imidazo[2,1-b]thiazolyl which may be substituted by 1, 2 or 3 substituents selected from the group consisting of fluorine, bromine, chlorine, methyl, phenyl, nitro, —C(═O)—CH 3 , —O—CH 3 and —O-phenyl and/or which may be bonded via a C 1-2 alkylene group or a C 2 alkenylene group,
or a radical chosen from the group consisting of
wherein X, Y, Z, independently from one another, each represent a radical selected from the group consisting of hydrogen, fluorine, chlorine, bromine, s nitro, acetyl, linear or branched C 1 -C 6 alkyl, linear or branched C 1 -C 6 alkoxy, linear or branched C 1 -C 6 alkylthio, a trifluoromethyl radical, a cyano radical and a —NR 12 R 13 radical,
wherein R 12 and R 13 , identical or different, each represent hydrogen or linear or branched C 1 -C 6 alkyl,
W represents a single chemical bond between the two rings, a CH 2 , O, S group or a NR 14 radical,
wherein R 14 is hydrogen or a linear or branched C 1 -C 6 alkyl,
m is 0, 1, 2, 3 or4 and
m1 is 1 or 2, preferably 2, and R 1 —R 9 and n are defined as above.
Furthermore sulfonamide derivatives of general formula (Ia) 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 (Ia) are selected from the group consisting of
[16] N-[1-(2-pyrrolidine-1-yl-ethyl)-1H-indole-5-yl]-naphthalene-2-sulfonamide,
[17] N-[1-(2-pyrrolidine-1-yl-ethyl)-1H-indole-5-yl]-naphthalene-1-sulfonamide,
[18] N-[1-(2-pyrrolidine-1-yl-ethyl)-1H-indole-5-yl]-5-chloro-3-methylbenzo[b]thiophene-2-sulfonamide,
[28] N-[1-(2-pyrrolidine-1-yl-ethyl)-1H-indole-5-yl]-]-6-chloroimidazo[2,1-b]thiazole-5-sulfonamide,
[43] 5-chloro-3-methyl-N-(1-(3-(piperidin-1-yl)propyl)-1H-indol-5-yl)benzo[b]thiophene-2-sulfonamide,
[44] N-(1-(3-(piperidin-1-yl)propyl)-1H-indol-5-yl)naphthalene-2-sulfonamide,
[45] N-(1-(3-(piperidin-1-yl)propyl)-1H-indol-5-yl)naphthalene-1-sulfonamide,
[46] 6-chloro-N-(1-(3-piperidin-1-yl)propyl)-1H-indol-5-yl)imidazo[2,1-b]thiazole-5-sulfonamide,
[47] 4-phenyl-N-(1-(3-(piperidin-1-yl)propyl)-1H-indol-5-yl)benzenesulfonamide,
[48] 2-(naphth-1-yl)-N-(1-(3-(piperidin-1-yl)propyl)-1H-indol-5-yl)ethanesulfonamide,
[49] 4-phenoxy-N-(1-(3-(piperidin-1-yl)propyl)-1H-indol-5-yl)benzenesulfonamide,
[50] 3,5-dichloro-N-(1-(3-(piperidin-1-yl)propyl)-1H-indol-5-yl)benzenesulfonylamide,
[51] 4,5-dichloro-N-(1-(3-(piperidin-1-yl)propyl)-l H-indol-5-yl)thiophene-2-sulfonamide and
[52] 5-chloro-N-(1-(3-(piperidin-1-yl)propyl)-1H-indol-5-yl)naphthalene-1-sulfonamide,
and their corresponding salts and solvates.
Furthermore, sulfonamide derivatives of general formula (Ib) 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 1 -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,
more preferably 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 1 -C 6 alkyl radical,
even more preferably 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 (Ib) are also preferred, wherein R 5 hydrogen, a linear or branched, optionally at least mono-substituted C 1 -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,
preferably that R 5 represents hydrogen or a linear or branched, optionally at least mono-substituted C 1 -C 6 alkyl radical,
even more preferably R 5 represents hydrogen or a C 1 -C 2 alkyl radical and R 1 —R 4 , R 6 —R 9 , A and n are defined as above.
Furthermore, sulfonamide derivatives of general formula (Ib) 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 C 1 -C 4 alkyl radical,
with the proviso that R 8 and R 9 are not hydrogen at the same time and R 1 —R 7 , A and n are defined as above.
Particularly preferred are sulfonamide derivatives of general formula (Ib) wherein R 8 and R 9 , identical or different, each represent hydrogen or a C 1 -C 2 alkyl radical,
with the proviso that R 8 and R 9 are not hydrogen at the same time, and R 1 —R 7 , A and n are defined as above.
Furthermore, sulfonamide derivatives of general formula (Ib) 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 1 -C 6 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,
preferably 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
wherein 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 1 -C 6 alkyl, linear or branched C 1 -C 6 alkoxy, linear or branched C 1 -C 6 alkylthio, a trifluoromethyl radical, a cyano radical and a —NR 12 R 13 radical,
wherein R 12 and R 13 , identical or different, each represent hydrogen or linear or branched C 1 -C 6 alkyl,
W represents a single chemical bond between the two rings, a CH 2 , O, S group or a NR 14 radical,
wherein R 14 is hydrogen or a linear or branched C 1 -C 6 alkyl,
m is 0, 1, 2, 3 or 4 and
m1 is 1 or 2, preferably 2, and R 1 —R 9 and n are defined as above.
Furthermore, sulfonamide derivatives of general formula (Ib) 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 1 -C 6 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,
more preferably 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
wherein X, Y, Z, independently from one another, each represent a radical selected from the group consisting of hydrogen, fluorine, chlorine, bromine, linear or branched C 1 -C 6 alkyl, linear or branched C 1 -C 6 alkoxy, linear or branched C 1 -C 6 alkylthio, a trifluoromethyl radical, a cyano radical and a —NR 12 R 13 radical,
wherein R 12 and R 13 , identical or different, each represent hydrogen or linear or branched C 1 -C 6 alkyl,
W represents a single chemical bond between the two rings, a CH 2 , O, S group or a NR 14 radical,
wherein R 14 is hydrogen or a linear or branched C 1 -C 6 alkyl,
and
m is 0, 1, 2, 3 or 4.
and R 1 —R 9 and n are defined as above.
Furthermore, sulfonamide derivatives of general formula (Ib) are preferred, wherein A represents a heteroaryl radical selected from the group consisting of quinolinyl, benzo[b]thiophenyl, benzo[1,2,5]thiadiazolyl, thiophenyl and imidazo[2,1-b]thiazolyl which may be substituted by 1, 2 or 3 substituents selected from the group consisting of fluorine, bromine, chlorine, methyl, phenyl, nitro, —C(═O)—CH 3 , —O—CH 3 and —O-phenyl and/or which may be bonded via a C 1-2 alkylene group or a C 2 alkenylene group,
or a radical chosen from the group consisting of
wherein 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 1 -C 6 alkyl, linear or branched C 1 -C 6 alkoxy, linear or branched C 1 -C 6 alkylthio, a trifluoromethyl radical, a cyano radical and a —NR 12 R 13 radical,
wherein R 12 and R 13 , identical or different, each represent hydrogen or linear or branched C 1 -C 6 alkyl,
W represents a single chemical bond between the two rings, a CH 2 , O, S group or a NR 14 radical,
wherein R 14 is hydrogen or a linear or branched C 1 -C 6 alkyl,
m is 0, 1, 2, 3 or 4 and
m1 is 1 or 2, preferably 2,
and R 1 —R 9 and n are defined as above.
Furthermore sulfonamide derivatives of general formula (Ib) 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 (Ib) are selected from the group consisting of
[1] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-5-chloro-3-methylbenzo[b]thiophene-2-sulfonamide,
[2] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-naphthalene-2-sulfonamide,
[3] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-naphthalene-1-sulfonamide,
[4] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-5-chloronaphthalene-1-sulfonamide,
[5] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-benzenesulfonamide,
[6] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-quinoline-8-sulfonamide,
[7] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-4-phenoxybenzenesulfonamide,
[8] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-4-methylbenzenesulfonamide,
[9] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-5-chlorothiophene-2-sulfonamide,
[10] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-benzo[1,2,5]thiadiazole-4-sulfonamide,
[11] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-6-chloroimidazo[2,1-b]thiazole-5-sulfonamide,
[12] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-3,5-dichlorobenzenesulfonamide,
[13] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-3-bromobenzenesulfonamide,
[14] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-3-nitrobenzenesulfonamide,
[15] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-1-phenylmethanesulfonamide,
[19] trans-N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-2-phenylethenesulfonamide,
[20] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-4,5-dichlorothiophene-2-sulfonamide,
[21] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-4-acetylbenzenesulfonamide,
[22] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-4-bromobenzenesulfonamide,
[23] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-4-methoxybenzenesulfonamide,
[24] N-[3-(2-diethylaminoethyl)-1H-indole-5-yl]-5-chloro-3-methylbenzo[b]thiophene-2-sulfonamide,
[25] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-4-nitrobenzenesulfonamide,
[26] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-4-fluorobenzenesulfonamide,
[27] N-[1-(2-diethylaminoethyl)-1H-indole-5-yl]-6-chloroimidazo[2, 1-b]thiazole-5-sulfonamide
[29] N-(1-(2-(diethylamino)ethyl)-1H-indol-5-yl)-naphthalene-2-sulfonamide,
[30] N-(1-(2-(diethylamino)ethyl)-1H-indol-5-yl)-naphthalene-1-sulfonamide,
[31] N-(1-(2-(diethylamino)ethyl)-1H-indol-5-yl)-4-phenylbenzenesulfonamide,
[32] 5-chloro-N-(1-(2-(dimethylamino)ethyl)-2-methyl-1H-indol-5-yl)-3-methylbenzo[b]thiophene-2-sulfonamide,
[33] N-(1-(2-(dimethylamino)ethyl)-2-methyl-1H-indol-5-yl)-naphthalene-2-sulfonamide,
[34] N-(1-(2-(dimethylamino)ethyl)-2-methyl-1H-indol-5-yl)-naphthalene-1-sulfonamide,
[35] 6-chloro-N-(1-(2-(dimethylamino)ethyl)-2-methyl-1H-indol-5-yl)imidazo[2,1-b]thiazole-5-sulfonamide,
[36] N-(1-(2-(dimethylamino)ethyl)-2-methyl-1H-indol-5-yl)-4-phenylbenzenesulfonamide,
[37] N-(1-(2-dimethylamino)ethyl)-2-methyl-1H-indol-5-yl)-2-(naphth-1-yl)-ethanesulfonamide,
[38] N-(1-(2-(dimethylamino)ethyl)-2-methyl-1H-indol-5-yl)-4-phenoxy-benzenesulfonamide,
[39] 3,5-dichloro-N-(1-(2-(dimethylamino)ethyl)-2-methyl-1H-indol-5-yl)-benzenesulfonamide,
[40] N-(1-(2-(dimethylamino)ethyl)-2-methyl-1H-indol-5-yl)benzo[b]thiophene-3-sulfonamide,
[41] N-(1-(2-(diethylamino)ethyl)-1H-indol-5-yl)benzo[b]thiophene-3-sulfonamide and
[42] N-(1-(2-(dimethylamino)ethyl)-1H-indol-5-yl)benzo[b]thiophene-3-sulfonamide,
and their corresponding salts and solvates.
Sulfonamide derivatives of general formula (Ic) are preferred, wherein 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,
more preferably R 1 represents an —NR 8 R 9 radical or a radical chosen from the group consisting of
wherein, if present, the dotted line is an optional chemical bond, and R 10 represents hydrogen, a linear or branched C 1 -C 6 alkyl radical or a benzyl radical, preferably hydrogen or a C 1 -C 2 alkyl radical and R 2 to R 9 , A and n are defined as above.
Sulfonamide derivatives of general formula (Ic) 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 1 -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,
more preferably 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 1 -C 6 alkyl radical,
even more preferably 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.
Sulfonamide derivatives of general formula (Ic) are also preferred, wherein R 5 represents hydrogen, a linear or branched, optionally at least mono-substituted C 1 -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,
more preferably R 5 represents hydrogen or a linear or branched, optionally at least mono-substituted C 1 -C6 alkyl radical,
even more preferably R 5 represents hydrogen or a C 1 -C 2 alkyl radical and R 1 —R 4 , R 6 —R 9 , A and n are defined as above.
Furthermore, sulfonamide derivatives of general formula (Ic) 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 10 alkenyl radical, a linear or branched, optionally at least mono-substituted C 2 -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 ring system are 5-6- or 7-membered and R 1 —R 7 , A and n are defined as above.
Particularly preferred are sulfonamide derivatives of general formula (Ic), wherein R 8 and R 9 , identical or different, each represent hydrogen or a linear or branched C 1 -C 10 alkyl radical, or
R 8 and R 9 together with the nitrogen atom bridge form a radical chosen from the group consisting of
wherein R 11 , if present, represents hydrogen, a linear or branched C 1 -C 6 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.
Furthermore, sulfonamide derivatives of general formula (Ic) 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 1 -C 6 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,
preferably 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
wherein 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 1 -C 6 alkyl, linear or branched C 1 -C 6 alkoxy, linear or branched C 1 -C 6 alkylthio, a trifluoromethyl radical, a cyano radical and a —NR 12 R 13 radical,
wherein R 12 and R 13 , identical or different, each represent hydrogen or linear or branched C 1 -C 6 alkyl,
W represents a single chemical bond between the two rings, a CH 2 , O, S group or a NR 14 radical,
wherein R 14 is hydrogen or a linear or branched C 1 -C 6 alkyl,
m is 0, 1, 2, 3 or 4 and
m1 is 1 or 2, preferably 2, and R 1 —R 9 and n are defined as above.
Furthermore, sulfonamide derivatives of general formula (Ic) 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 1 -C 6 alkylene group, an optionally at least mono-substituted C 2 -C 6 alkenylene group or an optionally at least mono-substituted C 2 -C 5 alkynylene group, and/or wherein the ring(s) may contain at least one heteroatom as a ring member,
more preferably 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
wherein X, Y, Z, independently from one another, each represent a radical selected from the group consisting of hydrogen, fluorine, chlorine, bromine, linear or branched C 1 -C 6 alkyl, linear or branched C 1 -C 6 alkoxy, linear or branched C 1 -C 6 alkylthio, a trifluoromethyl radical, a cyano radical and a —NR 12 R 13 radical,
wherein R 12 and R 13 , identical or different, each represent hydrogen or linear or branched C 1 -C 6 alkyl,
W represents a single chemical bond between the two rings, a CH 2 , O, S group or a NR 14 radical,
wherein R 14 is hydrogen or a linear or branched C 1 -C 6 alkyl,
and
m is 0, 1, 2, 3 or 4.
and R 1 —R 9 and n are defined as above.
Furthermore, sulfonamide derivatives of general formula (Ic) are preferred, wherein A represents a heteroaryl radical selected from the group consisting of quinolinyl, benzo[b]thiophenyl, benzo[1,2,5]thiadiazolyl, thiophenyl and imidazo[2,1-b]thiazolyl which may be substituted by 1, 2 or 3 substituents selected from the group consisting of fluorine, bromine, chlorine, methyl, phenyl, nitro, —C(═O)—CH 3 , —O—CH 3 and —O-phenyl and/or which may be bonded via a C 1-2 alkylene group or a C 2 alkenylene group,
or a radical chosen from the group consisting of
wherein 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 1 -C 6 alkyl, linear or branched C 1 -C 6 alkoxy, linear or branched C 1 -C 6 alkylthio, a trifluoromethyl radical, a cyano radical and a —NR 12 R 13 radical,
wherein R 12 and R 13 , identical or different, each represent hydrogen or linear or branched C 1 -C 6 alkyl,
W represents a single chemical bond between the two rings, a CH 2 , O, S group or a NR 14 radical,
is wherein R 14 is hydrogen or a linear or branched C 1 -C 6 alkyl,
m is 0, 1, 2, 3 or 4 and
m1 is 1 or 2, preferably 2, and R 1 —R 9 and n are defined as above.
Furthermore sulfonamide derivatives of general formula (Ic) 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 (Ic),
wherein
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,
or
R 8 and R 9 together with the bridging nitrogen form a 5- or 6-membered heterocyclic ring, more preferably form pyrrolidine or piperidine,
A represents an aryl or heteroaryl radical selected from the group consisting of phenyl, naphthyl, quinolinyl, benzo[b]thiophenyl, benzo[1,2,5]thiadiazolyl, thiophenyl and imidazo[2,1-b]thiazolyl which may be substituted by 1, 2 or 3 substituents selected from the group consisting of fluorine, bromine, chlorine, methyl, phenyl, nitro, —C(═O)—CH 3 , —O—CH 3 and —O-phenyl and/or which may be bonded via a C 1-2 alkylene group or a C 2 alkenylene group,
and
n is 2 or 3,
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 salt thereof, preferably a corresponding, physiologically acceptable salt thereof, or a corresponding solvate thereof.
The most preferred compounds of general formula (Ic) are selected from the group consisting of
[1] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-5-chloro-3-methylbenzo[b]thiophene-2-sulfonamide,
[2] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-naphthalene-2-sulfonamide,
[3] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-naphthalene-1-sulfonamide,
[4] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-5-chloronaphthalene-1-sulfonamide,
[5] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-benzenesulfonamide,
[6] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-quinoline-8- sulfonamide,
[7] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-4-phenoxybenzenesulfonamide,
[8] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-4-methylbenzenesulfonamide,
[9] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-5-chlorothiophene-2-sulfonamide,
[10] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-benzo[1,2,5]thiadiazole-4-sulfonamide,
[11] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-6-chloroimidazo[2,1-b]thiazole-5-sulfonamide,
[12] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-3,5-dichlorobenzenesulfonamide,
[13] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-3-bromobenzenesulfonamide,
[14] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-3-nitrobenzenesulfonamide,
[15] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-1-phenylmethanesulfonamide,
[16] N-[1-(2-pyrrolidine-1-yl-ethyl)-1H-indole-5-yl]-naphthalene-2-sulfonamide,
[17] N-[1-(2-pyrrolidine-1-yl-ethyl)-1H-indole-5-yl]-naphthalene-1-sulfonamide,
[18] N-[1-(2-pyrrolidine-1-yl-ethyl)-1H-indole-5-yl]-5-chloro-3-methylbenzo[b]thiophene-2-sulfonamide,
[19] trans-N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-2-phenylethenesulfonamide,
[20] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-4,5-dichlorothiophene-2-sulfonamide,
[21] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-4-acetylbenzenesulfonamide,
[22] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-4-bromobenzenesulfonamide,
[23] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-4-methoxybenzenesulfonamide,
[24] N-[3-(2-diethylaminoethyl)-1H-indole-5-yl]-5-chloro-3-methylbenzo[b]thiophene-2-sulfonamide,
[25] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-4-nitrobenzenesulfonamide,
[26] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-4-fluorobenzenesulfonamide,
[27] N-[1-(2-diethylaminoethyl)-1H-indole-5-yl]-6-chloroimidazo[2,1-b]thiazole-5-sulfonamide,
[28] N-[1-(2-pyrrolidine-1-yl-ethyl)-1H-indole-5-yl]-]-6-chloroimidazo[2,1-b]thiazole-5-sulfonamide,
[29] N-(1-(2-(diethylamino)ethyl)-1H-indol-5-yl)-naphthalene-2-sulfonamide,
[30] N-(1-(2-(diethylamino)ethyl)-1H-indol-5-yl)-naphthalene-1-sulfonamide,
[31] N-(1-(2-(diethylamino)ethyl)-1H-indol-5-yl)-4-phenylbenzenesulfonamide,
[32] 5-chloro-N-(1-(2-(dimethylamino)ethyl)-2-methyl-1H-indol-5-yl)-3-methylbenzo[b]thiophene-2-sulfonamide,
[33] N-(1-(2-(dimethylamino)ethyl)-2-methyl-1H-indol-5-yl)-naphthalene-2-sulfonamide,
[34] N-(1-(2-(dimethylamino)ethyl-2-methyl-1H-indol-5-yl)-naphthalene-1-sulfonamide,
[35] 6-chloro-N-(1-(2-(dimethylamino)ethyl)-2-methyl-1H-indol-5-yl)imidazo[2,1-b]thiazole-5-sulfonamide,
[36] N-(1-(2-(dimethylamino)ethyl)-2-methyl-1H-indol-5-yl)-4-phenylbenzenesulfonamide,
[37] N-(1-(2-dimethylamino)ethyl)-2-methyl-1H-indol-5-yl)-2-(naphth-1-yl)-ethanesulfonamide,
[38] N-(1-(2-(dimethylamino)ethyl)-2-methyl-1H-indol-5-yl)-4-phenoxybenzenesulfonamide,
[39] 3,5-dichloro-N-(1-(2-(dimethylamino)ethyl)-2-methyl-1H-indol-5-yl)-benzenesulfonamide,
[40] N-(1-(2-(dimethylamino)ethyl)-2-methyl-1H-indol-5-yl)benzo[b]thiophene-3-sulfonamide,
[41] N-(1-(2-(diethylamino)ethyl)-1H-indol-5-yl)benzo[b]thiophene-3-sulfonamide and
[42] N-(1-(2-(dimethylamino)ethyl)-1H-indol-5-yl)benzo[b]thiophene-3-sulfonamide,
[43] 5-chloro-3-methyl-N-(1-(3-(piperidin-1-yl)propyl)-1H-indol-5-yl)benzo[b]thiophene-2-sulfonamide,
[44] N-(1-(3-(piperidin-1-yl)propyl)-1H-indol-5-yl)naphthalene-2-sulfonamide,
[45] N-(1-(3-(piperidin-1-yl)propyl)-1H-indol-5-yl)naphthalene-1-sulfonamide,
[46] 6-chloro-N-(1-(3-piperidin-1-yl)propyl)-1H-indol-5-yl)imidazo[2,1-b]thiazole-5-sulfonamide,
[47] 4-phenyl-N-(1-(3-(piperidin-1-yl)propyl)-1H-indol-5-yl)benzenesulfonamide,
[48] 2-(naphth-1-yl)-N-(1-(3-(piperidin-1-yl)propyl)-1H-indol-5-yl)ethanesulfonamide,
[49] 4-phenoxy-N-1-(3-(piperidin-1-yl)propyl)-1H-indol-5-yl)benzenesulfonamide,
[50] 3,5-dichloro-N-(1-(3-(piperidin-1-yl)propyl)-1H-indol-5-yl)benzenesulfonylamide,
[51] 4,5-dichloro-N-(1-(3-(piperidin-1-yl)propyl)-1H-indol-5-yl)thiophene-2-sulfonamide and
[52] 5-chloro-N-(1-(3-(piperidin-1-yl)propyl)-1H-indol-5-yl)naphthalene-1-sulfonamide,
and their corresponding salts and solvates.
The present invention likewise refers to the salts, preferably the physiologically acceptable salts of the compounds of general formula (Ia) and/or (Ib) and/or of general formula (Ic), 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.
Below, the expression sulfonamide derivatives of the general formula (I), refers to one or more compounds of general formula (Ia) and/or to one or more compounds of general formula (Ib) and/or to one or more compounds of general formula (Ic), 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 (1), wherein R 1 —R 9 , n and A have the previously indicated meaning, according to which at least one compound of general formula (II),
wherein A has the previously mentioned meaning, and X is an acceptable leaving group, preferably an halogen atom, more preferably chlorine; reacts with at least one substituted 5-aminoindole of general formula (III)
wherein R 1 —R 7 and n have the previously indicated meaning, or one of their suitable protected derivatives, and, if necessary, the protective groups are removed in order to obtain the corresponding sulfonamide derivative of formula (I), which may be purified and/or isolated by means of conventional methods known in the prior art.
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. Naturally, mixtures of at least two of the classes of the mentioned compounds or at least two compounds of one class may also be used.
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.
The most suitable reaction temperatures range from 00C 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.
Preferably, 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; Werbenec, Jean Pierre; Broil, Madeleine. (Labaz S. A., Fr.). Ger. Offen. (1977). DE 2727047 19771229. Schwink, Lothar; Stengelin, Siegfried; Gossel, Matthias. Preparation of indol-5-ylureas and related compounds for the treatment of obesity and type II diabetes. WO 0315769 A1 20030227. One of them consists of nitro group reduction of derivatives of general formula (IV) by methods known in the prior art, as for example: BRATTON, L. D.; ROTH, B. D.; TRIVEDI, B. K.; UNANGST, P. C.; J Heterocycl Chem, 2000, 37 (5), 1103-1108. FANGHAENEL, E.; CHTCHEGLOV, D.; J Prakt Chem/Chem-Ztg, 1996, 338 (8), 731-737. KUYPER, L. F.; BACMAYARI, D. P.; JONES, M. L.; HUNTER, R. N.; TANSIK, R. L.; JOYNER, S. S.; BOYTOS, C. M.; RUDOLPH, S. K.; KNICK, V.; WILSON, H. R.; CADDELL, J. M.; FRIEDMAN, H. S.; ET AL.; J Med Chem, 1996, 39 (4), 892-903.
wherein 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. Preparation of indol-5-ylureas and relate compounds for the treatment of obesity and type II diabetes WO 0315769 A1 20030227; Baxter, Andrew; Brough, Stephen; Mcinally, Thomas; Mortimore, Michael; Cladingboel, David. Preparation of N-aryl-1-adamantaneacetamides and analogs as purinergic P2Z receptor antagonists WO 9929660 A1 19990617; Pigerol, Charles; De Cointet de Fillain, Paul; Eymard, Pierre; Werbenec, Jean Pierre; Broll, Madeleine. Indole derivatives. Ger. Offen. (1977), DE 2727047 19771229.
One of them consists of the alkylation of nitro derivatives of general formula (V) by methods known in the art, as for example: BHAGWAT, S. S.; GUDE, C.; Tetrahedron Lett, 1994, 35 (12), 1847-1850. BRATTON, L. D.; ROTH, B. D.; TRIVEDI, B. K.; UNANGST, P. C.; J Heterocycl Chem, 2000, 37 (5), 1103-1108
wherein 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. H.; Tetrahedron Lett ,1999, 40 (6),1117-1120. EZQUERRA, J.; PEDREGAL, is C.; LAMAS, C.; BARLUENGA, J.; PEREZ, M.; GARCIA-MARTIN, M. A.; GONZALEZ, J. M.; J Org Chem, 1996, 61 (17), 5804-5812. FADDA, A. A.; Indian J Chem, Sect B: Org Chem Inci Med Chem, 1990, 29 (11), 1017-1019. KATRITZKY, A. R.; RACHWAL, S.; BAYYUK, S.; Org Prep Proced Int, 1991, 23 (3), 357-363. Inada, A.; Nakamura, Y.; Morita, Y.; Chem Lett, 1980, 1287.
The respective literature descriptions are incorporated by reference and form part of the disclosure.
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 C 1 -C 6 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. Naturally, mixtures of at least two of the classes of the mentioned compounds or at least two compounds of one class may also be used.
The most suitable 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.
Preferably, 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.
The salts, preferably pharmaceutically acceptable salts of the compounds of general formula (I), 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.
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.
During some of the synthetic sequences described or in the preparation of the suitable reagents used, it may be necessary and/or desirable to protect sensitive or reactive groups in some of the molecules used. This may be carried out by means of the use of conventional protective groups preferably those described in the literature [Protective groups in Organic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; T. W. Greene & P. G. M. Wuts, Protective Groups in Organic Chemistry, John Wiley & Sons, 1991]. The protective groups may be removed in the suitable subsequent stage by methods known in the prior art. The respective literature descriptions are incorporated by reference and form part of the disclosure.
If 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.
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 preferably in humans.
Another aspect of the present invention is a medicament comprising at least one indol-5-yl sulfonamide derivative of general formula (Ia), 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.
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-HT6 serotonin receptor in humans and/or in animals, preferably in mammals, more preferably in humans,
more 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 in humans and/or in animals, preferably in mammals, more preferably in humans.
Another aspect of the present invention is a medicament comprising at least one indol-5-yl sulfonamide derivative of general formula (Ib), 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.
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 preferably in humans,
more suitable 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) improving cognition, for preventing and/or treating Central Nervous System Disorders, anxiety, panic disorders, depression, bipolar disorders, cognitive memory disorders, senile dementia processes, neurodegenerative disorders, preferably Alzheimers disease, Parkinson's disease, Huntington's disease and Multiple Sclerosis, schizophrenia, psychosis, infantile hyperkinesia (ADHD, attention deficit/hyperactivity disorder) in humans and/or in animals, preferably in mammals, more preferably in humans.
Another aspect of the present invention is a medicament composed of at least one indol-5-yl sulfonamide derivative of general formula (Ic), 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.
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 Alzheimers 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 preferably in humans.
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-HT6 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 is 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 preferably in humans.
Another aspect of the present invention is the use of at least one sulfonamide derivative of the previous general formula (Ia), 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 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) in humans and/or in animals, preferably in mammals, more preferably in humans,
preferably 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 in humans and/or in animals, preferably in mammals, more preferably in humans.
Another aspect of the present invention is the use of at least one sulfonamide derivative of the previous general formula (Ib), 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 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 is animals, preferably in mammals, more preferably in humans,
preferably 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) in humans and/or in animals, preferably in mammals, more preferably in humans.
Another aspect of the present invention is the use of at least one sulfonamide derivative of the previous general formula (Ic), 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 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 Alzheimers 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 preferably in humans.
The preparation of the corresponding pharmaceutical compositions as well as of the formulated medicaments may be carried out by means of conventional methods known in the prior art, for example, based on the indices of “Pharmaceutics: The Science of Dosage Forms”, Second Edition, Aulton, M. E. (ED. Churchill Livingstone, Edinburgh (2002); “Encyclopedia of Pharmaceutical Technology”, Second Edition, Swarbrick, J. and Boylan, J. C. (Eds.), Marcel Dekker, Inc. New York (2002); “Modern Pharmaceutics”, Fourth Edition, Banker G. S. and Rhodes C. T. (Eds.) Marcel Dekker, Inc. New York (2002), and “The Theory and Practice of Industrial Pharmacy”, Lachman L., Lieberman H. and Kanig J. (Eds.), Lea & Febiger, Philadelphia (1986). The respective literature descriptions are incorporated as a reference and are part of this disclosure.
The pharmaceutical compositions, as well as the formulated medicaments prepared according to the present invention, 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. As the skilled person in the art also knows, the choice of the auxiliary substances and the amounts thereof depend on the intended administration route, for example, rectal, intravenous, intraperitoneal, intramuscular, intranasal, oral, buccal or topical.
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, as well as the materials and methods for the preparation thereof, 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. 1, Basic Concepts, Bruck, S. D. (Ed.), CRD Press, Inc., Boca Raton (1983), and by Takada, K. and Yoshikawa, H., “Oral Drug Delivery”, Encyclopedia of Controlled Drug Delivery, Mathiowitz, E. (Ed.), John Wiley & Sons, Inc., New York (1999), Vol. 2, 728-742; Fix, J., “Oral drug delivery, small intestine and colon”, Encyclopedia of Controlled Drug Delivery, Mathiowitz, E. (Ed.), John Wiley & Sons, Inc., New York (1999), Vol. 2, 698-728. The respective literature references are incorporated by reference and form part of the disclosure.
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.
Typically, 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.
Pharmaceutical Methods:
Binding to the 5HT 6 Serotonin Receptor
HEK-293 cell membranes expressing the recombinant human 5HT 6 receptor were supplied by Receptor Biology. The receptor concentration in said membranes is 2.18 pmol/mg of protein and the protein concentration is 9.17 mg/ml. The experimental protocol follows the method of B. L. Roth et al. [B. L. Roth, S. C. Craigo, M. S. Choudhary, A. Uluer, F. J. Monsma, Y. Shen, H. Y. Meltzer, D. R. Sibley: Binding of Typical and Atypical Antipshychotic Agents to 5-Hydroxytryptamine-6 and Hydroxytryptamine-7 Receptors. The Journal of Pharmacology and Experimental Therapeutics, 1994, 268, 1403], with slight modifications. The commercial membrane is diluted (1:40 dilution) with the binding buffer: 50 mM Tris-HCl, 10 mM MgCl 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 μl. Incubation begins by adding 100 μl of the membrane suspension (≅22.9 μg of membrane protein), and is prolonged for 60 minutes at a temperature of 37° C. Incubation ends by quick filtration in a Harvester Brandel Cell through fiberglass filters of the Schleicher & Schuell GF 3362 trademark, pretreated with a 0.5% polyethyleneimine solution. The filters are washed three times with three milliliters of 50 mM Tris HCl buffer, pH 7.4. The filters are transferred to vials and 5 ml of Ecoscint H. liquid scintillation cocktail are added to each vial. The vials are left to equilibrate for several hours prior to their counting in a 1414 Wallac Winspectral scintillation counter. The non-specific binding is determined in the presence of 100 μM of serotonin. The assays are carried out in triplicate. The inhibition constants (K I , nM) are calculated by non-linear regression analysis using the EBDA/LIGAND program [Munson and Rodbard, Analytical Biochemistry, 1980, 107, 220].
The respective literature descriptions are incorporated by reference and form part of the disclosure.
Measurements of Food Ingestion (Behavioural Model)
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. After this period, 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. Immediately after this, 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 part of the disclosure.
The preparation of new compounds according to the invention is indicated in the following examples. The affinity for the 5HT 6 serotonin receptor, as well as the galenic formulas applicable to the compounds of the invention, is also described. The examples indicated below, given as an illustrative example, should in no way limit the scope of the invention.
EXAMPLES
Example 2
Preparation of N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-naphthalene-2-sulfonamide
150 mg (0.66 mMol) of naphthalene-2-sulfonyl chloride were added to a solution of 122 mg (0.6 mMol) of 5-amino-1-(2-dimethylaminoethyl)-1H-indole in 3 ml of dimethylformamide and 116 mg of N-ethyldiisopropylamine. The reaction mixture was stirred at the room temperature for 12 hours. Then it was evaporated to dryness, slightly alkalinized with sodium bicarbonate solution and extracted with chloroform. The organic phase was repeatedly washed with water and saturated solution of sodium bicarbonate, it was separated and dried with anhydrous sodium sulfate. The organic solution was evaporated to dryness and the resulting solid was purified by chromatography, obtaining 187 mg (80%) of N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-naphthalene-2-sulfonamide.
Example 10
Preparation of N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-benzo-[1,2,5]thiadiazole-4-sulfonamide 4-sulfonamide
116 mg (0.66 mMol) of benzo-[1,2,5]thiadiazole-4-sulfonyl chloride were added to a solution of 168 mg (0.6 mMol) of 5-amino-1-(2-dimethylaminoethyl)-1H-indole in 5 ml of pyridine and 311 mg of N-ethyldiisopropylamine. The reaction mixture was stirred at the room temperature for 2 hours. Then it was evaporated to dryness, slightly alkalinized with sodium bicarbonate solution and extracted with chloroform. The organic phase was repeatedly washed with water and saturated solution of sodium bicarbonate, it was separated and dried with anhydrous sodium sulfate. The organic solution was evaporated to dryness and the resulting solid was treated with diethyl ether obtaining 183 mg (76%) of N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-benzo-[1,2,5]thiadiazole-4-sulfonamide 4-sulfonamide.
Example 17
Preparation of N-[1-(2-pyrrolidine-1-yl-ethyl)-1H-indole-5-yl]-naphthalene-1-sulfonamide
199 mg (0.88 mMol) of naphthalene-1-sulfonyl chloride were added to a solution of 335 mg (0.8 mMol) of 5-amino-1-(2-pyrrolidine-1-yl-ethyl)-1H-indole in 10 ml of methylene chloride and 0,44 mg of triethylamine. The reaction mixture was stirred at the room temperature for 12 hours. Then it was slightly alkalinized with sodium bicarbonate solution and extracted with methylene chloride. The organic phase was repeatedly washed with water and saturated solution of sodium bicarbonate, it was separated and dried with anhydrous sodium sulfate. The organic solution was evaporated to dryness and the resulting solid was treated with diethyl ether obtaining 264 mg (79%) of N-[1-(2-pyrrolidine-1-yl-ethyl)-1H-indole-5-yl]-naphthalene-1-sulfonamide as a solid.
Example 29
Preparation of N-(1-(2-(diethylamino)ethyl)-1H-indol-5-yl)-naphthalene-2-sulfonamide
The reaction was carried out according to the procedure given in Example 1. 139 mg (0.6 mMol) of 5-amino-1-(2-(diethylamino)ethyl)-1H-indole and 150 mg (0.66 mMol) of 2-naphthyl-sulfonyl chloride were reacted to give 115 mg (45%) of the desired compound as a solid.
Example 30
Preparation of N-(1-(2-(diethylamino)ethyl)-1H-indol-5-yl)-naphthalene-1-sulfonamide
The reaction was carried out according to the procedure given in Example 1. 139 mg (0.6 mMol) of 5-amino-1-(2-(diethylamino)ethyl)-1H-indole and 150 mg (0.66 mMol) of 2-naphthyl-sulfonyl chloride were reacted to give 160 mg (63%) of the desired compound as a solid.
Example 31
Preparation of N-(1-(2-(diethylamino)ethyl)-1H-indol-5-yl)-4-phenylbenzenesulfonamide
The reaction was carried out according to the procedure given in Example 1. 139 mg (0.6 mMol) of 5-amino-1-(2-(diethylamino)ethyl)-1H-indole and 167 mg (0.66 mMol) of 4-phenylbenzenesulfonyl chloride were reacted to give 181 mg (68 %) of the desired compound as an oil.
Example 32
Preparation of 5-chloro-N-(1-(2-(dimethylamino)ethyl)-2-methyl-1H-indol-5-yl)-3-methylbenzo[b]thiophene-2-sulfonamide
The reaction was carried out according to the procedure given in Example 1. 130 mg (0.6 mMol) of 5-amino-1-(2-(dimethylamino)ethyl)-2-methyl-1H-indole and 186 mg (0.66 mMol) of 5-chloro-2-methylbenzo[b]thiophene-2-sulfonyl chloride were reacted to give 127 mg (46%) of the desired compound as a solid.
Example 33
Preparation of N-(1-(2-(dimethylamino)ethyl)-2-methyl-1H-indol-5-yl)-naphthalene-2-sulfonamide
The reaction was carried out according to the procedure given in Example 1. 130 mg (0.6 mMol) of 5-amino-1-(2-(dimethylamino)ethyl)-2-methyl-1H-indole and 150 mg (0.66 mMol) of naphthyl-2-sulfonyl chloride were reacted to give 142 mg (58 %) of the desired compound as a solid.
Example 34
Preparation of N-(1-(2-(dimethylamino)ethyl)-2-methyl-1H-indol-5-yl)-naphthalene-1-sulfonamide
The reaction was carried out according to the procedure given in Example 1. 130 mg (0.6 mMol) of 5-amino-1-(2-(dimethylamino)ethyl)-2-methyl-1H-indole and 150 mg (0.66 mMol) of naphthyl-1-sulfonyl chloride were reacted to give 81 mg (33%) of the desired compound as a solid.
Example 35
Preparation of 6-chloro-N-(1-(2-(dimethylamino)ethyl)-2-methyl-1H-indol-5-yl)imidazo[2,1-b]thiazole-5-sulfonamide
The reaction was carried out according to the procedure given in Example 1. 130 mg (0.6 mMol) of 5-amino-1-(2-(dimethylamino)ethyl)-2-methyl-1H-indole and 170 mg (0.66 mMol) of 6-chloro-imidazo[2,1-b]thiazole-5-sulfonyl chloride were reacted to give 96 mg (37%) of the desired compound as a solid.
Example 36
Preparation of N-(1-(2-(dimethylamino)ethyl)-2-methyl-1H-indol-5-yl)-4-phenylbenzenesulfonamide
The reaction was carried out according to the procedure given in Example 1. 130 mg (0.6 mMol) of 5-amino-I -(2-(dimethylamino)ethyl)-2-methyl-1H-indole and 167 mg (0.66 mMol) of 4-phenylbenzenesulfonyl chloride were reacted to give 160 mg (62%) of the desired compound as a solid.
Example 37
Preparation of N-(1-(2-dimethylamino)ethyl)-2-methyl-1H-indol-5-yl)-2-(naphth-1-yl)-ethanesulfonamide
The reaction was carried out according to the procedure given in Example 1. 130 mg (0.6 mMol) of 5-amino-1-(2-(dimethylamino)ethyl)-2-methyl-1H-indole and 168 mg (0.66 mMol) of 2-(naphth-1-yl)-ethanesulfonyl chloride were reacted to give 108 mg (41%) of the desired compound as a solid.
Example 38
Preparation of N-(1-(2-(dimethylamino)ethyl)-2-methyl-1H-indol-5-yl)-4-phenoxy-benzenesulfonamide
The reaction was carried out according to the procedure given in Example 1. 130 mg (0.6 mMol) of 5-amino-1-(2-(dimethylamino)ethyl)-2-methyl-1H-indole and 177 mg (0.66 mMol) of 4-phenoxy-benzenesulfonyl chloride were reacted to give 89 mg (33%) of the desired compound as a solid.
Example 39
Preparation of 3,5-dichloro-N-(1-(2-(dimethylamino)ethyl)-2-methyl-1H-indol-5-yl)-benzenesulfonamide
The reaction was carried out according to the procedure given in Example 1. 130 mg (0.6 mMol) of 5-amino-1-(2-(dimethylamino)ethyl)-2-methyl-1H-indole and 162 mg (0.66 mMol) of 3,5-dichloro-benzenesulfonyl chloride were reacted to give 81 mg (32%) of the desired compound as a solid.
Example 40
Preparation of N-(1-(2-(dimethylamino)ethyl)-2-methyl-1H-indol-5-yl)benzo[b]thiophene-3-sulfonamide
The reaction was carried out according to the procedure given in Example 1. 108 mg (0.5 mMol) of 5-amino-1-(2-(dimethylamino)ethyl)-2-methyl-1H-indole and 128 mg (0.55 mMol) of benzo[b]thiophene-3-sulfonyl chloride were reacted to give 82 mg (39%) of the desired compound as a solid.
Example 41
Preparation of N-(1-(2-(diethylamino)ethyl)-1H-indol-5-yl)benzo[b]thiophene-3-sulfonamide
The reaction was carried out according to the procedure given in Example 1. 115 mg (0.5 mMol) of 5-amino-1-(2-(diethylamino)ethyl)-1H-indole and 128 mg (0.55 mMol) of benzo[b]thiophene-3-sulfonyl chloride were reacted to give 91 mg (43%) of the desired compound as a solid.
Example 42
Preparation of N-(1-(2-(dimethylamino)ethyl)-1H-indol-5-yl)benzo[b]thiophene-3-sulfonamide
The reaction was carried out according to the procedure given in Example 1. 102 mg (0.5 mMol) of 5-amino-1-(2-(diethylamino)ethyl)-1H-indole and 128 mg (0.55 mMol) of benzo[b]thiophene-3-sulfonyl chloride were reacted to give 91 mg (43%) of the desired compound as a solid.
Example 43
Preparation of 5-chloro-3-methyl-N-(1-(3-(piperidin-1-yl)propyl)-1H-indol-5-yl)benzo[b]thiophene-2-sulfonamide
The reaction was carried out according to the procedure given in Example 1. 118 mg (0.46 mMol) of 5-amino-1-(3-(piperidin-1-yl)propyl))-1H-indole and 143 mg (0.51 mMol) of 5-chloro-3-methyl-benzo[b]thiophene-2-sulfonyl chloride were reacted to give 89 mg (38%) of the desired compound as a solid.
Example 44
Preparation of N-(1-(3-(piperidin-1-yl)propyl)-1H-indol-5-yl)naphthalene-2-sulfonamide
The reaction was carried out according to the procedure given in Example 1. 118 mg (0.46 mMol) of 5-amino-1-(3-(piperidin-1-yl)propyl))-1H-indole and 116 mg (0.51 mMol) of naphthyl-2-sulfonyl chloride were reacted to give 75 mg (37%) of the desired compound as a solid.
Example 45
Preparation of N-(1-(3-(piperidin-1-yl)propyl)-1H-indol-5-yl)naphthalene-1-sulfonamide
The reaction was carried out according to the procedure given in Example 1. 118 mg (0.46 mMol) of 5-amino-1-(3-(piperidin-1-yl)propyl))-1H-indole and 116 mg (0.51 mMol) of naphthyl-2-sulfonyl chloride were reacted to give 91 mg (44%) of the desired compound as a solid.
Example 46
Preparation of 6-chloro-N-(1-(3-piperidin-1-yl)propyl)-1H-indol-5-yl)imidazo[2,1-b]thiazole-5-sulfonamide
The reaction was carried out according to the procedure given in Example 1. 118 mg (0.46 mMol) of 5-amino-1-(3-(piperidin-1-yl)propyl))-1H-indole and 131 mg (0.51 mMol) of 6-chloro-imidazo[2,1-b]thiazole-5-sulfonyl chloride were reacted to give 91 mg (44%) of the desired compound as a solid.
Example 47
Preparation of 4-phenyl-N-(1-(3-(piperidin-1-yl)propyl)-1H-indol-5-yl)benzenesulfonamide
The reaction was carried out according to the procedure given in Example 1. 118 mg (0.46 mMol) of 5-amino-1-(3-(piperidin-1-yl)propyl))-1H-indole and 129 mg (0.51 mMol) of 4-phenylbenzenesulfonyl chloride were reacted to give 106 mg (49%) of the desired compound as a solid.
Example 48
Preparation of 2-(naphth-1-yl)-N-(1-(3-(piperidin-1-yl)propyl)-1H-indol-5-yl)ethanesulfonamide
The reaction was carried out according to the procedure given in Example 1. 118 mg (0.46 mMol) of 5-amino-1-(3-(piperidin-1-yl)propyl))-1H-indole and 130 mg (0.51 mMol) of 2-(naphth-1-yl)ethanesulfonyl chloride were reacted to give 68 mg (31%) of the desired compound as a solid.
Example 49
Preparation of 4-phenoxy-N-(1-(3-(piperidin-1-yl)propyl)-1H-indol-5-yl)benzenesulfonamide
The reaction was carried out according to the procedure given in Example 1. 118 mg (0.46 mMol) of 5-amino-1-(3-(piperidin-1-yl)propyl))-1H-indole and 137 mg (0.51 mMol) of 4-phenoxybenzenesulfonyl chloride were reacted to give 86 mg (38%) of the desired compound as a solid.
Example 50
Preparation of 3,5-dichloro-N-(1-(3-(piperidin-1-yl)propyl)-1H-indol-5-yl)benzenesulfonylamide
The reaction was carried out according to the procedure given in Example 1. 118 mg (0.46 mMol) of 5-amino-1-(3-(piperidin-1-yl)propyl))-1H-indole and 125 mg (0.51 mMol) of 3,5-dichlorobenzenesulfonyl chloride were reacted to give 79 mg (37%) of the desired compound as a solid.
Example 51
Preparation of 4,5-dichloro-N-(1-(3-(piperidin-1-yl)propyl)-1H-indol-5-yl)thiophene-2-sulfonamide
The reaction was carried out according to the procedure given in Example 1. 118 mg (0.46 mMol) of 5-amino-1-(3-(piperidin-1-yl)propyl))-1H-indole and 128 mg (0.51 mMol) of 4,5-dichlorothiophene-2-sulfonyl chloride were reacted to give 68 mg (31%) of the desired compound as a solid.
Example 52
Preparation of 5-chloro-N-(1-(3-(piperidin-1-yl)propyl)-1H-indol-5-yl)naphthalene-1-sulfonamide
The reaction was carried out according to the procedure given in Example 1. 118 mg (0.46 mMol) of 5-amino-1-(3-(piperidin-1-yl)propyl))-1H-indole and 133 mg (0.51 mMol) of 5-chloro-napthyl-1-sulfonyl chloride were reacted to give 81 mg (37%) of the desired compound as a solid.
The yields are indicative and no added effort was made to improve them.
The melting point and spectroscopic data for identifying some of the compounds of the present invention are indicated in the following table.
Ex R1 R2 R3 R4 R5 R6 R7 n A m.p. ° C. IR cm −1 1 H-NMR(300 MHz), δ(solvent) 1 (CH 3 ) 2 N— H H H H H H 2 71-73 2950, 1334, 1160, 1080, 862, 652, 560. 2.11(s, 6H); 2.36(s, 3H); 2.51(m, 2H); 4.14(t, 2H, J=6.6 Hz); 6.30(d, 1H, J=3 Hz); 7.32(m, 2H); 7.50(dd, 1H, J=8.7 Hz, J′=2.0 Hz); 7.93(d, 1H, J=2.0 Hz); 7.99(d, 1H, J=8.7 Hz). (DMSO-d6) 2 (CH 3 ) 2 N— H H H H H H 2 54-57 3254. 3049, 2945, 1463, 1330, 1160, 1074, 658 550. 2.26(s, 6H); 2.63(t, 2H, J=7.1 Hz); 4.14(t, 2H, J=7.1 Hz); 6.35(d, 1H, J=3.1 Hz); 6.88(dd, 1H, J=8.6 Hz, J′=2.0 Hz); 7.10(d, 1H, 3.1 Hz); 7.15(d, 1H, J=8.6 Hz); 7.31(d, 1H, 1H J=8.7 Hz, J′=1.8 Hz); 7.84(m, J=2.0 Hz); 7.50-7.63(m, 2H); 7.69(dd, 3H); 8.29(s, 1H). (CDCl 3 ) 3 (CH 3 ) 2 N— H H H H H H 2 179-181 3106, 2783, 1491, 1318, 1159, 1130, 763, 586, 503. 2.25(s, 6H); 2.63(t, 2H, J=7.0 Hz); 4.11(t, 2H, J=7.0 Hz); 6.28(d, 1H, J=3.1 Hz); 6.68(dd, 1H, J=8.6 Hz, J′=2.0 Hz); 7.03-7.11(m, 3H); 7.37(m, 1H); 7.58-7.70(m, 2H); 7.94(d, 1H, J=8.7 Hz); 8.00(d, 1H, J=7.9 Hz); 8.06(d, 1H, J=7.3 Hz); 8.73(d, 1H, J=8.7 Hz). (CDCl 3 ) 4 (CH 3 ) 2 N— H H H H H H 2 172-174 3257, 2935, 2768, 1488, 1334, 1167, 1138, 1013, 790, 606. 2.26(s, 6H); 2.63(t, 2H, J=7.1 Hz); 4.13(t, 2H, J=7.1 Hz); 6.30(d, 1H, J=3.1 Hz); 6.66(dd, 1H, J=8.6 Hz, J=2.0 Hz): 7.05(d, 1H, J=8.7 Hz); 7.08(d, 1H, J=3.1 Hz); 7.11(d, 1H, J=2.0 Hz); 7.46-7.58(m, 2H); 7.69(d, 1H, J=7.5 Hz); 8.13(d, 1H, J=7.5 Hz); 8.50(d, 1H, J=8.6 Hz); 8.69(d, # 1H, J=8.8 Hz). (CDCl 3 ) 5 (CH 3 ) 2 N— H H H H H H 2 139-141 1463, 1334, 1306, 1164, 1090, 725, 589. 2.28(s, 6H); 2.66(t, 2H, J=7.1 Hz); 4.17(t, 2H, J=7.1 Hz); 6.38(d, 1H, J=3.1 Hz); 6.88(dd, 1H, J=8.6 Hz, J′=2.0 Hz); 7.13(d, 1H, J=3.1 Hz); 7.18(d, 1H, J=8.6 Hz); 7.27(m, 1H); 7.39(m, 2H); 7.48(m, 1H); 7.69(m, 2H). (CDCl 3 ) 6 (CH 3 ) 2 N— H H H H H H 2 161-164 3095, 02821, 2776, 1492, 1459, 1322, 1158, 1141, 782, 736, 596, 507. 2.23(s, 6H); 2.58(t, 2H, J=7.1 Hz); 4.08(t, 2H, J=7.1 Hz); 6.24(d, 1H, J=3.1 Hz); 6.88(dd, 1H, J=8.8, J′=2.0 Hz); 7.03(d, 1H, J=3.1 Hz); 7.07(d, 1H, J=8.8 Hz); 7.10(d, 1H, J=2.0 Hz); 7.51(t, 1H, J=7.8 Hz); 7.64(dd, 1H, J=8.5, J′=4.3 Hz); 8.00(d, 1H, J=8.2 Hz); 8.26 # (m, 1H); 8.30(dd, 1H, J=8.2, J′1.5 Hz); 8.40(s, 1H); 9.20(dd, 1H, J=4.1 J′=1.4 Hz). (CDCl 3 ) 7 (CH 3 ) 2 N— H H H H H H 2 138-140 3255, 2951, 1583, 1488, 1332, 1245, 1156, 1092, 866, 695, 569. 2.28(s, 6H); 2.67(t, 2H, J=7.1 Hz); 4.18(t, 2H, J=7.1 Hz); 6.40(d, 1H, J=3.1 Hz); 6.92(m, 3H); 7.02(d, 2H, J=7.7 Hz); 7.14(d, 1H, J=3.1 Hz); 7.20(d, 2H, J=8.5 Hz); 7.28(d, 1H, J=1.9 Hz); 7.37(m, 2H); 7.64(d, 2H, J=8.6 Hz). (CDCl 3 ) 8 (CH 3 ) 2 N— H H H H H H 2 126-128 1474, 1287, 1156, 1088, 973, 730, 654, 554, 538. 2.31(s, 6H); 2.36(s, 3H); 2.72(t, 2H, J=7.1 Hz); 4.20(t, 2H, J=7.1 Hz); 6.39(d, 1H, J=3.1 Hz); 6.90(dd, 1H, J=8.6 Hz, J′=1.6 Hz); 7.13(d, 1H, J=3.1 Hz); 7.16-7.20(m, 3H); 7.26(m, 1H); 7.57(d, 2H, J=8.3 Hz). (CDCl 3 ) 9 (CH 3 ) 2 N— H H H H H H 2 145-147 3095, 2951, 1416, 1319, 1148, 989, 730, 605, 537. 2.33(s, 6H); 2.74(m, 2H); 4.24(t, 2H, J=7.1 Hz); 6.44(d, 1H, J=3.1 Hz); 6.79(d, 1H, J=4.0 Hz); 6.95(dd, 1H, J=8.7 Hz, J′=2.0 Hz); 7.15(d, 1H, J=4.0 Hz); 7.17(d, 1H, J=3.1 Hz); 7.24(d, 1H, J=8.7 Hz); 7.35(d, 1H, J=2.0 Hz). (DMSO-d6) 10 (CH 3 ) 2 N— H H H H H H 2 166-168 3103, 2784, 1526, 1488, 1331, 1154, 1140, 973, 734, 607. 2.26(s, 6H); 2.63(t, 2H, J=7.1 Hz); 4.12(t, 2H, J=7.1 Hz); 6.29(d, 1H, J=3.1 Hz); 6.80(dd, 1H, J=8.7 Hz, J′=2.0 Hz); 7.07(m, 2H); 7.15(d, 1H, J=1.5 Hz); 7.57(dd, 1H, J=8.8 Hz, J=7.1 Hz); 8.10(d, 1H, J=7.1 Hz); 8.16(d, 1H, J=8.8 Hz). (CDCl 3 ) 11 (CH 3 ) 2 N— H H H H H H 2 50-52 3103, 2943, 1457, 1336, 1326, 1244, 1177, 1142, 727, 628, 528. 2.26(s, 6H); 2.64(t, 2H, J=6.4 Hz); 4.16(t, 2H, J=6.4 Hz); 6.39(m, 1H); 6.78(d, 1H, J=4.0 Hz); 6.94(d, 1H, J=8.4 Hz); 7.15(m, 2H); 7.39(s, 1H); 7.55(d, 1H, J=4.0 Hz). (CDCl 3 ) 12 (CH 3 ) 2 N— H H H H H H 2 124-126 3064, 2935, 1333, 1166, 1136, 596, 587. 2.28(s, 6H); 2.67(t, 2H, J=7.0 Hz); 4.19(t, 2H, J=7.0 Hz); 6.43(d, 1H, J=3.1 Hz); 6.85(dd, 1H, J=8.6 Hz, J′=2.0 Hz); 7.17(d, 1H, J=3.1 Hz); 7.22(d, 1H, J=8.6 Hz); 7.31(d, 1H, J=2.0 Hz); 7.48(t, 1H, J=1.8 Hz); 7.56(d, 2H, J=1.8 Hz). (CDCl 3 ) 13 (CH 3 ) 2 N— H H H H H H 2 114-116 1464, 1335, 1286, 1161, 722, 584. 2.28(s, 6H); 2.67(t, 2H, J=7.0 Hz); 4.19(t, 2H, J=7.0 Hz); 6.41(d, 1H, J=2.9 Hz); 6.87(d, 1H, J=8.8 Hz); 7.15(d, 1H, J=2.9 Hz); 7.19-7.29(m, 3H): 7.56(d, 1H, J=7.8 Hz); 7.63(d, 1H, J=7.9 Hz); 7.88(s, 1H). (CDCl 3 ) 14 (CH 3 ) 2 N— H H H H H H 2 138-140 1541, 1481, 1365, 1330, 1235, 1150, 1124, 736, 580. 2.28(s, 6H); 2.66(t, 2H, J=7.1 Hz); 4.17(t, 2H, J=7.1 Hz); 6.40(d, 1H, J=2.9 Hz); 7.03(dd, 1H, J=8.7 Hz, J′1.8 Hz); 7.15(d, 1H, J=2.9 Hz); 7.21(d, 1H, J=8.7 Hz); 7.39(d, 1H, J=1.8 Hz); 7.48(m, 1H); 7.65(m, 1H); 7.71(d, 1H, J=8.8 Hz); 7.86(d, 1H, J=7.8 Hz). (CDCl 3 ) 15 (CH 3 ) 2 N— H H H H H H 2 163-166 1329, 1288, 1153, 1126, 694, 545, 509. 2.30(s, 6H); 2.70(t, 2H, J=7.1 Hz); 4.22(t, 2H, J=7.1 Hz); 4.29(s, 2H); 6.48(d, 1H, J=3.1 Hz); 7.04(dd, 1H, J=8.8 Hz, J′=2.2 Hz); 7.19(d, 1H, J=3.1 Hz); 7.31(d, 1H, J=8.8 Hz); 7.33-7.40(m, 5H); 7.49(d, 1H, J=2.2 Hz). (CDCl 3 ) 16 H H H H H H 2 138-140 2960, 1481, 1323, 1161, 1074, 659, 549, 480. 1.57(m, 4H); 2.37(m, 4H); 2.66(t, 2H, J=6.8 Hz); 4.12(t, 2H, J=6.8 Hz); 6.25(d, 1H, J=3.1 Hz); 6.82(dd, 1H, J=8.8 Hz, J′=2.0 Hz); 7.22(d, 1H, 2.0 Hz); 7.25(d, 1H, J=8.6 Hz); 7.29(d, 1H, J=3.l Hz); 7.54-7.66(m, 2H); 7.74(dd, 1H, J=8.7 Hz, J′=1.8 Hz); 7.94(m, 1H); 8.03(m, 2H); 8.28(s, 1H). (CDCl 3 ) 17 H H H H H H 2 186-189 2814, 1491, 1291, 1158, 1128, 763, 585. 1.59(m, 4H); 2.39(m, 4H); 2.67(t, 2H, J=6.8 Hz); 4.11(t, 2H, J=6.8 Hz); 6.21(d, 1H, J=3.1 Hz); 6.70(dd, 1H, J=8.8 Hz, J=1.8 Hz); 7.10(d, 1H, 1.8 Hz); 7.20(d, 1H, J=8.8 Hz); 7.27(d, 1H, J=3.1 Hz); 7.50(m, 1H); 7.60-7.74(m, 2H); 8.03(m 2H); 8.11(d, 1H, J=8.1 Hz); 8.76(d, 1H, J=8.6 Hz). (CDCl 3 ) 18 H H H H H H 2 156-158 2950, 2803, 1325, 1156, 1078, 650, 564. 1.59(m, 4H); 2.36(m, 4H); 2.69(t, 2H, J=6.6 Hz); 4.1 1(t, 2H, J=6.6 Hz); 6.30(d, 1H, J=3.1 Hz); 6.83(dd, 1H, J=8.7 Hz, J′=1.9 Hz); 7.25(d, 1H, 1.9 Hz); 7.32(m, 2H); 7.50(dd, 1H, J=8.6 Hz, J=2.0 Hz); 7.92(d, 1H, J=2.0 Hz); 7.98(d, 1H, J=8.8 Hz). (CDCl 3 ) 19 (CH 3 ) 2 N— H H H H H H 2 108-111 2943, 2821, 1516, 1139, 752, 728, 542, 531. 2.28(s, 6H); 2.68(t, 2H, J=7.1 Hz); 4.19(t, 2H, J=7.1 Hz); 6.43(d, 1H, J=3.1 Hz); 6.82(d, 1H, J=16.6 Hz); 7.09(dd, 1H, J=8.6, J′=2.0 Hz); 7.15(d, 1H, J=3.3 Hz); 7.25(m, 1H); 7.33-7.44(m, 6H); 7.49(d, 1H, J=2.0 Hz). (CDCl 3 ) 20 (CH 3 ) 2 N— H H H H H H 2 120-123 3095, 2943, 1421, 1325, 1148, 1020, 730, 609, 534 2.30(s, 6H); 2.69(t, 2H, J=7.1 Hz); 4.21(t, 2H, J=7.1 Hz); 6.46(d, 1H, J=3.1 Hz); 6.93(dd, 1H, J=8.6, J′=2.0 Hz); 7.17(s, 1H); 7.18(d, 1H, J=3.3 Hz); 7.25(m, 1H); 7.39(d, 1H, J=2.0 Hz). (CDCl 3 ) 21 (CH 3 ) 2 N— H H H H H H 2 175 (decom- position 1686, 1164, 1094, 637, 534, 475. 2.12(s, 6H); 2.53(t, 2H, J=6.6 Hz); 4.15(t, 2H, J=6.6 Hz); 6.30(d, 1H, J=3.1 Hz); 6.80(dd, 1H, J=8.6, J′=2.2 Hz): 7.19(d, 1H, J=2.0 Hz); 7.30-7.34(m, 2H); 7.57(AB sist., 2H, J=8.4 Hz); 7.70(AB sist., 2H, J=8.4 Hz). (DMSO-d6). 22 (CH 3 ) 2 N— H H H H H H 2 114-117 2943, 1573, 1469, 1321, 1161, 1088, 737, 630, 538. 2.13(s, 6H); 2.50-2.55(m, 5H); 4.14(t, 2H, J=6.3 Hz): 6.29(d, 1H, J=3.0 Hz); 6.82(d, 1H, J=8.2 Hz); 7.20(s, 1H); 7.29-7.32(m, 2H); 7.79(AB sist., 2H, J=8.4 Hz); 8.02(AB sist., 2H, J=8.4 Hz). (DMSO-d6). 23 (CH 3 ) 2 N— H H H H H H 2 141-144 2935, 1598, 1497, 1333, 1258, 1159, 1093, 1018, 836, 568, 560. 2.28(s, 6H); 2.67(t, 2H, J=7.1 Hz); 4.18(t, 2H, J=7.1 Hz); 6.38(d, 1H, J=3.1 Hz); 6.84(AB Sist., 2H, J=9.0 Hz); 6.90(dd, 1H, J=8.8, J′=2.0 Hz); 7.13(d, 1H, J=3.3 Hz); 7.19(d, 1H, J=8.8 Hz); 7.27(d, 1H, J=2.0 Hz); 7.62(AB sist., 2H, J=9 Hz). (CDCl 3 ) 24 (CH 3 CH 2 ) 2 N— H H H H H H 2 53-56 2969, 1486, 1334, 1161, 114, 1080, 862, 729, 652, 560. 0.78(m, 6H); 232(s, 3H); 2.42(m, 4H); 2.65(m, 2H); 4.12(m, 2H); 6.30(d, 1H, J=3.0 Hz); 6.82(d, 1H, J=8.6 Hz); 7.25(d, 1H, 1.7 Hz); 7.32(m, 2H); 7.50(dd, 1H, J=8.7 Hz, J′=1.9 Hz); 7.91(d, 1H, J=1.7 Hz); 7.99(d, 1H, J=8.6 Hz). (CDCl 3 ) 25 (CH 3 ) 2 N— H H H H H H 2 60-64 3095, 2768, 1529, 1349, 1165, 1090, 736. 2.29(s, 6H); 2.67(t, 2H, J=7.0 Hz); 4.18(t, 2H, J=7.0 Hz); 6.40(d, 1H, J=3.1 Hz); 6.85(dd, 1H, J=8.6 Hz, J=2.0 Hz); 7.16(d, 1H, J=3.1 Hz); 7.18(d, 1H, J=8.6 Hz); 7.29(d, 1H, J=2.0 Hz) 7.85(AB sys, J=8.8 Hz, 2H); 8.21(AB sys, J=8.8 Hz, 2H). (CDCl 3 ) 26 (CH 3 ) 2 N— H H H H H H 2 138-140 3103, 2951, 1587, 6.83, 1335, 1166, 1089, 557, 542. 2.35(s, 6H); 2.83(m, 2H); 4.28(t, 2H, J=6.7 Hz); 6.40(d, 1H, J=3.0 Hz); (dd, 1H, J=8.6 Hz, J′=2.0 Hz); 7.20(d, 1H, J=1.9 Hz); 7.30-7.38(m, 4H); 7.70-7.75(m, 2H). (DMSO-d6). 27 (CH 3 CH 2 ) 2 N— H H H H H H 2 68-70 3110, 2969, 1458, 1271, 1249, 1179, 1140, 727 651. 1.00(t, 6H, J=7.0 Hz), 2.60(q, 4H, J=7.0 Hz); 2.81(t, 2H, J=6.7 Hz); 4.21(t, 2H, J=6.7 Hz); 6.38(d, 1H J=3.0 Hz); 6.79(d, 1H, J=4.5 Hz); 6.96(dd, 1H, J=8.6, J=1.7 Hz); 7.14(d, 1H, 3.0 Hz); 7.19(d, 1H, J=8.8 Hz); 7.40(d, 1H, J=1.5 Hz); 7.59(d, 1H, J=4.4 Hz). (CDCl 3 ) 28 H H H H H H 2 81-84 3119, 2951, 2798, 1458, 1271, 1248, 1178, 1140, 727, 623. 1.85(m, 6H); 2.68(m, 4H); 3.00(m, 2H); 4.38(m, 2H): 6.40(d, 1H J=3.1 Hz); 6.82(d, 1H, J=4.5 Hz); 6.96(d, 1H, J=8.6 Hz); 7.19(d, 1H, 2.7 Hz); 7.22(m, 1H); 7.41(m, 1H); 7.64(d, 1H, J=4.5 Hz). (CDCl 3 ) 29 (CH 3 CH 2 ) 2 N— H H H H H H 2 97-104 0.95(t, 6H, J=7.l Hz); 2.54(q, 4H, J=7.0 Hz); 2.76(t, 2H, J=6.7 Hz); 4.07(t, 2H, J=6.7 Hz); 6.66(dd, 1H, J=8.5 J′=1.7 Hz); 6.91(s, 1H); 6.97(s, 1H); 7.01(d, 1H, J=8.8 Hz); 7.22(dd, 1H, J=8.6 , J′=1.6 Hz): 7.26(s, 1H); 7.42-7.55(m, 3H); 7.63(d, 1H, J=8.1 Hz); 7.70(d, 1H, J=8.2 Hz); 8.03(s, 1H); 9.95(s, 1H). (CDCl 3 ) 30 (CH 3 CH 2 ) 2 N— H H H H H H 2 133-135 0.87(m, 6H); 2.58(m, 4H); 2.76(m, 2H); 4.14(m, 2H); 6.24(s, 1H); 6.73(d, 1H, J=8.8 Hz); 7.11(s, 1H); 7.21(d, 1H, J=8.0 Hz); 7.29(s, 1H); 7.50(t, 1H, J=7.8 Hz); 7.63-7.71(m, 2H); 8.04(d, 2H, J=7.5 Hz); 8.13(d, 1H, J=8.2 Hz); 8.76(d, 1H, J=8.2 Hz); 10.21(s, 1H). (DMSO-d6) 31 (CH 3 CH 2 ) 2 N— H H H H H H 2 Oil 0.83(m, 6H); 2.50(m, 4H); 2.70(m, 2H); 4.13(m, 2H); 6.30(d, 1H, J=2.6 Hz); 6.87(d, 1H, J=8.6 Hz); 7.24(s, 1H); 7.30(m, 2H); 7.44(m, 3H); 7.66(d, 2H, J=7.2 Hz); 7.72(AB sys, 2H, J=8.5 Hz); 7.78(AB sys, 2H, J=8.5 Hz); 9.91(s, 1H). (DMSO-d6) 32 (CH 3 ) 2 N— CH 3 H H H H H 2 203-205 2.13(s, 6H); 2.33(s, 6H); 2.39(t, 2H, J=7.0 Hz); 4.07(t, 2H, J=6.8 Hz); 6.08(s, 1H); 6.76(dd, 1H, J=8.6, J′=2.0 Hz); 7.13(d, 1H, J=2.0 Hz); 7.20(d, 1H, J=8.6 Hz); 7.51(dd, 1H, J=8.7 , J′=2.0 Hz); 7.93(d, 1H, J=2.0 Hz); 8.00(d, 1H, J=8.8 Hz); 10.20(s, 1H). (DMSO-d6) 33 (CH 3 ) 2 N— CH 3 H H H H H 2 199-200 2.11(s, 6H); 2.30(s, 3H); 2.35(t, 2H, J=7.0 Hz); 4.03(t, 2H, J=7.0 Hz); 6.03(s, 1H); 6.75(dd, 1H, J=8.6, J′=2.0 Hz); 7.1O(d, 1H, J=2.0 Hz); 7.13(d, 1H, J=8.6 Hz); 7.54-7.67(m, 2H); 7.73(dd, 1H, J=8.6, J′=1.8 Hz); 7.95(d, 1H, J=7.9 Hz); 8.02(d, 2H, J=8.6 Hz); 8.27(d, 1H, J=1.5 Hz); 9.89(s, 1H). (DMSO-d6) 34 (CH 3 ) 2 N— CH 3 H H H H H 2 183-184 2.12(s, 6H); 2.29(s, 3H); 2.35(t, 2H, J=7.0 Hz); 4.01(t, 2H, J=7.0 Hz); 5.98(s, 1H); 6.62(dd, 1H, J=8.7, J′=1.9 Hz); 6.98(d, 1H, J=2.0 Hz); 7.07(d, 1H, J=8.6 Hz); 7.49(m, 1H); 7.63(m, 1H); 7.70(m, 1H); 8.02(d, 2H, J=7.5 Hz); 8.12(d, 1H, J=8.0 Hz); 8.75(d, 1H, J=8.4 Hz); 10.15(s, 1H). (DMSO-d6) 35 (CH 3 ) 2 N— CH 3 H H H H H 2 182-183 2.14(s, 6H); 2.34(s, 3H); 2.39(m, 2H); 4.01(m, 2H); 6.09(s, 1H); 6.70(dd, 1H, J=8.5 J′1.8 Hz); 7.08(d, 1H, J=1.8 Hz); 7.21(d, 1H, J=8.5 Hz); 7.51(d, 1H, J=4.5 Hz); 7.80(d, 1H, J=4.5 Hz). (DMSO-d6) 36 (CH 3 ) 2 N— CH 3 H H H H H 2 176-177 2.14(s, 6H); 2.33(s, 3H); 2.39(t, 2H, J=7.1 Hz); 4.06(t, 2H, J=7.1 Hz); 6.07(s, 1H); 6.79(dd, 1H, J=8.8, J′=2.0 Hz); 7.11(d, 1H, J=1.8 Hz); 7.19(d, 1H, J=8.8 Hz); 7.36-7.48(m, 3H); 7.66(m, 2H); 7.72(AB sys, 2H, J=8.8 Hz); 7.79(AB sys, 2H, J=8.8, Hz); 9.85(s, 1H). (DMSO-d6) 37 (CH 3 ) 2 N— CH 3 H H H H H 2 135-137 2.17(s, 6H); 2.38(s, 3H); 2.45(m, 2H); 3.30-3.45(m, 4H); 4.14(t, 2H, J=6.7 Hz); 6.15(s, 1H); 7.04(d, 1H, J=8.5 Hz); 7.26(m, 1H); 7.30-7.38(m, 4H); 7.44(m, 1H); 7.65(d, 1H, J=8.2 Hz); 7.62(m, 1H); 7.87(d, 1H, J=8.2 Hz); 9.56(s, 1H). (DMSO-d6) 38 (CH 3 ) 2 N— CH 3 H H H H H 2 147-149 2.20(s, 6H); 2.34(s, 3H); 2.45(m, 2H); 4.10(t, 2H, J=7.1 Hz); 6.08(s, 1H); 6.76(dd, 1H, J=8.6, J′=2.0 Hz); 6.99(d, 2H, J=8.8 Hz); 7.03-7.08(m, 3H); 7.17-7.24(m, 2H); 7.41(t, 2H, J=7.8 Hz); 7.63(d, 2H, J=8.8 Hz); 9.73(s, 1H). (DMSO-d6) 39 (CH 3 ) 2 N— CH 3 H H H H H 2 147-149 2.15(s, 6H); 2.35(s, 3H); 2.41(t, 2H, J=6.7 Hz); 4.10(t, 2H, J=7.1 Hz); 6.12(s, 1H); 6.71(dd, 1H, J=8.6, J′=2.0 Hz); 7.09(d, 1H, J=1.8 Hz); 7.24(d, 1H, J=9.0 Hz); 7.58(d, 2H, J=1.9 Hz); 7.90(t, 1H, J=1.9 Hz), (DMSO-d6) 40 (CH 3 ) 2 N— CH 3 H H H H H 2 167-169 2.14(s, 6H); 2.31(s, 3H); 2.38(m, 2H); 4.04(t, 2H, J=7.1 Hz); 6.02(s, 1H); 6.66(dd, 1H, J=8.4, J′=1.8 Hz); 7.04(d, 1H, J=1.6 Hz); 7.12(d, 1H, J=8.2 Hz): 7.40-7.51(m, 2H); 8.03(d, 1H, J=7.6 Hz); 8.21(d, 1H, J=7.9 Hz); 8.31(s, 1H); I0.08(s, 1H), (DMSO-d6) 41 (CH 3 CH 2 ) 2 N— H H H H H H 2 62-75 0.98(m, 6H); 2.54(m, 4H); 2.70(m, 2H); 4.18(m, 2H); 6.29(s, 1H); 6.77(d, 1H, J=8.5 Hz); 7.18(s, 1H); 7.34(m, 2H); 7.39-7.52(m, 2H); 8.03(d, 1H, J=7.9 Hz); 8.22(d, 1H, J=7.5 Hz); 8.34(s, 1H); 10.18(s, 1H), (CDCl 3 ) 42 (CH 3 ) 2 N— CH 3 H H H H H 2 61-72 2.12(s, 6H); 2.50(m, 2H); 4.12(t, 2H, J=6.7 Hz); 6.25(d, 1H, J=3.1 Hz); 6.75(dd, 1H, J=8.7, J=2.1 Hz); 7.17(d, 1H, J=1.9 Hz); 7.25(d, 1H, J=8.9 Hz); 7.30(d, 1H, J=3.2 Hz); 7.48(m, 2H); 8.04(d, 1H, J=7.0 Hz); 8.24(d, 1H, J=7.4 Hz); 8.34(s, 1H); 10.14(s, 1H); (CDCl 3 ) 43 H H H H H H 3 82-92 1.20-1.55(m, 6H); 1.88(m, 2H); 2.33(s, 3H); 2.16-2.60(m, 6H); 4.10(t, 2H, J=6.6 Hz); 6.34(d, 1H, J=3.2 Hz); 6.82(d, 1H, J=9.9 Hz); 7.27-7.35(m, 3H); 7.50(dd, 1H, J=8.7, J′=2.0 Hz); 7.91(d, 1H, J=2.2 Hz); 7.99(d, 1H, J=8.6 Hz); 10.20(bs, 1H). (DMSO-d6) 44 H H H H H H 3 92-108 1.20-1.55(m, 6H); 1.87(m, 2H); 2.22-2.62(m, 6H); 4.06(t, 2H, J=6.6 Hz); 6.28(d, 1H, J=2.9 Hz); 6.83(dd, 1H, J=8.7, J′=2.0 Hz); 7.24(d, 1H, J=2.0 Hz); 7.27(m, 2H); 7.59(m, 1H); 7.64(m, 1H); 7.75(dd, 1H, J=8.8, J′=1.9 Hz); 7.95(d, 1H, J=7.5 Hz); 8.03(d, 2H, J=8.5 Hz); 8.28(s, 1H); 9.97(s, 1H). (DMSO-d6) 45 H H H H H H 3 85-86 1.25-1.55(m, 6H); 1.81(m, 2H); 2.03-2.60(m, 6H); 4.03(t, 2H, J=6.4 Hz); 6.23(d, 1H, J=3.1 Hz); 6.70(d, 1H, J=8.9 Hz); 7.11(d, 1H, J=1.8 Hz); 7.20(d, 1H, J=8.9 Hz); 7.24(d, 1H, J=3.1 Hz); 7.49(dd, 1H, J=8.1, J′=7.4 Hz); 7.59-7.66(m, 1H); 7.66-7.73(m, 1H); 8-8.05(m, 2H); 8.12(d, 1H, J=8.2 Hz); 8.75(d, 1H, J=7.8 Hz); 10.20(bs, 1H). (DMSO-d6) 46 H H H H H H 3 85-86 1.36(m, 2H); 1.49(m, 4H); 1.86(m, 2H); 2.15-2.44(m, 6H); 4.10(t, 2H, J=6.7 Hz); 6.33(d, 1H, J=3.1 Hz); 6.79(dd, 1H, J=8.7, J′=2.0 Hz); 7.21(d, 1H, J=2.0 Hz); 7.30-7.36(m, 2H); 7.52(d, 1H, J=4.4 Hz); 7.83(d, 1H, J=4.4 Hz); 10.25(bs, 1H), (DMSO-d6) 47 H H H H H H 3 148-150 1.34(m, 2H); 1.47(m, 4H); 1.86(m, 2H); 2.03-2.55(m, 6H); 4.09(t, 2H, J=6.6 Hz); 6.32(d, 1H, J=2.8 Hz); 6.87(dd, 1H, J=8.9, J′=1.8 Hz); 7.26(d, 1H, J=1.9 Hz): 7.28-7.34(m, 2H); 7.36-7.49(m, 3H); 7.66(m, 2H); 7.73(AB sys, 2H, J=8.8 Hz); 7.79(AB sys, 2H, J=8.8 Hz); 9.91(s, 1H), (DMSO-d6) 48 H H H H H H 3 59-61 1.20-1.56(m, 6H); 1.89(m, 2H); 2.12-2.50(m, 6H); 3.26-3.47(m, 4H); 4.16(t, 2H, J=6.2 Hz); 6.40(d, 1H, J=2.3 Hz); 7.13(d, 1H, J=8.6 Hz); 7.24(t, 1H, J=7.5 Hz); 7.34-7.50(m, 6H); 7.64(d, 1H, J=8.4 Hz); 7.76(m, 1H); 7.87(d, 1H, J=8.2 Hz); 9.65(s, 1H). (DMSO-d6) 49 H H H H H H 3 64-66 120-1.58(m, 6H); 1.90(m, 2H); 2.20-2.55(m, 6H); 4.09(t, 2H, J=6.4 Hz); 6.33(s, 1H); 6.84(dd, 1H, J=8.4 Hz); 6.96-7.02(m, 2H); 7.04(d, 2H, J=7.9 Hz); 7.17-7.24(m, 2H); 7.32(m, 2H); 7.41(m, 2H); 7.64(d, 2H, J=8.6 Hz); 9.79(s, 1H). (DMSO-d6) 50 H H H H H H 3 56-58 1.35(m, 2H); 1.46(m, 4H); 1.83(m, 2H); 2.10(m, 2H); 2.24(m, 4H); 4.11(t, 2H, J=6.4 Hz); 6.36(d, 1H, J=2.6 Hz); 6.78(dd, 1H, J8.8, J′=1.8 Hz); 7.22(d, 1H, J=1.90 Hz); 7.33(d, 1H, J=2.9 Hz); 7.37(d, 1H, J=8.8 Hz); 7.58(d, 2H, J=8.6 Hz); 7.89(t, 1H, J=1.9 Hz); 9.99(s, 1H). (DMSO d6) 51 H H H H H H 3 70-72 1.38(m, 2H); 1.52(m, 4H); 1.91(m, 2H); 2.24(m, 2H); 2.37(m, 4H); 4.16(t, 2H, J=6.6 Hz); 6.42(d, 1H, J=2.5 Hz); 6.89(d, 1H, J=8.6 Hz); 7.32(s, 1H); 7.37(d, 1H, J=2.8 Hz); 7.43(d, 1H, J=8.6 Hz); 7.48(s, 1H), (DMSO-d6) 52 H H H H H H 3 92-96 1.13-1.70(m, 6H); 2.00(m, 2H); 2.68(m, 2H); 2.84(m, 2H); 3.26(m, 2H); 4.05(m, 2H); 6.22(d, 1H, J=3.1 Hz); 6.71(m, 1H); 7.10-7.18(m, 3H); 7.52-7.53(m, 2H); 7.72(m, 1H); 8.15(d, 1H, J=7.3 Hz); 8.37(d, 1H, J=8.5 Hz); 8.77(d, 1H, J=8.5 Hz); 8.97(bs, 1H); 10.23(bs, 1H). (DMSO d6 + TFA)
Pharmaceutical Particulars:
Binding of the new compounds of general formula (Ia) and (Ib) and (Ic) to the 5-HT 6 receptor was determined as previously described.
The binding results for some of the compounds of the present invention are indicated in the following table:
TABLE Example K i (nM) 3 94.2 4 112.4 11 1.89 12 104.6 13 82.5 20 84.8
The daily posology in human medicine is comprised between 1 milligram and 2 grams of medicinal product which may be administered in one or several doses. The compositions are prepared under forms that are compatible with the administration route used, preferably tablets, coated tablets, 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 substance (compound of general formula 1), and 40 to 99% by weight of the suitable pharmaceutical vehicle compatible with the active substance and the physical form of the composition used.
The formula of a tablet containing a product of the invention is, provided by way of example:
Example of formula per tablet:
Example 1 5 mg Lactose 60 mg Crystalline cellulose 25 mg Povidone K 90 5 mg Pregelatinized starch 3 mg Colloidal silicon dioxide 1 mg Magnesium stearate 1 mg Total weight per tablet 100 mg
1.PublishNumber: US-2007032520-A1
2.Date Publish: 20070208
3.Inventor: MERCE VIDAL RAMON
CODONY SOLER XAVIER
DORDAL ZUERAS ALBERTO
4.Inventor Harmonized: MERCE VIDAL RAMON(ES)
CODONY SOLER XAVIER(ES)
DORDAL ZUERAS ALBERTO(ES)
5.Country: US
6.Claims:
(en)The present invention refers to new sulfonamide derivatives, of general formula (1a, 1b, 1c) 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 their salts, preferably the corresponding, physiologically acceptable salts, or corresponding solvates; to the processes for their preparation, to their application as medicaments in human and/or veterinary therapeutics, and to the pharmaceutical compositions containing them.
7.Description:
(en)The present invention refers to new sulfonamide derivatives, of general formula (Ia, Ib, Ic),
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 their salts, preferably the corresponding, physiologically acceptable salts thereof, or corresponding solvates thereof; to the processes for their preparation, to their application in medicaments in human and/or veterinary therapeutics, and to the pharmaceutical compositions containing them.
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-HT 1 -5-HT 7 ), 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., 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. Neurochem., 1996, 66, 47]. The compounds with an affinity for the 5-HT 6 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. Ther., 1995, 274,173; A. J. Sleight, et al., Behav. Brain Res., 1996, 73, 245; T. A. Branchek, et al., Annu. Rev. Pharmacol. Toxicol., 2000, 40, 319; C. Routledge, et al., Br. J. Pharmacol., 2000,130,1606]. It has been shown that the typical and atypical antipsychotics for treating schizophrenia have a high affinity for the 5-HT 6 receptors [B. L. Roth, et al., J. Pharmacol. Exp. Ther., 1994, 268, 1403; C. E. Glatt, et al., Mol. Med., 1995, 1, 398; F. J. Mosma, et al., Mol. Pharmacol., 1993, 43, 320; T. Shinkai, et al, Am. J. Med. Genet, 1999, 88, 120]. 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. Gérard, et al., Brain Research, 1997, 746, 207; M. R. Pranzatelli, Drugs of Today, 1997, 33, 379].
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 6 receptor antagonist activity.
Patent application EP 0 733 628 discloses sulfonamides derived from indole with 5-HT 1F receptor antagonist activity, useful for the treatment of migraines.
Furthermore, it has been shown that the 5-HT 6 receptor plays a role in the ingestion of food [Neuropharmacology, 41, 2001, 210-219].
Eating disorders, particularly obesity, 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 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, preferably Alzheimers 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 preferably in humans.
It has been found that the indol-5-yl sulfonamide compounds of general formulas (Ia, Ib, Ic) described below show an affinity for the 5-HT 6 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 infantile hyperkinesia (ADHD, attention deficit/hyperactivity disorder) and other disorders mediated by the 5-HT 6 serotonin receptor in mammals, including humans. These compounds are also suitable for the preparation of a medicament for cognitive enhancement.
Thus, one aspect of the present invention are compounds of general formula (Ia),
wherein
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,
with the proviso that 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
and
n is 0, 1, 2, 3 or 4;
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 salt thereof, preferably a corresponding, physiologically acceptable salt thereof, or a corresponding solvate thereof.
Another aspect of the present invention are compounds of the general formula (Ib)
wherein
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;
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 salt thereof, preferably a corresponding, physiologically acceptable salt thereof, or a corresponding solvate thereof.
Yet, another aspect of the present invention are compounds of general formula (Ic),
wherein
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,
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
and
n is 0, 1, 2, 3or4;
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 salt thereof, preferably a corresponding, physiologically acceptable salt thereof, or a corresponding solvate thereof.
If one or more of the 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.
If 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 1 -C 6 alkyl, linear or branched C 1 -C 6 alkoxy, linear or branched C 1 -C 6 perfluoroalkyl, linear or branched C 1 -C 6 perfluoroalkoxy and benzyl, preferably from the group consisting of linear or branched C 1 -C 6 alkyl and benzyl.
The 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.
If 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 1 -C 6 alkyl, linear or branched C 1 -C 6 alkoxy, linear or branched C 1 -C 6 perfluoroalkyl, linear or branched C 1 -C 6 perfluoroalkoxy and benzyl, preferably from the group consisting of linear or branched C 1 -C 6 alkyl and benzyl.
If the 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 lo 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.
If 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, each one of these substituents may preferably be chosen from the group consisting of nitro, —O-phenyl, —O—C 1-6 alkyl, —C(═O)—C 1-6 alkyl, hydroxy, halogen, linear or branched C 1 -C 6 alkyl, linear or branched C 1 -C 6 alkoxy, linear or branched C 1 -C 6 perfluoroalkyl, linear or branched C 1 -C 6 perfluoroalkoxy, an optionally at least mono-substituted phenyl radical and 5- or 6-membered heteroaryl, more preferably from the group consisting of nitro, —O-phenyl, —C(═O)-C 1-6 alkyl, linear or branched C 1 -C 6 alkoxy, halogen, linear or branched C 1 -C 6 alkyl, an optionally at least mono-substituted phenyl radical and 5- or 6-membered heteroaryl, even more preferably from the group consisting of nitro, —O-phenyl, —O—CH 3 , —C(═O)—CH 3 , fluorine, chlorine, bromine, linear or branched C 1 -C 6 alkyl, an optionally at least mono-substituted phenyl radical and 5- or 6-membered heteroaryl.
If one or more of the rings of the mono- or polycyclic aromatic ring system contain one or more heteroatoms, these 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.
If the previously mentioned phenyl radical is itself substituted by one or more substituents, each one of these substituents may preferably be chosen from the group consisting of fluorine, chlorine, bromine, linear or branched C 1 -C 6 alkyl, linear or branched C 1 -C 6 alkoxy, linear or branched C 1 -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 1 -C 6 alkyl.
If the previously mentioned alkylene, alkenylene or alkynylene group is substituted by one or more substituents, each of these substituents may preferably be chosen from the group consisting of hydroxy, halogen, linear or branched C 1 -C 6 alkyl, linear or branched C 1 -C 6 alkoxy, linear or branched C 1 -C 6 perfluoroalkyl, linear or branched C 1 -C 6 perfluoroalkoxy or an optionally at least mono-substituted phenyl radical.
If said phenyl radical is itself substituted by one or more substituents, each one of these substituents may preferably be chosen from the group consisting of fluorine, chlorine, bromine, linear or branched C 1 -C 6 alkyl, linear or branched C 1 -C 6 alkoxy, linear or branched C 1 -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 1 -C 6 alkyl.
If one or more of the substituents R 2 , R 3 , R 4 , R 6 and R 7 represents an alcoxy radical, said radical may have 1 to 6, preferably 1 to 3 carbon atoms.
Those skilled in the art understand that the term “condensed” indicates that the condensed rings share more than one atom. The terms “annulated” or “fused” may also be used for this type of bonding.
Sulfonamide derivatives of general formula (la) are preferred, wherein 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,
more preferably R 1 represents an —NR 8 R 9 radical or a radical chosen from the group consisting of
wherein, if present, the dotted line is an optional chemical bond, and R 10 represents hydrogen, a linear or branched C 1 -C 6 alkyl radical or a benzyl radical, preferably hydrogen or a C 1 -C 2 alkyl radical and R 2 to R 9 , A and n are defined as above.
Sulfonamide derivatives of general formula (Ia) 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 1 -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,
more preferably 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 1 -C 6 alkyl radical,
even more preferably 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.
The use of sulfonamide derivatives of general formula (Ia) is also preferred, wherein R 5 represents hydrogen, a linear or branched, optionally at least mono-substituted C 1 -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,
more preferably R 5 represents hydrogen or a linear or branched, optionally at least mono-substituted C 1 -C 6 alkyl radical,
even more preferably R 5 represents hydrogen or a C 1 -C 2 alkyl radical and R 1 —R 4 , R 6 -R 9 , A and n are defined as above.
Furthermore, sulfonamide derivatives of general formula (Ia) 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 10 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.
Particularly preferred is the use of sulfonamide derivatives of general formula (la), wherein R 8 and R 9 , identical or different, each represent hydrogen or a linear or branched C 1 -C 10 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 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 nitrogen atom bridge form a radical chosen from the group consisting of
wherein R 11 , if present, represents hydrogen, a linear or branched C 1 -C 6 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.
Furthermore, sulfonamide derivatives of general formula (Ia) 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 1 -C 6 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,
preferably 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
wherein 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 1 -C 6 alkyl, linear or branched C 1 -C 6 alkoxy, linear or branched C 1 -C 6 alkylthio, a trifluoromethyl radical, a cyano radical and a —NR 12 R 13 radical,
wherein R 12 and R 13 , identical or different, each represent hydrogen or linear or branched C 1 -C 6 alkyl,
W represents a single chemical bond between the two rings, a CH 2 , O, S group or a NR 14 radical,
wherein R 14 is hydrogen or a linear or branched C 1 -C 6 alkyl,
m is 0, 1, 2, 3 or 4 and
m1 is 1 or 2, preferably 2, and R 1 —R 9 and n are defined as above.
Furthermore, sulfonamide derivatives of general formula (Ia) 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 1 -C 6 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,
more preferably 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
wherein X, Y, Z, independently from one another, each represent a radical selected from the group consisting of hydrogen, fluorine, chlorine, bromine, linear or branched C 1 -C 6 alkyl, linear or branched C 1 -C 6 alkoxy, linear or branched C 1 -C 6 alkylthio, a trifluoromethyl radical, a cyano radical and a —NR 12 R 13 radical,
wherein R 12 and R 13 , identical or different, each represent hydrogen or linear or branched C 1 -C 6 alkyl,
W represents a single chemical bond between the two rings, a CH 2 , O, S group or a NR 14 radical,
wherein R 14 is hydrogen or a linear or branched C 1 -C 6 alkyl,
and
m is 0, 1, 2, 3 or 4.
and R 1 —R 9 and n are defined as above.
Furthermore, sulfonamide derivatives of general formula (Ia) are preferred, wherein A represents a heteroaryl radical selected from the group consisting of quinolinyl, benzo[b]thiophenyl, benzo[1,2,5]thiadiazolyl, thiophenyl and imidazo[2,1-b]thiazolyl which may be substituted by 1, 2 or 3 substituents selected from the group consisting of fluorine, bromine, chlorine, methyl, phenyl, nitro, —C(═O)—CH 3 , —O—CH 3 and —O-phenyl and/or which may be bonded via a C 1-2 alkylene group or a C 2 alkenylene group,
or a radical chosen from the group consisting of
wherein X, Y, Z, independently from one another, each represent a radical selected from the group consisting of hydrogen, fluorine, chlorine, bromine, s nitro, acetyl, linear or branched C 1 -C 6 alkyl, linear or branched C 1 -C 6 alkoxy, linear or branched C 1 -C 6 alkylthio, a trifluoromethyl radical, a cyano radical and a —NR 12 R 13 radical,
wherein R 12 and R 13 , identical or different, each represent hydrogen or linear or branched C 1 -C 6 alkyl,
W represents a single chemical bond between the two rings, a CH 2 , O, S group or a NR 14 radical,
wherein R 14 is hydrogen or a linear or branched C 1 -C 6 alkyl,
m is 0, 1, 2, 3 or4 and
m1 is 1 or 2, preferably 2, and R 1 —R 9 and n are defined as above.
Furthermore sulfonamide derivatives of general formula (Ia) 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 (Ia) are selected from the group consisting of
[16] N-[1-(2-pyrrolidine-1-yl-ethyl)-1H-indole-5-yl]-naphthalene-2-sulfonamide,
[17] N-[1-(2-pyrrolidine-1-yl-ethyl)-1H-indole-5-yl]-naphthalene-1-sulfonamide,
[18] N-[1-(2-pyrrolidine-1-yl-ethyl)-1H-indole-5-yl]-5-chloro-3-methylbenzo[b]thiophene-2-sulfonamide,
[28] N-[1-(2-pyrrolidine-1-yl-ethyl)-1H-indole-5-yl]-]-6-chloroimidazo[2,1-b]thiazole-5-sulfonamide,
[43] 5-chloro-3-methyl-N-(1-(3-(piperidin-1-yl)propyl)-1H-indol-5-yl)benzo[b]thiophene-2-sulfonamide,
[44] N-(1-(3-(piperidin-1-yl)propyl)-1H-indol-5-yl)naphthalene-2-sulfonamide,
[45] N-(1-(3-(piperidin-1-yl)propyl)-1H-indol-5-yl)naphthalene-1-sulfonamide,
[46] 6-chloro-N-(1-(3-piperidin-1-yl)propyl)-1H-indol-5-yl)imidazo[2,1-b]thiazole-5-sulfonamide,
[47] 4-phenyl-N-(1-(3-(piperidin-1-yl)propyl)-1H-indol-5-yl)benzenesulfonamide,
[48] 2-(naphth-1-yl)-N-(1-(3-(piperidin-1-yl)propyl)-1H-indol-5-yl)ethanesulfonamide,
[49] 4-phenoxy-N-(1-(3-(piperidin-1-yl)propyl)-1H-indol-5-yl)benzenesulfonamide,
[50] 3,5-dichloro-N-(1-(3-(piperidin-1-yl)propyl)-1H-indol-5-yl)benzenesulfonylamide,
[51] 4,5-dichloro-N-(1-(3-(piperidin-1-yl)propyl)-l H-indol-5-yl)thiophene-2-sulfonamide and
[52] 5-chloro-N-(1-(3-(piperidin-1-yl)propyl)-1H-indol-5-yl)naphthalene-1-sulfonamide,
and their corresponding salts and solvates.
Furthermore, sulfonamide derivatives of general formula (Ib) 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 1 -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,
more preferably 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 1 -C 6 alkyl radical,
even more preferably 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 (Ib) are also preferred, wherein R 5 hydrogen, a linear or branched, optionally at least mono-substituted C 1 -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,
preferably that R 5 represents hydrogen or a linear or branched, optionally at least mono-substituted C 1 -C 6 alkyl radical,
even more preferably R 5 represents hydrogen or a C 1 -C 2 alkyl radical and R 1 —R 4 , R 6 —R 9 , A and n are defined as above.
Furthermore, sulfonamide derivatives of general formula (Ib) 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 C 1 -C 4 alkyl radical,
with the proviso that R 8 and R 9 are not hydrogen at the same time and R 1 —R 7 , A and n are defined as above.
Particularly preferred are sulfonamide derivatives of general formula (Ib) wherein R 8 and R 9 , identical or different, each represent hydrogen or a C 1 -C 2 alkyl radical,
with the proviso that R 8 and R 9 are not hydrogen at the same time, and R 1 —R 7 , A and n are defined as above.
Furthermore, sulfonamide derivatives of general formula (Ib) 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 1 -C 6 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,
preferably 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
wherein 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 1 -C 6 alkyl, linear or branched C 1 -C 6 alkoxy, linear or branched C 1 -C 6 alkylthio, a trifluoromethyl radical, a cyano radical and a —NR 12 R 13 radical,
wherein R 12 and R 13 , identical or different, each represent hydrogen or linear or branched C 1 -C 6 alkyl,
W represents a single chemical bond between the two rings, a CH 2 , O, S group or a NR 14 radical,
wherein R 14 is hydrogen or a linear or branched C 1 -C 6 alkyl,
m is 0, 1, 2, 3 or 4 and
m1 is 1 or 2, preferably 2, and R 1 —R 9 and n are defined as above.
Furthermore, sulfonamide derivatives of general formula (Ib) 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 1 -C 6 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,
more preferably 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
wherein X, Y, Z, independently from one another, each represent a radical selected from the group consisting of hydrogen, fluorine, chlorine, bromine, linear or branched C 1 -C 6 alkyl, linear or branched C 1 -C 6 alkoxy, linear or branched C 1 -C 6 alkylthio, a trifluoromethyl radical, a cyano radical and a —NR 12 R 13 radical,
wherein R 12 and R 13 , identical or different, each represent hydrogen or linear or branched C 1 -C 6 alkyl,
W represents a single chemical bond between the two rings, a CH 2 , O, S group or a NR 14 radical,
wherein R 14 is hydrogen or a linear or branched C 1 -C 6 alkyl,
and
m is 0, 1, 2, 3 or 4.
and R 1 —R 9 and n are defined as above.
Furthermore, sulfonamide derivatives of general formula (Ib) are preferred, wherein A represents a heteroaryl radical selected from the group consisting of quinolinyl, benzo[b]thiophenyl, benzo[1,2,5]thiadiazolyl, thiophenyl and imidazo[2,1-b]thiazolyl which may be substituted by 1, 2 or 3 substituents selected from the group consisting of fluorine, bromine, chlorine, methyl, phenyl, nitro, —C(═O)—CH 3 , —O—CH 3 and —O-phenyl and/or which may be bonded via a C 1-2 alkylene group or a C 2 alkenylene group,
or a radical chosen from the group consisting of
wherein 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 1 -C 6 alkyl, linear or branched C 1 -C 6 alkoxy, linear or branched C 1 -C 6 alkylthio, a trifluoromethyl radical, a cyano radical and a —NR 12 R 13 radical,
wherein R 12 and R 13 , identical or different, each represent hydrogen or linear or branched C 1 -C 6 alkyl,
W represents a single chemical bond between the two rings, a CH 2 , O, S group or a NR 14 radical,
wherein R 14 is hydrogen or a linear or branched C 1 -C 6 alkyl,
m is 0, 1, 2, 3 or 4 and
m1 is 1 or 2, preferably 2,
and R 1 —R 9 and n are defined as above.
Furthermore sulfonamide derivatives of general formula (Ib) 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 (Ib) are selected from the group consisting of
[1] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-5-chloro-3-methylbenzo[b]thiophene-2-sulfonamide,
[2] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-naphthalene-2-sulfonamide,
[3] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-naphthalene-1-sulfonamide,
[4] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-5-chloronaphthalene-1-sulfonamide,
[5] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-benzenesulfonamide,
[6] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-quinoline-8-sulfonamide,
[7] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-4-phenoxybenzenesulfonamide,
[8] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-4-methylbenzenesulfonamide,
[9] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-5-chlorothiophene-2-sulfonamide,
[10] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-benzo[1,2,5]thiadiazole-4-sulfonamide,
[11] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-6-chloroimidazo[2,1-b]thiazole-5-sulfonamide,
[12] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-3,5-dichlorobenzenesulfonamide,
[13] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-3-bromobenzenesulfonamide,
[14] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-3-nitrobenzenesulfonamide,
[15] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-1-phenylmethanesulfonamide,
[19] trans-N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-2-phenylethenesulfonamide,
[20] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-4,5-dichlorothiophene-2-sulfonamide,
[21] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-4-acetylbenzenesulfonamide,
[22] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-4-bromobenzenesulfonamide,
[23] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-4-methoxybenzenesulfonamide,
[24] N-[3-(2-diethylaminoethyl)-1H-indole-5-yl]-5-chloro-3-methylbenzo[b]thiophene-2-sulfonamide,
[25] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-4-nitrobenzenesulfonamide,
[26] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-4-fluorobenzenesulfonamide,
[27] N-[1-(2-diethylaminoethyl)-1H-indole-5-yl]-6-chloroimidazo[2, 1-b]thiazole-5-sulfonamide
[29] N-(1-(2-(diethylamino)ethyl)-1H-indol-5-yl)-naphthalene-2-sulfonamide,
[30] N-(1-(2-(diethylamino)ethyl)-1H-indol-5-yl)-naphthalene-1-sulfonamide,
[31] N-(1-(2-(diethylamino)ethyl)-1H-indol-5-yl)-4-phenylbenzenesulfonamide,
[32] 5-chloro-N-(1-(2-(dimethylamino)ethyl)-2-methyl-1H-indol-5-yl)-3-methylbenzo[b]thiophene-2-sulfonamide,
[33] N-(1-(2-(dimethylamino)ethyl)-2-methyl-1H-indol-5-yl)-naphthalene-2-sulfonamide,
[34] N-(1-(2-(dimethylamino)ethyl)-2-methyl-1H-indol-5-yl)-naphthalene-1-sulfonamide,
[35] 6-chloro-N-(1-(2-(dimethylamino)ethyl)-2-methyl-1H-indol-5-yl)imidazo[2,1-b]thiazole-5-sulfonamide,
[36] N-(1-(2-(dimethylamino)ethyl)-2-methyl-1H-indol-5-yl)-4-phenylbenzenesulfonamide,
[37] N-(1-(2-dimethylamino)ethyl)-2-methyl-1H-indol-5-yl)-2-(naphth-1-yl)-ethanesulfonamide,
[38] N-(1-(2-(dimethylamino)ethyl)-2-methyl-1H-indol-5-yl)-4-phenoxy-benzenesulfonamide,
[39] 3,5-dichloro-N-(1-(2-(dimethylamino)ethyl)-2-methyl-1H-indol-5-yl)-benzenesulfonamide,
[40] N-(1-(2-(dimethylamino)ethyl)-2-methyl-1H-indol-5-yl)benzo[b]thiophene-3-sulfonamide,
[41] N-(1-(2-(diethylamino)ethyl)-1H-indol-5-yl)benzo[b]thiophene-3-sulfonamide and
[42] N-(1-(2-(dimethylamino)ethyl)-1H-indol-5-yl)benzo[b]thiophene-3-sulfonamide,
and their corresponding salts and solvates.
Sulfonamide derivatives of general formula (Ic) are preferred, wherein 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,
more preferably R 1 represents an —NR 8 R 9 radical or a radical chosen from the group consisting of
wherein, if present, the dotted line is an optional chemical bond, and R 10 represents hydrogen, a linear or branched C 1 -C 6 alkyl radical or a benzyl radical, preferably hydrogen or a C 1 -C 2 alkyl radical and R 2 to R 9 , A and n are defined as above.
Sulfonamide derivatives of general formula (Ic) 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 1 -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,
more preferably 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 1 -C 6 alkyl radical,
even more preferably 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.
Sulfonamide derivatives of general formula (Ic) are also preferred, wherein R 5 represents hydrogen, a linear or branched, optionally at least mono-substituted C 1 -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,
more preferably R 5 represents hydrogen or a linear or branched, optionally at least mono-substituted C 1 -C6 alkyl radical,
even more preferably R 5 represents hydrogen or a C 1 -C 2 alkyl radical and R 1 —R 4 , R 6 —R 9 , A and n are defined as above.
Furthermore, sulfonamide derivatives of general formula (Ic) 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 10 alkenyl radical, a linear or branched, optionally at least mono-substituted C 2 -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 ring system are 5-6- or 7-membered and R 1 —R 7 , A and n are defined as above.
Particularly preferred are sulfonamide derivatives of general formula (Ic), wherein R 8 and R 9 , identical or different, each represent hydrogen or a linear or branched C 1 -C 10 alkyl radical, or
R 8 and R 9 together with the nitrogen atom bridge form a radical chosen from the group consisting of
wherein R 11 , if present, represents hydrogen, a linear or branched C 1 -C 6 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.
Furthermore, sulfonamide derivatives of general formula (Ic) 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 1 -C 6 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,
preferably 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
wherein 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 1 -C 6 alkyl, linear or branched C 1 -C 6 alkoxy, linear or branched C 1 -C 6 alkylthio, a trifluoromethyl radical, a cyano radical and a —NR 12 R 13 radical,
wherein R 12 and R 13 , identical or different, each represent hydrogen or linear or branched C 1 -C 6 alkyl,
W represents a single chemical bond between the two rings, a CH 2 , O, S group or a NR 14 radical,
wherein R 14 is hydrogen or a linear or branched C 1 -C 6 alkyl,
m is 0, 1, 2, 3 or 4 and
m1 is 1 or 2, preferably 2, and R 1 —R 9 and n are defined as above.
Furthermore, sulfonamide derivatives of general formula (Ic) 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 1 -C 6 alkylene group, an optionally at least mono-substituted C 2 -C 6 alkenylene group or an optionally at least mono-substituted C 2 -C 5 alkynylene group, and/or wherein the ring(s) may contain at least one heteroatom as a ring member,
more preferably 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
wherein X, Y, Z, independently from one another, each represent a radical selected from the group consisting of hydrogen, fluorine, chlorine, bromine, linear or branched C 1 -C 6 alkyl, linear or branched C 1 -C 6 alkoxy, linear or branched C 1 -C 6 alkylthio, a trifluoromethyl radical, a cyano radical and a —NR 12 R 13 radical,
wherein R 12 and R 13 , identical or different, each represent hydrogen or linear or branched C 1 -C 6 alkyl,
W represents a single chemical bond between the two rings, a CH 2 , O, S group or a NR 14 radical,
wherein R 14 is hydrogen or a linear or branched C 1 -C 6 alkyl,
and
m is 0, 1, 2, 3 or 4.
and R 1 —R 9 and n are defined as above.
Furthermore, sulfonamide derivatives of general formula (Ic) are preferred, wherein A represents a heteroaryl radical selected from the group consisting of quinolinyl, benzo[b]thiophenyl, benzo[1,2,5]thiadiazolyl, thiophenyl and imidazo[2,1-b]thiazolyl which may be substituted by 1, 2 or 3 substituents selected from the group consisting of fluorine, bromine, chlorine, methyl, phenyl, nitro, —C(═O)—CH 3 , —O—CH 3 and —O-phenyl and/or which may be bonded via a C 1-2 alkylene group or a C 2 alkenylene group,
or a radical chosen from the group consisting of
wherein 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 1 -C 6 alkyl, linear or branched C 1 -C 6 alkoxy, linear or branched C 1 -C 6 alkylthio, a trifluoromethyl radical, a cyano radical and a —NR 12 R 13 radical,
wherein R 12 and R 13 , identical or different, each represent hydrogen or linear or branched C 1 -C 6 alkyl,
W represents a single chemical bond between the two rings, a CH 2 , O, S group or a NR 14 radical,
is wherein R 14 is hydrogen or a linear or branched C 1 -C 6 alkyl,
m is 0, 1, 2, 3 or 4 and
m1 is 1 or 2, preferably 2, and R 1 —R 9 and n are defined as above.
Furthermore sulfonamide derivatives of general formula (Ic) 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 (Ic),
wherein
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,
or
R 8 and R 9 together with the bridging nitrogen form a 5- or 6-membered heterocyclic ring, more preferably form pyrrolidine or piperidine,
A represents an aryl or heteroaryl radical selected from the group consisting of phenyl, naphthyl, quinolinyl, benzo[b]thiophenyl, benzo[1,2,5]thiadiazolyl, thiophenyl and imidazo[2,1-b]thiazolyl which may be substituted by 1, 2 or 3 substituents selected from the group consisting of fluorine, bromine, chlorine, methyl, phenyl, nitro, —C(═O)—CH 3 , —O—CH 3 and —O-phenyl and/or which may be bonded via a C 1-2 alkylene group or a C 2 alkenylene group,
and
n is 2 or 3,
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 salt thereof, preferably a corresponding, physiologically acceptable salt thereof, or a corresponding solvate thereof.
The most preferred compounds of general formula (Ic) are selected from the group consisting of
[1] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-5-chloro-3-methylbenzo[b]thiophene-2-sulfonamide,
[2] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-naphthalene-2-sulfonamide,
[3] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-naphthalene-1-sulfonamide,
[4] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-5-chloronaphthalene-1-sulfonamide,
[5] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-benzenesulfonamide,
[6] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-quinoline-8- sulfonamide,
[7] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-4-phenoxybenzenesulfonamide,
[8] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-4-methylbenzenesulfonamide,
[9] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-5-chlorothiophene-2-sulfonamide,
[10] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-benzo[1,2,5]thiadiazole-4-sulfonamide,
[11] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-6-chloroimidazo[2,1-b]thiazole-5-sulfonamide,
[12] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-3,5-dichlorobenzenesulfonamide,
[13] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-3-bromobenzenesulfonamide,
[14] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-3-nitrobenzenesulfonamide,
[15] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-1-phenylmethanesulfonamide,
[16] N-[1-(2-pyrrolidine-1-yl-ethyl)-1H-indole-5-yl]-naphthalene-2-sulfonamide,
[17] N-[1-(2-pyrrolidine-1-yl-ethyl)-1H-indole-5-yl]-naphthalene-1-sulfonamide,
[18] N-[1-(2-pyrrolidine-1-yl-ethyl)-1H-indole-5-yl]-5-chloro-3-methylbenzo[b]thiophene-2-sulfonamide,
[19] trans-N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-2-phenylethenesulfonamide,
[20] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-4,5-dichlorothiophene-2-sulfonamide,
[21] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-4-acetylbenzenesulfonamide,
[22] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-4-bromobenzenesulfonamide,
[23] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-4-methoxybenzenesulfonamide,
[24] N-[3-(2-diethylaminoethyl)-1H-indole-5-yl]-5-chloro-3-methylbenzo[b]thiophene-2-sulfonamide,
[25] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-4-nitrobenzenesulfonamide,
[26] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-4-fluorobenzenesulfonamide,
[27] N-[1-(2-diethylaminoethyl)-1H-indole-5-yl]-6-chloroimidazo[2,1-b]thiazole-5-sulfonamide,
[28] N-[1-(2-pyrrolidine-1-yl-ethyl)-1H-indole-5-yl]-]-6-chloroimidazo[2,1-b]thiazole-5-sulfonamide,
[29] N-(1-(2-(diethylamino)ethyl)-1H-indol-5-yl)-naphthalene-2-sulfonamide,
[30] N-(1-(2-(diethylamino)ethyl)-1H-indol-5-yl)-naphthalene-1-sulfonamide,
[31] N-(1-(2-(diethylamino)ethyl)-1H-indol-5-yl)-4-phenylbenzenesulfonamide,
[32] 5-chloro-N-(1-(2-(dimethylamino)ethyl)-2-methyl-1H-indol-5-yl)-3-methylbenzo[b]thiophene-2-sulfonamide,
[33] N-(1-(2-(dimethylamino)ethyl)-2-methyl-1H-indol-5-yl)-naphthalene-2-sulfonamide,
[34] N-(1-(2-(dimethylamino)ethyl-2-methyl-1H-indol-5-yl)-naphthalene-1-sulfonamide,
[35] 6-chloro-N-(1-(2-(dimethylamino)ethyl)-2-methyl-1H-indol-5-yl)imidazo[2,1-b]thiazole-5-sulfonamide,
[36] N-(1-(2-(dimethylamino)ethyl)-2-methyl-1H-indol-5-yl)-4-phenylbenzenesulfonamide,
[37] N-(1-(2-dimethylamino)ethyl)-2-methyl-1H-indol-5-yl)-2-(naphth-1-yl)-ethanesulfonamide,
[38] N-(1-(2-(dimethylamino)ethyl)-2-methyl-1H-indol-5-yl)-4-phenoxybenzenesulfonamide,
[39] 3,5-dichloro-N-(1-(2-(dimethylamino)ethyl)-2-methyl-1H-indol-5-yl)-benzenesulfonamide,
[40] N-(1-(2-(dimethylamino)ethyl)-2-methyl-1H-indol-5-yl)benzo[b]thiophene-3-sulfonamide,
[41] N-(1-(2-(diethylamino)ethyl)-1H-indol-5-yl)benzo[b]thiophene-3-sulfonamide and
[42] N-(1-(2-(dimethylamino)ethyl)-1H-indol-5-yl)benzo[b]thiophene-3-sulfonamide,
[43] 5-chloro-3-methyl-N-(1-(3-(piperidin-1-yl)propyl)-1H-indol-5-yl)benzo[b]thiophene-2-sulfonamide,
[44] N-(1-(3-(piperidin-1-yl)propyl)-1H-indol-5-yl)naphthalene-2-sulfonamide,
[45] N-(1-(3-(piperidin-1-yl)propyl)-1H-indol-5-yl)naphthalene-1-sulfonamide,
[46] 6-chloro-N-(1-(3-piperidin-1-yl)propyl)-1H-indol-5-yl)imidazo[2,1-b]thiazole-5-sulfonamide,
[47] 4-phenyl-N-(1-(3-(piperidin-1-yl)propyl)-1H-indol-5-yl)benzenesulfonamide,
[48] 2-(naphth-1-yl)-N-(1-(3-(piperidin-1-yl)propyl)-1H-indol-5-yl)ethanesulfonamide,
[49] 4-phenoxy-N-1-(3-(piperidin-1-yl)propyl)-1H-indol-5-yl)benzenesulfonamide,
[50] 3,5-dichloro-N-(1-(3-(piperidin-1-yl)propyl)-1H-indol-5-yl)benzenesulfonylamide,
[51] 4,5-dichloro-N-(1-(3-(piperidin-1-yl)propyl)-1H-indol-5-yl)thiophene-2-sulfonamide and
[52] 5-chloro-N-(1-(3-(piperidin-1-yl)propyl)-1H-indol-5-yl)naphthalene-1-sulfonamide,
and their corresponding salts and solvates.
The present invention likewise refers to the salts, preferably the physiologically acceptable salts of the compounds of general formula (Ia) and/or (Ib) and/or of general formula (Ic), 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.
Below, the expression sulfonamide derivatives of the general formula (I), refers to one or more compounds of general formula (Ia) and/or to one or more compounds of general formula (Ib) and/or to one or more compounds of general formula (Ic), 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 (1), wherein R 1 —R 9 , n and A have the previously indicated meaning, according to which at least one compound of general formula (II),
wherein A has the previously mentioned meaning, and X is an acceptable leaving group, preferably an halogen atom, more preferably chlorine; reacts with at least one substituted 5-aminoindole of general formula (III)
wherein R 1 —R 7 and n have the previously indicated meaning, or one of their suitable protected derivatives, and, if necessary, the protective groups are removed in order to obtain the corresponding sulfonamide derivative of formula (I), which may be purified and/or isolated by means of conventional methods known in the prior art.
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. Naturally, mixtures of at least two of the classes of the mentioned compounds or at least two compounds of one class may also be used.
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.
The most suitable reaction temperatures range from 00C 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.
Preferably, 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; Werbenec, Jean Pierre; Broil, Madeleine. (Labaz S. A., Fr.). Ger. Offen. (1977). DE 2727047 19771229. Schwink, Lothar; Stengelin, Siegfried; Gossel, Matthias. Preparation of indol-5-ylureas and related compounds for the treatment of obesity and type II diabetes. WO 0315769 A1 20030227. One of them consists of nitro group reduction of derivatives of general formula (IV) by methods known in the prior art, as for example: BRATTON, L. D.; ROTH, B. D.; TRIVEDI, B. K.; UNANGST, P. C.; J Heterocycl Chem, 2000, 37 (5), 1103-1108. FANGHAENEL, E.; CHTCHEGLOV, D.; J Prakt Chem/Chem-Ztg, 1996, 338 (8), 731-737. KUYPER, L. F.; BACMAYARI, D. P.; JONES, M. L.; HUNTER, R. N.; TANSIK, R. L.; JOYNER, S. S.; BOYTOS, C. M.; RUDOLPH, S. K.; KNICK, V.; WILSON, H. R.; CADDELL, J. M.; FRIEDMAN, H. S.; ET AL.; J Med Chem, 1996, 39 (4), 892-903.
wherein 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. Preparation of indol-5-ylureas and relate compounds for the treatment of obesity and type II diabetes WO 0315769 A1 20030227; Baxter, Andrew; Brough, Stephen; Mcinally, Thomas; Mortimore, Michael; Cladingboel, David. Preparation of N-aryl-1-adamantaneacetamides and analogs as purinergic P2Z receptor antagonists WO 9929660 A1 19990617; Pigerol, Charles; De Cointet de Fillain, Paul; Eymard, Pierre; Werbenec, Jean Pierre; Broll, Madeleine. Indole derivatives. Ger. Offen. (1977), DE 2727047 19771229.
One of them consists of the alkylation of nitro derivatives of general formula (V) by methods known in the art, as for example: BHAGWAT, S. S.; GUDE, C.; Tetrahedron Lett, 1994, 35 (12), 1847-1850. BRATTON, L. D.; ROTH, B. D.; TRIVEDI, B. K.; UNANGST, P. C.; J Heterocycl Chem, 2000, 37 (5), 1103-1108
wherein 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. H.; Tetrahedron Lett ,1999, 40 (6),1117-1120. EZQUERRA, J.; PEDREGAL, is C.; LAMAS, C.; BARLUENGA, J.; PEREZ, M.; GARCIA-MARTIN, M. A.; GONZALEZ, J. M.; J Org Chem, 1996, 61 (17), 5804-5812. FADDA, A. A.; Indian J Chem, Sect B: Org Chem Inci Med Chem, 1990, 29 (11), 1017-1019. KATRITZKY, A. R.; RACHWAL, S.; BAYYUK, S.; Org Prep Proced Int, 1991, 23 (3), 357-363. Inada, A.; Nakamura, Y.; Morita, Y.; Chem Lett, 1980, 1287.
The respective literature descriptions are incorporated by reference and form part of the disclosure.
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 C 1 -C 6 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. Naturally, mixtures of at least two of the classes of the mentioned compounds or at least two compounds of one class may also be used.
The most suitable 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.
Preferably, 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.
The salts, preferably pharmaceutically acceptable salts of the compounds of general formula (I), 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.
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.
During some of the synthetic sequences described or in the preparation of the suitable reagents used, it may be necessary and/or desirable to protect sensitive or reactive groups in some of the molecules used. This may be carried out by means of the use of conventional protective groups preferably those described in the literature [Protective groups in Organic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; T. W. Greene & P. G. M. Wuts, Protective Groups in Organic Chemistry, John Wiley & Sons, 1991]. The protective groups may be removed in the suitable subsequent stage by methods known in the prior art. The respective literature descriptions are incorporated by reference and form part of the disclosure.
If 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.
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 preferably in humans.
Another aspect of the present invention is a medicament comprising at least one indol-5-yl sulfonamide derivative of general formula (Ia), 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.
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-HT6 serotonin receptor in humans and/or in animals, preferably in mammals, more preferably in humans,
more 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 in humans and/or in animals, preferably in mammals, more preferably in humans.
Another aspect of the present invention is a medicament comprising at least one indol-5-yl sulfonamide derivative of general formula (Ib), 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.
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 preferably in humans,
more suitable 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) improving cognition, for preventing and/or treating Central Nervous System Disorders, anxiety, panic disorders, depression, bipolar disorders, cognitive memory disorders, senile dementia processes, neurodegenerative disorders, preferably Alzheimers disease, Parkinson's disease, Huntington's disease and Multiple Sclerosis, schizophrenia, psychosis, infantile hyperkinesia (ADHD, attention deficit/hyperactivity disorder) in humans and/or in animals, preferably in mammals, more preferably in humans.
Another aspect of the present invention is a medicament composed of at least one indol-5-yl sulfonamide derivative of general formula (Ic), 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.
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 Alzheimers 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 preferably in humans.
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-HT6 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 is 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 preferably in humans.
Another aspect of the present invention is the use of at least one sulfonamide derivative of the previous general formula (Ia), 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 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) in humans and/or in animals, preferably in mammals, more preferably in humans,
preferably 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 in humans and/or in animals, preferably in mammals, more preferably in humans.
Another aspect of the present invention is the use of at least one sulfonamide derivative of the previous general formula (Ib), 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 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 is animals, preferably in mammals, more preferably in humans,
preferably 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) in humans and/or in animals, preferably in mammals, more preferably in humans.
Another aspect of the present invention is the use of at least one sulfonamide derivative of the previous general formula (Ic), 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 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 Alzheimers 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 preferably in humans.
The preparation of the corresponding pharmaceutical compositions as well as of the formulated medicaments may be carried out by means of conventional methods known in the prior art, for example, based on the indices of “Pharmaceutics: The Science of Dosage Forms”, Second Edition, Aulton, M. E. (ED. Churchill Livingstone, Edinburgh (2002); “Encyclopedia of Pharmaceutical Technology”, Second Edition, Swarbrick, J. and Boylan, J. C. (Eds.), Marcel Dekker, Inc. New York (2002); “Modern Pharmaceutics”, Fourth Edition, Banker G. S. and Rhodes C. T. (Eds.) Marcel Dekker, Inc. New York (2002), and “The Theory and Practice of Industrial Pharmacy”, Lachman L., Lieberman H. and Kanig J. (Eds.), Lea & Febiger, Philadelphia (1986). The respective literature descriptions are incorporated as a reference and are part of this disclosure.
The pharmaceutical compositions, as well as the formulated medicaments prepared according to the present invention, 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. As the skilled person in the art also knows, the choice of the auxiliary substances and the amounts thereof depend on the intended administration route, for example, rectal, intravenous, intraperitoneal, intramuscular, intranasal, oral, buccal or topical.
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, as well as the materials and methods for the preparation thereof, 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. 1, Basic Concepts, Bruck, S. D. (Ed.), CRD Press, Inc., Boca Raton (1983), and by Takada, K. and Yoshikawa, H., “Oral Drug Delivery”, Encyclopedia of Controlled Drug Delivery, Mathiowitz, E. (Ed.), John Wiley & Sons, Inc., New York (1999), Vol. 2, 728-742; Fix, J., “Oral drug delivery, small intestine and colon”, Encyclopedia of Controlled Drug Delivery, Mathiowitz, E. (Ed.), John Wiley & Sons, Inc., New York (1999), Vol. 2, 698-728. The respective literature references are incorporated by reference and form part of the disclosure.
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.
Typically, 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.
Pharmaceutical Methods:
Binding to the 5HT 6 Serotonin Receptor
HEK-293 cell membranes expressing the recombinant human 5HT 6 receptor were supplied by Receptor Biology. The receptor concentration in said membranes is 2.18 pmol/mg of protein and the protein concentration is 9.17 mg/ml. The experimental protocol follows the method of B. L. Roth et al. [B. L. Roth, S. C. Craigo, M. S. Choudhary, A. Uluer, F. J. Monsma, Y. Shen, H. Y. Meltzer, D. R. Sibley: Binding of Typical and Atypical Antipshychotic Agents to 5-Hydroxytryptamine-6 and Hydroxytryptamine-7 Receptors. The Journal of Pharmacology and Experimental Therapeutics, 1994, 268, 1403], with slight modifications. The commercial membrane is diluted (1:40 dilution) with the binding buffer: 50 mM Tris-HCl, 10 mM MgCl 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 μl. Incubation begins by adding 100 μl of the membrane suspension (≅22.9 μg of membrane protein), and is prolonged for 60 minutes at a temperature of 37° C. Incubation ends by quick filtration in a Harvester Brandel Cell through fiberglass filters of the Schleicher & Schuell GF 3362 trademark, pretreated with a 0.5% polyethyleneimine solution. The filters are washed three times with three milliliters of 50 mM Tris HCl buffer, pH 7.4. The filters are transferred to vials and 5 ml of Ecoscint H. liquid scintillation cocktail are added to each vial. The vials are left to equilibrate for several hours prior to their counting in a 1414 Wallac Winspectral scintillation counter. The non-specific binding is determined in the presence of 100 μM of serotonin. The assays are carried out in triplicate. The inhibition constants (K I , nM) are calculated by non-linear regression analysis using the EBDA/LIGAND program [Munson and Rodbard, Analytical Biochemistry, 1980, 107, 220].
The respective literature descriptions are incorporated by reference and form part of the disclosure.
Measurements of Food Ingestion (Behavioural Model)
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. After this period, 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. Immediately after this, 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 part of the disclosure.
The preparation of new compounds according to the invention is indicated in the following examples. The affinity for the 5HT 6 serotonin receptor, as well as the galenic formulas applicable to the compounds of the invention, is also described. The examples indicated below, given as an illustrative example, should in no way limit the scope of the invention.
EXAMPLES
Example 2
Preparation of N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-naphthalene-2-sulfonamide
150 mg (0.66 mMol) of naphthalene-2-sulfonyl chloride were added to a solution of 122 mg (0.6 mMol) of 5-amino-1-(2-dimethylaminoethyl)-1H-indole in 3 ml of dimethylformamide and 116 mg of N-ethyldiisopropylamine. The reaction mixture was stirred at the room temperature for 12 hours. Then it was evaporated to dryness, slightly alkalinized with sodium bicarbonate solution and extracted with chloroform. The organic phase was repeatedly washed with water and saturated solution of sodium bicarbonate, it was separated and dried with anhydrous sodium sulfate. The organic solution was evaporated to dryness and the resulting solid was purified by chromatography, obtaining 187 mg (80%) of N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-naphthalene-2-sulfonamide.
Example 10
Preparation of N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-benzo-[1,2,5]thiadiazole-4-sulfonamide 4-sulfonamide
116 mg (0.66 mMol) of benzo-[1,2,5]thiadiazole-4-sulfonyl chloride were added to a solution of 168 mg (0.6 mMol) of 5-amino-1-(2-dimethylaminoethyl)-1H-indole in 5 ml of pyridine and 311 mg of N-ethyldiisopropylamine. The reaction mixture was stirred at the room temperature for 2 hours. Then it was evaporated to dryness, slightly alkalinized with sodium bicarbonate solution and extracted with chloroform. The organic phase was repeatedly washed with water and saturated solution of sodium bicarbonate, it was separated and dried with anhydrous sodium sulfate. The organic solution was evaporated to dryness and the resulting solid was treated with diethyl ether obtaining 183 mg (76%) of N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-benzo-[1,2,5]thiadiazole-4-sulfonamide 4-sulfonamide.
Example 17
Preparation of N-[1-(2-pyrrolidine-1-yl-ethyl)-1H-indole-5-yl]-naphthalene-1-sulfonamide
199 mg (0.88 mMol) of naphthalene-1-sulfonyl chloride were added to a solution of 335 mg (0.8 mMol) of 5-amino-1-(2-pyrrolidine-1-yl-ethyl)-1H-indole in 10 ml of methylene chloride and 0,44 mg of triethylamine. The reaction mixture was stirred at the room temperature for 12 hours. Then it was slightly alkalinized with sodium bicarbonate solution and extracted with methylene chloride. The organic phase was repeatedly washed with water and saturated solution of sodium bicarbonate, it was separated and dried with anhydrous sodium sulfate. The organic solution was evaporated to dryness and the resulting solid was treated with diethyl ether obtaining 264 mg (79%) of N-[1-(2-pyrrolidine-1-yl-ethyl)-1H-indole-5-yl]-naphthalene-1-sulfonamide as a solid.
Example 29
Preparation of N-(1-(2-(diethylamino)ethyl)-1H-indol-5-yl)-naphthalene-2-sulfonamide
The reaction was carried out according to the procedure given in Example 1. 139 mg (0.6 mMol) of 5-amino-1-(2-(diethylamino)ethyl)-1H-indole and 150 mg (0.66 mMol) of 2-naphthyl-sulfonyl chloride were reacted to give 115 mg (45%) of the desired compound as a solid.
Example 30
Preparation of N-(1-(2-(diethylamino)ethyl)-1H-indol-5-yl)-naphthalene-1-sulfonamide
The reaction was carried out according to the procedure given in Example 1. 139 mg (0.6 mMol) of 5-amino-1-(2-(diethylamino)ethyl)-1H-indole and 150 mg (0.66 mMol) of 2-naphthyl-sulfonyl chloride were reacted to give 160 mg (63%) of the desired compound as a solid.
Example 31
Preparation of N-(1-(2-(diethylamino)ethyl)-1H-indol-5-yl)-4-phenylbenzenesulfonamide
The reaction was carried out according to the procedure given in Example 1. 139 mg (0.6 mMol) of 5-amino-1-(2-(diethylamino)ethyl)-1H-indole and 167 mg (0.66 mMol) of 4-phenylbenzenesulfonyl chloride were reacted to give 181 mg (68 %) of the desired compound as an oil.
Example 32
Preparation of 5-chloro-N-(1-(2-(dimethylamino)ethyl)-2-methyl-1H-indol-5-yl)-3-methylbenzo[b]thiophene-2-sulfonamide
The reaction was carried out according to the procedure given in Example 1. 130 mg (0.6 mMol) of 5-amino-1-(2-(dimethylamino)ethyl)-2-methyl-1H-indole and 186 mg (0.66 mMol) of 5-chloro-2-methylbenzo[b]thiophene-2-sulfonyl chloride were reacted to give 127 mg (46%) of the desired compound as a solid.
Example 33
Preparation of N-(1-(2-(dimethylamino)ethyl)-2-methyl-1H-indol-5-yl)-naphthalene-2-sulfonamide
The reaction was carried out according to the procedure given in Example 1. 130 mg (0.6 mMol) of 5-amino-1-(2-(dimethylamino)ethyl)-2-methyl-1H-indole and 150 mg (0.66 mMol) of naphthyl-2-sulfonyl chloride were reacted to give 142 mg (58 %) of the desired compound as a solid.
Example 34
Preparation of N-(1-(2-(dimethylamino)ethyl)-2-methyl-1H-indol-5-yl)-naphthalene-1-sulfonamide
The reaction was carried out according to the procedure given in Example 1. 130 mg (0.6 mMol) of 5-amino-1-(2-(dimethylamino)ethyl)-2-methyl-1H-indole and 150 mg (0.66 mMol) of naphthyl-1-sulfonyl chloride were reacted to give 81 mg (33%) of the desired compound as a solid.
Example 35
Preparation of 6-chloro-N-(1-(2-(dimethylamino)ethyl)-2-methyl-1H-indol-5-yl)imidazo[2,1-b]thiazole-5-sulfonamide
The reaction was carried out according to the procedure given in Example 1. 130 mg (0.6 mMol) of 5-amino-1-(2-(dimethylamino)ethyl)-2-methyl-1H-indole and 170 mg (0.66 mMol) of 6-chloro-imidazo[2,1-b]thiazole-5-sulfonyl chloride were reacted to give 96 mg (37%) of the desired compound as a solid.
Example 36
Preparation of N-(1-(2-(dimethylamino)ethyl)-2-methyl-1H-indol-5-yl)-4-phenylbenzenesulfonamide
The reaction was carried out according to the procedure given in Example 1. 130 mg (0.6 mMol) of 5-amino-I -(2-(dimethylamino)ethyl)-2-methyl-1H-indole and 167 mg (0.66 mMol) of 4-phenylbenzenesulfonyl chloride were reacted to give 160 mg (62%) of the desired compound as a solid.
Example 37
Preparation of N-(1-(2-dimethylamino)ethyl)-2-methyl-1H-indol-5-yl)-2-(naphth-1-yl)-ethanesulfonamide
The reaction was carried out according to the procedure given in Example 1. 130 mg (0.6 mMol) of 5-amino-1-(2-(dimethylamino)ethyl)-2-methyl-1H-indole and 168 mg (0.66 mMol) of 2-(naphth-1-yl)-ethanesulfonyl chloride were reacted to give 108 mg (41%) of the desired compound as a solid.
Example 38
Preparation of N-(1-(2-(dimethylamino)ethyl)-2-methyl-1H-indol-5-yl)-4-phenoxy-benzenesulfonamide
The reaction was carried out according to the procedure given in Example 1. 130 mg (0.6 mMol) of 5-amino-1-(2-(dimethylamino)ethyl)-2-methyl-1H-indole and 177 mg (0.66 mMol) of 4-phenoxy-benzenesulfonyl chloride were reacted to give 89 mg (33%) of the desired compound as a solid.
Example 39
Preparation of 3,5-dichloro-N-(1-(2-(dimethylamino)ethyl)-2-methyl-1H-indol-5-yl)-benzenesulfonamide
The reaction was carried out according to the procedure given in Example 1. 130 mg (0.6 mMol) of 5-amino-1-(2-(dimethylamino)ethyl)-2-methyl-1H-indole and 162 mg (0.66 mMol) of 3,5-dichloro-benzenesulfonyl chloride were reacted to give 81 mg (32%) of the desired compound as a solid.
Example 40
Preparation of N-(1-(2-(dimethylamino)ethyl)-2-methyl-1H-indol-5-yl)benzo[b]thiophene-3-sulfonamide
The reaction was carried out according to the procedure given in Example 1. 108 mg (0.5 mMol) of 5-amino-1-(2-(dimethylamino)ethyl)-2-methyl-1H-indole and 128 mg (0.55 mMol) of benzo[b]thiophene-3-sulfonyl chloride were reacted to give 82 mg (39%) of the desired compound as a solid.
Example 41
Preparation of N-(1-(2-(diethylamino)ethyl)-1H-indol-5-yl)benzo[b]thiophene-3-sulfonamide
The reaction was carried out according to the procedure given in Example 1. 115 mg (0.5 mMol) of 5-amino-1-(2-(diethylamino)ethyl)-1H-indole and 128 mg (0.55 mMol) of benzo[b]thiophene-3-sulfonyl chloride were reacted to give 91 mg (43%) of the desired compound as a solid.
Example 42
Preparation of N-(1-(2-(dimethylamino)ethyl)-1H-indol-5-yl)benzo[b]thiophene-3-sulfonamide
The reaction was carried out according to the procedure given in Example 1. 102 mg (0.5 mMol) of 5-amino-1-(2-(diethylamino)ethyl)-1H-indole and 128 mg (0.55 mMol) of benzo[b]thiophene-3-sulfonyl chloride were reacted to give 91 mg (43%) of the desired compound as a solid.
Example 43
Preparation of 5-chloro-3-methyl-N-(1-(3-(piperidin-1-yl)propyl)-1H-indol-5-yl)benzo[b]thiophene-2-sulfonamide
The reaction was carried out according to the procedure given in Example 1. 118 mg (0.46 mMol) of 5-amino-1-(3-(piperidin-1-yl)propyl))-1H-indole and 143 mg (0.51 mMol) of 5-chloro-3-methyl-benzo[b]thiophene-2-sulfonyl chloride were reacted to give 89 mg (38%) of the desired compound as a solid.
Example 44
Preparation of N-(1-(3-(piperidin-1-yl)propyl)-1H-indol-5-yl)naphthalene-2-sulfonamide
The reaction was carried out according to the procedure given in Example 1. 118 mg (0.46 mMol) of 5-amino-1-(3-(piperidin-1-yl)propyl))-1H-indole and 116 mg (0.51 mMol) of naphthyl-2-sulfonyl chloride were reacted to give 75 mg (37%) of the desired compound as a solid.
Example 45
Preparation of N-(1-(3-(piperidin-1-yl)propyl)-1H-indol-5-yl)naphthalene-1-sulfonamide
The reaction was carried out according to the procedure given in Example 1. 118 mg (0.46 mMol) of 5-amino-1-(3-(piperidin-1-yl)propyl))-1H-indole and 116 mg (0.51 mMol) of naphthyl-2-sulfonyl chloride were reacted to give 91 mg (44%) of the desired compound as a solid.
Example 46
Preparation of 6-chloro-N-(1-(3-piperidin-1-yl)propyl)-1H-indol-5-yl)imidazo[2,1-b]thiazole-5-sulfonamide
The reaction was carried out according to the procedure given in Example 1. 118 mg (0.46 mMol) of 5-amino-1-(3-(piperidin-1-yl)propyl))-1H-indole and 131 mg (0.51 mMol) of 6-chloro-imidazo[2,1-b]thiazole-5-sulfonyl chloride were reacted to give 91 mg (44%) of the desired compound as a solid.
Example 47
Preparation of 4-phenyl-N-(1-(3-(piperidin-1-yl)propyl)-1H-indol-5-yl)benzenesulfonamide
The reaction was carried out according to the procedure given in Example 1. 118 mg (0.46 mMol) of 5-amino-1-(3-(piperidin-1-yl)propyl))-1H-indole and 129 mg (0.51 mMol) of 4-phenylbenzenesulfonyl chloride were reacted to give 106 mg (49%) of the desired compound as a solid.
Example 48
Preparation of 2-(naphth-1-yl)-N-(1-(3-(piperidin-1-yl)propyl)-1H-indol-5-yl)ethanesulfonamide
The reaction was carried out according to the procedure given in Example 1. 118 mg (0.46 mMol) of 5-amino-1-(3-(piperidin-1-yl)propyl))-1H-indole and 130 mg (0.51 mMol) of 2-(naphth-1-yl)ethanesulfonyl chloride were reacted to give 68 mg (31%) of the desired compound as a solid.
Example 49
Preparation of 4-phenoxy-N-(1-(3-(piperidin-1-yl)propyl)-1H-indol-5-yl)benzenesulfonamide
The reaction was carried out according to the procedure given in Example 1. 118 mg (0.46 mMol) of 5-amino-1-(3-(piperidin-1-yl)propyl))-1H-indole and 137 mg (0.51 mMol) of 4-phenoxybenzenesulfonyl chloride were reacted to give 86 mg (38%) of the desired compound as a solid.
Example 50
Preparation of 3,5-dichloro-N-(1-(3-(piperidin-1-yl)propyl)-1H-indol-5-yl)benzenesulfonylamide
The reaction was carried out according to the procedure given in Example 1. 118 mg (0.46 mMol) of 5-amino-1-(3-(piperidin-1-yl)propyl))-1H-indole and 125 mg (0.51 mMol) of 3,5-dichlorobenzenesulfonyl chloride were reacted to give 79 mg (37%) of the desired compound as a solid.
Example 51
Preparation of 4,5-dichloro-N-(1-(3-(piperidin-1-yl)propyl)-1H-indol-5-yl)thiophene-2-sulfonamide
The reaction was carried out according to the procedure given in Example 1. 118 mg (0.46 mMol) of 5-amino-1-(3-(piperidin-1-yl)propyl))-1H-indole and 128 mg (0.51 mMol) of 4,5-dichlorothiophene-2-sulfonyl chloride were reacted to give 68 mg (31%) of the desired compound as a solid.
Example 52
Preparation of 5-chloro-N-(1-(3-(piperidin-1-yl)propyl)-1H-indol-5-yl)naphthalene-1-sulfonamide
The reaction was carried out according to the procedure given in Example 1. 118 mg (0.46 mMol) of 5-amino-1-(3-(piperidin-1-yl)propyl))-1H-indole and 133 mg (0.51 mMol) of 5-chloro-napthyl-1-sulfonyl chloride were reacted to give 81 mg (37%) of the desired compound as a solid.
The yields are indicative and no added effort was made to improve them.
The melting point and spectroscopic data for identifying some of the compounds of the present invention are indicated in the following table.
Ex R1 R2 R3 R4 R5 R6 R7 n A m.p. ° C. IR cm −1 1 H-NMR(300 MHz), δ(solvent) 1 (CH 3 ) 2 N— H H H H H H 2 71-73 2950, 1334, 1160, 1080, 862, 652, 560. 2.11(s, 6H); 2.36(s, 3H); 2.51(m, 2H); 4.14(t, 2H, J=6.6 Hz); 6.30(d, 1H, J=3 Hz); 7.32(m, 2H); 7.50(dd, 1H, J=8.7 Hz, J′=2.0 Hz); 7.93(d, 1H, J=2.0 Hz); 7.99(d, 1H, J=8.7 Hz). (DMSO-d6) 2 (CH 3 ) 2 N— H H H H H H 2 54-57 3254. 3049, 2945, 1463, 1330, 1160, 1074, 658 550. 2.26(s, 6H); 2.63(t, 2H, J=7.1 Hz); 4.14(t, 2H, J=7.1 Hz); 6.35(d, 1H, J=3.1 Hz); 6.88(dd, 1H, J=8.6 Hz, J′=2.0 Hz); 7.10(d, 1H, 3.1 Hz); 7.15(d, 1H, J=8.6 Hz); 7.31(d, 1H, 1H J=8.7 Hz, J′=1.8 Hz); 7.84(m, J=2.0 Hz); 7.50-7.63(m, 2H); 7.69(dd, 3H); 8.29(s, 1H). (CDCl 3 ) 3 (CH 3 ) 2 N— H H H H H H 2 179-181 3106, 2783, 1491, 1318, 1159, 1130, 763, 586, 503. 2.25(s, 6H); 2.63(t, 2H, J=7.0 Hz); 4.11(t, 2H, J=7.0 Hz); 6.28(d, 1H, J=3.1 Hz); 6.68(dd, 1H, J=8.6 Hz, J′=2.0 Hz); 7.03-7.11(m, 3H); 7.37(m, 1H); 7.58-7.70(m, 2H); 7.94(d, 1H, J=8.7 Hz); 8.00(d, 1H, J=7.9 Hz); 8.06(d, 1H, J=7.3 Hz); 8.73(d, 1H, J=8.7 Hz). (CDCl 3 ) 4 (CH 3 ) 2 N— H H H H H H 2 172-174 3257, 2935, 2768, 1488, 1334, 1167, 1138, 1013, 790, 606. 2.26(s, 6H); 2.63(t, 2H, J=7.1 Hz); 4.13(t, 2H, J=7.1 Hz); 6.30(d, 1H, J=3.1 Hz); 6.66(dd, 1H, J=8.6 Hz, J=2.0 Hz): 7.05(d, 1H, J=8.7 Hz); 7.08(d, 1H, J=3.1 Hz); 7.11(d, 1H, J=2.0 Hz); 7.46-7.58(m, 2H); 7.69(d, 1H, J=7.5 Hz); 8.13(d, 1H, J=7.5 Hz); 8.50(d, 1H, J=8.6 Hz); 8.69(d, # 1H, J=8.8 Hz). (CDCl 3 ) 5 (CH 3 ) 2 N— H H H H H H 2 139-141 1463, 1334, 1306, 1164, 1090, 725, 589. 2.28(s, 6H); 2.66(t, 2H, J=7.1 Hz); 4.17(t, 2H, J=7.1 Hz); 6.38(d, 1H, J=3.1 Hz); 6.88(dd, 1H, J=8.6 Hz, J′=2.0 Hz); 7.13(d, 1H, J=3.1 Hz); 7.18(d, 1H, J=8.6 Hz); 7.27(m, 1H); 7.39(m, 2H); 7.48(m, 1H); 7.69(m, 2H). (CDCl 3 ) 6 (CH 3 ) 2 N— H H H H H H 2 161-164 3095, 02821, 2776, 1492, 1459, 1322, 1158, 1141, 782, 736, 596, 507. 2.23(s, 6H); 2.58(t, 2H, J=7.1 Hz); 4.08(t, 2H, J=7.1 Hz); 6.24(d, 1H, J=3.1 Hz); 6.88(dd, 1H, J=8.8, J′=2.0 Hz); 7.03(d, 1H, J=3.1 Hz); 7.07(d, 1H, J=8.8 Hz); 7.10(d, 1H, J=2.0 Hz); 7.51(t, 1H, J=7.8 Hz); 7.64(dd, 1H, J=8.5, J′=4.3 Hz); 8.00(d, 1H, J=8.2 Hz); 8.26 # (m, 1H); 8.30(dd, 1H, J=8.2, J′1.5 Hz); 8.40(s, 1H); 9.20(dd, 1H, J=4.1 J′=1.4 Hz). (CDCl 3 ) 7 (CH 3 ) 2 N— H H H H H H 2 138-140 3255, 2951, 1583, 1488, 1332, 1245, 1156, 1092, 866, 695, 569. 2.28(s, 6H); 2.67(t, 2H, J=7.1 Hz); 4.18(t, 2H, J=7.1 Hz); 6.40(d, 1H, J=3.1 Hz); 6.92(m, 3H); 7.02(d, 2H, J=7.7 Hz); 7.14(d, 1H, J=3.1 Hz); 7.20(d, 2H, J=8.5 Hz); 7.28(d, 1H, J=1.9 Hz); 7.37(m, 2H); 7.64(d, 2H, J=8.6 Hz). (CDCl 3 ) 8 (CH 3 ) 2 N— H H H H H H 2 126-128 1474, 1287, 1156, 1088, 973, 730, 654, 554, 538. 2.31(s, 6H); 2.36(s, 3H); 2.72(t, 2H, J=7.1 Hz); 4.20(t, 2H, J=7.1 Hz); 6.39(d, 1H, J=3.1 Hz); 6.90(dd, 1H, J=8.6 Hz, J′=1.6 Hz); 7.13(d, 1H, J=3.1 Hz); 7.16-7.20(m, 3H); 7.26(m, 1H); 7.57(d, 2H, J=8.3 Hz). (CDCl 3 ) 9 (CH 3 ) 2 N— H H H H H H 2 145-147 3095, 2951, 1416, 1319, 1148, 989, 730, 605, 537. 2.33(s, 6H); 2.74(m, 2H); 4.24(t, 2H, J=7.1 Hz); 6.44(d, 1H, J=3.1 Hz); 6.79(d, 1H, J=4.0 Hz); 6.95(dd, 1H, J=8.7 Hz, J′=2.0 Hz); 7.15(d, 1H, J=4.0 Hz); 7.17(d, 1H, J=3.1 Hz); 7.24(d, 1H, J=8.7 Hz); 7.35(d, 1H, J=2.0 Hz). (DMSO-d6) 10 (CH 3 ) 2 N— H H H H H H 2 166-168 3103, 2784, 1526, 1488, 1331, 1154, 1140, 973, 734, 607. 2.26(s, 6H); 2.63(t, 2H, J=7.1 Hz); 4.12(t, 2H, J=7.1 Hz); 6.29(d, 1H, J=3.1 Hz); 6.80(dd, 1H, J=8.7 Hz, J′=2.0 Hz); 7.07(m, 2H); 7.15(d, 1H, J=1.5 Hz); 7.57(dd, 1H, J=8.8 Hz, J=7.1 Hz); 8.10(d, 1H, J=7.1 Hz); 8.16(d, 1H, J=8.8 Hz). (CDCl 3 ) 11 (CH 3 ) 2 N— H H H H H H 2 50-52 3103, 2943, 1457, 1336, 1326, 1244, 1177, 1142, 727, 628, 528. 2.26(s, 6H); 2.64(t, 2H, J=6.4 Hz); 4.16(t, 2H, J=6.4 Hz); 6.39(m, 1H); 6.78(d, 1H, J=4.0 Hz); 6.94(d, 1H, J=8.4 Hz); 7.15(m, 2H); 7.39(s, 1H); 7.55(d, 1H, J=4.0 Hz). (CDCl 3 ) 12 (CH 3 ) 2 N— H H H H H H 2 124-126 3064, 2935, 1333, 1166, 1136, 596, 587. 2.28(s, 6H); 2.67(t, 2H, J=7.0 Hz); 4.19(t, 2H, J=7.0 Hz); 6.43(d, 1H, J=3.1 Hz); 6.85(dd, 1H, J=8.6 Hz, J′=2.0 Hz); 7.17(d, 1H, J=3.1 Hz); 7.22(d, 1H, J=8.6 Hz); 7.31(d, 1H, J=2.0 Hz); 7.48(t, 1H, J=1.8 Hz); 7.56(d, 2H, J=1.8 Hz). (CDCl 3 ) 13 (CH 3 ) 2 N— H H H H H H 2 114-116 1464, 1335, 1286, 1161, 722, 584. 2.28(s, 6H); 2.67(t, 2H, J=7.0 Hz); 4.19(t, 2H, J=7.0 Hz); 6.41(d, 1H, J=2.9 Hz); 6.87(d, 1H, J=8.8 Hz); 7.15(d, 1H, J=2.9 Hz); 7.19-7.29(m, 3H): 7.56(d, 1H, J=7.8 Hz); 7.63(d, 1H, J=7.9 Hz); 7.88(s, 1H). (CDCl 3 ) 14 (CH 3 ) 2 N— H H H H H H 2 138-140 1541, 1481, 1365, 1330, 1235, 1150, 1124, 736, 580. 2.28(s, 6H); 2.66(t, 2H, J=7.1 Hz); 4.17(t, 2H, J=7.1 Hz); 6.40(d, 1H, J=2.9 Hz); 7.03(dd, 1H, J=8.7 Hz, J′1.8 Hz); 7.15(d, 1H, J=2.9 Hz); 7.21(d, 1H, J=8.7 Hz); 7.39(d, 1H, J=1.8 Hz); 7.48(m, 1H); 7.65(m, 1H); 7.71(d, 1H, J=8.8 Hz); 7.86(d, 1H, J=7.8 Hz). (CDCl 3 ) 15 (CH 3 ) 2 N— H H H H H H 2 163-166 1329, 1288, 1153, 1126, 694, 545, 509. 2.30(s, 6H); 2.70(t, 2H, J=7.1 Hz); 4.22(t, 2H, J=7.1 Hz); 4.29(s, 2H); 6.48(d, 1H, J=3.1 Hz); 7.04(dd, 1H, J=8.8 Hz, J′=2.2 Hz); 7.19(d, 1H, J=3.1 Hz); 7.31(d, 1H, J=8.8 Hz); 7.33-7.40(m, 5H); 7.49(d, 1H, J=2.2 Hz). (CDCl 3 ) 16 H H H H H H 2 138-140 2960, 1481, 1323, 1161, 1074, 659, 549, 480. 1.57(m, 4H); 2.37(m, 4H); 2.66(t, 2H, J=6.8 Hz); 4.12(t, 2H, J=6.8 Hz); 6.25(d, 1H, J=3.1 Hz); 6.82(dd, 1H, J=8.8 Hz, J′=2.0 Hz); 7.22(d, 1H, 2.0 Hz); 7.25(d, 1H, J=8.6 Hz); 7.29(d, 1H, J=3.l Hz); 7.54-7.66(m, 2H); 7.74(dd, 1H, J=8.7 Hz, J′=1.8 Hz); 7.94(m, 1H); 8.03(m, 2H); 8.28(s, 1H). (CDCl 3 ) 17 H H H H H H 2 186-189 2814, 1491, 1291, 1158, 1128, 763, 585. 1.59(m, 4H); 2.39(m, 4H); 2.67(t, 2H, J=6.8 Hz); 4.11(t, 2H, J=6.8 Hz); 6.21(d, 1H, J=3.1 Hz); 6.70(dd, 1H, J=8.8 Hz, J=1.8 Hz); 7.10(d, 1H, 1.8 Hz); 7.20(d, 1H, J=8.8 Hz); 7.27(d, 1H, J=3.1 Hz); 7.50(m, 1H); 7.60-7.74(m, 2H); 8.03(m 2H); 8.11(d, 1H, J=8.1 Hz); 8.76(d, 1H, J=8.6 Hz). (CDCl 3 ) 18 H H H H H H 2 156-158 2950, 2803, 1325, 1156, 1078, 650, 564. 1.59(m, 4H); 2.36(m, 4H); 2.69(t, 2H, J=6.6 Hz); 4.1 1(t, 2H, J=6.6 Hz); 6.30(d, 1H, J=3.1 Hz); 6.83(dd, 1H, J=8.7 Hz, J′=1.9 Hz); 7.25(d, 1H, 1.9 Hz); 7.32(m, 2H); 7.50(dd, 1H, J=8.6 Hz, J=2.0 Hz); 7.92(d, 1H, J=2.0 Hz); 7.98(d, 1H, J=8.8 Hz). (CDCl 3 ) 19 (CH 3 ) 2 N— H H H H H H 2 108-111 2943, 2821, 1516, 1139, 752, 728, 542, 531. 2.28(s, 6H); 2.68(t, 2H, J=7.1 Hz); 4.19(t, 2H, J=7.1 Hz); 6.43(d, 1H, J=3.1 Hz); 6.82(d, 1H, J=16.6 Hz); 7.09(dd, 1H, J=8.6, J′=2.0 Hz); 7.15(d, 1H, J=3.3 Hz); 7.25(m, 1H); 7.33-7.44(m, 6H); 7.49(d, 1H, J=2.0 Hz). (CDCl 3 ) 20 (CH 3 ) 2 N— H H H H H H 2 120-123 3095, 2943, 1421, 1325, 1148, 1020, 730, 609, 534 2.30(s, 6H); 2.69(t, 2H, J=7.1 Hz); 4.21(t, 2H, J=7.1 Hz); 6.46(d, 1H, J=3.1 Hz); 6.93(dd, 1H, J=8.6, J′=2.0 Hz); 7.17(s, 1H); 7.18(d, 1H, J=3.3 Hz); 7.25(m, 1H); 7.39(d, 1H, J=2.0 Hz). (CDCl 3 ) 21 (CH 3 ) 2 N— H H H H H H 2 175 (decom- position 1686, 1164, 1094, 637, 534, 475. 2.12(s, 6H); 2.53(t, 2H, J=6.6 Hz); 4.15(t, 2H, J=6.6 Hz); 6.30(d, 1H, J=3.1 Hz); 6.80(dd, 1H, J=8.6, J′=2.2 Hz): 7.19(d, 1H, J=2.0 Hz); 7.30-7.34(m, 2H); 7.57(AB sist., 2H, J=8.4 Hz); 7.70(AB sist., 2H, J=8.4 Hz). (DMSO-d6). 22 (CH 3 ) 2 N— H H H H H H 2 114-117 2943, 1573, 1469, 1321, 1161, 1088, 737, 630, 538. 2.13(s, 6H); 2.50-2.55(m, 5H); 4.14(t, 2H, J=6.3 Hz): 6.29(d, 1H, J=3.0 Hz); 6.82(d, 1H, J=8.2 Hz); 7.20(s, 1H); 7.29-7.32(m, 2H); 7.79(AB sist., 2H, J=8.4 Hz); 8.02(AB sist., 2H, J=8.4 Hz). (DMSO-d6). 23 (CH 3 ) 2 N— H H H H H H 2 141-144 2935, 1598, 1497, 1333, 1258, 1159, 1093, 1018, 836, 568, 560. 2.28(s, 6H); 2.67(t, 2H, J=7.1 Hz); 4.18(t, 2H, J=7.1 Hz); 6.38(d, 1H, J=3.1 Hz); 6.84(AB Sist., 2H, J=9.0 Hz); 6.90(dd, 1H, J=8.8, J′=2.0 Hz); 7.13(d, 1H, J=3.3 Hz); 7.19(d, 1H, J=8.8 Hz); 7.27(d, 1H, J=2.0 Hz); 7.62(AB sist., 2H, J=9 Hz). (CDCl 3 ) 24 (CH 3 CH 2 ) 2 N— H H H H H H 2 53-56 2969, 1486, 1334, 1161, 114, 1080, 862, 729, 652, 560. 0.78(m, 6H); 232(s, 3H); 2.42(m, 4H); 2.65(m, 2H); 4.12(m, 2H); 6.30(d, 1H, J=3.0 Hz); 6.82(d, 1H, J=8.6 Hz); 7.25(d, 1H, 1.7 Hz); 7.32(m, 2H); 7.50(dd, 1H, J=8.7 Hz, J′=1.9 Hz); 7.91(d, 1H, J=1.7 Hz); 7.99(d, 1H, J=8.6 Hz). (CDCl 3 ) 25 (CH 3 ) 2 N— H H H H H H 2 60-64 3095, 2768, 1529, 1349, 1165, 1090, 736. 2.29(s, 6H); 2.67(t, 2H, J=7.0 Hz); 4.18(t, 2H, J=7.0 Hz); 6.40(d, 1H, J=3.1 Hz); 6.85(dd, 1H, J=8.6 Hz, J=2.0 Hz); 7.16(d, 1H, J=3.1 Hz); 7.18(d, 1H, J=8.6 Hz); 7.29(d, 1H, J=2.0 Hz) 7.85(AB sys, J=8.8 Hz, 2H); 8.21(AB sys, J=8.8 Hz, 2H). (CDCl 3 ) 26 (CH 3 ) 2 N— H H H H H H 2 138-140 3103, 2951, 1587, 6.83, 1335, 1166, 1089, 557, 542. 2.35(s, 6H); 2.83(m, 2H); 4.28(t, 2H, J=6.7 Hz); 6.40(d, 1H, J=3.0 Hz); (dd, 1H, J=8.6 Hz, J′=2.0 Hz); 7.20(d, 1H, J=1.9 Hz); 7.30-7.38(m, 4H); 7.70-7.75(m, 2H). (DMSO-d6). 27 (CH 3 CH 2 ) 2 N— H H H H H H 2 68-70 3110, 2969, 1458, 1271, 1249, 1179, 1140, 727 651. 1.00(t, 6H, J=7.0 Hz), 2.60(q, 4H, J=7.0 Hz); 2.81(t, 2H, J=6.7 Hz); 4.21(t, 2H, J=6.7 Hz); 6.38(d, 1H J=3.0 Hz); 6.79(d, 1H, J=4.5 Hz); 6.96(dd, 1H, J=8.6, J=1.7 Hz); 7.14(d, 1H, 3.0 Hz); 7.19(d, 1H, J=8.8 Hz); 7.40(d, 1H, J=1.5 Hz); 7.59(d, 1H, J=4.4 Hz). (CDCl 3 ) 28 H H H H H H 2 81-84 3119, 2951, 2798, 1458, 1271, 1248, 1178, 1140, 727, 623. 1.85(m, 6H); 2.68(m, 4H); 3.00(m, 2H); 4.38(m, 2H): 6.40(d, 1H J=3.1 Hz); 6.82(d, 1H, J=4.5 Hz); 6.96(d, 1H, J=8.6 Hz); 7.19(d, 1H, 2.7 Hz); 7.22(m, 1H); 7.41(m, 1H); 7.64(d, 1H, J=4.5 Hz). (CDCl 3 ) 29 (CH 3 CH 2 ) 2 N— H H H H H H 2 97-104 0.95(t, 6H, J=7.l Hz); 2.54(q, 4H, J=7.0 Hz); 2.76(t, 2H, J=6.7 Hz); 4.07(t, 2H, J=6.7 Hz); 6.66(dd, 1H, J=8.5 J′=1.7 Hz); 6.91(s, 1H); 6.97(s, 1H); 7.01(d, 1H, J=8.8 Hz); 7.22(dd, 1H, J=8.6 , J′=1.6 Hz): 7.26(s, 1H); 7.42-7.55(m, 3H); 7.63(d, 1H, J=8.1 Hz); 7.70(d, 1H, J=8.2 Hz); 8.03(s, 1H); 9.95(s, 1H). (CDCl 3 ) 30 (CH 3 CH 2 ) 2 N— H H H H H H 2 133-135 0.87(m, 6H); 2.58(m, 4H); 2.76(m, 2H); 4.14(m, 2H); 6.24(s, 1H); 6.73(d, 1H, J=8.8 Hz); 7.11(s, 1H); 7.21(d, 1H, J=8.0 Hz); 7.29(s, 1H); 7.50(t, 1H, J=7.8 Hz); 7.63-7.71(m, 2H); 8.04(d, 2H, J=7.5 Hz); 8.13(d, 1H, J=8.2 Hz); 8.76(d, 1H, J=8.2 Hz); 10.21(s, 1H). (DMSO-d6) 31 (CH 3 CH 2 ) 2 N— H H H H H H 2 Oil 0.83(m, 6H); 2.50(m, 4H); 2.70(m, 2H); 4.13(m, 2H); 6.30(d, 1H, J=2.6 Hz); 6.87(d, 1H, J=8.6 Hz); 7.24(s, 1H); 7.30(m, 2H); 7.44(m, 3H); 7.66(d, 2H, J=7.2 Hz); 7.72(AB sys, 2H, J=8.5 Hz); 7.78(AB sys, 2H, J=8.5 Hz); 9.91(s, 1H). (DMSO-d6) 32 (CH 3 ) 2 N— CH 3 H H H H H 2 203-205 2.13(s, 6H); 2.33(s, 6H); 2.39(t, 2H, J=7.0 Hz); 4.07(t, 2H, J=6.8 Hz); 6.08(s, 1H); 6.76(dd, 1H, J=8.6, J′=2.0 Hz); 7.13(d, 1H, J=2.0 Hz); 7.20(d, 1H, J=8.6 Hz); 7.51(dd, 1H, J=8.7 , J′=2.0 Hz); 7.93(d, 1H, J=2.0 Hz); 8.00(d, 1H, J=8.8 Hz); 10.20(s, 1H). (DMSO-d6) 33 (CH 3 ) 2 N— CH 3 H H H H H 2 199-200 2.11(s, 6H); 2.30(s, 3H); 2.35(t, 2H, J=7.0 Hz); 4.03(t, 2H, J=7.0 Hz); 6.03(s, 1H); 6.75(dd, 1H, J=8.6, J′=2.0 Hz); 7.1O(d, 1H, J=2.0 Hz); 7.13(d, 1H, J=8.6 Hz); 7.54-7.67(m, 2H); 7.73(dd, 1H, J=8.6, J′=1.8 Hz); 7.95(d, 1H, J=7.9 Hz); 8.02(d, 2H, J=8.6 Hz); 8.27(d, 1H, J=1.5 Hz); 9.89(s, 1H). (DMSO-d6) 34 (CH 3 ) 2 N— CH 3 H H H H H 2 183-184 2.12(s, 6H); 2.29(s, 3H); 2.35(t, 2H, J=7.0 Hz); 4.01(t, 2H, J=7.0 Hz); 5.98(s, 1H); 6.62(dd, 1H, J=8.7, J′=1.9 Hz); 6.98(d, 1H, J=2.0 Hz); 7.07(d, 1H, J=8.6 Hz); 7.49(m, 1H); 7.63(m, 1H); 7.70(m, 1H); 8.02(d, 2H, J=7.5 Hz); 8.12(d, 1H, J=8.0 Hz); 8.75(d, 1H, J=8.4 Hz); 10.15(s, 1H). (DMSO-d6) 35 (CH 3 ) 2 N— CH 3 H H H H H 2 182-183 2.14(s, 6H); 2.34(s, 3H); 2.39(m, 2H); 4.01(m, 2H); 6.09(s, 1H); 6.70(dd, 1H, J=8.5 J′1.8 Hz); 7.08(d, 1H, J=1.8 Hz); 7.21(d, 1H, J=8.5 Hz); 7.51(d, 1H, J=4.5 Hz); 7.80(d, 1H, J=4.5 Hz). (DMSO-d6) 36 (CH 3 ) 2 N— CH 3 H H H H H 2 176-177 2.14(s, 6H); 2.33(s, 3H); 2.39(t, 2H, J=7.1 Hz); 4.06(t, 2H, J=7.1 Hz); 6.07(s, 1H); 6.79(dd, 1H, J=8.8, J′=2.0 Hz); 7.11(d, 1H, J=1.8 Hz); 7.19(d, 1H, J=8.8 Hz); 7.36-7.48(m, 3H); 7.66(m, 2H); 7.72(AB sys, 2H, J=8.8 Hz); 7.79(AB sys, 2H, J=8.8, Hz); 9.85(s, 1H). (DMSO-d6) 37 (CH 3 ) 2 N— CH 3 H H H H H 2 135-137 2.17(s, 6H); 2.38(s, 3H); 2.45(m, 2H); 3.30-3.45(m, 4H); 4.14(t, 2H, J=6.7 Hz); 6.15(s, 1H); 7.04(d, 1H, J=8.5 Hz); 7.26(m, 1H); 7.30-7.38(m, 4H); 7.44(m, 1H); 7.65(d, 1H, J=8.2 Hz); 7.62(m, 1H); 7.87(d, 1H, J=8.2 Hz); 9.56(s, 1H). (DMSO-d6) 38 (CH 3 ) 2 N— CH 3 H H H H H 2 147-149 2.20(s, 6H); 2.34(s, 3H); 2.45(m, 2H); 4.10(t, 2H, J=7.1 Hz); 6.08(s, 1H); 6.76(dd, 1H, J=8.6, J′=2.0 Hz); 6.99(d, 2H, J=8.8 Hz); 7.03-7.08(m, 3H); 7.17-7.24(m, 2H); 7.41(t, 2H, J=7.8 Hz); 7.63(d, 2H, J=8.8 Hz); 9.73(s, 1H). (DMSO-d6) 39 (CH 3 ) 2 N— CH 3 H H H H H 2 147-149 2.15(s, 6H); 2.35(s, 3H); 2.41(t, 2H, J=6.7 Hz); 4.10(t, 2H, J=7.1 Hz); 6.12(s, 1H); 6.71(dd, 1H, J=8.6, J′=2.0 Hz); 7.09(d, 1H, J=1.8 Hz); 7.24(d, 1H, J=9.0 Hz); 7.58(d, 2H, J=1.9 Hz); 7.90(t, 1H, J=1.9 Hz), (DMSO-d6) 40 (CH 3 ) 2 N— CH 3 H H H H H 2 167-169 2.14(s, 6H); 2.31(s, 3H); 2.38(m, 2H); 4.04(t, 2H, J=7.1 Hz); 6.02(s, 1H); 6.66(dd, 1H, J=8.4, J′=1.8 Hz); 7.04(d, 1H, J=1.6 Hz); 7.12(d, 1H, J=8.2 Hz): 7.40-7.51(m, 2H); 8.03(d, 1H, J=7.6 Hz); 8.21(d, 1H, J=7.9 Hz); 8.31(s, 1H); I0.08(s, 1H), (DMSO-d6) 41 (CH 3 CH 2 ) 2 N— H H H H H H 2 62-75 0.98(m, 6H); 2.54(m, 4H); 2.70(m, 2H); 4.18(m, 2H); 6.29(s, 1H); 6.77(d, 1H, J=8.5 Hz); 7.18(s, 1H); 7.34(m, 2H); 7.39-7.52(m, 2H); 8.03(d, 1H, J=7.9 Hz); 8.22(d, 1H, J=7.5 Hz); 8.34(s, 1H); 10.18(s, 1H), (CDCl 3 ) 42 (CH 3 ) 2 N— CH 3 H H H H H 2 61-72 2.12(s, 6H); 2.50(m, 2H); 4.12(t, 2H, J=6.7 Hz); 6.25(d, 1H, J=3.1 Hz); 6.75(dd, 1H, J=8.7, J=2.1 Hz); 7.17(d, 1H, J=1.9 Hz); 7.25(d, 1H, J=8.9 Hz); 7.30(d, 1H, J=3.2 Hz); 7.48(m, 2H); 8.04(d, 1H, J=7.0 Hz); 8.24(d, 1H, J=7.4 Hz); 8.34(s, 1H); 10.14(s, 1H); (CDCl 3 ) 43 H H H H H H 3 82-92 1.20-1.55(m, 6H); 1.88(m, 2H); 2.33(s, 3H); 2.16-2.60(m, 6H); 4.10(t, 2H, J=6.6 Hz); 6.34(d, 1H, J=3.2 Hz); 6.82(d, 1H, J=9.9 Hz); 7.27-7.35(m, 3H); 7.50(dd, 1H, J=8.7, J′=2.0 Hz); 7.91(d, 1H, J=2.2 Hz); 7.99(d, 1H, J=8.6 Hz); 10.20(bs, 1H). (DMSO-d6) 44 H H H H H H 3 92-108 1.20-1.55(m, 6H); 1.87(m, 2H); 2.22-2.62(m, 6H); 4.06(t, 2H, J=6.6 Hz); 6.28(d, 1H, J=2.9 Hz); 6.83(dd, 1H, J=8.7, J′=2.0 Hz); 7.24(d, 1H, J=2.0 Hz); 7.27(m, 2H); 7.59(m, 1H); 7.64(m, 1H); 7.75(dd, 1H, J=8.8, J′=1.9 Hz); 7.95(d, 1H, J=7.5 Hz); 8.03(d, 2H, J=8.5 Hz); 8.28(s, 1H); 9.97(s, 1H). (DMSO-d6) 45 H H H H H H 3 85-86 1.25-1.55(m, 6H); 1.81(m, 2H); 2.03-2.60(m, 6H); 4.03(t, 2H, J=6.4 Hz); 6.23(d, 1H, J=3.1 Hz); 6.70(d, 1H, J=8.9 Hz); 7.11(d, 1H, J=1.8 Hz); 7.20(d, 1H, J=8.9 Hz); 7.24(d, 1H, J=3.1 Hz); 7.49(dd, 1H, J=8.1, J′=7.4 Hz); 7.59-7.66(m, 1H); 7.66-7.73(m, 1H); 8-8.05(m, 2H); 8.12(d, 1H, J=8.2 Hz); 8.75(d, 1H, J=7.8 Hz); 10.20(bs, 1H). (DMSO-d6) 46 H H H H H H 3 85-86 1.36(m, 2H); 1.49(m, 4H); 1.86(m, 2H); 2.15-2.44(m, 6H); 4.10(t, 2H, J=6.7 Hz); 6.33(d, 1H, J=3.1 Hz); 6.79(dd, 1H, J=8.7, J′=2.0 Hz); 7.21(d, 1H, J=2.0 Hz); 7.30-7.36(m, 2H); 7.52(d, 1H, J=4.4 Hz); 7.83(d, 1H, J=4.4 Hz); 10.25(bs, 1H), (DMSO-d6) 47 H H H H H H 3 148-150 1.34(m, 2H); 1.47(m, 4H); 1.86(m, 2H); 2.03-2.55(m, 6H); 4.09(t, 2H, J=6.6 Hz); 6.32(d, 1H, J=2.8 Hz); 6.87(dd, 1H, J=8.9, J′=1.8 Hz); 7.26(d, 1H, J=1.9 Hz): 7.28-7.34(m, 2H); 7.36-7.49(m, 3H); 7.66(m, 2H); 7.73(AB sys, 2H, J=8.8 Hz); 7.79(AB sys, 2H, J=8.8 Hz); 9.91(s, 1H), (DMSO-d6) 48 H H H H H H 3 59-61 1.20-1.56(m, 6H); 1.89(m, 2H); 2.12-2.50(m, 6H); 3.26-3.47(m, 4H); 4.16(t, 2H, J=6.2 Hz); 6.40(d, 1H, J=2.3 Hz); 7.13(d, 1H, J=8.6 Hz); 7.24(t, 1H, J=7.5 Hz); 7.34-7.50(m, 6H); 7.64(d, 1H, J=8.4 Hz); 7.76(m, 1H); 7.87(d, 1H, J=8.2 Hz); 9.65(s, 1H). (DMSO-d6) 49 H H H H H H 3 64-66 120-1.58(m, 6H); 1.90(m, 2H); 2.20-2.55(m, 6H); 4.09(t, 2H, J=6.4 Hz); 6.33(s, 1H); 6.84(dd, 1H, J=8.4 Hz); 6.96-7.02(m, 2H); 7.04(d, 2H, J=7.9 Hz); 7.17-7.24(m, 2H); 7.32(m, 2H); 7.41(m, 2H); 7.64(d, 2H, J=8.6 Hz); 9.79(s, 1H). (DMSO-d6) 50 H H H H H H 3 56-58 1.35(m, 2H); 1.46(m, 4H); 1.83(m, 2H); 2.10(m, 2H); 2.24(m, 4H); 4.11(t, 2H, J=6.4 Hz); 6.36(d, 1H, J=2.6 Hz); 6.78(dd, 1H, J8.8, J′=1.8 Hz); 7.22(d, 1H, J=1.90 Hz); 7.33(d, 1H, J=2.9 Hz); 7.37(d, 1H, J=8.8 Hz); 7.58(d, 2H, J=8.6 Hz); 7.89(t, 1H, J=1.9 Hz); 9.99(s, 1H). (DMSO d6) 51 H H H H H H 3 70-72 1.38(m, 2H); 1.52(m, 4H); 1.91(m, 2H); 2.24(m, 2H); 2.37(m, 4H); 4.16(t, 2H, J=6.6 Hz); 6.42(d, 1H, J=2.5 Hz); 6.89(d, 1H, J=8.6 Hz); 7.32(s, 1H); 7.37(d, 1H, J=2.8 Hz); 7.43(d, 1H, J=8.6 Hz); 7.48(s, 1H), (DMSO-d6) 52 H H H H H H 3 92-96 1.13-1.70(m, 6H); 2.00(m, 2H); 2.68(m, 2H); 2.84(m, 2H); 3.26(m, 2H); 4.05(m, 2H); 6.22(d, 1H, J=3.1 Hz); 6.71(m, 1H); 7.10-7.18(m, 3H); 7.52-7.53(m, 2H); 7.72(m, 1H); 8.15(d, 1H, J=7.3 Hz); 8.37(d, 1H, J=8.5 Hz); 8.77(d, 1H, J=8.5 Hz); 8.97(bs, 1H); 10.23(bs, 1H). (DMSO d6 + TFA)
Pharmaceutical Particulars:
Binding of the new compounds of general formula (Ia) and (Ib) and (Ic) to the 5-HT 6 receptor was determined as previously described.
The binding results for some of the compounds of the present invention are indicated in the following table:
TABLE Example K i (nM) 3 94.2 4 112.4 11 1.89 12 104.6 13 82.5 20 84.8
The daily posology in human medicine is comprised between 1 milligram and 2 grams of medicinal product which may be administered in one or several doses. The compositions are prepared under forms that are compatible with the administration route used, preferably tablets, coated tablets, 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 substance (compound of general formula 1), and 40 to 99% by weight of the suitable pharmaceutical vehicle compatible with the active substance and the physical form of the composition used.
The formula of a tablet containing a product of the invention is, provided by way of example:
Example of formula per tablet:
Example 1 5 mg Lactose 60 mg Crystalline cellulose 25 mg Povidone K 90 5 mg Pregelatinized starch 3 mg Colloidal silicon dioxide 1 mg Magnesium stearate 1 mg Total weight per tablet 100 mg
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