EP1694663A1 - Nouveaux derives de benzofurane, pouvant etre utilises dans la prophylaxie ou le traitement des affections associees au recepteur de 5-ht6 - Google Patents

Nouveaux derives de benzofurane, pouvant etre utilises dans la prophylaxie ou le traitement des affections associees au recepteur de 5-ht6

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Publication number
EP1694663A1
EP1694663A1 EP04809122A EP04809122A EP1694663A1 EP 1694663 A1 EP1694663 A1 EP 1694663A1 EP 04809122 A EP04809122 A EP 04809122A EP 04809122 A EP04809122 A EP 04809122A EP 1694663 A1 EP1694663 A1 EP 1694663A1
Authority
EP
European Patent Office
Prior art keywords
alkyl
benzofuran
methyl
hydrogen
methoxy
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP04809122A
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German (de)
English (en)
Inventor
Gary Johansson
Peter Brandt
Björn M NILSSON
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
BenevolentAI Cambridge Ltd
Original Assignee
Biovitrum AB
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Filing date
Publication date
Priority claimed from SE0303480A external-priority patent/SE0303480D0/xx
Application filed by Biovitrum AB filed Critical Biovitrum AB
Publication of EP1694663A1 publication Critical patent/EP1694663A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • Novel benzofuran derivatives which can be used in prophylaxis or treatment of 5-HT6 receptor-related disorder TECHNICAL FIELD
  • the present invention relates to novel compounds, to pharmaceutical compositions comprising the compounds, to processes for their preparation, as well as to the use of the compounds for the preparation of a medicament against 5-HTg receptor-related disorders.
  • Obesity is a condition characterized by an increase in body fat content resulting in excess body weight above accepted norms. Obesity is the most important nutritional disorder in the western world and represents a major health problem in all industrialized countries. This disorder leads to increased mortality due to increased incidences of diseases such as cardiovascular disease, digestive disease, respiratory disease, cancer and type 2 diabetes. Searching for compounds, which reduce body weight has been going on for many decades.
  • One line of research has been activation of serotoninergic systems, either by direct activation of serotonin receptor subtypes or by inhibiting serotonin reuptake. The exact receptor subtype profile required is however not known.
  • Serotonin (5-hydroxytryptamine or 5-HT), a key transmitter of the peripheral and central nervous system, modulates a wide range of physiological and pathological functions, including anxiety, sleep regulation, aggression, feeding and depression.
  • Multiple serotonin receptor subtypes have been identified and cloned.
  • the 5-HTg receptor was cloned by several groups in 1993 (Ruat, M. et al. (1993) Biochem. Biophys. Res. Commun.193: 268-276; Sebben, M. et al. (1994) NeuroReport 5: 2553-2557). This receptor is positively coupled to adenylyl cyclase and displays affinity for antidepressants such as clozapine.
  • Compounds according to the present invention and their pharmaceutically acceptable salts have 5-HT6 receptor antagonist, agonist and partial agonist activity and are believed to be of potential use in the treatment or prophylaxis of obesity and type 2 diabetes, to achieve reduction of body weight and of body weight gain, as well as in the treatment or prophylaxis of disorders of the central nervous system such as anxiety, depression, panic attacks, memory disorders, cognitive disorders, epilepsy, sleep disorders, migraine, anorexia, bulimia, binge eating disorders, obsessive compulsive disorders, psychoses, Alzheimer's disease, Parkinson's disease, Huntington's chorea and/or schizophrenia, panic attacks, Attention Deficit Hyperactive Disorder (ADHD), withdrawal from drug abuse, neurodegenerative diseases characterized by impaired neuronal growth, and pain.
  • ADHD Attention Deficit Hyperactive Disorder
  • body weight disorders refers to the disorders caused by an imbalance between energy intake and energy expenditure, resulting in abnormal (e.g., excessive) body weight. Such body weight disorders include obesity.
  • One object of the present invention is a compound of the Formula (I):
  • P is selected from a substituent of Formula (II)-(NII):
  • R 1 is selected from: (a) C g-alkyl, (b) C 1-6 -alkoxy-C 1-6 -alkyl, (c) C 3-6 -alkenyl, (d) hydroxy-C ⁇ s-alkyl, (e) halo-C 1-6 -alkyl, (f) aryl, (g) arylcarbonylmethyl, (h) aryl-C 3-6 -alkenyl, (i) aryl-C ⁇ -6 -alkyl, 0) C 3-7 -cycloalkyl, (k) heteroaryl, (1) 4-piperidinyl, (m) ⁇ -substit
  • R is selected from: (a) hydrogen, (b) C ⁇ -alkyl, (c) C 1 . 6 -alkoxy-C 2 . 6 alkyl, (d) hydroxy-C 2 .
  • Wi and W 2 are each independently selected from: (a) hydrogen, (b) halogen, (c) d-6-alkyl, (d) hydroxy, (e) C 1-6 -alkoxy, (f) C ⁇ -6 -alkylthio, (g) C 2-6 -alkenyl, (h) phenyl, (i) phenoxy, (j) benzyloxy, (k) benzoyl, (1) benzyl, (m) -OCF 3 , (n) -C ⁇ , (o) hydroxy-C 1-6 -alkyl, (p) C 1-6 -alkoxy-C 1 6 -alkyl
  • R may also be a group selected from:
  • R 6 is selected from: (a) hydrogen, (b) C ⁇ - 4 -alkyl, (c) hydroxy-C 1 - 4 -alkyl, (d) C 1 - 4 -alkoxy-C 1 - 4 -alkyl, (e) hydroxy, provided that the said hydroxy group is not attached to a carbon atom adjacent to a heterocyclic ring nitrogen atom, and further provided that the said heterocyclic ring is not substituted with oxo, (f) fluorine, provided that the said fluorine atom is not attached to a carbon atom adjacent to a ring nitrogen atom, or (g) halo-C ⁇ - 4 -alkyl;
  • R 7 is each independently selected from: (a) hydrogen, provided that R 7 is not hydrogen when present simultaneously with r and said r is 1 or 2, (b) C ⁇ -4-alkyl, (c) hydroxy-C 2 - 4 -alkyl, or (d) methoxy-C 2 - 4 -alkyl;
  • R 8 is each independently selected from: (a) hydrogen, or (b) C ⁇ .- 4 -alkyl, and when both R 8 simultaneously are selected from C 1 - 4 -alkyl,said C ⁇ -alkyls may be attached to the same or different carbon atoms, or when two groups are present at the same carbon atom they may together form a cyclopropane ring;
  • R 9 is each independently selected from: (a) hydrogen, (b) Ci- ⁇ -alkyl (c) C 3 - 7 -cycloalkyl, or wherein the two R 9 groups together with the nitrogen to which they are attached fonn a heterocyclic ring; and provided that when
  • R 24 is selected from: (a) hydroxymethyl, (b) methoxymethyl, or (c) fluoromethyl;
  • R 25 is each independently selected from (a) hydrogen, (b) C ⁇ -4-alkyl, (c) hydroxy-d- 4 -alkyl, (d) C 1 - 4 -alkoxy-C 1 - 4 -alkyl, or (e) fluoromethyl; with the proviso that when both R 25 simultaneously are selected from C 1-4 -alkyl, said Cj -4 - alkyls may be attached to the same or different carbon atoms, and with the further proviso that when one R 25 is selected from hydroxy-C ⁇ -4 -alkyl, C 1-4 -alkoxy-C 1-4 -alkyl, and fluoromethyl, the other R 25 represents hydrogen; and R 26 is selected from (a) 2-cyanoethyl, (b) C 3-6 -alkenyl, (c) C 3-6 -alkynyl,
  • v 0, 1 or 2; and further provided that when R is selected from hydroxy, R is selected from hydrogen; and pharmaceutically acceptable salts, hydrates, solvates, geometrical isomers, tautomers, optical isomers, and prodrug forms thereof.
  • R is selected from hydroxy, R is selected from hydrogen; and pharmaceutically acceptable salts, hydrates, solvates, geometrical isomers, tautomers, optical isomers, and prodrug forms thereof.
  • Preferred is a compound of the Formula (lb):
  • P is selected from a substituent of Formula (II)-(NII):
  • NI (NI) (Nil) wherein: x, y and j are each independently selected from 0, 1, and 2 ; wherein the dashed bonds denote that R 3 may be attached to either the A or B ring at any carbon atom that allows the substitution; R 1 is selected from: (a) C 1 .
  • R 3 is a group selected from:
  • Xi is selected from NR 7 and S;
  • X is selected from O, NR 7 and S, provided that X 4 is selected from S and NR 7 when f is selected from 2 and 3, and
  • R 6 simultaneously is selected from hydrogen and d- 4 alkyl;
  • P is a group selected from a substituent of Formula (V) - (Nil)
  • R 3 is additionally selected from the following groups:
  • R 4 is selected from: (a) hydrogen, (b) C ⁇ -6-alkyl, (c) 2-cyanoethyl, (d) hydroxy-d- ⁇ -alkyl, (e) C 3 - 6 -alkenyl, (f) C 3 - 6 -alkynyl, (g) C 3 -7-cycloalkyl, (h) C 3 - 7 -cycloalkyl-C ⁇ - 4 -alkyl, (i) d- 6 -alkoxy-C 2 - 6 -alkyl (l) -CH 2 -CO-N-R ⁇ R n , or (m) 3,3,3-trifluoropropyl; R 5 is selected from: (a) hydrogen, (b) d-4-alkyl, (c) hydroxy-C ⁇ -4-alkyl,
  • R 6 is selected from: (a) hydrogen, (b) d- 4 -alkyl, (c) hydroxy-d- 4 -alkyl, (d) C 1 - 4 -alkoxy-C 1 - 4 -alkyl, (e) hydroxy, provided that the said hydroxy group is not attached to a carbon atom adjacent to a heterocyclic ring nitrogen atom, (f) fluorine, provided that the said fluorine atom is not attached to a carbon atom adjacent to a ring nitrogen atom, or (g) halo-C ⁇ -4-al yl;
  • R 7 is each independently selected from: (a) hydrogen, provided that R 7 is not hydrogen when present simultaneously with r and said r is 1 or 2, (b) d- 4 -alkyl, (c) hydroxy-C 2 - 4 -alkyl, or (d) methoxy-C 2 - 4 -alkyl;
  • R 8 is each independently selected from: (a) hydrogen, or (b) d- 4 -alkyl, with the proviso that when both R 8 simultaneously are selected from C ⁇ - -alkyl, said C 1 - 4 -alkyl may be attached to the same or different carbon atoms, or when two groups are present at the same carbon atom they may together form a cyclopropane ring;
  • R 9 is each independently selected from: (a) hydrogen, (b) Ci- ⁇ -alkyl (c) C 3 - 7 -cycloalkyl, or the two R 9 groups together with the nitrogen to which they are attached form a heterocyclic ring; and provided that when the two R 9 groups form a piperazine ring, the nitrogen of the said piperazine ring that allows the substitution may be optionally substituted with C ⁇ - 4 -alkyl; and further provided that when the two R 9 groups form a piperidine ring, any ring carbon atom in the said piperidine ring may be optionally substituted
  • R 14 is selected from: (a) aryl, (b) heteroaryl, (c) aryl-d- 3 -alkyl, or (d) heteroaryl-d- 3 -alkyl, wherein any heteroaryl or aiyl residue may be substituted in one or more positions with substituents selected from halogen, d- 4 -alkyl, d- 4 -alkoxy, cyano, and trifluoromethyl; on R is each independently selected from: (a) hydrogen, (b) methyl, with the proviso that when t 2 is 1, R 20 is H; 01 09 R and R are each independently selected from: (a) hydrogen, or (b) methyl, provided
  • P is selected from a substituent of Formula (II)-(V) (II) (HI) (IN) (N) wherein x is 2, y is 0 and j is 1;
  • R 1 is selected from: (f) aryl, (i) aryl-C 1-3 -alkyl, (k) heteroaryl, (o) heteroaryl-C ⁇ -3 -alkyl, wherein any heteroaryl or aryl residue, alone or as part of another group may be optionally substituted, independently, in one or more positions with a substituent selected from: (b) halogen, (c) C 1-4 -alkyl, (d) hydroxy, (e) C 1-4 -alkoxy, (m) -OCF 3 , (n) -C ⁇ , (o) hydroxy-Ci -4 -alkyl, (p) C ⁇ -2-alkoxy-C 1-2 -alkyl, (q) halo-
  • W 2 are each independently selected from: (a) hydrogen, (b) halogen, (c) C ⁇ -4-alkyl, (d) hydroxy, (e) C ⁇ -4 -alkoxy, (f) C ⁇ -4 -alkylthio, (m) -OCF 3 , (n) -CN, (o) hydroxy-C ⁇ -2-alkyl, (p) C ⁇ -2 -alkoxy-C 1 2 -alkyl, (q) -CF 3 , (r) -CONR 9 R 9 , (s) acetyl, (t) C ⁇ _4-alkoxycarbonyl, or with the proviso that when Wj and W 2 are not selected from hydroxy, methoxy, methyl and halogen, at least one of Wi and W2 is selected from hydrogen; R is a group selected from:
  • X ⁇ is selected from NR 7 and S;
  • X 4 is selected from O, NR 7 and S, provided that X4 is selected from S and NR 7 when f is selected from 2 and 3, and R 6 simultaneously is selected from hydrogen and d- 4 alkyl; or;
  • R 4 is selected from: (a) hydrogen, (b) d- 4 -alkyl, (d) hydroxy-C 2 - 4- alkyl, (g) C 3 - 6 -cycloalkyl, (h) C - 6 -cycloalkyl-d- 4 -alkyl, (i)C ⁇ - 4 -alkoxy-C 2 - 4 -alkyl (m) 3,3,3-trifluoropropyl;
  • R 5 is selected from: (a) hydrogen, (b) C ⁇ -4-alkyl, (c) hydroxy-d- 4 -alkyl, (d) C ⁇ - 4 -alkoxy methyl, (e) halo-C ⁇ - 4 -alkyl, (fj -NR 1 ⁇ 11 , (g) hydroxy, provided that the said hydroxy group is not attached to a carbon atom adjacent to a ring nitrogen atom, or (h) fluorine, provided that the said fluorine atom is not attached to
  • W la W 2 , P and R 3 are as defined for formula (lb).
  • Further preferred compounds of Formula (XII) are compounds wherein P is selected from a substituent of Formula (II) -(IN); x is 2 and y is 0; R 1 is selected from aryl and heteroaryl, wherein any heteroaryl or aryl residue may be optionally substituted, independently, in one or more positions with a substituent selected from halogen, C ⁇ -4 -alkyl, C ⁇ -4 -alkoxy and trifluoromethyl; R 2 is selected from hydrogen; Wi and W 2 are hydrogen; R 3 is a group selected from
  • R 4 is selected from: (a) hydrogen, or (b) d-4-alkyl
  • R 11 is each independently selected from: (a) hydrogen, or (b) methyl, (c) ethyl, provided that R selected from -CH 2 -CO- NR n R n
  • R 12 and R 13 are each independently selected from aryl and heteroaryl, wherein any heteroaryl or aryl residue may be optionally substituted, independently, in one or more positions with a substituent selected from halogen, C ⁇ -4 -alkyl, C 1-4 -alkoxy, and CF 3
  • R is selected from: (a) hydrogen, or (b) C ⁇ -4-al yl
  • R is selected from: (e) C 3 - 7 -cycloalkyl-C ⁇ - 4 -alkyl, (f) -CH 2 -CO-NR ⁇ R u , or (g) 3,3,3-trifluoropropyl.
  • P is selected from a substituent of Formula (II) -(IN); x is 2 and y is 0; R 1 , R 12 and R 13 are each independently selected from phenyl or substituted phenyl selected from 2-methoxy-5-methylphenyl, 2-methylphenyl, 4-methylphenyl, 4- fluorophenyl, 3,4-dimethoxyphenyl, 2-chlorophenyl, 2-trifluoromethylphenyl, 2,6- dichlorophenyl, 3-chloro-4-methylphenyl, 3-methylphenyl, 3,6-dichloro-2-methylphenyl, and 2-chloro-5-fluorophenyl; or heteroaryl or substituted heteroaryl selected from 2- thienyl, 5-chloro-2-thienyl, 5-chloro-and l,3-dimethyl-lH-pyrazol-4-yl; R 2 is selected from hydrogen; W t and W 2 are hydrogen;
  • R 4 is each independently selected from: (a) hydrogen, or (b) methyl
  • R 11 is each independently selected from: (a) hydrogen, or (b) methyl
  • R 25 is each independently selected from: (a) hydrogen, or (b) methyl.
  • a yet further set of preferred compounds within this invention are those of the general Formula (XIII):
  • R 4 is each independently selected from: (a) hydrogen, or (b) d-4-alk l
  • R 25 is each independently selected from: (a) hydrogen, or (b) C ⁇ - -alkyl, with the proviso that when both R 25 represent C ⁇ - 4 -alkyl, said d 4 -alkyl may be attached to the same or different carbon atoms
  • 10 1 ⁇ R and R are each independently selected from aryl and heteroaryl, wherein any heteroaryl or aryl residue may be optionally substituted, independently, in one or more postions with a substituent selected from halogen, d- 4 -alkyl, trifluoromethyl, and d- 4 - alkoxy.
  • P is selected from a substituent of Foraiula (II); R 1 is selected from 2-methoxy-5-methylphenyl; R 2 is selected from hydrogen; Wi and W 2 are hydrogen; R 3 is a group selected from:
  • R 4 is each independently selected from a) hydrogen, or b) methyl
  • R 25 is each independently selected from: a) hydrogen, or b) methyl.
  • Preferred compounds are N-(7- ⁇ Methyl[3-(methylamino)propyl]amino ⁇ -l-benzofuran-5- yl)benzenesulfonamide hydrochloride, N-(7-Piperidin- 1 -yl- 1 -benzofuran-5-yl)benzenesulfonamide, 4-Fluoro-N-(7-piperidin-l-yl-l-benzofuran-5-yl)benzenesulfonamide, 3 ,4-Dimethoxy-N-(7-piperidin- 1 -yl- 1 -benzofuran-5-yl)benzenesulfonamide hydrochloride, 3 ,4-Dimethoxy-N-(7-pyrrolidin- 1 -yl- 1
  • Another object of the present invention is a process for the preparation of a compound as mentioned above, comprising the following steps: (a) halogenation of 4-nitrophenol to give a dihalogenated 4-nitrophenol, (b) ring closure of a dihalogenated 4-nitrophenol using frimethylsilylacetylene to give a halogenated nifrobenzofuran, (c) nucleophilic displacement of a halogenated nifrobenzofuran with an amine to give an amine-substituted nifrobenzofuran, (d) BOC-protection of an amine-substituted benzofuran to give a BOC-protected amine-substituted nifrobenzofuran, (e) reduction of a BOC-protected amine-substituted nitrobenzofuran to give a BOC- protected amine-substituted aminobenzofuran, (f) coupling of a halogenated nitrobenzofuran with
  • BOC-protected amine-substituted benzoylaminobenzofuran (n) removal of the BOC-protecting group from a BOC-protected amine-substituted benzoylaminobenzofuran, (o) reaction of a BOC-protected amine-substituted aminobenzofuran with an aryl isocyanate to give a BOC-protected amine-substituted phenylaminocarbonylaminobenzofuran, and (p) removal of the BOC-protecting group from a BOC-protected amine-substituted phenylaminocarbonylaminobenzofuran.
  • Another object of the present invention is a compound as mentioned above for use in therapy, especially for use in the treatment or prophylaxis of a 5-HTg receptor-related disorder, to achieve reduction of body weight and of body weight gain.
  • Another object of the present invention is a pharmaceutical formulation comprising a compound as mentioned above as active ingredient, in combination with a pharmaceutically acceptable diluent or carrier, especially for use in the treatment or prophylaxis of a 5-HTg receptor-related disorder, to achieve reduction of body weight and of body weight gain.
  • Another object of the present invention is a method for treating a human or animal subject suffering from a 5-HTg receptor-related disorder, to achieve reduction of body weight and of body weight gain.
  • the method can include administering to a subject (e.g., a human or an animal, dog, cat, horse, cow) in need thereof an effective amount of one or more compounds of any of the formulae herein, their salts, or compositions containing the compounds or salts.
  • a subject e.g., a human or an animal, dog, cat, horse, cow
  • the methods delineated herein can also include the step of identifying that the subject is in need of treatment of the 5-HTg receptor-related disorder, to achieve reduction of body weight and of body weight gain. Identifying a subject in need of such treatment can be in the judgment of a subject or a health care professional and can be subjective (e.g., opinion) or objective (e.g., measurable by a test or diagnostic method).
  • Another object of the present invention is a method for the treatment or prophylaxis of a 5-HTg receptor-related disorder, to achieve reduction of body weight and of body weight gain, which comprises administering to a subject in need of such treatment an effective amount of a compound as mentioned above.
  • Another object of the present invention is a method for modulating (e g inhibiting or promoting) 5-HTg receptor activity, which comprises administering to a subject in need of such treatment an effective amount of a compound as mentioned above.
  • Another object of the present invention is the use of a compound as mentioned above for the manufacture of a medicament for use in the prophylaxis or treatment of a 5-HTg receptor-related disorder, to achieve reduction of body weight and of body weight gain.
  • the compounds as mentioned above may be agonists, partial agonists or antagonists for the 5-HT6 receptor.
  • the compounds act as partial agonists or antagonists for the 5-HT6 receptor.
  • Another object of the present invention is a cosmetic composition comprising a compound as mentioned above as active ingredient, in combination with a cosmetically acceptable diluent or carrier, especially for use in the prophylaxis or treatment of a 5-HTg receptor-related disorder, to achieve reduction of body weight and of body weight gain.
  • 5-HT6 receptor-related disorders are obesity; type II diabetes; disorders of the central nervous system such as anxiety, depression, panic attacks, memory disorders, cognitive disorders, epilepsy, sleep disorders, migraine, anorexia, bulimia, binge eating disorders, obsessive compulsive disorders, psychoses, Alzheimer's disease, Parkinson's disease, Huntington's chorea, schizophrenia, attention deficit hyperactive disorder (ADHD), withdrawal from drug abuse, neurodegenerative diseases characterized by impaired neuronal growth, and pain.
  • the compounds and compositions are useful for treating diseases, to achieve reduction of body weight and of body weight gain.
  • the diseases include obesity; type II diabetes; disorders of the central nervous system such as anxiety, depression, panic attacks, memory disorders, cognitive disorders, epilepsy, sleep disorders, migraine, anorexia, bulimia, binge eating disorders, obsessive compulsive disorders, psychoses, Alzheimer's disease, Parkinson's disease, Huntington's chorea, schizophrenia, attention deficit hyperactive disorder (ADHD), withdrawal from drug abuse, neurodegenerative diseases characterized by impaired neuronal growth, and pain.
  • the invention relates to a method for treating or preventing an aforementioned disease comprising administering to a subject in need of such treatment an effective amount or composition delineated herein.
  • C ⁇ -6 -alkyl denotes a straight or branched alkyl group having from 1 to 6 carbon atoms.
  • Examples of said C ⁇ -6 -alkyl include methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl and straight- and branched-chain pentyl and hexyl.
  • C 1-6 -alkyl For parts of the range "C 1-6 -alkyl" all subgroups thereof are contemplated such as C ⁇ -5 -alkyl, C ]-4 -alkyl, C 1-3 -alkyl, C 1-2 -alkyl, C 2-6 -alkyl, C 2-5 -alkyl, C 2-4 -alkyl, C 2-3 -alkyl, C 3-6 -alkyl, C 4-5 -alkyl, etc.
  • "Halo-C 1-6 -alkyl” means a C ⁇ -6 -alkyl group substituted by one or more halogen atoms.
  • halo-C ⁇ -6 -alkyl examples include 2- fluoroethyl, fluoromethyl, trifluoromethyl and 2,2,2-trifluoroethyl.
  • aryl-C 1-6 - alkyl means a C 1-6 -alkyl group substituted by one or more aryl groups.
  • hydroxy-C 1-6 -alkyl denotes a straight or branched alkyl group that has a hydrogen atom thereof replaced with OH. Examples of said hydroxy-C 1-6 -alkyl include hydroxymethyl, 2-hydroxy ethyl, 2-hydroxypropyl and 2- hydroxy-2-methylpropyl.
  • C ⁇ -6 -alkoxy denotes a straight or branched alkoxy group having from 1 to 6 carbon atoms.
  • Examples of said C 1-6 - alkoxy include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, t- butoxy and straight- and branched-chain pentoxy and hexoxy.
  • C 1-6 - alkoxy For parts of the range "C 1-6 - alkoxy" all subgroups thereof are contemplated such as C ⁇ - 5 -alkoxy, d -4 -alkoxy, C ⁇ -3 - alkoxy, C ⁇ -2 -alkoxy, C 2-6 -alkoxy, C 2-5 -alkoxy, C2 -4 -alkoxy, d-ralkoxy, C 3-6 -alkoxy, C 4-5 - alkoxy, etc.
  • the term C 1-6 -alkoxy-C 1-6 -alkyl denotes a straight or branched alkoxy group having from 1 to 6 carbon atoms connected to an alkyl group having from 1 to 6 carbon atoms.
  • Examples of said C 1-6 -alkoxy-C 1-6 -alkyl include methoxymethyl, ethoxymethyl, iso-propoxymethyl, n-butoxymethyl, t-butoxymethyl and straight- and branched-chain pentoxymethyl.
  • C ⁇ -6 -alkoxy-C 1-6 - alkyl all subgroups thereof are contemplated such as C 1-5 -alkoxy-C ⁇ -6 -alkyl, C 1-4 -alkoxy- C ⁇ - 6 -alkyl, C 1-3 -alkoxy-C ⁇ -6 -alkyl, C ⁇ .
  • C 2-6 -alkenyl denotes a straight or branched alkenyl group having from 2 to 6 carbon atoms.
  • examples of said d- ⁇ -alkenyl include vinyl, allyl, 2,3-dimethylallyl, 1-butenyl, 1-pentenyl, and 1-hexenyl.
  • d- ⁇ -alkenyl all subgroups thereof are contemplated such as C 2-5 -alkenyl, C 2-4 - alkenyl, C 2-3 -alkenyl, C 3-6 -alkenyl, C 4-5 -alkenyl, etc.
  • aryl-C 2-6 -alkenyl means a C 2-6 -alkenyl group substituted by one or more aryl groups.
  • aryl-C 2-6 - alkenyl include styryl and cinnamyl.
  • C 2-6 - alkynyl For parts of the range "C 2-6 - alkynyl” all subgroups thereof are contemplated such as C 2-5 -alkynyl, C 2-4 -alkynyl, C 2-3 - alkynyl, C 3-6 -alkynyl, C 4-5 -alkynyl, etc.
  • C 3- -cycloalkyl denotes a cyclic alkyl group having a ring size from 3 to 7 carbon atoms. Examples of said cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl,.cyclohexyl, methylcyclohexyl, and cycloheptyl.
  • C 3-7 -cycloalkyl For parts of the range "C 3-7 -cycloalkyl” all subgroups thereof are contemplated such as C 3-6 - cycloalkyl, C 3-5 -cycloalkyl, C 3-4 -cycloalkyl, C 4-7 -cycloalkyl, C 4-6 -cycloalkyl, C 4-5 - cycloalkyl, C 5-7 -cycloalkyl, C 6- -cycloalkyl, etc.
  • aryl refers to a hydrocarbon ring system having at least one aromatic ring.
  • aryls are phenyl, indenyl, indanyl, 1,2,3,4-tetrahydronaphthyl, 1-naphthyl, 2-naphthyl, and fluorenyl.
  • aryloxy refers to an aryl group bonded to an oxygen atom.
  • heteroaryl refers to a mono- or bicyclic aromatic ring system, only one ring need be aromatic, and the said heteroaryl moiety can be linked to the remainder of the molecule via a carbon or nitrogen atom in any ring, and having from 5 to 10 ring atoms (mono- or bicyclic), in which one or more of the ring atoms are other than carbon, such as nitrogen, sulphur, oxygen and selenium.
  • heteroaryl rings examples include furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, chromanyl, quinazolinyl, indolyl, isoindolyl, indolinyl, isoindolinyl, indazolyl, pyrazolyl, pyridazinyl, quinolinyl, isoquinolinyl, benzofuranyl, 2,3- dihydrobenzofuranyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, benzodioxolyl, benzodioxinyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzothiadiazolyl,
  • heterocyclic refers to a non-aromatic (i.e., partially or fully saturated) mono- or bicyclic ring system having 4 to 10 ring atoms with at least one heteroatom such as O, N, or S, and the remaining ring atoms are carbon.
  • heterocyclic groups include piperidyl, tetrahydropyranyl, tetrahydrofuranyl, azepinyl, azetidinyl, pyrrolidinyl, mo ⁇ holinyl, imidazolinyl, thiomo ⁇ holinyl, pyranyl, dioxanyl, piperazinyl, octahydrofuro[3,4b]pyrazinyl, and l-azabicyclo[2.2.2]oct-2-en-3-yl groups.
  • heterocyclic groups containing sulfur in oxidized form include octahydrothieno[3,4b]pyrazine 6,6-dioxide and thiomo ⁇ holine 1,1-dioxide.
  • halogen shall mean fluorine, chlorine, bromine or iodine.
  • -S(O) x - in Formula (IN) wherein x is 0, 1 or 2, has the meaning as illustrated by Formula (IX) - (XI):
  • leaving group refers to a group to be displaced from a molecule during a nucleophilic displacement reaction.
  • leaving groups are iodide, bromide, chloride, methanesulphonate, hydroxy, methoxy, thiomethoxy, tosyl, or suitable protonated forms thereof (e.g., H 2 O, MeOH), especially bromide and methanesulphonate.
  • Optional or “optionally” means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not.
  • “Pharmaceutically acceptable” means being useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable and includes being useful for veterinary use as well as human pharmaceutical use.
  • “Treatment” as used herein includes prophylaxis of the named disorder or condition, or amelioration or elimination of the disorder once it has been established.
  • “An effective amount” refers to an amount of a compound that confers a therapeutic effect on the treated subject. The therapeutic effect may be objective (i.e., measurable by some test or marker) or subjective (i.e., subject gives an indication of or feels an effect).
  • prodrug forms means a pharmacologically acceptable derivative, such as an ester or an amide, which derivative is biotransformed in the body to form the active drug.
  • pharmacologically acceptable derivative such as an ester or an amide
  • BINAP means 2,2'-bis(diphenylphosphino)l-r-binaphthyl
  • BOC means tert-butyloxycarbonyl
  • CN means Coefficient of Variation
  • DCM means dichloromethane
  • DME means 1,2-dimethoxyethane
  • DMSO means dimethyl sulphoxide
  • EDTA means ethylenediamine tetraacetic acid
  • EtOH means ethanol
  • EtOAc means ethyl acetate
  • EGTA means ethylenebis(oxyethylenenitrilo)tetraacetic acid
  • HEPES means 4-(2-hydroxyethyl)-l-piperazineethanesulfonic acid
  • HPLC means high performance liquid chromatography
  • LSD means lysergic acid
  • diethylamide means acetonitrile
  • SPA means Scintillation Proximity Assay
  • t-BuOK means potassium tert-butoxide
  • Compounds that have basic properties can be converted to their pharmaceutically acceptable acid addition salts by treating the base form with an appropriate acid.
  • exemplary acids include inorganic acids, such as hydrogen chloride, hydrogen bromide, hydrogen iodide, sulphuric acid, phosphoric acid; and organic acids such as formic acid, acetic acid, propanoic acid, hydroxyacetic acid, lactic acid, pyruvic acid, glycolic acid, maleic acid, malonic acid, oxalic acid, benzenesulphonic acid, toluenesulphonic acid, methanesulphonic acid, trifluoroacetic acid, fumaric acid, succinic acid, malic acid, tartaric acid, citric acid, salicylic acid, p-aminosalicylic acid, pamoic acid, benzoic acid, ascorbic acid and the like.
  • Exemplary base addition salt forms are the sodium, potassium, calcium salts, and salts with pharmaceutically acceptable amines such as, for example, ammonia, alkylamines, benzathine, and amino acids, such as, e.g. arginine and lysine.
  • amines such as, for example, ammonia, alkylamines, benzathine, and amino acids, such as, e.g. arginine and lysine.
  • sulfonamide derivatives of Formula (I) wherein P is selected from a substituent of Formula (II) and (III) and wherein R is hydrogen may be converted into their corresponding potassium, sodium or calcium salts, or salts of other alkali metals or alkaline earth metals.
  • the term addition salt as used herein also comprises solvates which the compounds and salts thereof are able to form, such as, for example, hydrates, alcoholates and the like.
  • the compounds of the invention are formulated into pharmaceutical formulations for oral, rectal, parenteral or other mode of administration.
  • Pharmaceutical formulations are usually prepared by mixing the active substance, or a pharmaceutically acceptable salt thereof, with conventional pharmaceutical excipients.
  • excipients are water, gelatin, gum arabicum, lactose, microcrystalline cellulose, starch, sodium starch glycolate, calcium hydrogen phosphate, magnesium stearate, talcum, colloidal silicon dioxide, and the like.
  • Such formulations may also contain other pharmacologically active agents, and conventional additives, such as stabilizers, wetting agents, emulsifiers, flavouring agents, buffers, and the like.
  • the amount of active compounds is between 0.1-95% by weight of the preparation, preferably between 0.2-20% by weight in preparations for parentral use and more preferably between 1-50% by weight in preparations for oral administration.
  • the formulations can be further prepared by known methods such as granulation, compression, microencapsulation, spray coating, etc.
  • the formulations may be prepared by conventional methods in the dosage form of tablets, capsules, granules, powders, syrups, suspensions, suppositories or injections.
  • Liquid formulations may be prepared by dissolving or suspending the active substance in water or other suitable vehicles. Tablets and granules may be coated in a conventional manner.
  • the invention relates to methods of making compounds of any of the formulae herein comprising reacting any one or more of the compounds of the formulae delineated herein, including any processes delineated herein.
  • the compounds of the formula (I) above may be prepared by, or in analogy with, conventional methods. The processes described above may be carried out to give a compound of the invention in the form of a free base or as an acid addition salt.
  • a pharmaceutically acceptable acid addition salt may be obtained by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds. Examples of addition salt forming acids are mentioned above.
  • the compounds of formula (I) may possess one or more chiral carbon atoms, and they may therefore be obtained in the form of optical isomers, e.g. as a pure enantiomer, or as a mixture of enantiomers (racemate) or as a mixture containing diastereomers.
  • optical isomers e.g. as a pure enantiomer, or as a mixture of enantiomers (racemate) or as a mixture containing diastereomers.
  • the separation of mixtures of optical isomers to obtain pure enantiomers is well known in the art and may, for example, be achieved by fractional crystallization of salts with optically active (chiral) acids or by chromatographic separation on chiral columns.
  • the chemicals used in the synthetic routes delineated herein may include, for example, solvents, reagents, catalysts, and protecting group and deprotecting group reagents.
  • the methods described above may also additionally include steps, either before or after the steps described specifically herein, to add or remove suitable protecting groups in order to ultimately allow synthesis of the compounds.
  • various synthetic steps may be performed in an alternate sequence or order to give the desired compounds.
  • Synthetic chemistiy transformations and protecting group methodologies protecting group methodologies useful in synthesizing applicable compounds are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 3 rd Ed., John Wiley and Sons (1999); L. Fieser and M.
  • the necessary starting materials for preparing the compounds of formula (I) are either known or may be prepared in analogy with the preparation of known compounds.
  • the dose level and frequency of dosage of the specific compound will vary depending on a variety of factors including the potency of the specific compound employed, the metabolic stability and length of action of that compound, the patient's age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drag combination, the severity of the condition to be treated, and the patient undergoing therapy.
  • the daily dosage may, for example, range from about 0.001 mg to about 100 mg per kilo of body weight, administered singly or multiply in doses, e.g. from about 0.01 mg to about 25 mg each. Normally, such a dosage is given orally but parenteral administration may also be chosen.
  • the invention will now be further illustrated by the following non-limiting Examples. The specific examples below are to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever. Without further elaboration, it is believed that one skilled in the art can, based on the description herein, utilize the present invention to its fullest extent. All publications cited herein are hereby inco ⁇ orated by reference in their entirety.
  • R H or SiMe 3
  • R 3 is as defined for Formula (I).
  • Het a heteroaryl group or a heterocyclic group within the scope of R 3 as defined for Formula (I).
  • Exemplary heteroaryl or heterocyclic groups are selected from 3-pyridyl, 4- pyridyl, pyrazinyl, 5-pyrimidyl, and l-azabicyclo[2.2.2]oct-3-en-2-yl R 1 is as defined for Formula (I).
  • R HorSiMe 3 R 3 and R 14 are as defined for Formula (I).
  • R HorSiMe 3 R 3 and R 14 are as defined for Formula (I).
  • R 1 is as defined for formula (I) and Am is attached to the remainder of the molecule via a nitrogen atom.
  • Exemplary Am groups are depicted in Figure 1.
  • R n is each independently selected from hydrogen or methyl.
  • R is as defined for formula (I) and Am is attached to the remainder of the molecule via a nitrogen atom.
  • Exemplary Am groups are shown in Figure 1.
  • R 12 is as defined for formula (I) and Am is attached to the remainder of the molecule via a nitrogen atom. Exemplary Am groups are shown i Figure 1.
  • R 1 is as defined for formula (I) and Am is attached to the remainder of the molecule via a nitrogen atom. Exemplary Am groups are shown in Figure 1. Scheme 13
  • R 1 is as defined for formula (I) and Am is attached to the remainder of the molecule via a nitrogen atom. Exemplary Am groups are shown in Figure 1.
  • R 12 is as defined for formula (I) and Am is attached to the remainder of the molecule via a nitrogen atom. Exemplary Am groups are shown in Figure 1.
  • Benzenesulfonyl chloride (115 ⁇ L, 0.9 mmol) was added to a mixture of tert-butyl 3-[(5- amino- l-benzofuran-7-yl)(methyl)amino]propyl(methyl)carbamate (Intermediate 2; 250 mg, 0.75 mmol) in DCM (2 mL) followed by addition of pyridine (1 mL). The reaction mixture was stirred at room temperature for 4 h.
  • Step 1 2-Bromo-6-iodo-4-nitrophenol.
  • a solution of 4-nitrophenol (130 g, 0.96 mol) in acetonitrile (500 mL) was cooled to 0 °C. While keeping the temperature below 5 °C, chlorosulfonic acid (120 g, 1.03 mol) was added. The resulting mixture was stirred for 30 min at 0-5 °C.
  • N-bromosuccinimide (181 g, 1.01 mol) was added portionwise to the mixture during 7 h, while keeping the temperature below 8 °C.
  • the reaction was then quenched by addition of a solution of NaHSO 3 (250 g, 2.4 mol) in water (600 mL) while the temperature was kept below 20 °C.
  • Step 3 l-(5-Nitro-l-benzofuran-7-yl)piperidine.
  • Pd(PPh 3 ) 4 (240 mg, 209 mmol) was added to 7-iodo-5-nitro-l-benzofurane (1.00 g, 3.45 mmol) in DME (11 mL) and the resulting mixture was stirred for 10 min. The color went from dark red to mustard yellow. Pyrimidine-5 -boronic acid (0.24 g, 0.21 mmol) and 1 M Na 2 CO 3 (5 mL) were added and the reaction mixture was refluxed at 100 °C for 2.5 h. The mixture was concentrated in vacuo and the residue was dissolved in 1 M HC1 (50 mL) and washed with diethyl ether (50 mL).
  • Benzenesulfonyl chloride (0.093 g, 0.524 mmol) and pyridine (347 ⁇ L, 430 mmol) were added to 7-pyrimidin-5-yl-l-benzofuran-5-amine (0.100 g, 0.473 mmol; Intermediate 18) in dichloromethane (2 mL). The mixture was shaken at room temperature for 1 h and the solvent was removed. The crude product was purified by preparative HPLC using acetonitrile- water gradients containing 0.1% trifluoroacetic acid and then converted into the hydrochloride salt by treatment with 2 M HCL in diethyl ether. This gave 0.071 g (43%) of the title compound as a yellow solid.
  • Step 1 3-f(Trimethylsilyl)ethynylJquinuclidin-3-ol.
  • Step 2 7-(l-Azabicyclo[2.2.2]oct-3-yloxy)-l-benzofuran-5-amine.
  • 3-[(5-Nitro-l-benzofuran-7-yl)oxy]quinuclidine (1.38 g, 4.79 mmol; obtained in Stepl) was dissolved in ethanokTHF (100 mL: 25 mL) and Raney-nickel (slurry in ethanol; 6 mL) and hydrazine (891 ⁇ L, 0.18 mmol) were added. The mixture was stirred at room temperature for 3 h and then filtered through Celite and the solvent was removed in vacuo.
  • Benzenesulfonyl chloride (30 ⁇ L, 0.232 mmol) and pyridine (141 ⁇ L, 1.74 mmol) were added to 7-(l-azabicyclo[2.2.2]oct-3-yloxy)-l-benzofuran-5-amine (0.50 g, 0.194 mmol; obtained in Step 2) in DCM (2 mL). The mixture was shaken at room temperature for 2 h and then the solvent was removed in vacuo. Purification of the product was done by preparative HPLC using acetonitrile- water gradients containing 0.1% trifluoroacetic acid. The obtained TFA salt was converted into the hydrochloride salt by treatment with 2 M HCl in ether.
  • Example 38 The title compound was prepared according to the procedure of Example 38, Step 3, starting from 7-(l-azabicyclo[2.2.2]oct-3-yloxy)-l-benzofuran-5-amine (obtained in Example 38, Step 2) and 2-chlorobenzenesulfonyl chloride (0.49 g, 0.232 mmol). Yield: 55 mg (54%). HPLC 100%, R ⁇ : 1.760 (System B; 10-97% MeCN over 3 min).
  • Step 2 N-(7- ⁇ [2(Dimethylamino)ethyl]amino ⁇ -l-benzofuran-5-yl)-2-rnethoxy ⁇ 5- benzenesulfonamide.
  • Step 2 N-(7-Bromo-2-trimethylsilanyl-benzofuran-5-yl)-2-methoxy-5-methyl- benzenesulfonamide.
  • Step 3 4-[5-(2-Methoxy-5-methyl-benzenesulfonylamino)-benzofuran- 7-carbonyl]- piperazine-1-carboxylic acid tert-butyl ester.
  • the Heck carbonylation was performed under controlled microwave heating at 150°C/15 min by mixing the above bromide (168 mg, 0.36 mmol) from Step 2, (tert- butoxycarbonyl)piperazine (134 mg, 0.72 mmol), Mo(CO) 6 (48 mg, 0.18 mmol), trans- di(acetato)bis[o-(di-o-tolylphosphino)benzyl]dipalladium (II) (Herrmann's catalyst, 36 mg, 0.04 mmol), aqueous K 2 CO 3 (4 M; 300 ⁇ L, 1.3 mmol) and diglyme (1 mL).
  • Step 4 2-Methoxy-5-methyl-N-[7-(piperazin-l-ylcarbonyl)-l-benzofuran-5- yl] benzenesulfonamide hydrochloride.
  • Deprotection of the N-t-BOC group in 4-[5-(2- methoxy-5-methyl-benzenesulfonylamino)-benzofuran-7-carbonyl]-piperazine-l- carboxylic acid tert-butyl ester (Step 3) was performed by adding HCl/ether to a solution of the said substrate in ethyl acetate and allowed to stir overnight at ambient temperature. Concentration of the solution gave the title product as a white solid. Yield: 31 mg.
  • Raney-nickel (slurry in ethanol; 2 mL) and hydrazine (204 mL, 4.20 mmol) were added to l-(5-nitro-l-benzofuran-7-yl)octahydrothieno[3,4-b]pyrazine 6,6-dioxide (0.354 g, 1.05 mmol; Intermediate 35) in a mixture of THF (20 mL) and EtOH (80 mL). The resulting mixture was stirred at room temperature overnight and then more Raney-nickel (slurry in ethanol; 2 mL) and hydrazine (204 mL, 4.20 mmol) were added and stirring was continued overnight.
  • Benzenesulfonyl chloride (0.076 g, 0.428 mmol) and pyridine (259 mL, 3.21 mmol) were added to 7-(6,6-dioxidohexahydrothieno[3,4-b]pyrazine-l(2H)-yl-l-benzofuran-5-amine (0.110 g, 0.357 mmol; Intermediate 36) in DCM (1 mL). The mixture was shaken at room temperature for 1 h, solvent removed in vacuo, and the residue was purified by preparative HPLC using acetonitrile-water gradients containing 0.1% trifluoroacetic acid.
  • the title compound was prepared from 5-(5-ammo-l-benzofuran-7-yl)pyridin-2-amine (Intermediate 40) according to the procedure of Example 41, except the purification step where flash chromatography (eluent: 30% EtOAc in hexane) was employed.
  • 1,1,1-Trifluoropropanone (50.0 g, 446.2 mmol) was dissolved in concentrated sulphuric acid (250 g). Br 2 (81.69 g, 510.1 mmol) was added dropwise, at room temperature, during 2 h and the mixture was stirred overnight. After this time, additional Br 2 (40.85 g, 255.6 mmol) was added and the mixture stirred overnight. Separated the two phases formed when allowed to stand and distilled the bottom layer to yield 3,3-dibromo-l,l,l- trifluoroacetone as a yellow oil (10.37 g, 8.6 %).
  • 1H NMR (270 MHz, CDC1 3 ) ⁇ ppm 6.23 (s, 1 H). *Previously described in Rec. Trav. Chim. Pays-Bas 1995, 114, 97-102.
  • Benzenesulfonyl chloride (64.0 mg, 0.36 mmol) and pyridine (219 ⁇ L) were added to tert- butyl [l-(5-amino-l-benzofuran-7-yl)piperidin-4-yl]carbamate (100.0 mg, 0.30 mmol; Intermediate 49) in DCM (1 mL). The mixture was shaken at room temperature for 1 h, solvent was removed in vacuo and the residue was purified by preparative HPLC using acetonitrile-water gradients containing 0.1% trifluoroacetic acid. N-deprotection and conversion into the hydrochloride salt was performed by treatment with 2 M HCl in ether. This furnished 31.3 mg (28%) of the title product.
  • Example 84 The title compound was prepared according to the same procedure as Example 84 starting from tert-butyl tr «5 , -4-[(5-amino- 1 -benzofuran-7-yl)oxy]-3-fluoropiperidine- 1 - carboxylate (Intermediate 53) and 6-methoxy-w-toluenesulfonyl chloride.
  • Example 84 The title compound was prepared according to the procedure described for Example 84 starting from tert-butyl tr ⁇ «5 , -4-[(5-amino-l-benzofuran-7-yl)oxy]-3-fluoropiperidine-l- carboxylate (Intermediate 53) and 2-chlorobenzenesulfonyl chloride.
  • Example 84 The title compound was prepared according to the procedure described for Example 84 starting from tert-butyl tr ⁇ r ⁇ -4-[(5-amino-l-benzofuran-7-yl)oxy]-3-fluoropiperidine-l- carboxylate (Intermediate 53) and 2-chloro-5-fluorobenzenesulfonyl chloride.
  • N-(2-Methylphenyl)-7-vinyl-l-benzofuran-5-sulfonamide (1.03 g, 3.3 mmol; Intermediate 59) was dissolved in dioxane (30 mL) and 2,6-lutidine (0.8 mL). Osmium tetroxide (84 mg, 0.33 mmol) was added with stirring followed by a solution of sodium periodate (2.82 g, 13.2 mmol) in water (10 mL). After stirring for 90 minutes, 1 M HCl (40 mL) was added followed by water (200 mL). The precipitated product was collected by filtration, washed with water and dried under vacuo. Yield: 0.95 g (91%) of an off white solid.
  • Osmium tetroxide (84 mg, 0.33 mmol) was added to a solution of N-(2-methoxy-5- methylphenyl)-7-vinyl-l-benzofuran-5-sulfonamide (1.25 g, 3.3 mmol; Intermediate 61) and lutidine (0.71 g, 6.6 mmol) in dioxane (30 mL).
  • a solution of sodium periodate (2.82 g, 13.2 mmol) in water (10 mL) was added under stirring. After 90 min, aqueous HCl (2 M; 40 mL) was added to give a clear solution. Addition of water (200 mL) gave a precipitate that was collected by filtration.
  • Step 2 4-(5-Amino-benzofuran-7-ylmethyl)-piperazine-l ⁇ carboxyIic acid tert-butyl ester
  • Example 106 The title compound was prepared according to the procedure of Example 106, Step 3, starting from 4-(5-amino-benzofuran-7-ylmethyl)-piperazine-l-carboxylic acid tert-butyl ester (40 mg, 0,12 mmol; obtained in Example 106, Step 2) and 2-methylbenzenesulfonyl chloride (26 ⁇ L, 0.18 mmol).
  • the crude product was purified with preperative HPLC (System B; 10-40% MeCN).
  • the title compound (10 mg, 19%) was obtained as a colorless solid.
  • Example 106 The title compound was prepared according to the procedure of Example 106, Step 3, starting from 4-(5-amino-benzofuran-7-ylmethyl)-piperazine- 1 -carboxylic acid tert-butyl ester (40 mg, 0,12 mmol; obtained in Example 106, Step 2) and 2-thiophenesulfonyl chloride (33 mg, 0.18 mmol). Additional 2-thiophenesulfonyl chloride (10 mg, 0.05 mmol) was added with continued stirring for 1 h. The crude product was purified with preperative HPLC (System B; 10-40% MeCN). The title compound (3 mg, 6%) was obtained as a colorless solid.
  • Step 1 tert-Butyl 4-[(5-nitro-l-benzofuran-7-yI)methyl]-l,4-diazepane-l-carboxylate
  • the title product obtained as a light yellow solid, was prepared according to the procedure of Example 106, Step 1, starting from 1-boc-homopiperazine (103 ⁇ L, 0.53 mmol). Yield: 109 mg (66%).
  • Step 2 4-(5-Amino-benzofuran-7-ylmethyl)-l,4-diazepane-l-carboxylic acid tert- butyl ester
  • the title compound was prepared according to the procedure of Example 106, Step 2, starting from tert-butyl 4-[(5-nitro-l-benzofuran-7-yl)methyl]-l,4-diazepane-l-carboxylate (obtained in Step 1).
  • Step 3 2-Chloro-N-[7-(l,4-diazepan-l-yImethyl)-l-benzofuran-5- yl] benzenesulfonamide dihydrochloride
  • the title compound was prepared according to the procedure of Example 106, Step 3, starting from 4-(5-amino-benzofuran-7-ylmethyl)-l,4-diazepane-l -carboxylic acid tert- butyl ester (36 mg, 0.10 mmol; obtained in Step 2) and 2-chlorobenzenesulfonyl chloride (21 ⁇ L, 0.16 mmol).
  • the crude material was purified with preperative HPLC (System B; 10-40% MeCN). The title compound (16 mg, 33%) was obtained as a colorless solid.
  • Example 106 The title compound was prepared according to the procedure of Example 106, Step 3, starting from 4-(5-amino-benzofuran-7-ylmethyl)-l,4-diazepane-l -carboxylic acid tert- butyl ester (36 mg, 0.10 mmol; obtained in Example 109, Step 2) and 2-thiophenesulfonyl chloride (29 mg, 0.16 mmol). Additional 2-thiophenesulfonyl chloride (10 mg, 0.06 mmol) was added with continous stirring for 1 h. The title compound (10 mg, 22%) was obtained as a colorless solid.
  • Step 1 tert-Butyl 3-methyl-4-[(5-nitro-l-benzofuran-7-yI)methyl]piperazine-l- carboxylate
  • Step 2 tert-Butyl 4-[(5-amino-l-benzofuran-7-yl)methyl]-3-methyIpiperazine-l- carboxylate
  • Raney nickel (slurry in ethanol) and hydrazine hydrate (97 ⁇ L, 2.0 mmol) were added to tert-butyl 3-methyl-4-[(5-nitro-l-benzofuran-7-yl)methyl]piperazine-l-carboxylate (115 mg, 0.31 mmol; obtained in Step 1) in ethanokTHF (4:1; 5 mL).
  • the resulting mixture was stirred at room temperature for 1.5 h, followed by filtration through Celite.
  • the Celite pad was rinsed several times with ethanol.
  • Step 3 2-Methoxy-5-methyl-N- ⁇ 7-[(2-methylpiperazin-l-yl)methyI]-l-benzofuran-5- yl ⁇ benzenesulfonamide, dihydrochloride
  • Step 2 tert-Butyl 2-methyl-4-[(5-nitro-l-benzofuran-7-yl)methyl]piperazine-l- carboxylate
  • Step 3 tert-Butyl 4-[(5-amino-l-benzofuran-7-yl)methyl]-2-methylpiperazine-l- carboxylate
  • Step 4 2-Methoxy-5-methyl-N- ⁇ 7-[(3-methylpiperazin-l-yl)methyl]-l-benzofuran-5- yl ⁇ benzenesulfonamide, dihydrochloride tert-Butyl 4-[(5-amino- 1 -benzofuran-7-yl)methyl]-2-methylpiperazine- 1 -carboxylate (41 mg crude starting material, 0.11 mmol; obtained in Step 3) was dissolved in dry DCM:THF (2:1; 3 mL). Pyridine (18 ⁇ L, 0.22 mmol) and 6-methoxy-m-toluenesulfonyl chloride (36 mg, 0.17 mmol) were added.
  • Step 1 tert-Butyl (lS,4S)-5-[(5-nitro-l-benzofuran-7-yl)methyI]-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate
  • Step 2 tert-Butyl (lS,4S)-5-[(5-amino-l-benzofuran-7-yI)methyl]-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate
  • the title compound was prepared according to the procedure of Example 112, Step 2, using using tert-butyl (lS,4S)-5-[(5-nitro-l-benzofuran-7-yl)methyl]-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (116 mg, 0.31 mmol; obtained in Step 1).
  • the title compound (133 mg) was obtained as a light green solid.. This material was used in the next step without further purification.
  • Step 3 /V- ⁇ 7-[(lS,4S)-2,5-Diazabicyclo[2.2.1]hept-2-ylmethyl]-l-benzofuran-5-yl ⁇ -2- methoxy-5-methylbenzenesulfonamide, dihydrochloride
  • Step 2 tert-Butyl tra «5-2,5-dimethyI-4-[(5-nitro-l-benzofuran-7-yl)methyl]piperazine- 1-carboxylate tr ⁇ «5 , -2,5-Dimethyl-l-[(5-nitro-l-benzofuran-7-yl)metl ⁇ yl]piperazine (0.11 g, 0.4 mmol; obtained in Step 1) was dissolved in MeOH. Boc-anhydride (0.114 g, 0.5 mmol) was added and the reaction was stirred at ambient temperature overnight. The solvent was evaporated and the residue was dissolved in DCM and washed with citric acid. The organic layer was dried (MgSO 4 ) and evaporated to give 0.135 g (91%) of the title product. HPLC 96%
  • Step 3 tert-Butyl tr ⁇ / ⁇ s-4-[(5-amino-l-benzofuran-7-yl)methyl]-2,5- dimethylpiperazine-1-carboxylate tert-Butyl tr ⁇ «5 , -2,5-dimethyl-4-[(5-nitro- 1 -benzofuran-7-yl)methyl]piperazine- 1 - carboxylate (0.14 g, 0.35 mmol; obtained in Step 2) was dissolved in THF/EtOH (4: 1 ; 5 mL). Excess Raney-Ni (slurry in EtOH) was added followed by hydrazine hydrate (0.07 g, 1.39 mmol).
  • Step 4 tert-Butyl tr ⁇ «s-4-[(5- ⁇ [(2-methoxy-5-methylphenyl)sulfonyl]amino ⁇ -l- benzofuran-7 ⁇ yl)methyl]-2,5-dimethylpiperazine-l-carboxylate
  • tert-Butyl trans-4-[(5-amino- 1 -benzofuran-7-yl)methyl]-2,5-dimethylpiperazine- 1 - carboxylate (0.037 g, 0.1 mmol; obtained in Step 3) was dissolved in DCM and reacted with 2-methoxy-5-methylbenzenesulfonyl chloride (0.045 g, 0.2 mmol) and pyridine (0.024 g, 0.3 mmol) overnight.
  • Step 5 2-Methoxy-5-methyI-N- ⁇ 7-[(tm «5-2,5-dimethylpiperazin-l-yl)methyl]-l- benzofuran-5-yl ⁇ benzenesulfonamide, bis(trifluoroacetate)
  • Step 1 tert-Butyl tr ⁇ «s-2,5-dimethyl-4-[(5- ⁇ [(2-methylphenyl)sulfonyl]amino ⁇ -l- benzofuran-7-yl)methyI]piperazine-l-carboxyIate
  • Example 121 The title product was prepared according to the procedure of Example 121, Step 4, starting from tert-butyl tr ⁇ n5 , -4-[(5-amino-l-benzofuran-7-yl)methyl]-2,5-dimethylpiperazine-l- carboxylate (obtained in Example 121, Step 3) and 2-methylbenzenesulfonyl chloride
  • Step 1 tert-Butyl t «5-4-[(5- ⁇ [(2-chlorophenyl)suIfonyl]amino ⁇ -l-benzofuran-7- yl)methyl]-2,5-dimethylpiperazine ⁇ l-carboxyIate
  • the title product was prepared according to the procedure of Example 121, Step 4, starting from tert-butyl tr /zs-4-[(5-amino- 1 -benzofuran-7-yl)methyl]-2,5-dimethylpiperazine- 1 - carboxylate (obtained in Example 121, Step 3) and 2-chlorobenzenesulfonyl chloride (0.043 g, 0.2 mmol).
  • Step 2 2-Chloro-N- ⁇ 7-[(tr ⁇ ns-2,5-dimethylpiperazin-l-yl)methyl]-l-benzofuran-5- yljbenzenesulfonamide, bis(trifluoroacetate)
  • Oxalyl chloride (0.1 mL, 1.1 mmol) was dissolved in dry DCM (2 mL) and DMF (0.9 mL,
  • EXAMPLE 124 l-( ⁇ 5-[(2-Methoxy-5-methylphenyl)sulfonyl]-l-benzofuran-7-yl ⁇ methyl)piperazine, trifluoroacetate 7-(Chloromethyl)-5-[(2-methoxy-5-methylphenyl)sulfonyl]-l-benzofuran (35 mg, O.lmmol; Intermediate 69) was dissolved in ethanol (2 mL) and N-t-Boc-piperazine (28 mg, 0.1 mmol) and sodium bicarbonate (13 mg, 0.1 mmol) were added. The mixture was heated at 80 °C in a StemBlock overnight.
  • Step 3 [5-(Phenylsulfonyl)-l-benzofuran-7-yl]methanoI
  • the title compound was prepared according to the procedure of Intermediate 68 starting from methyl 5-(phenylsulfonyl)-l-benzofuran-7-carboxylate (80 mg, 0.25 mmol; obtained in Step 2). The crude material was used directly in the subsequent reaction. MS (ESI+) for C ⁇ 5 H ⁇ 2 O 4 S m/z 289 (M+H) + .
  • N-t-BOC-piperazine 24 mg, 0.13 mmol
  • sodium bicarbonate 11 mg, 0.13 mmol
  • ethanol 2 mL
  • the mixture was stirred at 80 °C in a STEM-block overnight and the solvent was evaporated.
  • the obtained N-t-BOC derivative of the title compound was dissolved in DCM (1 mL) and TFA (1 mL) was added. After the mixture had been stirred at room temperature for 2 h, the solvent was evaporated to provide the title compound.
  • Step 1 Methyl 5-[(4-methyIphenyl) sulfonyl]-2,3-dihydro-l-benzofuran-7-carboxylate
  • the title compound was prepared according to the procedure of Intermediate 66 starting from methyl 2,3-dihydro-l-benzofuran-7-carboxylate (1 g, 5.6 mmol; Intermediate 65) and 4-methylbenzenesulfonic acid (0.97 g, 5.6 mmol). Yield: 405 mg (22%).
  • MS (ESI+) for C 17 H 16 O 5 S m/z 333 (M+H) + .
  • Step 3 ⁇ 5-[(4-Methylphenyl)sulfonyl]-l-benzofuran-7-yl ⁇ methanol
  • Step 5 l-( ⁇ 5-[(4-Methylphenyl)sulfonyl]-l-benzofuran-7-yl ⁇ methyl)piperazine, trifluoroacetate
  • Step 2 5-Bromo-7-nitro-l-benzofuran-3-carboxylic acid
  • Ethyl 5 -bromo-7-nitro-l-benzofuran-3 -carboxylate (5.5 g, 17.5 mmol; obtained in Step 1) was suspended in ethanol (20 mL). 2 M NaOH (20 mL) was added and the mixture was heated at reflux for 2 h. The ethanol was removed by evaporation and the remaining solution acidified with concentrated HCl (4 mL), diluted with water and the product collected by filtration, washed with water and dried in a vacuum oven. Yield: 4.65 g (93%).
  • Step 1 N-(5-Bromo-l-benzofuran-7-yl)-2-methoxy-5-methylbenzenesulfonamide
  • the alkene intermediate was dissolved in dioxane (6 mL) and lutidine (120 ⁇ L, 1.0 mmol). Osmium tetroxide (26 mg, 0.10 mmol) was added and a color change from light brown to dark brown/black was noticed. Sodium periodate (432 mg, 2.02 mmol) in water (1.5 mL, warmed to dissolve) was added while stirring. A light brown precipitation was formed after 1 min. The mixture was stirred for 2 h, and partitioned between 2 M aqueous HCl and DCM. The organic layer was dried ( ⁇ a 2 SO 4 ), filtered and concentrated to give the crude aldehyde as a black solid.
  • N-(2-MethyIphenyl)-7-(pyrrolidin-3-ylmethyl)-l-benzofuran-5-sulfonamide, trifluoroacetate 9 BBN (0.5 M in THF; 1.5 mL, 0.75 mmol) was added to a solution of tert-butyl 3- methylenepyrrolidine-1 -carboxylate (110 mg, 0.6 mmol; Intermediate 72) in dry THF (1 mL) under a nitrogen atmosphere at 0 °C. After stirring for 1 h at 0 °C, the solution was allowed to warm to room temperature for 3 h.
  • a microwave reaction tube was charged with 7-iodo-N-(2-methylphenyl)-l-benzofuran-5-sulfonamide (90 mg, 0.2 mmol; Intermediate 58), Herrmann's catalyst (10 mg), dry THF (2.5 mL), 4 M aqueous ⁇ aOH (0.2 mL) and half of the above solution of in situ generated 3-(9-borabicyclo[3.3.1]non-9- ylmethyl)-pyrrolidine-l -carboxylic acid tert-butyl ester (1.1 mL, 0.3 mmol). The mixture was heated under microwave irradiation at 140 °C for 5 min. This reaction mixture and a similar mixture were combined, filtered and evaporated.
  • the ability of a compound according to the invention to bind to the human 5-HTg receptor, and to be pharmaceutically useful, can be determined using in vivo and in vitro assays known in the art.
  • HEK-293 cell line transfected with the human 5-HT6 receptor was cultured in
  • the cells were passaged 1:10, twice a week.
  • radioligand [ 3 H] LSD 60-240 Ci/mmol obtained from Amersham Pharmacia Biotech, (Buckinghamshire, England) was in ethanol and stored at -20°C. The compounds were dissolved in 100% DMSO and diluted with binding buffer.
  • Disposable Compounds were diluted in Costar 96 well N-bottom polypropylene plates (Corning Inc. Costar, ⁇ Y, USA). Samples were incubated in Packard Optiplate (Packard Instruments B.N., Groningen, The Netherlands). The total amount of added radioligand was measured in Packard 24-well Barex plates (Packard Instruments B.N., Groningen, The Netherlands) in the presence of MicroscintTM 20 scintillation fluid (Packard Bioscience, Meriden, CT, USA).
  • the binding buffer consisted of 20 mM HEPES, 150 mM NaCl, 10 mM MgCl , and
  • Membrane preparation Cells were grown to approximately 90% confluence on 24.5 x 24.5 mm culture dishes. The medium was aspirated, and after rinsing with ice-cold PBS, the cells were scraped off using 25 mL Tris buffer (50 mM Tris-HCl, 1 mM EDTA, 1 mM EGTA, pH 7.4) and a window scraper. The cells were then broken with a Polytron homogeniser, and remaining particulate matter was removed by low-speed centrifugation, lOOOx g for 5 min. Finally, the membranes were collected by high-speed centrifugation (20 OOOx g), suspended in binding buffer, and frozen in aliquots at -70°C.
  • Tris buffer 50 mM Tris-HCl, 1 mM EDTA, 1 mM EGTA, pH 7.4
  • window scraper The cells were then broken with a Polytron homogeniser, and remaining particulate matter was removed by low-speed centrifugation,
  • Radioligand binding Frozen cell membranes were thawed, immediately rehomogenized with a Polytron homogenizer, and coupled to SPA wheat germ agglutinin beads (Amersham Life Sciences, Cambridge, England) for 30 min under continuous shaking of the tubes. After coupling, the beads were centrifuged for 10 minutes at 1000 g, and subsequently suspended in 20 mL of binding buffer per 96- well plate The binding reaction was then initiated by adding radioligand and test compounds to the bead-membrane suspension. Following incubation at room temperature, the assay plates were subjected to scintillation counting. The original SPA method was followed except for that membranes were prepared from HEK293 cells expressing the human 5-HTg receptor instead of from HeLa cells
  • 5-HT caused a concentration dependent inhibition of [ 3 H]-LSD binding with an over all average Ki value of 236 nM when tested against two different membrane preparations.
  • the inter assay variability over three experiments showed a CN of 10% with an average K; values of 173 nM (SD 30) and a Hill coefficient of 0.94 (SD 0.09).
  • the intra assay variation was 3% (n 4). All unlabelled ligands displaced the specific binding of [ 3 H]-LSD in a concentration-dependent manner, albeit at different potencies.
  • the rank order of affinity for the 5-HT 6 receptor of reference compounds was methiothepin (Ki 2 nM) >mianserin (190 nM) ⁇ 5-HT (236 nM) >methysergide (482 nM) > mesulergine (1970 nM). Protein determination Protein concentrations were determined with BioRad Protein Assay (Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal. Biochem. 1976;72:248-54). Bovine serum albumin was used as standard.
  • IC 50 value i.e. the concentration of test compound that inhibited 50% of the specific binding of radioligand
  • K value was calculated using equation 2 [Cheng Y.C. Biochem. Pharmacol. 22, 3099-3108, 1973].
  • ICs Ki (equation 2)
  • HEK293/5-HT6 cells were seeded in polylysine coated 96-well plates at a density of 25,000 / well and grown in DMEM (Dulbecco's Modified Eagle Medium) (without phenol-red) containing 5% dialyzed Foetal Bovine Serum for 48 h at 37°C in a 5% CO 2 incubator.
  • DMEM Dulbecco's Modified Eagle Medium
  • the medium was then aspirated and replaced by 0.1 mL assay medium (Hanks Balance Salt Solution containing 20 mM HEPES, 1.5 mM isobutylmethylxanthine and 1 mg/mL bovine serum albumin). After addition of test substances, 50 ⁇ l dissolved in assay medium, the cells were incubated for 10 min at 37°C in a 5% CO 2 incubator. The medium was again aspirated and the cAMP content was determined using a radioactive cAMP kit (Amersham Pharmacia Biotech, BIOTRAK RPA559).
  • the compounds in accordance with the invention have a selective affinity to 5-HTg receptors with Kj and IC 5 o )COrr values between 0.5 nM and 5 ⁇ M or display a % inhibition of [ 3 H]-LSD > 20 % at 50 nM and are antagonists, agonists or partial agonists at 5-HT ⁇ .
  • the compounds show good selectivity over 5-HT la , 5-HTib, 5-HT2 a , 5-HT 2 b, 5-HT 2c .
  • the animals are housed singly in cages at 23+l°C, 40- 60 % humidity and have free access to water and standard laboratory chow.
  • the 12/12-h light/dark cycle is set to lights off at 5 p.m.
  • the animals are conditioned for at least one week before start of study.
  • the test compounds are dissolved in solvents suitable for each specific compound such as cyclodextrin, cyclodextrin/methane sulphonic acid, polyethylene glycol/methane sulphonic acid, saline. Fresh solutions are made for each study.
  • the minipumps are implanted subcutaneously in the neck/back region under short acting anesthesia (metofane/enflurane). This surgical procedure lasts approximately 5 min.
  • the weight of the food pellets are measured at 5 p.m. and at 8 p. m. for two days before (baseline) and one day after the implantation of the osmotic minipumps.
  • the weigh- in is performed with a computer assisted Mettler Toledo PR 5002 balance. Occasional spillage is corrected for.
  • the animals are killed by neck dislocation and trunk blood sampled for later analysis of plasma drug concentrations.
  • the plasma sample proteins are precipitated with methanol, centrifuged and the supernatant is transferred to HPLC vials and injected into the liquid chromatography /mass spectrometric system.
  • the mass spectrometer is set for electrospray positive ion mode and Multiple Reaction Monitoring.
  • a linear regression analysis of the standards forced through the origin is used to calculate the concentrations of the unknown samples.
  • Food consumption for 15 hours is measured for the three consecutive days and the percentage of basal level values is derived for each animal from the day before and after treatment. The values are expressed as mean + SD and ⁇ SEM from eight animals per dose group.
  • Statistical evaluation is performed by Kruskal-Wallis one-way ANONA using the , percent basal values. If statistical significance is reached at the level of p ⁇ 0.05, Mann- Whitney U-test for statistical comparison between control and treatment groups is performed.
  • the compounds according to the invention show an effect (i.e., reduction of food intake) in the range of 5-200 mg/kg/d.

Abstract

Cette invention se rapporte à des composés représentés par la formule (I) ; dans laquelle P, R3, W1 et W2 sont tels que décrits dans les pièces descriptives de la demande, à des compositions pharmaceutiques comprenant ces composés, à des procédés pour leur préparation, ainsi qu'à l'utilisation de ces composés dans la préparation d'un médicament contre les affections associées au récepteur de 5-HT6.
EP04809122A 2003-12-19 2004-12-20 Nouveaux derives de benzofurane, pouvant etre utilises dans la prophylaxie ou le traitement des affections associees au recepteur de 5-ht6 Withdrawn EP1694663A1 (fr)

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SE0303480A SE0303480D0 (sv) 2003-12-19 2003-12-19 Benzofuranes
US54965204P 2004-03-03 2004-03-03
PCT/SE2004/001949 WO2005058858A1 (fr) 2003-12-19 2004-12-20 Nouveaux derives de benzofurane, pouvant etre utilises dans la prophylaxie ou le traitement des affections associees au recepteur de 5-ht6

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WO2007108744A2 (fr) * 2006-03-17 2007-09-27 Astrazeneca Ab Nouvelles quinazolines modulatrices du 5-ht6
CA2666193A1 (fr) 2006-08-08 2008-02-14 Sanofi-Aventis Imidazolidin-2,4-dione arylaminoaryl-alkyl-substituee, son procede de fabrication, medicament contenant ce compose et son utilisation
JP5349306B2 (ja) 2006-08-21 2013-11-20 ジェネンテック， インコーポレイテッド アザベンゾチオフェニル化合物および使用方法
HU230761B1 (hu) * 2007-05-30 2018-03-28 Egis Gyógyszergyár Nyilvánosan Működő Részvénytársaság Új, szelektív 5HT6-receptorgátló benzofurán-származékok és eljárás előállításukra
KR20110028376A (ko) 2008-07-01 2011-03-17 제넨테크, 인크. Ｍｅｋ 키나제 억제제로서의 이소인돌론 유도체 및 사용 방법
AU2009266956B2 (en) 2008-07-01 2014-03-20 Genentech, Inc. Bicyclic heterocycles as MEK kinase inhibitors
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KR101308819B1 (ko) * 2008-09-17 2013-09-13 수벤 라이프 사이언시스 리미티드 아릴 술폰아미드 아민 화합물 및 5-ｈｔ6 리간드로서의 용도
WO2010068601A1 (fr) 2008-12-08 2010-06-17 Sanofi-Aventis Hydrate de fluoroglycoside hétéroaromatique cristallin, ses procédés de fabrication, ses procédés d'utilisation et compositions pharmaceutiques le contenant
DK2470552T3 (en) 2009-08-26 2014-02-17 Sanofi Sa NOVEL, CRYSTALLINE, heteroaromatic FLUORGLYCOSIDHYDRATER, MEDICINES COVERING THESE COMPOUNDS AND THEIR USE
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MX2012007253A (es) * 2009-12-22 2012-07-17 Cephalon Inc Derivados triciclicos y sus usos y composiciones farmaceuticas.
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EP2683698B1 (fr) 2011-03-08 2017-10-04 Sanofi Dérivés benzyl-oxathiazine substitués avec adamantane ou noradamantane, médicaments contenant ces composés et leur utilisation
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WO2012120055A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine di- et tri-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
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EA010298B1 (ru) 2008-08-29
AU2004299438A1 (en) 2005-06-30
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