WO2005014000A1 - Active substance combination comprising a compound with npy receptor affinity and a compound with 5-ht6 receptor affinity - Google Patents

Active substance combination comprising a compound with npy receptor affinity and a compound with 5-ht6 receptor affinity Download PDF

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Publication number
WO2005014000A1
WO2005014000A1 PCT/EP2004/008515 EP2004008515W WO2005014000A1 WO 2005014000 A1 WO2005014000 A1 WO 2005014000A1 EP 2004008515 W EP2004008515 W EP 2004008515W WO 2005014000 A1 WO2005014000 A1 WO 2005014000A1
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Prior art keywords
mono
optionally
substituted
benzo
oxazin
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PCT/EP2004/008515
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French (fr)
Inventor
Antoni Torrens Jover
Josep Mas Prio
Alberto Dordal Zueras
Xavier Codony Soler
Ramon Merce Vidal
Jose Aurelio Castrillo Perez
Jordi Frigola Constansa
Helmut-Heinrich Buschmann
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Laboratorios Del Dr. Esteve S.A.
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Application filed by Laboratorios Del Dr. Esteve S.A. filed Critical Laboratorios Del Dr. Esteve S.A.
Priority to DE602004016752T priority Critical patent/DE602004016752D1/en
Priority to EP04763612A priority patent/EP1648468B1/en
Priority to MXPA06001232A priority patent/MXPA06001232A/en
Priority to US10/566,100 priority patent/US20070059364A1/en
Priority to CA002534100A priority patent/CA2534100A1/en
Priority to AU2004262489A priority patent/AU2004262489A1/en
Publication of WO2005014000A1 publication Critical patent/WO2005014000A1/en
Priority to US13/361,625 priority patent/US20120128768A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/536—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines ortho- or peri-condensed with carbocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
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    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
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    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • 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
    • A61P25/08—Antiepileptics; Anticonvulsants
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • 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
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
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    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • Active substance combination comprising a compound with NPY receptor affinity and a compound with 5-HT6 receptor affinity
  • the present invention relates to an active substance combination comprising at least one compound with neuropeptide Y-receptor affinity, preferably neuropeptide Y5- receptor affinity, and at least one compound with 5-HT ⁇ receptor affinity, a medicament comprising said active substance combination, and the use of said active substance combination for the manufacture of a medicament.
  • the superfamily of serotonin receptors includes 7 classes (5-HT 5-HT ) encompassing 14 human subclasses [D. Hoyer, et al., Neuropharmacology, 1997, 36, 419].
  • the 5-HT 6 receptor is the latest serotonin receptor identified by molecular cloning both in rats [F.J. Monsma, et al., Mol. Pharmacol., 1993, 43, 320; M. Ruat, et al., Biochem. Biophys. Res. Commun., 1993, 193, 268] and in humans [R. Kohen, et al., J. Neurochem., 1996, 66, 47].
  • Compounds with 5-HT ⁇ receptor affinity are useful for the treatment of various disorders of the Central Nervous System and of the gastrointestinal tract, such as irritable intestine syndrome.
  • Compounds with 5-HT 6 receptor affinity are also useful in the treatment of 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.j- Br. J. Pharmacol. Suppl., 1999, 127, 22P; A. Bourson, et al., J. Pharmacol. Exp. Ther.
  • Food ingestion disorders are a serious, fast growing threat to the health of humans of all age groups, since they increase the risk of developing other serious, even life-threatening diseases such as diabetes or coronary diseases.
  • Neuropeptide Y (NPY), first isolated in porcine brain extracts (Tatemoto et. al. Nature 1982, 296, 659), is a 36-aminoacid peptide belonging to the family of pancreatic polypeptides, and is one of the most abundant peptides in the brain and in the central nervous system. In addition, NPY is also distributed in several parts of the peripheral nervous system.
  • NPY neuropeptide Y
  • NPY neuropeptide Y
  • NPY is a powerful stimulant of food ingestion.
  • appetite is significantly increased when NPY is injected directly into the CNS of satiated mice (Clark J. T. et. al. Endocrinology 1984, 115, 427; Levine A. S. et. al. Peptides 1984, 5, 1025; Stanley B. G. et. al. Life Sci. 1984, 35, 2635; Stanley B. G. et. al. Proc. Nat. Acad. Sci. USA 1985, 82, 3940).
  • NPY may play a role in cognitive function regulation, e. g. memory (Flood J. F. et. al. Brain Res. 1987, 421 , 280; Redrobe J. P. et. Al. Brain Res. 1999, 848, 153), and be active in anxiety (Hobos M. et. al. Reg. Peptides 1992, 41 , 61) and depression (Hobos M. et. al. Eur. J. Pharmacol. 1988, 147, 465) processes.
  • NPY neuropeptide NPY is also distributed in the peripheral system. Some studies suggest that it might be involved in hypertensive (Michel M. C: et. al. J. Hypertens. 1995, 13, 385), and analgesic (Gehlert D. R. Life Sci. 1994, 55, 551) processes, among others.
  • NPY-binding receptors The endogenous proteins that constitute NPY-binding receptors have been widely studied. Several have been cloned and expressed. At present, six different receptor subtypes, named Y1 to Y6, are recognized (Hispkind P. A. et. al. Annu. Rep. Med. Chem. 1996, 31 , 1 ; Grundemar L. et. al. TIPS Reviews., 15, 153, 1994). Each NPY receptor subtype is generally associated to a different biological activity. For example, Y2 receptor is involved in the induction of convulsions in rats (Dumont Y. et. al. Brit. J. Pharmacol. 2000, 129, 1075).
  • Y5 The most recently identified receptor is Y5 (Hu et. al. J. Biol. Chem. 1996, 271 , 26315). There is evidence that Y5 receptor has a unique pharmacological profile related to food ingestion as compared to the other receptor subtypes.
  • [D-Trp 32 ]NPY peptide a selective Y5-receptor agonist with no affinity for Y1 receptor, stimulates food ingestion in rats (Gerald C. et. al. Nature, 1996, 382, 168), supports the hypothesis that Y5 receptor is related to exaggerated food consumption.
  • compounds having an affinity to the Y5 receptor should be effective to inhibit food ingestion and very useful to control diseases like obesity or other disorders of food ingestion (food intake), such as anorexia, bulimia, cachexia or type II diabetes. Moreover, it has been suggested that such compounds are useful to control diseases such as arthritis or epilepsy.
  • known compounds with NPY-receptor affinity and known compounds with 5-HT 6 receptor affinity are generally effective for treating disorders related to NPY- receptors and to 5-HT 6 receptors respectively, in some instances they show undesirable side effects.
  • the active substance combination of the present invention may comprise as a component (A) at least one compound with neuropeptide Y5 (NPY ⁇ )-receptor affinity.
  • A at least one compound with neuropeptide Y5 (NPY ⁇ )-receptor affinity.
  • the active substance combination of the present invention may comprise as a component (A) at least one compound with neuropeptide Y (NPY)-receptor affinity, preferably with neuropeptide Y5 (NPY5)-receptor affinity, which is selected form the group consisting of the 1 ,4-disubstituted piperidine compounds of general formula (la), ,
  • R 5a represents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical or a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic radical,
  • R 6a , R 7a , R 8a , R 9a are each independently selected from the group consisting of hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic radical, a cyano and a -COOR 17a moiety,
  • A represents a bridge member -CHR 18a - or -CHR 18a -CH 2 -,
  • R 10a represents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ringsystem, or an optionally at least mono-substituted aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,
  • R 11a represents an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic radical, which may be bonded via an optionally at least mono- substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ringsystem, or an optionally at least mono substituted aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ringsystem, or
  • R 10a and R 11a together with the bridging nitrogen atom form an optionally at least mono-substituted, saturated, unsaturated or aromatic heterocyclic ring that may contain at least one further heteroatom as a ring member and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ringsystem,
  • R 12a represents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, or an optionally at least mono-substituted aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,
  • R 13a represents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, or an optionally at least mono-substituted aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,
  • R 14a represents an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic radical, which may be bonded via an optionally at least mono- substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, or an optionally at least mono- substituted aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,
  • R 15a and R 16a are each independently selected from the group consisting of hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic radical, which may be bonded via an optionally at least mono- substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, or an optionally at least mono- substituted aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,
  • R 15a and R 16a together with the bridging nitrogen atom form a saturated, unsaturated or aromatic heterocyclic ring, which may be at least mono-substituted and/or contain at least one further heteroatom as ring member,
  • R 17a represents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic radical or an optionally at least mono-substituted aryl- or heteroaryl radical, which may be bonded via an optionally at least mono- substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,
  • R 18a represents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic radical or an optionally at least mono-substituted aryl- or heteroaryl radical, which may be bonded via an optionally at least mono- substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,
  • stereoisomers optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or physiologically acceptable salts thereof, or solvates, respectively.
  • a mono- or polycyclic ring-system means a mono- or polycyclic hydrocarbon ring-system that may be saturated, unsaturated or aromatic. If the ring system is polycyclic, each of its different rings may show a different degree of saturation, i.e. it may be saturated, unsaturated or aromatic. Optionally each of the rings of the mono- or polycyclic ring system may contain one or more heteroatoms as ring members, which may be identical or different and which can preferably be selected from the group consisting of N, O, S and P, more preferably be selected from the group consisting of N, O and S. Preferably the polycyclic ring-system may comprise two rings that are condensed. The rings of the mono- or polycyclic ring-sytem are prefarably 5- or 6-membered.
  • each of these substituents may preferably be selected from the group consisting of hydroxy, halogen, branched or unbranched C- ⁇ - 4 -alkoxy, branched or unbranched C 1 - 4 - perfluoroalkoxy, branched or unbranched C ⁇ - 4 -perfluoroalkyl, amino, carboxy, amido, cyano, nitro, -SO 2 NH 2 , -CO-C ⁇ -alkyl, -SO-C ⁇ _ 4 -alkyl, -S0 2 -Ci- 4 -alkyl, -NH-SOa-C ⁇ -
  • each of these substituents may preferably be selected from the group consisting of hydroxy, halogen, branched or unbranched C ⁇ - 4 -alkyl, branched or unbranched C 1 - 4 - alkoxy, branched or unbranched C- -perfluoroalkoxy, phenoxy, benzoyl, cyclohexyl, branched or unbranched C- ⁇ - 4 -perfluoroalkyl, -NR Aa R Ba wherein R Aa , R Ba are each independently selected from the group consisting of H, a branched or unbranched C-i- 4 -alkyl-radical, -CH 2 -CH2-OH and phenyl, carboxy, amido, cyano, nitro, -SO2NH 2 , - CO-C
  • each of these substituents may preferably be selected from the group consisting of hydroxy, halogen, branched or unbranched C- ⁇ - 4 -alkoxy, branched or unbranched C 1 - 4 - perfluoroalkoxy, branched or unbranched C- -perfluoroalkyl, amino, carboxy, amido, cyano, nitro, -SO 2 NH 2 , -CO-Ci- 4 -alkyl, -SO-C ⁇ - 4 -alkyl, -S0 2 -Ci- 4 -alkyl, -NH-SO 2 -C 1 - 4 - alkyl, wherein C- ⁇ - 4 -alkyl may be branched or unbranched, an unsubstituted or at least mono-sub
  • each of these substituents may preferably be selected from the group consisting of hydroxy, halogen, branched or unbranched C ⁇ - 4 -alkyl, branched or unbranched C- ⁇ -4-alkoxy, branched or unbranched C- ⁇ - 4 -perfluoroalkoxy, branched or unbranched C ⁇ - 4 -perfluoroalkyl, amino, carboxy, amido, cyano, keto, nitro, -SO 2 NH 2 , - CO-Ci- 4 -alkyl, -SO-d- 4 -alkyl, -S0 2 -C 1 - 4 -alkyl, -NH-S0 2 -C 1 - 4 -alkyl, wherein C ⁇ -alkyl may
  • any one of the above mentioned substitutents itself is at least mono-substituted, said substituents may preferably be selected from the group consisting of F, Cl, methyl and methoxy. If one or more of the residues R 1a -R 4a and R 10a -R 18a represents or comprises an aryl radical, which is substituted by one or more substituents, unless defined otherwise, each of these substituents may preferably be selected from the group consisting of hydroxy, halogen, branched or unbranched C- ⁇ - 4 -alkoxy, branched or unbranched C-j.
  • R Aa , R Ba are each independently selected from the group consisting of H, a branched or unbranched C-i- 4-alkyl-radical, -CH 2 -CH 2 -OH and phenyl, carboxy, amido, cyano, -CH(OH)(phenyl), nitro, -SO 2 NH 2 , -CO-d- 4 -alkyl, -CO-Od- 4 -alkyl, -SO-C ⁇ - 4 -alkyl, -S0 2 -C 1 .
  • C ⁇ - -alkyl may be branched or unbranched, an unsubstituted or at least mono-substituted phenyl or naphthyl radical and unsubstituted or at least mono-substituted furanyl-, thienyl-, pyrrolyl-, imidazolyl-, pyrazolyl-, pyridinyl-, pyrimidinyl-, quinolinyl- and isoquinolinyl radical, more preferably be selected from the group consisting of hydroxy, F, Cl, Br, methyl, ethyl, cyano, -CH(OH)(phenyl), methoxy, ethoxy, unsubstituted or at least mono-substituted benzoyl, unsubstituted or at least mono-substituted phenoxy, cyclohex
  • each of these substituents may preferably be selected from the group consisting of hydroxy, halogen, branched or unbranched C ⁇ - 4 -alkoxy, branched or unbranched C ⁇ - 4 -alkyl, branched or unbranched Ci- 4 -perfluoroalkoxy, unsubstituted or at least mono-substituted phenoxy, unsubstituted or at least mono-substituted benzoyl, cyclohexyl, branched or unbranched C- ⁇ - 4 -perfluoroalkyl, NR Aa R Ba wherein R Aa , R Ba are each independently selected from the group consisting of H, a branched or unbranched C ⁇ - 4 -alkyl-radical, -CH 2
  • 4 -alkyl may be branched or unbranched, an unsubstituted or at least mono-substituted phenyl or naphthyl radical and an unsubstituted or, at least mono-substituted furanyl-, thienyl-, pyrrolyl-, imidazolyl-, pyrazolyl-, pyridinyl-, pyrimidinyl-, quinolinyl- and isoquinolinyl radical, more preferably be selected from the group consisting of hydroxy, F, Cl, Br, methyl, ethyl, cyano, methoxy, ethoxy, unsubstituted or at least mono-substituted benzoyl, unsubstituted or at least mono-substituted phenoxy, cyclohexyl, CF 3 , - CH(OH)(phenyl), -CO-CH 3 , -CO-OCH 3 , -
  • each of these substituents may preferably be selected from the group consisting of hydroxy, halogen, branched or unbranched C- ⁇ - 4 -alkoxy, branched or unbranched C ⁇ - 4 -alkyl, branched or unbranched C ⁇ - 4 -perfluoroalkoxy, branched or unbranched C ⁇ - 4 -perfluoroalkyl, amino, carboxy, amido, cyano, nitro, -S0 2 NH 2 , -CO-C 1 .
  • C ⁇ - 4 -alkyl may be branched or unbranched, an unsubstituted or at least mono-substituted phenyl or naphthyl radical and an unsubstituted or at least mono-substituted furanyl-, thienyl-, pyrrolyl-, imidazolyl-, pyrazolyl-, pyridinyl-, pyrimidinyl-, quinolinyl- and isoquinolinyl radical, more preferably be selected from the group consisting of hydroxy, F, Cl, Br, methoxy, ethoxy, methyl, CF 3 and an unsubstituted phenyl radical. If any of the above mentioned substitutents itself is at least mono-sub
  • each of these heteroatoms may preferably be selected from the group consisting of N, O and S, more preferably from the group consisting of N and O.
  • residues R 1a -R 18a represents or comprises a cycloaliphatic radical, which contains one or more heteroatoms as ring members, unless defined otherwise, each of these heteroatoms may preferably be selected from the group consisting of N, O, S and P, more preferably from the group consisting of N, O and S.
  • each of these heteroatoms may preferably be selected from the group consisting of N, O, S and P, more preferably from the group consisting of N, O and S.
  • Preferred compounds of general formula (la) are those, wherein R 1a , R 2a , R 3a , R 4a are each independently selected from the group consisting of H, F, Cl, Br, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C- ⁇ - 6 - aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing C 3 - 8 -cycloaliphatic radical, which may be bonded via an optionally at least mono-substituted C-i- 6 - alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, an optionally at least mono-substituted, 5- or 6- membered aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted C- ⁇ - 6 -alkylene
  • R 5a represents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C ⁇ - 6 -aliphatic radical or a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing C3-8-cycloaliphatic radical,
  • R 6a , R 7a , R 8a , R 9a are each independently selected from the group consisting of hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C ⁇ - 6 -aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing C 3 . 8 - cycloaliphatic radical, a cyano and a COOR 17a moiety,
  • a a represents a bridge member -CHR 18a - or -CHR 18a -CH 2 -,
  • R 10a represents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C- ⁇ - 6 -aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing C 3 . 8 -cycloaliphatic radical or an optionally at least mono- substituted, 5- or 6-membered aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted C- ⁇ - 6 -alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,
  • R 11a represents an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C- ⁇ - 6 -aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing C3- 8 -cycloaliphatic radical, which may be bonded via an optionally at least mono- substituted C-i- 6 -alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ringsystem, or an optionally at least mono substituted 5- or 6-membered aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted d- ⁇ -alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ringsystem, or
  • R 10a and R 11a together with the bridging nitrogen atom form an optionally at least mono-substituted, saturated, unsaturated or aromatic, 5- or 6-membered heterocyclic ring, which may contain at least one further heteroatom as a ring member and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ringsystem,
  • R 12a represents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C- ⁇ - 6 -aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom containing as ring member C 3 - 8 -cycloaliphatic radical, which may be bonded via an optionally at least mono-substituted Ci- ⁇ -alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, or an optionally at least mono-substituted, 5- or 6-membered aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted C ⁇ - 6 -alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring- system,
  • R 13a represents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C-
  • R 14a represents an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C- ⁇ - 6 -aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing C 3 .
  • R 15a and R 16a each are independently selected from the group consisting of hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C ⁇ - 6 -aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing C 3 .
  • R 15a and R 16a together with the bridging nitrogen atom form a saturated, unsaturated or aromatic, 5- or 6-membered heterocyclic ring, which may be at least mono-substituted and/or contain at least one further heteroatom as a ring member,
  • R 17a represents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C ⁇ - 6 -aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing C 3 - 8 -cycloaliphatic radical or an optionally at least mono- substituted, 5- or 6- membered aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted C- ⁇ - 6 -alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,
  • R 18a represents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C- ⁇ - 6 -aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing C- 3 - 8 -cycloaliphatic radical or an optionally at least mono- substituted, 5- or 6-membered aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted C ⁇ - 6 -alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,
  • stereoisomers optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or physiologically acceptable salts thereof, or solvates, respectively.
  • R 5a represents H or a branched or unbranched C ⁇ - 3 -alkyl radical, preferably H, CH 3 or CH2CH 3
  • R 6a -R 18a and A a have the meaning given above, optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or physiologically acceptable salts thereof, or solvates, respectively.
  • R 6a , R 7a , R 8a , R 9a are each independently selected from the group consisting of H, a branched or unbranched C-
  • R 10a represents hydrogen or a branched or unbranched C ⁇ - 4 -alkyl radical
  • the remaining residues R 11a -R 18a and A a have the meaning given above, optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or physiologically acceptable salts thereof, or solvates, respectively.
  • R Aa , R Ba are each independently selected from the group consisting of H, a branched or unbranched C- ⁇ - 4 -alkyl-radical, -CH 2 -CH 2 -OH and an unsubstituted phenyl radical,
  • n 1 or 2
  • X represents CH or N
  • R c is H or a branched or unbranched d- 4 -alkyl radical
  • R D is H or a branched or unbranched C- ⁇ - -alkyl radical and a group of general formula (E),
  • R E represents H, a branched or unbranched C- ⁇ - 4 -alkyl radical or a branched or unbranched C ⁇ -4-alkoxy radical
  • R 10a and R 11a together with the bridging nitrogen atom form a saturated, 6-membered heterocyclic ring, which is at least mono-substituted with a methyl radical and/or condensed with an unsubstituted or at least mono-substituted phenyl- or cyclohexyl- radical, said phenyl- or cyclohexyl-radical preferably being at least mono-substituted with F and/or OCH 3 , and the remaining residues R 12a -R 18a and A a have the meaning given above, optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or physiologically acceptable salts thereof, or solvates, respectively.
  • R 12a represents H, a C ⁇ - 4 -alkyl radical, a cyclohexyl radical or a phenyl radical, preferably H, CH 3 , C 2 H 5 or a phenyl radical
  • R 13a -R 18a and A a have the meaning given above, optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or physiologically acceptable salts thereof, or solvates, respectively.
  • R 13a represents H, a C ⁇ - 4 -alkyl radical, cyclohexyl or a phenyl radical, preferably H, CH 3 , C 2 H 5 or phenyl
  • R 14a -R 18a and A a have the meaning given above, optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or physiologically acceptable salts thereof, or solvates, respectively.
  • R 14a represents H, a C- ⁇ - 4 -alkyl radical, cyclohexyl or a phenyl radical, preferably H, CH 3 , C 2 H 5 or phenyl
  • the remaining residues R 15a -R 18a and A a have the meaning given above, optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or physiologically acceptable salts thereof, or solvates, respectively.
  • R 15a and R 16a are each independently selected from the group consisting of H, a C ⁇ - 4 -alkyl radical, cyclohexyl and a phenyl radical, preferably from the group consisting of H, CH 3 , C 2 H 5 and phenyl, and the remaining residues R 17a and R 18a and A a have the meaning given above, optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or physiologically acceptable salts thereof, or solvates, respectively.
  • R 17a represents H, a C ⁇ - 4 -alkyl radical, cyclohexyl or a phenyl radical, preferably H, CH 3 , C- 2 H 5 or phenyl
  • the remaining residues R 18a and A a have the meaning given above, optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or physiologically acceptable salts thereof, or solvates, respectively.
  • R 18a represents H, a C ⁇ - 4 -alkyl radical or a phenyl radical, preferably H, CH 3 or phenyl, and the remaining residue A has the meaning given above, optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or physiologically acceptable salts thereof, or solvates, respectively.
  • R 5a is CH 3 or C 2 H 5
  • R 6a -R 18a and A a have the meaning given above, optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or physiologically acceptable salts thereof, or solvates, respectively.
  • benzoxazinone-derived compounds of general formula (la), wherein R 1a -R 11a and A a have the meaning given above, may be prepared preferably by reaction of one compound of general formula (Ila),
  • R 10a and R 11a have the meaning given above, with at least one compound of general formula (Ilia),
  • a a has the meaning given above, F a represents halogen, hydroxy or an O-acyl group and G a represents halogen, preferably chlorine.
  • the reaction occurs in inert solvents and in the presence of a base or/and auxiliary agents, resulting in compounds of general formula (IVa)
  • R 1a to R 9a have the meaning as definded above, in a suitable reaction medium and in the presence of base and/or auxiliary agents when it is necessary.
  • R >1a + to-- ⁇ R->11a and A have the meaning as given above.
  • Suitable reaction media are e.g. organic solvents, such as ethers, preferably diethyl ether, dioxane, tetrahydrofurane, dimethyl glycol ether, or alcohols, e.g. methanol, ethanol, propanol, isopropanol, butanol, isobutanol, tert-butanol, or hydrocarbons, preferably benzene, toluene, xylene, hexane, cyclohexane, petroleum ether, or halogenated hydrocarbons, e.g.
  • organic solvents such as ethers, preferably diethyl ether, dioxane, tetrahydrofurane, dimethyl glycol ether, or alcohols, e.g. methanol, ethanol, propanol, isopropanol, butanol, isobutanol, tert-butanol, or hydrocarbons,
  • sodium hydroxyde or potassium hydroxyde or obtained from other metals such as barium hydroxyde or different carbonates, preferably potassium carbonate, sodium carbonate, calcium carbonate, or alkoxides, e.g. sodium methoxide, potassium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide or potassium tert-butoxide, or organic amines, preferably triethylamine, diisopropyethylamine or heterocycles, e.g.
  • bases may be used for the process as auxiliary agents, when appropriate.
  • suitable auxiliary agents for the above mentioned reactions are, for example, dehydrating agents like carbodiimides, e.g. diisopropylcarbodiimide, cyclohexylcarbodiimide or N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride, or carbonylic compounds, e.g. carbonyldiimidazol or compounds like isobutylchloroformiate or methansulfonyl chloride, among others.
  • These reagents are generally used in an amount comprised between 0.5 and 3 mol versus 1 mol of the corresponding carboxylic acids.
  • bases are generally used in an amount comprised between 0.05 and 10 mol versus 1 mol of the compounds of the invention.
  • the protection of sensitive groups or of reagents may be necessary and/or desirable. This can be performed by using conventional protective groups like 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 eliminated in the convenient later stage by means of methods well-known to those skilled in the art.
  • the compounds of general formulas (Ila), (Ilia), (IVa) and (Va) are either commercially available or can be produced according to methods known to those skilled in the art.
  • the reaction of a compound of formula (IVa) with a compound of formula (Va) yield a benzoxazinone-derived compound of general formula (la) using conventional methods known to those skilled in the art.
  • the substituted benzoxazinone compounds of general formula (Va), wherein R 5a represents H, are preferably synthesized from substituted anthranilic acid or esters thereof by reduction to the corresponding benzylalcohol (see scheme 2, method A).
  • R 5a represents H
  • the benzoxazinone-ring is formed by cyclisation with triphosgene, a treatment in acidic media allows the elimination the protecting group of the piperidine according to the method described in Williams et al., J. Med. Chem. 1995 38, 4634 and later by Bell et al., J. Med.
  • R 5a substituted 2-amino- benzylalcohols are obtained, intermediates which allow, via the same previous synthetic process, to obtain compounds of general formula (la), wherein R 5a may be an unbranched or branched, saturated or unsaturated, optionally at least mono- substituted aliphatic radical, optionally may contain at least an heteroatom as ring member of a cycloaliphatic ring or alkyl (denoted by Z in the method B)
  • the compounds of general formula (IVa) are commercially available or may be produced according to scheme 1 by conventional methods known to those skilled in the art. Essentially the respective compound of general formula (Ila) is reacted with chloroacetyl chloride or the respective compound of general formula (Ilia) in the presence of an organic reaction medium, preferably dichloromethane and a base, preferably triethylamine and/or diisopropylethylamine.
  • an organic reaction medium preferably dichloromethane and a base, preferably triethylamine and/or diisopropylethylamine.
  • the salts of benzoxazinone-derived compounds of general formula (la), wherein R 1a - R 11a and A a have the meaning as definded above, may be prepared in a way that at least one compound of general formula (la) having at least one basic group is reacted with an inorganic or organic acid, preferably in the presence of a suitable reaction medium.
  • Suitable reaction media are the ones given above.
  • Suitable inorganic acids are for example hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, nitric acid
  • suitable organic acids are e.g. citric acid, maleic acid, fumaric acid, tartaric acid, or derivatives thereof, such as p-toluenesulfonic acid, methanesulfonic acid or camphersulfonic acid.
  • the salts of benzoxazinone-derived compounds of general formula (la), wherein R 1a - R 11a and A a have the meaning as definded above, may be prepared in a way that at least one compound of general formula (la) having at least one acidic group is reacted with one or more suitable bases, preferably in the presence of a suitable reaction medium.
  • suitable bases are e.g. hydroxides, carbonates or alkoxides, which include suitable cations, derived e.g. from alkaline metals, alkaline earth metals or organic cations, e.g. [NH n R4- n ] + > wherein n is 0, 1 , 2, 3 or 4 and R represents a branched or unbranched C ⁇ - 4 -alkyl-radical.
  • Solvates, preferably hydrates, of the Benzoxazinone-derived compounds of general formula (la) may also be obtained by standard procedures known to those skilled in the art.
  • Benzoxazinone-derived compounds of general formula (la) are obtained in form of a mixture of stereoisomers, particularly enantiomers or diastereomers, said mixtures may be separated by standard procedures known to those skilled in the art, e.g. chromatographic methods or crystallization with chiral reagents.
  • Benzoxazinone-derived compounds of general formula (la) or a corresponding stereoisomer, or salt, or solvate respectively, if required may be carried out by conventional methods known to those skilled in the art, e.g. chromatographic methods or recrystallization.
  • the active substance combination of the present invention may comprise as a component (B) at least one compound with 5-HT 6 receptor affinity, which is selected form the group consisting of the benzoxazinone-derived sulfonamide compounds of general formula (lb),
  • R 1b , R 2b , R 3b , R 4b are each independently selected from the group consisting of hydrogen, halogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic radical, which may be bonded via an optionally at least mono- substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, an optionally at least mono- substituted aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ringsystem, a nitro group, a cyano group, - OR 10b , -0(
  • R 6b , R 7b , R 8b , R 9b are each independently selected from the group consisting of hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic radical, a cyano group and a COOR 15b moiety,
  • W b represents an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical
  • an optionally at least mono-substituted aryl or heteroaryl radical which may be bonded via an optionally mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system
  • R 10b represents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, or an optionally at least mono-substituted aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,
  • R 11b represents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, or an optionally at least mono-substituted aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,
  • R 12b represents an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic radical, which may be bonded via an optionally at least mono- substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, or an optionally at least mono- substituted aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,
  • R 13b and R 14b each are independently selected from the group consisting of hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic radical, which may be bonded via an optionally at least mono- substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, or an optionally at least mono- substituted aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, or R 13b and R 14b together with the bridging nitrogen atom form a saturated, unsaturated or aromatic heterocyclic ring, which may be at
  • R 15b represents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic radical or an optionally at least mono-substituted aryl- or heteroaryl radical, which may be bonded via an optionally at least mono- substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,
  • R 16b represents an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical
  • R 17b represents an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical
  • R 18b represents an optionally at least mono-substituted aryl radical
  • R 1c represents hydrogen, an optionally at least mono-substituted, linear or branched alkyl radical, an optionally at least mono-substituted phenyl radical or an optionally at least mono-substituted benzyl radical,
  • R 2c represents a -NR c R 5c moiety or a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic radical, which may be condensed with a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing mono- or bicyclic cycloaliphatic ringsystem,
  • R 3c represents hydrogen or an optionally at least mono-substituted, linear or branched alkyl radical
  • R 4c and R 5c identical or different, represent hydrogen or an optionally at least mono- substituted, linear or branched alkyl radical, or R 4c and R 5c together with the bridging nitrogen atom form an optionally at least mono- substituted, saturated or unsaturated heterocyclic ring, which may contain at least one further heteroatom as a ring member and/or may be condensed with a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing mono- or bicyclic cycloaliphatic ringsystem,
  • a c represents an optionally at least mono-substituted mono- or polycyclic aromatic ringsystem, which may be bonded via an optionally at least mono-substituted alkylene group, an optionally at least mono-substituted alkenylene group or an optionally at least mono-substituted alkynylene group and/or may contain at least one heteroatom as a ring member in one or more of its rings,
  • nc 0, 1 , 2, 3 or 4;
  • R 1d represents a -NR 8d R 9d radical or a saturated or unsaturated, optionally at least mono-substituted cycloaliphatic radical, which may 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, optionally at least one heteroatom as a ring member containing mono- or bicyclic cycloaliphatic ring system,
  • R 2d , R 3d , R 5d , R 6d and R 7d 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 radical or an optionally at least mono-substituted heteroaryl radical,
  • R 4d is hydrogen or a saturated or unsaturated, linear or branched, optionally at least mono-substituted aliphatic radical
  • R 8d and R 9d identical or different, each represent hydrogen or a saturated or unsaturated, linear or branched, optionally at least mono-substituted aliphatic radical,
  • R 8d and R 9d together with 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 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 d 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,
  • nd is O, 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, and
  • R 1e represents a -NR 8e R 9e 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 2e , R 3e , R 4e , R 6e and R 7e 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 radical or an optionally at least mono-substituted heteroaryl radical,
  • R represents hydrogen or a saturated or unsaturated, linear or branched, optionally at least mono-substituted aliphatic radical
  • R 8e and R 9e identical or different, each represent hydrogen or a saturated or unsaturated, linear or branched, optionally at least mono-substituted aliphatic radical
  • R 8e and R 9e 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 e 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
  • ne is O, 1 , 2, 3 or 4;
  • R 1f represents a -NR 8f R 9f radical or a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as a ring member containing cycloaliphatic radical, which may be condensed with a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as a ring member containing mono- or bicyclic cycloaliphatic ring system,
  • R 2f , R 3f , R 4f , R 5f and R 7f 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 radical or optionally at least mono-substituted heteroaryl radical,
  • R 6f represents hydrogen or a saturated or unsaturated, linear or branched, optionally at least mono-substituted aliphatic radical
  • R 8f and R 9f identical or different, each represent hydrogen or a saturated or unsaturated, linear or branched, optionally at least mono-substituted aliphatic radical,
  • R 8f and R 9f 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 may be condensed with a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as a ring member containing mono- or bicyclic cycloaliphatic ring system,
  • a f 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,
  • nf O, 1 , 2, 3 or 4;
  • R 1g is a -NR 8g R 9g 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 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 2g , R 3g , R 4g , R 5g and R 6g 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 radical or an optionally at least mono-substituted heteroaryl radical,
  • R 7g represents hydrogen or a saturated or unsaturated, linear or branched, optionally at least mono-substituted aliphatic radical
  • R 8g and R 9g identical or different, represent hydrogen or a saturated or unsaturated, linear or branched, optionally at least mono-substituted aliphatic radical,
  • R 8g and R 9g 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 g 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,
  • ng is O, 1 , 2, 3 or 4; optionally in the form of one of its stereoisomers, preferably enantiomers or diastereomers, its racemate or in the form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, at any mixture ratio, or a corresponding, physiologically acceptable salt, or a corresponding solvate,
  • R h represents a -NR 7h R 8h radical or a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as a ring member containing cycloaliphatic radical, which may be condensed with a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as a ring member containing mono- or bicyclic cycloaliphatic ring system,
  • R 2h , R 3h , R 4h , R 5h and R 6h identical or different, each represent hydrogen, halogen, cyano, nitro, a saturated or unsaturated, linear or branched aliphatic radical, a linear or branched alkoxy radical, a linear or branched alkylthio radical, hydroxy, trifluoromethyl, a saturated or unsaturated cycloaliphatic radical, an alkylcarbonyl radical, a phenylcarbonyl or a -NR 9h R 10h group,
  • R 7h and R 8h identical or different, each represent hydrogen or a saturated or unsaturated, optionally at least mono-substituted linear or branched aliphatic radical, or
  • R 7h and R 8h together with the bridging nitrogen atom form a saturated or unsaturated, optionally at least mono-substituted, optionally at least one further heteroatom as a ring member containing heterocyclic ring which may be condensed with a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as a ring member containing mono- or bicyclic cycloaliphatic ring system,
  • R 9h and R 10h identical or different, each represent hydrogen or a saturated or unsaturated, linear or branched, optionally at least mono-substituted aliphatic radical,
  • R 9h and R 10h together with the bridging nitrogen atom form a saturated or unsaturated, optionally at least mono-substituted, optionally at least one further heteroatom as a ring member containing heterocyclic ring which may be condensed with a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as a ring member containing mono- or bicyclic cycloaliphatic ring system,
  • a h and B h identical or different, each represent a saturated or unsaturated, linear or branched, optionally at least mono-substituted aliphatic radical
  • a h and B h together with the carbon atom to which they are bonded, form a saturated or unsaturated, but not aromatic, optionally at least mono-substituted cycloalkyl ring,
  • nh is O, 1 , 2, 3, or 4, 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.
  • the active substance combination according to the present invention may comprise one or more compounds of one class of active substances with 5-HT_ receptor affinity or one or more compounds of one or more classes of active substances with 5-HT ⁇ receptor affinity.
  • each of these substituents may preferably be selected from the group consisting of hydroxy, halogen, branched or unbranched C- ⁇ - 4 -alkoxy, branched or unbranched C- ⁇ - 4 -perfluoroalkoxy, branched or unbranched C- -perfluoroalkyl, amino, carboxy, amido, cyano, nitro, -S0 2 NH 2 , -CO-C- ⁇ - 4 -alkyl, -SO-C ⁇ - -alkyl, -S0 2 -Ci- -alkyl, -NH-SO 2 -C ⁇ - 4 -alkyl , wherein the C- M -alkyl may in each case be branched or unbranched, an unsubstituted or at least mono-substit
  • each of these substituents may preferably be selected from the group consisting of hydroxy, halogen, branched or unbranched C- M -alkyl, branched or unbranched C 1 - 4 - alkoxy, branched or unbranched Ci- 4 -perfluoroalkoxy, phenoxy, benzoyl, cyclohexyl, branched or unbranched C ⁇ - 4 -perfluoroalkyl, -NR Ab R Bb wherein R Ab , R Bb are each independently selected from the group consisting of H, a branched or unbranched Ci- 4 -alkyl-radical, -CH 2 -CH 2 -OH and phenyl, carboxy, keto, amido, cyano, nitro, - SO 2 NH 2 , -CO
  • C ⁇ - 4 -alkyl wherein C ⁇ - 4 -alkyl may in each case be branched or unbranched, unsubstituted or at least mono-substituted phenyl or naphthyl and unsubstituted or at least mono-substituted furanyl-, thienyl-, pyrrolyl-, imidazolyl-, pyrazolyl-, pyridinyl-, pyrimidinyl-, quinolinyl- and isoquinolinyl radical, more preferably be selected from the group consisting of hydroxy, F, Cl, Br, methyl, ethyl, methoxy, ethoxy, keto, benzoyl, phenoxy, cyclohexyl, -CF 3 , -CO-CH 3 , -CO-OCH 3 , -NR Ab R Bb wherein R Ab , R Bb are each independently selected from the group consisting of H, a branched
  • each of these substituents may preferably be selected from the group consisting of hydroxy, halogen, branched or unbranched C ⁇ - 4 -alkoxy, branched or unbranched Ci.
  • C- M -alkyl may be branched or unbranched, an unsubstituted or at least mono-substituted phenyl or naphthyl radical and an unsubstituted or at least mono-substituted furanyl-, thienyl-, pyrrolyl-, imidazolyl-, pyrazolyl-, pyridinyl-, pyrimidinyl-, quinolinyl- and isoquinolin
  • each of these substituents may preferably be selected from the group consisting of hydroxy, halogen, branched or unbranched C- M -alkyl, branched or unbranched C- ⁇ - 4 -alkoxy, branched or unbranched Ci_ 4 -perfluoroalkoxy, branched or unbranched C ⁇ - 4 -perfluorocarbonyl, branched or unbranched C- -perfluoroalkyl, amino, carboxy, amido, cyano, keto, nitro, -SO2NH 2 , -CO-C- M -alkyl, -SO-C ⁇ - 4 -alkyl, - SO 2 -C- ⁇ - 4 -alkyl, -NH-S0 2 -C- ⁇ - ⁇ -
  • each of these substituents may preferably be selected from the group consisting of hydroxy, halogen, branched or unbranched C- ⁇ _ 4 -alkoxy, branched or unbranched C ⁇ - -alkyl, branched or unbranched C ⁇ - 4 -perfluoroalkoxy, unsubstituted or at least mono-substituted phenoxy, unsubstituted or at least mono-substituted benzoyl, cyclohexyl, branched or unbranched C ⁇ - 4 -perfluoroalkyl, NR Ab R B wherein R Ab , R Bb are each independently selected from the group consisting of H, a branched or unbranched d- 4 -alkyl-radical, -
  • an unsubstituted or at least mono-substituted phenyl or naphthyl radical and unsubstituted or at least mono-substituted furanyl-, thienyl-, pyrrolyl-, imidazolyl-, pyrazolyl-, pyridinyl-, pyrimidinyl-, quinolinyl- and isoquinolinyl radical more preferably be selected from the group consisting of hydroxy, F, Cl, Br, methyl, ethyl, cyano, nitro, -CH(OH)(phenyl), methoxy, ethoxy, unsubstituted or at least mono- substituted benzoyl, unsubstituted or at least mono-substituted phenoxy, cyclohexyl, CF 3 , OCF 3 , -CO-CH 3 , -CO-OCH 3 , SO 2 -CH 3
  • any of the above mentioned substitutents itself is at least mono-substituted, said substituents may preferably be selected from the group consisting of F, Cl, Br, CF3, OCF 3 , methyl and methoxy.
  • each of these substituents may preferably be selected from the group consisting of hydroxy, halogen, branched or unbranched C ⁇ _ 4 -alkoxy, branched or unbranched C ⁇ -alky!, branched or unbranched Ci- 4 -perfluoroalkoxy, unsubstituted or at least mono-substituted phenoxy, unsubstituted or at least mono-substituted benzoyl, cyclohexyl, branched or unbranched Ci- 4 -perfluoroalkyl,
  • R 13b and R 14b form a heterocyclic ring, which is substituted by one or more substituents, unless defined otherwise, each of these substituents may preferably be selected from the group consisting of hydroxy, halogen, branched or unbranched C ⁇ -4-alkoxy, branched or unbranched C ⁇ - -alkyl, branched or unbranched C 1 . 4 - perfluoroalkoxy, branched or unbranched C- M -perfluoroalkyl, amino, carboxy, amido, cyano, nitro, -S0 2 NH 2 , -CO-C-M-alkyl. -SO-C- M -alkyl, -S0 2 -Ci.
  • C ⁇ - 4 -alkyl may be branched or unbranched, an unsubstituted or at least mono-substituted phenyl or naphthyl radical and an unsubstituted or at least mono-substituted furanyl-, thienyl-, pyrrolyl-, imidazolyl-, pyrazolyl-, pyridinyl-, pyrimidinyl-, quinolinyl- and isoquinolinyl radical, more preferably be selected from the group consisting of hydroxy, F, Cl, Br, methoxy, ethoxy, methyl, CF 3 and an unsubstituted phenyl radical. If any of the above mentioned substitutents itself is at least mono-substituted, said substituents may preferably be selected from the group consisting of F, Cl, methyl and methoxy.
  • R 13b and R 14b form a heterocyclic ring, which contains one or more further heteroatoms as ring members, unless defined otherwise, each of these heteroatoms may preferably be selected from the group consisting of N, O and S, more preferably from the group consisting of N and O.
  • residues R 1b -R 15b and W b represents or comprises a cycloaliphatic radical, which contains one or more heteroatoms as ring members, unless defined otherwise, each of these heteroatoms may preferably be selected from the group consisting of N, O, S and P, more preferably from the group consisting of N, O and S.
  • each of these heteroatoms may preferably be selected from the group consisting of N, O, S and P, more preferably from the group consisting of N, O and S.
  • R Ab and R Bb are independently selected from the group consisting of H, C ⁇ - 4 -alkyl and phenyl, NH- (1 ,3-Dihydro-1-oxo-2H-isoindol-2-yl), N-Phthalimidinyl-, (1 ,3-Dioxo-2-azaspiro[4,4]-non-2-yl, substituted or unsubstituted phenyl, -S0 2 -phenyl, phenoxy, pyridinyl, pyridinyloxy, pyrazolyl, pyrimidinyl, pyrrolidinyl-, -S ⁇ 2 -
  • R 1b , R 2b , R 3b , R 4b are each independently selected from the group consisting of H, F, Cl, Br, an unbranched or branched, saturated or unsaturated, optionally at least mono- substituted C ⁇ - 6 -aliphatic radical, a saturated or unsaturated, optionally at least mono- substituted, optionally at least one heteroatom as ring member containing C 3 -8- cycloaliphatic radical, which may be bonded via an optionally at least mono- substituted C-i- ⁇ -alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, an optionally at least mono- substituted, 5- or 6-membered aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted C- ⁇ - 6 -alkylene group and/or may be condensed with an optionally
  • R 5b -R 18b and W b have the meaning as defined above, optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or corresponding salts thereof, or corresponding solvates.
  • R 5b represents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C-i- ⁇ -aliphatic radical or a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing C 3 . 8 -cycloaliphatic radical,
  • R 1b -R 4b , R 6b -R 18b and W b have the meaning given above, optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or corresponding salts thereof, or corresponding solvates.
  • R 6b , R 7b , R 8b , R 9b are each independently selected from the group consisting of hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono- substituted C- ⁇ - 6 -aliphatic radical, a saturated or unsaturated, optionally at least mono- substituted, optionally at least one heteroatom as ring member containing C 3 - 8 - cycloaliphatic radical, a cyano and COOR 15b moiety,
  • R 1b -R 5b , R 10b -R 18b and W b have the meaning given above, optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or corresponding salts thereof, or corresponding solvates.
  • W b represents an an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C- ⁇ - 6 -aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing C 3 - 8 -cycloaliphatic radical, which may be bonded via an optionally at least mono- substituted C- ⁇ - 6 -alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, an optionally at least mono- substituted, 5- or 6-membered aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted C-i- ⁇ -alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ringsystem, a NR i
  • R 1 -R 18b have the meaning given above, optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or corresponding salts thereof, or corresponding solvates.
  • W b represents a linear or branched C- ⁇ - 2 o-alkyl radical, preferably an alkyl radical selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec- butyl, tert-butyl and 1 ,1-dimethyl-propyl; a linear or branched C 2 .
  • each of these afore mentioned cyclic moieties may optionally be substituted with 1 , 2, 3, 4 or 5 substituents independently selected from the group consisting of methyl; ethyl; n-propyl; iso-propyl; n-butyl; iso-butyl; sec-butyl; tert-butyl; 1 ,1- dimethyl-propyl; n-pentyl; vinyl; cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl; morpholino; methoxy; ethoxy; n-propoxy; iso-propoxy; n-propoxy; F; Cl; Br; I; -CN; - OH; -CF 3 ; -CF 2 H; -CH 2 F; -CCI 3 ; -CCIH 2 ; -CHCI 2 ; -CH 2 -F; -CH 2 -CI;-CH 2 -B
  • each of the cyclic moieties of these afore mentioned substituents may optionally be substituted with 1 , 2, 3, 4 or 5 substituents that are independently selected from the group consisting of methyl; ethyl; n-propyl; iso-propyl; F; Cl; Br; I; CN; -CH 2 -F; -CH 2 -CI; -CH 2 -Br; -CF 3 and -S-CH 3 ,
  • W b represents
  • R 1 -R 18b have the meaning given above, optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or corresponding salts thereof, or corresponding solvates.
  • R 10 represents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C ⁇ _ 6 -aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing C 3 - 8 -cycloaliphatic radical, which may be bonded via an optionally at least mono-substituted C- ⁇ - 6 -alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, or an at least mono-substituted, 5- or 6-membered aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted C- ⁇ - 6 -alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-
  • R 1b -R 9b , R 11b -R 18b and W b have the meaning given above, optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or corresponding salts thereof, or corresponding solvates.
  • R 11b represents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C-i- ⁇ -aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing C 3 - 8 -cycloaliphatic radical, which may be bonded via an optionally at least mono-substituted C- ⁇ - 6 -alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, or an at least mono-substituted, 5- or 6-membered aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted C- ⁇ - 6 -alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system
  • R 1b -R 10b , R 12b -R 18b and W b have the meaning given above, optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or corresponding salts thereof, or corresponding solvates.
  • R 12b represents an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C- ⁇ - 6 -aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing C 3 - 8 -cycloaliphatic radical, which may be bonded via an optionally at least mono- substituted C-i- ⁇ -alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, or an optionally at least mono- substituted, 5- or 6- membered aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted Ci- ⁇ -alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,
  • R 1b -R 1 b , R 13b -R 18b and W b have the meaning given above, optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or corresponding salts thereof, or corresponding solvates.
  • R 13b and R 14b are each independently selected from the group consisting of hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono- substituted C ⁇ - 6 -aliphatic radical, a saturated or unsaturated, optionally at least mono- substituted, optionally at least one heteroatom as ring member containing C 3 _ 8 - cycloaliphatic radical, which may be bonded via an optionally at least mono- substituted C- ⁇ _ 6 -alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, or an optionally at least mono- substituted, 5- or 6-membered aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted C- ⁇ - 6 -alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic
  • preferably are each independently selected from the group consisting of H, a C1-4- alkyl radical, cyclohexyl and a phenyl radical,
  • R 1b -R 12b , R 15b -R 18b and W b have the meaning given above, optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or corresponding salts thereof, or corresponding solvates.
  • R 1b -R 12b , R 15b -R 18b and W b have the meaning given above, optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or corresponding salts thereof, or corresponding solvates.
  • R 15b represents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C ⁇ . 6 -aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing C 3 . 8 - cycloaliphatic radical or an optionally at least mono-substituted, 5- or 6- membered aryl- or heteroaryl radical, which may be bonded via an optionally at least mono- substituted C- ⁇ - 6 -alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,
  • R 1b -R 14b , R 16b - R 18b and W b have the meaning given above, optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or corresponding salts thereof, or corresponding solvates.
  • R 16b represents an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C- ⁇ - 6 aliphatic radical
  • R 1b -R 15b , R 17b , R 18b and W b have the meaning given above, optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or corresponding salts thereof, or corresponding solvates.
  • R 17b represents an unbranched or branched, saturated or unsaturated, optionally at least mono- substituted C- ⁇ - 6 aliphatic radical
  • R 1b -R 16b , R 18b and W b have the meaning given above, optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or corresponding salts thereof, or corresponding solvates.
  • R 18b represents a phenyl radical, which is optionally at least mono-substituted by a C-i- ⁇ aliphatic radical, more preferably a phenyl radical, which is optionally at least mono- substituted by a methyl group
  • R 1b -R 17b and W b have the meaning given above, optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or corresponding salts thereof, or corresponding solvates.
  • R 1b , R 2b , R 3b , R 4b are each independently selected from the group consisting of a hydrogen atom; a fluorine atom; a chlorine atom; a bromine atom; a methyl group and a methoxy group;
  • R 5b represents a hydrogen atom
  • R 6b , R 7b , R 8b , R 9b each represent a hydrogen atom
  • 6-Methyl-1 -[1 -(2-trifluoromethyl- benzenesulfonyl)-piperidin-4-yl]-1 ,4- dihydro-benzo[d][1 ,3]oxazin-2-one 1 -[1 -(3-Methoxy-benzenesulfonyl)- piperidin-4-yl]-6-methyl-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one

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Abstract

The present invention relates to an active substance combination comprising at least one compound with neuropeptide Y-receptor affinity and at least one compound with 5-HT6 receptor affinity, a medicament comprising said active substance combination, and the use of said active substance combination for the manufacture of a medicament.

Description

Active substance combination comprising a compound with NPY receptor affinity and a compound with 5-HT6 receptor affinity
The present invention relates to an active substance combination comprising at least one compound with neuropeptide Y-receptor affinity, preferably neuropeptide Y5- receptor affinity, and at least one compound with 5-HTβ receptor affinity, a medicament comprising said active substance combination, and the use of said active substance combination for the manufacture of a medicament.
The superfamily of serotonin receptors (5-HT) includes 7 classes (5-HT 5-HT ) encompassing 14 human subclasses [D. Hoyer, et al., Neuropharmacology, 1997, 36, 419]. The 5-HT6 receptor is the latest serotonin receptor identified by molecular cloning both in rats [F.J. Monsma, et al., Mol. Pharmacol., 1993, 43, 320; M. Ruat, et al., Biochem. Biophys. Res. Commun., 1993, 193, 268] and in humans [R. Kohen, et al., J. Neurochem., 1996, 66, 47]. Compounds with 5-HTβ receptor affinity are useful for the treatment of various disorders of the Central Nervous System and of the gastrointestinal tract, such as irritable intestine syndrome. Compounds with 5-HT6 receptor affinity are also useful in the treatment of 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.j- 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 typical and atypical antipsychotic drugs for treating schizophrenia have a high affinity for 5-HT6 receptors [B.L. Roth, et al., J. Pharmacol. Exp. Ther. , 1994, 268, 1403; CE. 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]. Compounds with 5-HT6 receptor affinity are useful for treating infant hyperkinesia (ADHD, attention deficit / hyperactivity disorder) [W.D. Hirst, et al., Br. J. Pharmacol. , 2000, 130, 1597; C. Gerard, et al., Brain Research , 1997, 746, 207; M.R. Pranzatelli, Drugs of Today , 1997, 33, 379]. Moreover, it has been shown that the 5-HT6 receptor also plays a role in food ingestion [Neuropharmacology, 41 , 2001 , 210-219].
Food ingestion disorders, particularly obesity, are a serious, fast growing threat to the health of humans of all age groups, since they increase the risk of developing other serious, even life-threatening diseases such as diabetes or coronary diseases.
Neuropeptide Y (NPY), first isolated in porcine brain extracts (Tatemoto et. al. Nature 1982, 296, 659), is a 36-aminoacid peptide belonging to the family of pancreatic polypeptides, and is one of the most abundant peptides in the brain and in the central nervous system. In addition, NPY is also distributed in several parts of the peripheral nervous system.
Several studies suggest a significant role of NPY in food ingestion regulation and particularly in food dysfunctions like obesity, anorexia and bulimia. Specifically, NPY is a powerful stimulant of food ingestion. Thus, appetite is significantly increased when NPY is injected directly into the CNS of satiated mice (Clark J. T. et. al. Endocrinology 1984, 115, 427; Levine A. S. et. al. Peptides 1984, 5, 1025; Stanley B. G. et. al. Life Sci. 1984, 35, 2635; Stanley B. G. et. al. Proc. Nat. Acad. Sci. USA 1985, 82, 3940). On the other hand, NPY may play a role in cognitive function regulation, e. g. memory (Flood J. F. et. al. Brain Res. 1987, 421 , 280; Redrobe J. P. et. Al. Brain Res. 1999, 848, 153), and be active in anxiety (Heilig M. et. al. Reg. Peptides 1992, 41 , 61) and depression (Heilig M. et. al. Eur. J. Pharmacol. 1988, 147, 465) processes.
NPY is also distributed in the peripheral system. Some studies suggest that it might be involved in hypertensive (Michel M. C: et. al. J. Hypertens. 1995, 13, 385), and analgesic (Gehlert D. R. Life Sci. 1994, 55, 551) processes, among others.
The endogenous proteins that constitute NPY-binding receptors have been widely studied. Several have been cloned and expressed. At present, six different receptor subtypes, named Y1 to Y6, are recognized (Hispkind P. A. et. al. Annu. Rep. Med. Chem. 1996, 31 , 1 ; Grundemar L. et. al. TIPS Reviews., 15, 153, 1994). Each NPY receptor subtype is generally associated to a different biological activity. For example, Y2 receptor is involved in the induction of convulsions in rats (Dumont Y. et. al. Brit. J. Pharmacol. 2000, 129, 1075).
The most recently identified receptor is Y5 (Hu et. al. J. Biol. Chem. 1996, 271 , 26315). There is evidence that Y5 receptor has a unique pharmacological profile related to food ingestion as compared to the other receptor subtypes. The fact that [D-Trp32 ]NPY peptide, a selective Y5-receptor agonist with no affinity for Y1 receptor, stimulates food ingestion in rats (Gerald C. et. al. Nature, 1996, 382, 168), supports the hypothesis that Y5 receptor is related to exaggerated food consumption. Consequently, compounds having an affinity to the Y5 receptor should be effective to inhibit food ingestion and very useful to control diseases like obesity or other disorders of food ingestion (food intake), such as anorexia, bulimia, cachexia or type II diabetes. Moreover, it has been suggested that such compounds are useful to control diseases such as arthritis or epilepsy.
Whereas known compounds with NPY-receptor affinity and known compounds with 5-HT6 receptor affinity are generally effective for treating disorders related to NPY- receptors and to 5-HT6 receptors respectively, in some instances they show undesirable side effects.
It was therefore an object of the present invention to provide a medicament suitable for the prophylaxis and/or treatment of disorders related to NPY-receptors, preferably NPY5-receptors, and to 5-HTβ receptors, which preferably does not show the undesired side effects of the conventional compounds with NPY-receptor affinity or 5- HTβ receptor affinity, or at least less frequent and/or less pronounced.
Said object was achieved by providing an active substance combination comprising
(A) at least one compound with neuropeptide Y (NPY)-receptor affinity and
(B) at least one compound with 5-HTβ receptor affinity It has surprisingly been found that the compounds with NPY-receptor affinity and the compounds with 5-HT6 receptor affinity show a synergic effect in their pharmacological activities. Consequently, the dose of the corresponding compounds may be reduced in comparison to the dose necessary for an individual administration of said compounds.
Preferably, the active substance combination of the present invention may comprise as a component (A) at least one compound with neuropeptide Y5 (NPYδ)-receptor affinity.
Preferably, the active substance combination of the present invention may comprise as a component (A) at least one compound with neuropeptide Y (NPY)-receptor affinity, preferably with neuropeptide Y5 (NPY5)-receptor affinity, which is selected form the group consisting of the 1 ,4-disubstituted piperidine compounds of general formula (la), ,
Figure imgf000005_0001
(I)
wherein R1a, R2a, R3a, R4a are each independently selected from the group consisting of hydrogen, halogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic radical, which may be bonded via an optionally at least mono- substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, an optionally at least mono- substituted aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ringsystem, a nitro, cyano, -OR12a, - OC(=0)R13a, -SR14a, -SOR14a, -SO2R14a, -NH-S02R14a, -SO2NH2 and -NR15aR16a moiety,
R5a represents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical or a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic radical,
R6a, R7a, R8a, R9a are each independently selected from the group consisting of hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic radical, a cyano and a -COOR17a moiety,
A represents a bridge member -CHR18a- or -CHR18a-CH2-,
R10a represents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ringsystem, or an optionally at least mono-substituted aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,
R11a represents an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic radical, which may be bonded via an optionally at least mono- substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ringsystem, or an optionally at least mono substituted aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ringsystem, or
R10a and R11a together with the bridging nitrogen atom form an optionally at least mono-substituted, saturated, unsaturated or aromatic heterocyclic ring that may contain at least one further heteroatom as a ring member and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ringsystem,
R12a represents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, or an optionally at least mono-substituted aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,
R13a represents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, or an optionally at least mono-substituted aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,
R14a represents an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic radical, which may be bonded via an optionally at least mono- substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, or an optionally at least mono- substituted aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,
R15a and R16a are each independently selected from the group consisting of hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic radical, which may be bonded via an optionally at least mono- substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, or an optionally at least mono- substituted aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,
or R15a and R16a together with the bridging nitrogen atom form a saturated, unsaturated or aromatic heterocyclic ring, which may be at least mono-substituted and/or contain at least one further heteroatom as ring member,
R17a represents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic radical or an optionally at least mono-substituted aryl- or heteroaryl radical, which may be bonded via an optionally at least mono- substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,
R18a represents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic radical or an optionally at least mono-substituted aryl- or heteroaryl radical, which may be bonded via an optionally at least mono- substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,
optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or physiologically acceptable salts thereof, or solvates, respectively.
A mono- or polycyclic ring-system according to the present invention means a mono- or polycyclic hydrocarbon ring-system that may be saturated, unsaturated or aromatic. If the ring system is polycyclic, each of its different rings may show a different degree of saturation, i.e. it may be saturated, unsaturated or aromatic. Optionally each of the rings of the mono- or polycyclic ring system may contain one or more heteroatoms as ring members, which may be identical or different and which can preferably be selected from the group consisting of N, O, S and P, more preferably be selected from the group consisting of N, O and S. Preferably the polycyclic ring-system may comprise two rings that are condensed. The rings of the mono- or polycyclic ring-sytem are prefarably 5- or 6-membered.
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. If one or more of the residues R1a-R18a represents an aliphatic radical, which is substituted by one or more substituents, unless defined otherwise, each of these substituents may preferably be selected from the group consisting of hydroxy, halogen, branched or unbranched C-ι-4-alkoxy, branched or unbranched C1-4- perfluoroalkoxy, branched or unbranched Cι-4-perfluoroalkyl, amino, carboxy, amido, cyano, nitro, -SO2NH2, -CO-C^-alkyl, -SO-Cι_4-alkyl, -S02-Ci-4-alkyl, -NH-SOa-C^- alkyl , wherein the C- -alkyl may in each case be branched or unbranched, an unsubstituted or at least mono-substituted phenyl or naphthyl radical and an unsubstituted or at least mono-substituted furanyl-, thienyl-, pyrrolyl-, imidazolyl-, pyrazolyl-, pyridinyl-, pyrimidinyl-, quinolinyl- and isoquinolinyl radical, more preferably be selected from the group consisting of hydroxy, F, Cl, Br, methoxy, ethoxy, CF3 and an unsubstituted phenyl radical. If any one of the above mentioned substitutents itself is at least mono-substituted, said substituents may preferably be selected from the group consisting of F, Cl, methyl and methoxy.
If one or more of the residues R1a-R18a represents or comprises a cycloaliphatic radical, which is substituted by one or more substituents, unless defined otherwise, each of these substituents may preferably be selected from the group consisting of hydroxy, halogen, branched or unbranched Cι-4-alkyl, branched or unbranched C1-4- alkoxy, branched or unbranched C- -perfluoroalkoxy, phenoxy, benzoyl, cyclohexyl, branched or unbranched C-ι-4-perfluoroalkyl, -NRAaRBa wherein RAa, RBa are each independently selected from the group consisting of H, a branched or unbranched C-i- 4-alkyl-radical, -CH2-CH2-OH and phenyl, carboxy, amido, cyano, nitro, -SO2NH2, - CO-C-M-alkyl, -CO-OCι-4-alkyl, -SO-d-4-alkyl, -SO2-C1-4-alkyl, -NH-S02-Ci-4-alkyl, wherein Cι-4-alkyl may in each case be branched or unbranched, unsubstituted or at least mono-substituted phenyl or naphthyl and unsubstituted or at least mono- substituted furanyl-, thienyl-, pyrrolyl-, imidazolyl-, pyrazolyl-, pyridinyl-, pyrimidinyl-, quinolinyl- and isoquinolinyl radical, more preferably be selected from the group consisting of hydroxy, F, Cl, Br, methyl, ethyl, methoxy, ethoxy, benzoyl, phenoxy, cyclohexyl, -CF3, -CO-CH3, -CO-OCH3, -NRAaRBa wherein RAa, RBa are each independently selected from the group consisting of H, a branched or unbranched C-i- 4-alkyl-radical, -CH2-CH2-OH and phenyl, and an unsubstituted phenyl radical. If any one of the above mentioned substitutents itself is at least mono-substituted, said substituents may preferably be selected from the group consisting of F, Cl, methyl and methoxy.
If one or more of the residues R1a-R4a and R10a-R18a comprises an alkylene group, which is substituted by one or more substituents, unless defined otherwise, each of these substituents may preferably be selected from the group consisting of hydroxy, halogen, branched or unbranched C-ι-4-alkoxy, branched or unbranched C1-4- perfluoroalkoxy, branched or unbranched C- -perfluoroalkyl, amino, carboxy, amido, cyano, nitro, -SO2NH2, -CO-Ci-4-alkyl, -SO-Cι-4-alkyl, -S02-Ci-4-alkyl, -NH-SO2-C1-4- alkyl, wherein C-ι-4-alkyl may be branched or unbranched, an unsubstituted or at least mono-substituted phenyl or naphthyl radical and an unsubstituted or at least mono- substituted furanyl-, thienyl-, pyrrolyl-, imidazolyl-, pyrazolyl-, pyridinyl-, pyrimidinyl-, quinolinyl- and isoquinolinyl radical, more preferably be selected from the group consisting of hydroxy, F, Cl, Br, methoxy, ethoxy, CF3 and unsubstituted phenyl. If any one of the above mentioned substitutents itself is at least mono-substituted, said substituents may preferably be selected from the group consisting of F, Cl, methyl and methoxy.
If one or more of the residues R1a-R4a and R10a-R18a comprises a mono- or polycyclic ringsystem, which is substituted by one or more substituents, unless defined otherwise, each of these substituents may preferably be selected from the group consisting of hydroxy, halogen, branched or unbranched Cι-4-alkyl, branched or unbranched C-ι-4-alkoxy, branched or unbranched C-ι-4-perfluoroalkoxy, branched or unbranched Cι-4-perfluoroalkyl, amino, carboxy, amido, cyano, keto, nitro, -SO2NH2, - CO-Ci-4-alkyl, -SO-d-4-alkyl, -S02-C1-4-alkyl, -NH-S02-C1-4-alkyl, wherein C^-alkyl may be branched or unbranched, an unsubstituted or at least mono-substituted phenyl or naphthyl radical and unsubstituted or at least mono-substituted furanyl-, thienyl-, pyrrolyl-, imidazolyl-, pyrazolyl-, pyridinyl-, pyrimidinyl-, quinolinyl- and isoquinolinyl, more preferably from the group consisting of hydroxy, F, Cl, Br, methyl, ethyl, methoxy, ethoxy, CF3, keto, cyano and an unsubstituted phenyl radical. If any one of the above mentioned substitutents itself is at least mono-substituted, said substituents may preferably be selected from the group consisting of F, Cl, methyl and methoxy. If one or more of the residues R1a-R4a and R10a-R18a represents or comprises an aryl radical, which is substituted by one or more substituents, unless defined otherwise, each of these substituents may preferably be selected from the group consisting of hydroxy, halogen, branched or unbranched C-ι-4-alkoxy, branched or unbranched C-j. 4-alkyl, branched or unbranched C- -perfluoroalkoxy, unsubstituted or at least mono- substituted phenoxy, unsubstituted or at least mono-substituted benzoyl, cyclohexyl, branched or unbranched C^-perfluoroalkyl, NRAaRBa wherein RAa, RBa are each independently selected from the group consisting of H, a branched or unbranched C-i- 4-alkyl-radical, -CH2-CH2-OH and phenyl, carboxy, amido, cyano, -CH(OH)(phenyl), nitro, -SO2NH2, -CO-d-4-alkyl, -CO-Od-4-alkyl, -SO-Cι-4-alkyl, -S02-C1.4-alkyl, -NH- S02-Cι-4-alkyl, wherein Cι- -alkyl may be branched or unbranched, an unsubstituted or at least mono-substituted phenyl or naphthyl radical and unsubstituted or at least mono-substituted furanyl-, thienyl-, pyrrolyl-, imidazolyl-, pyrazolyl-, pyridinyl-, pyrimidinyl-, quinolinyl- and isoquinolinyl radical, more preferably be selected from the group consisting of hydroxy, F, Cl, Br, methyl, ethyl, cyano, -CH(OH)(phenyl), methoxy, ethoxy, unsubstituted or at least mono-substituted benzoyl, unsubstituted or at least mono-substituted phenoxy, cyclohexyl, CF3, -CO-CH3, -CO-OCH3, -NRARB wherein RA, RB are each independently selected from the group consisting of H, a branched or unbranched Cι-4-alkyl-radical, -CH2-CH2-OH and phenyl, and an unsubstituted phenyl radical. If any of the above mentioned substitutents itself is at least mono-substituted, said substituents may preferably be selected from the group consisting of F, Cl, methyl and methoxy.
If one or more of the residues R1a-R4a and R10a-R18a represents or comprises a heteroaryl radical, which is substituted by one or more substituents, unless defined otherwise, each of these substituents may preferably be selected from the group consisting of hydroxy, halogen, branched or unbranched Cι-4-alkoxy, branched or unbranched Cι-4-alkyl, branched or unbranched Ci-4-perfluoroalkoxy, unsubstituted or at least mono-substituted phenoxy, unsubstituted or at least mono-substituted benzoyl, cyclohexyl, branched or unbranched C-ι-4-perfluoroalkyl, NRAaRBa wherein RAa, RBa are each independently selected from the group consisting of H, a branched or unbranched Cι-4-alkyl-radical, -CH2-CH2-OH and phenyl, carboxy, amido, cyano, nitro, -CH(OH)(phenyl), -S02NH2, -CO-Cι.4-aikyl, -CO-OC^-alkyl, SO-C1.4-alkyl, Sθ2-Cι-4-alkyl, -NH-S02-Cι-4-alkyl, wherein C-|.4-alkyl may be branched or unbranched, an unsubstituted or at least mono-substituted phenyl or naphthyl radical and an unsubstituted or, at least mono-substituted furanyl-, thienyl-, pyrrolyl-, imidazolyl-, pyrazolyl-, pyridinyl-, pyrimidinyl-, quinolinyl- and isoquinolinyl radical, more preferably be selected from the group consisting of hydroxy, F, Cl, Br, methyl, ethyl, cyano, methoxy, ethoxy, unsubstituted or at least mono-substituted benzoyl, unsubstituted or at least mono-substituted phenoxy, cyclohexyl, CF3, - CH(OH)(phenyl), -CO-CH3, -CO-OCH3, -NRAaRBa wherein RAa, RBa are each independently selected from the group consisting of H, a branched or unbranched C-i- 4-alkyl-radical, -CH2-CH2-OH and phenyl, and an unsubstituted phenyl radical. If any one of the above mentioned substitutents itself is at least mono-substituted, said substituents may preferably be selected from the group consisting of F, Cl, methyl and methoxy.
If R10a and R11a and/or R15a and R16a form a heterocyclic ring, which is substituted by one or more substituents, unless defined otherwise, each of these substituents may preferably be selected from the group consisting of hydroxy, halogen, branched or unbranched C-ι-4-alkoxy, branched or unbranched Cι-4-alkyl, branched or unbranched Cι-4-perfluoroalkoxy, branched or unbranched Cι-4-perfluoroalkyl, amino, carboxy, amido, cyano, nitro, -S02NH2, -CO-C1.4-alkyl, -SO-Ci-4-alkyl, -S02-C1-4-alkyl, -NH- Sθ2-Cι- -alkyl, wherein Cι-4-alkyl may be branched or unbranched, an unsubstituted or at least mono-substituted phenyl or naphthyl radical and an unsubstituted or at least mono-substituted furanyl-, thienyl-, pyrrolyl-, imidazolyl-, pyrazolyl-, pyridinyl-, pyrimidinyl-, quinolinyl- and isoquinolinyl radical, more preferably be selected from the group consisting of hydroxy, F, Cl, Br, methoxy, ethoxy, methyl, CF3 and an unsubstituted phenyl radical. If any of the above mentioned substitutents itself is at least mono-substituted, said substituents may preferably be selected from the group consisting of F, Cl, methyl and methoxy.
If R10a and R11a and/or R15a and R16a form a heterocyclic ring, which contains one or more further heteroatoms as ring members, unless defined otherwise, each of these heteroatoms may preferably be selected from the group consisting of N, O and S, more preferably from the group consisting of N and O. If one or more of the residues R1a-R18a represents or comprises a cycloaliphatic radical, which contains one or more heteroatoms as ring members, unless defined otherwise, each of these heteroatoms may preferably be selected from the group consisting of N, O, S and P, more preferably from the group consisting of N, O and S.
If one or more of the residues R1a-R4a and R10a_ 18a represents or comprises an heteroaryl radical, which contains one or more heteroatoms as ring members, unless defined otherwise, each of these heteroatoms may preferably be selected from the group consisting of N, O, S and P, more preferably from the group consisting of N, O and S.
Preferred compounds of general formula (la) are those, wherein R1a, R2a, R3a, R4a are each independently selected from the group consisting of H, F, Cl, Br, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C-ι-6- aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing C3-8-cycloaliphatic radical, which may be bonded via an optionally at least mono-substituted C-i-6- alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, an optionally at least mono-substituted, 5- or 6- membered aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted C-ι-6-alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ringsystem, a nitro group, a cyano group, -OR12a, -OC(=0)R13a, -SR14a, -SOR14a, -S02R14a, -NH-S02R1 a, -S02NH2 and -
NR15aR16a ^^
R5a represents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted Cι-6-aliphatic radical or a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing C3-8-cycloaliphatic radical,
R6a, R7a, R8a, R9a are each independently selected from the group consisting of hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted Cι-6-aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing C3.8- cycloaliphatic radical, a cyano and a COOR17a moiety,
Aa represents a bridge member -CHR18a- or -CHR18a-CH2-,
R10a represents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C-ι-6-aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing C3.8-cycloaliphatic radical or an optionally at least mono- substituted, 5- or 6-membered aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted C-ι-6-alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,
R11a represents an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C-ι-6-aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing C3-8-cycloaliphatic radical, which may be bonded via an optionally at least mono- substituted C-i-6-alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ringsystem, or an optionally at least mono substituted 5- or 6-membered aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted d-β-alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ringsystem, or
R10a and R11a together with the bridging nitrogen atom form an optionally at least mono-substituted, saturated, unsaturated or aromatic, 5- or 6-membered heterocyclic ring, which may contain at least one further heteroatom as a ring member and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ringsystem,
R12a represents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C-ι-6-aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom containing as ring member C3-8-cycloaliphatic radical, which may be bonded via an optionally at least mono-substituted Ci-β-alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, or an optionally at least mono-substituted, 5- or 6-membered aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted Cι-6-alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring- system,
R13a represents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C-|.6-aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing C3.8-cycloaliphatic radical, which may be bonded via an optionally at least mono-substituted Cι-6-alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, or an optionally at least mono-substituted, 5- or 6-membered aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted Cι.6-alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring- system,
R14a represents an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C-ι-6-aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing C3.8-cycloaliphatic radical, which may be bonded via an optionally at least mono- substituted Cι-6-alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, or an optionally at least mono- substituted, 5- or 6- membered aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted C-|.6-alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,
R15a and R16a each are independently selected from the group consisting of hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted Cι-6-aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing C3.8- cycloaliphatic radical, which may be bonded via an optionally at least mono- substituted Cι-6-alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, or an optionally at least mono- substituted, 5- or 6-membered aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted Cι-6-alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,
or R15a and R16a together with the bridging nitrogen atom form a saturated, unsaturated or aromatic, 5- or 6-membered heterocyclic ring, which may be at least mono-substituted and/or contain at least one further heteroatom as a ring member,
R17a represents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted Cι-6-aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing C3-8-cycloaliphatic radical or an optionally at least mono- substituted, 5- or 6- membered aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted C-ι-6-alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,
R18a represents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C-ι-6-aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing C-3-8-cycloaliphatic radical or an optionally at least mono- substituted, 5- or 6-membered aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted Cι-6-alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,
optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or physiologically acceptable salts thereof, or solvates, respectively.
Particularly preferred are compounds of general formula (la), wherein R1a, R2a, R3a, R4a are each independently selected from the group consisting of H, F, Cl, Br, a saturated, branched or unbranched, optionally at least mono-substituted C1-3- aliphatic radical, a saturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing C5- or C6- cycloaliphatic radical, which may be bonded via an optionally at least mono-substituted C or C2-alkylene group, a nitro group, a cyano group, -OR12a, -OC(=0)R13a, -SR14a and -NR15aR16a moiety, preferably be selected from the group consisting of H, F, Cl, CH3, CH2CH3, CF3, CF2CF3, cyclopentyl, cyclohexyl, nitro, cyano and -OR12a and the remaining residues R5a-R18a and Aa have the meaning given above, optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or physiologically acceptable salts thereof, or solvates, respectively.
Also particularly preferred are compounds of general formula (la), wherein R5a represents H or a branched or unbranched Cι-3-alkyl radical, preferably H, CH3 or CH2CH3, and the remaining residues R6a-R18a and Aa have the meaning given above, optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or physiologically acceptable salts thereof, or solvates, respectively.
Also particularly preferred are compounds of general formula (la), wherein R6a, R7a, R8a, R9a are each independently selected from the group consisting of H, a branched or unbranched C-|.3-alkyl radical, a cyano and a COOR17a moiety, preferably selected from the group consisting of H, CH3, CH2CH3 and a cyano moiety, and the remaining residues R10a-R18a and Aa have the meaning given above, optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or physiologically acceptable salts thereof, or solvates, respectively.
Also particularly preferred are compounds of general formula (la), wherein R10a represents hydrogen or a branched or unbranched Cι-4-alkyl radical, and the remaining residues R11a-R18a and Aa have the meaning given above, optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or physiologically acceptable salts thereof, or solvates, respectively.
Also particularly preferred are compounds of general formula (la), wherein R11a is selected from the group consisting of an unsubstituted phenyl radical, a phenyl radical optionally at least mono-substituted with a branched or unbranched Cι-4-alkyl- radical, a branched or unbranched C- -alkoxy-radical, a branched or unbranched C-i- 4-perfluoroalkyl-radical, a branched or unbranched Cι-4-perfluoroalkoxy-radical, F, Cl, Br, cyclohexyl, phenyl, phenoxy, phenylthio, benzoyl, cyano, -C(=0)Cι-2-alkyl, - C(=0)OC1.2-alkyl, -carboxy, -CH(OH)(phenyl), -NRAaRBa wherein RAa, RBa are each independently selected from the group consisting of H, a branched or unbranched C-ι-4-alkyl-radical, -CH2-CH2-OH and an unsubstituted phenyl radical,
an unsubstituted thiazole radical,
a group of general formula (A)
Figure imgf000019_0001
wherein
n is 1 or 2,
X represents CH or N,
Y represents CH2, O, N-Rc, CH-OH or C(=O),
Rc is H or a branched or unbranched d-4-alkyl radical,
a group of formula (B),
Figure imgf000020_0001
(B) a group of formula (C),
Figure imgf000020_0002
(C)
a group of general formula (D),
Figure imgf000020_0003
(D)
wherein RD is H or a branched or unbranched C-ι- -alkyl radical and a group of general formula (E),
Figure imgf000020_0004
(E) wherein
RE represents H, a branched or unbranched C-ι-4-alkyl radical or a branched or unbranched Cι-4-alkoxy radical,
W represents a bond between the two aromatic rings, CH2, CH-OH or C(=0),
Z represents CH2, O, S, CH-OH, C(=0) or N-RF where RF represents H or a branched or unbranched Cι-4-alkyl-radical, and the remaining residues R12a-R18a and Aa have the meaning given above, optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or physiologically acceptable salts thereof, or solvates, respectively.
Also particularly preferred are compounds of general formula (la), wherein R10a and R11a together with the bridging nitrogen atom form a saturated, 6-membered heterocyclic ring, which is at least mono-substituted with a methyl radical and/or condensed with an unsubstituted or at least mono-substituted phenyl- or cyclohexyl- radical, said phenyl- or cyclohexyl-radical preferably being at least mono-substituted with F and/or OCH3, and the remaining residues R12a-R18a and Aa have the meaning given above, optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or physiologically acceptable salts thereof, or solvates, respectively.
Also particularly preferred are compounds of general formula (la), wherein R12a represents H, a Cι-4-alkyl radical, a cyclohexyl radical or a phenyl radical, preferably H, CH3, C2H5 or a phenyl radical, and the remaining residues R13a-R18a and Aa have the meaning given above, optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or physiologically acceptable salts thereof, or solvates, respectively. Also particularly preferred are compounds of general formula (la), wherein R13a represents H, a Cι-4-alkyl radical, cyclohexyl or a phenyl radical, preferably H, CH3, C2H5 or phenyl, and the remaining residues R14a-R18a and Aa have the meaning given above, optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or physiologically acceptable salts thereof, or solvates, respectively.
Also particularly preferred are compounds of general formula (la), wherein R14a represents H, a C-ι-4-alkyl radical, cyclohexyl or a phenyl radical, preferably H, CH3, C2H5 or phenyl, and the remaining residues R15a-R18a and Aa have the meaning given above, optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or physiologically acceptable salts thereof, or solvates, respectively.
Also particularly preferred are compounds of general formula (la), wherein R15a and R16a are each independently selected from the group consisting of H, a Cι-4-alkyl radical, cyclohexyl and a phenyl radical, preferably from the group consisting of H, CH3, C2H5 and phenyl, and the remaining residues R17a and R18a and Aa have the meaning given above, optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or physiologically acceptable salts thereof, or solvates, respectively.
Also particularly preferred are compounds of general formula (la), wherein R17a represents H, a Cι-4-alkyl radical, cyclohexyl or a phenyl radical, preferably H, CH3, C-2H5 or phenyl, and the remaining residues R18a and Aa have the meaning given above, optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or physiologically acceptable salts thereof, or solvates, respectively. Also particularly preferred are compounds of general formula (la), wherein R18a represents H, a Cι-4-alkyl radical or a phenyl radical, preferably H, CH3 or phenyl, and the remaining residue A has the meaning given above, optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or physiologically acceptable salts thereof, or solvates, respectively.
More particularly preferred are compounds of general formula (la), wherein at least two of the residues R1a, R2a, R3a, R4a, preferably R a and R3a, do not represent hydrogen, and the residues from the group R1a, R2a, R3a and R4a that do not represent hydrogen as well as the remaining residues R5a-R18a and Aa have the meaning given above, optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or physiologically acceptable salts thereof, or solvates, respectively.
More particularly preferred are compounds of general formula (la), wherein R5a is CH3 or C2H5, and the remaining residues R1a-R4a and R6a-R18a and Aa have the meaning given above, optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or physiologically acceptable salts thereof, or solvates, respectively.
Most preferred are the following benzoxazin-derived compounds of general formula (la):
[1 ] 2-[4-(2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidin-1 -yl]-N-(9-oxo-9H-f luoren-2- yl)-acetamide,
[2] 2-[4-(2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidin-1 -yl]-N-(9-oxo-9H-f luoren-3- yl)-acetamide), [3] 2-[4-(2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidin-1 -yl]-N-(9-oxo-9H-f luoren-3- yl)-acetamide hydrochloride,
[4] N-(4-benzoyl-phenyl)-2-[4-(2-oxo-4H-benzo[d][1 ,3]oxazin-1-yl)-piperidin-1-yl]- acetamide,
[5] N-(4-benzoyl-phenyl)-2-[4-(2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidin-1 -yl]- acetamide hydrochloride,
[6] 2-[4-(2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidin-1 -yl]-N-(5-oxo-5, 6,7,8- tetrahidro-naphthalene-2-yl)-acetamide hydrochloride,
[7] 2-[4-(2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidin-1 -yl]-N-(9-oxo-9H-f luoren-4- yl)-acetamide hydrochloride,
[8] N-(3-benzoyl-phenyl)-2-[4-(2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidin-1 -yl]- acetamide hydrochloride,
[9] 2-[4-(2-oxo-4H-benzo[d][1 ,3]oxazin-1-yl)-piperidin-1-yl]-N-(1-oxo-indan-5-yl)- acetamide,
[10] 2-[4-(2-oxo-4H-benzo[d][1 ,3]oxazin-1-yl)-piperidin-1-yl]-N-(1-oxo-indan-5-yl)- acetamide hydrochloride,
[11 ] N-lndan-5-yl-2-[4-(2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidin-1 -yl]- acetamide hydrochloride,
[12] N-(2-Methoxy-dibenzofuran-3-yl)-2-[4-(2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)- piperidin-1-yl]- acetamide hydrochloride),
[13] N-(4-Cyclohexyl-phenyl)-2-[4-(2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidin-1 - yl]- acetamide hydrochloride, [14] 1 -{1 -[2-(3,4-Dihidro-2H-quinolin-1 -yl)-2-oxo-ethyl]piperidin-4-yl}-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one hydrochloride,
[15] 2-[4-(2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidin-1 -yl]-N-(9-oxo-9H-fluoren-3- yl)-2-phenyl-acetamide hydrochloride,
[16] 2-[4-(2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidin-1 -yl]-N-(9-oxo-9H-fluoren-3- yl)-propionamide hydrochloride,
[17] N-(9-Ethyl-9H-carbazol-3-yl)-2-[4-(2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)- piperidin-1 -yl]-acetamide,
[18] N-(9-Ethyl-9H-carbazol-3-yl)-2-[4-(2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)- piperidin-1-yl]-acetamide hydrochloride,
[19] 2-[4-(6-methyl-2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidin-1 -yl]-N-(9-oxo-9H- fluoren-3-yl)-acetamide,
[20] 2-[4-(6-methyl-2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidin-1 -yl]-N-(9-oxo-9H- fluoren-3-yl)-acetamide hydrochloride,
[21] N-(9-Ethyl-9H-carbazol-3-yl)-2-[4-(6-methyl-2-oxo-4H-benzo[d][1 ,3]oxazin-1- yl)-piperidin-1 -yl]-acetamide hydrochloride,
[22] N-(4-Cyclohexyl-phenyl)-2-[4-(6-methyl-2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)- piperidin-1 -yl]-acetamide,
[23] N-(4-Cyclohexyl-phenyl)-2-[4-(6-methyl-2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)- piperidin-1 -yl]-acetamide hydrochloride,
[24] N-(4-benzoyl-phenyl)-2-[4-(6-methyl-2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)- piperidin-1-yl]- acetamide hydrochloride, [25] N-(9-Methyl-9H-carbazol-3-yl)-2-[4-(2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)- piperidin-1 -yl]-acetamide hydrochloride,
[26] N-(9,10-Dioxo-9,10-dihydro-anthracene-2-yl)-2-[4-(2-oxo-4H- benzo[d][1 ,3]oxazin-1 -yl)-piperidin-1 -yl]-acetamide hydrochloride,
[27] N-[4-(Ethyl-phenyl-amino)-phenyl]-2-[4-(2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)- piperidin-1 -yl]-acetamide hydrochloride,
[28] 2-[4-(6-Methyl-2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidin-1 -yl]-N-[4-methyl- phenyl-amino)-phenyl]-acetamide hydrochloride,
[29] 2-[4-(2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidin-1 -yl]-N-[4-phenoxy-phenyl)- acetamide hydrochloride,
[30] N-[4-(lsopropyl-phenyl-amino)-phenyl]-2-[4-(2-oxo-4H-benzo[d][1 ,3]oxazin-1 - yl)-piperidin-1 -yl]-acetamide hydrochloride,
[31 ] 3-[4-(2-Oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidin-1 -yl]-N-(9-oxo-9H-fluoren-3- yl)-propionamide hydrochloride,
[32] 2-[4-(6-Chloro-2-oxo-4H-benzo[d][1 ,3]oxazin-1-yl)-piperidin-1-yl]-N-(9-ethyl- 9H-carbazol-3-yl)-acetamide hydrochloride,
[33] N-(4-Chloro-phenyl)-2-[4-(2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidin-1 -yl]- acetamide hydrochloride,
[34] 2-[4-(6-Chloro-2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidin-1 -yl]-N-(4-chloro- phenyl)-acetamide hydrochloride,
[35] 2-[4-(8-Methyl-2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidin-1 -yl]-N-(9-oxo-9H- fluoren-3-yl)-acetamide hydrochloride, [36] 2-[4-(6-Chloro-2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidin-1 -yl]-N-(9-oxo-9H- fluoren-3-yl)-acetamide hydrochloride,
[37] N-(9-Hydroxy-9H-fluoren-3-yl)-2-[4-(8-methyl-2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)- piperidin-1 -yl]-acetamide hydrochloride,
[38] N-(9-Hydroxy-9H-fluoren-2-yl)-2-[4-(2-oxo-4H-benzo[d][1 ,3]oxazin-1-yl)-piperidin- 1 -yl]-acetamide hydrochloride,
[39] 2-[4-(6-Chloro-2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidin-1 -yl]-N-(9-hydroxy- 9H-fluoren-3-yl)-acetamide hydrochloride,
[40] N-(9-Ethyl-9H-carbazol-3-yl)-2-[4-(8-methyl-2-oxo-4H-benzo[d][1 ,3]oxazin-1 - yl)-piperidin-1 -yl]-acetamide hydrochloride,
[41 ] 2-[4-(8-Methyl-2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidin-1 -yl]-N-(4- trifluoromethyl-phenyl)-acetamide hydrochloride,
[42] 2-[4-(8-Methyl-2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidin-1 -yl]-N-phenyl- acetamide hydrochloride,
[43] 2-[4-(2-oxo-4H-benzo[d][1 ,3]oxazin-1-yl)-piperidin-1-yl]-N-(4-trifluoromethyl- phenyl)-acetamide hydrochloride,
[44] 2-[4-(6-Chloro-2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidin-1 -yl]-N-phenyl- acetamide hydrochloride,
[45] 2-[4-(6-Chloro-2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidin-1 -yl]-N-(4- trifluoromethyl-phenyl)-acetamide hydrochloride,
[46] 2-[4-(2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidin-1 -yl]-N-phenyl-acetamide hydrochloride, [47] N-(4-Chloro-phenyl)-2-[4-(8-Methyl-2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)- piperidin-1 -yl]-acetamide hydrochloride,
[48] N-(4-Cyano-phenyl)-2-[4-(2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidin-1 -yl]- acetamide hydrochloride,
[49] N-(4-Cyano-phenyl)-2-[4-(8-methyl-2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)- piperidin-1 -yl]-acetamide hydrochloride,
[50] 2-[4-(6-Chloro-2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidin-1 -yl]-N-(4-cyano- phenyl)-acetamide hydrochloride,
[51 ] N-(4-AcethyI-phenyl)-2-[4-(2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidin-1 -yl]- acetamide hydrochloride,
[52] 2-[4-(8-Methyl-2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidin-1 -yl]-N-(4- phenoxy-phenyl)-acetamide hydrochloride,
[53] N-(4-Acethyl-phenyl)-2-[4-(6-chloro-2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)- piperidin-1 -yl]-acetamide hydrochloride,
[54] N-(4-Acethyl-phenyl)-2-[4-(8-methyl-2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)- piperidin-1-yl]-acetamide hydrochloride,
[55] 2-[4-(6-Chloro-2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidin-1 -yl]-N-(4- phenoxy-phenyl)-acetamide hydrochloride,
[56] N-(4-Benzoyl-phenyl)-2-[4-(8-methyl-2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)- piperidin-1 -yl]-acetamide hydrochloride,
[57] N-(4-Benzoyl-phenyl)-2-[4-(6-chloro-2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)- piperidin-1 -yl]-acetamide hydrochloride, [58] N-(2-Chloro-phenyl)-2-[4-(6-methyl-2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)- piperidin-1 -yl]-acetamide,
[59] 2-[4-(6-Methyl-2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidin-1 -yl]-N-(2- trifluoromethyl-phenyl)-acetamide,
[60] 2-[4-(6-Methyl-2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidin-1 -yl]-N-phenyl- acetamide,
[61 ] N-(4-Cyclohexyl-phenyl)-2-[4-(8-methyl-2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)- piperidin-1 -yl]-acetamide hydrochloride,
[62] 2-[4-(6-Chloro-2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidin-1 -yl]-N-(4- cyclohexyl-phenyl)-acetamide hydrochloride,
[63] N-(2-Benzoyl-phenyl)-2-[4-(2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidin-1 -yl]- acetamide hydrochloride,
[64] N-(2-Benzoyl-phenyl)-2-[4-(8-methyl-2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)- piperidin-1 -yl]-acetamide hydrochloride,
[65] N-(2-Benzoyl-phenyl)-2-[4-(6-chloro-2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)- piperidin-1 -yl]-acetamide hydrochloride,
[66] N-(2-Benzoyl-phenyl)-2-[4-(6-methyl-2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)- piperidin-1 -yl]-acetamide,
[67] 2-[4-(6-Methyl-2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidin-1 -yl]-N-(4- phenoxy-phenyl)-acetamide hydrochloride,
[68] N-(4-Acethyl-phenyl)-2-[4-(6-methyl-2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)- piperidin-1-yl]-acetamide hydrochloride, [69] N-(9-Hydroxy-9H-fluoren-3-yl)-2-[4-(2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)- piperidin-1 -yl]-acetamide hydrochloride,
[70] 2-[4-(6-Chloro-2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidin-1 -yl]-N-(9-oxo-9H- fluoren-2-yl)-acetamide hydrochloride,
[71 ] 2-[4-(6-Methyl-2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidin-1 -yl]-N-(9-oxo-9H- fluoren-2-yl)-acetamide hydrochloride,
[72] 2-[4-(8-Methyl-2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidin-1 -yl]-N-(9-oxo-9H- fluoren-2-yl)-acetamide hydrochloride,
[73] 2-[4-(6-Chloro-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-N-(9-hydroxy- 9H-fluoren-2-yl)-acetamide hydrochloride,
[74] N-(9-Hydroxy-9H-fluoren-2-yl)-2-[4-(6-methyl-2-oxo-4H-benzo[d][1 ,3]oxazin-1 - yl)-piperidin-1 -yl]-acetamide hydrochloride,
[75] N-(9-Hydroxy-9H-fluoren-2-yl)-2-[4-(8-methyl-2-oxo-4H-benzo[d][1 ,3]oxazin-1 - yl)-piperidin-1 -yl]-acetamide hydrochloride,
[76] N-(9-Hydroxy-9H-fluoren-3-yl)-2-[4-(6-methyl-2-oxo-4H-benzo[d][1 ,3]oxazin-1 - yl)-piperidin-1-yl]-acetamide hydrochloride,
[77] N-(4-Cyclohexyl-phenyl)-2-[4-(7-fluoro-2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)- piperidin-1-yl]-acetamide hydrochloride,
[78]. N-(9-Ethyl-9H-carbazol-3-yl)-2-[4-(5-fluoro-2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)- piperidin-1 -yl]-acetamide hydrochloride,
[79] N-(9-Ethyl-9H-carbazol-3-yl)-2-[4-(6-metoxy-2-oxo-4H-benzo[d][1 ,3]oxazin-1 - yl)-piperidin-1 -yl]-acetamide hydrochloride, [80] N-(9-Ethyl-9H-carbazol-3-yl)-2-[4-(7-methyl-2-oxo-4H-benzo[d][1 ,3]oxazin-1 - yl)-piperidin-1 -yl]-acetamide hydrochloride,
[81 ] 2-[4-(5-Chloro-2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidin-1 -yl]-N-(9-ethyl- 9H-carbazol-3-yl)acetamide hydrochloride,
[82] 2-[4-(5-Fluoro-2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidin-1 -yl]-N-(4- phenoxy-phenyl)-acetamide hydrochloride,
[83] 2-[4-(6-metoxy-2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidin-1 -yl]-N-(9-oxo-9H- fluoren-3-yl)-acetamide,
[84] N-Dibenzofuran-2-yl-2-[4-(8-metoxy-2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)- piperidin-1-yl]- acetamide,
[85] 2-[4-(7-Chloro-2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidin-1 -yl]-N- dibenzofuran-2-yl-acetamide,
[86] 2-[4-(6-Fluoro-2-oxo-4H-benzo[d][1 ,3]oxazin-1-yl)-piperidin-1-yl]-N-(9-oxo-9H- fluoren-3-yl)- acetamide,
[87] 2-[4-(7-Fluoro-2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidin-1 -yl]-N-(9-hydroxy- 9H-fluoren-3-yl)-acetamide,.
[88] N-(9H-Carbazol-3-yl)-2-[4-(5-methyl-2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)- piperidin-1 -yl]-acetamide,
[89] N-(9H-Carbazol-3-yl)-2-[4-(5-fluoro-2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)- piperidin-1 -yl]-acetamide,
[90] N-(9H-carbazol-3-yl)-2-[4-(6-metoxy-2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)- piperidin-1 -yl]-acetamide, [91 ] N-(9-Ethyl-9H-carbazol-3-yl)-2-[4-(5-metoxy-2-oxo-4H-benzo[d][1 ,3]oxazin-1 - yl)-piperidin-1 -yl]-acetamide,
[92] 2-[4-(5-Metoxy-2-oxo-4H-benzo[d][1 ,3]oxazin-1-yl)-piperidin-1-yl]-N-(4- phenoxy-phenyl)-acetamide,
[93] N-(9-Hydroxy-9H-fluoren-3-yl)-2-[4-(7-methyl-2-oxo-4H-benzo[d][1 ,3]oxazin-1 - yl)-piperidin-1 -yl]-acetamide,
[94] N-(9-Hydroxy-9H-fluoren-3-yl)-2-[4-(8-metoxy-2-oxo-4H-benzo[d][1 ,3]oxazin-1 - yl)-piperidin-1 -yl]-acetamide,
[95] N-Dibenzofuran-2-yl-2-[4-(5-methyl-2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)- piperidin-1-yl]- acetamide,
[96] N-[4-(Ethyl-phenyl-amino)-phenyl]-2-[4-(7-methyl-2-oxo-4H- benzo[d][1 ,3]oxazin-1 -yl)-piperidin-1 -yl]-acetamide,
[97] N-(9H-Carbazol-3-yl)-2-[4-(8-chloro-2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)- piperidin-1 -yl]-acetamide,
[98] N-[4-(Ethyl-phenyl-amino)-phenyl]-2-[4-(8-metoxi-2-oxo-4H- benzo[d][1 ,3]oxazin-1 -yl)-piperidin-1 -yl]-acetamide,
[99] N-(9-Hydroxy-9H-fluoren-4-yl)-2-[4-(2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidin- 1-yl]-acetamide,
[100] N-[4-(Hydroxy-phenyl-methyl)-phenyl-2-[4-(2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)- piperidin-1-yl]-acetamide,
[101] N-[4-Chloro-2-(2-chloro-benzoyl)-phenyl]-2-[4-(6-methyl-2-oxo-4H- benzo[d][1 ,3]oxazin-1 -yl)-piperidin-1 -yl]-acetamide, [102] N-[4-Chloro-2-(2-chloro-benzoyl)-phenyl]-2-[4-(2-oxo-4H-benzo[d][1 ,3]oxazin- 1 -yl)-piperidin-1 -yl]-acetamide hydrochloride,
[103] N-[4-Chloro-2-(2-chloro-benzoyl)-phenyl]-2-[4-(8-methyl-2-oxo-4H- benzo[d][1 ,3]oxazin-1-yl)-piperidin-1-yl]-acetamide hydrochloride,
[104] N-[4-Chloro-2-(2-chloro-benzoyl)-phenyl]-2-[4-(6-chloro-2-oxo-4H- benzo[d][1 ,3]oxazin-1-yl)-piperidin-1-yl]-acetamide hydrochloride,
[105] 2-[4-(7-Methyl-2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidin-1 -yl]-N-thiazole-2- yl-acetamide,
[106] 2-[4-(6-Fluoro-2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidin-1 -yl]-N-thiazole-2- yl-acetamide,
[107] N-Dibenzothiophene-2-yl-2-[4-(5-methoxy-2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)- piperidin-1 -yl]~acetamide,
[108] 2-[4-(7-Chloro-2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidin-1 -yl]-N- dibenzothiophene-2-yl-acetamide,
[109] 2-[4-(5-Hydroxy-2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidin-1 -yl]-N-(4- phenoxy-phenyl)-acetamide,
[110] 1-{1-[2-(3,4-Dihydro-1 H-isoquinoline-2-yl)-2-oxo-ethyl]-piperidin-4-yl}-1 ,4- dihydro-benzo[d][1 ,3]oxazin-2-one hydrochloride,
[111] 2-[4-(6-Fluoro-2-oxo-4H-benzo[d][1 ,3]oxazin-1-yl)-piperidin-1-yl]-N-quinoline-6- yl-acetamide,
[112] 2-[4-(6-Methoxy-2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidin-1 -yl]-N- quinoline-6-yl-acetamide, [113] 2-[4-(6-Chloro-2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidin-1 -yl]-N-quinoline- 6-yl-acetamide,
[114] 2-[4-(6-Fluoro-2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidin-1 -yl]-N-(2-methyl- benzothiazole-5-yl)-acetamide,
[115] 2-[4-(6-Chloro-2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidin-1 -yl]-N-(2-methyl- benzothiazole-5-yl)-acetamide,
[116] 2-[4-(6-Methoxy-2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidin-1 -yl]-N-(2- methyl-benzothiazole-5-yl)-acetamide,
[117] N-(3-Dimethylamino-phenyl)-2-[4-(2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)- piperidin-1 -yl]-acetamide,
[118] N-(4-Dimethylamino-phenyl)-2-[4-(2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)- piperidin-1 -yl]-acetamide,
[119] N-(3-Dimethylamino-phenyl)-2-[4-(8-methyl-2-oxo-4H-benzo[d][1 ,3]oxazin-1 - yl)-piperidin-1 -yl]-acetamide,
[120] N-(4-Dimethylamino-phenyl)-2-[4-(8-methyl-2-oxo-4H-benzo[d][1 ,3]oxazin-1 - yl)-piperidin-1 -yl]-acetamide,
[121] N-(3-Dimethylamino-phenyl)-2-[4-(6-methyl-2-oxo-4H-benzo[d][1 ,3]oxazin-1- yl)-piperidin-1 -yl]-acetamide,
[122] N-(4-Dimethylamino-phenyl)-2-[4-(6-methyl-2-oxo-4H-benzo[d][1 ,3]oxazin-1 - yl)-piperidin-1 -yl]-acetamide,
[123] N-(4-Diethylamino-phenyl)-2-[4-(2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidin- 1 -yl]-acetamide, [124] 2-{2-[4-(2-Oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidin-1 -yl]-acethylamino}- benzoic acid methyl ester,
[125] 2-{2-[4-(8-Methyl- 2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidin-1 -yl]- acethylaminoj-benzoic acid methyl ester,
[126] N-(2-Methoxy-dibenzofuran-3-yl)-2-[4-(2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)- piperidin-1 -yl]-acetamide hydrochloride,
[127] N-2-[4-(6-Chloro-2-oxo-4H-benzo[d][1 ,3]oxazin-1-yl)-piperidin-1-yl]-N-(2- methoxy-dibenzofuran-3-yl -acetamide hydrochloride,
[128] 2-{2-[4-(6-Chloro-2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidin-1 -yl]- acethylamino}-benzoic acid methyl ester,
[129] 2-{2-[4-(6-Methyl -2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidin-1 -yl]- acethylaminoj-benzoic acid methyl ester,
[130] 2-[4-(6-Chloro-2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidin-1 -yl]- N-(4- diethylamino-phenyl)-acetamide dihydrochloride,
[131] 2-[4-(6-Chloro-2-oxo-4H-benzo[d][1 ,3]oxazin-1-yl)-piperidin-1-yl]- N-{4-[ethyl- (2-hydroxy-ethyl)-amino]-phenyl}acetamide dihydrochloride,
[132] N-{4-[Ethyl-(2-hydroxy-ethyl)-amino]-phenyl}-2-[4-(6-methyl-2-oxo-4H- benzo[d][1 ,3]oxazin-1 -yl)-piperidin-1 -yl]-acetamide dihydrochloride,
[133] N-(4-Diethylamino-phenyl)-2-[4-(6-methyl-2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)- piperidin-1 -yl]-acetamide dihydrochloride,
[134] N-(4-Diethylamino-phenyl)-2-[4-(8-methyl-2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)- piperidin-1 -yl]-acetamide dihydrochloride, [135] N-{4-[ethyl-(2-hydroxy-ethyl)-amino]-phenyl}-2-[4-(8-methyl-2-oxo-4H- benzo[d][1 ,3]oxazin-1 -yl)-piperidin-1 -yl]-acetamide dihydrochloride,
[136] N-Benzo[1 ,3]dioxol-5-yl-2-[4-(2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidin-1 - yl]-acetamide,
[137] N-Benzo[1 ,3]dioxol-5-yl-2-[4-(6-methyl-2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)- piperidin-1 -yl]-acetamide,
[138] N-Benzo[1 ,3]dioxol-5-yl-2-[4-(6-chloro-2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)- piperidin-1 -yl]-acetamide,
[139] N-Benzo[1 ,3]dioxol-5-yl-2-[4-(8-methyl-2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)- piperidin-1 -yl]-acetamide,
[140] N-{4-[ethyl-(2-hydroxy-ethyl)-amino]-phenyl}-2-[4-(2-oxo-4H- benzo[d][1 ,3]oxazin-1 -yl)-piperidin-1 -yl]-acetamide dihydrochloride,
[141] 2-[4-(6-Chloro-2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidin-1 -yl]-N-(4- dimethylamino-phenyl)-acetamide dihydrochloride,
[142] N-(9-Hydroxy-9H-fluoren-3-yl)-2-[4-(4-methyl-2-oxo-4H-benzo[d][1 ,3]oxazin-1 - yl)-piperidin-1 -yl]-acetamide,
[143] N-(9-Ethyl-9H-carbazol-3-yl)-2-[4-(4-methyl-2-oxo-4H-benzo[d][1 ,3]oxazin-1 - yl)-piperidin-1 -yl]-acetamide,
[144] 2-[4-(4-Methyl-2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidin-1 -yl]-N-(4- phenoxy-phenyl)-acetamide,
[145] 2-{2-[4-(2-Oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-acetamino}-benzoic acid, [146] 1 -{1 -[2-(6-Fluoro-2-methyl-3,4-dihydro-2H-quinoline-1 -yl)-2-oxo-ethyl]- piperidin-4-yl}-1 ,4-dihydro-benzo[d][1 ,3]oxazin-2-one,
[147] 6-Chloro-1 -{1 -[2-(6-fluoro-2-methyl-3,4-dihydro-2H-quinoline-1 -yl)-2-oxo-ethyl]- piperidin-4-yl}-1 ,4-dihydro-benzo[d][1 ,3]oxazin-2-one,
[148] 1-{1-[2-(6-Fluoro-2-methyl-3,4-dihydro-2H-quinoline-1-yl)-2-oxo-ethyl]- piperidin-4-yl}-6-methyl-1 ,4-dihydro-benzo[d][1 ,3]oxazin-2-one,
[149] 1 -{1 -[2-(6-Fluoro-2-methyl-3,4-dihydro-2H-quinoline-1 -yl)-2-oxo-ethyl]- piperidin-4-yl}-8-methyl-1 ,4-dihydro-benzo[d][1 ,3]oxazin-2-one,
[150] 1 -{1 -[2-(6-Methoxy-2,2,4-trimethyl-3,4-dihydro-2H-quinoline-1 -yl)-2-oxo-ethyl]- pi perid in-4-yl}- 1 ,4-dihydro-benzo[d][1 ,3]oxazin-2-one;
[151] 6-Chloro-1-{1-[2-(6-methoxy-2,2,4-trimethyl-3,4-dihydro-2H-quinoline-1-yl)-2- oxo-ethyl]-piperidin-4-yl}-1 ,4-dihydro-benzo[d][1 ,3]oxazin-2-one,
[152] 1 -{1 -[2-(6-Methoxy-2,2,4-trimethyl-3,4-dihydro-2H-quinoline-1 -yl)-2-oxo-ethyl]- piperidin-4-yl}-8-methyl-1 ,4-dihydro-benzo[d][1 ,3]oxazin-2-one,
[153] 1 -{1 -[2-(6-Methoxy-2,2,4-trimethyl-3,4-dihydro-2H-quinoline-1 -yl)-2-oxo-ethyl]- piperidin-4-yl}-6-methyl-1 ,4-dihydro-benzo[d][1 ,3]oxazin-2-one,
[154] N-(9-Hydroxy-9H-fluoren-3-yl)-2-[4-(2-oxo-7-trifluormethyl-4H- benzo[d][1 ,3]oxazin-1 -yl)-piperidin-1 -yl]-acetamide,
[155] N-(9H-carbazol-3-yl)-2-[4-(2-oxo-7-trifluormethyl-4H-benzo[d][1 ,3]oxazin-1 -yl)- piperidin-1 -yl]-acetamide,
[156] 2-[4-(2-Oxo-7-trifluormethyl-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidin-1 -yl]-N-(4- phenoxy-phenyl)-acetamide, [157] N-(9-Ethyl-9H-carbazol-3-yl)-2-[4-(2-oxo-7-trifluormethyl-4H- benzo[d][1 ,3]oxazin-1 -yl)-piperidin-1 -yl]-acetamide,
[158] 2-4-(6,7-Difluoro-2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidin-1 -yl]-N-(9- hydroxy-9H-fluoren-3-yl)-acetamide,
[159] N-(9H-carbazol-3-yl)-2-[4-(6,7-difluoro-2-oxo-4H-benzo[d][1 ,3]oxazin-1-yl)- piperidin-1 -yl]-acetamide,
[160] 2-4-(6,7-Difluoro-2-oxo-4H-benzo[d][1 ,3]oxazin-1-yl)-piperidin-1-yl]-N-(4- phenoxy-phenyl)-acetamide,
[161] 2-4-(6,7-Difluoro-2-oxo-4H-benzo[d][1 ,3]oxazin-1-yl)-piperidin-1-yl]-N-(9-ethyl- 9H-carbazol-3-yl)-acetamide,
[162] 2-[4-(4-Methyl-2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidin-1 -yl]-N-(9-oxo-9H- fluoren-3-yl)-acetamide,
[163] 2-[4-(6-ChIoro-2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidin-1 -yl]-N-(3- dimethylamino-phenyl)-acetamide.
The benzoxazinone-derived compounds of general formula (la), wherein R1a-R11a and Aa have the meaning given above, may be prepared preferably by reaction of one compound of general formula (Ila),
H
.NL R 10a- ~R 11a
(Ila)
wherein
R10a and R11a have the meaning given above, with at least one compound of general formula (Ilia),
Figure imgf000039_0001
wherein
Aa has the meaning given above, Fa represents halogen, hydroxy or an O-acyl group and Ga represents halogen, preferably chlorine. The reaction occurs in inert solvents and in the presence of a base or/and auxiliary agents, resulting in compounds of general formula (IVa)
Figure imgf000039_0002
(IVa),
wherein
A ι a , r Ga , D R10 a „„ndJ D R11 have the above defined meaning.
These compounds are reacted wit amines of general fomula (Va) and/or a salt, preferably hydrochloride, thereof,
Figure imgf000040_0001
(Va),
wherein R1a to R9a have the meaning as definded above, in a suitable reaction medium and in the presence of base and/or auxiliary agents when it is necessary.
The process may be illustrated as an example by the following reaction scheme:
Scheme 1 :
Figure imgf000041_0001
(Ila) (Ilia) (IVa)
Figure imgf000041_0002
wherein R >1a + to-- ι R->11a and A have the meaning as given above.
Suitable reaction media are e.g. organic solvents, such as ethers, preferably diethyl ether, dioxane, tetrahydrofurane, dimethyl glycol ether, or alcohols, e.g. methanol, ethanol, propanol, isopropanol, butanol, isobutanol, tert-butanol, or hydrocarbons, preferably benzene, toluene, xylene, hexane, cyclohexane, petroleum ether, or halogenated hydrocarbons, e.g. dichloromethane, trichloromethane, tetrachloromethane, dichloroethylene, trichloroethylene, chlorobenzene or/and other solvents, preferably ethyl acetate, triethylamine, pyridine, dimethylsulfoxide, diemthylformamide, hexamethylphosphoramide, acetonitril, acetone or nitromethane, are included. Mixtures based one or more of the afore mentioned solvents may also be used. Bases that may be used in the processes according to the present invention are generally organic or inorganic bases, preferably alkali metal hydroxides, e.g. sodium hydroxyde or potassium hydroxyde, or obtained from other metals such as barium hydroxyde or different carbonates, preferably potassium carbonate, sodium carbonate, calcium carbonate, or alkoxides, e.g. sodium methoxide, potassium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide or potassium tert-butoxide, or organic amines, preferably triethylamine, diisopropyethylamine or heterocycles, e.g. 1 ,4-diazabicyclo[2.2.2] octane, 1 ,8-diazabicyclo[5.4.0]undec-7-ene pyridine, diamino pyridine, dimethylaminopyridine, methylpiperidine or morpholine. Alkali metals such as sodium or ist hydrides, e.g. sodium hydride, may also be used. Mixtures based one or more of the afore mentioned bases may also be used.
The above mentioned bases may be used for the process as auxiliary agents, when appropriate. Other suitable auxiliary agents for the above mentioned reactions are, for example, dehydrating agents like carbodiimides, e.g. diisopropylcarbodiimide, cyclohexylcarbodiimide or N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride, or carbonylic compounds, e.g. carbonyldiimidazol or compounds like isobutylchloroformiate or methansulfonyl chloride, among others. These reagents are generally used in an amount comprised between 0.5 and 3 mol versus 1 mol of the corresponding carboxylic acids. These bases are generally used in an amount comprised between 0.05 and 10 mol versus 1 mol of the compounds of the invention.
During some of the synthetic reactions described or while preparing the compounds of general formulas (la), (Ila), (Ilia), (IVa) and (Va), the protection of sensitive groups or of reagents may be necessary and/or desirable. This can be performed by using conventional protective groups like 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 eliminated in the convenient later stage by means of methods well-known to those skilled in the art. The compounds of general formulas (Ila), (Ilia), (IVa) and (Va) are either commercially available or can be produced according to methods known to those skilled in the art. The reaction of a compound of formula (IVa) with a compound of formula (Va) yield a benzoxazinone-derived compound of general formula (la) using conventional methods known to those skilled in the art.
The substituted benzoxazinone compounds of general formula (Va), wherein R5a represents H, are preferably synthesized from substituted anthranilic acid or esters thereof by reduction to the corresponding benzylalcohol (see scheme 2, method A). By reductive amination with 1-Boc-4-piperidone the Boc-piperidin-moiety is introduced. The benzoxazinone-ring is formed by cyclisation with triphosgene, a treatment in acidic media allows the elimination the protecting group of the piperidine according to the method described in Williams et al., J. Med. Chem. 1995 38, 4634 and later by Bell et al., J. Med. Chem., 1998, 41 , 2146 which are hereby incorporated by reference and form part of the disclosure. By reacting such a substituted benzoxazinone compound of general formula (Va) with a halogenated amide of general formula (IVa) benzoxazinone derived compounds of general formula (la) are obtained.
By reduction of the corresponding ketones with NaBH4 in methanol or via other conventional methods (see scheme 2, method B, R5=Z) R5a substituted 2-amino- benzylalcohols are obtained, intermediates which allow, via the same previous synthetic process, to obtain compounds of general formula (la), wherein R5a may be an unbranched or branched, saturated or unsaturated, optionally at least mono- substituted aliphatic radical, optionally may contain at least an heteroatom as ring member of a cycloaliphatic ring or alkyl (denoted by Z in the method B)
scheme 2:
hylam ine
Figure imgf000044_0001
The compounds of general formula (IVa) are commercially available or may be produced according to scheme 1 by conventional methods known to those skilled in the art. Essentially the respective compound of general formula (Ila) is reacted with chloroacetyl chloride or the respective compound of general formula (Ilia) in the presence of an organic reaction medium, preferably dichloromethane and a base, preferably triethylamine and/or diisopropylethylamine.
The salts of benzoxazinone-derived compounds of general formula (la), wherein R1a - R11a and Aa have the meaning as definded above, may be prepared in a way that at least one compound of general formula (la) having at least one basic group is reacted with an inorganic or organic acid, preferably in the presence of a suitable reaction medium. Suitable reaction media are the ones given above. Suitable inorganic acids are for example hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, nitric acid, suitable organic acids are e.g. citric acid, maleic acid, fumaric acid, tartaric acid, or derivatives thereof, such as p-toluenesulfonic acid, methanesulfonic acid or camphersulfonic acid.
The salts of benzoxazinone-derived compounds of general formula (la), wherein R1a - R11a and Aa have the meaning as definded above, may be prepared in a way that at least one compound of general formula (la) having at least one acidic group is reacted with one or more suitable bases, preferably in the presence of a suitable reaction medium. Suitable bases are e.g. hydroxides, carbonates or alkoxides, which include suitable cations, derived e.g. from alkaline metals, alkaline earth metals or organic cations, e.g. [NHnR4-n]+ > wherein n is 0, 1 , 2, 3 or 4 and R represents a branched or unbranched Cι-4-alkyl-radical.
Solvates, preferably hydrates, of the Benzoxazinone-derived compounds of general formula (la) may also be obtained by standard procedures known to those skilled in the art.
If the Benzoxazinone-derived compounds of general formula (la) are obtained in form of a mixture of stereoisomers, particularly enantiomers or diastereomers, said mixtures may be separated by standard procedures known to those skilled in the art, e.g. chromatographic methods or crystallization with chiral reagents.
The purification and isolation of the Benzoxazinone-derived compounds of general formula (la) or a corresponding stereoisomer, or salt, or solvate respectively, if required, may be carried out by conventional methods known to those skilled in the art, e.g. chromatographic methods or recrystallization.
Preferably, the active substance combination of the present invention may comprise as a component (B) at least one compound with 5-HT6 receptor affinity, which is selected form the group consisting of the benzoxazinone-derived sulfonamide compounds of general formula (lb),
Figure imgf000046_0001
(lb)
wherein
R1b, R2b, R3b, R4b are each independently selected from the group consisting of hydrogen, halogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic radical, which may be bonded via an optionally at least mono- substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, an optionally at least mono- substituted aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ringsystem, a nitro group, a cyano group, - OR10b, -0(C=0)R11b, -(C=O)-O-R11b, -SR12b, -SOR12b, -S02R12b, -NH-SO2R12b, - SO2NH2 and a -NR13bR14b moiety, R5b represents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical or a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic radical,
R6b, R7b, R8b, R9b are each independently selected from the group consisting of hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic radical, a cyano group and a COOR15b moiety,
Wb represents an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical,
a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic radical, which may be bonded via an optionally mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,
an optionally at least mono-substituted aryl or heteroaryl radical, which may be bonded via an optionally mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,
NR16bR17b-moiety,
or a COR18b-moiety,
R10b represents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, or an optionally at least mono-substituted aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,
R11b represents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, or an optionally at least mono-substituted aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,
R12b represents an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic radical, which may be bonded via an optionally at least mono- substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, or an optionally at least mono- substituted aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,
R13b and R14b each are independently selected from the group consisting of hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic radical, which may be bonded via an optionally at least mono- substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, or an optionally at least mono- substituted aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, or R13b and R14b together with the bridging nitrogen atom form a saturated, unsaturated or aromatic heterocyclic ring, which may be at least mono-substituted and/or contain at least one further heteroatom as a ring member,
R15b represents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic radical or an optionally at least mono-substituted aryl- or heteroaryl radical, which may be bonded via an optionally at least mono- substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,
R16b represents an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical,
R17b represents an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, and
R18b represents an optionally at least mono-substituted aryl radical,
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 salt thereof, preferably physiologically acceptable salts thereof, or a solvate, respectively,
and sulphonamide-derived compounds of general formula (Ic),
Figure imgf000050_0001
(Ic)
wherein
R1c represents hydrogen, an optionally at least mono-substituted, linear or branched alkyl radical, an optionally at least mono-substituted phenyl radical or an optionally at least mono-substituted benzyl radical,
R2c represents a -NR cR5c moiety or a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic radical, which may be condensed with a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing mono- or bicyclic cycloaliphatic ringsystem,
R3c represents hydrogen or an optionally at least mono-substituted, linear or branched alkyl radical,
R4c and R5c, identical or different, represent hydrogen or an optionally at least mono- substituted, linear or branched alkyl radical, or R4c and R5c together with the bridging nitrogen atom form an optionally at least mono- substituted, saturated or unsaturated heterocyclic ring, which may contain at least one further heteroatom as a ring member and/or may be condensed with a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing mono- or bicyclic cycloaliphatic ringsystem,
Ac represents an optionally at least mono-substituted mono- or polycyclic aromatic ringsystem, which may be bonded via an optionally at least mono-substituted alkylene group, an optionally at least mono-substituted alkenylene group or an optionally at least mono-substituted alkynylene group and/or may contain at least one heteroatom as a ring member in one or more of its rings,
nc represents 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 corresponding physiologically acceptable salt or a corresponding solvate,
and compounds of the general formula (Id)
Figure imgf000051_0001
(Id) R1d represents a -NR8dR9d radical or a saturated or unsaturated, optionally at least mono-substituted cycloaliphatic radical, which may 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, optionally at least one heteroatom as a ring member containing mono- or bicyclic cycloaliphatic ring system,
R2d, R3d, R5d, R6d and R7d, 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 radical or an optionally at least mono-substituted heteroaryl radical,
R4d is hydrogen or a saturated or unsaturated, linear or branched, optionally at least mono-substituted aliphatic radical,
R8d and R9d, identical or different, each represent hydrogen or a saturated or unsaturated, linear or branched, optionally at least mono-substituted aliphatic radical,
or
R8d and R9d together with 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 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,
Ad 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
nd is O, 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, and
and sulphonamide-derived compounds of general formula (Ie),
Figure imgf000053_0001
(Ie) wherein
R1e represents a -NR8eR9e 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,
R2e, R3e, R4e, R6e and R7e, 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 radical or an optionally at least mono-substituted heteroaryl radical,
R represents hydrogen or a saturated or unsaturated, linear or branched, optionally at least mono-substituted aliphatic radical, R8e and R9e, identical or different, each represent hydrogen or a saturated or unsaturated, linear or branched, optionally at least mono-substituted aliphatic radical,
or
R8e and R9e 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,
Ae 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
ne is O, 1 , 2, 3 or 4;
optionally in the form of one of its stereoisomers, preferably enantiomers or diastereomers, its racemate or in the form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, at any mixture ratio, or a corresponding, physiologically acceptable salt, or a corresponding solvate and sulphonamide-derived compounds of general formula (If),
Figure imgf000055_0001
(If)
wherein
R1f represents a -NR8fR9f radical or a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as a ring member containing cycloaliphatic radical, which may be condensed with a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as a ring member containing mono- or bicyclic cycloaliphatic ring system,
R2f, R3f, R4f, R5f and R7f, 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 radical or optionally at least mono-substituted heteroaryl radical,
R6f represents hydrogen or a saturated or unsaturated, linear or branched, optionally at least mono-substituted aliphatic radical,
R8f and R9f, identical or different, each represent hydrogen or a saturated or unsaturated, linear or branched, optionally at least mono-substituted aliphatic radical,
or
R8f and R9f, 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 may be condensed with a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as a ring member containing mono- or bicyclic cycloaliphatic ring system,
Af 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
nf is O, 1 , 2, 3 or 4;
optionally in the form of one of its stereoisomers, preferably enantiomers or diastereomers, its racemate or in the form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, at any mixture ratio, or a corresponding, physiologically acceptable salt, or a corresponding solvate
and sulphonamide-derived compounds of general formula (Ig).
Figure imgf000056_0001
(ig) wherein
R1g is a -NR8gR9g 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 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,
R2g, R3g, R4g, R5g and R6g, 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 radical or an optionally at least mono-substituted heteroaryl radical,
R7g represents hydrogen or a saturated or unsaturated, linear or branched, optionally at least mono-substituted aliphatic radical,
R8g and R9g, identical or different, represent hydrogen or a saturated or unsaturated, linear or branched, optionally at least mono-substituted aliphatic radical,
or
R8g and R9g 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,
Ag 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,
ng is O, 1 , 2, 3 or 4; optionally in the form of one of its stereoisomers, preferably enantiomers or diastereomers, its racemate or in the form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, at any mixture ratio, or a corresponding, physiologically acceptable salt, or a corresponding solvate,
and sulphonamide-derived compounds of general formula (Ih)
Figure imgf000058_0001
(Ih)
wherein
R h represents a -NR7hR8h radical or a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as a ring member containing cycloaliphatic radical, which may be condensed with a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as a ring member containing mono- or bicyclic cycloaliphatic ring system,
R2h, R3h, R4h, R5h and R6h, identical or different, each represent hydrogen, halogen, cyano, nitro, a saturated or unsaturated, linear or branched aliphatic radical, a linear or branched alkoxy radical, a linear or branched alkylthio radical, hydroxy, trifluoromethyl, a saturated or unsaturated cycloaliphatic radical, an alkylcarbonyl radical, a phenylcarbonyl or a -NR9hR10h group,
R7h and R8h, identical or different, each represent hydrogen or a saturated or unsaturated, optionally at least mono-substituted linear or branched aliphatic radical, or
R7h and R8h, together with the bridging nitrogen atom form a saturated or unsaturated, optionally at least mono-substituted, optionally at least one further heteroatom as a ring member containing heterocyclic ring which may be condensed with a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as a ring member containing mono- or bicyclic cycloaliphatic ring system,
R9h and R10h, identical or different, each represent hydrogen or a saturated or unsaturated, linear or branched, optionally at least mono-substituted aliphatic radical,
or
R9h and R10h, together with the bridging nitrogen atom form a saturated or unsaturated, optionally at least mono-substituted, optionally at least one further heteroatom as a ring member containing heterocyclic ring which may be condensed with a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as a ring member containing mono- or bicyclic cycloaliphatic ring system,
Ah and Bh, identical or different, each represent a saturated or unsaturated, linear or branched, optionally at least mono-substituted aliphatic radical
or
Ah and Bh, together with the carbon atom to which they are bonded, form a saturated or unsaturated, but not aromatic, optionally at least mono-substituted cycloalkyl ring,
and
nh is O, 1 , 2, 3, or 4, 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.
The persons skilled in the state of the art understand that the active substance combination according to the present invention may comprise one or more compounds of one class of active substances with 5-HT_ receptor affinity or one or more compounds of one or more classes of active substances with 5-HTβ receptor affinity.
If one or more of the residues R1b-R17b and Wb represents an aliphatic radical, which is substituted by one or more substituents, unless defined otherwise, each of these substituents may preferably be selected from the group consisting of hydroxy, halogen, branched or unbranched C-ι-4-alkoxy, branched or unbranched C-ι-4-perfluoroalkoxy, branched or unbranched C- -perfluoroalkyl, amino, carboxy, amido, cyano, nitro, -S02NH2, -CO-C-ι-4-alkyl, -SO-Cι- -alkyl, -S02-Ci- -alkyl, -NH-SO2-Cι-4-alkyl , wherein the C-M-alkyl may in each case be branched or unbranched, an unsubstituted or at least mono-substituted phenyl or naphthyl radical and an unsubstituted or at least mono-substituted furanyl-, thienyl-, pyrrolyl-, imidazolyl-, pyrazolyl-, pyridinyl-, pyrimidinyl-, quinolinyl- and isoquinolinyl radical, more preferably be selected from the group consisting of hydroxy, F, Cl, Br, methoxy, ethoxy, CF3 and an unsubstituted phenyl radical. If any one of the above mentioned substitutents itself is at least mono-substituted, said substituents may preferably be selected from the group consisting of F, Cl, methyl and methoxy.
If one or more of the residues R1b-R15b represents or comprises a cycloaliphatic radical, which is substituted by one or more substituents, unless defined otherwise, each of these substituents may preferably be selected from the group consisting of hydroxy, halogen, branched or unbranched C-M-alkyl, branched or unbranched C1-4- alkoxy, branched or unbranched Ci-4-perfluoroalkoxy, phenoxy, benzoyl, cyclohexyl, branched or unbranched Cι-4-perfluoroalkyl, -NRAbRBb wherein RAb, RBb are each independently selected from the group consisting of H, a branched or unbranched Ci- 4-alkyl-radical, -CH2-CH2-OH and phenyl, carboxy, keto, amido, cyano, nitro, - SO2NH2, -CO-C- -alkyl, -CO-OCι-4-alkyl, -SO-CM-alkyl, -S02-Ci-4-alkyl, -NH-S02-C!. 4-alkyl, wherein Cι-4-alkyl may in each case be branched or unbranched, unsubstituted or at least mono-substituted phenyl or naphthyl and unsubstituted or at least mono-substituted furanyl-, thienyl-, pyrrolyl-, imidazolyl-, pyrazolyl-, pyridinyl-, pyrimidinyl-, quinolinyl- and isoquinolinyl radical, more preferably be selected from the group consisting of hydroxy, F, Cl, Br, methyl, ethyl, methoxy, ethoxy, keto, benzoyl, phenoxy, cyclohexyl, -CF3, -CO-CH3, -CO-OCH3, -NRAbRBb wherein RAb, RBb are each independently selected from the group consisting of H, a branched or unbranched Ci -4-alkyl-radical, -CH2-CH2-OH and phenyl, and an unsubstituted phenyl radical. If any one of the above mentioned substitutents itself is at least mono- substituted, said substituents may preferably be selected from the group consisting of F, Cl, methyl and methoxy.
If one or more of the residues R1b-R4b, R10b-R15b and Wb comprises an alkylene group, which is substituted by one or more substituents, unless defined otherwise, each of these substituents may preferably be selected from the group consisting of hydroxy, halogen, branched or unbranched Cι-4-alkoxy, branched or unbranched Ci. 4-alkyl, branched or unbranched Cι-4-perfluoroalkoxy, branched or unbranched C1-4- perfluoroalkyl, amino, carboxy, amido, cyano, nitro, -SO2NH2, -CO-C-M-alkyl, -SO-C1- 4-alkyl, -Sθ2-Cι- -alkyl, -NH-S02-CM-alkyl, wherein C-M-alkyl may be branched or unbranched, an unsubstituted or at least mono-substituted phenyl or naphthyl radical and an unsubstituted or at least mono-substituted furanyl-, thienyl-, pyrrolyl-, imidazolyl-, pyrazolyl-, pyridinyl-, pyrimidinyl-, quinolinyl- and isoquinolinyl radical, more preferably be selected from the group consisting of hydroxy, F, Cl, Br, methyl, methoxy, ethoxy, CF3 and unsubstituted phenyl. If any one of the above mentioned substitutents itself is at least mono-substituted, said substituents may preferably be selected from the group consisting of F, Cl, methyl and methoxy.
If one or more of the residues R1b-R4b and R10b-R15b comprises a mono- or polycyclic ringsystem, which is substituted by one or more substituents, unless defined otherwise, each of these substituents may preferably be selected from the group consisting of hydroxy, halogen, branched or unbranched C-M-alkyl, branched or unbranched C-ι-4-alkoxy, branched or unbranched Ci_4-perfluoroalkoxy, branched or unbranched Cι-4-perfluorocarbonyl, branched or unbranched C- -perfluoroalkyl, amino, carboxy, amido, cyano, keto, nitro, -SO2NH2, -CO-C-M-alkyl, -SO-Cι-4-alkyl, - SO2-C-ι-4-alkyl, -NH-S02-C-ι-4-alkyl, wherein Cι-4-alkyl may be branched or unbranched, an unsubstituted or at least mono-substituted phenyl or naphthyl radical and unsubstituted or at least mono-substituted furanyl-, thienyl-, pyrrolyl-, imidazolyl-, pyrazolyl-, pyridinyl-, pyrimidinyl-, quinolinyl- and isoquinolinyl, more preferably from the group consisting of hydroxy, F, Cl, Br, methyl, ethyl, methoxy, ethoxy, CF3, - (C=0)-CF3, keto, cyano and an unsubstituted phenyl radical. If any one of the above mentioned substitutents itself is at least mono-substituted, said substituents may preferably be selected from the group consisting of F, Cl, methyl and methoxy.
If one or more of the residues R1b-R4b, R10b-R15b and R18b represents or comprises an aryl radical, which is substituted by one or more substituents, unless defined otherwise, each of these substituents may preferably be selected from the group consisting of hydroxy, halogen, branched or unbranched C-ι_4-alkoxy, branched or unbranched Cι- -alkyl, branched or unbranched Cι-4-perfluoroalkoxy, unsubstituted or at least mono-substituted phenoxy, unsubstituted or at least mono-substituted benzoyl, cyclohexyl, branched or unbranched Cι-4-perfluoroalkyl, NRAbRB wherein RAb, RBb are each independently selected from the group consisting of H, a branched or unbranched d-4-alkyl-radical, -CH2-CH2-OH and phenyl, carboxy, amido, cyano, -CH(OH)(phenyl), nitro, -S02NH2, -CO-C^-alkyl, -CO-OC^-alkyl, -SO-Cι-4-alkyl, - Sθ2-Cι-4-alkyl, -NH-S02-Cι-4-alkyl, wherein C^-alky! may be branched or unbranched, an unsubstituted or at least mono-substituted phenyl or naphthyl radical and unsubstituted or at least mono-substituted furanyl-, thienyl-, pyrrolyl-, imidazolyl-, pyrazolyl-, pyridinyl-, pyrimidinyl-, quinolinyl- and isoquinolinyl radical, more preferably be selected from the group consisting of hydroxy, F, Cl, Br, methyl, ethyl, cyano, nitro, -CH(OH)(phenyl), methoxy, ethoxy, unsubstituted or at least mono- substituted benzoyl, unsubstituted or at least mono-substituted phenoxy, cyclohexyl, CF3, OCF3, -CO-CH3, -CO-OCH3, SO2-CH3, -NRAbRBb wherein RAb, RB are each independently selected from the group consisting of H, a branched or unbranched C-i- 4-alkyl-radical, -CH2-CH2-OH and phenyl, and an unsubstituted phenyl radical. If any of the above mentioned substitutents itself is at least mono-substituted, said substituents may preferably be selected from the group consisting of F, Cl, Br, CF3, OCF3, methyl and methoxy. If one or more of the residues R1b-R4b and R10b-R15b represents or comprises a heteroaryl radical, which is substituted by one or more substituents, unless defined otherwise, each of these substituents may preferably be selected from the group consisting of hydroxy, halogen, branched or unbranched Cι_4-alkoxy, branched or unbranched C^-alky!, branched or unbranched Ci-4-perfluoroalkoxy, unsubstituted or at least mono-substituted phenoxy, unsubstituted or at least mono-substituted benzoyl, cyclohexyl, branched or unbranched Ci-4-perfluoroalkyl, NRAbRBb wherein RAb, RBb are each independently selected from the group consisting of H, a branched or unbranched C-M-alkyl-radical, -CH2-CH2-OH and phenyl, carboxy, amido, cyano, - CH(OH)(phenyl), nitro, -S02NH2, -CO-C- -alkyl, -CO-OC1-4-alkyl, SO-Cι-4-alkyl, S02- Cι-4-alkyl, -NH-S02-C<M-alkyl, wherein Cι-4-alkyl may be branched or unbranched, an unsubstituted or at least mono-substituted phenyl or naphthyl radical and an unsubstituted or at least mono-substituted furanyl-, thienyl-, pyrrolyl-, imidazolyl-, pyrazolyl-, pyridinyl-, pyrimidinyl-, quinolinyl- and isoquinolinyl radical, more preferably be selected from the group consisting of hydroxy, F, Cl, Br, methyl, ethyl, cyano, nitro, -CH(OH)(phenyl), methoxy, ethoxy, unsubstituted or at least mono- substituted benzoyl, unsubstituted or at least mono-substituted phenoxy, cyclohexyl, CF3, OCF3, -CO-CH3, -CO-OCH3, -SO2CH3, -NRAbRBb wherein RAb, RBb are each independently selected from the group consisting of H, a branched or unbranched Ci-4-alkyl-radical, -CH2-CH2-OH and phenyl, and an unsubstituted phenyl radical. If any one of the above mentioned substitutents itself is at least mono-substituted, said substituents may preferably be selected from the group consisting of F, Cl, Br, CF3, OCF3, methyl and methoxy.
If R13b and R14b form a heterocyclic ring, which is substituted by one or more substituents, unless defined otherwise, each of these substituents may preferably be selected from the group consisting of hydroxy, halogen, branched or unbranched Cι-4-alkoxy, branched or unbranched Cι- -alkyl, branched or unbranched C1.4- perfluoroalkoxy, branched or unbranched C-M-perfluoroalkyl, amino, carboxy, amido, cyano, nitro, -S02NH2, -CO-C-M-alkyl. -SO-C-M-alkyl, -S02-Ci.4-alkyl, -NH-SO2-Ci-4-alkyl, wherein Cι-4-alkyl may be branched or unbranched, an unsubstituted or at least mono-substituted phenyl or naphthyl radical and an unsubstituted or at least mono-substituted furanyl-, thienyl-, pyrrolyl-, imidazolyl-, pyrazolyl-, pyridinyl-, pyrimidinyl-, quinolinyl- and isoquinolinyl radical, more preferably be selected from the group consisting of hydroxy, F, Cl, Br, methoxy, ethoxy, methyl, CF3 and an unsubstituted phenyl radical. If any of the above mentioned substitutents itself is at least mono-substituted, said substituents may preferably be selected from the group consisting of F, Cl, methyl and methoxy.
If R13b and R14b form a heterocyclic ring, which contains one or more further heteroatoms as ring members, unless defined otherwise, each of these heteroatoms may preferably be selected from the group consisting of N, O and S, more preferably from the group consisting of N and O.
If one or more of the residues R1b-R15b and Wb represents or comprises a cycloaliphatic radical, which contains one or more heteroatoms as ring members, unless defined otherwise, each of these heteroatoms may preferably be selected from the group consisting of N, O, S and P, more preferably from the group consisting of N, O and S.
If one or more of the residues R1b-R4b, R10b- 15b and Wb represents or comprises an heteroaryl radical, which contains one or more heteroatoms as ring members, unless defined otherwise, each of these heteroatoms may preferably be selected from the group consisting of N, O, S and P, more preferably from the group consisting of N, O and S.
If Wb represents or comprises a cycloaliphatic radical, a heteroaryl radical, an aryl radical and/or a mono- or polycyclic ring system which is substituted by one or more substituents, unless defined otherwise, each of these substituents may preferably be selected from the group consisting of hydroxy, nitro, carboxy, cyano, keto, halogen, Cι_2o-alkyl, partially fluorinated C alkyl, partially chlorinated C alkyl, partially brominated C alkyl, C-ι-5-alkoxy, partially fluorinated C alkoxy, partially chlorinated C-M alkoxy, partially brominated CM alkoxy, C2-6-alkenyl, Sθ2-Cι-4-alkyl, - =O)-0-C1.5-alkyl, -(C=0)-Cl, -S-d-4-alkyl-, -(C=0)-H, -NH-
Figure imgf000064_0001
-(C=O)-C1.4-perfluoroalkyl, -NRAbRBb, wherein RAb and RBb are independently selected from the group consisting of H, Cι-4-alkyl and phenyl, NH-
Figure imgf000064_0002
(1 ,3-Dihydro-1-oxo-2H-isoindol-2-yl), N-Phthalimidinyl-, (1 ,3-Dioxo-2-azaspiro[4,4]-non-2-yl, substituted or unsubstituted phenyl, -S02-phenyl, phenoxy, pyridinyl, pyridinyloxy, pyrazolyl, pyrimidinyl, pyrrolidinyl-, -Sθ2-pyrrolidinyl, morpholinyl, S02-morpholinyl-, thiadiazolyl, oxadiazolyl, oxazolyl, thiazolyl, isoxazolyl, 0-CH2-thiazolyl,-, NH-phenyl, and -C1-4- Alkylen-NH-(C=0)-phenyl, more preferably from the group consisting of hydroxy, nitro, carboxy, cyano, keto, F, Cl, Br, I, C^-alkyl, CH2F, CHF2, CF3, CH2CI, CH2CI2, CCI3, CH2Br, CHBr2, CBr3, OCF3, OCHF2, OCH2F, O-CH2-CF3, vinyl, S02-CH3, - (C=O)-CH3, -(C=0)-C2H5, -(C=0)-0-CH3, -(C=0)-0-C2CH5, -(C=0)-Cl, -S-CH3-, - (C=0)-H, -NH-(C=O)-NH-CH3, -(C=0)-CF3, dimethylamino, diethylamino, di-n- propylamino, di-iso-propylamino, di-n-butylamino, di-tert-butyamino, NH-(C=0)-CH3, - CH2-(C=0)-CH3, -CH2-(C=O)-C2H5, (1 ,3-Dihydro-1-oxo-2H-isoindol-2-yl), N- Phthalimidinyl-, (1 ,3-Dioxo-2-azaspiro[4,4]-non-2-yl, substituted or unsubstituted phenyl, -S02-phenyl, phenoxy, pyridinyl, pyridinyloxy, pyrazolyl, pyrimidinyl, pyrrolidinyl-, -S02-pyrrolidinyl, morpholinyl, Sθ2-morpholinyl-, thiadiazolyl, oxadiazolyl, oxazolyl, thiazolyl, isoxazolyl, 0-CH2-thiazolyl,-, NH-phenyl, and -CH2- NH-(C=0)-phenyl.
If any of the afore mentioned substituents itself is substituted by one or more substituents, said substituents may preferably be selected from the group consisting of halogen, nitro, cyano, hydroxy, -(C=0)-Cι.4-alkyl, Cι- -alkyl, at least partially fluorinated C-M-alkyl, at least partially chlorinated Cι. -alkyl, at least partially brominated C-M-alkyl, -S-CM-alkyl,
Figure imgf000065_0001
-(C=0)-CH2-F, -(C=0)-CH2- Cl, -(C=0)-CH2-Br, preferably from the group consisting of F, Cl, Br, CH2F, CHF2, CF3, CH2CI, CHCI2, CCI3, CH2Br, CHBr2, CBr3, nitro, cyano, hydroxy, -(C=0)-CH3, CH3, C2H5, -S-CH3, -C(=0)-0-CH3, -C(=O)-0-C2H5, -(C=O)-CH2-F, -(C=O)-CH2-CI and -(C=0)-CH2-Br.
The substituents for Wb may preferably also be selected from the group consisting of hydroxy, nitro, carboxy, cyano, keto, halogen, Cι-20-alkyl, partially fluorinated CM alkyl, partially chlorinated CM alkyl, partially brominated C alkyl, Cι-5-alkoxy, partially fluorinated CM alkoxy, partially chlorinated C alkoxy, partially brominated C1-4 alkoxy, C2-6-alkenyl, SO2-Cι-4-alkyl, -(C=O)-C1.5-alkyl, -(C=0)-O-C1.5-alkyl, - (C=O)-CI, -S-CM-alkyl-, -(C=O)-H, -NH-(C=O)-NH-C1.5-alkyl, -(C=0)-CM- perfluoroalkyl, -NRARB, wherein RA and RB are independently selected from the group consisting of H, Cι-4-alkyl and phenyl, NH-(C=0)-Ci-5-alkyl, -C1-5-alkylen-(C=O)-C1-5- alkyl, (1 ,3-Dihydro-1-oxo-2H-isoindol-2-yl), N-Phthalimidinyl-, (1 ,3-Dioxo-2- azaspiro[4,4]-non-2-yl, substituted or unsubstituted phenyl, -Sθ2-phenyl, phenoxy, pyridinyl, pyridinyloxy, pyrazolyl, pyrimidinyl, pyrrolidinyl-, -Sθ2-pyrrolidinyl, morpholinyl, Sθ2-morpholinyl-, thiadiazolyl, oxadiazolyl, oxazolyl, thiazolyl, isoxazolyl, 0-CH2-thiazolyl,-, NH-phenyl, and -C1.4-Alkylen-NH-(C=O)-phenyl, more preferably from the group consisting of hydroxy, nitro, carboxy, cyano, keto, F, Cl, Br, I, C1-12- alkyl, CH2F, CHF2, CF3, CH2CI, CH2CI2, CCI3, CH2Br, CHBr2, CBr3, OCF3, OCHF2, OCH2F, 0-CH2-CF3, vinyl, S02-CH3, -(C=0)-CH3, -(C=0)-C2H5, -(C=0)-0-CH3, - (C=0)-0-C2CH5, -(C=0)-Cl, -S-CH3-, -(C=0)-H, -NH-(C=0)-NH-CH3, -(C=0)-CF3, dimethylamino, diethylamino, di-n-propylamino, di-iso-propylamino, di-n-butylamino, di-tert-butyamino, NH-(C=0)-CH3, -CH2-(C=0)-CH3, -CH2-(C=0)-C2H5, (1 ,3-Dihydro- 1-oxo-2H-isoindol-2-yl), N-Phthalimidinyl-, (1 ,3-Dioxo-2-azaspiro[4,4]-non-2-yl, substituted or unsubstituted phenyl, -SO2-phenyl, phenoxy, pyridinyl, pyridinyloxy, pyrazolyl, pyrimidinyl, pyrrolidinyl-, -SO2-pyrrolidinyl, morpholinyl, S02-morpholinyl-, thiadiazolyl, oxadiazolyl, oxazolyl, thiazolyl, isoxazolyl, 0-CH2-thiazolyl,-, NH-phenyl, and -CH2-NH-(C=0)-phenyl.
If any of the afore mentioned substituents itself is substituted by one or more substituents, said substituents may preferably be selected from the group consisting of halogen, nitro, cyano, hydroxy, -(C=O)-Cι-4-alkyl, CM-alkyl, at least partially fluorinated CM-alkyl, at least partially chlorinated CM-alkyl, at least partially brominated d-4-alkyl, -S-d-4-alkyl, -C(=0)-O-C-i-5-alkyl, -(C=O)-CH2-F, -(C=0)-CH2- Cl, -(C=0)-CH2-Br, preferably from the group consisting of F, Cl, Br, CH2F, CHF2, CF3, CH2CI, CHCI2, CCI3, CH2Br, CHBr2, CBr3, nitro, cyano, hydroxy, -(C=0)-CH3, CH3, C2H5, -S-CH3, -C(=0)-O-CH3, -C(=0)-0-C2H5, -(C=0)-CH2-F, -(C=O)-CH2-CI and -(C=0)-CH2-Br.
The use of compounds of general formula (lb) is preferrred, wherein R1b, R2b, R3b, R4b are each independently selected from the group consisting of H, F, Cl, Br, an unbranched or branched, saturated or unsaturated, optionally at least mono- substituted Cι-6-aliphatic radical, a saturated or unsaturated, optionally at least mono- substituted, optionally at least one heteroatom as ring member containing C3-8- cycloaliphatic radical, which may be bonded via an optionally at least mono- substituted C-i-β-alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, an optionally at least mono- substituted, 5- or 6-membered aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted C-ι-6-alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ringsystem, a nitro, cyano, -OR10b, -OC(=0)R11b, -SR12 , -SOR 2b, -SO2R12b, -NH-S02R12b, -S02NH2 and a -NR 3bR14b moiety,
preferably selected from the group consisting of H, F, Cl, Br, a saturated, branched or unbranched, optionally at least mono-substituted C-ι-3-aliphatic radical, a saturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing C5- or Cβ- cycloaliphatic radical, which may be bonded via an optionally at least mono-substituted C or C2-alkylene group, a nitro, cyano, -OR10b, - OC(=0)R11b, -SR12b and -NR13 R14b moiety,
more preferably selected from the group consisting of H, F, Cl, CH3, CH2CH3, CF3, CF2CF3, cyclopentyl, cyclohexyl, nitro, cyano and -OR10b,
and R5b-R18b and Wb have the meaning as defined above, optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or corresponding salts thereof, or corresponding solvates.
Also preferred is the use of compounds of general formula (lb), wherein R5b represents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C-i-β-aliphatic radical or a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing C3.8-cycloaliphatic radical,
preferably represents H or a branched or unbranched C-j-3-alkyl radical,
more preferably H, CH3 or CH2CH3, and R1b-R4b, R6b-R18b and Wb have the meaning given above, optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or corresponding salts thereof, or corresponding solvates.
Preferred is also the use of compounds of general formula (lb), wherein R6b, R7b, R8b, R9b are each independently selected from the group consisting of hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono- substituted C-ι-6-aliphatic radical, a saturated or unsaturated, optionally at least mono- substituted, optionally at least one heteroatom as ring member containing C3-8- cycloaliphatic radical, a cyano and COOR15b moiety,
preferably selected from the group consisting of H, a branched or unbranched Chalky! radical, a cyano and a COOR15b group,
more preferably from the group consisting of H, CH3, CH2CH3 and a cyano moiety,
and R1b-R5b, R10b-R18b and Wb have the meaning given above, optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or corresponding salts thereof, or corresponding solvates.
Also preferred is the use of compounds of general formula (lb), wherein W b represents an an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C-ι-6-aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing C3-8-cycloaliphatic radical, which may be bonded via an optionally at least mono- substituted C-ι-6-alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, an optionally at least mono- substituted, 5- or 6-membered aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted C-i-β-alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ringsystem, a NRi6bRi7b_mojety or a cOR18b-moiety,
preferably selected from the group consisting of 1 -Naphthyl-, 5-Dimethylamino-napth- 1-yl, 2-Naphthyl-, 2-Acetamido-4-methyl-5-thiazolyl-, 2-Thienyl-, 8-Quinolinyl-, Phenyl-, Pentafluorophenyl-, 2,4,5-Trichloro-phenyl-, 2,5-Dichloro-phenyl-, 2- Nitrophenyl-, 2,4-Dinitro-phenyl-, 3,5-Dichloro-2-hydroxy-phenyl-, 2,4,6-Trisisopropyl- phenyl-, 2-Mesityl-, 3-Nitro-phenyl-, 4-Bromo-phenyl-, 4-Fluoro-phenyl-, 4- Chlorophenyl-, 4-Chloro-3-nitro-phenyl-, 4-lodo-phenyl-, N-Acetyl-sulfanilyl-, 4-Nitro- phenyl-, 4-Methoxy-phenyl-, Benzoic-acid-4-yl-, 4-tert-Butyl-phenyl-, p-Tolyl-, Trifluoromethyl-, Trichloromethyl-, Isopropyl-, Methyl-,
Benzyl-, trans-styryl-, 2,2,2-Trifluoroethyl-, Ethyl-, Hexadecyl-, 2-Chloroethyl-, n- Propyl-, 3-Chloro-propyl-, n-Butyl-, Methyl-benzoate-2-yl-, 2-Nitro-4-(trifluoromethyl)- phenyl-, Pentamethyl-phenyl-, 2,3,5,6-Tetramethyl-phenyl-, 3-(Trifluoromethyl)- phenyl-, 3,5-Bis-(Trifluoromethyl)-phenyl-, Dichloromethyl-, Chloromethyl-, Dodecyl-, 1 -Octyl-, 2,3,4-Trichloro-phenyl-, 2,5-Dimethoxy-phenyl-, o-Tolyl-, p-xylyl-2-yl-, Benzoic-acid-3-yl-, 4-Chloro-3-(trifluoromethyl)-phenyl-, 4-Chloro-5-nitro-benzoic acid-3-yl-, 6-(p-toluidino)-naphth-2-yl-, 4-Methoxy-2,3,6-trimethylphenyl-, 3,4- Dichlorophenyl-, 4,5-Dibromo-thiophene-2-yl-, 3-Chloro-4-fluoro-phenyl-, 4-Ethyl- phenyl-, 4-n-Propyl-phenyl-, 4-(1 ,1-Dimethylpropyl)-phenyl-, 4-lsopropyl-phenyl-, 4- Bromo-2,5-difluoro-phenyl-, 2-Fluoro-phenyl-, 3-Fluoro-phenyl-, 4-(Trifluoromethoxy)- phenyl-, 4-(Trifluoromethyl)-phenyl-, 2,4-Difluoro-phenyl-, 2,4-Dichloro-5-methyl- phenyl-, 4-Chloro-2,5-dimethyl-phenyl-, 5-Diethylamino-napth-2-yl-, Benzoyl chloride- 3-yl-, 2-Chloro-phenyl-, 1-Octadecyl-, 4-Bromo-2,5-dichloro-thiophene-3-yl-, 2,5- Dichloro-thiophene-3-yl-, 5-Chloro-thiophene-2-yl-, 2-Methyl-5-nitro-phenyl-, 2- (Trifluoromethyl)-phenyl-, 3-Chloro-phenyl-, 3,5-Dichloro-phenyl-, 1 -Decyl-, 3-Methyl- phenyl-, 2-Chloro-6-methyl-, 5-Bromo-2-methoxy-phenyl-, 3,4-Dimethoxy-phenyl-, 2- 3-Dichloro-phenyl-, 2-Bromo-phenyl-, 3,5-Dichloro-4-(2-chloro-4-nitrophenoxy)- phenyl-, 2,3-Dichloro-thiophene-5-yl-, 3-Bromo-2-chloro-thiophene-5-yl-, 3-Bromo-5- chloro-thiophene-2-yl-, 2-(Benzoylaminomethyl)-thiophene-5-yl-, 4-(Phenyl- sulphonyl)-thiophene-2-yl-, 2-Phenyl-sulphonyl-thiophene-5-yl-, 3-Chloro-2-methyl- phenyl-, 2-[1 -Methyl-5-(trif luoromethyl)pyrazol-3-yl]-thiophene-5-yl-, 5-Pyrid-2-yl- thiophene-2-yl-, 2-Chloro-5-(trifluoromethyl)-phenyl-, 2,6-Dichloro-phenyl-, 3-Bromo- phenyl-, 2-(Trifluoromethoxy)-phenyl-, 4-Cyano-phenyl-, 2-Cyano-phenyl-, 4-n- Butoxy-phenyl-, 4-Acetamido-3-chloro-phenyl, 2,5-Dibromo-3,6-difluoro-phenyl-, 5- Chloro-1 ,3-dimethylpyrazole-4-yl-, 3,5-Dimethylisoxazole-4-yl-, 2-(2,4- Dichlorophenoxy)-phenyl-, 4-(2-Chloro-6-nitro-phenoxy)-phenyl-, 4-(3-Chloro-2- cyano-phenoxy)-phenyl-, 2,4-Dichloro-phenyl-, 2,4-Dimethyl-1 ,3-thiazole-5-yl-, Methyl-methane-sulfonyl-, 2,5-Bis-(2,2,2-Trifluoroethoxy)-phenyl-, 2-Chloro-4- (trifluoromethyl)-phenyl-, 2-Chloro-4-fluoro-phenyl-, 5-Fluoro-2-methyl-phenyl-, 5- Chloro-2-methoxy-phenyl-, 2,4,6-Trichloro-phenyl-, 2-Hydroxy-benzoic acid-5-yl-, 5- (Di-n-propylamino)-naphth-l-yl-, 6-Methoxy-m-tolyl-, 2,5-Difluoro-phenyl-, 2,4- Dimethoxy-phenyl-, 2,5-Dibromo-phenyl-, 3,4-Dibromo-phenyl-, 2,2,5,7,8- Pentamethyl-chroman-6-yl-, 2-Methoxy-benzoic-acid-5-yl-, 5-Chloro-4-nitro- thiophene-2-yl-, 2,1 ,3-Benzothiadiazole-4-yl-, 1-Methyl-imidazole-4-yl-, Benzofurazan-4-yl-, 2-(Methoxycarbonyl)-thiophene-3-yl-, 5-(lsoxazol-3-yl)- thiophene-2-yl-, 2,4,5-Trifluoro-phenyl-, Biphenyl-4-yl-, Vinyl-phenyl-4-yl-, 2-Nitro- benzyl-, 5-Dichloro-methyl-furan-2-yl-, 5-Bromo-thiophene-2-yl-, 5-(4- Chlorobenzamidomethyl)-thiophene-2-yl-, 2,6-Difluoro-phenyl-, 2,5-Dimethoxy-4- nitro-phenyl-, Dibenzo[B,D]-furan-2-yl-, 2,3,4-Trifluoro-phenyl-, 3-Nitro-p-tolyl-, 4- Methoxy-2-nitro-phenyl-, 3,4-Difluoro-phenyl-, 4-(Bromoethyl)-phenyl-, 3,5-Dichloro- 4-hydroxy-phenyl-, 4-n-Amyl-phenyl-, 5-Chloro-3-methylbenzo[B]-thiophene-2-yl-, 3- Methoxy-4-(methoxycarbonyl)-thiophene-2-yl-, 4-n-Butyl-phenyl-, 2-Chloro-4-cyano- phenyl-, 5-[2-(Methylthio)-pyrimidin-4-yl-]-thiophene-2-yl-, 3,5-Dinitro-4-methoxy- phenyl-, 4-Bromo-2-(trifluoromethoxy)-phenyl-, 4-Chloro-2,1 ,3-Benzoxadiazole-7-yl-, 2-(1-Naphthyl)-ethyl-, 3-Cyano-phenyl-, 5-Chloro-2,1 ,3-Benzoxadiazole-4-yl-, 3- Chloro-4-methyl-phenyl-, 4-Bromo-2-ethyl-phenyl-, 2,4-Dichloro-6-methyl-phenyl-, 6- Chloro-imidazo(2,1 -B)-thiazole-5-yl-, 3-Methyl-benzo[B]-thiophene-2-yl-, 4-Methyl- sulphonyl-phenyl-, 2-Methyl-sulphonyI-phenyl-, 4-Bromo-2-methyl-phenyl-, 2,6- Dichloro-4-(trifluoromethyl)-phenyl-, 4-[[3-Chloro-5-(trifluoromethyl)-2-pyridinyl]oxy]- phenyl-, 5-Chloro-naphth-1-yl-, 5-Chloro-naphth-2-yl-, 9,10-Dibromoanthracene-2-yl-, lsoquinoline-5-yl-, 4-Methoxy-2,3,6-trimethyl-phenyl-, 4'-Nitro-biphenyl-4-yl-, [(4- Phenoxy)-phenyl-, (1 ,3-Dihydro-1-oxo-2H-isoindol-2-yl-)-4-phenyl-, 4-Acetyl-phenyl-, 5-(2-Methyl-1 ,3-thiazole-4-yl)-thiophene-2-yl-, 5-(1 -Methyl-3-(trifluoromethyl)pyrazol- 5-yl-]-thiophene-2-yl-, 5-[5-Trifluoromethyl)-isoxazol-3-yl]-thiophene-2-yl-, 2-lodo- phenyl-, p-Dodecyl-phenyl-, 4-[(3-Cyano-4-methoxy-2-pyridinyl)oxy]-phenyl-, 4-(N- phthalimidinyl)-phenyl-, 1 ,2,3,4-Tetrahydro-2-(trifluoroacetyl)-isoquinoline-7-yl-, 4- Bromo-2-fluoro-phenyl-, 2-Fluoro-5-(trifluoromethyl)-phenyl-, 4-Fluoro-2- (trifluoromethyl)-phenyl-, 4-Fluoro-3-(trifluoromethyl)-phenyl-, 2,4,6-Trifluoro-phenyl-, 3-(Trifluoromethoxy)-phenyl-, 1 ,2-Dimethylimidazole-4-yl-, Ethyl-4-Carboxylate-3-yl-, 2,2,4,6, 7-Pentamethyldihydrobenzofuran-5-yl-, 3-Bromo-2-chloropyridine-5-yl-, 3- Methoxy-phenyl-, 2-Methoxy-4-methyl-phenyl-, 2-Chloro-4-fluorobenzoic-acid-5-yl-, 4-Chloro-naphth-1 -yl-, 2,5-Dichloro-4-nitro-thiophene-3-yl-, 4-(4-Methoxy-phenoxy)- phenyl-, 4-(4-Chloro-phenoxy)-phenyl-, 4-(3,5-Dichloro-phenoxy)-phenyl-, 4-(3,4-Dichloro-phenoxy)-phenyl-, 4-(4-Fluoro-phenoxy)-phenyl-, 4-(4-Methyl- phenoxy)-phenyl-, 4-[4-(Trifluormethyl)-phenoxy-phenyl-, 4-[3,5-Bis-(trifluoromethyl)- phenoxyj-phenyl-, 3-(2-Methoxy-phenoxy)-phenyl-, [3-(2-Chloro-phenoxy)-phenyl-, 3- (2-Methyl-phenoxy)-phenyl-, 4-[2-(Trifluoromethyl)-phenoxy]-phenyl-, 3-Phenyl- phenyl-, 3-(4-Methoxy-phenyl)-phenyl-, 3-(4-Chloro-phenyl)-phenyl-, 3-(3,5-Dichloro- phenyl)-phenyl-, 3-(3,4-Dichioro-phenyl)-phenyl-, 3-(4-Fluorophenyl)-phenyl-, 3-(4- Methylphenyl)-phenyl-, 3-[4-(Trifluoromethyl)-phenyl]-phenyl-, 3-[3,5-Bis- (Trifluoromethyl)-phenyl]-phenyl-, 4-(4-Pyridyloxy)-phenyl)-, 4-(2-Methoxy-phenoxy)- phenyl-, 4-(2-Chloro-phenoxy)-phenyl-, 4-(2-Methyl-phenoxy)-phenyl-, 4-(4-Methoxy- phenoxy)-phenyl-, 4-(4-Chlorophenyl)-phenyl-, 4-(3,5-Dichlorophenyl)-phenyl-, 4-(3,4- Dichlorophenyl)-phenyl-, 4-(4-Fluorophenyl)-phenyi-, 4-(4-Methylphenyl)-phenyl-, 4- [4-(Trifluormethyl)-phenyl]-phenyl-, 4-[3,5-Bis-(Trifiuoromethyl)-phenyl]-phenyl-, [3- (Trifluoromethyl)-phenyl]-methyl-, (4-Chlorophenyl)-methyl-, (3,5-Dichlorophenyl)- methyl-, (3,5-Dichlorophenyl)-methyl-, (4-Fluorophenyl)-methyl-, 4- Methylphenylmethyl-, [4-(Trifluoromethyl)-phenyl]-methyl-, Cyclopropyl-, 2-(2- Chlorophenyl)-2-Phenylethyl-, 2-(2-Trifluoromethylphenyl)-2-phenylethyl-, 5-[4- Cyano-1 -methyl-5-(methylthio)-1 H-pyrazol-3-yl-thiophene-2-yl-, 3-Cyano-2,4-bis- (2,2,2-Trifluorothoxy)-phenyl-, 4-[(2-Chloro-1 ,3-Thiazol-5-yl)-methoxy]-phenyl-, 3- Nitro-phenylmethyl-, 4-Formylphenyl-, 2-(1 ,3-Dioxo-1 ,3-dihydro-isoindol-2-yl)-ethyl-, [3,5-Bis-(Trifluoromethyl)-phenyl]-methyl-, (4-(2-Pyridyloxy)-phenyl)-, (4-(3- Pyridyloxy)-phenyl)-, 5-lodo-naphth-1 -yl-, Ethyl-2,5-dimethyl-1 -phenylpyrrole-4- carboxylate-3-yl-, Ethyl-2-methyl-1 ,5-diphenyl-1 H-pyrrole-3-carboxylate-4-yl-, Ethyl-5- (4-chlorophenyl)-2-methyl-3-furoate-4-yl, Ethyl-5-(4-chlorophenyl)-2-methyl-1-phenyl- 3-carboxylate-4-yl-, Ethyl-2,5-dimethyl-3-furoate-4-yl-, 3-Chloro-4-(1 ,3-dioxo-2- Azaspiro[4,4]non-2-yl)-phenyl-, 5-Bromo-2,4-difluoro-phenyl-, 5-Chloro-2,4- difluorophenyl-, Coumarin-6-yl, 2-Methoxy-phenyl, (3-Phenoxy)-phenyl-, 3-(4- Methoxy-phenoxy)-phenyl-, 3-(4-Chlorophenoxy)-phenyl-, 3-(3,5-Dichlorophenoxy)- phenyl-, 3-(3,4-Dichlorophenoxy)-phenyl-, 3-(4-Fluorophenoxy)-phenyl-, 3-(4- Methylphenoxy)-phenyl-, 3-[4-(Trifluoromethyl)-phenoxy]~phenyl-, 3-[3,5- (Trifluoromethyl)-phenoxy]-phenyl-, 3-[2-(Trifluoromethyl)-phenoxy]-phenyl-, 2,2- Diphenylethyl-, 4-Phenyl-5-(trifluoromethyl)-thiophene-3-yl-, Methyl-4-Phenyl-5- (TrifIuoromethyl)-thiophene-2-carboxylate-3-yl-, Methyl-1 , 2, 5-trimethylpyrrole-3- Carboxylate-4-yl-, 4-Fluoro-naphth-1-yl-, 3,5-Difluorophenyl-, 3-Fluoro-4-methoxy- phenyl-, 4-Chloro-2,5-difluorophenyl-, 2-Chloro-4,5-difluoro-phenyl-, 5-Fluoro-3- methylbenzo[B]-thiophene-2-yl-, Methyl-3-phenylpropionate-4-yl, Dihydrocinnamic Acid-4-yl-, Methyl-2,5-dimethyl-3-furoate-4-yl-, Methyl-2-furoate-5-yl-, Methyl-2- methyl-3-furoate-5-yl-, Methyl-1 -methyl-1 H-pyrrole-2-Carboxylate-5-yl-, 2-(5-Chloro- 1 ,2,4-Thiadiazol-3-yl)-thiophene-5-yl-, 1 ,3,5-Trimethyl-1 H-pyrazole-4-yl-, 3-Chloro-5- fluoro-2-methylphenyl-, Pentafluoroethoxytetrafluoroethyl-, 5-(5-lsoxazyl)-thiophene- 2-yl-, 5-(5-lsoxazol-yl)-2-furyl-, 5-Methyl-2,1 ,3-benzothiadiazole-4-yl-, Biphenyl-2-yl-, 2,3-Dihydro-1 ,4-benzodioxine-6-yl-, 4-Methyl-Naphth-1-yl-, 5-Methyl-2- (Trif luormethyl)-3-Furyl-, 2,3-Dihydrobenzo[B]furan-5-yl-, 1 -Benzothiophene-3-yl-, 4-Methyl-3,4-dihydro-2H-1 ,4-Benzoxazine-7-yl-, 5-Methyl-1-phenyl-1 H-pyrazole-4-yl-, 6-Morpholino-3-Pyridinyl-, 4-(1 H-Pyrazol-1-yl)-phenyl-, 6-Phenoxy-3-Pyridyl-, 3,4- Dihydro-2H-1 ,5-benzodioxepine-7-yl-, 5-(1 ,3-Oxazol-5-yl)-2-thienyl-, 4-(1 ,3-Oxazol-5- yl)-phenyl-, 5-Methyl-4-isoxazolyl, 2,1 ,3-Benzothiadiazole-5-yl-, 3-Thienyl-, 2-Methyl- benzyl-, 3-Chloro-benzyl-, 5-Acetamido-naphth-1 -yl-, 3-Methyl-8-Quinolinyl-, 4- Chloro-2-nitrophenyl-, 6-Quinolinyl-, 1 ,3-Benzothiazole-6-yl-, 2-Morpholino-3-Pyridyl-, 2,5-Dimethyl-3-thienyl-, 5-[5-(Chloromethyl)-1 ,2,4-oxadiazol-3-yl]-2-thienyl-, Ethyl-3- [5-yl-2-thienyl-]1 ,2,4-oxadiazole-5-carboxylate-, 3-(5-Methyl-1 ,3,4-oxadiazol-2-yl)- phenyl-, 4-lsopropoxyphenyl-, 2,4-Dibromophenyl-, 3-Cyano-4-fluorophenyl-, 2,5-Bis- (Trifluoromethyl)-phenyl, 2-Bromo-4-fluorophenyl-, 4-Bromo-3-fluorophenyl-, 4- (Difluoromethoxy)-phenyl-, 3-(Difluoromethoxy)-phenyl-, 5-Chloro-2-fluoro-phenyl-, 3-Chloro-2-fluorophenyl-, 2-Fluoro-4-methylphenyl-, 4 Nitro-3-(trifluoromethyl)- phenyl-, 3-Fluoro-4-methylphenyl-, 4-Fluoro-2-methylphenyl-, 4-Bromo-3- (tifluoromethyl)-phenyl-, 4-Bromo-2-(trifluoromethyl)-phenyl-, 3-Bromo-5- (trifluoromethyl)-phenyl-, 2-Bromo-4-(trifluoromethyl)-phenyl-, 2-Bromo-5- (trifluoromethyl)-phenyl-, 2,4-Dichloro-5-fluorophenyl-, 4,5-Dichloro-2-fluorophenyl-, 3,4,5-Trifluorophenyl-, 4-Chloro-2-fluorophenyl-, 2-Bromo-4,6-Difluorophenyl-, 2- Ethylphenyl-, 4-Bromo-2-chlorophenyl-, 4-Bromo-2,6-dichlorophenyl-, 2-Bromo-4,6- dichloro-phenyl-, 4-Bromo-2,6-dimethyIphenyl-, 3,5-Dimethylphenyl-, 4-Bromo-3- methylphenyl-, 2-Methoxy-4-nitrophenyl-, 2,2-Dimethyl-6-Chromanyl-, Ethyl-3,5- dimethyl-1 H-pyrrole-2-carboxylate-4-yl-, lmidazo[1 ,2-A]pyridine-3-yl-, 3-(1 ,3-Oxazol- 5-yl)-phenyl-, Ethyl-5-[4-yl)-phenyl]-2-methyl-3-furoate, Methyl-3-(yl)-4- methoxybenzoate, 1 -Pyrrolidinylphenylsulfonyl-, Methyl-5-yl-4-methyl-2-thiophene- carboxylate, Methyl-3-yl-4-(isopropylsulfonyl)-2-thiophene, 2-Pyridyl-, 3-Fluoro-4- nitrophenyl-, 7-Chlorochromone-3-yl-, 4'-Bromobiphenyl-4-yl-, 4'-Acetyl-biphenyl-4-yl-, 4'-Bromo-2'-fiuoro-biphenyl-4-yl-, 2-Chloro-4-(3-propyl- Ureido)-phenyl-, 3-(-Bromoacetyl)-phenyl-, 2-Bromo-3-(trifluoromethyl)-phenyl-, 1- Methyl-5-isatinyl-, 4-lsopropyl-benzoic-acid-3-yl-, 2-Chloro-3-thiophenecarboxylic- acid-5-yl-, 3-Pyridyl-, Cyclohexylmethyl-, 2-Methoxy-5-(N-phthalimidinyl)-phenyl-, 1- Benzothiophene-2-yl-, Morpholinophenylsulfonyl-, 3-(2-Methyl-4-pyrimidinyl)-phenyl-, and 2-Cyano-5-methylphenyl-,
and R1-R18b have the meaning given above, optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or corresponding salts thereof, or corresponding solvates.
Also preferred is the use of compounds of general formula (lb), wherein W b represents a linear or branched C-ι-2o-alkyl radical, preferably an alkyl radical selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec- butyl, tert-butyl and 1 ,1-dimethyl-propyl; a linear or branched C2.2o-alkenyl radical; preferably a vinyl radical; -CF3; -CHF2; -CH2F; -CCI3; -CHCI2; -CH2CI; -CH2-CF3; - CH2-CH2-CI; -CH2-CH2-CH2-CI; -CH -S(=0)2-CH3; a cyclopropyl radical; a cyclobutyl radical; a cyclopentyl radical; a cyclohexyl radical; -CH2-cyclopropyl; -CH2-cyclobutyl; -CH2-cyclopentyl; -CH2-cyclohexyl; -N(CH3)2; -N(C2H5)2; -N(n-CH2-CH2-CH3)2; phenyl; benzyl; naphthyl; -CH=CH-phenyl; -(CF2)-(CF2)-0-phenyl; -(CH2)-naphtyl; - (CH2)-(CH2)-naphthyl; anthracenyl; -(C=0)-phenyl; thiophenyl; benzo[b]thiophenyl; furanyl; 2-oxo-2H-chromenyl; dibenzofuranyl; 2,3-dihydrobenzofuranyl; chromanyl; 2,3-dihydro-benzo[1 ,4]dioxinyl; 3,4-dihydro-2H-1 ,5-benzo-dioxepinyl; chromonyl; 1H- imidazolyl; pyridinyl; pyrrolidine-2,5-dionyl; pyrrolyl; 1 H-pyrazolyl; 1H-pyrimidine-2,4- dionyl; quinolinyl; isoquinolinyl; 1H-Benzoimidazolyl; 1 ,4-dihydro-quinoxaline-2,3- dionyl; 1 ,2,3,4-tetrahydro-isoquinolinyl; 1 ,4-dihydro-benzo[b][1 ,4]diazepine-2,4-dionyl; 1 ,3-dihydro-1-oxo-2H-isoindolyl; phthalimidinyl; 2-(1 ,3-dioxo-1 ,3-dihydro-isoindol-2- yl)-ethyl; imidazo[1 ,2-a]pyridine; isatinyl; thiazolyl; 1 ,3-thiazolyl; 1 ,2,4-thiadiazolyl; imidazo[2,1-b]thiazolyl; 1 ,3-benzothiazolyl; benzo[1 ,2,5]thiadiazolyl; 2-oxo-2,3- dihydro-benzothiazolyl; 2,1 ,3-benzothiadiazolyl; imidazo[2,1-b]thiazolyl; isoxazolyl; benzo[1 ,2,5]oxadiazolyl; benzo[d]isoxazolyl; benzofurazanyl; 2-oxo-2,3-dihydro-benzooxazolyl; 3,4-dihydro-2H-benzo[1 ,4]oxazinyl; or 2,1 ,3- benzoxadiazolyl;
whereby each of these afore mentioned cyclic moieties may optionally be substituted with 1 , 2, 3, 4 or 5 substituents independently selected from the group consisting of methyl; ethyl; n-propyl; iso-propyl; n-butyl; iso-butyl; sec-butyl; tert-butyl; 1 ,1- dimethyl-propyl; n-pentyl; vinyl; cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl; morpholino; methoxy; ethoxy; n-propoxy; iso-propoxy; n-propoxy; F; Cl; Br; I; -CN; - OH; -CF3; -CF2H; -CH2F; -CCI3; -CCIH2; -CHCI2; -CH2-F; -CH2-CI;-CH2-Br; -(C=O)- CH2-Br; -OCF3; -0-CH2-CF3; -O-CHF2; -N02; -NH2; -N(CH3)2; -N(C2H5) ; -N(n-CH2- CH2-CH3)2; -N(n-CH2-CH2-CH2-CH3)2;-NH-(C=0)-CH3; -NH-phenyl; -(C=0)-CF3; - (C=O)-OH; =0 (oxo); -(C=O)-H; -S(=0)2-CH3; -S(=0)2-isopropyl; -S(=0)2-phenyi; - S(=0)2-pyrrolidinyl; -S(=O)2-morpholino; -(CH2)-(CH2)-(C=O)-0-CH3; -NH-(C=0)-NH- CH2-CH2-CH3; -(C=0)-CH3; -(C=0)-0-CH3; -(C=0)-0-C2H5; -(CH2)-NH-(C=0)- phenyl; -CH2-C(H)(phenyl)(phenyl); -0-CH2-thiazolyl; 1 ,3-dioxo-2-azaspiro[4.4]non-2- yl; phenyl; phenoxy; isoxazolyl; 1 ,3-oxazolyl; 1 ,2,4-oxadiazolyl; 1 ,3,4-oxadiazolyl; pyridinyl; pyridinyloxy; pyrazolyl; pyrimidinyl and phthalimidinyl; and
whereby each of the cyclic moieties of these afore mentioned substituents may optionally be substituted with 1 , 2, 3, 4 or 5 substituents that are independently selected from the group consisting of methyl; ethyl; n-propyl; iso-propyl; F; Cl; Br; I; CN; -CH2-F; -CH2-CI; -CH2-Br; -CF3 and -S-CH3,
more preferably Wb represents
an alkyl radical selected from the group consisting of methyl; ethyl; n-propyl; isopropyl; n-butyl; sec.butyl; iso-butyl and tert-butyl; vinyl (CH2=CH-); -N(CHs)2; 1- naphthyl; benzyl; 2-naphtyl; phenyl; 2-methyl-phenyl; 3-methyl-phenyl; 4-methyl- phenyl; 2-ethyl-phenyl; 3-ethyl-phenyl; 4-ethyl-phenyl; 2-n-propyl-phenyl; 3-n-propyl- phenyl; 4-n-propyl-phenyl; 2-isopropyl-phenyl; 3-isopropyl-phenyl; 4-isopropyl-phenyl; 2-n-butyl-phenyl; 3-n-butyl-phenyl; 4-n-butyl-phenyl; 2-iso-butyl-phenyl; 3-iso-butyl- phenyl; 4-iso-butyl-phenyl; 2-tert-butyl-phenyl; 3-tert-butyl-phenyl; 4-tert-butyl-phenyl; 1 ,1-dimethylpropyl-phenyl; 2-cyclopentyl-phenyl; 3-cyclopentyl-phenyl; 4-cyclopentyl- phenyl 2-cyclohexyl-phenyl; 3-cyclohexyl-phenyl; 4-cyclohexyl-phenyl; 2-methoxy- phenyl; 3-methoxy-phenyl; 4-methoxy-phenyl; 2-ethoxy-phenyl; 3-ethoxy-phenyl; 4- ethoxy-phenyl; 2-n-propoxy-phenyl; 3-n-propoxy-phenyl; 4-n-propoxy-phenyl; 2-iso- propoxy-phenyl; 3-iso-propoxy-phenyl; 4-isopropoxy-phenyl;2-fluoro-phenyl; 3-fluoro- phenyl; 4-fluoro-phenyl; 2-chloro-phenyl; 3-chloro-phenyl; 4-chloro-phenyl; 2-bromo- phenyl; 3-bromo-phenyl; 4-bromo-phenyl; 2-trifluoromethyl-phenyl; 3-trifluoromethyl- phenyl; 4-trifluoromethyl-phenyl; 2-trifluoromethoxy-phenyl; 3-trifluoromethoxy- phenyl; 4-trifluoromethoxy-phenyl; 2-carboxy-phenyl; 3-carboxy-phenyl; 4-carboxy- phenyl; 2-acetyl-phenyl; 3-acetyl-phenyl; 4-acetyl-phenyl; 2-(C=0)-0-CH3-phenyl; 3- (C=O)-0-CH3-phenyl; 4-(C=0)-0-CH3-phenyl; 2-(CH2)-(CH2)-(C=0)-0-CH3; 3-(CH2)- (CH2)-(C=0)-0-CH3; 4-(CH2)-(CH2)-(C=0)-0-CH3; 2-cyano-phenyl; 3-cyano-phenyl; 4-cyano-phenyl; 2-nitro-phenyl; 3-nitro-phenyl; 4-nitro-phenyl; 4-(4-bromophenoxy)- phenyl; 2-methylsulfonyl-phenyl; 3-methylsulfonyl-phenyl; 4-methylsulfonyl-phenyl; 2- phenyl-phenyl (biphenyl-2-yl); 3-phenyl-phenyl (biphenyl-3-yl); 4-phenyl-phenyl (biphenyl-4-yl); 2-phenoxy-phenyl; 3-phenoxy-phenyl; 4-phenoxy-phenyl; 2,4- dimethyl-phenyl; 3,4-dimethyl-phenyl; 2,4,6-trimethyl-phenyl; 2,3,5,6-tetramethyl- phenyl; pentamethyl-phenyl; 2,5-dimethoxy-phenyl; 3,4-dimethoxy-phenyl; 2,3- dichloro-phenyl; 2,4-dichloro-phenyl; 2,5-dichloro-phenyl; 3,4-dichloro-phenyl; 3,5- dichloro-phenyl; 2,6-dichloro-phenyl; 2,4-difluoro-phenyl; 3,4-difluoro-phenyl; 2,5- difluoro-phenyl; 2,6-difluoro-phenyl; 3-chloro-2-fluoro-phenyl; 3-chloro-4-fluoro- phenyl; 5-chloro-2-fluoro-phenyl; 2,3,4-trichloro-phenyl; 2,4,5-trichloro-phenyl; 2,4,6- trichloro-phenyl; 2,4,5-trifluoro-phenyl; 2,3,4-trifluoro-phenyl-; 2-chloro-4,5-difluoro- phenyl; 2-bromo-4-fluoro-phenyl; 2-bromo-4,6-difluoro-phenyl; 4-chloro-2,5-difluoro- phenyl; 5-chloro-2,4-difluoro-phenyl; 4-bromo-2,5-difluoro-phenyl; 5-bromo-2,4- difluoro-phenyl; pentafluoro-phenyl; 2,4-dinitro-phenyl; 4-chloro-3-nitro-phenyl; 2- methyl-5-nitro-phenyl; 5-bromo-2-methoxy-phenyl; 3-chloro-2-methyl-phenyl; 4- bromo-3-methyl-phenyl; 4-chloro-2,5-dimethyl-phenyl; 4-fluoro-3-methyl-phenyl; 5- fluoro-2-methyl-phenyl; 2-nitro-4-trifluoromethyl-phenyl; 2-methoxy-4-methyl-phenyl; 3,5-dichloro-2-hydroxy-phenyl; 3,5-dichloro-4-hydroxy-phenyl; 5-chloro-2,4-difluoro- phenyl; 3-chloro-4-(NH)-(C=O)-CH3-phenyl; 2-chloro-6-methyl-phenyl; 2-chloro-5- trifluoromethyl-phenyl; 2-chloro-5-trifluoromethoxy-phenyl; 4-bromo-2- trifluoromethoxy-phenyl; 4-bromo-2-trifluoromethyl-phenyl; 4-bromo-3-trifluoromethyl- phenyl; 3-carboxy-4-fluoro-phenyl; 3-carboxy-4-chloro-6-fluoro-phenyl; 4-methoxy- 2,3,6-trimethyl-phenyl-; or one of the following groups:
Figure imgf000076_0001
Figure imgf000077_0001
Figure imgf000078_0001
78
Figure imgf000079_0001
Figure imgf000080_0001
Figure imgf000080_0002
whereby in each case X denotes the position by which the respective substituent Wb is bonded to the -SO2 group of formula (lb),
and R1-R18b have the meaning given above, optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or corresponding salts thereof, or corresponding solvates. Furthermore, the use of compounds of general formula (lb) is preferred, wherein R10 represents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted Cι_6-aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing C3-8-cycloaliphatic radical, which may be bonded via an optionally at least mono-substituted C-ι-6-alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, or an at least mono-substituted, 5- or 6-membered aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted C-ι-6-alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring- system,
preferably H, a C-ι-4-alkyl radical, cyclohexyl or a phenyl radical,
more preferably H, CH3, C2H5 or phenyl,
and R1b-R9b, R11b-R18b and Wb have the meaning given above, optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or corresponding salts thereof, or corresponding solvates.
Moreover, the use of compounds of general formula (lb) is preferred, wherein R11b represents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C-i-β-aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing C3-8-cycloaliphatic radical, which may be bonded via an optionally at least mono-substituted C-ι-6-alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, or an at least mono-substituted, 5- or 6-membered aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted C-ι-6-alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring- system, preferably H, a C-ι- -alkyl radical, cyclohexyl or a phenyl radical, more preferably H, CH3, C2H5 or phenyl,
and R1b-R10b, R12b-R18b and Wb have the meaning given above, optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or corresponding salts thereof, or corresponding solvates.
Preference is also given to the use of compounds of general formula (lb), wherein R12b represents an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C-ι-6-aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing C3-8-cycloaliphatic radical, which may be bonded via an optionally at least mono- substituted C-i-β-alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, or an optionally at least mono- substituted, 5- or 6- membered aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted Ci-β-alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,
preferably represents H, a C-ι-4-alkyl radical, cyclohexyl or a phenyl radical,
more preferably H, CH3, C2H5 or phenyl,
and R1b-R1 b, R13b-R18b and Wb have the meaning given above, optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or corresponding salts thereof, or corresponding solvates. Also preferred is the use of compounds of general formula (lb), wherein R13b and R14b are each independently selected from the group consisting of hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono- substituted Cι-6-aliphatic radical, a saturated or unsaturated, optionally at least mono- substituted, optionally at least one heteroatom as ring member containing C3_8- cycloaliphatic radical, which may be bonded via an optionally at least mono- substituted C-ι_6-alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, or an optionally at least mono- substituted, 5- or 6-membered aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted C-ι-6-alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,
preferably are each independently selected from the group consisting of H, a C1-4- alkyl radical, cyclohexyl and a phenyl radical,
more preferably are each independently selected from the group consisting of H, CH3, C2H5 and phenyl,
and R1b-R12b, R15b-R18b and Wb have the meaning given above, optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or corresponding salts thereof, or corresponding solvates.
Furthermore, the use of compounds of general formula (lb) is preferred, wherein R13b and R14b together with the bridging nitrogen atom form a saturated, unsaturated or aromatic, 5- or 6-membered heterocyclic ring, which may be at least mono- substituted and/or contain at least one further heteroatom as a ring member,
preferably form an unsubstituted piperidin or morpholine group,
and R1b-R12b, R15b-R18b and Wb have the meaning given above, optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or corresponding salts thereof, or corresponding solvates.
Also preferred are compounds of general formula (lb), wherein R15b represents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted Cι.6-aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing C3.8- cycloaliphatic radical or an optionally at least mono-substituted, 5- or 6- membered aryl- or heteroaryl radical, which may be bonded via an optionally at least mono- substituted C-ι-6-alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,
preferably represents H, a C-ι-4-alkyl radical, cyclohexyl or a phenyl radical,
more preferably represents H, CH3, C2H5 or phenyl,
and R1b-R14b, R16b- R18b and Wb have the meaning given above, optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or corresponding salts thereof, or corresponding solvates.
Also preferred is the use of compounds of general formula (lb), wherein R16b represents an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C-ι-6 aliphatic radical,
preferably an unbranched or branched, saturated, unsubstituted Cι-3 alkyl radical,
more preferably a methyl radical,
and R1b-R15b, R17b, R18b and Wb have the meaning given above, optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or corresponding salts thereof, or corresponding solvates.
Also preferred are compounds of general formula (lb), wherein R17b represents an unbranched or branched, saturated or unsaturated, optionally at least mono- substituted C-ι-6 aliphatic radical,
preferably an unbranched or branched, saturated, unsubstituted Cι-3 alkyl radical,
more preferably a methyl radical,
and R1b-R16b, R18b and Wb have the meaning given above, optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or corresponding salts thereof, or corresponding solvates.
Also preferred are compounds of general formula (lb) given above, wherein R18b represents a phenyl radical, which is optionally at least mono-substituted by a C-i-β aliphatic radical, more preferably a phenyl radical, which is optionally at least mono- substituted by a methyl group, and R1b-R17b and Wb have the meaning given above, optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or corresponding salts thereof, or corresponding solvates.
More preferred are compounds of general formula (lb) given above, wherein
R1b, R2b, R3b, R4b are each independently selected from the group consisting of a hydrogen atom; a fluorine atom; a chlorine atom; a bromine atom; a methyl group and a methoxy group;
R5b represents a hydrogen atom;
R6b, R7b, R8b, R9b each represent a hydrogen atom;
W represents
an alkyl radical selected from the group consisting of methyl; ethyl; n-propyl; isopropyl; n-butyl; sec.butyl; iso-butyl and tert-butyl; vinyl (CH2=CH-); -N(CH3)2; 1- naphthyl; benzyl; 2-naphtyl; phenyl; 2-methyl-phenyl; 3-methyl-phenyl; 4-methyl- phenyl; 2-ethyl-phenyl; 3-ethyl-phenyl; 4-ethyl-phenyl; 2-n-propyl-phenyl; 3-n-propyl- phenyl; 4-n-propyl-phenyl; 2-isopropyl-phenyl; 3-isopropyl-phenyl; 4-isopropyl-phenyl; 2-n-butyl-phenyl; 3-n-butyl-phenyl; 4-n-butyl-phenyl; 2-iso-butyl-phenyl; 3-iso-butyl- phenyl; 4-iso-butyl-phenyl; 2-tert-butyl-phenyl; 3-tert-butyl-phenyl; 4-tert-butyl-phenyl; 1 ,1-dimethylpropyl-phenyl; 2-cyclopentyl-phenyl; 3-cyclopentyl-phenyl; 4-cyclopentyl- phenyl 2-cyclohexyl-phenyl; 3-cyclohexyl-phenyl; 4-cyclohexyl-phenyl; 2-methoxy- phenyl; 3-methoxy-phenyl; 4-methoxy-phenyl; 2-ethoxy-phenyl; 3-ethoxy-phenyl; 4- ethoxy-phenyl; 2-n-propoxy-phenyl; 3-n-propoxy-phenyl; 4-n-propoxy-phenyl; 2-iso- propoxy-phenyl; 3-iso-propoxy-phenyl; 4-isopropoxy-phenyl;2-fluoro-phenyl; 3-fluoro- phenyl; 4-fluoro-phenyl; 2-chloro-phenyl; 3-chloro-phenyl; 4-chloro-phenyl; 2-bromo- phenyl; 3-bromo-phenyl; 4-bromo-phenyl; 2-trifluoromethyl-phenyl; 3-trifluoromethyl- phenyl; 4-trifluoromethyl-phenyl; 2-trifluoromethoxy-phenyl; 3-trifluoromethoxy- phenyl; 4-trifluoromethoxy-phenyl; 2-carboxy-phenyl; 3-carboxy-phenyl; 4-carboxy- phenyl; 2-acetyl-phenyl; 3-acetyl-phenyl; 4-acetyl-phenyl; 2-(C=0)-O-CH3-phenyl; 3- (C=0)-0-CH3-phenyl; 4-(C=O)-0-CH3-phenyl; 2-(CH2)-(CH2)-(C=0)-0-CH3; 3-(CH2)- (CH2)-(C=0)-0-CH3; 4-(CH2)-(CH2)-(C=O)-0-CH3; 2-cyano-phenyl; 3-cyano-phenyl; 4-cyano-phenyl; 2-nitro-phenyl; 3-nitro-phenyl; 4-nitro-phenyl; 4-(4-bromophenoxy)- phenyl; 2-methylsulfonyl-phenyl; 3-methylsulfonyl-phenyl; 4-methylsulfonyl-phenyl; 2- phenyl-phenyl (biphenyl-2-yl); 3-phenyl-phenyl (biphenyl-3-yl); 4-phenyl-phenyl (biphenyl-4-yl); 2-phenoxy-phenyl; 3-phenoxy-phenyl; 4-phenoxy-phenyl; 2,4- dimethyl-phenyl; 3,4-dimethyl-phenyl; 2,4,6-trimethyl-phenyl; 2,3,5,6-tetramethyl- phenyl; pentamethyl-phenyl; 2,5-dimethoxy-phenyl; 3,4-dimethoxy-phenyl; 2,3- dichloro-phenyl; 2,4-dichloro-phenyl; 2,5-dichloro-phenyl; 3,4-dichloro-phenyl; 3,5- dichloro-phenyl; 2,6-dichloro-phenyl; 2,4-difluoro-phenyl; 3,4-difluoro-phenyl; 2,5- difluoro-phenyl; 2,6-difluoro-phenyl; 3-chloro-2-fluoro-phenyl; 3-chloro-4-fluoro- phenyl; 5-chloro-2-fluoro-phenyl; 2,3,4-trichloro-phenyl; 2,4,5-trichloro-phenyl; 2,4,6- trichloro-phenyl; 2,4,5-trifiuoro-phenyl; 2,3,4-trifluoro-phenyl-; 2-chloro-4,5-difluoro- phenyl; 2-bromo-4-fluoro-phenyl; 2-bromo-4,6-difluoro-phenyl; 4-chloro-2,5-difluoro- phenyl; 5-chloro-2,4-difluoro-phenyl; 4-bromo-2,5-difluoro-phenyl; 5-bromo-2,4- difluoro-phenyl; pentafluoro-phenyl; 2,4-dinitro-phenyl; 4-chloro-3-nitro-phenyl; 2- methyl-5-nitro-phenyl; 5-bromo-2-methoxy-phenyl; 3-chloro-2-methyl-phenyl; 4- bromo-3-methyl-phenyl; 4-chloro-2,5-dimethyl-phenyl; 4-fluoro-3-methyl-phenyl; 5- fluoro-2-methyl-phenyl; 2-nitro-4-trifiuoromethyl-phenyl; 2-methoxy-4-methyl-phenyl; 3,5-dichloro-2-hydroxy-phenyl; 3,5-dichloro-4-hydroxy-phenyl; 5-chloro-2,4-difluoro- phenyl; 3-chloro-4-(NH)-(C=0)-CH3-phenyl; 2-chloro-6-methyl-phenyl; 2-chloro-5- trifluoromethyl-phenyl; 2-chloro-5-trifluoromethoxy-phenyl; 4-bromo-2- trifluoromethoxy-phenyl; 4-bromo-2-trifluoromethyl-phenyl; 4-bromo-3-trifluoromethyl- phenyl; 3-carboxy-4-fluoro-phenyl; 3-carboxy-4-chloro-6-fluoro-phenyl; 4-methoxy- 2,3,6-trimethyl-phenyl-; or one of the following groups:
Figure imgf000088_0001
Figure imgf000089_0001
Figure imgf000090_0001
Figure imgf000092_0001
Figure imgf000092_0002
whereby in each case X denotes the position by which the respective substituent Wb is bonded to the -SO2 group of formula (lb).
optionally in form of one of its stereoisomers, preferably enantiomers or diastereomers, its racemate or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or a physiologically acceptable salt thereof, or a solvate, respectively. Particularly preferred is the use of one or more benzoxazinone-derived sulfonamide compounds of general formula (lb) selected from the group consisting of:
nyl)-piperidin- [1 ,3]oxazin-2-
Figure imgf000093_0001
-(Toluene-4-sulfonyl)-piperidin-4- ,4-dihydro-benzo[d][1 ,3]oxazin-2-
Figure imgf000093_0002
henylmethanesulfonyl-piperidin- ,4-dihydro-benzo[d][1 ,3]oxazin-
Figure imgf000093_0003
1 -(1 -BenzenesuIfonyl-piperidin-4-yl)-6- -1 ,4-dihydro-benzo[d][1 ,3]oxazin-
Figure imgf000093_0004
6-Chloro-1 -[1 -(toluene-4-sulfonyl)- piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000093_0005
6-Chloro-1 -(1 -phenylmethanesulfonyl- piperidin-4-yl)-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000093_0006
6-Chloro-1 -[1 -(naphthalene-1 -sulfonyl)- piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000094_0001
6-Chloro-1 -[1 -(naphthalene-2-sulfonyl)- piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000094_0002
6-Chloro-1-[1-(5-chloro-3-methyl- benzo[b]thiophene-2-sulfonyl)- piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000094_0003
6-Chloro-1 -[1 -(5-chloro-3-methyl- benzo[b]thiophene-2-sulfonyl)- piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000094_0004
1 -[1 -(4-Acetyl-benzenesulfonyl)- piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000094_0005
2-[4-(2-Oxo-4H-benzo[d][1 ,3]oxazin-1 • yl)-piperidine-1-sulfonyl]-benzonitrile
Figure imgf000094_0006
1 -[1 -(2,4-Dimethyl-benzenesulfonyl)- piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000094_0007
1 -[1 -(4-Methoxy-benzenesulfonyl)- piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
4-(2-Oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)- piperidine-1-sulfonic acid dimethylamide
Figure imgf000095_0001
1-[1-(2-Naphthalen-1-yl- ethanesulfonyl)-piperidin-4-yl]-1 ,4- dihydro-benzo[d][1,3]oxazin-2-one
Figure imgf000095_0002
8-Methyl-1 -[1 -(thiophene-2-sulfonyl)- piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000095_0003
1 -[1 -(4-Acetyl-benzenesulfonyl)- piperidin-4-yl]-8-methyl-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
2-[4-(8-Methyl-2-oxo-4H- benzo[d][1 ,3]oxazin-1 -yl)-piperidine-1 ■ sulfonyl]-benzonitrile
1 -[1 -(2,4-Dimethyl-benzenesulfonyl)- piperidin-4-yl]-8-methyl-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000095_0004
1 -[1 -(4-Methoxy-benzenesulfonyl)- piperidin-4-yl]~8-methyl-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000096_0001
4-(8-Methyl-2-oxo-4H- benzo[d][1 ,3]oxazin-1-yl)-piperidine-1- sulfonic acid dimethylamide
Figure imgf000096_0002
8- et yH -[1 -(2-naphthalen-1 -yl- ethanesulfonyl)-piperidin-4-yl]-1 ,4- dihydro-benzo[d][1,3]oxazin-2-one
Figure imgf000096_0003
4-(6-Chloro-2-oxo-4H- benzo[d][1 ,3]oxazin-1 -yl)-piperidine-1 ■ sulfonic acid dimethylamide
2-[4-(2-Oxo-4H-benzo[d][1 ,3]oxazin-1 ■ yl)-piperidine-1 -sulfonyl]-benzoic acid methyl ester
1-[1-(3-Trifluoromethyl- benzenesulfonyl)-piperidin-4-yl]-1 ,4- dihydro-benzo[d][1 ,3]oxazin-2-one
2-[4-(8-Methyl-2-oxo-4H- benzo[d][1 ,3]oxazin-1 -yl)-piperidine-1 ■ sulfonyl]-benzoic acid methyl ester
Figure imgf000096_0004
8-Methyl-1 -[1 -(3-trifluoromethyl- benzenesulfonyl)-piperidin-4-yl]-1 ,4- dihydro-benzo[d][1 ,3]oxazin-2-one
1 -[1 -(4-Acetyl-benzenesulfonyl)- piperidin-4-yl]-6-chloro-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000097_0001
2-[4-(6-Chloro-2-oxo-4H- benzo[d][1 ,3]oxazin-1 -yl)-piperidine-1 - sulfonyl]-benzonitrile
6-Chloro-1 -[1 -(4-methoxy- benzenesulfonyI)-piperidin-4-yl]-1,4- dihydro-benzo[d][1 ,3]oxazin-2-one
Figure imgf000097_0002
2-[4-(6-Chloro-2-oxo-4H- benzo[d][1 ,3]oxazin-1 -yl)-piperidine-1 ■ sulfonyl]-benzoic acid methyl ester
Figure imgf000097_0003
6-Chloro-1 -[1 -(2,4-dimethyl- benzenesulfonyl)-piperidin-4-yl]-1 ,4- dihydro-benzo[d][1 ,3]oxazin-2-one
Figure imgf000097_0004
6-Chloro-1 -[1 -(3-trif luoromethyl- benzenesulfonyI)-piperidin-4-yl]-1 ,4- dihydro-benzo[d][1,3]oxazin-2-one
Figure imgf000097_0005
1-[1-(5-Chloro-3-methyl- benzo[b]thiophene-2-sulfonyl)- piperidin-4-yl]-8-methyl-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000098_0001
1 -{1 -[4-(4-Bromo-phenoxy)- benzenesulfonyl]-piperidin-4-yl}-8- methyl-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000098_0002
1 -[1 -(4-Fluoro-benzenesulfonyl)- piperidin-4-yl]-8-methyl-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
8-Methyl-1 -[1 -(naphthalene-2-sulfonyl)- piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000098_0003
8-Methyl-1 -(1 -phenylmethanesulfonyl- piperidin-4-yl)-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
1 -[1 -(4-Bromo-benzenesulfonyl)- piperidin-4-yl]-6-chloro-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
6-Chloro-1 -[1 -(4-methanesulfonyl- benzenesulfonyl)-piperidin-4-yl]-1 ,4- dihydro-benzo[d][1 ,3]oxazin-2-one
Figure imgf000098_0004
1 -[1 -(Butane-1 -sulfonyl)-piperidin-4-yl]- 6-chloro-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
1 -[1 -(4-Bromo-benzenesulfonyl)- piperidin-4-yl]-8-methyl-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
1 -[1 -(4-Methanesulfonyl- benzenesulfonyl)-piperidin-4-yl]-8- methyl-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
1 -[1 -(Butane-1 -sulfonyl)-piperidin-4-yl]- 8-methyl-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
6-Chloro-1-[1-(2-nitro- benzenesulfonyl)-piperidin-4-yl]-1 ,4- dihydro-benzo[d][1 ,3]oxazin-2-one
Figure imgf000099_0001
6-Chloro-1-[1-(3-nitro- benzenesulfonyl)-piperidin-4-yl]-1 ,4- dihydro-benzo[d][1 ,3]oxazin-2-one
1 -[1 -(Biphenyl-4-sulfonyl)-piperidin-4- yl]-6-chloro-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000099_0002
8-Methyl-1-[1-(2-nitro- benzenesulfonyl)-piperidin-4-yl]-1,4- dihydro-benzo[d][1,3]oxazin-2-one
8-Methyl-1-[1-(3-nitro- benzenesulfonyl)-piperidin-4-yl]-1 ,4- dihydro-benzo[d][1 ,3]oxazin-2-one
1 -[1 -(Biphenyl-4-sulfonyl)-piperidin-4- yl]-8-methyl-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
8-Methyl-1-[1-(4-nitro- benzenesulfonyl)-piperidin-4-yl]-1 ,4- dihydro-benzo[d][1 ,3]oxazin-2-one
6-Chloro-1-[1-(4~nitro- benzenesulfonyl)-piperidin-4-yl]-1 ,4- dihydro-benzo[d][1 ,3]oxazin~2-one
Figure imgf000100_0001
1 -(1 -Ethanesulfonyl-piperidin-4-yl)-1 ,4- dihydro-benzo[d][1 ,3]oxazin-2-one
Figure imgf000101_0001
-
Figure imgf000101_0002
6-Chloro-1 -[1 -(propane-1 -sulfonyl)- piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
6-Chloro-1 -[1 -(propane-2-sulfonyl)- piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000101_0003
6-Chloro-1 -[1 -(quinoline-8-sulfonyl)- piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000102_0001
1 -[1 -(4-Nitro-benzenesulfonyl)- piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
6-Methyl-1 -[1 -(quinoline-8-sulfonyl)- piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000102_0002
6-Methyl-1 -[1 -(2-naphthalen-1 -yl- ethanesulfonyl)-piperidin-4-yl]-1 ,4- dihydro-benzo[d][1 ,3]oxazin-2-one
Figure imgf000102_0003
6-Methyl-1 -[1 -(toluene-4-sulfonyl)- piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000102_0004
1 -[1 -(4-Fluoro-benzenesulfonyl)- piperidin-4-yl]-6-methyl-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000102_0005
102 6-Methyl-1 -[1 -(naphthalene-1 -sulfonyl)- piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000103_0001
6-Methyl-1 -[1 -(naphthalene-2-sulfonyl)- piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000103_0002
1-[1-(5-Chloro-3-methyl- benzo[b]thiophene-2-sulfonyl)- piperidin-4-yl]-6-methyl-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000103_0003
6-Methyl-1-[1-(4-nitro- benzenesulfonyl)-piperidin-4-yl]-1 ,4- dihydro-benzo[d][1 ,3]oxazin-2-one
Figure imgf000103_0004
1 -(1 -Benzenesulfonyl-piperidin-4-yl)-6- methyl-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000103_0005
1-[1-(4-Chloro-3-nitro- benzenesulfonyl)-piperidin-4-yl]-6- methyl-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000103_0006
1 -[1 -(5-Dimethylamino-naphthalene-1 ■ sulfonyl)-piperidin-4-yl]-6-methyl-1 ,4- dihydro-benzo[d][1 ,3]oxazin-2-one
Figure imgf000103_0007
1-[1-(4-Chloro-3-nitro- benzenesulfonyl)-piperidin-4-yl]-8- methyl-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000104_0001
1-[1-(4-Chloro-3-nitro- benzenesulfonyl)-piperidin-4-yl]-1 ,4- dihydro-benzo[d][1 ,3]oxazin-2-one
Figure imgf000104_0002
6-Chloro-1 -[1 -(4-chloro-3-nitro- benzenesulfonyl)-piperidin-4-yl]-1 ,4- dihydro-benzo[d][1 ,3]oxazin-2-one
Figure imgf000104_0003
6-Chloro-1 -[1 -(5-dimethylamino- naphthalene-1-sulfonyl)-piperidin-4-yl]- 1 ,4-dihydro-benzo[d][1 ,3]oxazin-2-one
Figure imgf000104_0004
1-[1-(4-Methoxy-2,3,6-trimethyl- benzenesulfonyl)-piperidin-4-yl]-1 ,4- dihydro-benzo[d][1 ,3]oxazin-2-one
1 -[1 -(4-Methoxy-2,3,6-trimethyl- benzenesulfonyl)-piperidin-4-yl]-8- methyl-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000104_0005
-
Figure imgf000104_0006
104 1 -[1 -(4-Methoxy-2,3,6-trimethyl- benzenesulfonyl)-piperidin-4-yl]-6- methyl-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000105_0001
1 -[1 -(2-Bromo-benzenesulfonyl)- piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
1 -[1 -(2-Bromo-benzenesulfonyl)- piperidin-4-yl]-8-methyl-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
1 -[1 -(2-Bromo-benzenesulfonyl)- piperidin-4-yl]-6-chloro-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
1 -[1 -(2-Bromo-benzenesulfonyl)- piperidin-4-yl]-6-methyl-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000105_0002
6-Chloro-1 -[1 -(2,3-dichloro- benzenesulfonyl)-piperidin-4-yl]-1 ,4- dihydro-benzo[d][1 ,3]oxazin-2-one
Figure imgf000105_0003
1 -[1 -(2,3-Dichloro-benzenesulfonyl)- piperidin-4-yl]-6-methyl-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000105_0004
1 -[1 -(2,4,5-Trichloro-benzenesulfonyl)- piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000106_0001
8-Methyl-1 -[1 -(2,4,5-trichloro- benzenesulfonyl)-piperidin-4-yl]-1 ,4- dihydro-benzo[d][1 ,3]oxazin-2-one
Figure imgf000106_0002
6-Chloro-1 -[1 -(2,4,5-trichloro- benzenesulfonyl)-piperidin-4-yl]-1 ,4- dihydro-benzo[d][1 ,3]oxazin-2-one
Figure imgf000106_0003
6-Methyl-1 -[1 -(2,4,5-trichloro- benzenesulfonyl)-piperidin-4-yl]-1 ,4- dihydro-benzo[d][1 ,3]oxazin-2-one
Figure imgf000106_0004
1 -[1 -(5-Bromo-2-methoxy- benzenesulfonyl)-piperidin-4-yl]-1 ,4- dihydro-benzo[d][1 ,3]oxazin-2-one
Figure imgf000106_0005
1 -[1 -(5-Bromo-2-methoxy- bbeennzzeenneessuullffoonnyyll))--ppiippeerriiddiinn--4-yl]-8- mmeetthhyyll--11 ,,44--ddiihhyyddrroo-- benzo[d][1 ,3]oxazin-2-one
Figure imgf000106_0006
-yl]-6- 1 ,3]oxazin-
Figure imgf000106_0007
1 -[1 -(5-Bromo-2-methoxy- benzenesulfonyl)-piperidin-4-yl]-6- methyl-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000107_0001
1 -[1 -(2,6-Dimethoxy-benzenesulfonyl)- piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000107_0002
1 -[1 -(2,6-Dimethoxy-benzenesulfonyl)- piperidin-4-yl]-8-methyl-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000107_0003
6-Chloro-1 -[1 -(2,6-dimethoxy- benzenesulfonyl)-piperidin-4-yl]-1 ,4- dihydro-benzo[d][1 ,3]oxazin-2-one
Figure imgf000107_0004
1 -[1 -(2,6-Dimethoxy-benzenesulfonyl)- piperidin-4-yl]-6-methyl-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000107_0005
1-(1-Pentamethylbenzenesulfonyl- piperidin-4-yl)-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000107_0006
8-Methyl-1-(1- pentamethylbenzenesulfonyl-piperidin- 4_y|)"1.4-dihydro-benzo[d][1 ,3]oxazin-
Figure imgf000107_0007
107 esulfonyl-piperidin- nzo[d][1 ,3]oxazin-
Figure imgf000108_0001
enesulfonyl-piperidin- benzo[d][1 ,3]oxazin-
Figure imgf000108_0002
1 -{1 -[2-(2,2,2-Trifluoro-acetyl)-1 ,2,3,4- tetrahydro-isoquinoline-7-sulfonyl]- piperidin-4-yl}-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000108_0003
8-Methyl-1 -{1 -[2-(2,2,2-trifluoro-acetyl)- 1 ,2,3,4-tetrahydro-isoquinoline-7- sulfonyl]-piperidin-4-yl}-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000108_0004
6-Chloro-1 -{1 -[2-(2,2,2-trifluoro-acetyl)- 1 ,2,3,4-tetrahydro-isoquinoline-7- sulfonyl]-piperidin-4-yl}-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000108_0005
6-Methyl-1-{1-[2-(2,2,2-trifluoro-acetyl)- 1 ,2,3,4-tetrahydro-isoquinoline-7- sulfonyl]-piperidin-4-yl}-1,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000108_0006
1-[1-(2-Methyl-5-nitro- benzenesulfonyl)-piperidin-4-yl]-1,4- dihydro-benzo[d][1 ,3]oxazin-2-one
Figure imgf000108_0007
108 8-Methyl-1 -[1 -(2-methyl-5-nitro- benzenesulfonyl)-piperidin-4-yl]-1 ,4- dihydro-benzo[d][1 ,3]oxazin-2-one
Figure imgf000109_0001
6-Chloro-1 -[1 -(2-methyl-5-nitro- benzenesulfonyl)-piperidin-4-yl]-1 ,4- dihydro-benzo[d][1 ,3]oxazin-2-one
Figure imgf000109_0002
6-Methyl-1 -[1 -(2-methyl-5-nitro- benzenesulfonyl)-piperidin-4-yl]-1 ,4- dihydro-benzo[d][1 ,3]oxazin-2-one
Figure imgf000109_0003
1 -[1 -(4-Bromo-2,5-difluoro- benzenesulfonyl)-piperidin-4-yl]-1 ,4- dihydro-benzo[d][1 ,3]oxazin-2-one
Figure imgf000109_0004
1 -[1 -(4-Bromo-2,5-difluoro- benzenesulfonyl)-piperidin-4-yl]-8- methyl-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000109_0005
-yl]-6- 1 ,3]oxazin-
Figure imgf000109_0006
1 -[1 -(4-Bromo-2,5-difluoro- -'° ^N AH, benzenesulfonyl)-piperidin-4-yl]-6- ~^( λ XT methyl-1 ,4-dihydro- F~ rF ^YY benzo[d][1 ,3]oxazin-2-one Br 0^ -0. 109 1 -[1 -(4-Chloro-2,5-dimethyl- benzenesulfonyl)-piperidin-4-yl]-1 ,4- dihydro-benzo[d][1 ,3]oxazin-2-one
Figure imgf000110_0001
1 -[1 -(4-Chloro-2,5-dimethyl- benzenesulfonyl)-piperidin-4-yl]-8- methyl-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000110_0002
6-Chloro-1 -[1 -(4-chloro-2,5-dimethyl- benzenesulfonyl)-piperidin-4-yl]-1 ,4- dihydro-benzo[d][1 ,3]oxazin-2-one
Figure imgf000110_0003
1 -[1 -(4-Chloro-2,5-dimethyl- benzenesulfonyl)-piperidin-4-yl]-6- methyl-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000110_0004
1 -[1 -(4-Methoxy-benzenesulfonyl)- piperidin-4-yl]-6-methyl-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000110_0005
1 -[1 -(4-lsopropyl-benzenesulfonyl)- piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000110_0006
1 -[1 -(4-lsopropyl-benzenesulfonyl)- piperidin-4-yl]-8-methyl-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000110_0007
6-Chloro-1 -[1 -(4-isopropyl- benzenesulfonyl)-piperidin-4-yl]-1 ,4- dihydro-benzo[d][1 ,3]oxazin-2-one
Figure imgf000111_0001
1 -[1 -(4-lsopropyl-benzenesulfonyl)- piperidin-4-yl]-6-methyl-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000111_0002
1 -[1 -(3-Chloro-4-fluoro- benzenesulfonyl)-piperidin-4-yl]-1 ,4- dihydro-benzo[d][1 ,3]oxazin-2-one
Figure imgf000111_0003
1-[1-(3-Chloro-4-fluoro- benzenesulfonyl)-piperidin-4-yl]-8- methyl-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000111_0004
6-Chloro-1 -[1 -(3-chloro-4-fluoro- benzenesulfonyl)-piperidin-4-yl]-1 ,4- dihydro-benzo[d][1 ,3]oxazin-2-one
Figure imgf000111_0005
1-[1-(3-Chloro-4-fluoro- benzenesulfonyl)-piperidin-4-yl]-6- methyl-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000111_0006
1 -[1 -(4-Bromo-benzenesulfonyl)- piperidin-4-yl]-6-methyl-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000111_0007
111 6-Methyl-1-[1-(3-nitro- benzenesulfonyl)-piperidin-4-yl]-1,4- dihydro-benzo[d][1 ,3]oxazin-2-one
Figure imgf000112_0001
6-Methyl-1 -[1 -(3-trifluoromethyi- benzenesulfonyl)-piperidin-4-yl]-1 ,4 dihydro-benzo[d][1,3]oxazin-2-one
Figure imgf000112_0002
1 -[1 -(4-Trifluoromethoxy- benzenesulfonyl)-piperidin-4-yl]-1 ,4- dihydro-benzo[d][1 ,3]oxazin-2-one
Figure imgf000112_0003
1 -[1 -(2-Nitro-4-trifluoromethyl- benzenesulfonyl)-piperidin-4-yl]-1 ,4- dihydro-benzo[d][1 ,3]oxazin-2-one
Figure imgf000112_0004
1 -[1 -(3-Fluoro-benzenesulfonyl)- piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000112_0005
1 -[1 -(2,4-Dichloro-benzenesulfonyl)- piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000112_0006
1 -[1 -(2,4,6-Trimethyl-benzenesulfonyl)- piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000112_0007
112 1 -[1 -(2-Trifluoromethyl- benzenesulfonyl)-piperidin-4-yl]-1 ,4- dihydro-benzo[d][1 ,3]oxazin-2-one
Figure imgf000113_0001
8-Methyl-1 -[1 -(4-trifiuoromethoxy- benzenesulfonyl)-piperidin-4-yl]-1 ,4- dihydro-benzo[d][1 ,3]oxazin-2-one
Figure imgf000113_0002
8-Methyl-1 -[1 -(2-nitro-4-trifluoromethyl- benzenesulfonyl)-piperidin-4-yl]-1,4- dihydro-benzo[d][1 ,3]oxazin-2-one
1 -[1 -(3-Fiuoro-benzenesulfonyl)- piperidin-4-yl]-8-methyl-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000113_0003
1 -[1 -(2,4-Dichloro-benzenesulfonyl)- piperidin-4-yl]-8-methyl-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000113_0004
8-Methyl-1 -[1 -(2,4,6-trimethyl- bbeennzzeenneessuullffoonnyyll))--ppiippeerriiddiinn--44--^yl]-1 ,4- dihydro-benzo[d][1 ,3]oxazin-2-one
Figure imgf000113_0005
8-Methyl-1 -[1 -(2-trifluoromethyi- benzenesulfonyl)-piperidin-4-yl]-1 ,4- dihydro-benzo[d][1 ,3]oxazin-2-one
Figure imgf000113_0006
05/014 113 1 -[1 -(4-Fluoro-benzenesulfonyl)- piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000114_0001
1 -[1 -(4-Bromo-benzenesulfonyl)- piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000114_0002
1 -[1 -(3-Nitro-benzenesulfonyl)- piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000114_0003
1 -{1 -[4-(4-Bromo-phenoxy)- benzenesulfonyl]-piperidin-4-yl}-1 ,4- dihydro-benzo[d][1 ,3]oxazin-2-one
Figure imgf000114_0004
1 -[1 -(3-Methoxy-benzenesulfonyl)- ppiippeerriiddiinn--44--yyll]]--11 ,,44--ddiihhyyddrroo-- benzo[d][1 ,3]oxazin-2-one
Figure imgf000114_0005
1 -[1 -(2-Nitro-benzenesulfonyl)- piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000114_0006
8-Methyl-1 -[1 -(toluene-4-sulfonyl)- piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000114_0007
1 -(1 -Benzenesulfonyl-piperidin-4-yl)-8- methyl-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000115_0001
1 -[1 -(3-Methoxy-benzenesulfonyl)- piperidin-4-yl]-8-methyl-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000115_0002
1 -[1 -(2,4-Dimethyl-benzenesulfonyl)- piperidin-4-yl]-6-methyl-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000115_0003
1 -{1 -[4-(4-Bromo-phenoxy)- benzenesulfonyl]-piperidin-4-yl}-6- methyl-1 ,4-dihydro-
Figure imgf000115_0004
benzo[d][1 ,3]oxazin-2-one
6-Methyl-1 -[1 -(thiophene-2-sulfonyl)- piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000115_0005
luene-3-sulfonyl)-piperidin-4- ihydro-benzo[d][1 ,3]oxazin-2-
Figure imgf000115_0006
1 -[1 -(5-Fluoro-2-methyl- benzenesulfonyl)-piperidin-4-yl]-1 ,4- dihydro-benzo[d][1 ,3]oxazin-2-one
Figure imgf000115_0007
1 -[1 -(4-lsopropoxy-benzenesulfonyl)- piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000116_0001
1 -[1 -(3-Chloro-benzenesulfonyl)- piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000116_0002
1 -[1 -(3,4-Dimethoxy-benzenesulfonyl)- piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000116_0003
1 -(1 -Pentafluorobenzenesulfonyl- piperidin-4-yl)-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000116_0004
8-Methyl-1 -[1 -(toluene-3-sulfonyl)- piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000116_0005
1-[1-(5-Fluoro-2-methyl- benzenesulfonyl)-piperidin-4-yl]-8- methyl-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000116_0006
1 -[1 -(4-lsopropoxy-benzenesulfonyl)- piperidin-4-yl]-8-methyl-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000116_0007
2005/01400 116 1 -[1 -(3-Chloro-benzenesulfonyl)- piperidin-4-yl]-8-methyl-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000117_0001
1 -[1 -(3,4-Dimethoxy-benzenesulfonyl)- piperidin-4-yl]-8-methyl-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000117_0002
yl-piperidin- [1 ,3]oxazin-
Figure imgf000117_0003
6-Methyl-1 -[1 -(toluene-3-sulfonyl)- piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000117_0004
1 -[1 -(5-Fluoro-2-methyl- benzenesulfonyl)-piperidin-4-yl]-6- methyl-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000117_0005
1 -[1 -(4-lsopropoxy-benzenesulfonyl)- piperidin-4-yl]-6-methyl-1,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000117_0006
1 -[1 -(3-Chloro-benzenesulfonyl)- piperidin-4-yl]-6-methyl-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000117_0007
117 1 -[1 -(3,4-Dimethoxy-benzenesulfonyl)- piperidin-4-yl]-6-methyl-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000118_0001
6-Methyl-1-(1- -piperidin- ,3]oxazin-
Figure imgf000118_0002
6-Methyl-1 -[1 -(4-trifluoromethoxy- benzenesulfonyl)-piperidin-4-yl]-1 ,4- dihydro-benzo[d][1 ,3]oxazin-2-one
Figure imgf000118_0003
6-Methyl-1 -[1 -(2-nitro-4-trifluoromethyl- benzenesulfonyl)-piperidin-4-yl]-1 ,4- dihydro-benzo[d][1 ,3]oxazin-2-one
Figure imgf000118_0004
1 -[1 -(3-Fluoro-benzenesulfonyl)- piperidin-4-yl]-6-methyl-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000118_0005
1 -[1 -(2,4-Dichloro-benzenesulfonyl)- piperidin-4-yl]-6-methyl-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000118_0006
6-Methyl-1 -[1 -(2,4,6-trimethyl- benzenesulfonyl)-piperidin-4-yl]-1 ,4- dihydro-benzo[d][1 ,3]oxazin-2-one
Figure imgf000118_0007
6-Methyl-1 -[1 -(2-trifluoromethyl- benzenesulfonyl)-piperidin-4-yl]-1 ,4- dihydro-benzo[d][1 ,3]oxazin-2-one
Figure imgf000119_0001
1 -[1 -(3-Methoxy-benzenesulfonyl)- piperidin-4-yl]-6-methyl-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000119_0002
6-Methyl-1-[1-(2-nitro- benzenesulfonyl)-piperidin-4-yl]-1 ,4- dihydro-benzo[d][1 ,3]oxazin-2-one
Figure imgf000119_0003
1 -[1 -(4-Acetyl-benzenesulfonyl)- piperidin-4-yl]-6-methyl-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000119_0004
1 -[1 -(4-Methanesulfonyl- benzenesulfonyl)-piperidin-4-yl]-6- methyl-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000119_0005
6-Methyl-1-(1-phenylmethanesulfonyl- piperidin-4-yl)-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000119_0006
2-[4-(6-Methyl-2-oxo-4H- benzo[d][1 ,3]oxazin-1 -yl)-piperidine-1 ■ sulfonyl]-benzoic acid methyl ester
Figure imgf000119_0007
6-Methyl-1 -[1 -(2-oxo-2H-chromene-6- sulfonyl)-piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000120_0001
6-Chloro-1 -[1 -(4-fluoro- benzenesulfonyl)-piperidin-4-yl]-1 ,4- dihydro-benzo[d][1 ,3]oxazin-2-one
Figure imgf000120_0002
6-Chloro-1 -[1 -(3,5-dichloro- benzenesulfonyl)-piperidin-4-yl]-1 ,4- dihydro-benzo[d][1 ,3]oxazin-2-one
Figure imgf000120_0003
1 -{1 -[4-(4-Bromo-phenoxy)- nesulfonyl]-piperidin-4-yl}-6- -1 ,4-dihydro-benzo[d][1 ,3]oxazin-
Figure imgf000120_0004
6-Chloro-1 -[1 -(thiophene-2-sulfonyl)- piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000120_0005
6-Chloro-1 -[1 -(3-methoxy- benzenesulfonyl)-piperidin-4-yl]-1 ,4- dihydro-benzo[d][1 ,3]oxazin-2-one
Figure imgf000120_0006
6-Chloro-1 -[1 -(2-oxo-2H-chromene-6- sulfonyl)-piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000120_0007
6-Chloro-1 -[1 -(toluene-3-sulfonyl)- ppiippeerriiddiinn--44--yyll]]--11 ,,44--ddiihhyyddrroo- benzo[d][1 ,3]oxazin-2-one
Figure imgf000121_0001
6-Chloro-1 -[1 -(5-fluoro-2-methyl- benzenesulfonyl)-piperidin-4-yl]-1 ,4- dihydro-benzo[d][1 ,3]oxazin-2-one
Figure imgf000121_0002
6-Chloro-1 -[1 -(4-isopropoxy- benzenesulfonyl)-piperidin-4-yl]-1 ,4- dihydro-benzo[d][1 ,3]oxazin-2-one
Figure imgf000121_0003
6-Chloro-1 -[1 -(3-chloro- benzenesulfonyl)-piperidin-4-yl]-1 ,4- dihydro-benzo[d][1 ,3]oxazin-2-one
Figure imgf000121_0004
6-Chloro-1 -[1 -(3,4-dimethoxy- benzenesulfonyl)-piperidin-4-yl]-1 ,4- dihydro-benzo[d][1,3]oxazin-2-one
Figure imgf000121_0005
yl-piperidin- [1 ,3]oxazin-
Figure imgf000121_0006
6-Chloro-1 -[1 -(4-trifluoromethoxy- benzenesulfonyl)-piperidin-4-yl]-1 ,4- dihydro-benzo[d][1 ,3]oxazin-2-one
Figure imgf000121_0007
6-Chloro-1 -[1 -(2-nitro-4-trifluoromethyl- benzenesulfonyl)-piperidin-4-yl]-1 ,4- dihydro-benzo[d][1 ,3]oxazin
Figure imgf000122_0001
6-Chloro-1-[1-(3-fiuoro- benzenesulfonyl)-piperidin-4-yl]-1 ,4- dihydro-benzo[d][1 ,3]oxazin-2-one
Figure imgf000122_0002
6-Chloro-1 -[1 -(2,4-dichloro- benzenesulfonyl)-piperidin-4-yl]-1 ,4- dihydro-benzo[d][1 ,3]oxazin-2-one
Figure imgf000122_0003
6-Chloro-1 -[1 -(2,4,6-trimethyl- benzenesulfonyl)-piperidin-4-yl]-1 ,4- dihydro-benzo[d][1 ,3]oxazin-2-one
Figure imgf000122_0004
6-Chloro-1 -[1 -(2-trifluoromethyl- benzenesulfonyl)-piperidin-4-yl]-1 ,4- dihydro-benzo[d][1 ,3]oxazin-2-one
Figure imgf000122_0005
1 -[1 -(2-Oxo-2H-chromene-6-sulfonyl)- piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000122_0006
1 -[1 -(3,5-Dichloro-benzenesulfonyl)- piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000122_0007
122 1-[1-(2,5-Dichloro-benzenesulfonyl)- piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
1 -[1 -(5-Bromo-6-chloro-pyridine-3- sulfonyl)-piperidin-4-yl]-1,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000123_0001
1 -[1 -(4-Chloro-benzenesulfonyl)- piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
1 -[1 -(2,6-Dichloro-benzenesulfonyl)- piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000123_0002
8-Methyl-1 -[1 -(2-oxo-2H-chromene-6- sulfonyl)-piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000123_0003
1 -[1 -(3,5-Dichloro-benzenesulfonyl)- piperidin-4-yl]-8-methyl-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000123_0004
1 -[1 -(2,5-Dichloro-benzenesulfonyl)- piperidin-4-yl]-8-methyl-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000123_0005
1 -[1 -(5-Bromo-6-chloro-pyridine-3- sulfonyl)-piperidin-4-yl]-8-methyl-1 ,4- dihydro-benzo[d][1 ,3]oxazin-2-one
Figure imgf000124_0001
1 -[1 -(4-Chloro-benzenesulfonyl)- piperidin-4-yl]-8-methyl-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000124_0002
1 -[1 -(2,6-Dichloro-benzenesulfonyl)- piperidin-4-yl]-8-methyl-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000124_0003
henyl-4-sulfonyl)-piperidin-4- hydro-benzo[d][1 ,3]oxazin-2-
Figure imgf000124_0004
6-Chloro-1 -[1 -(2,5-dichloro- benzenesulfonyl)-piperidin-4-yl]-1 ,4- dihydro-benzo[d][1 ,3]oxazin-2-one
Figure imgf000124_0005
1 -[1 -(5-Bromo-6-chloro-pyridine-3- sulfonyl)-piperidin-4-yl]-6-chloro-1 ,4- dihydro-benzo[d][1 ,3]oxazin-2-one
Figure imgf000124_0006
6-Chloro-1-[1-(4-chloro- benzenesulfonyl)-piperidin-4-yl]-1 ,4- dihydro-benzo[d][1 ,3]oxazin-2-one
Figure imgf000124_0007
124 6-Chloro-1 -[1 -(2,6-dichloro- benzenesulfonyl)-piperidin-4-yl]-1 ,4- dihydro-benzo[d][1,3]oxazin-2-one
Figure imgf000125_0001
1 -[1 -(Biphenyl-4-sulfonyl)-piperidin-4- yl]-6-methyl-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000125_0002
2-[4-(6-Methyl-2-oxo-4H- benzo[d][1 ,3]oxazin-1 -yl)-piperidine-1 ■ sulfonyl]-benzonitrile
1-[1-(2,5-Dichloro-benzenesulfonyl)- piperidin-4-yl]-6-methyl-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000125_0003
1 -[1 -(5-Bromo-6-chloro-pyridine-3- sulfonyl)-piperidin-4-yl]-6-methyl-1 ,4- dihydro-benzo[d][1 ,3]oxazin-2-one
Figure imgf000125_0004
1 -[1 -(4-Chloro-benzenesulfonyl)- piperidin-4-yl]-6-methyl-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
1 -[1 -(2,6-Dichloro-benzenesulfonyl)- piperidin-4-yl]-6-methyl-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000125_0005
1 -[1 -(3,5-Dichloro-benzenesulfonyl)- piperidin-4-yl]-6-methyl-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000126_0001
6-Methyl-1 -[1 -(1 -methyl-1 H-imidazole- 4-sulfonyl)-piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000126_0002
1 -[1 -(5-Bromo-2,4-difluoro- benzenesulfonyl)-piperidin-4-yl]-6- methyl-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000126_0003
1 -[1 -(4-Methanesulfonyl- benzenesulfonyl)-piperidin-4-yl]-1 ,4- dihydro-benzo[d][1 ,3]oxazin-2-one
1 -[1 -(1 -Methyl-1 H-imidazole-4- sulfonyl)-piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000126_0004
1 -[1 -(5-Bromo-2,4-difluoro- benzenesulfonyl)-piperidin-4-yl]-1 ,4- dihydro-benzo[d][1 ,3]oxazin-2-one
1 -[1 -(6-Chloro-imidazo[2, 1 -b]thiazole- 5-sulfonyl)-piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000126_0005
1 -[1 -(4-Ethyl-benzenesulfonyl)- piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000127_0001
1 -[1 -(Benzo[b]thiophene-3-sulfonyl)- piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
1-[1-(6-Chloro-imidazo[2,1-b]thiazole- 5-sulfonyl)-piperidin-4-yl]-8-methyl-1 ,4- dihydro-benzo[d][1 ,3]oxazin-2-one
1 -[1 -(4-Ethyl-benzenesulfonyl)- piperidin-4-yl]-8-methyl-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000127_0002
1 -[1 -(Benzo[b]thiophene-3-sulfonyl)- piperidin-4-yl]-8-methyl-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000127_0003
6-Chloro-1 -[1 -(6-chloro-imidazo[2J - b]thiazole-5-sulfonyl)-piperidin-4-yl]- 1 ,4-dihydro-benzo[d][1 ,3]oxazin-2-one
Figure imgf000127_0004
6-Chloro-1-[1-(4-ethyl- benzenesulfonyl)-piperidin-4-yl]-1,4- dihydro-benzo[d][1 ,3]oxazin-2-one
Figure imgf000127_0005
O 2005/014 127 1 -[1 -(Benzo[b]thiophene-3-sulfonyl)- piperidin-4-yl]-6-chloro-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000128_0001
1-[1-(6-Chloro-imidazo[2,1-b]thiazole- 5-sulfonyl)-piperidin-4-yl]-6-methyl-1 ,4- dihydro-benzo[d][1,3]oxazin-2-one
Figure imgf000128_0002
1 -[1 -(4-Ethyl-benzenesulfonyl)- piperidin-4-yl]-6-methyl-1,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000128_0003
1 -[1 -(Benzo[b]thiophene-3-sulfonyl)- piperidin-4-yl]-6-methyl-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000128_0004
1 -[1 -(7-Chloro-benzo[1 ,2,5]oxadiazole- 4-sulfonyl)-piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000128_0005
1 -[1 -(2-Methoxy-4-methyl- benzenesulfonyl)-piperidin-4-yl]-1 ,4- dihydro-benzo[d][1 ,3]oxazin-2-one
3-{4-[4-(2-Oxo-4H-benzo[d][1 ,3]oxazin- 1 -yl)-piperidine-1 -sulfonyl]-phenyl}- propionic acid methyl ester
Figure imgf000128_0006
128 1 -[1 -(2,4-Dinitro-benzenesulfonyl)- piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000129_0001
1 -[1 -(7-Chloro-benzo[1 ,2,5]oxadiazole- 4-sulfonyl)-piperidin-4-yl]-8-methyl-1 ,4- dihydro-benzo[d][1 ,3]oxazin-2-one 1 -[1 -(2-Methoxy-4-methyl- benzenesulfonyl)-piperidin-4-yl]-8- methyl-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
3-{4-[4-(8-Methyl-2-oxo-4H- benzo[d][1 ,3]oxazin-1 -yl)-piperidine-1 - sulfonyl]-phenyl}-propionic acid methyl ester
1 -[1 -(2,4-Dinitro-benzenesulfonyl)- piperidin-4-yl]-8-methyl-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000129_0003
1 -[1 -(7-Chloro-benzo[1 ,2,5]oxadiazole- 4-sulfonyl)-piperidin-4-yl]-6-methyl-1 ,4- dihydro-benzo[d][1 ,3]oxazin-2-one
Figure imgf000129_0004
1 -[1 -(2-Methoxy-4-methyl- benzenesulfonyl)-piperidin-4-yl]-6- methyl-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000129_0005
3-{4-[4-(6-Methyl-2-oxo-4H- benzo[d][1 ,3]oxazin-1 -yl)-piperidine-1 - sulfonyl]-phenyl}-propionic acid methyl ester
Figure imgf000130_0001
1 -[1 -(2,4-Dinitro-benzenesulfonyl)- piperidin-4-yl]-6-methyl-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
6-Chloro-1-[1-(7-chloro- benzo[1 ,2,5]oxadiazole-4-sulfonyl)- piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000130_0002
6-Chloro-1 -[1 -(2-methoxy-4-methyl- benzenesulfonyl)-piperidin-4-yl]-1 ,4- dihydro-benzo[d][1 ,3]oxazin-2-one
Figure imgf000130_0003
3-{4-[4-(6-Chloro-2-oxo-4H- benzo[d][1 ,3]oxazin-1 -yl)-piperidine-1 - sulfonyl]-phenyl}-propionic acid methyl ester
Figure imgf000130_0004
6-Chloro-1-[1-(2,4-dinitro- benzenesulfonyl)-piperidin-4-yl]-1 ,4- dihydro-benzo[d][1 ,3]oxazin-2-one
6-Chloro-1-[1-(1 -methyl-1 H-imidazole- 4-sulfonyl)-piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000130_0005
130 -yl]-6- 1 ,3]oxazin-
Figure imgf000131_0001
8-Methyl-1 -[1 -(1 -methyl-1 H-imidazole- 4-sulfonyl)-piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
1 -[1 -(5-Bromo-2,4-difluoro- benzenesulfonyl)-piperidin-4-yl]-8- methyl-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
1 -[1 -(Benzo[b]thiophene-2-sulfonyl)- piperidin-4-yl]-8-methyl-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000131_0002
1 -[1 -(Benzo[b]thiophene-2-sulfonyl)- piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000131_0003
1 -[1 -(Benzo[b]thiophene-2-sulfonyl)- piperidin-4-yl]-6-chloro-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000131_0004
1 -[1 -(Benzo[b]thiophene-2-sulfonyl)- piperidin-4-yl]-6-methyl-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000131_0005
1-[1-(2,5-Difluoro- benzenesulfonyl)-piperidin-4- yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
1-[1-(2,5-Difluoro- benzenesulfonyl)-piperidin-4- yl]-8-methyl-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000132_0001
6-Chloro-1 -[1 -(2,5-difluoro- benzenesulfonyl)-piperidin-4- yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000132_0002
1-[1-(2,5-Difluoro- benzenesulfonyl)-piperidin-4- yl]-6-methyl-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000132_0003
1-[1-(4-Chloro-2,5-difluoro- benzenesulfonyl)-piperidin-4- yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
1 -[1 -(4-Chloro-2,5-difluoro- benzenesulfonyl)-piperidin-4- yl]-8-methyl-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
6-Chloro-1 -[1 -(4-chloro-2,5- difluoro-benzenesulfonyl)- piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000132_0004
1 -[1 -(4-Chloro-2,5-difluoro- benzenesulfonyl)-piperidin-4- yl]-6-methyl-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000133_0001
1-[1-(2,4,5-Trifluoro- benzenesulfonyl)-piperidin-4- yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
8-Methyl-1 -[1 -(2,4,5-trifluoro- benzenesulfonyl)-piperidin-4- yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
6-Chloro-1 -[1 -(2,4,5-trifluoro- benzenesulfonyl)-piperidin-4- yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000133_0002
6-Methyl-1 -[1 -(2,4,5-trifluoro- benzenesulfonyl)-piperidin-4- yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
1-[1-(3,5-Dichloro-2-hydroxy- benzenesulfonyl)-piperidin-4- yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000133_0003
1-[1-(2,6-Difluoro- benzenesulfonyl)-piperidin-4- yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000133_0004
1-[1-(2,6-Difluoro- benzenesulfonyl)-piperidin-4- yl]-8-methyl-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
6-Chloro-1 -[1 -(2,6-difluoro- benzenesulfonyl)-piperidin-4- yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000134_0001
1-[1-(2,6-Difluoro- benzenesulfonyl)-piperidin-4- yl]-6-methyl-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
1 -[1 -(5-Chloro-2,4-difluoro- benzenesulfonyl)-piperidin-4- yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000134_0002
1 -[1 -(5-Chloro-2,4-difluoro- benzenesulfonyl)-piperidin-4- yl]-8-methyl-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
6-Chloro-1 -[1 -(5-chloro-2,4- difluoro-benzenesulfonyl)- piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000134_0003
1 -[1 -(5-Chloro-2,4-difluoro- benzenesulfonyl)-piperidin-4- yl]-6-methyl-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000134_0004
1-[1-(2-Chloro- benzenesulfonyl)-piperidin-4- yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
1-[1-(2-ChIoro- benzenesulfonyl)-piperidin-4- yl]-8-methyl-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
6-Chloro-1-[1-(2-chloro- benzenesulfonyl)-piperidin-4- yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000135_0001
1-[1-(2-Chloro- benzenesulfonyl)-piperidin-4- yl]-6-methyl-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000135_0002
6-Chloro-1 -[1 -(2-naphthalen- 1 -yl-ethanesulfonyl)-piperidin- 4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000135_0003
6-Bromo-1 -[1 -(4-bromo- benzenesulfonyl)-piperidin-4- yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000135_0004
ene-4- 4-yl]-1 ,4- ,3]oxazin-
Figure imgf000135_0005
6-Bromo-1-[1-(2,4-dimethyl- benzenesulfonyl)-piperidin-4- yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000136_0001
6-Bromo-1 -[1 -(2-naphthalen- 1 -yl-ethanesulfonyl)-piperidin- 4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000136_0002
Figure imgf000136_0003
6-Bromo-1-[1-(3-nitro- benzenesulfonyl)-piperidin-4- yl]-1 ,4-dihydro-
Figure imgf000136_0004
benzo[d][1 ,3]oxazin-2-one
ene-1 ■ 1 ,4- azin-
ne-2- ,4- zin-
Figure imgf000136_0005
,4- zin-
Figure imgf000137_0001
6-Bromo-1 -{1 -[4-(4-bromo- phenoxy)-benzenesulfonyl]- piperidin-4-yl}-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000137_0002
phene-2- 4-yl]-1 ,4- ,3]oxazin-
Figure imgf000137_0003
6-Bromo-1 -[1 -(2-methyl-5- nitro-benzenesulfonyl)- > JJff- piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
6-Bromo-1 -[1 -(4-bromo-2,5- difluoro-benzenesulfonyl)- piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000137_0004
ene-3- 4-yl]-1 ,4- ,3]oxazin-
Figure imgf000137_0005
6-Bromo-1 -[1 -(5-fluoro-2- methyl-benzenesulfonyl)- piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000137_0006
005/014000 137 6-Bromo-1 -[1 -(4-isopropoxy- benzenesulfonyl)-piperidin-4- yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000138_0001
6-Bromo-1 -[1 -(3-chloro- benzenesulfonyl)-piperidin-4- yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000138_0002
6-Bromo-1 -[1 -(3,4-dimethoxy- benzenesulfonyl)-piperidin-4- yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000138_0003
6-Bromo-1-(1- pentafluorobenzenesulfonyl- piperidin-4-yl)-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000138_0004
6-Bromo-1 -[1 -(4-chloro-2,5- dimethyl-benzenesulfonyl)- piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000138_0005
6-Bromo-1 -[1 -(3-methoxy- benzenesulfonyl)-piperidin-4- yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000138_0006
6-Bromo-1 -[1 -(4-isopropyl- benzenesulfonyl)-piperidin-4- yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000138_0007
138 6-Bromo-1 -[1 -(4-fluoro- benzenesulfonyl)-piperidin-4- yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000139_0001
6-Bromo-1 -[1 -(3-chloro-4- fluoro-benzenesulfonyl)- piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000139_0002
6-Bromo-1-(1- pentamethylbenzenesulfonyl- piperidin-4-yl)-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000139_0003
6-Bromo-1-[1-(2-nitro- benzenesulfonyl)-piperidin-4- yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000139_0004
6-Bromo-1 -[1 -(4-chloro-3- nitro-benzenesulfonyl)- piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000139_0005
e- ,4- n-
Figure imgf000139_0006
6-Bromo-1 -[1 -(4-nitro- xχχ 0 benzenesulfonyl)-piperidin-4- 0 yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one 'XX- 139
Figure imgf000140_0001
6-Bromo-1-(1- phenylmethanesulfonyl- piperidin-4-yl)-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000140_0002
6-Bromo-1 -[1 -(2,5-dimethoxy- XXX. benzenesulfonyl)-piperidin-4- yl]-1 ,4-dihydro- ■I- "" benzo[d][1 ,3]oxazin-2-one
-
Figure imgf000140_0003
6-Bromo-1 -[1 -(2,3-dichloro- benzenesulfonyl)-piperidin-4- yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000140_0004
6-Bromo-1 -[1 -(2,4,5-trichloro- benzenesulfonyl)-piperidin-4- yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
6-Bromo-1-[1-(5-bromo-2- methoxy-benzenesulfonyl)- piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
6-Bromo-1-[1-(4- trifluoromethoxy- benzenesulfonyl)-piperidin-4- yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
6-Bromo-1-[1-(2-nitro-4- trifluoromethyl- benzenesulfonyl)-piperidin-4- yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
6-Bromo-1 -[1 -(3-fluoro- benzenesulfonyl)-piperidin-4- yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
6-Bromo-1-[1-(2,4-dichloro- benzenesulfonyl)-piperidin-4- yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
6-Bromo-1-[1-(2,4,6-trimethyl- benzenesulfonyl)-piperidin-4- yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000141_0001
141 6-Bromo-1-[1-(2- "XX. trifluoromethyl- benzenesulfonyl)-piperidin-4- yl]-1 ,4-dihydro- o- A benzo[d][1 ,3]oxazin-2-one
6-Bromo-1 -[1 -(2-bromo- benzenesulfonyl)-piperidin-4- yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
6-Bromo-1 -[1 -(4-methoxy- 2,3,6-trimethyl- benzenesulfonyl)-piperidin-4- yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000142_0001
1-[1-(3,5-Dichloro-4-hydroxy- (J benzenesulfonyl)-piperidin-4- yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
1 -[1 -(3,5-Dichloro-4-hydroxy- benzenesulfonyl)-piperidin-4- yl]-8-methyl-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
6-Chloro-1-[1-(3,5-dichloro-4- hydroxy-benzenesulfonyl)- piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
1-[1-(3,5-Dichloro-4-hydroxy- benzenesulfonyl)-piperidin-4- yl]-6-methyl-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000142_0002
6-Bromo-1 -[1 -(3,5-dichloro-4- hydroxy-benzenesulfonyl)- piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
6-Chloro-1 -[1 -(3,5-dichloro-2- hydroxy-benzenesulfonyl)- piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000143_0001
6-Bromo-1 -[1 -(3,5-dichloro-2- A0 hydroxy-benzenesulfonyl)- piperidin-4-yl]-1 ,4-dihydro- rr ,cι benzo[d][1 ,3]oxazin-2-one
2-[4-(6-Bromo-2-oxo-4H- benzo[d][1 ,3]oxazin-1-yl)- piperidine-1 -sulfonyl]- benzonitrile
6-Bromo-1-[1-(4-methoxy- benzenesulfonyl)-piperidin-4- yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
2-[4-(6-Bromo-2-oxo-4H- benzo[d][1 ,3]oxazin-1-yl)- piperidine-1 -sulfonyl]-benzoic acid methyl ester
6-Bromo-1 -[1 -(2-oxo-2H- chromene-6-sulfonyl)- piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000143_0002
143 6-Bromo-1 -[1 -(3,5-dichloro- benzenesulfonyl)-piperidin-4- yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
6-Bromo-1 -[1 -(2,5-dichloro- benzenesulfonyl)-piperidin-4- yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
6-Bromo-1 -[1 -(5-bromo-6- chloro-pyridine-3-sulfonyl)- piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
6-Bromo-1 -[1 -(4-chloro- benzenesulfonyl)-piperidin-4- yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
6-Bromo-1 -[1 -(2,6-dichloro- benzenesulfonyl)-piperidin-4- yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
6-Bromo-1 -[1 -(1 -methyl-1 H- imidazole-4-sulfonyl)- piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
6-Bromo-1 -[1 -(5-bromo-2,4- difluoro-benzenesulfonyl)- piperidin-4-yl+-1 ,4-dihydro- benzo[d][1 ,3]oxacin-2-one
Figure imgf000144_0001
Furthermore, particularly preferred is the use of one or more benzoxazinone-derived sulfonamide compounds of general formula (lb) selected from the group consisting of:
Figure imgf000145_0001
2-[4-(2-Oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidine-1 -sulfonyl]-benzoic acid methyl ester
1 -[1 -(3-Trifluoromethyl-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
2-[4-(8-Methyl-2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidine-1 -sulfonyl]- benzoic acid methyl ester
8-Methyl-1 -[1 -(3-trifluoromethyl-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
1 -[1 -(4-Acetyl-benzenesulfonyl)-piperidin-4-yl]-6-chloro-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
2-[4-(6-Chloro-2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidine-1 -sulfonyl]- benzonitrile
6-Chloro-1 -[1 -(4-methoxy-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
2-[4-(6-Chloro-2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidine-1 -sulfonyl]- benzoic acid methyl ester
6-Chloro-1 -[1 -(2,4-dimethyl-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
6-Chloro-1 -[1 -(3-trifluoromethyl-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
1-[1-(5-Chloro-3-methyl-benzo[b]thiophene-2-sulfonyl)-piperidin-4-yl]-8- methyl-1 ,4-dihydro-benzo[d][1 ,3]oxazin-2-one
1 -{1 -[4-(4-Bromo-phenoxy)-benzenesulfonyl]-piperidin-4-yl}-8-methyl-1 ,4- dihydro-benzo[d][1 ,3]oxazin-2-one
1 -[1 -(4-Fluoro-benzenesulfonyl)-piperidin-4-yl]-8-methyl-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
8-Methyl-1 -[1 -(naphthalene-2-sulfonyl)-piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
8-Methyl-1-(1-phenylmethanesulfonyl-piperidin-4-yl)-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
1 -[1 -(4-Bromo-benzenesulfonyl)-piperidin-4-yl]-6-chloro-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
6-Chloro-1 -[1 -(4-methanesulfonyl-benzenesulfonyl)-piperidin-4-yl]-1 ,4- dihydro-benzo[d][1 ,3]oxazin-2-one
1 -[1 -(Butane-1 -sulfonyl)-piperidin-4-yl]-6-chloro-1 ,4-dihydro- benzofd][1 ,3]oxazin-2-one
1 -[1 -(4-Bromo-benzenesulfonyl)-piperidin-4-yl]-8-methyl-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
1 -[1 -(4-Methanesulfonyl-benzenesulfonyl)-piperidin-4-yl]-8-methyl-1 ,4- dihydro-benzo[d][1 ,3]oxazin-2-one
1 -[1 -(Butane-1 -sulfonyl)-piperidin-4-yl]-8-methyl-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
6-Chloro-1 -[1 -(2-nitro-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
6-Chloro-1 -[1 -(3-nitro-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
1 -[1 -(Biphenyl-4-sulfonyl)-piperidin-4-yl]-6-chloro-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
8-Methyl-1 -[1 -(2-nitro-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one 8-Methyl-1 -[1 -(3-nitro-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
1 -[1 -(Biphenyl-4-sulfonyl)-piperidin-4-yl]-8-methyl-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
8-Methyl-1-[1-(4-nitro-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
6-Chloro-1 -[1 -(4-nitro-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
1-(1-Ethanesulfonyl-piperidin-4-yl)-1 ,4-dihydro-benzo[d][1 ,3]oxazin-2-one
1-[1-(Propane-1-sulfonyl)-piperidin-4-yl]-1 ,4-dihydro-benzo[d][1 ,3]oxazin-2- one
1 -[1 -(Propane-2-sulfonyl)-piperidin-4-yl]-1 ,4-dihydro-benzo[d][1 ,3]oxazin-2- one
6-Chloro-1 -(1 -ethanesulfonyl-piperidin-4-yl)-1 ,4-dihydro-benzo[d][1 ,3]oxazin- 2-one
6-Chloro-1 -[1 -(propane-1 -sulfonyl)-piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
6-Chloro-1 -[1 -(propane-2-sulfonyl)-piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
6-Chloro-1 -[1 -(quinoline-8-sulfonyl)-piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
1 -[1 -(4-Nitro-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
6-Methyl-1 -[1 -(quinoline-8-sulfonyl)-piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
6-Methyl-1 -[1 -(2-naphthalen-1 -yl-ethanesulfonyl)-piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
6-Methyl-1 -[1 -(toluene-4-sulfonyl)-piperidin-4-yl]-1 ,4-dihydrσ- benzo[d][1 ,3]oxazin-2-one
1 -[1 -(4-Fluoro-benzenesulfonyl)-piperidin-4-yl]-6-methyl-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
6-Methyl-1 -[1 -(naphthalene-1 -sulfonyl)-piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
6-Methyl-1 -[1 -(naphthalene-2-sulfonyl)-piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
1-[1-(5-Chloro-3-methyl-benzo[b]thiophene-2-sulfonyl)-piperidin-4-yl]-6- methyl-1 ,4-dihydro-benzo[d][1 ,3]oxazin-2-one
6-Methyl-1 -[1 -(4-nitro-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
1 -(1 -Benzenesulfonyl-piperidin-4-yl)-6-methyl-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
1 -[1 -(4-Chloro-3-nitro-benzenesulfonyl)-piperidin-4-yl]-6-methyl-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
1 -[1 -(5-Dimethylamino-naphthalene-1 -sulfonyl)-piperidin-4-yl]-6-methyl-1 ,4- dihydro-benzo[d][1 ,3]oxazin-2-one
1 -[1 -(4-Chloro-3-nitro-benzenesulfonyl)-piperidin-4-yl]-8-methyl-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
1 -[1 -(4-Chloro-3-nitro-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
6-Chloro-1 -[1 -(4-chloro-3-nitro-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
6-Chloro-1-[1-(5-dimethylamino-naphthalene-1-sulfonyl)-piperidin-4-yl]-1 ,4- dihydro-benzo[d][1 ,3]oxazin-2-one
1 -[1 -(4-Methoxy-2,3,6-trimethyl-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
1-[1-(4-Methoxy-2,3,6-trimethyl-benzenesulfonyl)-piperidin-4-yl]-8-methyl- 1 ,4-dihydro-benzofd][1 ,3]oxazin-2-one
6-Chloro-1-[1-(4-methoxy-2,3,6-trimethyl-benzenesulfonyl)-piperidin-4-yl]- 1 ,4-dihydro-benzo[d][1 ,3]oxazin-2-one
1-[1-(4-Methoxy-2,3,6-trimethyl-benzenesulfonyl)-piperidin-4-yl]-6-methyl- 1 ,4-dihydro-benzo[d][1 ,3]oxazin-2-one
1-[1-(2-Bromo-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
1 -[1 -(2-Bromo-benzenesulfonyl)-piperidin-4-yl]-8-methyl-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
1 -[1 -(2-Bromo-benzenesulfonyl)-piperidin-4-yl]-6-chloro-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
1 -[1 -(2-Bromo-benzenesulfonyl)-piperidin-4-yl]-6-methyl-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
6-Chloro-1 -[1 -(2,3-dichloro-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
1 -[1 -(2,3-Dichloro-benzenesulfonyl)-piperidin-4-yl]-6-methyl-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
1 -[1 -(2,4,5-Trichloro-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
8-Methyl-1 -[1 -(2,4,5-trichloro-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
6-Chloro-1 -[1 -(2,4,5-trichloro-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
6-Methyl-1 -[1 -(2,4,5-trichloro-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
1 -[1 -(5-Bromo-2-methoxy-benzenesulfonyi)-piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
1 -[1 -(5-Bromo-2-methoxy-benzenesulfonyl)-piperidin-4-yl]-8-methyl-1 ,4- dihydro-benzo[d][1 ,3]oxazin-2-one
1 -[1 -(5-Bromo-2-methoxy-benzenesulfonyl)-piperidin-4-yl]-6-chloro-1 ,4- dihydro-benzo[d][1 ,3]oxazin-2-one
1 -[1 -(5-Bromo-2-methoxy-benzenesulfonyl)-piperidin-4-yl]-6-methyl-1 ,4- dihydro-benzo[d][1 ,3]oxazin-2-one
1 -[1 -(2,5-Dimethoxy-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
1 -[1 -(2,5-Dimethoxy-benzenesulfonyl)-piperidin-4-yl]-8-methyl-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
6-Chloro-1-[1-(2,5-dimethoxy-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro- benzo[d][1 ,3]oxazin-2-one
1-[1-(2,5-Dimethoxy-benzenesulfonyl)-piperidin-4-yl]-6-methyl-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
1 -(1 -Pentamethylbenzenesulfonyl-piperidin-4-yl)-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one 98 8-Methyl-1-(1-pentamethylbenzenesulfonyi-piperidin-4-yl)-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one 6-Chloro-1 -(1 -pentamethylbenzenesulfonyl-piperidin-4-yl)-1 ,4-dihydro-
99 benzo[d][1 ,3]oxazin-2-one 6-Methyl-1 -(1 -pentamethylbenzenesulfonyl-piperidin-4-yl)-1 ,4-dihydro-
100 benzo[d][1 ,3]oxazin-2-one 1-{1-[2-(2,2,2-Trifluoro-acetyl)-1 ,2,3,4-tetrahydro-isoquinoline-7-sulfonyl]-
101 piperidin-4-yl}-1 ,4-dihydro-benzo[d][1 ,3]oxazin-2-one 8-Methyl-1 -{1 -[2-(2,2,2-trifluoro-acetyl)-1 ,2,3,4-tetrahydro-isoquinoline-7-
102 sulfonyl]-piperidin-4-yl}-1 ,4-dihydro-benzo[d][1 ,3]oxazin-2-one 6-Chloro-1 -{1 -[2-(2,2,2-trifluoro-acetyl)-1 ,2,3,4-tetrahydro-isoquinoline-7-
103 sulfonyl]-piperidin-4-yl}-1,4-dihydro-benzo[d][1,3]oxazin-2-one
104 6-Methyl-1 -{1 -[2-(2,2,2-trifluoro-acetyl)-1 ,2,3,4-tetrahydro-isoquinoline-7- sulfonyl]-piperidin-4-yl}-1 ,4-dihydro-benzo[d][1 ,3]oxazin-2-one
105 1 -[1 -(2-Methyl-5-nitro-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
106 8-Methyl-1 -[1 -(2-methyl-5-nitro-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
107 6-Chloro-1 -[1 -(2-methyl-5-nitro-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one 6-Methyl-1 -[1 -(2-methyl-5-nitro-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
108 benzo[d][1 ,3]oxazin-2-one 1 -[1 -(4-Bromo-2,5-difluoro-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
109 benzo[d][1 ,3]oxazin-2-one 1 -[1 -(4-Bromo-2,5-difluoro-benzenesulfonyl)-piperidin-4-yl]-8-methyl-1 ,4-
110 dihydro-benzo[d][1 ,3]oxazin-2-one 1-[1-(4-Bromo-2,5-difluoro-benzenesulfonyl)-piperidin-4-yl]-6-chloro-1 ,4-
111 dihydro-benzo[d][1 ,3]oxazin-2-one
112 1 -[1 -(4-Bromo-2,5-difluoro-benzenesulfonyl)-piperidin-4-yl]-6-methyl-1 ,4- dihydro-benzo[d][1 ,3]oxazin-2-one
113 1-[1-(4-Chloro-2,5-dimethyl-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one 1 -[1 -(4-Chloro-2,5-dimethyl-benzenesulfonyl)-piperidin-4-yl]-8-methyl-1 ,4-
114 dihydro-benzo[d][1 ,3]oxazin-2-one
115 6-Chloro-1 -[1 -(4-chloro-2,5-dimethyl-benzenesulfonyl)-piperidin-4-yl]-1 ,4- dihydro-benzo[d][1 ,3]oxazin-2-one 1 -[1 -(4-Chloro-2,5-dimethyl-benzenesulfonyl)-piperidin-4-yl]-6-methyl-1 ,4-
116 dihydro-benzo[d][1 ,3]oxazin-2-one
117 1 -[1 -(4-Methoxy-benzenesuIfonyl)-piperidin-4-yl]-6-methyl-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
118 1 -[1 -(4-lsopropyl-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one 1 -[1 ~(4-lsopropyl-benzenesulfonyl)-piperidin-4-yl]-8-methyl-1 ,4-dihydro-
119 benzo[d][1 ,3]oxazin-2-one 6-Chloro-1 -[1 -(4-isopropyl-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
120 benzo[d][1 ,3]oxazin-2-one
121 1-[1-(4-lsopropyl-benzenesulfonyl)-piperidin-4-yl]-6-methyl-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one 1 -[1 -(3-Chloro-4-fluoro-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
122 benzo[d][1 ,3]oxazin-2-one 1 -[1 -(3-Chloro-4-fluoro-benzenesulfonyl)-piperidin-4-yl]-8-methyl-1 ,4-dihydro-
123 benzo[d][1 ,3]oxazin-2-one 6-Chloro-1 -[1 -(3-chloro-4-fluoro-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
124 benzo[d][1 ,3]oxazin-2-one 1 -[1 -(3-Chloro-4-fluoro-benzenesulfonyl)-piperidin-4-yl]-6-methyl-1 ,4-dihydro-
125 benzo[d][1 ,3]oxazin-2-one 1 -[1 -(4-Bromo-benzenesulfonyl)-piperidin-4-yl]-6-methyl-1 ,4-dihydro-
126 benzo[d][1 ,3]oxazin-2-one
127 6-Methyl-1 -[1 -(3-nitro-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
128 6-Methyl-1 -[1 -(3-trifluoromethyl-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
129 1 -[1 -(4-Trifluoromethoxy-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
130 1 -[1 -(2-Nitro-4-trifluoromethyl-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
131 1 -[1 -(3-Fluoro-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
132 1-[1-(2,4-Dichloro-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
133 1 -[1 -(2,4,6-Trimethyl-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
134 1 -[1 -(2-Trifluoromethyl-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one 8-Methyl-1 -[1 -(4-trifluoromethoxy-benzenesulfonyl)-piperidin-4-yl]-1 ,4-
135 dihydro-benzo[d][1 ,3]oxazin-2-one
136 8-Methyl-1 -[1 -(2-nitro-4-trifluoromethyl-benzenesulfonyl)-piperidin-4-yl]-1 ,4- dihydro-benzo[d][1 ,3]oxazin-2-one 1-[1-(3-Fluoro-benzenesulfonyl)-piperidin-4-yl]-8-methyl-1 ,4-dihydro-
137 benzo[d][1 ,3]oxazin-2-one
138 1 -[1 -(2,4-Dichloro-benzenesulfonyl)-piperidin-4-yl]-8-methyl-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
139 8-Methyl-1 -[1 -(2,4,6-trimethyl-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
140 8-Methyl-1 -[1 -(2-trifluoromethyl-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one 1 -[1 -(4-Fluoro-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
141 benzo[d][1 ,3]oxazin-2-one
142 1 -[1 -(4-Bromo-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
143 1 -[1 -(3-Nitro-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one 1 -{1 -[4-(4-Bromo-phenoxy)-benzenesulfonyl]-piperidin-4-yl}-1 ,4-dihydro-
144 benzo[d][1 ,3]oxazin-2-one
145 1-[1-(3-Methoxy-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
146 1 -[1 -(2-Nitro-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
147 8-Methyl-1 -[1 -(toluene-4-sulfonyl)-piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one 148 1 -(1 -Benzenesulfonyl-piperidin-4-yl)-8-methyl-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one 1-[1-(3-Methoxy-benzenesulfonyl)-piperidin-4-yl]-8-methyl-1 ,4-dihydro-
149 benzo[d][1 ,3]oxazin-2-one
150 1 -[1 -(2,4-Dimethyl-benzenesulfonyl)-piperidin-4-yl]-6-methyl-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
151 1 -{1 -[4-(4-Bromo-phenoxy)-benzenesulfonyl]-piperidin-4-yl}-6-methyl-1 ,4- dihydro-benzo[d][1 ,3]oxazin-2-one
152 6-Methyl-1 -[1 -(thiophene-2-sulfonyl)-piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
153 1 -[1 -(Toluene-3-sulfonyl)-piperidin-4-yl]-1 ,4-dihydro-benzo[d][1 ,3]oxazin-2- one
154 1 -[1 -(5-FIuoro-2-methyl-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
155 1 -[1 -(4-lsopropoxy-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
156 1-[1-(3-Chloro-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
157 1 -[1 -(3,4-Dimethoxy-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
158 1-(1-Pentafluorobenzenesulfonyl-piperidin-4-yl)-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
159 8-Methyl-1 -[1 -(toluene-3-sulfonyl)-piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
160 1 -[1 -(5-Fluoro-2-methyl-benzenesulfonyl)-piperidin-4-yl]-8-methyl-1 ,4- ihydrobenzo[d][1 ,3] oxazin-2-one
161 1 -[1 -(4-lsopropoxy-benzenesulfonyl)-piperidin-4-yl]-8-methyl-1 ,4-dihydro- benzo[d][1 ,3] oxazin-2-one
162 1 -[1 -(3-Chloro-benzenesulfonyl)-piperidin-4-yl]-8-methyl-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
163 1 -[1 -(3,4-Dimethoxy-benzenesulfonyl)-piperidin-4-yl]-8-methyl-1 ,4-dihydro- benzo[d][1 ,3] oxazin-2-one
164 8-Methyl-1 -(1 -pentafluorobenzenesulfonyl-piperidin-4-yl)-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
165 6-Methyl-1 -[1 -(toluene-3-sulfonyl)-piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one 1 -[1 -(5-Fluoro-2-methyl-benzenesulfonyl)-piperidin-4-yl]-6-methyl-1 ,4-
166 dihydro-benzo[d][1 ,3]oxazin-2-one 1 -[1 -(4-lsopropoxy-benzenesulfonyl )-piperidin-4-yl]-6-methyl-1 ,4-dihydro-
167 benzo[d][1 ,3]oxazin-2-one 1-[1-(3-Chloro-benzenesulfonyl)-piperidin-4-yl]-6-methyl-1 ,4-dihydro-
168 benzo[d][1 ,3]oxazin-2-one 1-[1-(3,4-Dimethoxy-benzenesulfonyl)-piperidin-4-yl]-6-methyl-1 ,4-dihydro-
169 benzo[d][1 ,3]oxazin-2-one
170 6-Methyl-1 -(1 -pentafluorobenzenesulfonyl-piperidin-4-yl)-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
171 6-Methyl-1 -[1 -(4-trif luoromethoxy-benzenesulfonyl)-piperidin-4-yl]-1 ,4- dihydro-benzo[d][1 ,3]oxazin-2-one
172 6-MethyI-1 -[1 -(2-nitro-4-trifluoromethyl-benzenesulfonyI)-piperidin-4-yl]-1 ,4- dihydro-benzo[d][1 ,3]oxazin-2-one 173 1-[1-(3-Fluoro-benzenesulfonyl)-piperidin-4-yl]-6-methyl-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one 1 -[1 -(2,4-Dichloro-benzenesulfonyl)-piperidin-4-yl]-6-methyl-1 ,4-dihydro-
174 benzo[d][1 ,3]oxazin-2-one 6-Methyl-1 -[1 -(2,4,6-trimethyl-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
175 benzo[d][1 ,3]oxazin-2-one 6-Methyl-1 -[1 -(2-trifluoromethyl-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
176 benzo[d][1 ,3]oxazin-2-one
177 1 -[1 -(3-Methoxy-benzenesulfonyl)-piperidin-4-yl]-6-methyl-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
178 6-Methyl-1 -[1 -(2-nitro-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one 1 -[1 -(4-Acetyl-benzenesulfonyl)-piperidin-4-yl]-6-methyl-1 ,4-dihydro-
179 benzo[d][1 ,3]oxazin-2-one 1-[1-(4-Methanesulfonyl-benzenesulfonyl)-piperidin-4~yl]-6-methyl-1,4-
180 dihydro-benzo[d][1 ,3]oxazin-2-one 6-Methyl-1 -(1 -phenylmethanesulfonyl-piperidin-4-yl)-1 ,4-dihydro-
181 benzo[d][1 ,3]oxazin-2-one
182 2-[4-(6-Methyl-2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidine-1 - sulfonyljbenzoic acid methyl ester 6-Methyl-1 -[1 -(2-oxo-2H-chromene-6-sulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
183 benzo[d][1 ,3]oxazin-2-one
184 6-Chloro-1 -[1 -(4-fluoro-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one 6-Chloro-1 -[1 -(3,5-dichloro-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
185 benzo[d][1 ,3]oxazin-2-one
186 1 -{1 -[4-(4-Bromo-phenoxy)-benzenesulfonyl]-piperidin-4-yl}-6-chloro-1 ,4- dihydro-benzo[d][1 ,3]oxazin-2-one 6-Chloro-1 -[1 -(thiophene-2-sulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
187 benzo[d][1 ,3]oxazin-2-one
188 6-Chloro-1 -[1 -(3-methoxy-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one 6-Chloro-1 -[1 -(2-oxo-2H-chromene-6-sulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
189 benzo[d][1 ,3]oxazin-2-one 6-Chloro-1 -[1 -(toluene-3-sulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
190 benzo[d][1 ,3]oxazin-2-one
191 6-Chloro-1 -[1 -(5-fluoro-2-methyl-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one 6-Chloro-1 -[1 -(4-isopropoxy-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
192 benzo[d][1 ,3] oxazin-2-one 6-Chloro-1 -[1 -(3-chloro-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
193 benzo[d][1 ,3]oxazin-2-one 6-Chloro-1 -[1 -(3,4-dimethoxy-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
194 benzo[d][1 ,3]oxazin-2-one 6-Chloro-1 -(1 -pentafluorobenzenesulfonyl-piperidin-4-yl)-1 ,4-dihydro-
195 benzo[d][1 ,3]oxazin-2-one 6-Chloro-1 -[1 -(4-trifluoromethoxy-benzenesulfonyl)-piperidin-4-yl]-1 ,4-
196 dihydro-benzo[d][1 ,3]oxazin-2-one 6-Chloro-1 -[1 -(2-nitro-4-trifluoromethyl-benzenesulfonyl)-piperidin-4-yl]-1 ,4-
197 dihydro-benzo[d][1 ,3]oxazin-2-one 6-Chloro-1 -[1 -(3-fluoro-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
198 benzo[d][1 ,3]oxazin-2-one 6-Chloro-1 -[1 -(2,4-dichloro-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
199 benzo[d][1 ,3]oxazin-2-one 6-Chloro-1 -[1 -(2,4,6-trimethyl-benzenesulfoήyl)-piperidin-4-yl]-1 ,4-dihydro-
200 benzo[d][1 ,3]oxazin-2-one 6-Chloro-1 -[1 -(2-trifluoromethyl-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
201 benzo[d][1 ,3]oxazin-2-one 1 -[1 -(2-Oxo-2H-chromene-6-sulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
202 benzo[d][1 ,3]oxazin-2-one 1 -[1 -(3,5-Dichloro-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
203 benzo[d][1 ,3]oxazin-2-one 1 -[1 -(2,5-Dichloro-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
204 benzo[d][1 ,3]oxazin-2-one 1 -[1 -(5-Bromo-6-chloro-pyridine-3-sulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
205 benzo[d][1 ,3]oxazin-2-one 1 -[1 -(4-Chloro-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
206 benzo[d][1 ,3]oxazin-2-one 1 -[1 -(2,6-Dichloro-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
207 benzo[d][1 ,3]oxazin-2-one 8-Methyl-1 -[1 -(2-oxo-2H-chromene-6-sulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
208 benzo[d][1 ,3]oxazin-2-one 1 -[1 -(3,5-Dichloro-benzenesulfonyl)-piperidin-4-yl]-8-methyl-1 ,4-dihydro-
209 benzo[d][1 ,3]oxazin-2-one
210 1 -[1 -(2,5-Dichloro-benzenesulfonyl)-piperidin-4-yl]-8-methyl-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
211 1 -[1 -(5-Bromo-6-chloro-pyridine-3-sulfonyl)-piperidin-4-yl]-8-methyl-1 ,4- dihydro-benzo[d][1 ,3]oxazin-2-one
212 1 -[1 -(4-Chloro-benzenesulfonyl)-piperidin-4-yl]-8-methyl-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
213 1 -[1 -(2,6-Dichloro-benzenesulfonyl)-piperidin-4-yl]-8-methyl-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
214 1 -[1 -(Biphenyl-4-sulfonyl)-piperidin-4-yl]-1 ,4-dihydro-benzo[d][1 ,3]oxazin-2- one
215 6-Chloro-1 -[1 -(2,5-dichloro-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
216 1 -[1 -(5-Bromo-6-chloro-pyridine-3-sulfonyl)-piperidin-4-yl]-6-chloro-1 ,4- dihydro-benzo[d][1 ,3]oxazin-2-one
217 6-Chloro-1 -[1 -(4-chloro-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one 6-Chloro-1 -[1 -(2,6-dichloro-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
218 benzo[d][1 ,3]oxazin-2-one 1 -[1 -(Biphenyl-4-sulfonyl)-piperidin-4-yl]-6-methyl-1 ,4-dihydro-
219 benzo[d][1 ,3]oxazin-2-one 2-[4-(6-Methyl-2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidine-1 -sulfonyl]-
220 benzonitrile 1 -[1 -(2,5-Dichloro-benzenesulfonyl)-piperidin-4-yl]-6-methyl-1 ,4-dihydro-
221 benzo[d][1 ,3]oxazin-2-one 1 -[1 -(5-Bromo-6-chloro-pyridine-3-sulfonyl)-piperidin-4-yl]-6-methyl-1 ,4-
222 dihydro-benzo[d][1 ,3]oxazin-2-one 1 -[1 -(4-Chloro-benzenesulfonyl)-piperidin-4-yl]-6-methyl-1 ,4-dihydro-
223 benzo[d][1 ,3]oxazin-2-one 1 -[1 -(2,6-Dichloro-benzenesulfonyl)-piperidin-4-yl]-6-methyl-1 ,4-dihydro-
224 benzo[d][1 ,3]oxazin-2-one 1 -[1 -(3,5-Dichloro-benzenesulfonyl)-piperidin-4-yl]-6-methyl-1 ,4-dihydro-
225 benzo[d][ ,3]oxazin-2-one 6-Methyl-1 -[1 -(1 -methyl-1 H-imidazole-4-sulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
226 benzo[d][1 ,3]oxazin-2-one 1 -[1 -(5-Bromo-2,4-difluoro-benzenesulfonyl)-piperidin-4-yl]-6-methyl-1 ,4-
227 dihydro-benzo[d][1 ,3]oxazin-2-one 1 -[1 -(4-Methanesulfonyl-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
228 benzo[d][1 ,3]oxazin-2-one 1 -[1 -(1 -Methyl-1 H-imidazole-4-sulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
229 benzo[d][1 ,3]oxazin-2-one 1-[1-(5-Bromo-2,4-difluoro-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
230 benzo[d][1 ,3]oxazin-2-one
231 1-[1-(6-Chloro-imidazo[2,1-b]thiazole-5-sulfonyl)-piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one 1 -[1 -(4-Ethyl-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
232 benzo[d][1 ,3]oxazin-2-one 1 -[1 -(Benzo[b]thiophene-3-sulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
233 enzo[d][1 ,3]oxazin-2-one 1-[1-(6-Chloro-imidazo[2,1-b]thiazole-5-sulfonyl)-piperidin-4-yl]-8-methyl-1 ,4-
234 dihydro-benzo[d][1 ,3]oxazin-2-one 1 -[1 -(4-Ethyl-benzenesulfonyl)-piperidin-4-yl]-8-methyl-1 ,4-dihydro-
235 benzo[d][1 ,3]oxazin-2-one 1 -[1 -(Benzo[b]thiophene-3-sulfonyl)-piperidin-4-yl]-8-methyl-1 ,4-dihydro-
236 benzo[d][1 ,3]oxazin-2-one 6-Chloro-1 -[1 -(6-chloro-imidazo[2, 1 -b]thiazole-5-sulfonyl)-piperidin-4-yl]-1 ,4-
237 dihydro-benzo[d][1 ,3]oxazin-2-one 6-Chloro-1 -[1 -(4-ethyl-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
238 benzo[d][1 ,3]oxazin-2-one 1 -[1 -(Benzo[b]thiophene-3-sulfonyl)-piperidin-4-yl]-6-chloro-1 ,4-dihydro-
239 benzo[d][1 ,3]oxazin-2-one 1 -[1 -(6-Chloro-imidazo[2, 1 -b]thiazole-5-sulfonyl)-piperidin-4-yl]-6-methyl-1 ,4-
240 dihydro-benzo[d][1 ,3]oxazin-2-one 1 -[1 -(4-Ethyl-benzenesulfonyl)-piperidin-4-yl]-6-methyM ,4-dihydro-
241 benzo[d][1 ,3]oxazin-2-one 1 -[1 -(Benzo[b]thiophene-3-sulfonyl)-piperidin-4-yl]-6-methyl-1 ,4-dihydro-
242 benzo[d][1 ,3]oxazin-2-one 1 -[1 -(7-Chloro-benzo[1 ,2,5]oxadiazole-4-sulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
243 benzo[d][1 ,3]oxazin-2-one 1 -[1 -(2-Methoxy-4-methyl-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
244 benzo[d][1 ,3]oxazin-2-one 3-{4-[4-(2-Oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidine-1 -sulfonyl]-phenyl}-
245 propionic acid methyl ester 1 -[1 -(2,4-Dinitro-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
246 benzo[d][1 ,3]oxazin-2-one 1 -[1 -(7-Chloro-benzo[1 ,2,5]oxadiazole-4-sulfonyl)-piperidin-4-yl]-8-methyl-
247 1 ,4-dihydro-benzo[d][1 ,3]oxazin-2-one 1 -[1 -(2-Methoxy-4-methyl-benzenesulfonyl)-piperidin-4-yl]-8-methyl-1 ,4-
248 dihydro-benzo[d][1 ,3]oxazin-2-one 3-{4-[4-(8-Methyl-2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-pipe
249 phenyl}-propionic acid methyl ester 1 -[1 -(2,4-Dinitro-benzenesulfonyl)-piperidin-4-yl]-8-methyl-1 ,4-dihydro-
250 benzo[d][1 ,3]oxazin-2-one 1 -[1 -(7-Chloro-benzo[1 ,2,5]oxadiazole-4-sulfonyl)-piperidin-4-yl]-6-methyl-
251 1 ,4-dihydro-benzo[d][1 ,3]oxazin-2-one 1 -[1 -(2-Methoxy-4-methyl-benzenesulfonyl)-piperidin-4-yl]-6-methyl-1 ,4-
252 dihydro-benzo[d][1 ,3]oxazin-2-one 3-{4-[4-(6-Methyl-2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidine-1 -sulfonyl]-
253 phenyl}-propionic acid methyl ester 1 -[1 -(2,4-Dinitro-benzenesulfonyl)-piperidin-4-yl]-6-methyl-1 ,4-dihydro-
254 benzo[d][1 ,3]oxazin-2-one 6-Chloro-1-[1-(7-chloro-benzo[1 ,2,5]oxadiazole-4-sulfonyl)-piperidin-4-yl]-
255 1 ,4-dihydro-benzo[d][1 ,3]oxazin-2-one 6-Chloro-1 -[1 -(2-methoxy-4-methyl-benzenesulfonyl)-piperidin-4-yl]-1 ,4-
256 dihydro-benzo[d][1 ,3]oxazin-2-one 3-{4-[4-(6-Chloro-2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidine-1 -sulfonyl]-
257 phenyl}-propionic acid methyl ester 6-Chloro-1 -[1 -(2,4-dinitro-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
258 benzo[d][1 ,3]oxazin-2-one 6-Chloro-1 -[1 -(1 -methyl-1 H-imidazole-4-sulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
259 benzo[d][1 ,3]oxazin-2-one 1-[1-(5-Bromo-2,4-difluoro-benzenesulfonyl)-piperidin-4-yl]-6-chloro-1 ,4-
260 dihydro-benzo[d][1 ,3]oxazin-2-one 8-Methyl-1-[1-(1 -methyl-1 H-imidazole-4-sulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
261 benzo[d][1 ,3]oxazin-2-one 1 -[1 -(5-Bromo-2,4-difluoro-benzenesulfonyl)-piperidin-4-yl]-8-methyl-1 ,4-
262 dihydro-benzo[d][1 ,3]oxazin-2-one 1 -[1 -(Benzo[b]thiophene-2-sulfonyl)-piperidin-4-yl]-8-methyl-1 ,4-dihydro-
263 benzo[d][1 ,3]oxazin-2-one 1-[1-(Benzo[b]thiophene-2-sulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
264 benzo[d][1 ,3]oxazin-2-one 1 -[1 -(Benzo[b]thiophene-2-sulfonyl)-piperidin-4-yl]-6-chloro-1 ,4-dihydro-
265 benzo[d][1 ,3]oxazin-2-one 1 -[1 -(Benzo[b]thiophene-2-sulfonyl)-piperidin-4-yl]-6-methyl-1 ,4-dihydro-
266 benzo[d][1 ,3]oxazin-2-one 1 -[1 -(2,5-Difluoro-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
267 benzo[d][1 ,3]oxazin-2-one 1-[1-(2,5-Difluoro-benzenesuIfonyl)-piperidin-4-yl]-8-methyl-1 ,4-dihydro-
268 benzo[d][1 ,3]oxazin-2-one 6-Chloro-1 -[1 -(2,5-difluoro-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
269 benzo[d][1 ,3]oxazin-2-one 1 -[1 -(2,5-Difluoro-benzenesulfonyl)-piperidin-4-yl]-6-methyl-1 ,4-dihydro-
270 benzo[d][1 ,3]oxazin-2-one
271 1 -[1 -(4-Chloro-2,5-difluoro-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one 1 -[1 -(4-Chloro-2,5-difluoro-benzenesulfonyl)-piperidin-4-yl]-8-methyl-1 ,4-
272 dihydro-benzo[d][1 ,3]oxazin-2-one 6-Chloro-1 -[1 -(4-chloro-2,5-difluoro-benzenesulfonyl)-piperidin-4-yl]- ,4- dihydro-benzo[d][1 ,31oxazin-2-one
1 -[1 -(4-Chloro-2,5-difluoro-benzenesulfonyl)-piperidin-4-yl]-6-methyl-1 ,4- dihydro-benzo[d][1 ,3]oxazin-2-one
1 -[1 -(2,4,5-Trifluoro-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
8-Methyl-1-[1-(2,4,5-trifluoro-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
6-Chloro-1-[1-(2,4,5-trifluoro-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
6-Methyl-1-[1-(2,4,5-trifluoro-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
1 -[1 -(3,5-Dichloro-2-hydroxy-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
1-[1-(2,6-Difluoro-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
1 -[1 -(2,6-Difluoro-benzenesulfonyl)-piperidin-4-yl]-8-methyl-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
6-Chloro-1 -[1 -(2,6-difluoro-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
1 -[1 -(2,6-Difluoro-benzenesulfonyl)-piperidin-4-yl]-6-methyl-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
1 -[1 -(5-Chloro-2,4-difluoro-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
1 -[1 -(5-Chloro-2,4-difluoro-benzenesulfonyl)-piperidin-4-yl]-8-methyl-1 ,4- dihydro-benzo[d][1 ,3]oxazin-2-one
6-Chloro-1 -[1 -(5-chloro-2,4-difluoro-benzenesulfonyl)-piperidin-4-yl]-1 ,4- dihydro-benzo[d][1 ,3]oxazin-2-one
1 -[1 -(5-Chloro-2,4-difluoro-benzenesulfonyl)-piperidin-4-yl]-6-methyl-1 ,4- dihydro-benzo[d][1 ,3]oxazin-2-one
1 -[1 -(2-Chloro-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
1 -[1 -(2-Chloro-benzenesulfonyl)-piperidin-4-yl]-8-methyl-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
6-Chloro-1 -[1 -(2-chloro-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
1 -[1 -(2-Chloro-benzenesulfonyl)-piperidin-4-yl]-6-methyl-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
6-Chloro-1 -[1 -(2-naphthalen-1 -yl-ethanesulfonyl)-piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
6-Bromo-1 -[1 -(4-bromo-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
6-Bromo-1 -[1 -(toluene-4-sulfonyl)-piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
6-Bromo-1 -[1 -(2,4-dimethyl-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
6-Bromo-1 -[1 -(2-naphthalen-1 -yl-ethanesulfonyl)-piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
6-Bromo-1 -[1 -(quinoline-8-sulfonyl)-piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000157_0001
1 -[1 -(4-Acetyl-benzenesulfonyl)-piperidin-4-yl]-6-bromo-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
6-Bromo-1-[1-(4-methanesulfonyl-benzenesulfonyl)-piperidin-4-yi]-1 ,4- dihydro-benzo[d][1 ,3]oxazin-2-one
1-[1-(Biphenyl-4-sulfonyl)-piperidin-4-yl]-6-bromo-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
6-Bromo-1 -(1 -phenylmethanesulfonyl-piperidin-4-yl)-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
6-Bromo-1 -[1 -(2,5-dimethoxy-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
6-Bromo-1 -{1 -[2-(2,2,2-trif luoro-acetyl)-1 ,2,3,4-tetrahydro-isoquinoline-7- sulfonyl]-piperidin-4-yl}-1 ,4-dihydro-benzo[d][1 ,3]oxazin-2-one
6-Bromo-1 -[1 -(2,3-dichloro-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
6-Bromo-1 -[1 -(2,4,5-trichloro-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
6-Bromo-1 -[1 -(5-bromo-2-methoxy-benzenesulfonyl)-piperidin-4-yl]-1 ,4- dihydro-benzo[d][1 ,3]oxazin-2-one
6-Bromo-1 -[1 -(4-trifluoromethoxy-benzenesulfonyl)-piperidin-4-yl]-1 ,4- dihydro-benzo[d][1 ,3]oxazin-2-one
6-Bromo-1 -[1 -(2-nitro-4-trifluoromethyl-benzenesulfonyl)-piperidin-4-yl]-1 ,4- dihydro-benzo[d][1 ,3]oxazin-2-one
6-Bromo-1 -[1 -(3-fluoro-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
6-Bromo-1 -[1 -(2,4-dichloro-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
6-Bromo-1 -[1 -(2,4,6-trimethyl-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
6-Bromo-1 -[1 -(2-trifluoromethyl-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
6-Bromo-1 -[1 -(2-bromo-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
6-Bromo-1-[1-(4-methoxy-2,3,6-trimethyl-benzenesulfonyl)-piperidin-4-yl]-
1 ,4-dihydro-benzo[d][1 ,3]oxazin-2-one
1 -[1 -(3,5-Dichloro-4-hydroxy-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
1 -[1 -(3,5-Dichloro-4-hydroxy-benzenesulfonyl)-piperidin-4-yl]-8-methyl-1 ,4- dihydro-benzo[d][1 ,3]oxazin-2-one
6-Chloro-1 -[1 -(3,5-dichloro-4-hydroxy-benzenesulfonyl)-piperidin-4-yl]-1 ,4- dihydro-benzo[d][1 ,3]oxazin-2-one
1 -[1 -(3,5-Dichloro-4-hydroxy-benzenesulfonyl)-piperidin-4-yl]-6-methyl-1 ,4- dihydro-benzo[d][1 ,3]oxazin-2-one
6-Bromo-1 -[1 -(3,5-dichloro-4-hydroxy-benzenesulfonyl)-piperidin-4-yl]-1 ,4- dihydro-benzo[d][1 ,3]oxazin-2-one
6-Chloro-1-[1-(3,5-dichloro-2-hydroxy-benzenesulfonyl)-piperidin-4-yl]-1 ,4- dihydro-benzo[d][1 ,3]oxazin-2-one
6-Bromo-1 -[1 -(3,5-dichloro-2-hydroxy-benzenesulfonyl)-piperidin-4-yl]-1 ,4- dihydro-benzo[d][1 ,3]oxazin-2-one
2-[4-(6-Bromo-2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidine-1 -sulfonyl]- benzonitrile 6-Bromo-1-[1-(4-methoxy-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
348 benzo[d][1 ,3]oxazin-2-one 2-[4-(6-Bromo-2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidine-1 -sulfonyl]-
349 benzoic acid methyl ester 6-Bromo-1 -[1 -(3-trifluoromethyl-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
350 benzo[d][1 ,3]oxazin-2-one 6-Bromo-1 -[1 -(2-oxo-2H-chromene-6-sulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
351 benzo[d][1 ,3]oxazin-2-one 6-Bromo-1 -[1 -(3,5-dichloro-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
352 benzo[d][1 ,3]oxazin-2-one 6-Bromo-1 -[1 -(2,5-dichloro-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
353 benzo[d][1 ,3]oxazin-2-one 6-Bromo-1 -[1 -(5-bromo-6-chloro-pyridine-3-sulfonyl)-piperidin-4-yl]-1 ,4-
354 dihydro-benzo[d][1,3]oxazin-2-one 6-Bromo-1 -[1 -(4-chloro-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
355 benzo[d][1 ,3]oxazin-2-one 6-Bromo-1 -[1 -(2,6-dichloro-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
356 benzo[d][1 ,3]oxazin-2-one 6-Bromo-1-[1-(1 -methyl-1 H-imidazole-4-sulfonyl)-piperidin-4-yl]-1,4-dihydro-
357 benzo[d][1 ,3]oxazin-2-one 6-Bromo-1-[1-(5-bromo-2,4-difluoro-benzenesulfonyl)-piperidin-4-yl]-1 ,4-
358 dihydro-benzo[d][1 ,3]oxazin-2-one 6-Bromo-1-[1-(4-ethyl-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
359 benzo[d][1 ,3]oxazin-2-one 6-Bromo-1-[1-(6-chloro-imidazo[2,1-b]thiazole-5-sulfonyl)-piperidin-4-yl]-1 ,4-
360 dihydro-benzo[d][1 ,3]oxazin-2-one
361 1 -[1 -(Benzo[b]thiophene-3-sulfonyl)-piperidin-4-yl]-6-bromo-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one 6-Bromo-1 -[1 -(7-chloro-benzo[1 ,2,5]oxadiazole-4-sulfonyl)-piperidin-4-yl]-
362 1 ,4-dihydro-benzo[d][1 ,3]oxazin-2-one 6-Bromo-1 -[1 -(2-methoxy-4-methyl-benzenesulfonyl)-piperidin-4-yl]-1 ,4-
363 dihydro-benzo[d][1 ,3]oxazin-2-one 3-{4-[4-(6-Bromo-2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidine-1 -sulfonyl]-
364 phenyl}-propionic acid methyl ester 6-Bromo-1 -[1 -(2,4-dinitro-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
365 benzo[d][1 ,3]oxazin-2-one 1 -[1 -(Benzo[b]thiophene-2-sulfonyl)-piperidin-4-yl]-6-bromo-1 ,4-dihydro-
366 benzo[d][1 ,3]oxazin-2-one 6-Bromo-1-[1-(2,5-difluoro-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
367 benzo[d][1 ,3]oxazin-2-one 6-Bromo-1-[1-(4-chloro-2,5-difluoro-benzenesulfonyl)-piperidin-4-yl]-1 ,4-
368 dihydro-benzo[d][1 ,3]oxazin-2-one 6-Bromo-1-[1-(2,4,5-trifluoro-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
369 benzo[d][1 ,3]oxazin-2-one 6-Bromo-1-[1-(2,6-difluoro-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
370 benzo[d][1 ,3]oxazin-2-one
371 6-Bromo-1 -[1 -(5-chloro-2,4-difluoro-benzenesulfonyl)-piperidin-4-yl]-1 ,4- dihydro-benzo[d][1 ,3]oxazin-2-one 6-Bromo-1 -[1 -(2-chloro-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
372 benzo[d][1 ,3]oxazin-2-one 6-Bromo-1 -[1 -(2,3,4-trifluoro-benzenesulfonyl)-piperidin-4-yl]- ,4-dihydro-
373 benzo[d][1 ,3]oxazin-2-one N-{4-[4-(6-Bromo-2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidine-1 -sulfonyl]-
374 2-chloro-phenyl}-acetamide 1 -[1 -(2,3,4-Trif luoro-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
375 benzo[d][1 ,3]oxazin-2-one 8-Methyl-1 -[1 -(2,3,4-trifluoro-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
376 benzo[d][1 ,3]oxazin-2-one 6-Chloro-1 -[1 -(2,3,4-trif luoro-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
377 benzo[d][1 ,3]oxazin-2-one 6-Methyl-1 -[1 -(2,3,4-trifluoro-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
378 benzo[d][1 ,3]oxazin-2-one N-{2-Chloro-4-[4-(6-methyl-2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidine-1 -
379 sulfonyl]-phenyl}-acetamide 1-[1-(3,4-Difluoro-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
380 benzo[d][1 ,3]oxazin-2-one
381 1 -[1 -(3,4-Difluoro-benzenesulfonyl)-piperidin-4-yl]-8-methyl-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one 6-Chloro-1 -[1 -(3,4-difluoro-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
382 benzo[d][1 ,3]oxazin-2-one 1 -[1 -(3,4-Difluoro-benzenesulfonyl)-piperidin-4-yl]-6-methyl-1 ,4-dihydro-
383 benzo[d][1 ,3]oxazin-2-one 6-Bromo-1 -[1 -(3,4-difluoro-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
384 benzo[d][1 ,3]oxazin-2-one N-{2-Chloro-4-[4-(8-methyl-2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidine-1 ■
385 sulfonyl]-phenyl}-acetamide 1 -[1 -(2-Chloro-4,5-difluoro-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
386 benzo[d][1 ,3]oxazin-2-one 1 -[1 -(2-Chloro-4,5-difluoro-benzenesulfonyl)-piperidin-4-yl]-8-methyl-1 ,4-
387 dihydro-benzo[d][1 ,3]oxazin-2-one 6-Chloro-1 -[1 -(2-chloro-4,5-difluoro-benzenesulfonyl)-piperidin-4-yl]-1 ,4-
388 dihydro-benzo[d][1 ,3]oxazin-2-one 1 -[1 -(2-Chloro-4,5-difluoro-benzenesulfonyl)-piperidin-4-yl]-6-methyl-1 ,4-
389 dihydro-benzo[d][1 ,3]oxazin-2-one 6-Bromo-1 -[1 -(2-chloro-4,5-difluoro-benzenesulfonyl)-piperidin-4-yl]-1 ,4-
390 dihydro-benzo[d][1 ,3]oxazin-2-one N-{2-Chloro-4-[4-(2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidine-1 -sulfonyl]-
391 phenyl}-acetamide 1 -[1 -(Benzo[1 ,2,5]oxadiazole-4-sulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
392 benzo[d][1 ,3]oxazin-2-one 1 -[1 -(Benzo[1 ,2,5]oxadiazole-4-sulfonyl)-piperidin-4-yl]-8-methyl-1 ,4-dihydro-
393 benzo[d][1 ,3]oxazin-2-one 1-[1-(Benzo[1 ,2,5]oxadiazole-4-sulfonyl)-piperidin-4-yl]-6-chloro-1 ,4-dihydro-
394 benzo[d][1 ,3]oxazin-2-one 1 -[1 -(Benzo[1 ,2,5]oxadiazole-4-sulfonyl)-piperidin-4-yl]-6-methyl-1 ,4-dihydro-
395 benzo[d][1 ,3]oxazin-2-one 1 -[1 -(Benzo[1 ,2,5]oxadiazole-4-sulfonyl)-piperidin-4-yl]-6-bromo-1 ,4-dihydro-
396 benzo[d][1 ,3]oxazin-2-one N-{2-Chloro-4-[4-(6-chloro-2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidine-1 -
397 sulfonyl]-phenyl}-acetamide
Figure imgf000161_0001
Figure imgf000162_0001
1-[1-(4-Bromo-2-trifluoromethoxy-benzenesulfonyl)-piperidin-4-yl]-6-methyl-
448 1 ,4-dihydro-benzo[d][1 ,3]oxazin-2-one 6-Bromo-1-[1-(4-bromo-2-trifluoromethoxy-benzenesulfonyl)-piperidin-4-yl]-
449 1 ,4-dihydro-benzo[d][1 ,3]oxazin-2-one 1-[1-(4-Phenoxy-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
450 benzo[d][1 ,3]oxazin-2-one 1 -[1 -(3-Bromo-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
451 benzo[d][1 ,3]oxazin-2-one 1 -[1 -(3-Bromo-benzenesulfonyl)-piperidin-4-yl]-8-methyl-1 ,4-dihydro-
452 benzo[d][1 ,3]oxazin-2-one 1 -[1 -(3-Bromo-benzenesulfonyl)-piperidin-4-yl]-6-chloro-1 ,4-dihydro-
453 benzo[d][1 ,3]oxazin-2-one 1 -[1 -(3-Bromo-benzenesulfonyl)-piperidin-4-yl]-6-methyl-1 ,4-dihydro-
454 benzo[d][1 ,3]oxazin-2-one 6-Bromo-1-[1-(3-bromo-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro
455 benzo[d][1 ,3]oxazin-2-one 8-Methyl-1 -[1 -(4-phenoxy-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
456 benzo[d][1 ,3]oxazin-2-one 1-[1-(4-tert-Butyl-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
457 benzo[d][1 ,3]oxazin-2-one 1-[1-(4-tert-Butyl-benzenesulfonyl)-piperidin-4-yl]-8-methyl-1 ,4-dihydro-
458 benzo[d][1 ,3]oxazin-2-one 1 -[1 -(4-tert-Butyl-benzenesulfonyl)-piperidin-4-yl]-6-chloro-1 ,4-dihydro-
459 benzo[d][1 ,3]oxazin-2-one 1-[1-(4-tert-Butyl-benzenesulfonyl)-piperidin-4-yl]-6-methyl-1 ,4-dihydro-
460 benzo[d][1 ,3]oxazin-2-one
461 6-Bromo-1 -[1 -(4-tert-butyl-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one 6-Chloro-1-[1-(4-phenoxy-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
462 benzo[d][1 ,3]oxazin-2-one 1-[1-(2-Bromo-4,6-difluoro-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
463 benzo[d][1 ,3]oxazin-2-one 1 -[1 -(2-Methanesulfonyl-benzenesulfonyl)-piperidin-4-yl]-8-methyl-1 ,4-
464 dihydro-benzo[d][1 ,3]oxazin-2-one 6-Chloro-1 -[1 -(2-methanesulfonyl-benzenesulfonyl)-piperidin-4-yl]-1 ,4-
465 dihydro-benzo[d][1 ,3]oxazin-2-one 1-[1-(2-MethanesuIfonyl-benzenesulfonyl)-piperidin-4-yl]-6-methyl-1 ,4-
466 dihydro-benzo[d][1 ,3]oxazin-2-one 6-Bromo-1 -[1 -(2-methanesulfonyl-benzenesulfonyl)-piperidin-4-yl]-1 ,4-
467 dihydro-benzo[d][1 ,3]oxazin-2-one 8-Methyl-1 -[1 -(4-propyl-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
468 benzo[d][1 ,3]oxazin-2-one 6-Chloro-1 -[1 -(4-propyl-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
469 benzo[d][1 ,3]oxazin-2-one 6-Methyl-1 -[1 -(4-propyl-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
470 benzo[d][1 ,3]oxazin-2-one 6-Bromo-1 -[1 -(4-propyl-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
471 benzo[d][1 ,3]oxazin-2-one 1 -[1 -(3-Chloro-2-methyl-benzenesulfonyl)-piperidin-4-yl]-8-methyl-1 ,4-
472 dihydro-benzo[d][1 ,3]oxazin-2-one
Figure imgf000164_0001
N-{4-Methyl-5-[4-(6-methyl-2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidine-1 ■
498 sulfonyl]-thiazol-2-yl}-acetamide N-{5-[4-(6-Bromo-2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidine-1 -sulfonyl]-
499 4-methyl-thiazol-2-yl}-acetamide 1 -[1 -(2-Bromo-4-fluoro-benzenesulfonyl)-piperidin-4-yl]-8-methyl-1 ,4-dihydro-
500 benzo[d][1 ,3]oxazin-2-one
501 1 -[1 -(2-Bromo-4-fluoro-benzenesulfonyl)-piperidin-4-yl]-6-chloro-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one 1 -[1 -(2-Bromo-4-fluoro-benzenesulfonyl)-piperidin-4-yl]-6-methyl-1 ,4-dihydro-
502 benzo[d][1 ,3]oxazin-2-one 6-Bromo-1-[1-(2-bromo-4-fluoro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-
503 benzo[d][1 ,3]oxazin-2-one 1 -[1 -(5-Chloro-2-fluoro-benzenesulfonyl)-piperidin-4-yl]-8-methyl-1 ,4-dihydro-
504 benzo[d][1 ,3]oxazin-2-one 6-Chloro-1 -[1 -(5-chloro-2-fluoro-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
505 benzo[d][1 ,3]oxazin-2-one 1 -[1 -(5-Chloro-2-fluoro-benzenesulfonyl)-piperidin-4-yl]-6-methyl-1 ,4-dihydro-
506 benzo[d][1 ,3]oxazin-2-one 6-Bromo-1 -[1 -(5-chloro-2-fluoro-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
507 benzo[d][1 ,3]oxazin-2-one 1-[1-(4-Bromo-3-trifluoromethyl-benzenesulfonyl)-piperidin-4-yl]-8-methyl-
508 1 ,4-dihydro-benzo[d][1 ,3]oxazin-2-one 1 -[1 -(4-Bromo-3-trifluoromethyl-benzenesulfonyl)-piperidin-4-yl]-6-chloro-1 ,4-
509 dihydro-benzo[d][1 ,3]oxazin-2-one 1-[1-(4-Bromo-3-trifluoromethyl-benzenesulfonyl)-piperidin-4-yl]-6-methyl-
510 1 ,4-dihydro-benzo[d][1 ,3]oxazin-2-one 6-Bromo-1-[1-(4-bromo-3-trifluoromethyl-benzenesulfonyl)-piperidin-4-yl]-
511 1 ,4-dihydro-benzo[d][1 ,3]oxazin-2-one
512 1 -[1 -(2-Methanesulfonyl-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one 1 -[1 -(4-Propyl-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
513 benzo[d][1 ,3]oxazin-2-one 1-[1-(3-Chloro-2-methyl-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
514 benzo[d][1 ,3]oxazin-2-one 1 -[1 -(4-Butyl-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
515 benzo[d][1 ,3]oxazin-2-one 1-[1-(4-Bromo-3-methyl-benzenesulfonyl)-piperidin-4-yl]-1 ,4-di
516 benzo[d][1 ,3]oxazin-2-one
517 1 -{1 -[4-(1 ,1 -Dimethyl-propyl)-benzenesulfonyl]-piperidin-4-yl}-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
518 N-{4-Methyl-5-[4-(2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidine-1 -sulfonyl]- thiazol-2-yl}-acetamide 1-[1-(3-Chloro-2-fluoro-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
519 benzo[d][1 ,3]oxazin-2-one 1 -[1 -(2-Bromo-4-fluoro-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
520 benzo[d][1 ,3]oxazin-2-one 1 -[1 -(4-Bromo-3-trifluoromethyl-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
521 benzo[d][1 ,3]oxazin-2-one 1 -[1 -(5-Chloro-2-fluoro-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
522 benzo[d][1 ,3]oxazin-2-one
Figure imgf000166_0001
5-Chloro-1-[1-(2-methanesulfonyl-benzenesulfonyl)-piperidin-4-yl]-1 ,4-
548 dihydro-benzo[d][1 ,3]oxazin-2-one 5-Chloro-1 -[1 -(4-propyl-benzenesulfonyI)-piperidin-4-yl]-1 ,4-dihydro-
549 benzo[d][1 ,3]oxazin-2-one 5-Chloro-1 -[1 -(3-chloro-2-methyl-benzenesulfonyl)-piperidin-4-yl]-1 ,4-
550 dihydro-benzo[d][1 ,3]oxazin-2-one 1 -[1 -(4-Butyl-benzenesulfonyl)-piperidin-4-yl]-5-chloro-1 ,4-dihydro-
551 benzo[d][1 ,3]oxazin-2-one 1 -[1 -(4-Bromo-3-methyl-benzenesulfonyl)-piperidin-4-yl]-5-chloro-1 ,4-
552 dihydro-benzo[d][1 ,3]oxazin-2-one 5-Chloro-1-{1-[4-(1 ,1-dimethyl-propyl)-benzenesulfonyl]-piperidin-4-yl}-1 ,4-
553 dihydro-benzo[d][1 ,3]oxazin-2-one N-{5-[4-(5-Chloro-2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidine-1 -sulfonyl]-
554 4-methyl-thiazol-2-yl}-acetamide 5-Chloro-1 -[1 -(3-chloro-2-fluoro-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
555 benzo[d][1 ,3]oxazin-2-one 1-[1-(2-Bromo-4-fluoro-benzenesulfonyl)-piperidin-4-yl]-5-chloro-1 ,4-dihydro-
556 benzo[d][1 ,3]oxazin-2-one 1 -[1 -(4-Bromo-3-trifluoromethyl-benzenesulfonyl)-piperidin-4-yl]-5-chloro-1 ,4-
557 dihydro-benzo[d][1 ,3]oxazin-2-one 5-Chloro-1-[1-(5-chloro-2-fluoro-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
558 benzo[d][1 ,3]oxazin-2-one 5-Chloro-1 -[1 -(isoquinoline-5-sulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
559 benzo[d][1 ,3]oxazin-2-one 1 -[1 -(2-Methanesulfonyl-benzenesulfonyl)-piperidin-4-yl]-8-methoxy-1 ,4-
560 dihydro-benzo[d][1 ,3]oxazin-2-one
561 1 -[1 -(2-Methanesulfonyl-benzenesulfonyl)-piperidin-4-yl]-8-methoxy-1 ,4- dihydro-benzo[d][1 ,3]oxazin-2-one 1 -[1 -(3-Chloro-2-methyl-benzenesulfonyl)-piperidin-4-yl]-8-methoxy-1 ,4-
562 dihydro-benzo[d][1 ,3]oxazin-2-one 1 -[1 -(4-Butyl-benzenesulfonyl)-piperidin-4-yl]-8-methoxy-1 ,4-dihydro-
563 benzo[d][1 ,3]oxazin-2-one 1 -[1 -(4-Bromo-3-methyl-benzenesulfonyl)-piperidin-4-yl]-8-methoxy-1 ,4-
564 dihydro-benzo[d][1 ,3]oxazin-2-one 1-{1-[4-(1 ,1-Dimethyl-propyl)-benzenesulfonyl]-piperidin-4-yl}-8-methoxy-1 ,4-
565 dihydro-benzo[d][1 ,3]oxazin-2-one N-{5-[4-(8-Methoxy-2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidine-1 -
566 sulfonyl]-4-methyl-thiazol-2-yl}-acetamide 1-[1-(3-Chloro-2-fluoro-benzenesulfonyl)-piperidin-4-yl]-8-methoxy-1 ,4-
567 dihydro-benzo[d][1 ,3]oxazin-2-one 1 -[1 -(2-Bromo-4-fluoro-benzenesulfonyl)-piperidin-4-yl]-8-methoxy-1 ,4-
568 dihydro-benzo[d][1 ,3]oxazin-2-one 1-[1-(4-Bromo-3-trifluoromethyl-benzenesulfonyl)-piperidin-4-yl]-8-methoxy-
569 1 ,4-dihydro-benzo[d][1 ,3]oxazin-2-one 1 -[1 -(5-Chloro-2-fluoro-benzenesulfonyl)-piperidin-4-yl]-8-methoxy-1 ,4-
570 dihydro-benzo[d][1 ,3]oxazin-2-one 1 -[1 -(lsoquinoline-5-sulfonyl)-piperidin-4-yl]-8-methoxy-1 ,4-dihydro-
571 benzo[d][1 ,3]oxazin-2-one; hydrochloride 1 -[1 -(4-Methyl-naphthalene-1 -sulfonyl)-piperidin-4-yI]-1 ,4-dihydro-
572 benzo[d][1 ,3]oxazin-2-one 6-Chloro-1-[1-(4-methyl-naphthalene-1-sulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
573 benzo[d][1 ,3]oxazin-2-one 6-Methyl-1-[1-(4-methyl-naphthalene-1 -sulfonyl )-piperidin-4-yl]-1 ,4-dihydro-
574 benzo[d][1 ,3]oxazin-2-one 8-Methyl-1-[1-(4-methyl-naphthalene-1-sulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
575 benzo[d][1 ,3]oxazin-2-one 6-Fluoro-1-[1-(4-methyl-naphthalene-1-sulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
576 benzo[d][1 ,3]oxazin-2-one 8-Methoxy-1-[1-(4-methyl-naphthalene-1-sulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
577 benzo[d][1 ,3]oxazin-2-one 5-Chloro-1 -[1 -(4~methyl-naphthalene-1 -sulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
578 benzo[d][1 ,3]oxazin-2-one 5-Chloro-1 -[1 -(naphthalene-1 -sulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
579 benzo[d][1 ,3]oxazin-2-one 5-Chloro-1 -[1 -(naphthaiene-2-sulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
580 benzo[d][1 ,3]oxazin-2-one
581 5-Chloro-1 -[1 -(quinoline-8-sulfonyl)-piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one 5-Chloro-1-[1-(5-chloro-3-methyl-benzo[b]thiophene-2-sulfonyl)-piperidin-4-
582 yl]-1 ,4-dihydro-benzo[d][1 ,3]oxazin-2-one 1 -[1 -(Benzo[b]thiophene-2-sulfonyl)-piperidin-4-yl]-5-chloro-1 ,4-dihydro-
583 benzo[d][1 ,3]oxazin-2-one 1 -[1 -(Benzo[b]thiophene-3-sulfonyl)-piperidin-4-yl]-5-chloro-1 ,4-dihydro-
584 benzo[d][1 ,3]oxazin-2-one 6-Bromo-1-[1-(4-methyl-naphthaIene-1 -sulfonyl )-piperidin-4-yl]-1 ,4-dihydro-
585 benzo[d][1 ,3]oxazin-2-one 2-Chloro-4-fluoro-5-[4-(8-methyl-2-oxo-4H-benzo[d][1 ,3]oxazin-1-yl)-
586 piperidine-1 -sulfonyl]-benzoic acid 2-Chloro-5-[4-(6-chloro-2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidine-1 ■
587 sulfonyl]-4-fluoro-benzoic acid 2-Chloro-4-fluoro-5-[4-(6-methyl-2-oxo-4H-benzo[d][1 ,3]oxazin-1-yl)-
588 piperidine-1 -sulfonyl]-benzoic acid 2-Chloro-4-fluoro-5-[4-(2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidine-1 -
589 sulfonylj-benzoic acid 2-Chloro-4-fluoro-5-[4-(8-methoxy-2-oxo-4H-benzo[d][1 ,3]oxazin-1-yl)-
590 piperidine-1 -sulfonyl]-benzoic acid 2-Chloro-5-[4-(5-chloro-2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidine-1 ■
591 sulfonyl]-4-fluoro-benzoic acid
592 3-[4-(2-Oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidine-1 -sulfonyl]-benzoic acid 3-[4-(8-Methoxy-2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidine-1 -sulfonyl]-
593 benzoic acid 3-[4-(5-Chloro-2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidine-1 -sulfonylj-
594 benzoic acid 1 -[1 -(lsoquinoline-5-sulfonyl)-piperidin-4-yl]-8-methyl-1 ,4-dihydro-
595 benzo[d][1 ,3]oxazin-2-one; hydrochloride 6-Chloro-1 -[1 -(isoquinoline-5-sulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
596 benzo[d][1 ,3]oxazin-2-one; hydrochloride -[1-(lsoquinoline-5-sulfonyl)-piperidin-4-yl]-6-methyl-1 ,4-dihydro-
597 benzo[d][1 ,3]oxazin-2-one;hydrochloride
598 6,7-Difluoro-1 -[1 -(quinoline-8-sulfonyl)-piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one 1-[1-(5-Chloro-3-methyl-benzo[b]thiophene-2-sulfonyl)-piperidin-4-yl]-6,7-
599 difluoro-1 ,4-dihydro-benzo[d][1 ,3]oxazin-2-one 6,7-Difluoro-1 -[1 -(naphthalene-1 -sulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
600 benzo[d][1 ,3]oxazin-2-one
601 6,7-Difluoro-1 -[1 -(naphthalene-2-sulfonyl)-piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one 1-[1-(Benzo[b]thiophene-2-sulfonyl)-piperidin-4-yl]-6,7-difluoro-1 ,4-dihydro-
602 benzo[d][1 ,3]oxazin-2-one 1 -[1 -(Benzo[b]thiophene-3-sulfonyl)-piperidin-4-yl]-6,7-difluoro-1 ,4-dihydro-
603 benzo[d][1 ,3]oxazin-2-one 1-[1-(5-Dimethylamino-naphthalene-1-sulfonyl)-piperidin-4-yl]-6,7-difluoro-
604 1 ,4-dihydro-benzo[d][1 ,3]oxazin-2-one 1-[1-(Biphenyl-4-sulfonyl)-piperidin-4-yl]-6,7-difluoro-1 ,4-dihydro
605 benzo[d][1 ,3]oxazin-2-one 1-[1-(Benzo[1,2,5]thiadiazole-4-sulfonyl)-piperidin-4-yl]-6,7-difluoro-1 ,4-
606 dihydro-benzo[d][1 ,3]oxazin-2-one 1-[1-(Benzo[1 ,2,5]oxadiazole-4-sulfonyl)-piperidin-4-yl]-6,7-difluoro-1 ,4-
607 dihydro-benzo[d][1 ,3]oxazin-2-one 1 -[1 -(7-Chloro-benzo[1 ,2,5]oxadiazole-4-sulfonyl)-piperidin-4-yl]-6,7-difluoro-
608 1 ,4-dihydro-benzo[d][1 ,3]oxazin-2-one 6,7-Difluoro-1 -[1 -(4-methyl-naphthalene-1 -sulfonyl)-piperidin-4-yl]-1 ,4-
609 dihydro-benzo[d][1 ,3]oxazin-2-one
610 1-[1-(4-Chloro-naphthalene-1-sulfonyl)-piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one 1 -[1 -(4-Fluoro-naphthalene-1 -sulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
611 benzo[d][1 ,3]oxazin-2-one
612 1 -[1 -(Dibenzofuran-2-sulfonyl)-piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
613 1 -[1 -(2,3-Dihydro-benzofuran-5-sulfonyl)-piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
614 1 -[1 -(Biphenyl-2-sulfonyl)-piperidin-4-yl]-1 ,4-dihydro-benzo[d][1 ,3]oxazin-2- one
615 1-[1-(5-lsoxazol-5-yl-thiophene-2-sulfonyl)-piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one 1 -[1 -(4-Chloro-naphthalene-1 -sulfonyl)-piperidin-4-yl]-8-methyl-1 ,4-dihydro-
616 benzo[d][1 ,3]oxazin-2-one
617 1-[1-(4-Fluoro-naphthalene-1-sulfonyl)-piperidin-4-yl]-8-methyl-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one 1 -[1 -(Dibenzofuran-2-sulfonyl)-piperidin-4-yl]-8-methyl-1 ,4-dihydro-
618 benzo[d][1 ,3]oxazin-2-one 1-[1-(2,3-Dihydro-benzofuran-5-sulfonyl)-piperidin-4-yl]-8-methyl-1 ,4-dihydro-
619 benzo[d][1 ,3]oxazin-2-one 1 -[1 -(Biphenyl-2-sulfonyl)-piperidin-4-yl]-8-methyl-1 ,4-dihydro-
620 benzo[d][1 ,3]oxazin-2-one
621 1 -[1 -(5-lsoxazol-5-yl-thiophene-2-sulfonyl)-piperidin-4-yl]-8-methyl-1 ,4- dihydro-benzo[d][1 ,3]oxazin-2-one 5-Chloro-1 -[1 -(4-chloro-naphthalene-1 -sulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
622 benzo[d][1 ,3]oxazin-2-one
623 j 5-Chloro-1-[1-(4-fluoro-naphthalene-1-sulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
Figure imgf000170_0001
benzo[d][1 ,3]oxazin-2-one
649 1 -[1 -(2,3-Dihydro-benzofuran-5-suIfonyl)-piperidin-4-yl]-6,7-difluoro-1 ,4- dihydro-benzo[d][1 ,3]oxazin-2-one 1 -[1 -(Biphenyl-2-sulfonyl)-piperidin-4-yl]-6,7-difluoro-1 ,4-dihydro-
650 benzo[d][1 ,3]oxazin-2-one 6,7-Difluoro-1-[1-(5-isoxazol-5-yl-thiophene-2-sulfonyl)-piperidin-4-yl]-1 ,4-
651 dihydro-benzo[d][1 ,3]oxazin-2-one 1-[1-(1 ,2-Dimethyl-1 H-imidazole-4-sulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
652 benzo[d][1 ,3]oxazin-2-one 1 -[1 -(5-Methyl-benzo[1 ,2,5]thiadiazole-4-sulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
653 benzo[d][1 ,3]oxazin-2-one 1 -[1 -(3,5-Dimethyl-isoxazole-4-sulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
654 benzo[d][1 ,3]oxazin-2-one 1-[1-(1 ,2-Dimethyl-1 H-imidazole-4-sulfonyl)-piperidin-4-yl]-8-methyl-1 ,4-
655 dihydro-benzo[d][1 ,3]oxazin-2-one , 8-Methyl-1-[1-(5-methyl-benzo[1 ,2,5]thiadiazole-4-sulfonyl)-piperidin-4-yl]-
656 1 ,4-dihydro-benzo[d][1 ,3]oxazin-2-one 1-[1-(3,5-Dimethyl-isoxazole-4-sulfonyl)-piperidin-4-yl]-8-methyl-1 ,4-dihydro-
657 benzo[d][1 ,3]oxazin-2-one 6-Chloro-1-[1-(1 ,2-dimethyl-1 H-imidazole-4-sulfonyl)-piperidin-4-yl]-1 ,4-
658 dihydro-benzo[d][1 ,3]oxazin-2-one 6-Chloro-1 -[1 -(5-methyl-benzo[1 ,2,5]thiadiazole-4-sulfonyl)-piperidin-4-yl]-
659 1 ,4-dihydro-benzo[d][1 ,3]oxazin-2-one 6-Chloro-1 -[1 -(3,5-dimethyl-isoxazole-4-sulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
660 benzo[d][1 ,3]oxazin-2-one 1-[1-(1 ,2-DimethyI-1 H-imidazole-4-sulfonyl)-piperidin-4-yl]-8-methoxy-1 ,4-
661 dihydro-benzo[d][1 ,3]oxazin-2-one 8-Methoxy-1 -[1 -(5-methyl-benzo[1 ,2,5]thiadiazole-4-sulfonyl)-piperidin-4-yl]-
662 1 ,4-dihydro-benzo[d][1 ,3]oxazin-2-one 1 -[1 -(3,5-Dimethyl-isoxazole-4-sulfonyl)-piperidin-4-yl]-8-methoxy-1 ,4-
663 dihydro-benzo[d][1 ,3]oxazin-2-one 5-Chloro-1-[1-(1 ,2-dimethyl-1 H-imidazole-4-sulfonyl)-piperidin-4-yl]-1 ,4-
664 dihydro-benzo[d][1 ,3]oxazin-2-one 5-Chloro-1 -[1 -(5-methyl-benzo[1 ,2,5]thiadiazole-4-sulfonyl)-piperidin-4-yl]-
665 1 ,4-dihydro-benzo[d][1 ,3]oxazin-2-one 5-Chloro-1 -[1 -(3,5-dimethyl-isoxazole-4-sulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
666 benzo[d][1 ,3]oxazin-2-one 1-[1-(1 ,2-Dimethyl-1 H-imidazole-4-sulfonyl)-piperidin-4-yI]-6-methyl-1 ,4-
667 dihydro-benzo[d][1 ,3]oxazin-2-one 6-Methyl-1 -[1 -(5-methyl-benzo[1 ,2,5]thiadiazole-4-sulfonyl)-piperidin-4-yl]-
668 1 ,4-dihydro-benzo[d][1 ,3]oxazin-2-one 1 -[1 -(3,5-Dimethyl-isoxazole-4-sulfonyl)-piperidin-4-yl]-6-methyl-1 ,4-dihydro-
669 benzo[d][1 ,3]oxazin-2-one 1-[1-(1 ,2-Dimethyl-1 H-imidazole-4-sulfonyl)-piperidin-4-yl]-6-fluoro-1 ,4-
670 dihydro-benzo[d][1 ,3]oxazin-2-one
671 6-Fluoro-1 -[1 -(5-methyl-benzo[1 ,2,5]thiadiazole-4-sulfonyl)-piperidin-4-yl]- 1 ,4-dihydro-benzo[d][1 ,3]oxazin-2-one 1 -[1 -(3,5-Dimethyl-isoxazole-4-sulfonyl)-piperidin-4-yl]-6-fluoro-1 ,4-dihydro-
672 benzo[d][1 ,3]oxazin-2-one
673 1-[1-(1 ,2-Dimethyl-1 H-imidazole-4-sulfonyl)-piperidin-4-yl]-6,7-difluoro-1 ,4- dihydro-benzo[d][1 ,3]oxazin-2-one 6,7-Difluoro-1 -[1 -(5-methyl-benzo[1 ,2,5]thiadiazole-4-sulfonyl)-piperidin-4-yl]-
674 1 ,4-dihydro-benzo[d][1 ,3]oxazin-2-one 1 -[1 -(3,5-Dimethyl-isoxazole-4-sulfonyl)-piperidin-4-yl]-6,7-difluoro-1 ,4-
675 dihydro-benzo[d][1 ,3]oxazin-2-one 1-[1-(5-Chloro-naphthalene-1-sulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
676 benzo[d][1 ,3]oxazin-2-one 1 -[1 -(5-Chloro-naphthalene-2-suIfonyl)-piperidin-4-yl]-1 ,4-dihydro-
677 benzo[d][1 ,3]oxazin-2-one N-{5-[4-(2-Oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidine-1 -sulfonyl]-
678 naphthalen-1-yl}-acetamide 1-[1-(5-Chloro-naphthalene-1-suIfonyl)-piperidin-4-yl]-8-methyl-1 ,4-dihydro-
679 benzo[d][1 ,3]oxazin-2-one 1 -[1 -(5-Chloro-naphthalene-2-sulfonyl)-piperidin-4-yl]-8-methyl-1 ,4-dihydro-
680 benzo[d][1 ,3]oxazin-2-one
681 N-{5-[4-(8-Methyl-2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidine-1 -sulfonyl]- naphthalen-1 -yl}-acetamide 5-Chloro-1 -[1 -(5-chloro-naphthalene-1 -sulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
682 benzo[d][1 ,3]oxazin-2-one 5-Chloro-1 -[1 -(5-chloro-naphthalene-2-sulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
683 benzo[d][1 ,3]oxazin-2-one N-{5-[4-(5-Chloro-2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidine-1 -sulfonyl]-
684 naphthalen-1 -yl}-acetamide 1 -[1 -(5-Chloro-naphthalene-1 -sulfonyl)-piperidin-4-yl]-8-methoxy-1 ,4-dihydro-
685 benzo[d][1 ,3]oxazin-2-one 1 -[1 -(5-Chloro-naphthalene-2-sulfonyl)-piperidin-4-yl]-8-methoxy-1 ,4-dihydro-
686 benzo[d][1 ,3]oxazin-2-one N-{5-[4-(8-Methoxy-2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidine-1 ■
687 sulfonyl]-naphthalen-1-yl}-acetamide 2,5-Dimethyl-4-[4-(8-methyl-2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidine-1 ■
688 sulfonyl]-furan-3-carboxylic acid methyl ester 8-Methyl-1-[1-(2-oxo-2,3-dihydro-benzothiazole-6-sulfonyl)-piperidin-4-yl]-
689 1 ,4-dihydro-benzo[d][1 ,3]oxazin-2-one 1 -[1 -(4-Fluoro-3-methyl-benzenesulfonyl)-piperidin-4-yl]-8-methyl-1 ,4-
690 dihydro-benzo[d][1 ,3]oxazin-2-one 8-Methyl-1-[1-(2-oxo-2,3-dihydro-benzooxazole-6-sulfonyl)-piperidin-4-yl]-
691 1 ,4-dihydro-benzo[d][1 ,3]oxazin-2-one 1 -[1 -(4-Cyclohexyl-benzenesulfonyl)-piperidin-4-yl]-8-methyl-1 ,4-dihydro-
692 benzo[d][1 ,3]oxazin-2-one 2,5-Dimethyl-4-[4-(2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidine-1 -sulfonyl]-
693 furan-3-carboxylic acid methyl ester 1 -[1 -(4-Fluoro-3-methyl-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
694 benzo[d][1 ,3]oxazin-2-one 1 -[1 -(2-Oxo-2,3-dihydro-benzooxazole-6-sulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
695 benzo[d][1 ,3]oxazin-2-one 1 -[1 -(4-Cyclohexyl-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
696 benzo[d][1 ,3]oxazin-2-one 2-Fluoro-5-[4-(8-methyl-2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidine-1 ■
697 sulfonylj-benzoic acid
698 2-Fluoro-5-[4-(2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidine-1 -sulfonyl]- benzoic acid 1-[1 -(2-0x0-2, 3-dihydro-benzothiazole-6-sulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
699 benzo[d][1 ,3]oxazin-2-one 1-[1-(5-Pyridin-2-yl-thiophene-2-sulfonyl)-piperidin-4-yl]-1 ,4-dihydro
700 benzo[d][1 ,3]oxazin-2-one
701 3-[4-(2-Oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidine-1 -sulfonyl]-benzonitrile 3-[4-(2-Oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidine-1 -sulfonyl]-thiophene-2-
702 carboxylic acid methyl ester 1 -{5-[4-(2-Oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidine-1 -sulfonyl]-
703 naphthalen-1-yl}-pyrrolidine-2,5-dione 1 -[1 -(2-Chloro-5-trifluoromethyl-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
704 benzo[d][1 ,3]oxazin-2-one 1-[1-(3,4-Dimethyl-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro
705 benzo[d][1 ,3]oxazin-2-one 8-Methyl-1 -[1 -(5-pyridin-2-yl-thiophene-2-sulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
706 benzo[d][1 ,3]oxazin-2-one 3-[4-(8-Methyl-2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidine-1 -sulfonyl]-
707 benzonitrile 3-[4-(8-Methyl-2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidine-1 -sulfonyl]-
708 thiophene-2-carboxylic acid methyl ester
709 1 -{5-[4-(8-Methyl-2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidine-1 -sulfonyl]- naphthalen-1-yl}-pyrrolidine-2,5-dione
710 1-[1-(2-Chloro-5-trifluoromethyl-benzenesulfonyl)-piperidin-4-yl]-8-methyl 1 ,4-dihydro-benzo[d][1 ,3]oxazin-2-one 1 -[1 -(3,4-Dimethyl-benzenesulfonyl)-piperidin-4-yl]-8-methyl-1 ,4-dihydro-
711 benzo[d][1 ,3]oxazin-2-one 5-Chloro-1 -[1 -(5-pyridin-2-yl-thiophene-2-sulfonyl)-piperidin-4-yi]-1 ,4-dihydro-
712 benzo[d][1 ,3]oxazin-2-one
713 3-[4-(5-Chloro-2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidine-1 -sulfonyl]- benzonitrile
714 3-[4-(5-Chloro-2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidine-1 -sulfonyl]- thiophene-2-carboxylic acid methyl ester
715 1 -{5-[4-(5-Chloro-2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidine-1 -sulfonyl]- naphthalen-1-yl}-pyrrolidine-2,5-dione
716 5-Chloro-1 -[1 -(2-chloro-5-trif luoromethyl-benzenesulfonyl)-piperidin-4-yl]-1 ,4- dihydro-benzo[d][1 ,3]oxazin-2-one 5-Chloro-1 -[1 -(3,4-dimethyl-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
717 benzo[d][1 ,3]oxazin-2-one
718 6-Methyl-1-[1-(5-pyridin-2-yl-thiophene-2-sulfonyl)-piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one 3-[4-(6-Methyl-2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidine-1 -sulfonyl]-
719 benzonitrile 3-[4-(6-Methyl-2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidine-1 -sulfonyl]-
720 thiophene-2-carboxylic acid methyl ester
721 1 -{5-[4-(6-Methyl-2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidine-1 -sulfonyl]- naphthalen-1-yl}-pyrrolidine-2,5-dione 1-[1-(2-Chloro-5-trifluoromethyl-benzenesulfonyl)-piperidin-4-yl]-6-methyl-
722 1 ,4-dihydro-benzo[d][1 ,3]oxazin-2-one 1 -[1 -(3,4-Dimethyl-benzenesulfonyl)-piperidin-4-yl]-6-methyl-1 ,4-dihydro-
723 benzo[d][1 ,3]oxazin-2-one 6-Chloro-1 -[1 -(5-pyridin-2-yl-thiophene-2-sulfonyl)-piperidin-4-yl]-1 ,4-dihydro- 724 benzo[d][1 ,3]oxazin-2-one 3-[4-(6-Chloro-2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidine-1 -sulfonyl]- 725 benzonitrile 3-[4-(6-Chloro-2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidine-1 -sulfonyl]- 726 thiophene-2-carboxylic acid methyl ester 1 -{5-[4-(6-Chloro-2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidine-1 -sulfonyl]- 727 naphthalen-1 -yl}-pyrrolidine-2,5-dione 6-Chloro-1 -[1 -(2-chloro-5-trifluoromethyl-benzenesulfonyl)-piperidin-4-yl]-1 ,4- 728 dihydro-benzo[d][1 ,3]oxazin-2-one 6-Chloro-1 -[1 -(3,4-dimethyl-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro- 729 benzo[d][1 ,3]oxazin-2-one 1 -[1 -(5-Methyl-isoxazole-4-sulfonyl)-piperidin-4-yl]-1 ,4-dihydro- 730 benzo[d][1 ,3]oxazin-2-one 731 1 -[1 -(2,2-Dimethyl-chroman-6-sulfonyl)-piperidin-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one 1 -[1 -(4-Methyl-3,4-dihydro-2H-benzo[1 ,4]oxazine-7-sulfonyl)-piperidin-4-yl]-
1732 1 ,4-dihydro-benzo[d][1 ,3]oxazin-2-one 1 -[1 -(2,3-Dihydro-benzo[ ,4]dioxine-6-sulfonyl)-piperidin-4-yl]-1 ,4-dihydro- 733 benzo[d][1 ,3]oxazin-2-one 1-[1-(1 ,3,5-Trimethyl-1 H-pyrazole-4-sulfonyl)-piperidin-4-yl]-1 ,4-dihydro~ 734 benzo[d][1 ,3]oxazin-2-one 1-[1-(3-Methyl-2-oxo-2,3-dihydro-benzooxazole-6-sulfonyl)-piperidin-4~yl]- 735 1 ,4-dihydro-benzo[d][1 ,3]oxazin-2-one 8-Methyl-1 -[1 -(5-methyl-isoxazole-4-sulfonyl)-piperidin-4-yl]-1 ,4-dihydro- 736 benzo[d][ ,3]oxazin-2-one 1 -[1 -(2,2-Dimethyl-chroman-6-sulfonyl)-piperidin-4-yl]-8-methyl-1 ,4-dihydro- 737 benzo[d][1 ,3]oxazin-2-one 8-Methyl-1 -[1 -(4-methyl-3,4-dihydro-2H-benzo[1 ,4]oxazine-7-sulfonyl)- 738 piperidin-4-yl]-1 ,4-dihydro-benzo[d][1 ,3]oxazin-2-one 1 -[1 -(2,3-Dihydro-benzo[1 ,4]dioxine-6-sulfonyl)-piperidin-4-yl]-8-methyl-1 ,4- 739 dihydro-benzo[d][1 ,3]oxazin-2-one 8-Methyl-1 -[1 -(1 ,3,5-trimethyl-1 H-pyrazole-4-sulfonyl)-piperidin-4-yl]-1 ,4- 740 dihydro-benzo[d][1 ,3]oxazin-2-one 741 8-Methyl-1-[1-(3-methyl-2-oxo-2,3-dihydro-benzooxazole-6-sulfonyl)- piperidin-4-yl]-1 ,4-dihydro-benzo[d][1 ,3]oxazin-2-one 8-Methoxy-1-[1-(1 ,3,5-trimethyl-1 H-pyrazole-4-sulfonyl)-piperidin-4-yl]-1 ,4- 742 dihydro-benzo[d][1 ,3]oxazin-2-one 8-Methoxy-1-[1-(3-methyl-2-oxo-2,3-dihydro-benzooxazole-6-sulfonyl)- 743 piρeridin-4-yl]-1 ,4-dihydro-benzo[d][1 ,3]oxazin-2-one 1 -[1 -(Benzo[d]isoxazol-3-ylmethanesulfonyl)-piperidin-4-yl]-1 ,4-dihydro- 744 benzo[d][1 ,3]oxazin-2-one 1-[1-(2,2,4,6,7-Pentamethyl-2,3-dihydro-benzofuran-5-sulfonyl)-piperidin-4- 745 yl]-1 ,4-dihydro-benzo[d][1 ,3]oxazin-2-one 6-Methyl-5-[4-(2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidine-1 -sulfonyl]-1 H- 746 pyrimidine-2,4-dione 1 -[1 -(3-Methyl-quinoline-8-sulfonyl)-piperidin-4-yl]-1 ,4-dihydro- 747 benzo[d][1 ,3]oxazin-2-one 1 -[1 -(2,2,5, 7,8-Pentamethyl-chroman-6-sulfonyl)-piperidin-4-yl]-1 ,4-dihydro- 748 benzo[d][1 ,3]oxazin-2-one 1 ,4-Dimethyl-6-[4-(2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidine-1 -sulfonyl]-
749 1 ,4-dihydro-quinoxaline-2,3-dione 1-[1-(1 H-lmidazole-4-sulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
750 benzo[d][1 ,3]oxazin-2-one
751 1-[1-(2-Oxo-1 ,2,3,4-tetrahydro-quinoline-6-sulfonyl)-piperidin-4-yl]-1 ,4- dihydro-benzo[d][1 ,3]oxazin-2-one 7-[4-(2-Oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidine-1 -sulfonyl]-1 ,5-dihydro-
752 benzo[b][1 ,4]diazepine-2,4-dione 8-Methyl-1 -[1 -(3-methyl-quinoline-8-sulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
753 benzo[d][1 ,3]oxazin-2-one 6-Chloro-1 -[1 -(3-methyl-quinoline-8-sulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
754 benzo[d][1 ,3]oxazin-2-one 5-Chloro-1 -[1 -(3-methyl-quinoline-8-sulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
755 benzo[d][1 ,3]oxazin-2-one 8-Methoxy-1-[1-(3-methyl-quinoline-8-sulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
756 benzo[d][1 ,3]oxazin-2-one 1 -[1 -(Pyridine-2-sulfonyl)-piperidin-4-yl]-1 ,4-dihydro-benzo[d][1 ,3]oxazin-2-
757 one 1-[1-(6,7-Dihydroxy-naphthalene-1-sulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
758 benzo[d][1 ,3]oxazin-2-one Acetic acid 3-acetoxy-5-[4-(2-oxo-4H-benzo[d][1 ,3]oxazin-1-yl)-piperidine-1-
759 sulfonyl]-naphthalen-2-yl ester 1 -[1 -(1 H-Benzoimidazole-2-sulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
760 benzo[d][1 ,3]oxazin-2-one
761 1 -[1 -(1 H-Benzoimidazole-2-sulfonyl)-piperidin-4-yl]-8-methoxy-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one 1 -[1 -(1 H-Benzoimidazole-2-sulfonyl)-piperidin-4-yl]-5-chloro-1 ,4-dihydro-
762 benzo[d][1 ,3]oxazin-2-one 1 -[1 -(2,5-Dimethoxy-benzenesulfonyl)-piperidin-4-yl]-6-fluoro-1 ,4-dihydro-
763 benzo[d][1 ,3]oxazin-2-one 1 -[1 -(2,5-Dimethoxy-benzenesulfonyl)-piperidin-4-yl]-8-methoxy-1 ,4-dihydro-
764 benzo[d][1 ,3]oxazin-2-one 1 -[1 -(2,5-Dimethoxy-benzenesulfonyl)-piperidin-4-yl]-6,7-difluoro-1 ,4-
765 dihydro-benzo[d][1 ,3]oxazin-2-one 5-Chloro-1 -[1 -(2,5-dimethoxy-benzenesulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
766 benzo[d][1 ,3]oxazin-2-one 1 -[1 -(5-Dimethylamino-naphthalene-1 -sulfonyl)-piperidin-4-yl]-8-methoxy-
767 1 ,4-dihydro-benzo[d][1 ,3]oxazin-2-one 5-Chloro-1 -[1 -(5-dimethylamino-naphthalene-1 -sulfonyl)-piperidin-4-yl]-1 ,4-
768 dihydro-benzo[d][1 ,3]oxazin-2-one 6-Chloro-1 -[1 -(5-chloro-naphthalene-1 -sulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
769 benzo[d][1 ,31oxazin-2-one 1 -[1 -(5-Chloro-naphthalene-1 -sulfonyl)-piperidin-4-yl]-6-methyl-1 ,4-dihydro-
770 benzo[d][1 ,3]oxazin-2-one
771 1-[1-(5-Chloro-naphthalene-1-sulfonyl)-piperidin-4-yl]-6-fluoro-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one 6-Chloro-1 -[1 -(5-chIoro-naphthalene-2-sulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
772 benzo[d][1 ,3]oxazin-2-one 1-[1-(5-Chloro-naphthalene-2-sulfonyl)-piperidin-4-yl]-6-methyl-1 ,4-dihydro-
773 benzo[d][1 ,3]oxazin-2-one 1 -[1 -(5-Chloro-naphthalene-2-sulfonyl)-piperidin-4-yl]-6-fluoro-1 ,4-dihydro-
774 benzo[d][1 ,3]oxazin-2-one 6-Methyl-1-[1-(3-methyl-quinoline-8-sulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
775 benzo[d][1 ,3]oxazin-2-one 6-Fluoro-1 -[1 -(3-methyl-quinoline-8-sulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
776 benzo[d][1 ,3]oxazin-2-one 6,7-Difluoro-1 -[1 -(3-methyl-quinoline-8-sulfonyl)-piperidin-4-yl]-1 ,4-dihydro-
777 benzo[d][1 ,3]oxazin-2-one 6-Chloro-1-[1-(3-methyl-2-oxo-2,3-dihydro-benzooxazole-6-sulfonyl)-
778 piperidin-4-yl]-1 ,4-dihydro-benzo[d][1 ,3]oxazin-2-one 6-Methyl-1-[1-(3-methyl-2-oxo-2,3-dihydro-benzooxazole-6-sulfonyl)-
779 piperidin-4-yl]-1 ,4-dihydro-benzo[d][1 ,3]oxazin-2-one 6-Fluoro-1-[1-(3-methyl-2-oxo-2,3-dihydro-benzooxazole-6-sulfonyl)-
780 piperidin-4-yl]-1 ,4-dihydro-benzo[d][1 ,3]oxazin-2-one
781 6,7-Difluoro-1-[1-(3-methyl-2-oxo-2,3-dihydro-benzooxazole-6-sulfonyl)- piperidin-4-yl]-1 ,4-dihydro-benzo[d][1 ,3]oxazin-2-one 5-Chloro-1-[1-(3-methyl-2-oxo-2,3-dihydro-benzooxazole-6-sulfonyl)-
782 piperidin-4-yl]-1 ,4-dihydro-benzo[d][1 ,3]oxazin-2-one 6-Chloro-1 -[1 -(4-methyl-3,4-dihydro-2H-benzo[1 ,4]oxazine-7-sulfonyl)-
783 piperidin-4-yl]-1 ,4-dihydro-benzo[d][1 ,3]oxazin-2-one 6-Methyl-1-[1-(4-methyl-3,4-dihydro-2H-benzo[1 ,4]oxazine-7-sulfonyl)-
784 piperidin-4-yl]-1 ,4-dihydro-benzo[d][1 ,3]oxazin-2-one 6-Fluoro-1 -[1 -(4-methyl-3,4-dihydro-2H-benzo[1 ,4]oxazine-7-sulfonyl)-
785 piperidin-4-yl]-1 ,4-dihydro-benzo[d][1 ,3]oxazin-2-one 8-Methoxy-1 -[1 -(4-methyl-3,4-dihydro-2H-benzo[1 ,4]oxazine-7-sulfonyl)-
786 piperidin-4-yl]-1 ,4-dihydro-benzo[d][1 ,3]oxazin-2-one 5-Chloro-1 -[1 -(4-methyl-3,4-dihydro-2H-benzo[1 ,4]oxazine-7-sulfonyl)-
787 piperidin-4-yl]-1 ,4-dihydro-benzo[d][1 ,3]oxazin-2-one.
The benzoxazinone-derived sulphonamide compounds of general formula (lb), wherein R1b-R9b and Wb have the meaning given above, may be prepared preferably by way of reaction of at least one piperidine compound of general formula (lib) and/or a corresponding salt thereof, preferably a hydrochloride salt,
Figure imgf000177_0001
(lib)
wherein R1b to R9b have the meaning given above, with at least one compound of general formula (lllb),
Figure imgf000177_0002
(lllb)
wherein Wb has the meaning given above, in a suitable reaction medium, optionally in the presence of at least one base and/or at least one auxiliary agent, to yield a compound of general formula (lb).
Suitable reaction media include e.g. organic solvents, such as ethers, preferably diethyl ether, dioxane, tetrahydrofurane, dimethyl glycol ether, or alcohols, e.g. methanol, ethanol, propanol, isopropanol, butanol, isobutanol, tert-butanol, or hydrocarbons, preferably benzene, toluene, xylene, hexane, cyclohexane, petroleum ether, or halogenated hydrocarbons, e.g. dichloromethane, trichloromethane, tetrachloromethane, dichloroethylene, trichloroethylene, chlorobenzene or/and other solvents, preferably ethyl acetate, triethylamine, pyridine, dimethylsulfoxide, diemthylformamide, hexamethylphosphoramide, acetonitril, acetone or nitromethane, are included. Mixtures based one or more of the afore mentioned solvents may also be used.
Bases that may be used in the processes according to the present invention are generally organic or inorganic bases, preferably alkali metal hydroxides, e.g. sodium hydroxyde or potassium hydroxyde, or obtained from other metals such as barium hydroxyde or different carbonates, preferably potassium carbonate, sodium carbonate, calcium carbonate, or alkoxides, e.g. sodium methoxide, potassium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide or potassium tert-butoxide, or organic amines, preferably triethylamine, diisopropyethylamine or heterocycles, e.g. 1 ,4-diazabicyclo[2.2.2] octane, 1 ,8-diazabicyclo[5.4.0]undec-7-ene pyridine, diamino pyridine, dimethylaminopyridine, methylpiperidine or morpholine. Alkali metals such as sodium or ist hydrides, e.g. sodium hydride, may also be used. Mixtures based one or more of the afore mentioned bases may also be used.
During the synthetic reactions described above or while preparing the compounds of general formulas (lib) or (lllb) the protection of sensitive groups or of reagents may be necessary and/or desirable. This can be performed by using conventional protective groups like 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. Said literature description is hereby incorporated by reference as part of the disclosure. The protective groups may also be eliminated as convenient by means well-known to those skilled in the art.
The compounds of general formulas (lib) and (lllb) are either commercially available or can be produced according to methods known to those skilled in the art. The reaction of compounds of general formulas (lib) and (lllb) to yield benzoxazinone- derived sulphonamide compounds of general formula (lb) may also be facilitated by conventional methods known to those skilled in the art. The substituted benzoxazinone compounds of general formula (lib), wherein R5 represents H, are preferably synthesized from substituted anthranilic acid or a corresponding ester via the corresponding substituted benzylalcohol (see scheme 1 , method A). By reductive amination with 1-Boc-(tert.-Butylcarbonyloxy)-4-piperidone the Boc-piperidin-moiety is introduced into the substituted benzylalcohol. The benzoxazinone-ring is formed by cyclisation with triphosgene. The elimination of the Boc-protecting group is carried out by treatment in acidic media according to the method described in Williams et al., J. Med. Chem. 1995 38, 4634 and later by Bell et al., J. Med. Chem., 1998, 41 , 2146 which are hereby incorporated by reference and form part of the disclosure. By reacting such a substituted benzoxazinone compound of general formula (lib) with a substituted sulfuryl chloride of general formula (lllb) compounds of general formula (lb) are obtained.
By reduction of the corresponding ketones via conventional methods known to those skilled in the art, e.g. by reduction with sodium borohydride (see scheme 1 , method B, R5b=Z) benzoxazinone derived sulphonamide compounds of general formula (lb), wherein R5b represents an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical or a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic radical (denoted by Z in method B) can be obtained.
The respective reagents used in said process for the preparation of benzoxazinone derived sulphonamide compounds of general formula (lb) are either commercially available or can be obtained by methods well known to those skilled in the art.
Scheme 1: ine
Figure imgf000180_0001
(I) (li)
The salts of benzoxazinone-derived sulphonamide compounds of general formula (lb), may be prepared in a way that at least one compound of general formula (lb) having at least one basic group is reacted with at least one inorganic and/or organic acid, preferably in the presence of a suitable reaction medium. Suitable reaction media are, for example, the ones given above. Suitable inorganic acids include hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, nitric acid, suitable organic acids are e.g. citric acid, maleic acid, fumaric acid, tartaric acid, or derivatives thereof, p-toluenesulfonic acid, methanesulfonic acid or camphersulfonic acid.
The salts of benzoxazinone-derived sulphonamide compounds of general formula (lb), may be prepared in a way that at least one compound of general formula (lb) having at least one acidic group is reacted with one or more suitable bases, preferably in the presence of a suitable reaction medium. Suitable bases are e.g. hydroxides, carbonates or alkoxides, which include suitable cations, derived e.g. from alkaline metals, alkaline earth metals or organic cations, e.g. [NHnR4-n]+, wherein n is 0, 1 , 2, 3 or 4 and R represents a branched or unbranched C-ι-4-alkyl-radical. Suitable reaction media are, for example, the ones given above.
Solvates, preferably hydrates, of the Benzoxazinone-derived sulphonamide compounds of general formula (lb) or of the salts thereof may also be obtained by standard procedures known to those skilled in the art.
If the Benzoxazinone-derived compounds of general formula (lb) are obtained in form of a mixture of stereoisomers, particularly enantiomers or diastereomers, said mixtures may be separated by standard procedures known to those skilled in the art, e.g. chromatographic methods or crystallization with chiral reagents.
The purification and isolation of the Benzoxazinone-derived sulphonamide compounds of general formula (lb) or a corresponding stereoisomer, or salt, or solvate respectively, if required, may be carried out by conventional methods known to those skilled in the art, e.g. chromatographic methods or recrystallization.
If one or more of the residues R1c, R3c, R c and R5c represents an alkyl radical, which is substituted with one or more substituents, unless defined otherwise, each of the substituents may preferably be selected from the group consisting of hydroxy, fluorine, chlorine, bromine and trifluoromethyl.
If R1c represents a phenyl radical or a benzyl radical, which is substituted with one or more substituents, unless defined otherwise, each of the substituents may preferably be selected from the group consisting of hydroxy, fluorine, chlorine, bromine, branched or unbranched Cι-C4-alkyl, branched or unbranched C-ι-C4-alkoxy, branched or unbranched Cι-C4-perfluoroalkyl and branched or unbranched C1-C4- perfluoroalkoxy.
If R2c represents a saturated or unsaturated, optionally at least one heteroatom as ring member containing cycloaliphatic radical, which is substituted with one or more substituents and/or if it comprises a saturated or unsaturated, optionally at least one heteroatom as ring member containing mono- or bicyclic cycloaliphatic ringsystem, which is substituted with one or more substituents, unless defined otherwise, each of the substituents may preferably be selected from the group consisting of hydroxy, fluorine, chlorine, bromine, branched or unbranched CrC4-alkyl, branched or unbranched C-ι-C4-alkoxy, branched or unbranched C-ι-C4-perfluoroalkyl, branched or unbranched Cι-C4-perfluoroalkoxy and benzyl, preferably from the group consisting of branched or unbranched CrC4-alkyl and benzyl. The heteroatoms of the cycloaliphatic radical and/or of the mono- or bicyclic cycloaliphatic ringsystem may, independent from one another, preferably be selected from the group consisting of nitrogen, sulphur and oxygen, more preferably the heteroatom is nitrogen.
If R4c and R5c together with the bridging nitrogen atom form a saturated or unsaturated, optionally at least one further heteroatom as ring member containing heterocyclic ring, which is substituted with one or more substituents and/or which is condensed with a saturated or unsaturated, optionally at least one heteroatom as ring member containing mono- or bicyclic cycloaliphatic ringsystem, which is substituted with one or more substituents, unless otherwise defined, each of the substituents, may preferably be selected from the group consisting of hydroxy, fluorine, chlorine, bromine, branched or unbranched C-ι-C4-alkyl, branched or unbranched C-ι-C4-alkoxy, branched or unbranched C-i-C4-perfluoroalkyl, branched or unbranched Cι-C4-perfluoroalkoxy and benzyl, preferably from the group consisting of branched or unbranched C-ι-C4-alkyl and benzyl. If the hetereocyclic ring contains one or more further heteroatoms and/or one or both of the mono- or bicyclic rings contain one or more heteroatoms, these heteroatoms may, independent from one another, preferably be selected from the group consisting of nitrogen, sulphur and oxygen, more preferably the heteroatom is nitrogen.
If Ac represents a mono- or polycyclic aromatic ringsystem, which is substituted with one or more substituents, and which may be bonded via an optionally at least mono- substituted alkylene-, alkenylene- or alkynylene group and/or may contain at least one heteroatom as a ring member, unless otherwise defined, each of th--. ~-r substituents, may preferably be selected from the group consisting of hydroxy, halogen, branched or unbranched C-i-C4-alkyl, branched or unbranched C1-C4- alkoxy, branched or unbranched Cι-C4-perfluoroalkyl, branched or unbranched C-r C -perfluoroalkoxy, an optionally at least mono-substituted phenyl radical and 5-or 6 membered heteroaryl, preferably from the group consisting of halogen, branched or unbranched C-ι-C4-alkyl, an optionally at least mono-substituted phenyl radical and 5- or 6-membered heteroaryl, more preferably from the group consisting of fluorine, chlorine, branched or unbranched C-ι-C4-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 ringsystem contains one or more heteroatoms, these heteroatoms - like the heteroatoms of the afore mentioned 5-or 6 membered heteroaryl radical - may preferably be selected from the group consisting of oxygen, sulphur and nitrogen. If the afore mentioned phenyl radical is itself substituted with one or more substituents, each of the substituents may preferably be selected from the group consisting of fluorine, chlorine, bromine, linear or branched C C4-alkyl, linear or branched C-j-C4-alkoxy, linear or branched C-ι-C4-alkylthio, a trifluoromethyl moiety, a cyano moiety and a NR8cR9c-moiety, wherein R8c and R9c, identical or different, represent hydrogen or linear or branched C-ι-C4-alkyl.
If the afore mentioned alkylene-, alkenylene- or alkynylene group is substituted with one or more substituents, each of the substituents may preferably be selected from the group consisting of hydroxy, halogen, branched or unbranched C-ι-C4-alkyl, branched or unbranched C-ι-C4-alkoxy, branched or unbranched Cι-C4-perfluoroalkyl, branched or unbranched Cι-C4-perfluoroalkoxy or an optionally at least mono- substituted phenyl radical. If said phenyl radical is itself substituted by one or more substituents, each of the substituents may preferably be selected from the group consisting of fluorine, chlorine, bromine, linear or branched C-ι-C4-alkyl, linear or branched C-ι-C4-alkoxy, linear or branched C-ι-C4-alkylthio, a trifluoromethyl moiety, a cyano moiety and a NR8cR9c-moiety, wherein R8c and R9c, identical or different, represent hydrogen or linear or branched C-ι-C4-alkyl.
Preferably used are sulphonamide derivatives of general formula (Ic), wherein R1c represents hydrogen, an optionally at least mono-substituted, linear or branched C-M- alkyl radical, an optionally at least mono-substituted phenyl radical or an optionally at least mono-substituted benzyl radical, preferably hydrogen, a linear or branched C-M- alkyl radical or a benzyl radical, more preferably hydrogen, and R2c to R5c, Ac and nc are as defined above. Preference is also given to the use of sulphonamide derivatives of general formula (Ic), wherein R2c represents a -NR4cR5c moiety or a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing 5- or 6-membered cycloaliphatic radical, which may be condensed with a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing mono- or bicyclic cycloaliphatic ringsystem, wherein the ring(s) is/are 5- or 6-membered, preferably a NR4cR5° moiety or a moiety selected from the group consisting of
Figure imgf000184_0001
wherein, if present, the dotted line represents an optional chemical bond and R6 represents hydrogen, a linear or branched C-ι-C4-alkyl radical or a benzyl radical, preferably hydrogen or a C1-C2 alkyl radical, and R1c, R3c-R5c, Ac and nc are as defined above.
Also preferred is the use of sulphonamide derivatives of general formula (Ic), wherein R3c represents hydrogen or an optionally at least mono-substituted, linear or branched C C4-alkyl radical, preferably hydrogen or a linear or branched C-ι-C4-alkyl radical, more preferably hydrogen or a C1-C2 alkyl radical, and R1c, R2c R4c, R5c, Ac and nc are as defined above. Furthermore, preference is also given to the use of sulphonamide derivatives of general formula (Ic), wherein R4c and R5°, identical or different, represent hydrogen or an optionally at least mono-substituted, linear or branched Cι-C -alkyl radical, or
R4c and R5c together with the bridging nitrogen atom form an optionally at least mono- substituted, saturated or unsaturated, 5- or 6-membered heterocyclic ring, which may contain at least one further heteroatom as a ring member and/or may be condensed with a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing mono- or bicyclic aliphatic ringsystem, wherein the ring(s) is/are 5-, 6- or 7-membered, and R1c, R2c, R3c, Ac and nc are as defined above.
Particularly preferred is the use of sulphonamide derivatives of general formula (Ic), wherein R4c and R5c, identical or different, represent hydrogen or a linear or branched Cι-C4-alkyl radical, preferably a linear or branched C-ι-C4-alkyl radical, or
R4c and R5c together with the bridging nitrogen atom form a moiety selected from the group consisting of
Figure imgf000185_0001
wherein R7 represents hydrogen, a linear or branched C-ι-C4-alkyl radical or a benzyl radical, preferably hydrogen or a C-ι-C2 alkyl radical, and R1c-R3c, Ac and nc are as defined above. Moreover, the use of sulphonamide derivatives of general formula (Ic) is preferred, wherein Ac represents an optionally at least mono-substituted mono- or bicyclic aromatic ringsystem, wherein the ring(s) is/are 5- or 6-membered, which may be bonded via a an optionally at least mono-substituted C-ι-C4-alkylene group, an optionally at least mono-substituted C2-C4-alkenylene or an optionally at least mono- substituted C2-C4-alkinylene group and/or may contain at least one heteroatom as a ring member, preferably an optionally at least mono-substituted mono- or bicyclic aromatic ringsystem, wherein the ring(s) is/are 5- or 6-membered and wherein one or both of the rings contain(s) at least one heteroatom, or a moiety selected from the group consisting of
Figure imgf000186_0001
wherein X, Y, Z are each independently selected from the group consisting of hydrogen, fluorine, chlorine, bromine, linear or branched C-ι-C4-alkyl, linear or branched C-ι-C4-alkoxy, linear or branched Cι-C4-alkylthio, a trifluoromethyl moiety, a cyano moiety and a NR8R9-moiety, wherein R8 and R9, identical or different, represent hydrogen or linear or branched C-ι-C4-alkyl,
W represents a single chemical bond between the two rings, a CH2-group, O, S or a NR10-moiety, wherein R10 is hydrogen or linear or branched d-C4-alkyl and
m is O, 1 , 2, 3 or 4.
and R j1c -R D5C and nc are as defined above. Most preferred is the use of one or more sulphonamide derivatives selected from the group consisting of:
[1 ] N-[3-(2-diethylaminoethyl)-1 H-indol-5-yl]-5-chloro-3-methyibenzo[b]thiophene-2- sulphonamide,
[2] N-[3-(2-diethylaminoethyl)-1 H-indol-5-yl]naphthalene-1 -sulphonamide,
[3] Hydrochloride N-[3-(2-diethylaminoethyl)-1 - -indol-5-yl]naphthalene-1 - sulphonamide, [4] N-[3-(2-diethylaminoethyl)-1H-indol-5-yl]-3,5-dichlorobenzenesulphonamide,
[5] N-[3-(2-diethylaminoethyl)-1 - -indol-5-yl]-4-phenylbenzenesulphonamide,
[6] N-[3-(2-diethylaminoethyl)-1H-indol-5-yl]-5-chlorothiophene-2-sulphonamide,
[7] N-[3-(2-dimethylaminoethyl)-1 - -indol-5-yl]-5-chloro-3-methylbenzo[b]thiophene- 2-sulphonamide,
[8] N-[3-(2-dimethylaminoethyl)-1 H-indol-5-yl]naphthalene-1 -sulphonamide,
[9] N-[3-(2-dimethylamino-ethyl)-1 H-indol-5-yl]-6-chloroimidazo[2,1 -b]thiazol-5- sulphonamide,
[10] N-[3-(1 -methylpiperidin-4-yl)-1 H-indol-5-yl]-5-chloro-3-methylbenzo[b]thiophene- 2-sulphonamide,
[11 ] N-[3-(1 -methylpiperidin-4-yl)-1 H-indol-5-yl]-5-chloro-3-methylbenzo[b]thiophene- 2-sulphonamide hydrochloride,
[12] N-[3-(1-methylpiperidin-4-yl)-1H-indol-5-yl]naphthalene-1 -sulphonamide,
[13] N-[3-(1 -methylpiperidin-4-yl)-1 H-indol-5-yl]naphthalene-1 -sulphonamide hydrochloride, [14] N-[3-(1-methylpiperidin-4-yl)-1H-indol-5-yl]-5-chlorothiophene-2-sulphonamide,
[15] N-[3-(1-methylpiperidin-4-yl)-1H-indol-5-yl]-4-phenylbenzenesulphonamide,
[16] N-[3-(1 -methylpiperidin-4-yl)-1 - -indol-5-yl]quinoline-8-sulphonamide,
[17] N-[3-(2-diethylaminoethyl)-1 --indol-5-yl]naphthalene-2-sulphonamide,
[18] N-[3-(1 -methyl-1 ,2,3,6-tetrahydropyridin-4-yl)-1 H-indol-5-yl]naphthalene-1 - sulphonamide,
[19] N-[3-(4-methylpiperazin-1 -yl)methyl-1 A -indol-5-yl]-5-chloro-3- methylbenzo[b]thiophene-2-sulphonamide,
[20] N-[3-(2-dimethylaminoethyl)-1H-indol-5-yl]-5-(2-pyridil)thiophene-2- sulphonamide,
[21] N-[3-(2-dimethylaminoethyl)-1 H-indol-5-yl]-2,1 ,3- benzothiadiazol-4- sulphonamide,
[22] N-[3-(2-dimethylaminoethyl)-1H-indol-5-yl]quinoline-8-sulphonamide,
[23] N-[3-(2-dimethylaminoethyl)-1 - -indol-5-yl]-5-chloronaphthalene-2-sulphonamide,
[24] N-[3-(2-dimethylaminoethyl)-1 - -indol-5-yl]-4-phenoxybenzenesulphonamide,
[25] N-[3-(2-dimethylaminoethyl)-1H-indol-5-yl]-4-phenylbenzenesulphonamide,
[26] N-[3-(2-diethylaminoethyl)-1 --indol-5-yl]-N-ethyl-naphthalene-2-sulphonamide,
[27] N-{3-[2-(morpholin-4-yl)ethyl]-1 H-indol-5-yl}-5-chloro-3-methylbenzo[b]thiophene- 2-sulphonamide, [28] N-{3-[2-(morpholin-4-yl)ethyl]-1 H-indol-5-yl}naphthalene-1 -sulphonamide,
[29] N-[3-(2-diethylaminoethyl)-1 H-indol-5-yl]naphthalene-2-sulphonamide,
[30] N-[3-dimethylaminomethyl-1 H-indol-5-yl]-5-chloro-3-methylbenzo[b]thiophene-2- sulphonamide,
[31] N-[3-(2-dipropylaminoethyl)-1 H-indol-5-yl]naphthalene-1 -sulphonamide,
[32] N-[3-(2-dipropylaminoethyl)-1 H-indol-5-yl]-5-chloro-3-methylbenzo[b]thiophene-2- sulphonamide,
[33] N-[3-(2-dibutylaminoethyl)-1 H-indol-5-yl]-5-chloro-3-methylbenzo[b]thiophene-2- sulphonamide,
[34] N-[3-(2-dibutylaminoethyl)-1 H-indol-5-yl]naphthalene-1 -sulphonamide,
[35] N-[3-(2-diethylaminoethyl)-1 H-indol-5-yl]-5-chloronaphthalene-1 -sulphonamide,
[36] N-[3-(2-diethylaminoethyl)-1 H-indol-5-yl]-trans-β-styrenesulphonamide,
[37] N-[3-(4-methylpiperazin-1 -yl)methyl-1 - -indol-5-yl]-trans-β-styrenesulphonamide,
[38] N-[3-(octahydroindolizin-7-yl)-1 H-indol-5-yl]-5-chloro-3-methylbenzo[b]thiophene-2- sulphonamide,
[39] N-[3-(2-diethylaminoethyl)-1H-indol-5-yl]-6-chloroimidazo[2,1-b]thiazol-5- sulphonamide,
[40] N-{3-[2-(morpholin-4-yl)ethyl]-1H-indol-5-yl}naphthalene-2-sulphonamide,
[41 ] N-[3-(4-methylpiperazin-1 -yl)methyl-1 H-indol-5-yl]-α-toluenesulphonamide,
[42] N-[3-(3-diethylaminopropyl)-1 H-indol-5-yl]naphthalene-2-sulphonamide, [43] N-[3-(3-diethyIaminopropyl)-1H-indol-5-yl]-5-chloro-3-methylbenzo[b]thiophene-2- sulphonamide,
[44] N-{3-[2-(pyrrolidin-1 -yl)ethyl]-1 H-indol-5-yl}-5-chloro-3-methylbenzo[b]thiophene- 2-sulphonamide,
[45] N-{3-[2-(pyrrolidin-1 -yl)ethyl]-1 H-indol-5-yl}naphthalene-1 -sulphonamide,
[46] N-{3-[2-(pyrrolidin-1 -yl)ethyl]-1 H-indol-5-yl}naphthalene-2-sulphonamide,
[47] N-[3-(2-dipropylaminoethyl)-1 H-indol-5-yl]naphthalene-2-sulphonamide,
[48] N-[3-(2-dimethylaminoethyl)-1 H-indol-5-yl]-5-chloronaphthalene-1 -sulphonamide,
[49] N-[3-(2-dimethylaminoethyl)-1 H-indol-5-yl]naphthalene-2-sulphonamide,
[50] N-{3-[2-(morpholin-4-yl)ethyl]-1 H-indol-5-yl}quinoline-8-sulphonamide,
[51 ] N-{3-[2-(morpholin-4-yl)ethyl]-1 H-indol-5-yl}-4-phenylbenzenesulphonamide,
[52] N-[3-(4-methylpiperazin-1 -yl)ethyl-1 - -indol-5-yl]naphthalene-2-sulphonamide and
[53] N-[3-(4-methylpiperazin-1 -yl)ethyl-1 - -indol-5-yl]-5-chloronaphthalene-1 - sulphonamide.
The sulphonamide derivatives of general formula (Ic), wherein R1c, R2c, R3c, nc and Ac have the above defined meaning, may preferably be prepared according to the following methods, wherein R1, R2, R3, n and A are R1c, R2c, R3c, nc and Ac. METHOD A:
At least one compound of general formula (lie),
Figure imgf000191_0001
(He),
wherein A has the meaning as defined above in the general formula (Ic) and X is a suitable leaving group, preferably a halogen atom, more preferably chlorine; is reacted with at least one substituted 5-aminoindol of general formula (lllc)
Figure imgf000191_0002
(lllc)
wherein R-i, R , R3 and n have the meaning as defined above, or a suitably protected derivative thereof, and, if present, the protective groups are removed, in order to obtain the corresponding sulphonamide derivative of general formula (Ic), which may be purified and/or may be isolated by conventional methods known to those skilled in the art.
The reaction between the compounds of general formulas (lie) and (lllc) is usually carried out in the presence of an organic reaction medium, such as an dialkyl ether, particularly diethyl ether, or a cyclic ether, particularly tetrahydrofurane or dioxane, a halogenated organic hydrocarbon, particularly methylene chloride or chloroform, an alcohol, particularly methanol or ethanol, an aprotic dipolar solvent, particularly acetonitrile, pyridine or dimethylformamide, or any other suitable reaction medium. Mixtures of at least two of the above mentioned classes of compounds or of at least two compounds of one class may, of course, also be used. The reaction is preferably carried out in the presence of a suitable base, e.g. an inorganic base such as hydroxides and/or carbonates of alkali metals, or an organic base, particularly triethylamine or pyridine.
The most suitable reaction temperatures range from 0° C to ambient temperature, i.e. approximately 25 °C, and the reaction time is preferably from 5 minutes to 24 hours.
The resulting sulphonamide derivative of general formula (Ic) may be purified and/or isolated according to conventional methods known to those skilled in the art.
Preferably the sulphonamide derivatives of general formula (Ic) can be isolated by evaporating the reaction medium, adding water and eventually adjusting the pH so that it is obtained as a solid that can be isolated by filtration; or it can be extracted by a solvent immiscible with water, such as chloroform, and purified by chromatography or recrystallisation from a suitable solvent.
The compounds of general formula (lie) are commercially available or can be prepared according to standard methods known to those skilled in the art, e.g. by methods analogous to those described in the literature [E.E. Gilbert, Synthesis, 1969, 1, 3]. The compounds of general formula (lllc) may also be prepared according to standard methods known to those skilled in the art, e.g. by methods analogous to those described in the literature [J.E. Macor, R. Post and K. Ryan, Synt Comm., 1993, 23, 1 , 65-72.; J. Guillaume, C. Dumont, J. Laurent and N. Nedelec, Eur. J. Med. Chem., 1987, 22, 33-43; M.L. Saccarello, R. Stradi, Synthesis, 1979, 727]. The respective literature descriptions are incorporated by reference and form part of the disclosure.
METHOD B
The sulphonamide derivatives of general formula (Ic), wherein R1, R2, n and A are as defined above and R3 represents an optionally at least mono-substituted, linear or branched C1-C4 alkyl radical, may also be prepared by alkylation of a corresponding sulphonamide derivative of general formula (Ic), wherein R1, R2, n and A are as defined above and R3 represents a hydrogen atom, with an alkyl halogenide or a dialkyl sulphate.
The alkylation reaction is preferably carried out in the presence of a suitable base, such as hydroxides and/or carbonates of alkali metals, metal hydrides, alkoxides such as sodium methoxide or potassium tert-butoxide, organometallic compounds such as butyl lithium or tert-butyl lithium, in the presence of an organic reaction medium, such as dialkyl ether, particularly diethyl ether, or a cyclic ether, particularly tetrahydrofurane or dioxane, a hydrocarbon, particularly toluene, an alcohol, particularly methanol or ethanol, an aprotic dipolar solvent, particularly acetonitrile, pyridine or dimethylformamide, or any other suitable reaction medium. Mixtures of at least two of the above mentioned classes of compounds and/or of at least two compounds of one class may, of course, also be used.
The most suitable reaction temperatures range from 0° C to the boiling point of the reaction medium, and reaction times preferably range from 1 to 24 hours.
The resulting sulphonamide derivative of general formula (Ic) can preferably be isolated by filtration, concentrating the filtrate at reduced pressure, adding water and eventually adjusting the pH so that it is obtained as a solid that can be isolated by filtration, or it can be extracted with a solvent immiscible in water such as chloroform and purified by chromatography or recrystallisation from a suitable solvent.
METHOD C
By condensation of a compound of general formula (Ic), wherein R-i, R3, and A are as defined above, n is 0 and R2 represents a hydrogen atom, with a suitably substituted 4-piperidone the corresponding compound of general formula (Ic) is obtained, wherein Ri, R3 and A are as defined above, n is 0 and R2 represents a suitably substituted 1 ,2,3,6-tetrahydropyridine-4-yl radical.
The reaction can take place in both an acid and a basic reaction medium, preferably in a suitable solvent, preferably at temperatures ranging from 25 to 150°C.
Suitable basic conditions may be provided by the use of inorganic bases such as sodium or potassium hydroxide, or organic bases such as pyrrolidine or triethylamine in solvents such as methanol or ethanol. Preferably, solutions of sodium methoxide in methanol under reflux are used. Reaction times range from 1 to 48 hours.
Suitable acidic conditions may be provided by the use of hydrochloric acid in ethanol or trifluoroacetic acid in acetic acid at temperatures ranging preferably from 50 to 100 °C and reaction times ranging from 1 to 48 hours.
The resulting sulphonamide derivative of general formula (Ic) can be isolated by dilution in water, eventually adjusting the pH, to obtain a solid that can be isolated by filtration; or it can be extracted with a solvent immiscible in water such as chloroform and purified by chromatography or by recrystallisation from a suitable solvent.
The compounds of general formula (Ic) wherein R-i, R3 and A are as defined above, n is 0 and R2 represents a hydrogen atom, can be prepared according to the method A from a corresponding 5-aminoindol. METHOD D
The compound of general formula (Ic) wherein R-i, R3 and A are as defined above, n is 0 and R2 represents a suitably substituted 4-piperidinyl radical, can be prepared by reducing a compound of general formula (Ic) wherein R-i, R3 and A are as defined above, n is 0 and R2 represents a suitably substituted 1 ,2,3,6-tetrahydropyridin-4-yl radical prepared according to the method C.
Hydrogenation preferably takes place with the aid of a metallic catalyst such as palladium, platinum or rhodium on a suitable support such as carbon, aluminum oxide or barium sulphate, preferably palladium on carbon, with an initial hydrogen pressure of between 1 and 10 atmospheres, preferably between 2 and 5 atmospheres, in a solvent such as methanol or ethanol. The reaction time ranges from 1 hour to 3 days.
The resulting sulphonamide can be isolated by filtering the catalyst and concentrating the filtrate at reduced pressure. The product recovered can be used as is or it can be purified by chromatography or by recrystallisation from a suitable solvent.
METHOD E
The salts, preferably the pharmacologically acceptable salts of compounds with the general formula (Ic) can be prepared by conventional methods known to those skilled in the art, preferably by reaction with a mineral acid, such as hydrochloric, hydrobromic, phosphoric, sulphuric, nitric acids or with organic acids such as citric, maleic, fumaric, tartaric acids or their derivatives, p-toluensulphonic acid, methansulphonic acid, etc., in a suitable solvent such as methanol, ethanol, diethyl ether, ethyl acetate, acetonitrile or acetone and obtained with the usual techniques of precipitation or crystallisation of the corresponding salts.
Preferred physiologically acceptable salts of the sulphonamide derivatives of general formula (Ic) are the additions salts of mineral acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulphuric acid, nitric acid, and of organic acids, such as citric acid, maleic acid, tartaric acid or derivatives thereof, p-toluenesulphonic acid, methansulphonic acid, camphorsulphonic acid, etc.
The solvates, preferably the physiologically acceptable solvates, particularly hydrates, of the sulphonamide derivatives of general formula (Ic) or of the corresponding physiologically acceptable salts may be prepared by conventional methods known to those skilled in the art.
During one of the synthesis sequences described above, or in the preparation of suitable reactands used it may be necessary and/or desirable to protect sensitive or reactive groups in some of the molecules employed. This can be performed by means of conventional protective groups such as 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 can be eliminated in a suitable latter stage by methods known to those skilled in the art. The respective literature descriptions are hereby incorporated by reference and form part of the disclosure.
If the sulphonamide derivatives of general formula (Ic) are obtained in form of a mixture of stereoisomers, particularly enantiomers or diastereomers, said mixtures may be separated by standard procedures known to those skilled in the art, e.g. chromatographic methods or crystallization with chiral reagents.
If one or more of the R2d-R9d moieties are an alkyl radical which is substituted by one or more substituents, unless otherwise defined, each one of the substituents can preferably be chosen from the group consisting of hydroxy, fluorine, chlorine, bromine and trifluoromethyl.
If R1d is a saturated or unsaturated cycloaliphatic radical, optionally containing at least one heteroatom as a ring member, which is substituted by one or more substituents and/or if it comprises a saturated or unsaturated, mono- or bi- cyclic cycloaliphatic ring system, optionally containing at least one heteroatom as a ring member, which is substituted by one or more substituents, unless otherwise defined, each one of the substituents can preferably be chosen from the group consisting of hydroxy, fluorine, chlorine, bromine, linear or branched Ci-Cβ alkyl, linear or branched CrC6 alkoxy, linear or branched C C6 perfluoroalkyl, linear or branched Cι-C6 perfluoroalkoxy and benzyl, preferably from the group consisting of linear or branched CrC6 alkyl and benzyl. The heteroatoms of the cycloaliphatic radical and/or of the mono- or bi- cyclic cycloaliphatic ring can, independently from one another, be chosen preferably from the group consisting of nitrogen, sulfur and oxygen, more preferably nitrogen as an heteroatom.
If R8d and R9d together with the nitrogen atom bridge form a saturated or unsaturated heterocyclic ring, which can contain at least one additional heteroatom as a ring member, which is substituted by one or more substituents and/or condensed with a saturated or unsaturated mono- or bi- cyclic cycloaliphatic ring system, which can contain at least one heteroatom as a ring member, which is substituted by one or more substituents, unless otherwise defined, each one of the substituents can preferably be chosen from the group consisting of hydroxy, fluorine, chlorine, bromine, linear or branched C-ι-C6 alkyl, linear or branched C-ι-C6 alkoxy, linear or branched C Cβ perfluoroalkyl, linear or branched C1-C-6 perfluoroalkoxy and benzyl, preferably from the group consisting of linear or branched Ci-Cβ alkyl and benzyl. If the heterocyclic ring contains one or more additional heteroatoms, and/or if one or both mono- or bi- cyclic rings contain one or more heteroatoms, these heteroatoms can, independently from one another, be preferably chosen from the group consisting of nitrogen, sulfur and oxygen, more preferably nitrogen as heteroatom.
If Ad is a mono or poly-cyclic aromatic ring system, which is substituted by one or more substituents, which can be bonded by means of an alkylene, alkenylene or alkynylene group, which is optionally at least monosubstituted, and/or can contain at least one heteroatom as a ring member, unless otherwise defined, each one of the substituents can be preferably chosen from the group consisting of hydroxy, halogen, linear or branched C-ι-C6 alkyl, linear or branched C Cβ alkoxy, linear or branched Ci- Ce perfluoroalkyl, linear or branched Cι-C6 perfluoroalkoxy, a phenyl radical, optionally at least monosubstituted, and heteroaryl of 5 or 6 members, more preferably from the group consisting of halogen, linear or branched C Cβ alkyl, phenyl optionally at least monosubstituted and heteroaryl of 5 or 6 members, much more preferably from the group consisting of fluorine, chlorine, linear or branched C Cβ alkyl, phenyl radical, optionally at least monosubstituted and heteroaryl of 5 or 6 members. If one or more of the rings of a mono or poly-cyclic aromatic ring system contains one or more heteroatoms, these heteroatoms - like the heteroatoms of a previously mentioned heteroaryl radical of 5 or 6 members - can be preferably chosen from the group consisting of nitrogen, sulfur and oxygen. If the previously mentioned phenyl radical is itself substituted by one or more substituents, each one of the substituents can be preferably chosen from the group consisting of fluorine, chlorine, bromine, linear or branched Ci-Cβ alkyl, linear or branched C Cβ alkoxy, linear or branched C Cβ alkylthio, trifluoromethyl radical, cyano radical and an NR12dR13d radical, wherein R12d and R13d, identical or different, are hydrogen or linear or branched Cι-C6 alkyl.
The substituents for Ad may preferably be selected from the group consisting of hydroxy, halogen, linear or branched CrC6 alkyl, linear or branched Ci-Cβ alkoxy, -O- phenyl, linear or branched Cι-C6 perfluoroalkyl, linear or branched CrC6 perfluoroalkoxy, an optionally at least mono-substituted phenyl radical and 5- or 6- membered heteroaryl, more preferably from the group consisting of halogen, linear or branched C Cβ alkyl, -O-phenyl, an optionally at least mono-substituted phenyl radical and 5- or 6-membered heteroaryl, even more preferably from the group consisting of fluorine, chlorine, -O-phenyl, linear or branched C Cβ alkyl, an optionally at least mono-substituted phenyl radical and 5- or 6-membered heteroaryl. 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 Cι-C6 alkyl, linear or branched CrC6 alkoxy, linear or branched Ci-Ce alkylthio, trifluoromethyl radical, cyano radical and a -NR12dR13d radical, wherein R12d and R13d, identical or different, represent hydrogen or a linear or branched CrC6 alkyl.
If the previously mentioned alkylene, alkenylene or alkynylene group is substituted by one or more substituents, each of the substituents can be preferably chosen from the group consisting of hydroxy, halogen, linear or branched Ci-Ce alkyl, linear or branched C Cβ alkoxy, linear or branched C Cβ perfluoroalkyl, linear or branched Cι-C6 perfluoroalkoxy or a phenyl radical, optionally at least monosubstituted. If said phenyl radical is itself substituted by one or more substituents, each one of the substituents can be preferably chosen from the group consisting of fluorine, chlorine, bromine, linear or branched C C6 alkyl, linear or branched C C6 alkoxy, linear or branched C C6 alkylthio, trifluoromethyl radical, cyano radical and an NR12dR13d radical, wherein R12d and R13d, identical or different, are hydrogen or linear or branched C Cβ alkyl.
Sulfonamide derivatives of general formula (Id) are preferred, wherein R1d is an -NR8dR9d radical or a saturated or unsaturated, optionally at least monosubstituted cycloaliphatic radical of 5 or 6 members, which can optionally contain at least one heteroatom as a ring member, and which can be condensed with a saturated or unsaturated, mono- or bi- cyclic cycloaliphatic ring system, optionally at least monosubstituted, which can optionally contain at least one heteroatom as a ring member, and wherein the ring/rings is/are of 5 or 6 members, preferably an -NR8dR9d radical or a radical chosen from the group consisting of
Figure imgf000199_0001
Figure imgf000199_0002
where, if present, the dotted line is an optional chemical bond, and R10 is hydrogen, a linear or branched CrCβ alkyl radical or a benzyl radical, preferably hydrogen or a C1-C2 alkyl radical, and R2d-R9d, Ad and nd are defined as above.
Sulfonamide derivatives of general formula (Id) are also preferred, wherein R2d, R3d, R5d, R6d and R7d are hydrogen, a linear or branched Cι.C6 alkyl radical, a linear or branched C2-C6 alkenyl radical, or a linear or branched C2-C6 alkynyl radical, preferably hydrogen and R1d, R4d, R8d, R9d, Ad and nd are defined as above. The use of sulfonamide derivatives of general formula (Id) is also preferred, wherein R4d, is hydrogen, a linear or branched CrC6 alkyl radical, optionally at least monosubstituted, preferably hydrogen or a linear or branched CrC6 alkyl radical, more preferably hydrogen or CrC2 alkyl radical and R1d-R3d, R5d-R9d, Ad and nd are defined as above.
Furthermore, sulfonamide derivatives of general formula (Id) are also preferred, wherein R8d and R9d, identical or different, are hydrogen or a linear or branched optionally at least monosubstituted d-Cβ alkyl radical, or
R8d and R9d, together with the nitrogen atom bridge, form a saturated or unsaturated heterocyclic ring of 5 or 6 members, which is optionally at least mono-substituted, which can contain at least one additional heteroatom as a ring member, and/or which can be condensed with a saturated or unsaturated, mono- or bi- cyclic cycloaliphatic ring system, which is optionally at least monosubstituted, which can optionally contain at least one heteroatom as a ring member, and wherein the ring/rings is/are of 5, 6 or 7 members, and R1d-R7d, Ad and nd are defined as above.
Particularly preferred is the use of sulfonamide derivatives of general formula (Id), wherein R8d and R9d, identical or different, are hydrogen or a linear or branched CrC6 alkyl radical, preferably a linear or branched CrCβ alkyl radical, or
R8d and R9d together with the nitrogen atom bridge form a radical chosen from the group consisting of
Figure imgf000200_0001
Figure imgf000200_0002
wherein R11 is hydrogen, a linear or branched CrC6 alkyl radical or a benzyl radical, preferably hydrogen, or a C1-C2 alkyl radical, and R1d-R9d, Ad and nd are defined as above.
Furthermore, sulfonamide derivatives of general formula (Id) are preferred, wherein Ad is a mono or poly-cyclic aromatic ring system, which is optionally at least monosubstituted, wherein the ring/rings is/are of 5 or 6 members and which can be bonded by means of an optionally at least monosubstituted Cι_C6 alkyleen group, an optionally at least monosubstituted C2— Cβ alkenylene group or an optionally at least monosubstituted C2— Cβ alkynylene group, and/or which may can contain at least one heteroatom as a ring member, preferably a mono or poly-cyclic aromatic ring system which is optionally at least monosubstituted, wherein the ring/rings is/are of 5 or 6 members and in which one or more of the rings contain(s) at least one heteroatom or a radical chosen from the group consisting of
Figure imgf000201_0001
in which X, Y and Z are each one independently chosen from a group consisting of hydrogen, fluorine, chlorine, bromine, linear or branched CrCβ alkyl, linear or branched CrCβ alkoxy, linear or branched CrC6 alkylthio, trifluoromethyl radical, cyano radical and an NR12R13 radical, in which R12 and R13, identical or different, are hydrogen or linear or branched CrC6 alkyl,
W is a single chemical bond between the two rings, a CH2, O, S group or an NR14 radical, wherein R14 is hydrogen or linear or branched CrC6 alkyl, and
m is 0, 1 , 2, 3 or 4; and R >1d - DR11d and nd are defined as above.
Furthermore, sulfonamide derivatives of general formula (Id) are preferred, Ad 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 Cι_C6 alkylene group, an optionally at least mono-substituted C2— C6 alkenylene group or an optionally at least mono-substituted C2—C6 alkynylene group and/or wherein the ring(s) may contain at least one heteroatom as a ring member,
preferably Ad 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
Figure imgf000202_0001
Figure imgf000202_0002
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 CrCβ alkyl, linear or branched CrCβ alkoxy, linear or branched C Cβ alkylthio, a trifluoromethyl radical, a cyano radical and a -NR12R13 radical, wherein R12 and R13, identical or different, each represent hydrogen or linear or branched CrC6 alkyl,
W represents a single chemical bond between the two rings, a CH2, O, S group or a NR14 radical,
wherein R14 is hydrogen or a linear or branched CrCβ alkyl,
m is 0, 1 , 2, 3 or 4 and
ml is 1 or 2, preferably 2, and R1d-R9d and nd are defined as above.
Also, particularly preferred are compounds of general formula (Id) given above,
wherein
R1d represents a -NR8dR9d radical,
R2d, R3d, R5d, R6d and R7d each represent hydrogen,
R4d represents hydrogen,
R8d and R9d, identical or different, each represent methyl, ethyl, n-propyl, iso-propyl, more preferably methyl,
and
Ad represents an aryl or heteroaryl radical selected from the group consisting of phenyl, naphthyl, benzo[b]thiophenyl and imidazo[2,1-b]thiazolyl which may be substituted by 1 , 2 or 3 substituents selected from the group consisting of chlorine, methyl, phenyl and -O-phenyl and/or which may be bonded via a C 2 alkylene group, and nd is 2;
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 (Id) may be selected from the group consisting of
[1 ] N-[1 -(2-dimethylaminoethyl)-1 H-indole-4-yl]-5-chloro-3- methylbenzo[b]thiophene-2-sulfonamide,
[2] N-[1 -(2-dimethylaminoethyl)-1 H-indole-4-yl]-naphtalene-2-sulfonamide,
[3] N-[1 -(2-dimethylaminoethyl)-1 H-indole-4-yl]-naphtalene-1 -sulfonamide,
[4] N-[1 -(2-dimethylaminoethyl)-1 H-indole-4-yl]-4-phenylbenzenesulfonamide,
[5] N-[1 -(2-dimethylaminoethyl)-1 H-indole-4-yl]-2-(naphtalene-1 -yl)- ethanesulfonamide,
[6] N-[1 -(2-dimethylaminoethyl)-1 H-indole-4-yl]-4-phenoxybenzenesulfonamide,
[7] N-[1-(2-dimethylaminoethyl)-1 H-indole-4-yl]-3,5- dichlorobenzenesulfonamide and
and their corresponding salts and solvates. Furthermore, the most preferred compounds of general formula (Id) may be selected from the group consisting of
[1] N-[1-(2-dimethylaminoethyl)-1 H-indole-4-yl]-5-chloro-3- methylbenzo[b]thiophene-2-sulfonamide,
[2] N-[1 -(2-dimethylaminoethyl)-1 H-indole-4-yl]-naphtalene-2-sulfonamide,
[3] N-[1 -(2-dimethylaminoethyl)-1 H-indole-4-yl]-naphtalene-1 -sulfonamide,
[4] N-[1 -(2-dimethylaminoethyl)-1 H-indole-4-yl]-4-phenylbenzenesulfonamide,
[5] N-[1 -(2-dimethylaminoethyl)-1 H-indole-4-yl]-2-(naphtalene-1 -yl)- ethanesulfonamide,
[6] N-[1 -(2-dimethylaminoethyl)-1 H-indole-4-yl]-4-phenoxybenzenesulfonamide,
[7] N-[1 -(2-dimethylaminoethyl)-1 H-indole-4-yl]-3,5- dichlorobenzenesulfonamide and
[8] 6-chloro-N-[1-(2-dimethylaminoethyl)-1 H-indol-4-yl]-imidazo[2,1-b]thiazole-5- 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 (Id), particularly the addition salts of mineral acids, such as hydrochloric, hydrobromic, phosphoric, sulfuric, nitric acids, and with organic acids such as citric, maleic, fumaric, tartaric acids or their derivatives, p-toluenesulfonic, methanesulfonic, camphorsulfonic acids, etc.
Below, the residues R1-R7, A and n in the general formulas (lid) and (Hid) are R1d- R7d, Ad and nd. The derivatives of general formula (Id), wherein R1d-R9d, nd and Ad have the previously indicated meaning, may be preferably prepared in a way that:
At least one compound of general Formula (lid),
Figure imgf000206_0001
(lid)
wherein A has the previously mentioned meaning in the general formula (Id), and X is an acceptable leaving group, preferably an halogen atom, more preferably chlorine; reacts with at least one substituted 4-aminoindole of general formula (llld)
Figure imgf000206_0002
(llld)
wherein R1-R7 and nd 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 (Id), which can be purified and/or isolated by means of conventional methods known in the state of the art.
The reaction between the compounds of general Formula (lid) and (llld) is usually carried out in the presence of an organic reaction medium such as dialkyl ether, particularly diethyl ether or a cyclic ether, particularly tetrahydrofuran or dioxane, an halogenated organic hydrocarbon, particularly methylene chloride or chloroform, an alcohol, particularly methanol or ethanol, a dipolar aprotic solvent, particularly 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 can also be used.
The reaction is preferably carried out in the presence of a suitable base, for example, an inorganic base such as alkaline metal hydroxides and carbonates, or in the presence of an organic base, particularly triethylamine or pyridine.
The most suitable reaction temperatures range between 0°C and room temperature, that is, approximately 25°C, and the reaction time is preferably comprised between 5 minutes and 24 hours.
The resulting sulfonamide derivative of general Formula (Id) can be purified and/or isolated according to conventional methods known in the state of the art.
Preferably, the sulfonamide derivatives of general Formula (Id) can be isolated by evaporating the reaction medium, adding water and, if necessary, adjusting the pH so that a solid which can be isolated by filtration is obtained; or it can be extracted with a water immiscible solvent, such as chloroform, and be purified by chromatography or recrystallization of a suitable solvent.
The compounds of general formula (lid) are commercially available, or they can be prepared according to standard methods known in the state of the art, for example by methods similar to those described in the literature [E.E.Gilbert, Synthesis, 1969, 1, 3]. The compounds of general formula (llld) can also be prepared according to standard methods known in the state of the art, for example by methods similar to those described in: [Abou-Gharbia, Magid; Patel, Usha; Tokolics, Joseph; Freed, Meier. European Journal of Medicinal Chemistry (1988), 23(4), 373-7].
The sulfonamide derivatives of general Formula (Id), wherein R1d-R3d, R5d-R9d, nd and Ad have the previously indicated meaning and R4d is an alkyl radical, preferably a linear or branched CrCβ alkyl radical, optionally at least monosubstituted, they can also be prepared by alkylation of a sulfonamide derivative of general Formula (Id), wherein R1d-R3d, R5d-R9d, nd and Ad have the previously indicated meaning, and R4d is an hydrogen atom, with an alkyl halogenide or a dialkyl sulfate. The alkylation reaction is carried out preferably in the presence of a suitable base, such as alkaline metal hydroxides and carbonates, metal hydrides, alkoxides such as sodium metoxide or potassium tert-butoxide, organometallic compounds such as butyllithium or tert-butyllithium, in the presence of an organic reaction medium such as dialkyl ether, particularly diethyl ether, or a cyclic ether, particularly tetrahydrofuran or dioxane, an hydrocarbon, particularly toluene, an alcohol, particularly methanol or ethanol, a dipolar aprotic solvent, particularly 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 can also be used.
The most suitable reaction temperatures range between 0°C and the boiling temperature of the reaction medium, and the reaction times are preferably comprised between 1 and 24 hours.
Preferably, the resulting sulfonamide derivative of general Formula (Id) can be isolated by filtration, concentrating the filtrate under reduced pressure, adding water and, if necessary, adjusting the pH so that a solid which can be isolated by filtration is obtained; or it can be extracted with a water immiscible solvent, such as chloroform, and be purified by chromatography or recrystallization of a suitable solvent.
The pharmaceutically acceptable salts of the compounds of general formula (Id), can be prepared by means of conventional methods known in the state of the art, preferably by reaction with a mineral acid, such as hydrochloric, hydrobromic, phosphoric, sulfuric, nitric acids, or with organic acids, such as citric, maleic, fumaric, tartaric acids, or their derivatives, p-toluenesulfonic, methanesulfonic, camphorsulfonic acids, etc., in a suitable solvent, such as methanol, ethanol, diethyl ether, ethyl acetate, acetonitrile or acetone, being obtained with the usual techniques for the precipitation or crystallization of the corresponding salts.
The preferred physiologically acceptable salts of the sulfonamide derivatives of general formula (Id) are the addition salts of mineral acids, such as hydrochloric, hydrobromic, phosphoric, sulfuric, nitric acids, and of organic acids, such as citric, maleic, fumaric, tartaric acids, or their derivatives, p-toluenesulfonic, methanesulfonic, camphorsulfonic acids, etc.
The physiologically acceptable solvates, particularly hydrates, of the sulfonamide derivatives of general formula (Id) or of the corresponding, physiologically acceptable salts, can be prepared by methods known in the state of the 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 can be carried out by means of the use of conventional protective groups such as 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 can be removed in the suitable subsequent stage by methods known in the state of the art. The respective literature descriptions are incorporated by reference and form part of the disclosure.
If the sulfonamide derivatives of general formula (Id) are obtained in the form of a mixture of stereoisomers, particularly enantiomers or diastereomers, said mixtures can be separated by means of standard processes known in the state of the art, for example chromatographic methods or crystallization with chiral agents.
If one or more of the R2e-R9e moieties are an alkyl radical which is substituted by one or more substituents, unless otherwise defined, each one of the substituents can preferably be chosen from the group consisting of hydroxy, fluorine, chlorine, bromine and trifluoromethyl.
If R1e is a saturated or unsaturated cycloaliphatic radical, which is optionally containing at least one heteroatom as a ring member, which is substituted by one or more substituents and/or if it comprises a saturated or unsaturated, mono- or bicyclic cycloaliphatic ring system, which is optionally containing at least one heteroatom as a ring member, which is substituted by one or more substituents, unless otherwise defined, each one of the substituents can preferably be chosen from the group consisting of hydroxy, fluorine, chlorine, bromine, linear or branched CrCβ alkyl, linear or branched CrC6 alkoxy, linear or branched CrC6 perfluoroalkyl, linear or branched CrC6 perfluoroalkoxy and benzyl, preferably from the group consisting of linear or branched CrC6 alkyl and benzyl. The heteroatoms of the cycloaliphatic radical and/or of the mono- or bi- cyclic cycloaliphatic ring can, independently from one another, be chosen preferably from the group consisting of nitrogen, sulfur and oxygen, more preferably nitrogen as an heteroatom.
If R8e and R9e together with the nitrogen atom bridge form a saturated or unsaturated heterocyclic ring, which can contain at least one additional heteroatom as a ring member, which is substituted by one or more substituents and/or condensed with a saturated or unsaturated mono- or bi- cyclic cycloaliphatic ring system, which can contain at least one heteroatom as a ring member, which is substituted by one or more substituents, unless otherwise defined, each one of the substituents can preferably be chosen from the group consisting of hydroxy, fluorine, chlorine, bromine, linear or branched CrC6 alkyl, linear or branched C Cβ alkoxy, linear or branched d-Cβ perfluoroalkyl, linear or branched CrCβ perfluoroalkoxy and benzyl, more preferably from the group consisting of linear or branched CrCβ alkyl and benzyl. If the heterocyclic ring contains one or more additional heteroatoms, and/or if one or both mono- or bi- cyclic rings contain one or more heteroatoms, these heteroatoms can, independently from one another, be preferably chosen from the group consisting of nitrogen, sulfur and oxygen, more preferably nitrogen as heteroatom.
If Ae is a mono or poly-cyclic aromatic ring system, which is substituted by one or more substituents, and which can be bonded by means of an optionally at least monosubstituted alkylene, alkenylene or alkynylene group, and/or can contain at least one heteroatom as a ring member, unless otherwise defined, each one of the substituents can be preferably chosen from the group consisting of hydroxy, halogen, linear or branched CrCβ alkyl, linear or branched CrC6 alkoxy, linear or branched Ci- Ce perfluoroalkyl, linear or branched CrCe perfluoroalkoxy, a phenyl radical, optionally at least monosubstituted, and heteroaryl of 5 or 6 members, more preferably from the group consisting of halogen, linear or branched CrCβ alkyl, phenyl optionally at least monosubstituted and heteroaryl of 5 or 6 members, much more preferably from the group consisting of fluorine, chlorine, linear or branched d- C6 alkyl, phenyl radical, optionally at least monosubstituted and heteroaryl of 5 or 6 members. If one or more of the rings of a mono or poly-cyclic aromatic ring system contains one or more heteroatoms, these heteroatoms - like the heteroatoms of a previously mentioned heteroaryl radical of 5 or 6 members - can be preferably chosen from the group consisting of nitrogen, sulfur and oxygen. If the previously mentioned phenyl radical is itself substituted by one or more substituents, each one of the substituents can be preferably chosen from the group consisting of fluorine, chlorine, bromine, linear or branched Ci-Ce alkyl, linear or branched Ci-Cβ alkoxy, linear or branched CrCβ alkylthio, trifluoromethyl radical, cyano radical and an NR i2e R i3e radical wherein R12e and R13e, identical or different, are hydrogen or linear or branched CrCβ alkyl.
Preferably the substituents for Ae may also be selected from the group consisting of nitro, -O-phenyl, -O-C1-6 alkyl, -C(=0)-Cι.6 alkyl, hydroxy, halogen, linear or branched CrCβ alkyl, linear or branched CrCβ alkoxy, linear or branched CrCβ perfluoroalkyl, linear or branched d-C6 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(=0)-Cι-6 alkyl, linear or branched CrC6 alkoxy, halogen, linear or branched Ci-Ce 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-CH3, -C(=0)-CH3, fluorine, chlorine, bromine, linear or branched CrC6 alkyl, an optionally at least mono-substituted phenyl radical and 5- or 6-membered heteroaryl. 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 Ci-Cβ alkyl, linear or branched CrCβ alkoxy, linear or branched Ci-Cβ alkylthio, trifluoromethyl radical, cyano radical and a -NR 2eR13e radical, wherein R12e and R13e, identical or different, represent hydrogen or a linear or branched d-C6 alkyl.
If the previously mentioned alkylene, alkenylene or alkynylene group is substituted by one or more substituents, each of the substituents can be preferably chosen from the group consisting of hydroxy, halogen, linear or branched CrC6 alkyl, linear or branched Ci-Cβ alkoxy, linear or branched CrC6 perfluoroalkyl, linear or branched CrC6 perfluoroalkoxy or a phenyl radical, optionally at least monosubstituted. If said phenyl radical is itself substituted by one or more substituents, each one of the substituents can be preferably chosen from the group consisting of fluorine, chlorine, bromine, linear or branched d-Cβ alkyl, linear or branched CrCβ alkoxy, linear or branched CrC6 alkylthio, trifluoromethyl radical, cyano radical and an NR12eR13e radical, wherein R12e and R13e, identical or different, are hydrogen or linear or branched CrC6 alkyl.
Sulfonamide derivatives of general formula (Ie) are preferred, wherein R1e is an -NR8eR9e radical or a saturated or unsaturated cycloaliphatic radical of 5 or 6 members, which is optionally at least monosubstituted, which can optionally contain at least one heteroatom as a ring member, which can be condensed with a saturated or unsaturated, mono- or bi- cyclic cycloaliphatic ring system, which is optionally at least monosubstituted, which can optionally contain at least one heteroatom as a ring member and wherein the ring/rings is/are of 5 or 6 members, preferably an -NR8eR9e radical or a radical chosen from the group consisting of
Figure imgf000212_0001
Figure imgf000212_0002
where, if present, the dotted line is an optional chemical bond, and R10 is hydrogen, a linear or branched CrCe alkyl radical or a benzyl radical, preferably hydrogen or a Cι-C2 alkyl radical, and R2e-R9e, Ae and ne are defined as above.
Sulfonamide derivatives of general formula (Ie) are also preferred, wherein R2e, R3e, R4e, R6e and R7e, are hydrogen, a linear or branched C2-C6 alkyl radical, a linear or branched Ci-Cβ alkenyl radical, or a linear or branched C2.Ce alkynyl radical, preferably hydrogen and R1e, R5e, R8e, R9e, Ae and ne are defined as above. The use of sulfonamide derivatives of general formula (Ie) is also preferred, wherein R5e, is hydrogen or a linear or branched Ci-Ce alkyl radical, optionally at least monosubstituted, preferably hydrogen or a linear or branched CrC6 alkyl radical, more preferably hydrogen or an C -C2 alkyl radical and R1e-R4e, R6e-R9e, Ae and ne are defined as above.
Furthermore, the use of sulfonamide derivatives of general formula (Ie) is also preferred, wherein R8e and R9e, identical or different, are hydrogen or a linear or branched CrCβ alkyl radical, optionally at least monosubstituted, or
R8e and R9e, together with the nitrogen atom bridge, form a saturated or unsaturated heterocyclic ring of 5 or 6 members, which is optionally at least monosubstituted, which can contain at least one additional heteroatom as a ring member, and/or can be condensed with a saturated or unsaturated, mono- or bi- cyclic cycloaliphatic ring system, which is optionally at least monosubstituted, which can optionally contain at least one heteroatom as a ring member, and wherein the ring/rings is/are of 5, 6 or 7 members, and R e-R7e, Ae and ne are defined as above.
Particularly preferred is the use of sulfonamide derivatives of general formula (Ie), wherein R8e and R9e, identical or different, are hydrogen or a linear or branched d-Cβ alkyl radical, preferably a linear or branched CrC6 alkyl radical, or
R8e and R9e together with the nitrogen atom bridge form a radical chosen from the group consisting of
Figure imgf000213_0001
Figure imgf000213_0002
wherein R11, if it is present, is hydrogen, a linear or branched Ci-Cβ alkyl radical or a benzyl radical, preferably hydrogen, or a C1-C-2 alkyl radical, and R1e-R9e, Ae and ne are defined as above.
Furthermore, sulfonamide derivatives of general formula (Ie) are preferred, wherein Ae is a mono or poly-cyclic aromatic ring system, which is optionally at least monosubstituted, wherein the ring/rings is/are of 5 or 6 members, which can be bonded by means of an optionally at least mono-substituted d_C6 alkylene group, an optionally at least monosubstituted C2— C6 alkenylene group, or an optionally at least monosubstituted C2— C6 alkynylene group, and/or can contain at least one heteroatom as a ring member, preferably a mono or poly-cyclic aromatic ring system which is optionally at least monosubstituted, wherein the ring/rings is/are of 5 or 6 members and in which one or more of the rings contain(s) at least one heteroatom or a radical chosen from the group consisting of
Figure imgf000214_0001
in which X, Y and Z are each one independently chosen from a group consisting of hydrogen, fluorine, chlorine, bromine, linear or branched -Cβ alkyl, linear or branched Ci-Ce alkoxy, linear or branched CrCβ alkylthio, trifluoromethyl radical, cyano radical and an NR12R13 radical, in which R 2 and R13, identical or different, are hydrogen or linear or branched C Cβ alkyl,
W is a single chemical bond between the two rings, a CH2, O, S group or an NR 14 radical, wherein R s14 is hydrogen or linear or branched CrC6 alkyl, and
m is O, 1 , 2, 3 or 4; and R1e-R11e and ne are defined as above.
Furthermore, sulfonamide derivatives of general formula (Ie) are preferred, wherein AΘ 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 Cι_C6 alkylene group, an optionally at least mono-substituted C2— Cβ alkenylene group or an optionally at least mono-substituted C2— C6 alkynylene group and/or wherein the ring(s) may contain at least one heteroatom as a ring member,
preferably Ae 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
Figure imgf000215_0001
Figure imgf000215_0002
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 CrC6 alkyl, linear or branched Ci-Ce alkoxy, linear or branched CrCβ alkylthio, a trifluoromethyl radical, a cyano radical and a -NR12R13 radical,
wherein R12 and R13, identical or different, each represent hydrogen or linear or branched C Cβ alkyl,
W represents a single chemical bond between the two rings, a CH2, O, S group or a NR14 radical,
wherein R14 is hydrogen or a linear or branched CrCβ alkyl,
m is 0, 1 , 2, 3 or 4 and
ml is 1 or 2, preferably 2, and R1e-R11e and ne are defined as above.
Also preferred are compounds of general formula (Ie),
wherein
R1e represents a -NR8eR9e radical,
R2e represents hydrogen or an alkyl radical selected from the group consisting of methyl, ethyl, n-propyl and iso-propyl, more preferably hydrogen or methyl,
R3e, R4e, R6e and R7e each represent hydrogen,
R5e represents hydrogen,
R8e and R9e , identical or different, each represent methyl, ethyl, n-propyl or isopropyl, more preferably methyl or ethyl,
or R8e and R9e together with the bridging nitrogen form a 5- or 6-membered heterocyclic ring, more preferably form pyrrolidine or piperidine,
Ae 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(=0)-CH3, -0-CH3 and -O-phenyl and/or which may be bonded via a C 2 alkylene group or a C2 alkenylene group,
and
ne 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 (Ie) may be selected from the group consisting of
[1] N-[1-(2-dimethylaminoethyl)-1 H-indole-5-yl]-5-chloro-3- methylbenzo[b]thiophene-2-sulfonamide,
[2] N-[1 -(2-dimethylaminoethyl)-1 H-indole-5-yl]-naphthalene-2-sulfonamide,
[3] N-[1 -(2-dimethylaminoethyl)-1 H-indole-5-yl]-naphthalene-1 -sulfonamide,
[4] N-[1 -(2-dimethylaminoethyl)-1 H-indole-5-yl]-5-chloronaphthalene-1 - sulfonamide, [5] N-[1 -(2-dimethylaminoethyl)-1 H-indole-5-yl]-benzenesulfonamide,
[6] N-[1-(2-dimethylaminoethyl)-1 H-indole-5-yl]-quinoline-8- sulfonamide,
[7] N-[1 -(2-dimethylaminoethyl)-1 H-indole-5-yl]-4-phenoxybenzenesulfonamide,
[8] N-[1 -(2-dimethylaminoethyl)-1 H-indole-5-yl]-4-methylbenzenesulfonamide,
[9] N-[1 -(2-dimethylaminoethyl)-1 H-indole-5-yl]-5-chlorothiophene-2-sulfonamide,
[10] N-[1-(2-dimethylaminoethyl)-1 H-indole-5-yl]-benzo[1 ,2,5]thiadiazole-4- sulfonamide,
[11] N-[1-(2-dimethylaminoethyl)-1 H-indole-5-yl]-6-chloroimidazo[2,1-b]thiazole-5- sulfonamide,
[12] N-[1 -(2-dimethylaminoethyl)-1 H-indole-5-yl]-3,5-dichlorobenzenesulfonamide,
[13] N-[1 -(2-dimethylaminoethyl)-1 H-indole-5-yl]-3-bromobenzenesulfonamide,
[14] N-[1 -(2-dimethylaminoethyl)-1 H-indole-5-yl]-3-nitrobenzenesulfonamide,
[15] N-[1 -(2-dimethylaminoethyl)-1 H-indole-5-yl]-1 -phenylmethanesulfonam.de,
[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] frans-N-[1 -(2-dimethylaminoethyl)-1 H-indole-5-yl]-2-phenylethenesulfonamide, [20] N-[1 -(2-dimethylaminoethyl)-1 H-indole-5-yl]-4,5-dichlorothiophene-2- sulfonamide,
[21] N-[1-(2-dimethylaminoethyl)-1 H-indole-5-yl]-4-acetylbenzenesulfonamide,
[22] N-[1 -(2-dimethylaminoethyl)-1 H-indole-5-yl]-4-bromobenzenesulfonamide,
[23] N-[1 -(2-dimethylaminoethyl)-1 H-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)-1 H-indole-5-yl]-4-nitrobenzenesulfonamide,
[26] N-[1 -(2-dimethylaminoethyl)-1 H-indole-5-yl]-4-fluorobenzenesulfonamide,
[27] N-[1-(2-diethylaminoethyl)-1 H-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,
The most preferred compounds of general formula (Ie) may also be selected from the group consisting of
[1 ] N-[1 -(2-dimethylaminoethyl)-1 H-indole-5-yl]-5-chloro-3- methylbenzo[b]thiophene-2-sulfonamide,
[2] N-[1 -(2-dimethylaminoethyl)-1 H-indole-5-yl]-naphthalene-2-sulfonamide,
[3] N-[1 -(2-dimethylaminoethyl)-1 H-indole-5-yl]-naphthalene-1 -sulfonamide,
[4] N-[1 -(2-dimethylaminoethyl)-1 H-indole-5-yl]-5-chloronaphthalene-1 - sulfonamide, [5] N-[1-(2-dimethylaminoethyl •1 H-indole-5-yl]-benzenesulfonamide,
[6] N-[1-(2-dimethylaminoethyl 1 H-indole-5-yl]-quinoline-8- sulfonamide,
[7] N-[1-(2-dimethylaminoethyl •1 H-indole-5-yl]-4-phenoxybenzenesulfonamide,
[8] N-[1-(2-dimethylaminoethyl 1H-indole-5-yl]-4-methylbenzenesulfonamide,
[9] N-[1-(2-dimethylaminoethyl ■1 H-indole-5-yl]-5-chlorothiophene-2-sulfonamide,
[10] N-[1-(2-dimethylaminoethyl 1 H-indole-5-yl]-benzo[1 ,2,5]thiadiazole-4- sulfonamide,
[11 ] N-[1 -(2-dimethylaminoethyl ■1 H-indole-5-yl]-6-chloroimidazo[2,1-b]thiazole-5- sulfonamide,
[12] N-[1 -(2-dimethylaminoethyl ■1 H-indole-5-yl]-3,5-dichlorobenzenesulfonamide,
[13] N-[1 -(2-dimethylaminoethyl ι-1 H-indole-5-yl]-3-bromobenzenesulfonamide,
[14] N-[1 -(2-dimethylaminoethyl ■1 H-indole-5-yl]-3-nitrobenzenesulfonamide,
[15] N-[1 -(2-dimethylaminoethyl)-1 H-indole-5-yl]-1 -phenylmethanesulfonamide,
[16] N-[1 -(2-pyrrolidine-1 -yl-ethyl)-1 H-indole-5-yl]-naphthalene-2-sulfonamide,
[17] N-[1 -(2-pyrrolidine-1 -yl-ethyl)-1 H-indole-5-yl]-naphthalene-1 -sulfonamide,
[18] N-[1 -(2-pyrrolidine-1 -yl-ethyl)-1 H-indole-5-yl]- 5-chloro-3- methylbenzo[b]thiophene-2-sulfonamide,
[19] frat?s-N-[1 -(2-dimethylaminoethyl)-1 H-indole-5-yl]-2-phenylethenesulfonamide, [20] N-[1 -(2-dimethylaminoethyl)-1 H-indole-5-yl]-4,5-dichlorothiophene-2- sulfonamide,
[21] N-[1 -(2-dimethylaminoethyl)-1 H-indole-5-yl]-4-acetylbenzenesulfonamide,
[22] N-[1 -(2-dimethylaminoethyl)-1 H-indole-5-yl]-4-bromobenzenesulfonamide,
[23] N-[1 -(2-dimethylaminoethyl)-1 H-indole-5-yl]-4-methoxybenzenesulfonamide,
[24] N-[3-(2-diethylaminoethyl)-1 H-indole-5-yl]-5-chloro-3-methylbenzo[b]thiophene- 2-sulfonamide,
[25] N-[1 -(2-dimethylaminoethyl)-1 H-indole-5-yl]-4-nitrobenzenesulfonamide,
[26] N-[1 -(2-dimethylaminoethyl)-1 H-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)-1 H-indole-5-yl]- ]-6-chloroimidazo[2,1-b]thiazole- 5-sulfonamide,
[29] N-(1 -(2-(diethylamino)ethyl)-1 H-indol-5-yl)-naphthalene-2-sulfonamide,
[30] N-(1 -(2-(diethylamino)ethyl)-1 H-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-1 H-indol-5-yl)-3- methylbenzo[b]thiophene-2-sulfonamide,
[33] N-(1 -(2-(dimethylamino)ethyl)-2-methyl-1 H-indol-5-yl)-naphthalene-2- sulfonamide, [34] N-(1 -(2-(dimethylamino)ethyl)-2-methyl-1 H-indol-5-yl)-naphthalene-1 - sulfonamide,
[35] 6-chloro-N-(1-(2-(dimethylamino)ethyl)-2-methyl-1 H-indol-5-yl)imidazo[2,1- b]thiazole-5-sulfonamide,
[36] N-(1 -(2-(dimethylamino)ethyl)-2-methyl-1 H-indol-5-yl)-4- phenylbenzenesulfonamide,
[37] N-(1-(2-dimethylamino)ethyl)-2-methyl-1 H-indol-5-yl)-2-(naphth-1-yl)- ethanesulfonamide,
[38] N-(1 -(2-(dimethylamino)ethyl)-2-methyl-1 H-indol-5-yl)-4-phenoxy- benzenesulfonamide,
[39] 3,5-dichloro-N-(1-(2-(dimethylamino)ethyl)-2-methyl-1 H-indol-5-yl)- benzenesulfonamide,
[40] N-(1 -(2-(dimethylamino)ethyl)-2-methyl-1 H-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)-1 H-indol-5-yl)benzo[b]thiophene-3-sulfonamide,
[43] 5-chloro-3-methyl-N-(1-(3-(piperidin-1-yl)propyl)-1 H-indol-5- yl)benzo[b]thiophene-2-sulfonamide,
[44] N-(1 -(3-(piperidin-1 -yl)propyl)-1 H-indol-5-yl)naphthalene-2-sulfonamide,
[45] N-(1 -(3-(piperidin-1 -yl)propyl)-1 H-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)-1 H-indol-5-yl)benzenesulfonamide,
[48] 2-(naphth-1-yl)-N-(1-(3-(piperidin-1-yl)propyl)-1 H-indol-5- yl)ethanesulfonamide,
[49] 4-phenoxy-N-(1 -(3-(piperidin-1 -yl)propyl)-1 H-indol-5-yl)benzenesulfonamide,
[50] 3,5-dichloro-N-(1-(3-(piperidin-1-yl)propyl)-1 H-indol-5- yl)benzenesulfonylamide,
[51] 4,5-dichloro-N-(1-(3-(piperidin-1-yl)propyl)-1 H-indol-5-yl)thiophene-2- sulfonamide and
[52] 5-chloro-N-(1 -(3-(piperidin-1 -yl)propyl)-1 H-indol-5-yl)naphthalene-1 - sulfonamide,
and their corresponding salts and solvates.
The present invention likewise refers to the physiologically acceptable salts of the compounds of general formula (Ie), particularly the addition salts of mineral acids, such as hydrochloric, hydrobromic, phosphoric, sulfuric, nitric acids, and with organic acids such as citric, maleic, fumaric, tartaric acids or their derivatives, p- toluenesulfonic, methanesulfonic, camphorsulfonic acids, etc.
Below, the residues R1-R7, A and n in the general formulas (lie) to (Ve) are R1e-R7e, Ae and ne.
The derivatives of general formula (Ie), wherein R1e-R9e, ne and Ae have the previously indicated meaning, may be preferably prepared in a way that: At least one compound of general Formula (lie),
Figure imgf000224_0001
(lie)
wherein A has the previously mentioned meaning in the general formula (Ie), 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 (I lie)
Figure imgf000224_0002
(llle) wherein R1-R7 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 (Ie), which can be purified and/or isolated by means of conventional methods known in the state of the art.
The reaction between the compounds of general Formula (lie) and (llle) is usually carried out in the presence of an organic reaction medium such as dialkyl ether, particularly diethyl ether or a cyclic ether, particularly tetrahydrofuran or dioxane, an halogenated organic hydrocarbon, particularly methylene chloride or chloroform, an alcohol, particularly methanol or ethanol, a dipolar aprotic solvent, particularly 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 can also be used. The reaction is preferably carried out in the presence of a suitable base, for example, an inorganic base such as alkaline metal hydroxides and carbonates, or in the presence of an organic base, particularly triethylamine, N-ethyldiisopropylamine or pyridine.
The most suitable reaction temperatures range between 0°C and room temperature, that is, approximately 25°C, and the reaction time is preferably comprised between 5 minutes and 24 hours.
The resulting sulfonamide derivative of general Formula (Ie) can be purified and/or isolated according to conventional methods known in the state of the art.
Preferably, the sulfonamide derivatives of general Formula (Ie) can be isolated by evaporating the reaction medium, adding water and, if necessary, adjusting the pH so that a solid which can be isolated by filtration is obtained; or it can be extracted with a water immiscible solvent, such as chloroform, and be purified by chromatography or recrystallization of a suitable solvent.
The compounds of general formula (lie) are commercially available, or they can be prepared according to standard methods known in the state of the art, for example by methods similar to those described in the literature [E.E.Gilbert, Synthesis, 1969, 1 , 3]. The compounds of general formula (llle) can also be prepared according to standard methods known in the state of the 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 relate 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 (IVe) by methods known in the 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.; BACCANARI, 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,
Figure imgf000226_0001
(IVe)
wherein R1-R7 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 (llle), which can be purified and/or isolated by means of conventional methods known in the state of the art.
The compounds of general formula (IVe) can also be prepared according to standard methods known in the state of the 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; Broil, Madeleine. Indole derivatives. Ger. Offen. (1977), DE 2727047 19771229
One of them consists in the alkylation of nitro derivatives of general formula (Ve) 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
Figure imgf000227_0001
(Ve)
wherein R2-R7 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 (llle), which can be purified and/or isolated by means of conventional methods known in the state of the art.
The compounds of general formula (Ve) are commercially available or can also be prepared according to standard methods known in the state of the 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, 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 Incl 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.
The sulfonamide derivatives of general Formula (Ie), wherein R1e-R4e, R6e-R7e, Ae, ne and Ae have the previously indicated meaning and R5e is an alkyl radical, preferably a linear or branched CrC6 alkyl radical, optionally at least monosubstituted, they can also be prepared by alkylation of a sulfonamide derivative of general Formula (Ie), wherein R1e-R4e, R6e-R7e, ne and Ae have the previously indicated meaning, and R5e is an hydrogen atom, with an alkyl halogenide or dialkyl sulfate. The alkylation reaction is carried out preferably in the presence of a suitable base, such as alkaline metal hydroxides and carbonates, metal hydrides, alkoxides such as sodium metoxide or potassium tert-butoxide, organometallic compounds such as butyllithium or tert-butyllithium, in the presence of an organic reaction medium such as dialkyl ether, particularly diethyl ether, or a cyclic ether, particularly tetrahydrofuran or dioxane, an hydrocarbon, particularly toluene, an alcohol, particularly methanol or ethanol, a dipolar aprotic solvent, particularly 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 can also be used.
The most suitable reaction temperatures range between 0°C and the boiling temperature of the reaction medium, and the reaction times are preferably comprised between 1 and 24 hours.
Preferably, the resulting sulfonamide derivative of general Formula (Ie) can be isolated by filtration, concentrating the filtrate under reduced pressure, adding water and, if necessary, adjusting the pH so that a solid which can be isolated by filtration is obtained; or it can be extracted with a water immiscible solvent, such as chloroform, and be purified by chromatography or recrystallization of a suitable solvent.
The pharmaceutically acceptable salts of the compounds of general formula (Ie), can be prepared by means of conventional methods known in the state of the art, preferably by reaction with a mineral acid, such as hydrochloric, hydrobromic, phosphoric, sulfuric, nitric acids, or with organic acids, such as citric, maleic, fumaric, tartaric acids, or their derivatives, p-toluenesulfonic, methanesulfonic, camphorsulfonic acids, etc., in a suitable solvent, such as methanol, ethanol, diethyl ether, ethyl acetate, acetonitrile or acetone, being obtained with the usual techniques for the precipitation or crystallization of the corresponding salts.
The preferred physiologically acceptable salts of the sulfonamide derivatives of general formula (Ie) are the addition salts of mineral acids, such as hydrochloric, hydrobromic, phosphoric, sulfuric, nitric acids, and of organic acids, such as citric, maleic, fumaric, tartaric acids, or their derivatives, p-toluenesulfonic, methanesulfonic, camphorsulfonic acids, etc.
The physiologically acceptable solvates, particularly hydrates, of the sulfonamide derivatives of general formula (Ie) or of the corresponding physiologically acceptable salts, can be prepared by methods known in the state of the 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 can be carried out by means of the use of conventional protective groups such as 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 can be removed in the suitable subsequent stage by methods known in the state of the art. The respective literature descriptions are incorporated by reference and form part of the disclosure.
If the sulfonamide derivatives of general formula (Ie) are obtained in the form of a mixture of stereoisomers, particularly enantiomers or diastereomers, said mixtures can be separated by means of standard processes known in the state of the art, for example chromatographic methods or crystallization with chiral agents.
If one or more of the residues R2f-R9f reprsents an alkyl radical, which is substituted by one or more substituents, unless otherwise defined, each one of the substituents can preferably be chosen from the group consisting of hydroxy, fluorine, chlorine, bromine and trifluoromethyl.
If R1f is a saturated or unsaturated cycloaliphatic radical, which is optionally containing at least one heteroatom as a ring member, which is substituted by one or more substituents and/or if it comprises a saturated or unsaturated, mono- or bicyclic cycloaliphatic ring system, which is optionally containing at least one heteroatom as a ring member, which is substituted by one or more substituents, unless otherwise defined, each one of the substituents can preferably be chosen from the group consisting of hydroxy, fluorine, chlorine, bromine, linear or branched CrCβ alkyl, linear or branched Ci-Cβ alkoxy, linear or branched CrCβ perfluoroalkyl, linear or branched CrC6 perfluoroalkoxy and benzyl, preferably from the group consisting of linear or branched Ci-Cβ alkyl and benzyl. The heteroatoms of the cycloaliphatic radical and/or of the mono- or bi- cyclic cycloaliphatic ring can, independently from one another, be chosen preferably from the group consisting of nitrogen, sulfur and oxygen, more preferably nitrogen as an heteroatom.
If R8f and R9f together with the nitrogen atom bridge form a saturated or unsaturated heterocyclic ring, which can contain at least one additional heteroatom as a ring member, which is substituted by one or more substituents and/or condensed with a saturated or unsaturated mono- or bi- cyclic cycloaliphatic ring system, which can contain at least one heteroatom as a ring member, which is substituted by one or more substituents, unless otherwise defined, each one of the substituents can preferably be chosen from the group consisting of hydroxy, fluorine, chlorine, bromine, linear or branched CrCβ alkyl, linear or branched CrC6 alkoxy, linear or branched CrCβ perfluoroalkyl, linear or branched CrCβ perfluoroalkoxy and benzyl, preferably from the group consisting of linear or branched CrCβ alkyl and benzyl. If the heterocyclic ring contains one or more additional heteroatoms, and/or if one or both mono- or bi- cyclic rings contain one or more heteroatoms, these heteroatoms can, independently from one another, be preferably chosen from the group consisting of nitrogen, sulfur and oxygen, more preferably nitrogen as heteroatom.
If Af is a mono or poly-cyclic aromatic ring system, substituted by one or more substituents, and which can be bonded by means of an optionally at least monosubstituted alkylene, alkenylene or alkynylene, and/or can contain at least one heteroatom as a ring member, unless otherwise defined, each one of the substituents can be preferably chosen from the group consisting of hydroxy, halogen, linear or branched CrC6 alkyl, linear or branched Ci-Ce alkoxy, linear or branched CrCβ perfluoroalkyl, linear or branched CrCβ perfluoroalkoxy, a phenyl radical, optionally at least monosubstituted, and heteroaryl of 5 or 6 members, preferably from the group consisting of halogen, linear or branched Ci-Ce alkyl, phenyl optionally at least monosubstituted and heteroaryl of 5 or 6 members, more preferably from the group consisting of fluorine, chlorine, linear or branched CrCβ alkyl, phenyl radical, optionally at least monosubstituted and heteroaryl of 5 or 6 members. If one or more of the rings of a mono or poly-cyclic aromatic ring system contains one or more heteroatoms, these heteroatoms - like the heteroatoms of a previously mentioned heteroaryl radical of 5 or 6 members - can be preferably chosen from the group consisting of nitrogen, sulfur and oxygen. If the previously mentioned phenyl radical is itself substituted by one or more substituents, each one of the substituents can be preferably chosen from the group consisting of fluorine, chlorine, bromine, linear or branched CrC6 alkyl, linear or branched CrC6 alkoxy, linear or branched CrC6 alkylthio, trifluoromethyl radical, cyano radical and an NR12fR13f radical, wherein R12f and R13f, identical or different, are hydrogen or linear or branched CrCβ alkyl.
Preferably the substituents for Af may also be selected from the group consisting of hydroxy, halogen, linear or branched -Cβ alkyl, linear or branched Ci-Cβ alkoxy, -O- phenyl, linear or branched d-Cβ perfluoroalkyl, linear or branched d-Cβ perfluoroalkoxy, an optionally at least mono-substituted phenyl and 5- to 6-membered heteroaryl, more preferably from the group consisting of halogen, linear or branched Cι-C6 alkyl, -O-phenyl, optionally at least mono-substituted phenyl and 5- to 6- membered heteroaryl, even more preferably from the group consisting of fluorine, chlorine, -O-phenyl, linear or branched -Cβ alkyl, optionally at least mono- substituted phenyl and 5- to 6-membered heteroaryl. 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 -Ce alkyl, linear or branched CrC6 alkoxy, linear or branched Ci-Ce alkylthio, trifluoromethyl radical, cyano radical and a -NR12fR13f radical, wherein R12f and R13f, identical or different, each represent hydrogen or linear or branched CrCβ alkyl.
If the previously mentioned alkylene, alkenylene or alkynylene group is substituted by one or more substituents, each of the substituents can be preferably chosen from the group consisting of hydroxy, halogen, linear or branched CrCβ alkyl, linear or branched CrC6 alkoxy, linear or branched CrC6 perfluoroalkyl, linear or branched d-Cβ perfluoroalkoxy or a phenyl radical, optionally at least monosubstituted. If said phenyl radical is itself substituted by one or more substituents, each one of the substituents can be preferably chosen from the group consisting of fluorine, chlorine, bromine, linear or branched CrC6 alkyl, linear or branched Ci-Cβ alkoxy, linear or branched CrCβ alkylthio, trifluoromethyl radical, cyano radical and an NR12fR13f radical, wherein R12f and R13f, identical or different, are hydrogen or linear or branched Ci-Cβ alkyl.
Sulfonamide derivatives of general formula (If) are preferred, wherein R1f is an -NR8fR9f radical or a saturated or unsaturated cycloaliphatic radical of 5 or 6 members, which is optionally at least monosubstituted, which can optionally contain at least one heteroatom as a ring member, and which can be condensed with a saturated or unsaturated, mono- or bi- cyclic cycloaliphatic ring system, which is optionally at least monosubstituted, which can optionally contain at least one heteroatom as a ring member, and wherein the ring/rings is/are of 5 or 6 members, preferably an -NR8fR9f radical or a radical chosen from the group consisting of
Figure imgf000232_0001
Figure imgf000232_0002
where, if present, the dotted line is an optional chemical bond, and R10 is hydrogen, a linear or branched CrCβ alkyl radical or a benzyl radical, preferably hydrogen or a C1-C2 alkyl radical, and R2f-R9f, Af and nf are defined as above.
Sulfonamide derivatives of general formula (If) are also preferred, wherein R2f, R3f, R4f, R5f and R7f are hydrogen, a linear or branched Ci-Cβ alkyl radical, a linear or branched C2-C6 alkenyl radical, or a linear or branched C2-C6 alkynyl radical, preferably hydrogen and R1f, R 6f, R8fl R , Af and nf are defined as above. Sulfonamide derivatives of general formula (If) are also preferred, wherein R6f, is hydrogen, a linear or branched CrC6 alkyl radical, which is optionally at least monosubstituted, preferably hydrogen or a linear or branched C -Ce alkyl radical, more preferably hydrogen or an CrC2 alkyl radical and R1f-R5f, R7f-R9f, Af and nf are defined as above.
Furthermore, sulfonamide derivatives of general formula (If) are also preferred, wherein R8f and R9f, identical or different, are hydrogen, a linear or branched Ci-Cβ alkyl radical, which is optionally at least monosubstituted, or
R8f and R9f, together with the nitrogen atom bridge, form a saturated or unsaturated heterocyclic ring of 5 or 6 members, which is optionally at least monosubstituted, which can contain at least one additional heteroatom as a ring member, and/or can be condensed with a saturated or unsaturated, mono- or bi- cyclic cycloaliphatic ring system, which is optionally at least monosubstituted, which can optionally contain at least one heteroatom as a ring member, and wherein the ring/rings is/are of 5, 6 or 7 members, and R1f-R7f, Af and nf are defined as above.
Particularly preferred are sulfonamide derivatives of general formula (If), wherein R8f and R9f, identical or different, are hydrogen or a linear or branched Ci-Cβ alkyl radical, preferably a linear or branched CrC6 alkyl radical, or
R8f and R9f together with the nitrogen atom bridge form a radical chosen from the group consisting of
Figure imgf000233_0001
Figure imgf000233_0002
wherein R11 is hydrogen, a linear or branched CrCβ alkyl radical or a benzyl radical, preferably hydrogen, or a CrC2 alkyl radical, and R1f-R9f, Af and nf are defined as above.
Furthermore, sulfonamide derivatives of general formula (If) are preferred, wherein Af is a mono or poly-cyclic aromatic ring system, which is optionally at least monosubstituted, wherein the ring/rings is/are of 5 or 6 members and which can be bonded by means of an optionally at least mono-substituted Cι_Cβ alkylen group, an optionally at least monosubstituted C2_ Cβ alkenylen group or optionally at least monosubstituted, or a C2— Cβ alkynylen group and/or can contain at least one heteroatom as a ring member, preferably a mono or poly-cyclic aromatic ring system that is optionally at least monosubstituted, wherein the ring/rings is/are of 5 or 6 members and in which one or more of the rings contain(s) at least one heteroatom or a radical chosen from the group consisting of
Figure imgf000234_0001
in which X, Y and Z are each one independently chosen from a group consisting of hydrogen, fluorine, chlorine, bromine, linear or branched d-Cβ alkyl, linear or branched C1-C-6 alkoxy, linear or branched CrCβ alkylthio, trifluoromethyl radical, cyano radical and an NR12fR13f radical, in which R12f and R13f, identical or different, are hydrogen or linear or branched CrCβ alkyl,
W is a single chemical bond between the two rings, a CH2, O, S group or an NR14 radical, wherein R14 is hydrogen or linear or branched d-Cβ alkyl,
m is O, 1 , 2, 3 or 4; and R >1f - rR->1ι1πf and nf are defined as above.
Furthermore, sulfonamide derivatives of general formula (If) are preferred, wherein Af 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 Cι_Cβ alkylene group, an optionally at least mono-substituted C2— C6 alkenylene group or an optionally at least mono-substituted C2_ C6 alkynylene group and/or wherein the ring(s) may contain at least one heteroatom as a ring member,
preferably Af 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
Figure imgf000235_0001
Figure imgf000235_0002
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 Ci-C6 alkyl, linear or branched CrCβ alkoxy, linear or branched CrC6 alkylthio, a trifluoromethyl radical, a cyano radical and a -NR12R13 radical,
wherein R12 and R13, identical or different, each represent hydrogen or linear or branched CrCβ alkyl,
W represents a single chemical bond between the two rings, a CH2, O, S group or a NR14 radical,
wherein R14 is hydrogen or a linear or branched Ci-Cβ alkyl,
m is 0, 1 , 2, 3 or 4 and
ml is 1 or 2, preferably 2, and R1f-R9f and nf are defined as above.
Also preferred are compounds of general formula (If),
wherein
R1f represents a -NR8fR9f radical,
R2f, R3f, R4f, R5f and R7f each represent hydrogen,
R6f represents hydrogen,
R8f and R9f, identical or different, each represent methyl, ethyl, n-propyl or n-propyl, more preferably methyl,
or R8f and R9f, together with the bridging nitrogen atom form a 5- or 6-membered heterocyclic ring, more preferably form a pyrrolidine ring or a piperidine ring
and
Af represents an aryl or heteroaryl radical selected from the group consisting of phenyl, naphthyl, benzo[b]thiophenyl and imidazo[2,1-b]thiazo!yl which may be substituted by 1 , 2 or 3 substituents selected from the group consisting of chlorine, methyl, phenyl and -O-phenyl and/or which may be bonded via a C1-2 alkylene group,
and nf is 2,
optionally in form of one of its stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of its stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a salt thereof, preferably a corresponding, physiologically acceptable salt thereof, or a corresponding solvate thereof.
Those most preferred sulfonamide derivatives of general formula (If) may be selected from the group consisting of
[1 ] N-[1 -(2-Dimethylaminoethyl)-1 H-indol-6-yl]-5-chloro-3- methylbenzo[b]thiophene-2-sulfonamide,
[2] N-[1 ~(2-Dimethylaminoethyl)-1 H-indol-6-yl]-naphthalene-2-sulfonamide,
[3] N-[1 -(2-Dimethylaminoethyl)-1 H-indol-6-yl]-naphthalene-1 -sulfonamide,
[4] N-[1-(2-Dimethylaminoethyl)-1 H-indol-6-yl]-6-chloroimidazo[2,1-b]thiazole-5- sulfonamide,
[5] N-[1 -(2-Dimethylaminoethyl)-1 H-indol-6-yl]-4-phenylbenzenesulfonamide,
[6] N-[1 -(2-Dimethylaminoethyl)-1 H-indol-6-yl]-2-(naphthalene-1 -yl)- ethanesulfonamide,
[7] N-[1 -(2-Dimethylaminoethyl)-1 H-indol-6-yl]-4-phenoxybenzenesulfonamide,
[8] N-[1 -(2-Dimethylaminoethyl)-1 H-indol-6-yl]-3,5-dichlorobenzenesulfonamide,
and their corresponding salts and solvates.
Those most preferred sulfonamide derivatives of general formula (If) may also be selected from the group consisting of
[1 ] N-[1 -(2-Dimethylaminoethyl)-1 H-indol-6-yl]-5-chloro-3- methylbenzo[b]thiophene-2-sulfonamide,
[2] N-[1 -(2-Dimethylaminoethyl)-1 H-indol-6-yl]-naphthalene-2-sulfonamide,
[3] N-[1 -(2-Dimethylaminoethyl)-1 H-indol-6-yl]-naphthalene-1 -sulfonamide,
[4] N-[1-(2-Dimethylaminoethyl)-1 H-indol-6-yl]-6-chloroimidazo[2,1-b]thiazole-5- sulfonamide,
[5] N-[1 -(2-Dimethylaminoethyl)-1 H-indol-6-yl]-4-phenylbenzenesulfonamide,
[6] N-[1 -(2-Dimethylaminoethyl)-1 H-indol-6-yl]-2-(naphthalene-1 -yl)- ethanesulfonamide,
[7] N-[1 -(2-Dimethylaminoethyl)-1 H-indol-6-yl]-4-phenoxybenzenesulfonamide,
[8] N-[1 -(2-Dimethylaminoethyl)-1 H-indol-6-yl]-3,5-dichlorobenzenesuIfonamide,
[9] 5-Chloro-3-methyI-N-[1 -[2-(pyrrolidin-1 -yl)ethyl-1 H-indol-6-yl]- benzo[b]thiophene-2-sulfonamide, [10] N-(1 -[2-(Pyrrolidin-1 -yl)ethyl]-1 H-indol-6-yl]-napthyl-2-sulfonamide,
[11 ] N-[1 -[2-Pyrrolidin-1 -yl]ethyl]-1 H-indol-6-yl]-naphthalene-1 -sulfonamide,
[12] 6-Chloro-N-[1-[2-(ρyrrolidin-1-yl)ethyl]-1 H-indol-6-yl]-imidazo[2,1-b]thiazole-5- sulfonamide,
[13] 4-Phenyl-N-(1 -(2-(pyrrolidin-1 -yl)ethyl)-1 H-indol-6-yl)-benzenesulfonamide
[14] 2-(Naphth-1-yl)-N-(1-(2-(pyrrolidin-1-yl)ethyl)-1 H-indol-6-yl)-ethansulfonamide,
[15] 4-Phenoxy-N-(1 -(2-(pyrrolidin-1 -yl)ethyl)-1 H-indol-6-yl)-benzenesulfonamide and
[16] 3,5-Dichloro-N-(1 -(2-(pyrrolidin-1 -yl)-1 H-indol-6-yl)-benzenesulfonamide,
and their corresponding salts and solvates.
The present invention likewise refers to the physiologically acceptable salts of the compounds of general formula (If), particularly the addition salts of mineral acids, such as hydrochloric, hydrobromic, phosphoric, sulfuric, nitric acids, and with organic acids such as citric, maleic, fumaric, tartaric acids or their derivatives, p- toluenesulfonic, methanesulfonic, camphorsulfonic acids, etc.
Below, the residues R1-R7, A and n in the general formulas (llf) to (Vf) are R1f-R7f, Af and nf.
The derivatives of general formula (If), wherein R1f-R9f, nf and Af have the previously indicated meaning, may be preferably prepared in a way that: At least one compound of general Formula (llf),
Figure imgf000240_0001
(llf)
wherein A has the previously mentioned meaning in the general formula (If), and X is an acceptable leaving group, preferably an halogen atom, more preferably chlorine; reacts with at least one substituted 6-aminoindole of general formula (lllf)
Figure imgf000240_0002
(lllf)
wherein R1-R7 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 (If), which can be purified and/or isolated by means of conventional methods known in the state of the art.
The reaction between the compounds of general Formula (llf) and (lllf) is usually carried out in the presence of an organic reaction medium such as dialkyl ether, particularly diethyl ether or a cyclic ether, particularly tetrahydrofuran or dioxane, an halogenated organic hydrocarbon, particularly methylene chloride or chloroform, an alcohol, particularly methanol or ethanol, a dipolar aprotic solvent, particularly 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 can also be used.
The reaction is preferably carried out in the presence of a suitable base, for example, an inorganic base such as alkaline metal hydroxides and carbonates, or in the presence of an organic base, particularly triethylamine, N-ethyldiisopropylamine or pyridine.
The most suitable reaction temperatures range between 0°C and room temperature, that is, approximately 25°C, and the reaction time is preferably comprised between 5 minutes and 24 hours.
The resulting sulfonamide derivative of general Formula (If) can be purified and/or isolated according to conventional methods known in the state of the art.
Preferably, the sulfonamide derivatives of general Formula (If) can be isolated by evaporating the reaction medium, adding water and, if necessary, adjusting the pH so that a solid which can be isolated by filtration is obtained; or it can be extracted with a water immiscible solvent, such as chloroform, and be purified by chromatography or recrystallization of a suitable solvent.
The compounds of general formula (llf) are commercially available, or they can be prepared according to standard methods known in the state of the art, for example by methods similar to those described in the literature [E.E.Gilbert, Synthesis, 1969, 1 , 3]. The compounds of general formula (lllf) can also be prepared according to standard methods known in the state of the art, for example by methods similar to those described in the literature [Ham, Peter; Gaster, Laramie Mary; King, Francis David; Duckworth, David Malcolm. Preparation of N-heteroaryl-4'- oxadiazolylbiphenylcarboxamides as 5HT1D antagonists. WO 9532967 A1 19951207; Basanagoudar, L.D.; Siddappa, S. Cyanoethylation of nitroindoles. Journal of the Indian Chemical Society (1972), 49 (8), 811-13.; Chen, Guoqing; Adams, Jeffrey; Bemis, Jean; Booker, Shon; Cai, Guolin; Croghan, Michael; Dipietro, Lucian; Dominguez, Celia; Elbaum, Daniel; Germain, Julie; Geuns-Meyer, Stephanie; Handley, Michael; Huang, Qi; Kim, Joseph L.; Kim, Tae-seong; Kiselyov, Alexander; Ouyang, Xiaohu; Patel, Vinod F.; Smith, Leon M.; Stec, Markian; Tasker, Andrew; Xi, Ning; Xu, Shimin; Yuan, Chester Chenguang. Preparation of heterocyclylalkylamine derivatives as remedies for angiogenesis mediated diseases. WO 0266470 A1 20020829. European Journal of Medicinal Chemistry, 23 (4), 373-7; 1988], One of them consists of nitro group reduction of derivatives of general formula (IVf) by methods known in the art, as for example YAMASHKIN, S.A.; YUROVSKAYA, M.A.; Chem Heterocycl Compd (N.Y.), 1999, 35 (12), 1426-1432. BOOTHROYD, S.R.; KERR, M.A.; Tetrahedron Lett, 1995, 36 (14), 2411-2414. MACOR, J.E.; POST, R.; RYAN, K.; Synth Common, 1993, 23 (1 ), 65-72,
Figure imgf000242_0001
(IVf)
wherein R1-R7 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 (lllf), which can be purified and/or isolated by means of conventional methods known in the state of the art.
The compounds of general formula (IVf) can also be prepared according to standard methods known in the state of the art, for example by methods similar to those described in the European Journal of Medicinal Chemistry, 23 (4), 373-7; 1988; Farmaco, 51 (1), 75-8; 1996; Heterocycles, 55 (6), 1151-1159; 2001 ; Ham, Peter; Gaster, Laramie Mary; King, Francis David; Duckworth, David Malcolm. Preparation of N-heteroaryl-4'-oxadiazolylbiphenylcarboxamides as 5HT1D antagonists, WO 9532967 A1 19951207.
One of them consists in the alkylation of nitro derivatives of general formula (IVf) by methods known in the art: MACCHIA, M.; MANERA, C; NENCETTI, S.; ROSSELLO, A.; BROCCALI, G.; LIMONTA, D.; Farmaco, Ed Sci [FRPSAX] 1996, 51 (1), 75-78. 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,
Figure imgf000243_0001
(Vf)
wherein R2-R7 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 (lllf), which can be purified and/or isolated by means of conventional methods known in the state of the art.
The compounds of general formula (Vf) are commercially available or can also be prepared according to standard methods known in the state of the art, as for example OTTONI, O.; CRUZ, R.; KRAMMER, N.H.; Tetrahedron Lett [TELEAY] 1999, 40 (6), 1117-1120. VOROB'EVA, S.L.; BUYANOV, V.N.; SUVOROV, N.N.; Khim Geterosikl Soedin [KGSSAQ] 1991, (5), 636-637. KATRITZKY, A.R.; RACHWAL, S.; BAYYUK, S.; Org Prep Proceed Int [OPPIAK] 1991 , 23 (3), 357-363. MOSKALEV, N.; MAKOSZA, M.; Heterocycles [HTCYAM] 2000, 52 (2), 533-536.
The respective literature descriptions are incorporated by reference and form part of the disclosure.
The sulfonamide derivatives of general formula (If), wherein Rif, nf and Af have the previously indicated meaning and R6f is an alkyl radical, preferably a linear or branched CrCβ alkyl radical, optionally at least monosubstituted, they can also be prepared by alkylation of a sulfonamide derivative of general Formula (If), wherein R1f-R5f, R7f, nf and Af have the previously indicated meaning, and R6f is an hydrogen atom, with an alkyl halogenide or dialkyl sulfate. The alkylation reaction is carried out preferably in the presence of a suitable base, such as alkaline metal hydroxides and carbonates, metal hydrides, alkoxides such as sodium metoxide or potassium tert-butoxide, organometallic compounds such as butyllithium ortert-butyllithium, in the presence of an organic reaction medium such as dialkyl ether, particularly diethyl ether, or a cyclic ether, particularly tetrahydrofuran or dioxane, an hydrocarbon, particularly toluene, an alcohol, particularly methanol or ethanol, a dipolar aprotic solvent, particularly 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 can also be used.
The most suitable reaction temperatures range between 0°C and the boiling temperature of the reaction medium, and the reaction times are preferably comprised between 1 and 24 hours.
Preferably, the resulting sulfonamide derivative of general formula (If) can be isolated by filtration, concentrating the filtrate under reduced pressure, adding water and, if necessary, adjusting the pH so that a solid which can be isolated by filtration is obtained; or it can be extracted with a water immiscible solvent, such as chloroform, and be purified by chromatography or recrystallization of a suitable solvent.
The pharmaceutically acceptable salts of the compounds of general formula (If), can be prepared by means of conventional methods known in the state of the art, preferably by reaction with a mineral acid, such as hydrochloric, hydrobromic, phosphoric, sulfuric, nitric acids, or with organic acids, such as citric, maleic, fumaric, tartaric acids, or their derivatives, p-toluenesulfonic, methanesulfonic, camphorsulfonic acids, etc., in a suitable solvent, such as methanol, ethanol, diethyl ether, ethyl acetate, acetonitrile or acetone, being obtained with the usual techniques for the precipitation or crystallization of the corresponding salts.
The preferred physiologically acceptable salts of the sulfonamide derivatives of general formula (If) are the addition salts of mineral acids, such as hydrochloric, hydrobromic, phosphoric, sulfuric, nitric acids, and of organic acids, such as citric, maleic, fumaric, tartaric acids, or their derivatives, p-toluenesulfonic, methanesulfonic, camphorsulfonic acids, etc.
The physiologically acceptable solvates, particularly hydrates, of the sulfonamide derivatives of general formula (If) or of the corresponding physiologically acceptable salts, can be prepared by methods known in the state of the 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 can be carried out by means of the use of conventional protective groups such as 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 can be removed in the suitable subsequent stage by methods known in the state of the art. The respective literature descriptions are incorporated by reference and form part of the disclosure.
If the sulfonamide derivatives of general formula (If) are obtained in the form of a mixture of stereoisomers, particularly enantiomers or diastereomers, said mixtures can be separated by means of standard processes known in the state of the art, for example chromatographic methods or crystallization with chiral agents.
If one or more of the R29-R9g moieties represent an alkyl radical which is substituted by one or more substituents, unless otherwise defined, each one of the substituents can preferably be chosen from the group consisting of hydroxy, fluorine, chlorine, bromine and trifluoromethyl.
If R19 represents a saturated or unsaturated cycloaliphatic radical, which is optionally containing at least one heteroatom as a ring member, which is substituted by one or more substituents and/or if it comprises a saturated or unsaturated, mono- or bi- cyclic cycloaliphatic ring system, which is optionally containing at least one heteroatom as a ring member, which is substituted by one or more substituents, unless otherwise defined, each one of the substituents can preferably be chosen from the group consisting of hydroxy, fluorine, chlorine, bromine, linear or branched C C6 alkyl, linear or branched C C6 alkoxy, linear or branched C C6 perfluoroalkyl, linear or branched C C6 perfluoroalkoxy and benzyl, preferably from the group consisting of linear or branched C C6 alkyl and benzyl. The heteroatoms of the cycloaliphatic radical and/or of the mono- or bi- cyclic cycloaliphatic ring can, independently from one another, be chosen preferably from the group consisting of nitrogen, sulfur and oxygen, more preferably nitrogen as an heteroatom.
If R8g and R" together with the nitrogen atom bridge form a saturated or unsaturated heterocyclic ring, which can contain at least one additional heteroatom as a ring member, which is substituted by one or more substituents and/or condensed with a saturated or unsaturated mono- or bi- cyclic cycloaliphatic ring system, which can contain at least one heteroatom as a ring member, which is substituted by one or more substituents, unless otherwise defined, each one of the substituents can preferably be chosen from the group consisting of hydroxy, fluorine, chlorine, bromine, linear or branched C C6 alkyl, linear or branched C C6 alkoxy, linear or branched C C6 perfluoroalkyl, linear or branched C C6 perfluoroalkoxy and benzyl, preferably from the group consisting of linear or branched CrC6 alkyl and benzyl. If the heterocyclic ring contains one or more additional heteroatoms, and/or if one or both mono- or bi- cyclic rings contain one or more heteroatoms, these heteroatoms can, independently from one another, be preferably chosen from the group consisting of nitrogen, sulfur and oxygen, more preferably nitrogen as heteroatom.
If A9 is a mono or poly-cyclic aromatic ring system, which is substituted by one or more substituents, and which can be bonded by means of an optionally at least mono-substituted alkylene, alkenylene or alkynylene, and/or can contain at least one heteroatom as a ring member, unless otherwise defined, each one of the substituents can be preferably chosen from the group consisting of hydroxy, halogen, linear or branched C-|-C6 alkyl, linear or branched C C6 alkoxy, linear or branched C C6 perfluoroalkyl, linear or branched C C6 perfluoroalkoxy, a phenyl radical, optionally at least monosubstituted, and heteroaryl of 5 or 6 members, more preferably from the group consisting of halogen, linear or branched C C6 alkyl, phenyl optionally at least monosubstituted and heteroaryl of 5 or 6 members, much more preferably from the group consisting of fluorine, chlorine, linear or branched C C6 alkyl, phenyl radical, optionally at least monosubstituted and heteroaryl of 5 or 6 members. If one or more of the rings of a mono or poly-cyclic aromatic ring system contains one or more heteroatoms, these heteroatoms - like the heteroatoms of a previously mentioned heteroaryl radical of 5 or 6 members - can be preferably chosen from the group consisting of nitrogen, sulfur and oxygen. If the previously mentioned phenyl radical is itself substituted by one or more substituents, each one of the substituents can be preferably chosen from the group consisting of fluorine, chlorine, bromine, linear or branched C C6 alkyl, linear or branched Ci- Ce alkoxy, linear or branched Cι-C6 alkylthio, trifluoromethyl radical, cyano radical and an NR129R139 radical, wherein R129 and R13g, identical or different, are hydrogen or linear or branched C C6 alkyl.
The substituents of A9 may also preferably be selected from the group consisting of hydroxy, halogen, linear or branched Ci-Cβ alkyl, linear or branched CrCβ alkoxy, linear or branched CrCβ perfluoroalkyl, linear or branched CrCβ perfluoroalkoxy, an optionally at least mono-substituted phenyl, -O-phenyl and 5- to 6-membered heteroaryl, more preferably from the group consisting of halogen, linear or branched Ci-Ce alkyl, optionally at least mono-substituted phenyl, -O-phenyl and 5- to 6-membered heteroaryl, even more preferably from the group consisting of fluorine, chlorine, linear or branched Ci-Ce alkyl, optionally at least mono-substituted phenyl, -O-phenyl, and 5- to 6-membered heteroaryl. If the previously mentioned phenyl radical is itself substituted by one or more substituents, each one of the substituents may be preferably chosen from the group consisting of fluorine, chlorine, bromine, linear or branched CrC6 alkyl, linear or branched CrC6 alkoxy, linear or branched Cι-C6 alkylthio, trifluoromethyl radical, cyano radical and an NR12gR13g radical, wherein R12g and R13g, identical or different, are hydrogen or linear or branched Ci-Cβ alkyl.
If the previously mentioned alkylene, alkenylene or alkynylene group is substituted by one or more substituents, each of the substituents can be preferably chosen from the group consisting of hydroxy, halogen, linear or branched C C6 alkyl, linear or branched C C6 alkoxy, linear or branched C C6 perfluoroalkyl, linear or branched C C6 perfluoroalkoxy or a phenyl radical, optionally at least monosubstituted. If said phenyl radical is itself substituted by one or more substituents, each one of the substituents can be preferably chosen from the group consisting of fluorine, chlorine, bromine, linear or branched d-Cβ alkyl, linear or branched C C6 alkoxy, linear or branched C C6 alkylthio, trifluoromethyl radical, cyano radical and an NR12gR13g radical, wherein R12g and R13g, identical or different, are hydrogen or linear or branched C C6 alkyl.
Sulfonamide derivatives of general formula (Ig) are preferred, wherein R1g is an -NR8gR" radical or a saturated or unsaturated cycloaliphatic radical of 5 or 6 members, which is optionally at least monosubstituted, which can optionally contain at least one heteroatom as a ring member, and which can be condensed with a saturated or unsaturated, mono- or bi- cyclic cycloaliphatic ring system, which is optionally at least monosubstituted, which can optionally contain at least one heteroatom as a ring member, and wherein the ring/rings is/are of 5 or 6 members, preferably an -NR8gR9g radical or a radical chosen from the group consisting of
Figure imgf000248_0001
Figure imgf000248_0002
where, if present, the dotted line is an optional chemical bond, and R10 is hydrogen, a linear or branched d-d alkyl radical or a benzyl radical, preferably hydrogen or a C C2 alkyl radical, and R2g-R9g, Ag and ng are defined as above.
Sulfonamide derivatives of general formula (Ig) are also preferred, wherein R2g, R3g, R4g, R5g and R6g, are hydrogen, a linear or branched d-d alkyl radical, a linear or branched C2-C6 alkenyl radical, or a linear or branched C2-C6 alkinyl radical, preferably hydrogen, and R1g- R7g, R8g, R", A9 and ng are defined as above.
The use of sulfonamide derivatives of general formula (Ig) is also preferred, wherein R7g, is hydrogen or a linear or branched CrCβ alkyl radical, which is optionally at least monosubstituted, preferably hydrogen or a linear or branched d-d alkyl radical, more preferably hydrogen or an d-C2 alkyl radical and R1g-R6g, R8g, R9g, A9 and ng are defined as above.
Furthermore, sulfonamide derivatives of general formula (Ig) are also preferred, wherein R8g and R9g, identical or different, are hydrogen or a linear or branched C C6 alkyl radical, which is optionally at least monosubstituted, or
R8g and R", together with the nitrogen atom bridge, form a saturated or unsaturated heterocyclic ring of 5 or 6 members, which is optionally at least monosubstituted, which can contain at least one additional heteroatom as a ring member, and/or which can be condensed with a saturated or unsaturated, mono- or bi- cyclic cycloaliphatic ring system, which is optionally at least monosubstituted, which can optionally contain at least one heteroatom as a ring member, and wherein the ring/rings is/are of 5, 6 or 7 members, and R1g-R7g, A9 and ng are defined as above.
Particularly preferred is the use of sulfonamide derivatives of general formula (Ig), wherein R8g and R9g, identical or different, are hydrogen or a linear or branched C C6 alkyl radical, preferably a linear or branched d-C6 alkyl radical, or
R8g and R9g together with the nitrogen atom bridge form a radical chosen from the group consisting of
Figure imgf000249_0001
Figure imgf000249_0002
wherein R11, if it is present, is hydrogen, a linear or branched C C6 alkyl radical or a benzyl radical, preferably hydrogen, or a d-C2 alkyl radical, and R1g-R9g, A9 and ng are defined as above.
Furthermore, sulfonamide derivatives of general formula (Ig) are preferred, wherein A9 is a mono or poly-cyclic aromatic ring system, which is optionally at least monosubstituted, wherein the ring/rings is/are of 5 or 6 members, and which can be bonded by means of an optionally at least mono-substituted d---C6 alkylene group, an optionally at least monosubstituted C2_C6 alkenylene group, or an optionally at least monosubstituted - alkynyleen group, and/or can contain at least one heteroatom as a ring member, preferably a mono or poly-cyclic aromatic ring system, which is optionally at least monosubstituted, wherein the ring/rings is/are of 5 or 6 members and in which one or more of the rings contain(s) at least one heteroatom or a radical chosen from the group consisting of
Figure imgf000250_0001
in which X, Y and Z are each one independently chosen from a group consisting of hydrogen, fluorine, chlorine, bromine, linear or branched d-C6 alkyl, linear or branched d-d alkoxy, linear or branched CrC6 alkylthio, trifluoromethyl radical, cyano radical and an NR12R13 radical, in which R12 and R13, identical or different, are hydrogen or linear or branched C C6 alkyl,
W is a single chemical bond between the two rings, a CH2, O, S group or an NR14 radical, wherein R14 is hydrogen or linear or branched Cι-C6 alkyl, and
m is 0, 1, 2, 3 or 4;
and R1g-R11g and ng are defined as above.
Furthermore, sulfonamide derivatives of general formula (Ig) are preferred, wherein A9 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 Cι_C6 alkylene group, an optionally at least mono-substituted — d alkenylene group or an optionally at least mono-substituted —d alkynylene group and/or wherein the ring(s) may contain at least one heteroatom as a ring member,
preferably A9 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
Figure imgf000251_0001
Figure imgf000251_0002
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 d-d alkyl, linear or branched Ci-Cβ alkoxy, linear or branched CrCβ alkylthio, a trifluoromethyl radical, a cyano radical and a -NR12R13 radical,
wherein R12 and R13, identical or different, each represent hydrogen or linear or branched d-d alkyl,
W represents a single chemical bond between the two rings, a CH2, O, S group or a NR14 radical,
wherein R14 is hydrogen or a linear or branched d- alkyl,
m is 0, 1 , 2, 3 or 4 and
ml is 1 or 2, preferably 2, and R1g-R11g and ng are defined as above.
Also preferred are compounds of general formula (Ig),
wherein
R1g is a -NR8gR" radical,
R2g, R3g, R4g, R5g and R6g each represent hydrogen,
R7g represents hydrogen,
R8g and R9g, identical or different, each represent methyl, ethyl, n-propyl or iso-propyl, more preferably methyl,
or
R8g and R9g together with the bridging nitrogen atom form a 5- or 6-membered heterocyclic ring, more preferably form a pyrrolidine or piperidine ring,
A9 represents an aryl or heteroaryl radical selected from the group consisting of phenyl, naphthyl, benzo[b]thiophenyl and imidazo[2,1-b]thiazolyl which may be substituted by 1 , 2 or 3 substituents selected from the group consisting of chlorine, methyl and phenyl and/or which may be bonded via a C1-2 alkylene group,
and
ng is 2;
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 general formula (Ig) may be selected from the group consisting of
[1 ] N-[1 -(2-dimethylaminoethyl)-1 H-indole-7-yl]-naphtalene-1 -sulfonamide,
[2] N-[1 -(2-dimethylaminoethyl)-1 H-indole-7-yl]-5-chloro-3- methylbenzo[b]thiophene-2-sulfonamide,
[3] N-[1-(2-dimethylaminoethyl)-1 H-indole-7-yl]-4-phenylbenzenesulfonamide and
[4] N-[1 -(2-dimethylaminoethyl)-1 H-indole-7-yl]-6-chloroimidazo[2,1 -b]thiazole-5- sulfonamide
and their corresponding salts and solvates
The most preferred compounds general formula (Ig) may also be selected from the group consisting of
[1 ] N-[1 -(2-dimethylaminoethyl)-1 H-indole-7-yl]-naphtalene-1 -sulfonamide,
[2] N-[1 -(2-dimethylaminoethyl)-1 H-indole-7-yl]-5-chloro-3- methylbenzo[b]thiophene-2-sulfonamide,
[3] N-[1 -(2-dimethylaminoethyl)-1 H-indole-7-yl]-4-phenylbenzenesulfonamide and
[4] N-[1-(2-dimethylaminoethyl)-1 H-indole-7-yl]-6-chloroimidazo[2,1-b]thiazole-5- sulfonamide
[5] 5-chloro-3-methyl-N-(1-(2-(pyrrolidin-1-yl)ethyl)-1 H-indol-7-yl)- benzo[b]thiophen-2-sulfonamide,
[6] N-(1 -(2-(pyrrolidin-1 -yl)ethyl)-1 H-indol-7-yl)naphthalene-1 -sulfonamide, [7] 6-chloro-N-(1-(2-(pyrroldin-1-yl)ethyl)-1 H-indol-7-yl)imidazo[2,1-b]thiazole-5- sulfonamide and
[8] 2-(naphth-1 -yl)-N-(1 -(2-(pyrrolidin-1 -yl)ethyl)-1 H-indol-7- yl)ethansulfonamide
and their corresponding salts and solvates.
The present invention likewise refers to the physiologically acceptable salts of the compounds of general formula (Ig), particularly the addition salts of mineral acids, such as hydrochloric, hydrobromic, phosphoric, sulfuric, nitric acids, and with organic acids such as citric, maleic, fumaric, tartaric acids or their derivatives, p-toluenesulfonic, methanesulfonic, camphorsulfonic acids, etc.
Below, the residues R1-R7, A and n in the general formulas (llg) and (lllg) are R1g- R7g, Ag and ng.
The derivatives of general formula (Ig), wherein R1g-R9g, ng and A9 have the previously indicated meaning, may be preferably prepared in a way that:
At least one compound of general Formula (llg),
Figure imgf000254_0001
(iig)
wherein A has the previously mentioned meaning in the general formula (Ig), and X is an acceptable leaving group, preferably an halogen atom, more preferably chlorine; reacts with at least one substituted 7-aminoindole of general formula (lllg)
Figure imgf000255_0001
(mg)
wherein R1-R7 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 general formula (Ig), which can be purified and/or isolated by means of conventional methods known in the state of the art.
The reaction between the compounds of general formula (llg) and (lllg) is usually carried out in the presence of an organic reaction medium such as dialkyl ether, particularly diethyl ether or a cyclic ether, particularly tetrahydrofuran or dioxane, an halogenated organic hydrocarbon, particularly methylene chloride or chloroform, an alcohol, particularly methanol or ethanol, a dipolar aprotic solvent, particularly 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 can also be used.
The reaction is preferably carried out in the presence of a suitable base, for example, an inorganic base such as alkaline metal hydroxides and carbonates, or in the presence of an organic base, particularly triethylamine or pyridine.
The most suitable reaction temperatures range between 0°C and room temperature, that is, approximately 25°C, and the reaction time is preferably comprised between 5 minutes and 24 hours. The resulting sulfonamide derivative of general Formula (Ig) can be purified and/or isolated according to conventional methods known in the state of the art.
Preferably, the sulfonamide derivatives of general Formula (Ig) can be isolated by evaporating the reaction medium, adding water and, if necessary, adjusting the pH so that a solid which can be isolated by filtration is obtained; or it can be extracted with a water immiscible solvent, such as chloroform, and be purified by chromatography or recrystallization of a suitable solvent.
The compounds of general formula (llg) are commercially available, or they can be prepared according to standard methods known in the state of the art, for example by methods similar to those described in the literature [E.E.Gilbert, Synthesis, 1969, 1 , 3]. The compounds of general formula (lllg) can also be prepared according to standard methods known in the state of the art, for example by methods similar to those described in: [Abou-Gharbia, Magid; Patel, Usha; Tokolics, Joseph; Freed, Meier. European Journal of Medicinal Chemistry (1988), 23(4), 373-7].
The sulfonamide derivatives of general Formula (Ig), wherein R1g, ng and A9 have the previously indicated meaning and R7g is an alkyl radical, preferably a linear or branched -d alkyl radical, optionally at least monosubstituted, they can also be prepared by alkylation of a sulfonamide derivative of general formula (Ig), wherein R1g-R6g, ng and A9 have the previously indicated meaning, and R7g is an hydrogen atom, with an alkyl halogenide or dialkyl sulfate.
The alkylation reaction is carried out preferably in the presence of a suitable base, such as alkaline metal hydroxides and carbonates, metal hydrides, alkoxides such as sodium metoxide or potassium tert-butoxide, organometallic compounds such as butyllithium or tert-butyllithium, in the presence of an organic reaction medium such as dialkyl ether, particularly diethyl ether, or a cyclic ether, particularly tetrahydrofuran or dioxane, an hydrocarbon, particularly toluene, an alcohol, particularly methanol or ethanol, a dipolar aprotic solvent, particularly 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 can also be used. The most suitable reaction temperatures range between 0°C and the boiling temperature of the reaction medium, and the reaction times are preferably comprised between 1 and 24 hours.
Preferably, the resulting sulfonamide derivative of general formula (Ig) can be isolated by filtration, concentrating the filtrate under reduced pressure, adding water and, if necessary, adjusting the pH so that a solid which can be isolated by filtration is obtained; or it can be extracted with a water immiscible solvent, such as chloroform, and be purified by chromatography or recrystallization of a suitable solvent.
The pharmaceutically acceptable salts of the compounds of general formula (Ig), can be prepared by means of conventional methods known in the state of the art, preferably by reaction with a mineral acid, such as hydrochloric, hydrobromic, phosphoric, sulfuric, nitric acids, or with organic acids, such as citric, maleic, fumaric, tartaric acids, or their derivatives, p-toluenesulfonic, methanesulfonic, camphorsulfonic acids, etc., in a suitable solvent, such as methanol, ethanol, diethyl ether, ethyl acetate, acetonitrile or acetone, being obtained with the usual techniques for the precipitation or crystallization of the corresponding salts.
The preferred physiologically acceptable salts of the sulfonamide derivatives of general formula (Ig) are the addition salts of mineral acids, such as hydrochloric, hydrobromic, phosphoric, sulfuric, nitric acids, and of organic acids, such as citric, maleic, fumaric, tartaric acids, or their derivatives, p-toluenesulfonic, methanesulfonic, camphorsulfonic acids, etc.
The physiologically acceptable solvates, particulariy hydrates, of the sulfonamide derivatives of general formula (Ig) or of the salts, preferably the corresponding, physiologically acceptable salts, can be prepared by methods known in the state of the 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 can be carried out by means of the use of conventional protective groups such as 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 can be removed in the suitable subsequent stage by methods known in the state of the art. The respective literature descriptions are incorporated by reference and form part of the disclosure.
If the sulfonamide derivatives of general formula (Ig) are obtained in the form of a mixture of stereoisomers, particularly enantiomers or diastereomers, said mixtures can be separated by means of standard processes known in the state of the art, for example chromatographic methods or crystallization with chiral agents.
If one or more of the substituents R2h-R8h represents an alkyl radical, an alkenyl radical, or an alkinyl radical, which is substituted by one or more substituents, each one of the substituents can preferably be chosen from the group consisting of hydroxy, halogen, linear or branched d-d alkyl, linear or branched d- alkoxy, linear or branched d-d perfluoroalkyl, linear or branched d-C6 perfluoroalkoxy, or a phenyl radical optionally at least monosubstituted. If said phenyl radical is the same one substituted by one or more substituents, each one of the substituents can preferably be chosen from the group consisting of fluorine, chlorine, bromine, a linear or branched d- alkyl, a linear or branched d-d alkoxy, a linear or branched Ci- Cβ alkylthio, a trifluoromethyl radical, a cyano radical and an NR11hR12h radical, where R11h and R12h, identical or different, are defined like R7h and R8h.
If R1h represents a saturated or unsaturated cycloaliphatic radical, which is optionally containing at least one heteroatom as a ring member, which is substituted by one or more substituents and/or if it comprises a saturated or unsaturated, mono- or bicyclic cycloaliphatic ring system, optionally containing at least one heteroatom as a ring member, which is substituted by one or more substituents, unless otherwise defined, each one of the substituents can preferably be chosen from the group consisting of hydroxy, fluorine, chlorine, bromine, linear or branched -d alkyl, linear or branched d-d alkoxy, linear or branched CrCβ perfluoroalkyl, linear or branched d- perfluoroalkoxy and benzyl, more preferably from the group consisting of linear or branched Ci-Ce alkyl and benzyl. The heteroatoms of the cycloaliphatic radical and/or of the mono- or bi- cyclic cycloaliphatic ring can, independently from one another, be chosen preferably from the group consisting of nitrogen, sulfur and oxygen, more preferably nitrogen as a heteroatom.
If R7h and R8h together with the nitrogen atom to which they are bonded form a saturated or unsaturated heterocyclic ring, which can optionally contain at least one additional heteroatom as a ring member, which is substituted by one or more substituents and/or condensed with a saturated or unsaturated mono- or bi- cyclic cycloaliphatic ring system, which can contain at least one heteroatom as a ring member, which is substituted by one or more substituents, unless otherwise defined, each one of the substituents can preferably be chosen from the group consisting of hydroxy, fluorine, chlorine, bromine, linear or branched d-d alkyl, linear or branched d-d alkoxy, linear or branched d- perfluoroalkyl, linear or branched d-d perfluoroalkoxy and benzyl, preferably from the group consisting of linear or branched d-d alkyl and benzyl. If the heterocyclic ring contains one or more additional heteroatoms, and/or if one or both mono- or bi- cyclic rings contains one or more heteroatoms, these heteroatoms can, independently from one another, be preferably chosen from the group consisting of nitrogen, sulfur and oxygen, more preferably nitrogen as a heteroatom.
If Ah represents an alkyl radical, an alkenyl radical, or an alkinyl radical, which is substituted by one or more substituents, each one of the substituents can preferably be chosen from the group consisting of hydroxy, halogen, linear or branched d-d alkyl, linear or branched d-d alkoxy, linear or branched d-d perfluoroalkyl, linear or branched d- perfluoroalkoxy or a phenyl radical, optionally at least monosubstituted. If said phenyl radical is the same one substituted by one or more substituents, each one of the substituents can preferably be chosen from the group consisting of fluorine, chlorine, bromine, linear or branched d- alkyl, linear or branched d-d alkoxy, linear or branched Ci-Ce alkylthio, a trifluoromethyl radical, a cyano radical and an NR13hR14h radical, where R13h and R14h, identical or different, are defined as R7h and R8h. If Bh represents an alkyl radical, an alkenyl radical, or an alkinyl radical, which is substituted by one or more substituents, each one of the substituents can preferably be chosen from the group consisting of hydroxy, halogen, linear or branched d-d alkyl, linear or branched d-d alkoxy, linear or branched d-d perfluoroalkyl, linear or branched d- perfluoroalkoxy, or a phenyl radical optionally at least monosubstituted. If said phenyl radical is the same one substituted by one or more substituents, each one of the substituents can preferably be chosen from the group consisting of fluorine, chlorine, bromine, linear or branched d-d alkyl, linear or branched d-d alkoxy, linear or branched d-d alkylthio, a trifluoromethyl radical, a cyano radical and an NR15hR16h radical, where R15h and R16h, identical or different, are defined as R7h and R8h.
If Ah and Bh together with the carbon atom to which they are bonded form a saturated or unsaturated, but not aromatic, cycloalkyl ring, which is substituted by one or more substituents, each one of the substituents can preferably be chosen from the group consisting of hydroxy, halogen, linear or branched CrCβ alkyl, linear or branched d- d alkoxy, linear or branched d-d perfluoroalkyl, linear or branched d-d perfluoroalkoxy or a phenyl radical, optionally at least monosubstituted. If said phenyl radical is the one substituted by one or more substituents, each one of the substituents can preferably be chosen from the group consisting of fluorine, chlorine, bromine, linear or branched d-d alkyl, linear or branched CrCβ alkoxy, linear or branched d- alkylthio, a trifluoromethyl radical, a cyano radical and an NR17hR18h radical, where R17h and R18h, identical or different, are defined like R7h and R8h.
Sulfonamide derivatives of general formula (Ih) are preferred, where R1h represents an NR7hR8h radical or a saturated or unsaturated cycloaliphatic radical of 5 or 6 members, which is optionally at least monosubstituted, which can optionally contain at least one heteroatom as a ring member, and which can be condensed with a saturated or unsaturated, mono- or bi- cyclic cycloaliphatic ring system, which is optionally at least monosubstituted, which can optionally contain at least one heteroatom as a ring member, and wherein the ring/rings is/are of 5 or 6 members, preferably an -NR7hR8h radical or a radical chosen from the group consisting of
Figure imgf000261_0001
Figure imgf000261_0002
where, if present, the dotted line represents an optional chemical bond, and R19 is hydrogen, a linear or branched d-d alkyl radical or a benzyl radical, preferably hydrogen or a d-d alkyl radical, and R2h-R6h, Ah, Bh and nh are defined as above.
Furthermore, sulfonamide derivatives of general formula (Ih) are also preferred, where R7h and R8h, identical or different, are hydrogen, a linear or branched Cι-6 alkyl radical, which is optionally at least monosubstituted, a linear or branched C2-6 alkenyl radical, which is optionally at least monosubstituted, or a linear or branched C2-6 alkynyl radical, which is optionally at least monosubstituted, or
R7h and R8h, together with the nitrogen atom bridge, form a saturated or unsaturated heterocyclic ring of 5 or 6 members, which is optionally at least monosubstituted, which can contain at least one additional heteroatom as a ring member, and/or which can be condensed with a saturated or unsaturated, mono- or bi- cyclic cycloaliphatic ring system, which is optionally at least monosubstituted, which can optionally contain at least one heteroatom as a ring member, and wherein the ring/rings is/are of 5, 6 or 7 members, and R1h-R6h, Ah, Bh and nh are defined as above.
Particularly preferred are sulfonamide derivatives of general formula (Ih), where R7h and R8h, identical or different, are hydrogen or a linear or branched d-d alkyl radical, preferably a linear or branched Ci-Cβ alkyl radical, or
R7h and R8h together with the nitrogen atom bridge form a radical chosen from the group consisting of
Figure imgf000262_0001
Figure imgf000262_0002
where R20, if present, is hydrogen, a linear or branched d-d alkyl radical or a benzyl radical, preferably hydrogen, or a d-d alkyl radical, and R1h-R6h, Ah, Bh and nh are defined as above.
Furthermore, sulfonamide derivatives of general formula (Ih) are preferred, where Ah and Bh, identical or different, are a linear or branched Ci-Ce alkyl radical, a linear or branched d-d alkenyl radical, or a linear or branched d-C6 alkinyl radical, preferably a linear or branched d-d alkyl radical radical, or
Ah and Bh, together with the carbon atom to which they are bonded, form a saturated or unsaturated, but not aromatic, cycloalkyl ring, which is optionally substituted by one or more substituents, preferably a C3-d cycloalkyl ring. Particularly preferred a cyclohexyl ring.
Sulfonamide derivatives of general Formula (Ih) are also preferred, wherein R2h, R3h, R4h, R5h and R6h, identical or different, independently from one another, are, hydrogen, halogen, cyano, nitro, a linear or branched d-d alkyl radical, a linear or branched d- alkenyl radical, a linear or branched d-d alkinyl adical, Cι-6-alkoxy, Cι-6-alkylthio, hydroxy, trifluoromethyl, C3-8 cycloalk(en)yl, Cι-6-alkylcarbonyl, phenylcarbonyl or a -NR9hR10h group, where where R9h and R10h, are defined as R7h and R8h. Also preferred are compounds of general formula (Ih),
wherein
R1h represents an unsaturated, optionally at least one nitrogen atom as a ring member containing 5- or 6-membered cycloaliphatic radical, which may be substituted by a methyl group and/or which may be condensed with a 5-membered cycloaliphatic ring, more preferably R1 represents a moiety selected from the group consisting of
Figure imgf000263_0001
R ,2hπ, D FT3h, D FC4hπ and R >6Dhn each represent hydrogen,
R j5h represents H, fluorine, chlorine, nitro or a -NR 9D R10 group,
R ,9h and R >1ι0uhn each represent hydrogen,
Ah and Bh together with the carbon atom to which they are bonded form a saturated or unsaturated, but not aromatic, C3-C8 cycloalkyl ring, more preferably form a cyclohexyl ring,
and
nh is 0;
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. Those most preferred compounds of general formula (Ih) are selected from the group consisting of
[1] 1-Cyclohexanesulfonyl-3-(1 -methyl-1 ,2,3,6-tetrahydropyridine-4-yl)-5-nitro-1 H- indole,
[2] 5-Chloro-1 -cyclohexanesulfonyl-3-(1 -methyl-1 ,2,3,6-tetrahydropyridine-4-yl)- 1 H-indole,
[3] 5-Amino-1 -cyclohexanesulfonyl-3-(1 -methyl-1 ,2,3,6-tetrahydropyridine-4-yl)- 1 H-indole and
[4] 1 -Cyclohexanesulfonyl-5-fluoro-3-(1 ,2,3,5,8,8a-hexahydro-indolizine-7-yl)-1 H- indole hydrochloride
and their corresponding salts and solvates.
The present invention likewise refers to the physiologically acceptable salts of the compounds of general formula (Ih), particularly the addition salts of mineral acids, such as hydrochloric, hydrobromic, phosphoric, sulfuric, nitric acids, and of organic acids, such as citric, maleic, fumaric, tartaric acids, or their derivatives, p- toluenesulfonic, methanesulfonic, camphorsulfonic acids, etc.
Below, the residues R1-R6, A, B and n in the general formulas (I Ih) to (IVh) are R1h- R6h, Ah, Bh and nh.
The derivatives of general formula (Ih), wherein R1h-R6h, Ah, Bh and nh have the previously indicated meaning, may be preferably prepared in a way that: At least one compound of general Formula (llh),
Figure imgf000265_0001
(llh)
wherein A and B have the previously mentioned meaning in the general formula (Ih), and X is an acceptable leaving group, preferably an halogen atom, more preferably chlorine; reacts with at least one substituted indole of general formula (lllh)
Figure imgf000265_0002
(lllh)
where R1-R6 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 (Ih), which can be purified and/or isolated by means of conventional methods known in the state of the art.
The reaction is preferably carried out in the presence of a suitable strong base, for example, lithium diisopropylamide, butyllithium, sodium hydride, or sodium bis(trimethylsilyl)amide in an inert solvent, such as tetrahydrofurane, hexane or dimethylformamide.
The most suitable reaction temperatures range between -100°C and room temperature, and the reaction time is preferably comprised between 5 minutes and 24 hours. The preferred conditions are sodium hydride in dimethylformamide at approximately 0°C. The resulting sulfonamide derivative of general formula (Ih) can be purified and/or isolated according to conventional methods known in the state of the art.
Preferably, the sulfonamide derivatives of general formula (Ih) can be isolated by evaporating the reaction medium, adding water and, if necessary, adjusting the pH so that a solid which can be isolated by filtration is obtained; or it can be extracted with a water immiscible solvent, such as chloroform, and be purified by chromatography or recrystallization of a suitable solvent.
The compounds of general formula (llh) are commercially available, or they can be prepared according to standard methods known in the state of the art, for example by methods similar to those described in the literature [KHANNA, V.; TAMILSELVAN, P.; KALRA, S.J.S.; IQBAL, J.; Tetrahedron 1994, 35 (32), 5935-5938; L.N. Aristarkhova et al., J. Org. Chem. USSR, 1970, 6, 2454-2458; E.E. Gilbert, Synthesis, 1969, 1 ,3]. The compounds of general Formula (lllh) can also be prepared according to standard methods known in the state of the art, for example, methods similar to those described in the literature. Substituted aromatic 5-HT1f agonist, WO9846570. Piperidine-indole compounds having 5-HT6 affinity, US 6,133,287.
The respective descriptions in the literature are incorporated by reference and form part of the disclosure.
The sulfonamide derivatives of general formula (Ih), wherein R2h, R3h, R4h, R5h or R6h are an amino group by reduction of the nitro group of derivatives of general formula (IVh) by methods known in the art, 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.; BACCANARI, D.P.; JONES, M.L.; HUNTER, R.N.; TANSIK, R.L.; JOYNER, S.S.; BOYTOS, CM.; RUDOLPH, S.K.; KNICK, V.; WILSON, H.R.; CADDELL, J.M.; FRIEDMAN, H.S.; ET AL.; J Med Chem, 1996, 39 (4), 892-903,
Figure imgf000267_0001
(IVh)
and the others R1-R6, A, B and n have the previously mentioned meaning, or one of their derivatives suitably protected, and, if necessary, the protective groups are removed in order to obtain the corresponding amine of general Formula (Ih), which can be purified and/or isolated by means of conventional methods known in the state of the art.
The respective literature descriptions are incorporated by reference and form part of the disclosure.
The pharmaceutically acceptable salts of the compounds of general Formula (Ih), can be prepared by means of conventional methods known in the state of the art, preferably by reaction with a mineral acid, such as hydrochloric, hydrobromic, phosphoric, sulfuric, nitric acids, or with organic acids, such as citric, maleic, fumaric, tartaric acids, or their derivatives, p-toluenesulfonic, methanesulfonic acids, etc., in a suitable solvent, such as methanol, ethanol, diethyl ether, ethyl acetate, acetonitrile or acetone, being obtained with the usual techniques for the precipitation or crystallization of the corresponding salts.
The preferred physiologically acceptable salts of the sulfonamide derivatives of general formula (Ih) are the addition salts of mineral acids, such as hydrochloric, hydrobromic, phosphoric, sulfuric, nitric acids, and of organic acids, such as citric, maleic, fumaric, tartaric acids, or their derivatives, p-toluenesulfonic, methanesulfonic, camphorsulfonic acids, etc. The physiologically acceptable solvates, particularly hydrates, of the sulfonamide derivatives of general formula (Ih) or of the corresponding physiologically acceptable salts, can be prepared by methods known in the state of the 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 can be carried out by means of the use of conventional protective groups such as 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 can be removed in the suitable subsequent stage by methods known in the state of the art. The respective literature descriptions are incorporated by reference and form part of the disclosure.
If the sulfonamide derivatives of general Formula (Ih) are obtained in the form of a mixture of stereoisomers, particularly enantiomers or diastereomers, said mixtures can be separated by means of standard processes known in the state of the art, for example chromatographic methods or crystallization with chiral agents.
The active substance combination according to this invention comprises preferably 1- 99% by weight of the component (A) and 99-1 % by weight of the component (B), more preferably 10-80% by weight of the component (A) and 90-20% by weight of the component (B), these percentages being based on the total weight of both components (A) and (B).
Another aspect of the present invention is a medicament, which comprises an inventive active substance combination and optionally one or more pharmacologically acceptable adjuvants. Said medicament is particularly suitable for simultaneous regulation of neuropeptide Y-receptors, preferably neuropeptide Y5-receptors, and 5-HTβ receptors, for the regulation of appetite, for maintenance, increase or reduction of body weight, for prophylaxis and/or treatment of disorders related to food ingestion, preferably for prophylaxis and/or treatment of obesity, anorexia, cachexia, bulimia, diabetes, preferably type II diabetes (non-insulin-dependent diabetes mellitus), or for prophylaxis and/or treatment of gastrointestinal tract disorders, preferably of the irritable bowel syndrome, for prophylaxis and/or treatment of Peripheral Nervous System Disorders, Central Nervous System Disorders, arthritis, epilepsy, anxiety, panic, depression, cognitive disorders, memory disorders, cardiovascular diseases, senile dementia processes, such as Alzheimer's, Parkinson's and/or Huntington's Disease, schizophrenia, psychosis, infantile hyperkinesia (ADHD, attention deficit / hyperactivity disorder), pain, hypertensive syndrome, inflammatoric diseases, immunologic diseases or for improvement of cognition.
Said medicament is more particularly suitable for simultaneous regulation of neuropeptide Y-receptors, preferably neuropeptide Y5-receptors, and 5-HT6 receptors, for the regulation of appetite, for maintenance, increase or reduction of body weight, for prophylaxis and/or treatment of disorders related to food ingestion, preferably for prophylaxis and/or treatment of obesity, anorexia, cachexia, bulimia, diabetes, preferably type II diabetes (non-insulin-dependent diabetes mellitus), or for prophylaxis and/or treatment of gastrointestinal tract disorders, preferably of the irritable bowel syndrome.
Another aspect of the present invention is the use of an inventive active substance combination for the manufacture of a medicament for simultaneous regulation of neuropeptide Y-receptors, preferably neuropeptide Y5-receptors, and 5-HTβ receptors, for the regulation of appetite, for maintenance, increase or reduction of body weight, for prophylaxis and/or treatment of disorders related to food ingestion, preferably for prophylaxis and/or treatment of obesity, anorexia, cachexia, bulimia, diabetes, preferably type II diabetes (non-insulin-dependent diabetes mellitus), or for prophylaxis and/or treatment of gastrointestinal tract disorders, preferably of the irritable bowel syndrome, for prophylaxis and/or treatment of Peripheral Nervous System Disorders, Central Nervous System Disorders, arthritis, epilepsy, anxiety, panic, depression, preferably biploar disorders, cognitive disorders, memory disorders, cardiovascular diseases, senile dementia processes, neurodegenerative disorders, preferably Alzheimer's disease, Parkinson's disease, Huntington's disease and/or multiple sclerosis, schizophrenia, psychosis, infantile hyperkinesia (ADHD, attention deficit / hyperactivity disorder), pain, hypertensive syndrome, inflammatoric diseases, immunologic diseases or for improvement of cognition.
Particularly preferred is the use of an inventive active substance combination for the manufacture of a medicament for simultaneous regulation of neuropeptide Y- receptors, preferably neuropeptide Y5-receptors, and 5-HTβ receptors, for the regulation of appetite, for maintenance, increase or reduction of body weight, for prophylaxis and/or treatment of disorders related to food ingestion, preferably for prophylaxis and/or treatment of obesity, anorexia, cachexia, bulimia, diabetes, preferably type II diabetes (non-insulin-dependent diabetes mellitus), or for prophylaxis and/or treatment of gastrointestinal tract disorders, preferably of the irritable bowel syndrome.
Those skilled in the art understand that the components (A) and (B) of the active substance combination according to the present invention may be administered simultaneously or sequentially to one another, whereby in each case components (A) and (B) may be administerd via the same or different administration pathways, e.g. orally or parenterally. preferably both components (A) and (B) are administered simultaneously in one and the same administration form.
Yet another aspect of the present invention are pharmaceutical formulations in different pharmaceutical forms comprising an inventive active substance combination and optionally one or more pharmacologically acceptable adjuvants.
As well known to somebody skilled in the art the pharmaceutical formulations may - depending on their route of administration, also contain one or more auxiliary substances known to those skilled in the art. The pharmaceutical formulations according to the present invention may be produced according to standard procedures known to those skilled in the art, e.g. from the tables of contents from ..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 CT. (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 descriptions are incorporated by reference and are part of the disclosure.
Preferred pharmaceutical formulations are solid pharmaceutical forms, preferably tablets, chewing tablets, chewing gums, dragees, capsules, suppositories, powder preparations, transdermal therapeutic systems, transmucosal therapeutic systems, preferably tablets or capsules.
Preferred pharmaceutical formulations are also liquid and semi-liquid pharmaceutical forms such as drops or such as juice, sirup, solution, emulsion, suspension, preferably drops or solutions.
In an additional preferred embodiment, the pharmaceutical formulations are in the form of multiple particles, preferably microtablets, microcapsules, microspheroids, granules, crystals and pellets, optionally compacted in a tablet, filled in a capsule or suspended in a suitable liquid.
The pharmaceutical formulations according to the present invention are particularly suitable for oral, intravenous, intramuscular, subcutaneous, intrathecal, epidural, buccal, sublingual, pulmonal, rectal, transdermal, nasal or intracerebroventricular application, more particularly for oral, intravenous or intraperitoneal application.
In one embodiment of the present invention the pharmaceutical formulation comprises at least one of the components (A) and (B) of the active substance combination at least partially in a sustained-release form. By incorporating one or both of these components (A) and (B) at least partially or completely in a sustained-release form it is possible to extend the duration of their effect, allowing for the beneficial effects of such a sustained-release form, e.g. the maintenance of even concentrations in the blood.
Suitable sustained-release forms as well as materials and methods for their preparation are known to those skilled in the art, e.g. from the tables of contents from „Modified-Release Drug Delivery Technology", Rathbone, M.J. Hadgraft, J. and Roberts, M.S. (Eds.), Marcel Dekker, Inc., New York (2002); „Handbook of Pharmaceutical Controlled Release Technology", Wise, D.L. (Ed.), Marcel Dekker, Inc. New York, (2000);"Controlled Drug Delivery", Vol. I, Basic Concepts, Bruck, S.D. (Ed.), CRC Press Inc., Boca Raton (1983) and from 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", Encylopedia of Controlled Drug Delivery, Mathiowitz, E. (Ed.), John Wiley & Sons, Inc., New York (1999), Vol. 2, 698-728. The respective descriptions are incorporated by reference and are part of the disclosure.
If the pharmaceutical formulation according to the present invention comprises at least one of the components (A) and (B) at least partially in a sustained-release form, said sustained release may preferably be achieved by the application of at least one coating or provision of a matrix comprising at least one sustained-release material.
The sustained-release material is preferably based on an optionally modified, water- insoluble, natural, semisynthetic or synthetic polymer, or a natural, semisynthetic or synthetic wax or fat or fatty alcohol or fatty acid, or on a mixture of at least two of these afore mentioned components.
The water-insoluble polymers used to produce a sustained-release material are preferably based on an acrylic resin, which is preferably selected from the group of poly(meth)acrylates, particularly preferably poly(Cι-4)alkyl (meth)acrylates, poly(Cι-4)dialkylamino(C -4)alkyl (meth)acrylates and/or copolymers or mixtures thereof, and very particularly preferably copolymers of ethyl acrylate and methyl methacrylate with a monomer molar ratio of 2:1 (Eudragit NE30D®), copolymers of ethyl acrylate, methyl methacrylate and trimethylammonium ethyl methacrylate- chloride with a monomer molar ratio of 1 :2:0.1 (Eudragit RS®), copolymers of ethyl acrylate, methyl methacrylate and trimethylammonium ethyl methacrylate-chloride with a monomer molar ratio of 1 :2:0.2 (Eudragit RL®), or a mixture of at least two of the above-mentioned copolymers. These coating materials are commercially available as 30 wt.% aqueous latex dispersions, i.e. as Eudragit RS30D®, Eudragit NE30D® or Eudragit RL30D®, and may also be used as such for coating purposes.
In another embodiment, the sustained-release material is based on water-insoluble cellulose derivatives, preferably alkyl celluloses, particularly preferably ethyl cellulose, or cellulose esters, e.g. cellulose acetate. Aqueous ethyl cellulose dispersions are commercially available, for example, under the trademarks Aquacoat® or Surelease®.
As natural, semisynthetic or synthetic waxes, fats or fatty alcohols, the sustained- release material may be based on carnauba wax, beeswax, glycerol monostearate, glycerol monobehenate, glycerol ditripalmitostearate, microcrystalline wax, cetyl alcohol, cetylstearyl alcohol or a mixture of at least two of these components.
The afore mentioned polymers of the sustained-release material may also comprise a conventional, physiologically acceptable plasticizer in amounts known to those skilled in the art.
Examples of suitable plasticizers are lipophilic diesters of a - o aliphatic or aromatic dicarboxylic acid and a Ci-Cs aliphatic alcohol, e.g. dibutyl phthalate, diethyl phthalate, dibutyl sebacate or diethyl sebacate, hydrophilic or lipophilic citric acid esters, e.g. triethyl citrate, tributyl citrate, acetyltributyl citrate or acetyltriethyl citrate, polyethylene glycols, propylene glycol, glycerol esters, e.g. triacetin, Myvacet® (acetylated mono- and diglycerides, C23H44O5 to C2sH4707), medium-chain triglycerides (Miglyol®), oleic acid or mixtures of at least two of said plasticizers. Aqueous dispersions of Eudragit RS® and optionally Eudragit RL® preferably contain triethyl citrate. The sustained-release material may comprise one or more plasticisers in amounts of, for example, 5 to 50 wt.% based on the amount of polymer(s) used.
The sustained-release material may also contain other conventional auxiliary substances known to those skilled in the art, e.g. lubricants, coloured pigments or surfactants.
The pharmaceutical formulation of the present invention may also comprise at least one of the components (A) and (B) coverd by an enteric coating form which dissolves as a function of pH. Because of this coating, part or all of the pharmaceutical formulation can pass through the stomach undissolved and the components (A) and/or (B) are only released in the intestinal tract. The enteric coating preferably dissolves at a pH of between 5 and 7.5.
The enteric coating may be based on any enteric material known to those skilled in the art, e.g. on methacrylic acid/methyl methacrylate copolymers with a monomer molar ratio of 1 :1 (Eudragit L®), methacrylic acid/methyl methacrylate copolymers with a monomer molar ratio of 1 :2 (Eudragit S®), methacrylic acid/ethyl acrylate copolymers with a monomer molar ratio of 1 :1 (Eudragit L30D-55®), methacrylic acid/methyl acrylate/methyl methacrylate copolymers with a monomer molar ratio of 7:3:1 (Eudragit FS®), shellac, hydroxypropyl methyl cellulose acetate-succinates, cellulose acetate-phthalates or a mixture of at least two of these components, which can optionally also be used in combination with the above-mentioned water-insoluble poly(meth)acrylates, preferably in combination with Eudragit NE30D® and/or Eudragit RL® and/or Eudragit RS®.
The coatings of the pharmaceutical formulations of the present invention may be applied by the conventional processes known to those skilled in the art, e.g. from Johnson, J.L., „Pharmaceutical tablet coating", Coatings Technology Handbook (Second Edition), Satas, D. and Tracton, A.A. (Eds), Marcel Dekker, Inc. New York, (2001 ), 863-866; Carstensen, T., „Coating Tablets in Advanced Pharmaceutical Solids", Swarbrick, J. (Ed.), Marcel Dekker, Inc. New York (2001), 455-468; Leopold, C.S., „Coated dosage forms for colon-specific drug delivery", Pharmaceutical Science & Technology Today, 2(5), 197-204 (1999), Rhodes, CT. and Porter, S.C, Coatings, in Encyclopedia of Controlled Drug Delivery. Mathiowitz, E. (Ed.), John Wiley & Sons, Inc., New York (1999), Vol. 1 , 299-31 . The respective descriptions are incorporated by reference and are part of the disclosure.
In another embodiment, the pharmaceutical formulation of the present invention contains one or both of components (A) and (B) not only in sustained-release form, but also in non-sustained-release form. By combination with the immediately released form, a high initial dose can be achieved for the rapid onset of the beneficial effect. The slow release from the sustained-release form then prevents the beneficial effect from diminishing. Such a pharmaceutical formulation is particularly useful for the treatment of acute health problems.
This may be achieved, for example, by a pharmaceutical formulation having at least one immediate-release coating comprising at least one of the components (A) and (B) to provide for rapid onset of the beneficial effect after administration to the patient.
Pharmaceutical Methods:
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 effect of the active substance combination and of each one of the components (A) and (B) 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 distributed in four groups. To three of these groups doses of the component (A) (with vehicle), of the component (B) (with vehicle) and of the active substance combination (vehicle) have been administered respectively by the intraperitoneal route. To the fourth group just vehicle has been administered in the same way.
Immediately after this, the rat is left in the cage 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. Pharmacological Methods:
Neuropeptide Y5 Receptor binding studies:
Method (I)
The experimental protocol follows the method by M. Gobbi et al. as decribed in M. Gobbi, T. Mennini, A. Vezzani: Autoradiographic Reevaluation of the Binding Properties of [125l][Leu31, Pro34] Peptide YY and [125l] Peptide YY3-36to Neuropeptide Y Receptor Subtypes in Rat Forebrain, The Journal of Neurochemistry, 1999, 72, 1663-1670, which is hereby incorporated by reference and is part of the disclosure, with modifications. Male Wistar rats are sacrificed by decapitation, their brains are rapidly removed and the cortex is dissected. Homogenization is performed in cold conditions in the buffer: 120 mM NaCl, 4.7 mM KCI, 2.2 mM CaCI2, 1.2 mM KH2P04, 1.2 mM MgS04, 25 mM NaHC03, 5.5 mM glucose, pH 7.4, by means of a Ultra- Turrax homogenizer for 15 seconds at 13,500 rpm. The ratio between fresh tissue weight and buffer volume is of twenty times. The membrane is centrifuged for 10 min at 48,000 g. The supernatant is discarded and the pellet is washed, resuspended and recentrifuged three more times. The final membrane resuspension is performed in the buffer: 120 mM NaCl, 4.7 mM KCI, 2.2 mM CaCI2, 1.2 mM KH2P04, 1.2 mM MgS04, 25 mM NaHC03, 5.5 mM glucose, 0.1 % BSA, 0.05% bacitracin, pH 7.4, at a 20 ml/g ratio of fresh tissue. The radioligand used is [125l]-PYY3-36 at the concentration of 28 pM. Incubation volume: 500 μl. A 1 μM concentration of BIBP 3226 is added to the incubation medium in order to saturate receptor Yi. Incubation is performed at 25 °C for 120 minutes and ended by rapid filtration in a Harvester Brandel Cell through fiber glass filters of the brand Schleicher & Schuell GF 3362 pretreated with a 0.5% polyethylenimine solution. The filters are cold-washed three times with two milliliters of the same buffer used in homogenization. The filters are transferred to vials and 5 ml of Ecoscint H liquid scintillation cocktail are added to each vial. The vials are allowed to reach steady state for a few hours before counting in a Wallac Winspectral 1414 scintillation counter. Non-specific binding is determined in the presence of 1 μM of pNPY (Neuropeptide Y of porcine origin). The assays are performed in triplicate. Method (II)
The experimental protocol follows the method described by Y. Hu, B. T. Bloomquist et al. in Y. Hu, B. T. Bloomquist et al., The Journal of Biological Chemistry, 1996, 271 , 26315-26319 with modifications. Cells C6 were transfected with the rat Y5 receptor. The cells were grown under standard culture conditions in 150 cm2 dishes and they were harvested using a rubber scraper and 10 ml PBS. The cells from five dishes were collected and centrifuged 2.500 g for 5 min. The pellet was washed by resuspending in 3 ml buffer (Tris-HCl 10 mM, pH 7.4), homogenized using a Potter S homogenizer, 10 strokes at 600 rpm and centrifuged in cold conditions at 48.000 g for 20 min (4°C). The resulting pellet was resuspended in cold 8 ml membrane buffer (Tris-HCl 25 mM, NaCl 120 mM, KCI 5 mM, KH2P04 1 ,2 mM, CaCI2 2,5 mM, MgS04 1 ,2 mM, BSA 0,15 mg/ml, Bacitracine 0,5 mg/ml, pH 7,4) and rehomogenized using the Potter S, 10 strokes at 600 rpm. The protein concentration of the used membran in the incubation was approximately 40 μg/ml. The radioligand is [125I]-PYY in a concentration of 100 pM. The incubation volume is 200μl. The incubation occurs at 25°C for 2 h and is stopped by rapid filtration in a in a Harvester Brandell Cell through fiber glass filters of the brand Schleicher & Schuell GF 3362 pretreated for two hours with 0,5% polyethyleneimine solution. Filters are cold-washed two times with 5 ml cold filtration buffer: Tris-HCl 25 mM, NaCl 120 mM, KCI 5 mM, KH2P04 1 ,2 mM, CaCI2 2,5 mM, MgSθ4 1 ,2 mM, pH 7,4. The filters were transferred into vials and 5 ml of Ecoscint H liquid scintillation cocktail are added to each vial. The vials are allowed to reach steady state for a few hours before counting with a Wallac Winspectral 1414 scintillation counter. Non-specific binding is determined in the presence of 1 μM of NPY. All binding assays were done in triplicate.
Method (III)
Binding to Neuropeptide Y
The experimental protocol follows the method by Y. Dumont et al. as described in Y. Dumont, A. Fournier, S. St-Pierre, R. Quirion: Characterization of Neuropeptide Y Binding Sites in Rat Brain Preparations Using [125l][Leu31, Pro34]Peptide YY and [125l]Peptide YY3-36 as Selective Y1 and Y2 Radioligands, The Journal of Pharmacology and Experimental Therapeutics, 1995, 272, 673-680, with slight modifications. Male Wistar rats are sacrificed by decapitation, their brains are rapidly removed and the hypoccampus is dissected. Homogenization is performed in cold conditions in the buffer: 120 mM NaCl, 4.7 mM KCI, 2.2 mM CaCI2, 1.2 mM KH2P04, 1.2 mM MgS04, 25 mM NaHC03, 5.5 mM glucose, pH 7.4, by means of a Ultra- Turrax homogenizer for 15 seconds at 13,500 rpm. The ratio between fresh tissue weight and buffer volume is of ten times. The membrane is centrifuged for 10 min at 48,000 g. The supernatant is discarded and the pellet is washed, resuspended and recentrifuged two more times. The final membrane resuspension is performed in the buffer: 120 mM NaCl, 4.7 mM KCI, 2.2 mM CaCI2, 1.2 mM KH2P04, 1.2 mM MgS04, 25 mM NaHC03, 5.5 mM glucose, 0.1% BSA, 0.05% bacitracin, pH 7.4, at a 90 ml/g ratio of fresh issue. The radioligand used is [125l]-PYY3-36 at the concentration of 28 pM. Incubation volume: 500 μl. Incubation is performed at 25 °C for 150 minutes and ended by rapid filtration in a Harvester Brandel Cell through fiber glass filters of the brand Schleicher & Schuell GF 3362 pretreated with a 0.5% polyethylenimine solution. The filters are cold-washed three times with three milliliters of the same buffer used in homogenization. The filters are transferred to vials and 5 ml of Ecoscint H liquid scintillation cocktail are added to each vial.The vials are allowed to reach steady state for a few hours before counting in a Wallac Winspectral 1414 scintillation counter. Non-specific binding is determined in the presence of 1 μM of pNPY (Neuropeptide Y of porcine origin). The assays are performed in triplicate. BINDING TO THE 5HT6 SEROTONIN RECEPTOR
HEK-293 cell membranes expressing the recombinant human 5HT6 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 following slight modifications. The respective part of the literature descriptions is incorporated here by reference and form part of the disclosure. The commercial membrane is diluted (1 :40 dilution) with the binding buffer: 50 mM Tris-HCl, 10 mM MgCI2, 0.5 mM EDTA (pH 7.4). The radioligand used is [3H]-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 HCI 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-, nM) are calculated by non-linear regression analysis using the EBDA/LIGAND program [Munson and Rodbard, Analytical Biochemistry, 1980, 107, 220], which is incorporated here by reference and form part of the disclosure.
The present invention is ilustrated below by the aid of examples. These ilustrations are given solely by way of example and do not limit the general spirit of the present invention. Examples:
Preparation of the compounds of general formula (la):
The intermediates of general formulas (IVa) and (Va) were prepared by means of conventional methods known to those skilled in the art. The preparation of some of the intermediates of general formulas (IVa) and (Va) is shown below:
Example Aa:
Synthesis of a compound of general formula (IVa)
2-chloro-N-(4-phenoxyphenyl)acetamide
Figure imgf000281_0001
To a solution of 4-phenoxyaniline (1 ,85g, 10 mmoles) and triethylamine (2,07 ml, 15 mmoles) in 25 ml dry dichloromethane, is added drop by drop to a solution of chloroacetyl chloride (1 ,18g, 10,5 mmoles) in 10 ml dry dichloromethane. The resulting reaction mixture is stirred for 1 hour at room temperature. Afterwards said reaction mixture is washed with 2x30 ml HCI (2 N) 1x30 ml water, dried over sodium sulfate and evaporated. 2,48 g. (Yield 95 %) of 2-chloro-N-(4-phenoxyphenyl)acetamide were obtained.
IR cm_1(KBr) :3270,1660, 1506, 1490, 1236, 843, 752, 691. Example Ba:
Synthesis of a compound of general formula (Va)
Preparation of 6-Chloro-1-(piperidin-4-yl)-1,4-dihydro-2H-3,1-benzoxazin-2-one hydrochloride
Figure imgf000282_0001
a) 1-(ferf-Butyloxycarbonyl)-4-[4-chloro-(2-hydroxymethylphenylamine)] piperidine
A solution of 1-(ferf-butyloxycarbonyl)-4-piperidinone (20 g, 0.10 mol), 2-amino-5- chlorobenzylic alcohol (17.34 g, 0.11 mol) and acetic acid (14 mL, 0.22 mol) in dry toluene (500 mL) was heated at reflux temperature, with water elimination by means of azeotrope distillation with Dean-Stark, for 6 hours. The mixture was then cooled and vacuum concentrated up to half volume. NaBHsCN (20 g, 0.32 mol) and dry THF (300 mL) were added to the resulting solution. Acetic acid (10 mL, 0.17 mol) was then dripped for one hour. The reaction was stirred at room temperature for 24 hours. The mixture was vacuum concentrated and the residue was dissolved in ethyl acetate (750 mL), washed with a NaHC03-saturated solution (4 x 250 mL) and a NaCI-saturated solution (250 mL), dried and evaporated to dryness. The residue was purified by means of flash chromatography eluting with a mixture of ethyl acetate: petroleum ether (1 :3). The desired product was thus obtained as an oil (32.7 g, 96%). 1H NMR (CDCIs): 1.32 (d, J=11.2 Hz, 2H), 1.41 (s, 9H), 1.92 (d, J=11.2 Hz, 2H), 2.92 (t, =12.0 Hz, 1 H), 3.10 (s, 1 H), 3.37 (m, 1 H), 3.88 (d, J= 13.7 Hz, 2H), 4.49 (s, 2H), 4.75 (s, 1 H), 6.52 (d, J= 8.6 Hz, 1 H), 6.96 (s, 1 H), 7.07 (d, J= 8.6 Hz, 1 H). b.) 1-(1-tert-Butyloxycarbonyl-4-piperidinyl)-6-chloro-1,4-dihydro-2H-3,1- benzoxazin-2-one
N, N-diisopropylethylamine (DIEA) (43 mL, 0.25 mol) and triphosgene (8.65 g, 29.2 mmol) were added to a solution of 1 -( erf-Butyloxycarbonyl)-4-[(4- chloro-(2-hydroxymethyl) phenyl-amino)]piperidine (27.0 g, 79 mmol) in dry THF (250 mL) cooled at 0°C The reaction was stirred at 0°C for 1 h and at room temperature for 72 h. Ethyl ether was added and the mixture was cooled at 0°C for 3 h and the DIEA hydrochloride was then filtered. The filtered solution was evaporated to dryness and the residue was dissolved in ethyl acetate (750 mL), washed with 5% solution of critic acid (2 x 500 mL), water (250 mL) and NaHC03- saturated solution (2 x 500 mL). The ethyl acetate solution was dried (MgS04), filtered and evaporated under reduced pressure. The residue was brought to a boil with ethyl ether until the whole solid was dissolved and then cooled overnight to yield the desired compound in crystalline form (28.9 g, 67%). Melting point: 177-179 °C
1H NMR (CDCI3): 1.46 (s, 9H), 1.79 (d, J= 10.1 Hz, 1 H), 2.54 (m, 2H), 2.78 (m, 2H), 3.96 (m, 1H), 4.28 (m, 2H), 5.02 (s, 2H), 6.98 (d, J= 8.7 Hz, 1H) 7.13 (d, J= 2.4 Hz, 1 H), 7.28 (dd, J= 8.7 Hz, J= 2.4 Hz, 1 H).
c.) 6-chloro-1-(piperidin-4-yl)-1,4-dihydro-2H-3,1-benzoxazin-2-one hydrochloride
A solution of 1-[(1-tetf-Butyloxycarbonyl)-4-piperidinyl]-6-chloro-1 ,4-dihydro-2H-3,1- benzoxazin-2-one (24 g, 65 mmol) in ethyl acetate (500 mL) was cooled at 0°C Afterwards a 5 M solution of hydrogen chloride in ethyl ether (500 mL) was added and the resulting mixture was stirred at 0°C for 4 h. The precipitate formed was collected by filtration, washed with ether and vacuum dried to yield the desired product as a solid (16.95 g, 97%). Melting point: 254-257 °C 1H NMR (CD3OD): 2.13 (d, J= 12.2 Hz, 2H), 2.88 (m, 2H), 3.20 (m, 2H), 3.53 (d, J= 12.8 Hz, 2H), 4.24 (m, 1 H), 5.16 (s, 2H), 7.31 (m, 2H), 7.41 (dd, J= 8.8 Hz, J= 2.6 Hz, 1H).
Several substituted 3,1-benzoxazin-2-one compounds were prepared via the respectively substituted benzyl alcohols obtained by reduction of the corresponding substituted anthranilic acids with lithium aluminium hydride and other reducing agents known and used in the state of the art (see scheme 2), e.g. por ejemplo 6-methyl-1- (piperidin-4-yl)-1 ,4-dihydro-2H-3,1-benzoxazin-2-one, 7-methyl-1-(piperidin-4-yl)-1 ,4- dihydro-2H-3,1-benzoxazin-2-one, 8-methyl-1-(piperidin-4-yl)-1 ,4-dihydro-2H-3,1- benzoxazin-2-one , 5-methoxy-1-(piperidin-4-yl)-1 ,4-dihydro-2H-3,1-benzoxazin-2- one, 6-fluoro-1-(piperidin-4-yl)-1 ,4-dihydro-2H-3,1-benzoxazin-2-one, 8-methoxy-1- (piperidinyl)-1 ,4-dihydro-2H-3,1-benzoxazin-2-one, 5-methyl-1-(piperidin-4-yl)-1 ,4- dihydro-2H-3,1-benzoxazin-2-one, 7-fluoro-1-(piperidin-4-yl)-1 ,4-dihydro-2H-3,1- benzoxazin-2-one, 5-fluoro-1 -(piperidin-4-yl)-1 ,4-dihydro-2H-3, 1 -benzoxazin-2-one, 6-methoxy-1-(piperidinyl)-1 ,4-dihydro-2H-3,1-benzoxazin-2-one, 5-chloro-1- (piperidinyl)-l ,4-dihydro-2H-3,1-benzoxazin-2-one, 7-chloro-1-(piperidinyl)-1 ,4- dihydro-2H-3,1-benzoxazin-2-one, 8-chloro-1-(piperidinyl)-1 ,4-dihydro-2H-3,1- benzoxazin-2-one and others. The removal of the protecting group of the corresponding 8-methoxy-1-(piperidinyl)-1 ,4-dihydro-2H-3,1-benzoxazin-2-one 6- methoxy-1-(piperidinyl)-1 ,4-dihydro-2H-3,1-benzoxazin-2-one and 5-methoxy-1- (piperidinyl)-1 ,4-dihydro-2H-3,1-benzoxazin-2-one compounds according to conventional methods, e.g. BBr3 in an inert organic solvent yields the respective 8- hydroxy-1 -(piperidinyl)-l ,4-dihydro-2H-3,1 -benzoxazin-2-one, 6-hydroxy-1 - (piperidinyl)-l ,4-dihydro-2H-3,1-benzoxazin-2-one and 5-hydroxy-1-(piperidinyl)-1 ,4- dihydro-2H-3,1-benzoxazin-2-one compounds. The unsubstituted benzoxazin-2-one 1-(piperidin-4-yl)-1 ,4-dihydro-2H-3,1-benzoxazin-2-one is prepared according the method described in J. Med. Chem. 1995, 38, 4634 and J.Med.Chem. 1998, 41 , 2146, which are hereby incorporated by reference and form part of the disclosure.
Reduction of the substituted anthranilics:
The reduction of the substituted anthranilic acids was performed by conventional methods known in the state of the art, e.g. by the use of L.AIH4 as reducing agent in anhydrous THF under an inert-gas atmosphere, e.g. argon or nitrogen. The process is very efficient and in most cases the corresponding 2-aminobenzylalcohols are obtained in very good yields.
General method for the reduction of substituted anthranilic acids: To a three neck flask, equipped with a mechanical stirrer and an inlet for gaseous nitrogen, 100 mL anhydrous THF and 116,6 mmoles of LiAIH4 were given and the resulting suspension cooled to 0 °C After the addition of 58,3 mmoles of the corresponding substituted anthranilic acid in 150 mL anhydrous THF, the resulting reaction mixture is warmed to room temperature and stirred or about an hour. Under cooling to 0° C 4,7 mL water , 4,7 mL NaOH 15 wt.-%, and finally 14 mL water are carefully added to the mixture. The resulting suspension is filtered and washed with ethylacetate.
The organic phase is washed with water, dried and evaporated. In some cases the resulting product may be used without further purification.
Example 1a:
Preparation of 1 -{1 -[N-(9-oxo-9H-fluoren-2-yl)aminocarbonylmethyl]-4- (piperidinyl)}-1 ,4-dihydro-2H-3, 1 -benzoxazin-2-one hydrochloride.
A mixture of 1-(4-piperidinyl)-1 ,4-dihydro-2H-3,1 -benzoxazinone hydrochloride (2.68 g, 10 mmol), N-(9-oxo-9H-fluoren-2-yl)-2-chloroacetamide (2.99 g, 11 mmol) and K2CO3 (5.53 g, 40 mmol) in DMF (40 mL) was stirred overnight at room temperature. H20 (100 mL) was then added and the precipitate formed was collected by filtration.The solid was dissolved in hot ethyl acetate, washed with water, decanted, dried and evaporated to dryness. The residue dissolved in EtOH was brought to pH=3 with a 1 M solution of hydrogen chloride in EtOH and filtered to yield the desired hydrochloride in crystalline form (3.73 g, 74%). Example 104a:
Preparation of N-[4-chloro-2-(2-chloro-benzoyl)-phenyl]-2-[4-(6-chloro-2-oxo-4H- benzo[d][1 ,3]oxazin-1 -yl]-piperidin-1 -yl]-acetamide hydrochloride
Figure imgf000286_0001
A mixture of 1-(4-piperidinyl)-1 ,4-dihydro-2H-3,1 -benzoxazinone hydrochloride (161 mg, 0,60 mmol), 2-(2-chloroacetamide)-2',5-dichlorobenzophenone (226 mg, 0,66 mmol) and K2C03 (330 mg, 2,40 mmol) in DMF (10 mL) is stirred at room temperature overnight. Afterwards H20 (15 mL) is added and the formed precipitate harvested by filtration. The solid is dissolved in ethyl acetate, washed with water, decanted, dryed and evaporated. The residue dissolved in ethanol and upon addition of 0,22 ml of a 2,8 M solution of hydrochloric acid in ethanol abs. the hydrochloride salt is crystallized, which was filtered and dryed. 209 mg of a white solid were obtained. Yield 61 %.
IR (cm"1) KBr: 3398, 2860, 1702, 1493, 1295, 1246, 1202, 1042, 946, 758. 1H-NMR: 1.9 (d, J=12.9 Hz, 2 H) 2.9 (m, 2 H) 3.2 (m, 2 H) 3.5 (d, J=11.2 Hz, 2 H) 4.0 (s, 2 H) 4.2 (m, 1 H) 5.0 (s, 2 H) 7.3 (m, 4 H) 7.4 (m, 1 H) 7.5 (m, 2 H) 7.5 (m, 1 H) 7.6 (dd, J=8.5, 2.4 Hz, 1 H) 7.8 (d, J=8.5 Hz, 1 H) 10.2 (s, 1 H) 10.9 (s, 1 H) (DMSO- d6).
Melting point: 201-204 °C The melting point data of some of the benzoxazinone-derived compounds of general formula (la) prepared according to the analog method described in examples 1 and 104 are shown in the following table.
In the compounds according to examples 1-100 three of the substitutents R1a, R2a, R3a and R4a as well as the substituents R5 to R9 all represent H. Thus, the general formula (la) may be written in the simplified form (la) given below, wherein Rx indicates the respective substituents R1a-R4a.
Figure imgf000288_0001
Figure imgf000288_0002
Figure imgf000289_0001
Figure imgf000290_0001
Figure imgf000291_0001
Figure imgf000292_0001
Figure imgf000293_0001
Figure imgf000294_0001
Figure imgf000295_0001
Figure imgf000296_0001
Figure imgf000297_0001
Figure imgf000298_0001
Figure imgf000299_0001
Figure imgf000300_0001
Figure imgf000301_0001
Figure imgf000302_0001
Figure imgf000303_0001
Figure imgf000304_0001
Figure imgf000305_0001
Figure imgf000306_0001
Figure imgf000307_0001
Figure imgf000308_0001
Figure imgf000309_0001
Figure imgf000310_0001
Figure imgf000311_0001
Figure imgf000312_0001
Figure imgf000313_0001
313
Figure imgf000314_0001
Figure imgf000315_0001
Figure imgf000316_0001
Figure imgf000317_0001
Figure imgf000318_0001
Figure imgf000319_0001
Figure imgf000320_0001
Figure imgf000321_0001
Figure imgf000322_0001
Figure imgf000323_0001
Figure imgf000324_0001
Figure imgf000325_0001
Figure imgf000326_0001
Example 142:
N-(9-Hydroxy-9H-fluoren-3-yl)-2-[4-(4-methyl-2-oxo-4H-benzo[d][1 ,3]oxazin-1- yl)-piperidin-1 -yl]-acetamide.
Example 143:
N-(9-EthyI-9H-carbazol-3-yl)-2-[4-(4-methyl-2-oxo-4H-benzo[d][1 ,3]oxazin-1-yl)- piperidin-1 -yl]-acetamide.
Example 144:
2-[4-(4-Methyl-2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidin-1 -yl]-N-(4-phenoxy- phenyl)-acetamide. Example 145:
2-{2-[4-(2-Oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidin-1 -yl]-acetamino}-benzoic acid.
Example 146:
1 -{1 -[2-(6-Fluoro-2-methyl-3,4-dihydro-2H-quinoline-1 -yl)-2-oxo-ethyl]-piperidin- 4-yl}-1 ,4-dihydro-benzo[d][1 ,3]oxazin-2-one.
Example 147:
6-Chloro-1 -{1 -[2-(6-fluoro-2-methyl-3,4-dihydro-2H-quinoline-1 -yl)-2-oxo-ethyl]- piperidin-4-yl}-1 ,4-dihydro-benzo[d][1 ,3]oxazin-2-one.
Example 148:
1 -{1 -[2-(6-Fluoro-2-methyl-3,4-dihydro-2H-quinoline-1 -yl)-2-oxo-ethyl]-piperidin- 4-yl}-6-methyl-1 ,4-dihydro-benzo[d][1 ,3]oxazin-2-one.
Example 149:
1-{1-[2-(6-Fluoro-2-methyl-3,4-dihydro-2H-quinoline-1-yl)-2-oxo-ethyl]-piperidin- 4-yl}-8-methyl-1 ,4-dihydro-benzo[d][1 ,3]oxazin-2-one.
Example 150:
1-{1-[2-(6-Methoxy-2,2,4-trimethyl-3,4-dihydro-2H-quinoline-1-yl)-2-oxo-ethyl]- piperidin-4-yl}-1 ,4-dihydro-benzo[d][1 ,3]oxazin-2-one. Example 151 :
6-Chloro-1-{1-[2-(6-methoxy-2,2,4-trimethyl-3,4-dihydro-2H-quinoline-1-yl)-2- oxo-ethyl]-piperidin-4-yl}-1 ,4-dihydro-benzo[d][1 ,3]oxazin-2-one.
Example 152:
1-{1-[2-(6-Methoxy-2,2,4-trimethyl-3,4-dihydro-2H-quinoline-1-yl)-2-oxo-ethyl]- piperidin-4-yl}-8-methyl-1 ,4-dihydro-benzo[d][1 ,3]oxazin-2-one.
Example 153:
1-{1-[2-(6-Methoxy-2,2,4-trimethyl-3,4-dihydro-2H-quinoline-1-yl)-2-oxo-ethyl]- piperidin-4-yl}-6-methyl-1 ,4-dihydro-benzo[d][1,3]oxazin-2-one.
Example 154:
N-(9-Hydroxy-9H-fluoren-3-yl)-2-[4-(2-oxo-7-trifluormethyl-4H- benzo[d][1 ,3]oxazin-1 -yl)-piperidin-1 -yl]-acetamide.
Example 155:
N-(9H-carbazol-3-yl)-2-[4-(2-oxo-7-trifluormethyl-4H-benzo[d][1 ,3]oxazin-1-yl)- piperidin-1 -yl]-acetamide.
Example 156:
2-[4-(2-Oxo-7-trifluormethyl-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidin-1 -yl]-N-(4- phenoxy-phenyl)-acetamide. Example 157:
N-(9-Ethyl-9H-carbazol-3-yl)-2-[4-(2-oxo-7-trifluormethyl-4H- benzo[d][1 ,3]oxazin-1 -yl)-piperidin-1 -yl]-acetamide.
Example 158:
2-4-(6,7-Difluoro-2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidin-1 -yl]-N-(9- hydroxy-9H-fluoren-3-yl)-acetamide.
Example 159:
N-(9H-carbazol-3-yl)-2-[4-(6,7-difluoro-2-oxo-4H-benzo[d][1 ,3]oxazin-1-yl)- piperidin-1 -yl]-acetamide.
Example 160:
2-4-(6,7-Difluoro-2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidin-1 -yl]-N-(4- phenoxy-phenyl)-acetamide.
Example 161:
2-4-(6,7-Difluoro-2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidin-1 -yl]-N-(9-ethyl- 9H-carbazol-3-yl)-acetamide.
Example 162:
2-[4-(4-Methyl-2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidin-1 -yl]-N-(9-oxo-9H- fluoren-3-yl)-acetamide. Example 163:
2-[4-(6-Chloro-2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yi)-piperidin-1 -yl]-N-(3- dimethylamino-phenyl)-acetamide.
Preparation of the compound of general formula (lb):
Example Ab:
Synthesis of an intermediate compound of general formula (Mb)
Preparation of 6-Chloro-1-(piperidine-4-yl)-1 ,4-dihydro-2H-3,1-benzoxazin-2- one hydrochloride
Figure imgf000330_0001
b) 1-(teAf-Butyloxycarbonyl)-4-[4-chloro-(2- hydroxymethylphenylamine)] piperidine
A solution of 1-(fer-butyloxycarbonyl)-4-piperidinone (20 g, 0J0 mol), 2-amino- 5-chlorobenzylic alcohol (17.34 g, 0.11 mol) and acetic acid (14 mL, 0.22 mol) in dry toluene (500 mL) was heated at reflux temperature, with water elimination by means of azeotrope distillation with Dean-Stark, for 6 hours. The mixture was then cooled and vacuum concentrated up to half volume. NaBH3CN (20 g, 0.32 mol) and dry THF (300 mL) were added to the resulting solution. Acetic acid (10 mL, 0.17 mol) was then dripped for one hour. The reaction was stirred at room temperature for 24 hours. The mixture was vacuum concentrated and the residue was dissolved in ethyl acetate (750 mL), washed with a NaHC03- saturated solution (4 x 250 mL) and a NaCI-saturated solution (250 mL), dried and evaporated to dryness. The residue was purified by means of flash chromatography eluting with a mixture of ethyl acetate: petroleum ether (1 :3). The desired product was thus obtained as an oil (32.7 g, 96%). 1H NMR (CDCI3): 1.32 (d, J=11.2 Hz, 2H), 1.41 (s, 9H), 1.92 (d, J=11.2 Hz, 2H), 2.92 (t, =12.0 Hz, 1 H), 3.10 (s, 1 H), 3.37 (m, 1 H), 3.88 (d, J= 13.7 Hz, 2H), 4.49 (s, 2H), 4.75 (s, 1 H), 6.52 (d, J= 8.6 Hz, 1 H), 6.96 (s, 1 H), 7.07 (d, J= 8.6 Hz, 1 H).
d.) 1-(1-fe^Butyloxycarbonyl-4-piperidinyl)-6-chloro-1,4-dihydro-2H- 3,1-benzoxazin-2-one
N, N-diisopropylethylamine (DIEA) (43 mL, 0.25 mol) and triphosgene
(8.65 g, 29.2 mmol) were added to a solution of 1-(tert-ButyIoxycarbonyl)-4-[(4- chloro-(2-hydroxymethyl) phenyl-amino)]piperidine (27.0 g, 79 mmol) in dry THF
(250 mL) cooled at 0°C. The reaction was stirred at 0°C for 1 h and at room temperature for 72 h. Ethyl ether was added and the mixture was cooled at 0°C for
3 h and the DIEA hydrochloride was then filtered. The filtered solution was evaporated to dryness and the residue was dissolved in ethyl acetate (750 mL), washed with 5% solution of critic acid (2 x 500 mL), water (250 mL) and
NaHC03-saturated solution (2 x 500 mL). The ethyl acetate solution was dried
(MgS04), filtered and evaporated under reduced pressure. The residue was brought to the boil with ethyl ether until the whole solid was dissolved and then cooled overnight to yield the desired compound in crystalline form (28.9 g,
67%).
Melting point: 177-179 °C
1H NMR (CDCI3): 1.46 (s, 9H), 1.79 (d, J= 10.1 Hz, 1 H), 2.54 (m, 2H), 2.78 (m, 2H), 3.96 (m, 1 H), 4.28 (m, 2H), 5.02 (s, 2H), 6.98 (d, J= 8.7 Hz, 1 H) 7.13 (d, J= 2.4 Hz, 1 H), 7.28 (dd, J= 8.7 Hz, J= 2.4 Hz, 1H). e.) 6-chloro-1-(piperidin-4-yl)-1,4-dihydro-2H-3,1-benzoxazin-2-one hydrochloride
A solution of 1-[(1-te/ -Butyloxycarbonyl)-4-piperidinyl]-6-chloro-1 ,4-dihydro-2H- 3,1-benzoxazin-2-one (24 g, 65 mmol) in ethyl acetate (500 mL) was cooled at 0°C. A 5 M solution of hydrogen chloride in ethyl ether (500 mL) was then added and the resulting mixture was stirred at 0°C for 4 h. The precipitate formed was collected by filtration, washed with ether and vacuum dried to yield the desired product as a solid (16.95 g, 97%). Melting point: 254-257 °C
1H NMR (CD3OD): 2.13 (d, J= 12.2 Hz, 2H), 2.88 (m, 2H), 3.20 (m, 2H), 3.53 (d, J= 12.8 Hz, 2H), 4.24 (m, 1 H), 5.16 (s, 2H), 7.31 (m, 2H), 7.41 (dd, J= 8.8 Hz, = 2.6 Hz, 1 H).
Several substituted 3,1-benzoxazin-2-one compounds were prepared via the respectively substituted benzyl alcohols by reducing the respectively substituted anthranilic acids with lithium aluminium hydride and other known reducing agents by methods well known to those skilled in the art (see scheme 1), e.g. por ejemplo 6-methyl-1-(piperidin-4-yl)-1 ,4-dihydro-2H-3,1-benzoxazin-2-one, 7- methyl-1-(piperidin-4-yl)-1 ,4-dihydro-2H-3,1-benzoxazin-2-one, 8-methyl-1- (piperidin-4-yl)-1 ,4-dihydro-2H-3,1-benzoxazin-2-one , 5-methoxy-1-(piperidin-4- yl)-1 ,4-dihydro-2H-3,1-benzoxazin-2-one, 6-fluoro-1-(piperidin-4-yl)-1 ,4-dihydro- 2H-3,1-benzoxazin-2-one, 8-methoxy-1-(piperidinyl)-1 ,4-dihydro-2H-3,1- benzoxazin-2-one, 5-methyl-1-(piperidin-4-yl)-1 ,4-dihydro-2H-3,1-benzoxazin-2- one, 7-fluoro-1-(piperidin-4-yl)-1 ,4-dihydro-2H-3,1-benzoxazin-2-one, 5-fluoro-1- (piperidin-4-yl)-1 ,4-dihydro-2H-3,1-benzoxazin-2-one, 6-methoxy-1-(piperidinyl)- 1 ,4-dihydro-2H-3,1-benzoxazin-2-one, 5-chloro-1-(piperidinyl)-1 ,4-dihydro-2H- 3,1-benzoxazin-2-one, 7-chloro-1-(piperidinyl)-1 ,4-dihydro-2H-3,1-benzoxazin- 2-one, 8-chloro-1-(piperidinyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one and others. The reaction of the respective 5-methoxy-1-(piperidinyl)-1 ,4-dihydro-2H-3,1- benzoxazin-2-one, 8-methoxy-1-(piperidinyl)-1 ,4-dihydro-2H-3,1-benzoxazin-2- one and 6-methoxy-1-(piperidinyI)-1 ,4-dihydro-2H-3,1-benzoxazin-2-one compounds according to conventional methods, e.g. BBr3 in an inert organic solvent yields the respective 5-hydroxy-1-(piperidinyl)-1 ,4-dihydro-2H-3,1- benzoxazin-2-one, 8-hydroxy-1-(piperidinyl)-1 ,4-dihydro-2H-3,1-benzoxazin-2- one and 6-hydroxy-1-(piperidinyl)-1 ,4-dihydro-2H-3,1-benzoxazin-2-one compounds. The unsubstituted benzoxazin-2-one 1-(pϊperidin-4-yl)-1 ,4-dihydro- 2H-3,1-benzoxazin-2-one is prepared according the method described in J. Med. Chem. 1995, 38, 4634 and J.Med.Chem. 1998, 41 , 2146, which are hereby incorporated by reference and form part of the disclosure.
The substituted anthranilic acids were reduced by conventional methods known to those skilled in the art, e.g. by the use of LiAIH4 as reducing agent in anhydrous THF under an inert-gas atmosphere, e.g. argon or nitrogen. This process is very efficient and in most cases the respective 2- aminobenzylalcohols are obtained in very good yields.
General instruction for the reduction of substituted anthranilic acids:
To a three neck flask, equipped with a mechanical stirrer and an inlet for gaseous nitrogen, 100 mL anhydrous THF and 116,6 mmoles of LiAIH4 were given and the resulting suspension cooled to 0 °C. After the addition of 58,3 mmoles of the respective substituted anthranilic acid in 150 mL anhydrous THF, the resulting reaction mixture is warmed to room temperature and stirred or about an hour. Under cooling to 0° C 4,7 mL water , 4,7 mL NaOH 15 wt.-%, and finally 14 mL water are carefully added to the mixture. The resulting suspension is filtered and washed with ethylacetate.
The organic phase is washed with water, dried and the solvent evaporated. In most cases the resulting product may be used without further purification. Example 5b:
Preparation of 1-[1-quinoline-8-sulfonyl)-piperidine-4-yl]-1 ,4-dihydro- benzo[d][1 ,3]oxazin-2-one
Figure imgf000334_0001
150 mg (0,66 mmol) quinoline-8-sulfonyl chloride are added to a mixture of 1-(4- piperidinyl)-1 ,4-dihydro-2H-3,1 -benzoxazinone hydrochloride (161 mg, 0,60 mmol) and diisopropylethylamin (230 mg, 1 ,80 mmol) in dichloromethane (10 ml) and the resulting reaction mixture was stirred overnight at room temperature. The reaction mixture was then washed with water (3 x 15 mL) and the organic phase was separated, dryed and evaporated to dryness. A solid was obtained, which was recrystallized from ethanol. 182 mg of 1-[1-quinoline- 8-sulfonyl)-piperidine-4-yl]-1 ,4-dihydro-benzo[d][1 ,3]oxazin-2-one were obtained as a white solid (yield 69 %).
IR(cm ,-"1')KBr: 1712, 1337, 1291, 1205, 1162, 1144, 1034,717,583
1H-NMR(δ in ppm): 1.8 (d, J=9.5 Hz, 2 H) 2.6 (qd, J=12.6, 4.4 Hz, 2 H) 3.0 (td, J=12.8, 2.5 Hz, 2 H) 4.1 (tt, J=12.5, 3.8 Hz, 1 H) 4.3 (ddd, J=13.0, 2.3 Hz, 2 H)
5.0 (s, 2 H) 7.1 (m, 3 H) 7.3 (m, 1 H) 7.6 (dd, J=8.4, 4.2 Hz, 1 H) 7.6 (m, 1 H)
8.1 (dd, J=8.2, 1.3 Hz, 1 H) 8.3 (dd, J=8.3, 1.7 Hz, 1 H) 8.5 (dd, J=7.3, 1.5 Hz, 1 H) 9.1 (dd, =4.2, 1.8 Hz, 1 H) (CDCI3-d).
Melting point: 170-172 °C. The compounds according to examples 1b-4b and 6b-10b given in the following table lb were prepared analogously to the methods described above:
Table 1b:
Figure imgf000336_0001
Figure imgf000337_0001
Figure imgf000337_0002
Figure imgf000338_0001
Figure imgf000339_0001
Preparation of the compounds of general formula (Ic):
METHOD Ac
Example 7c:
Preparation of N-[3-(2-dimethylaminoethyl)-1 H-indol-5-yl]-5-chloro-3-methyl- benzo[b]thiophene-2-sulphonamide.
To a solution of 3.05 g (15 mMol) of 5-amino-3-(2-dimethylaminoethyl)-1 H-indol in 100 ml of pyridine is added dropwise at ambient temperature a solution of 4.21 g (15 mMol) of 5-chloro-3-methyl-benzo[b]thiophene-2-sulphonyl chloride in 20 ml of pyridine. The reaction mixture is stirred at ambient temperature for 20 hours. It is then evaporated to dryness, slightly alkalinised with diluted ammonia and dissolved in ethyl acetate. The organic phase is washed with water and a saturated solution of sodium bicarbonate, it is separated and dried with anhydrous sodium sulphate. The organic solution is evaporated to dryness and the resulting solid is repeatedly washed with ethyl ether, to yield 5.5 g (82%) of N-[3-(2-dimethylaminoethyl)-1 H-indol-5-yl]-5-chloro-3-methyl- benzo[b]thiophene-2-sulphonamide as a solid with m.p. = 226-227°C.
METHOD Be
Example 26c:
Preparation of N-[3-(2-diethylaminoethyl)-1 H-indol-5-yl]-N-ethyl-naphthalene-2- sulphonamide.
To a mixture of 285 mg (0.7 mMol) of N-[3-(2-diethylaminoethyl)-1 H-indol- 5yl]naphthalene-2-sulphonamide (example 17) and 80 mg (0.7 mMol) of potassium t-butoxide in 3 ml of DMSO are stirred for 30 minutes at ambient temperature. Then are added 105 mg (0.7 mMol) of ethyl iodide and left with stirring for 3 hours. Water is added and is extracted with ethyl acetate. The organic solution is evaporated to dryness and the resulting crude is purified by chromatography on silica gel, using as an eluent mixtures of methylene chloride / methanol /ammonia, yielding N-[3-(2-diethylaminoethyl)-1 H-indol-5-yl]-N-ethyl- naphthalene-2-sulphonamide as a solid with m.p. = 49-50°C.
METHOD Cc
Example 18c:
Preparation of N-[3-(1 -methyl-1 ,2,3,6-tetrahydropyridin-4-yl)-1H-indol-5- yl]naphthalene-1 -sulphonamide.
To a solution of 712 mg (13.2 mMol) of sodium methoxide in 100 ml of methanol are added 850 mg (2.64 mMol) of N-[1H-indol-5-yl]naphthalene-1 -sulphonamide followed by 596 mg (5.28 mMol) of 1-methyl-4-piperidone and the resulting solution is heated to reflux for 48 hours. The reaction mixture is concentrated at reduced pressure and the residue obtained is purified by chromatography over silica gel, using as eluent mixtures of methylene chloride/ methanol /ammonia, to yield 573 mg (52%) of N-[3-(1 -methyl-1 ,2,3,6-tetrahydropyridin-4-yl)-1 H-indol- 5-yl]naphthalene-1 -sulphonamide as a solid with m.p. = 244-245°C.
METHOD Dc
Example 12c:
Preparation of N-[3-(1 -methyl-piperidin-4-yl)-1 H-indol-5-yl]naphthalene-1 - sulphonamide. To a solution of 417 mg (1 mMol) of N-[3-(1 -methyl-1 , 2,3,6-tetrahydropyridin-4- yl)-1H-indol-5-yl]naphthalene-1 -sulphonamide in 50 ml of methanol are added 100 mg of 5% palladium on carbon. The mixture is hydrogenated at ambient temperature at an initial hydrogen pressure of 3 atmospheres for 20 hours. The reaction mixture is filtered and the filtrate is concentrated at reduced pressure to provide a crude that is suspended in ethyl ether, yielding 272 mg (65%) of N-[3- (1-methyl-piperidin-4-yl)-1H-indol-5-yl]naphthalene-1 -sulphonamide as a solid with m.p.= 254-256°C
METHOD Ec
Example 3c:
Preparation of N-[3-(2-diethylaminoethyl)-1 H-indol-5-yl]naphthalene-1 - sulphonamide hydrochloride.
1.05 g (2.5 mMol) of N-[3-(2-diethylaminoethyl)-1H-indol-5-yl]naphthalene-1- sulphonamide (example 2) are dissolved in 10 ml of ethanol and 0.6 ml are added of a 4.2 N solution of hydrochloric acid in ethanol. It is allowed to crystallise at ambient temperature. N-[3-(2-diethylaminoethyl)-1H-indol-5- yl]naphthalene-1 -sulphonamide hydrochloride is obtained as a solid with m.p.= 255-257°C.
The melting point and spectroscopic data for identifying some of the compounds used according to the present invention are shown in the following table:
Figure imgf000343_0001
Ex R ,1c R ι2c nc R 3c Salt m.p. °C IR cm"1 H-RMN (300 MHz),δ (solvent)
0.88(t, 6H, J=7.1 Hz); 2.28(s, 3H); 3387, 2970, 2.30-2.46(m, 6H); 2.58(m, 2H); 2931, 1466, 6.85(dd, 1 H, J=8.6, 2.0 Hz); 7.10(m, 1236, 1158, 2H); 7.20(d, 1H, J=8.6 Hz); 7.50(dd,
1c H (CH3CH2)2N- H 170-173 1107,1080, 1H, J=8.7, 2.0 Hz); 7.90(d, 1H, J=2.0 993, 862, 805, Hz); 7.98(d, 1H, J=8.7 Hz); 10.10 (bb,
Figure imgf000343_0002
657, 565. 1H); 10.80(s, 1H). (DMS0-d6) 0.90(t, 6H, J=7.1 Hz); 2.33-2,55(m, 3451, 3337, 8H); 6.69(dd, 1 H, J=8J, 1.8 Hz); 6, 2972, 1466, 95(s, 1 H); 7,02(d, 1H, J=1 ,8 Hz); 1319, 1237, 7.05(d, 1H, J=8J Hz); 7.47(t, 1 H,
2c H (CH3CH2)2N- H 170 1157, 1132, J=7J Hz); 7.63(m, 1H); 7.70(m, 1H); 1091, 991 , 770, 8.01(m, 2H); 8.12(d, 1 H, J=7.5 Hz);
Figure imgf000343_0003
675, 583, 481. 8.77(d, 1 H, J=8.1 Hz); 10.10(bb, 1H);1 10,66(8, 1H) (DMSO-d6)
Figure imgf000344_0001
Figure imgf000345_0001
Figure imgf000346_0001
Figure imgf000347_0001
Figure imgf000348_0001
Figure imgf000349_0001
Figure imgf000350_0001
Figure imgf000351_0001
Figure imgf000352_0001
Figure imgf000353_0001
Figure imgf000354_0001
Figure imgf000355_0001
Figure imgf000356_0001
Figure imgf000357_0001
Figure imgf000358_0001
Figure imgf000359_0001
Figure imgf000360_0001
Figure imgf000361_0001
Preparation of the compounds of general formula (Id):
Example 1d.- Preparation of N-[1-(2-dimethylaminoethyl)-1 H-indole-4-yl]-5- chloro-3-methyl-benzo[b]thiophene-2-sulfonamide.
185.5 mg (0.66 mMol) of 5-chloro-3-methyl-benzo[b] thiophene-2-sulfonyl chloride were added to a solution of 122 mg (0.6 mMol) of 4-amino-3-(2- dimethylaminoethyl)-1 H-indole in 2 ml of dimethylformamide and 116 mg of N- ethyldiisopropylamine. The reaction mixture was stirred at the room temperature for 20 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 111 mg (42%) of N-[1 -(2-dimethylaminoethyl)-1 H- indole-4-yl]-5-choloro-3-methyl-benzo[b]thiophene-2-sulfonamide as a creamy solid.
Example 2d.- Preparation of N-[1-(2-dimethylaminoethyl)-1 H-indole-4-yl]- naphtalene-2-sulfonamide
121 mg (51%) of the mentioned compound were obtained from 122 mg (0.6 mMol) of 4-amino-1-(2-dimethylaminoethyl)-1 H-indole and 149.5 mg (0.66 mMol) of naphtalene-2-sulfonyl chloride, by means of the process described in the Example 1d, as a creamy solid.
Example 3d.- Preparation of N-[1-(2-dimethylaminoethyl)-1 H-indole-4-yl]- naphtalene-1 -sulfonamide
130 mg (55%) of the mentioned compound are obtained from 122 mg (0.6 mMol) of 4-amino-1-(2-dimethylaminoethyl)-1 H-indole and 149.5 mg (0.66 mMol) of naphtalene-1 -sulfonyl chloride, by means of the process described in the Example 1d, as a creamy solid.
Example 4d.- Preparation of N-[1-(2-dimethylaminoethyl)-1 H-indole-4-yl]-4 phenylbenzenesulfonamide
107 mg (42%) of the mentioned compound were obtained from 122 mg (0.6 mMol) of 4-amino-1-(2-dimethylaminoethyl)-1 H-indole and 169 mg (0.66 mMol) of 4- phenylbenzenesulfonyl chloride, by means of the process described in the Example 1d, as a creamy solid.
Example 5d.- Preparation of N-[1-(2-dimethylaminoethyl)-1 H-indole-4-yl]-2- (naphthalene-l-yl)-ethanesulfonamide
52 mg (21 %) of the mentioned compound were obtained from 122 mg (0.6 mMol) of 4-amino-1-(2-dimethylaminoethyl)-1 H-indole and 168 mg (0.66 mMol) of 2-(naphthalene-1-yl)- ethanesulfonyl chloride, by means of the process described in the Example 1d, as a yellowish solid.
Example 6d.- Preparation of N-[1 -(2-dimethylaminoethyl)-1 H-indole-4-yl]-4- phenoxybenzenesulfonamide
220 mg (84%) of the mentioned compound were obtained from 122 mg (0.6 mMol) of 4-amino-1-(2-dimethylaminoethyl)-1 H-indole and 177 mg (0.66 mMol) of 4-phenoxybenzenesulfonyl chloride, by means of the process described in the Example 1d, as a oil.
Example 7d.- Preparation of N-[1-(2-dimethylaminoethyl)-1 H-indole-4-yl]-3,5- dichlorobenzenesulfonamide
93 mg (38%) of the mentioned compound are obtained from 122 mg (0.6 mMol) of 7-amino-1 -(2-dimethylaminoethyl)- 1 H-indole and 162 mg (0.66 mMol) of 3,5- dichlorobenzenesulfonyl chloride, by means of the process described in Example 1d, as a creamy solid.
Example 8d.- Preparation of 6-chloro-N-[1-(2-dimethylaminoethyl)-1H-indol-4- yl]-imidazo[2, 1 -b]thiazole-5-sulfonamide
100 mg (39%) of the mentioned compound are obtained from 122 mg (0.6 mMol) of 4-amino-1-(2-dimethylaminoethyl)-1 H-indole and 170 mg (0.66 mMol) of 6-chloro-imidazo[2,1-b]-thiazole-5-sulfonyl chloride via the process described in Example 1 as a creamy 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 object of the present invention are indicated in the following table.
Figure imgf000364_0001
(Id)
Figure imgf000365_0001
Figure imgf000366_0001
Figure imgf000367_0001
Preparation of the compounds of general formula (Ie):
Example 2e.- Preparation of N-[1-(2-dimethylaminoethyl)-1 H-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)-1 H-indole in 3 ml of dimethylformamide and 116 mg of N-ethyldiisopropylamine. The reaction mixture is stirred at the room temperature for 12 hours. Then it is evaporated to dryness, slightly alkalinized with sodium bicarbonate solution and extracted with chloroform. The organic phase is repeatedly washed with water and saturated solution of sodium bicarbonate, it is separated and dried with anhydrous sodium sulfate. The organic solution is evaporated to dryness and the resulting solid is purified by chromatography, obtaining 187 mg (80%) of N- [1 -(2-dimethylaminoethyl)-1 H-indole-5-yl]-naphthalene-2-sulfonamide.
Example 10e.- Preparation of N-[1-(2-dimethylaminoethyl)-1 H-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)-1 H- indole in 5 ml of pyridine and 311 mg of N-ethyldiisopropylamine. The reaction mixture is stirred at the room temperature for 2 hours. Then it is evaporated to dryness, slightly alkalinized with sodium bicarbonate solution and extracted with chloroform. The organic phase is repeatedly washed with water and saturated solution of sodium bicarbonate, it is separated and dried with anhydrous sodium sulfate. The organic solution is evaporated to dryness and the resulting solid is treated with diethyl ether obtaining 183 mg (76%) of N-[1-(2- dimethylaminoethyl)-1 H-indole-5-yl]-benzo-[1 ,2,5]thiadiazole-4-sulfonamide 4- sulfonamide. Example 17e.- 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)-1 H-indole in 10 ml of methylene chloride and 0,44 mg of triethylamine. The reaction mixture is stirred at the room temperature for 12 hours. Then it is slightly alkalinized with sodium bicarbonate solution and extracted with methylene chloride. The organic phase is repeatedly washed with water and saturated solution of sodium bicarbonate, it is separated and dried with anhydrous sodium sulfate. The organic solution is evaporated to dryness and the resulting solid is treated with diethyl ether obtaining 264 mg (79%) of N-[1-(2-pyrrolidine-1-yl-ethyl)-1 H- indole-5-yl]-naphthalene-1 -sulfonamide as a solid.
Example 29e. Preparation of N-(1-(2-(diethylamino)ethyl)-1 H-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)-1 H-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 30e. Preparation of N-(1-(2-(diethylamino)ethyl)-1 H-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)-1 H-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 e. Preparation of N-(1-(2-(diethylamino)ethyl)-1 H-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)-1 H-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 32e. Preparation of 5-chloro-N-(1 -(2-(dimethylamino)ethyl)-2-methyl- 1 H-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-methyI-1 H-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 33e. Preparation of N-(1-(2-(dimethylamino)ethyl)-2-methyl-1 H-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-1 H-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 34e. Preparation of N-(1-(2-(dimethylamino)ethyl)-2-methyl-1 H-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-1 H-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 35e. Preparation of 6-chloro-N-(1-(2-(dimethylamino)ethyl)-2-methyl- 1 H-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-1 H-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 36e. Preparation of N-(1-(2-(dimethylamino)ethyl)-2-methyl-1 H-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-1-(2-(dimethylamino)ethyl)-2-methyl-1 H-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 37e. Preparation of N-(1-(2-dimethylamino)ethyl)-2-methyl-1 H-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-1 H-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 38e. Preparation of N-(1-(2-(dimethylamino)ethyl)-2-methyl-1 H-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-1 H-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 39e. Preparation of 3,5-dichloro-N-(1-(2-(dimethylamino)ethyl)-2- methyl-1 H-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-1 H-indole and 162mg (0.66 mMol) of 3,5-dichloro-benzenesulfonyl chloride were reacted to give 81 mg (32 %) of the desired compound as a solid.
Example 40e. Preparation of N-(1-(2-(dimethylamino)ethyl)-2-methyl-1 H-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-1 H-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 e. Preparation of N-(1-(2-(diethylamino)ethyl)-1 H-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)-1 H-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 42e. Preparation of N-(1-(2-(dimethylamino)ethyl)-1 H-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)-1 H-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 43e. Preparation of 5-chloro-3-methyl-N-(1-(3-(piperidin-1-yl)propyl)- 1 H-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))-1 H-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 44e. Preparation of N-(1-(3-(piperidin-1-yl)propyl)-1 H-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))-1 H-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 45e. Preparation of N-(1 -(3-(piperidin-1 -yl)propyl)-1 H-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))-1 H-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 46e. Preparation of 6-chloro-N-(1-(3-piperidin-1-yl)propyl)-1 H-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))-1 H-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 47e. 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))-1 H-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 48e. Preparation of 2-(naphth-1-yl)-N-(1-(3-(piperidin-1-yl)propyl)-1 H- 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))-1 H-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 49e. Preparation of 4-phenoxy-N-(1 -(3-(piperidin-1 -yl)propyl)-1 H-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))-1 H-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 50e. Preparation of 3,5-dichloro-N-(1-(3-(piperidin-1-yl)propyl)-1 H- 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))-1 H-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 e. Preparation of 4,5-dichloro-N-(1-(3-(piperidin-1-yl)propyl)-1 H- 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))-1 H-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 52e. Preparation of 5-chloro-N-(1-(3-(piperidin-1-yl)propyl)-1 H-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))-1 H-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 object of the present invention are indicated in the following table
Figure imgf000376_0001
Figure imgf000376_0002
Figure imgf000377_0001
Figure imgf000378_0001
Figure imgf000379_0001
Figure imgf000380_0001
Figure imgf000381_0001
Figure imgf000382_0001
Figure imgf000383_0001
Figure imgf000384_0001
Figure imgf000385_0001
Figure imgf000386_0001
2H, 66JJ22((ss,, J=9,0| 1H, 2H);
1H); 2H); 1H, 1H);
Hz); J=7,4
Figure imgf000387_0001
Figure imgf000388_0001
Figure imgf000389_0001
Figure imgf000389_0002
Figure imgf000390_0001
Figure imgf000391_0001
Preparation of the compounds of general formula (If):
Example 1f.- Preparation of N-[1-(2-dimethylaminoethyl)-1 H-indole-6-yl]-5- chloro-3-methyl-benzo[b]thiophene-2-sulfonamide. 185.6 mg (0.66 mMol) of 5-chloro-3-methyl-benzo[b] thiophene-2-sulfonyl chloride were added to a solution of 122 mg (0.6 mMol) of 6-amino-1-(2- dimethylaminoethyl)-1 H-indole in 2 ml of dimethylformamide and 116 mg of N- ethyldiisopropylamine. The reaction mixture is stirred at the room temperature for 20 hours. Then it is evaporated to dryness, slightly alkalinized with sodium bicarbonate solution and extracted with chloroform. The organic phase is repeatedly washed with water and saturated solution of sodium bicarbonate, it is separated and dried with anhydrous sodium sulfate. The organic solution is evaporated to dryness and the resulting solid is purified by chromatography, obtaining 180 mg (67%) of N-[1-(2-dimethylaminoethyl)-1 H-indole-6-yl]-5- choloro-3-methyl-benzo[b]thiophene-2-sulfonamide as an amorphous solid.
Example 2f.- Preparation of N-[1-(2-dimethylaminoethyl)-1 H-indole-6-yl]- naphtalene-2-sulfonamide
187 mg (80%) of the mentioned compound are obtained from 122 mg (0.6 mMol) of 6-amino-1-(2-dimethylaminoethyl)-1 H-indole and 150 mg (0.66 mMol) of 2-naphtalenesulfonyl chloride, by means of the process described in the Example 1f, as a solid.
Example 3f.- Preparation of N-[1-(2-dimethylaminoethyl)-1 H-indole-6-yl]- naphtalene-1 -sulfonamide 157 mg (67%) of the mentioned compound are obtained from 122 mg (0.6 mMol) of 6-amino-1-(2-dimethylaminoethyl)-1 H-indole and 150 mg (0.66 mMol) of 1-naphtalenesulfonyl chloride, by means of the process described in the Example 1f, as a solid.
Example 4f.- Preparation of N-[1-(2-dimethylaminoethyl)-1 H-indole-6-yl]-6- chloroimidazo[2,1-b]thiazole-5-sulfonamide 170 mg (67%) of the mentioned compound are obtained from 122 mg (0.6 mMol) of 6-amino-1-(2-dimethylaminoethyl)-1 H-indole and 170 mg (0.66 mMol) of 6-chloroimidazo[2,1-b]thiazole-5-sulfonyl chloride, by means of the process described in the Example 1f, as a solid.
Example 5f.- Preparation of N-[1-(2-dimethylaminoethyl)-1 H-indole-6-yl]-4 phenylbenzenesulfonamide
184 mg (73%) of the mentioned compound are obtained from 122 mg (0.6 mMol) of 6-amino-1-(2-dimethylaminoethyl)-1 H-indole and 167 mg (0.66 mMol) of 4- phenylbenzenesulfonyl chloride, by means of the process described in the Example 1f, as a solid.
Example 6f.- Preparation of N-[1-(2-dimethylaminoethyl)-1H-indole-6-yl]-2- (naphthalene-1 -yl)-ethanesulfonamide 100 mg (40%) of the mentioned compound are obtained from 122 mg (0.6 mMol) of 6-amino-1-(2-dimethylaminoethyl)-1 H-indole and 168 mg (0.66 mMol) of 2-(naphthalene-1-yl)- ethanesulfonyl chloride, by means of the process described in the Example 1f, as a solid.
Example 7f.- Preparation of N-[1-(2-dimethylaminoethyl)-1 H-indole-6-yl]-4- phenoxybenzenesulfonamide
190 mg (73%) of the mentioned compound are obtained from 122 mg (0.6 mMol) of 6-amino-1-(2-dimethylaminoethyl)-1 H-indole and 177 mg (0.66 mMol) of 4-phenoxybenzenesulfonyl chloride, by means of the process described in the Example 1f, as a solid. Example 8f.- Preparation of N-[1-(2-dimethylaminoethyl)-1 H-indole-6-yl]-3,5- dichlorobenzenesulfonam.de
100 mg (41%) of the mentioned compound were obtained from 122 mg (0.6 mMol) of 6-amino-1 -(2-dimethylaminoethyl)-1 H-indole and 162 mg (0.66 mMol) of 3,5-dichlorobenzenesulfonyl chloride, by means of the process described in Example 1 , as a solid.
Example 9f.- Preparation of 5-Chloro-3-methyl-N-[1-[2-(pyrrolidin-1-yl)ethyl-1 H- indol-6-yl]-benzo[b]thiophene-2-sulfonamide
165 mg (58 %) of the mentioned compound were obtained from 137 mg (0.6 mMol) of 6-amino-1-(2-(pyrrolidin-1-yl)ethyl)-1 H-indol and 186 mg (0.66 mMol) of 5-chloro-3-methyl-benzo[b]-thiophene-2-sulfonyl chloride by means of the process described in Example 1 as a solid.
Example 10f.- Preparation of N-(1-[2-(Pyrrolidin-1-yl)ethyl]-1 H-indol-6-yl]- napthyl-2-sulfonamide
142 mg (57 %) of the mentioned compound were obtained from 137 mg (0.6 mMol) of 6-amino-1-(2-(pyrrolidin-1-yl)ethyl)-1 H-indol and 150 mg (0.66 mMol) naphthalenesulfonyl chloride by means of the process described in Example 1 as a solid.
Example 11f.- Preparation of N-[1-[2-Pyrrolidin-1-yl]ethyl]-1 H-indol-6-yl]- naphthalene-1 -sulfonamide
166 (66 %) of the mentioned compound were obtained from 137 mg (0.6 mMol) of 6-amino-1-(2-(pyrrolidin-1-yl)ethyl)-1 H-indol and 150 mg (0.66 mMol) naphthalenesulfonyl chloride by means of the process described in Example 1 as a solid. Example 12f.- Preparation of 6-Chloro-N-[1-[2-(pyrrolidin-1-yl)ethyl]-1 H-indol-6- yl]-imidazo[2,1-b]thiazole-5-sulfonamide
170 mg (59%) of the mentioned compound were obtained from 137 mg (0.6 mMol) of 6-amino-1 -(2-(pyrrolidin-1 -yl)ethyl)-1 H-indol and 170 mg 6-chloro- imidazo[2,1-b]thiazole-5-sulfonyl chloride by means of the process described in Example 1 as a solid.
Example 13f.- Preparation of 4-Phenyl-N-(1-(2-(pyrrolidin-1-yl)ethyl)-1 H-indol-6- yl)benzenesulfonamide
205 mg (77%) of the mentioned compound were obtained from 137 mg (0.6 mMol) of 6-amino-1-(2-(pyrrolidin-1-yl)ethyl)-1 H-indol and 169 mg (0.66 mmol) of 4-phenylbenzenesulfonyl chloride by means of the process described in Example 1 as an oil.
Example 14f.- Preparation of 2-(Naphthyl-1-yl)-N-(1-(2-(pyrrolidin-1-yl)- ethansulfonamid
182 mg (68%) of the mentioned compound were obtained from 137 mg (0.6 mMol) of 6-amino-1-(2-(pyrrolidin-1-yl)ethyl)-1 H-indol and 182 mg (0.66 mmol) of 2-naphthalene-ethansulfonyl chloride by means of the process described in Example 1 as a solid.
Example 15f.- Preparation of 4-Phenoxy-N-(1 -(2-(pyrrolidin-1 -yl)ethyl)-1 H-indol- 6-yl)-benzenesulfonamide
185 mg (67%) of the mentioned compound were obtained from 137 mg (0.6 mMol) of 6-amino-1-(2-(pyrrolidin-1-yl)ethyl)-1 H-indol and 177 mg (0.66 mmol) of 4-phenoxybenzenesulfonyl chloride by means of the process described in Example 1 as a solid. Example 16f. -Preparation of 3,5-Dichloro-N-(1-(2-(Pyrrolidin-1-yl)-1H-indol-6-yl)- benzenesulfonamide
122 mg (46%) of the mentioned compound were obtained from 137 mg (0.6 mMol) of 6-amino-1 -(2-(pyrrolidin-1 -yl)ethyl)-1 H-indol and 162 mg (0.66 mmol) of 3,5-dichlorobenzenesulfonyl chloride by means of the process described in Example 1 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 object of the present invention are indicated in the following table.
396
Figure imgf000397_0001
Figure imgf000398_0001
Figure imgf000399_0001
Figure imgf000400_0001
Figure imgf000401_0001
Figure imgf000402_0001
Figure imgf000403_0001
Examples:
Example 1g.- Preparation of N-[1-(2-dimethylaminoethyl)-1 H-indole-7-yl]- naphtalene-1 -sulfonamide.
149.5 mg (0.66 mMol) of naphtalene-1 -sulfonyl chloride were added to a solution of 122 mg (0.6 mMol) of 7-amino-3-(2-dimethylaminoethyl)-1 H-indole in 2 ml of dimethylformamide and 116 mg of N-ethyldiisopropylamine. The reaction mixture was stirred at the room temperature for 20 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 120 mg (51 %) of N-[1-(2-dimethylaminoethyl)-1 H-indole-7-yl]-naphtalene-1 -sulfonamide as a solid cream.
Example 2g.- Preparation of N-[1-(2-dimethylaminoethyl)-1 H-indole-7-yl]-5- chloro-3-methyl-benzo[b]thiophene-2-sulfonamide
80 mg (30%) of the mentioned compound are obtained from 122 mg (0.6 mMol) of 7-amino-1-(2-dimethylaminoethyl)-1 H-indole and 166 mg (0.66 mMol) of 5- chloro-3-methyl-benzo[b]thiophene-2-sulfonyl chloride, by means of the process described in the Example 1g, as a yellowish solid.
Example 3g.- Preparation of N-[1 -(2-dimethylaminoethyl)-1 H-indole-7-yl]-4 phenylbenzenesulfonamide 27 mg (11%) of the mentioned compound are obtained from 122 mg (0.6 mMol) of 7-amino-1-(2-dimethylaminoethyl)-1 H-indole and 167 mg (0.66 mMol) of 4- phenylbenzenesulfonyl chloride, by means of the process described in the Example 1g, as a solid cream. Example 4g.- Preparation of N-[1-(2-dimethylaminoethyl)-1 H-indole-7-yl]-6- chloroimidazo[2, 1 -b]thiazole-5-sulfonamide
69 mg (27%) of the mentioned compound are obtained from 122 mg (0.6 mMol) of 7-amino-1-(2-dimethylaminoethyl)-1 H-indole and 170 mg (0.66 mMol) of 6- chloroimidazo[2,1-b]thiazole-5-sulfonyl chloride, by means of the process described in the Example 1g, as a solid cream.
Example 5g.- Preparation of 5-chloro-3-methyl-N-(1-(2-(pyrrolidinyl)ethyl)-1 H- indol-7-yl)-benzo[b]thiophen-2-sulfonamide
146 mg (51%) of the mentioned compound were obtained from 137 mg (0.6 mMol) of 7-amino-1-(2-pyrrolidin-1-yl)ethyl)-1 H-indole and 186 mg (0.66 mMol) of 5-chloro-3-methyl-benzo[b]thiophen-2-sulfonyl chloride via the process described in Example 1 , as a solid.
Example 6g.-Preparation of N-(1-(2-(pyrrolidin-1-yl)ethyl)-1 H-indol-7- yl)naphthalene-1 -sulfonamide
120 mg (48 %) of the mentioned compound were obtained from 137 mg (0.6 mMol) of 7-amino-1 -(2-pyrrolidin-1 -yl)ethyl)-1 H-indole and 150 mg (0.66 mMol) of naphthalene-1 -sulfonyl chloride via the process described in Example 1 , as a solid.
Example 7g. Preparation of 6-chloro-N-(1-(2-(pyrroldin-1-yl)ethyl)-1 H-indol-7- yl)imidazo[2, 1 -b]thiazole-5-sulfonamide
100 mg (37 %) of the mentioned compound were obtained from 137 mg (0.6 mMol) of 7-amino-1-(2-pyrrolidin-1-yl)ethyl)-1 H-indole and 170 mg (0.66 mMol) 6-chloro-imidazo[2,1-b]thiazole-5-sulfonyl chloride via the process described in Example 1 , as a solid. Example 8g. Preparation of 2-(naphth-1-yl)-N-(1-(2-(pyrrolidin-1-yl)ethyl)-1 H- indol-7-yl)ethansulfonamide
130 mg (49 %) of the mentioned compound were obtained from 137 mg (0.6 mMol) of 7-amino-1 -(2-pyrrolidin-1 -yl)ethyl)-1 H-indole and 168 mg (0.66 mMol) of 2-(naphth-1-yl)ethansulfonyl chloride via the process described in Example 1 , 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 object of the present invention are indicated in the following table.
Figure imgf000407_0001
Figure imgf000407_0002
Figure imgf000408_0001
Figure imgf000409_0001
Examples:
Example 1 h.- Preparation of 1-cyclohexanesulfonyl-3-(1 -methyl-1 , 2,3,6- tetrahydropyridine-4-yl)-5-nitro-1 H-indole
468 mg (9.8 mMol) of 50% sodium hydride in oil were added at 0°C to a solution of 1.0 g (3.9 mMol) of 3-(1 -methyl-1 ,2,3,6-tetrahydropyridine-4-yl)-5-nitro-1 H- indole in 50 ml of anhydrous dimethylformamide, and the mixture was left to stir for 30 minutes. Then 2.14 g of cyclohexanesulfonyl chloride were added, and the stirring continued for 3 hours at room temperature. Water was added and evaporated to dryness. The resulting crude was treated with sodium bicarbonate and was extracted with chloroform. The organic phase was dried with anhydrous sodium sulfate and evaporated to dryness; the resulting solid was purified by chromatography, obtaining 900 mg (57%) of 1- cyclohexanesulfonyl-3-(1 -methyl-1 ,2, 3,6-tetrahydropyridine-4-yl)-5-nitro-1 H- indole as a yellow solid.
Example 2h.- 5-chloro-1-cyclohexanesulfonyl-3-(1 -methyl-1 ,2,3,6- tetrahydropyridine-4-yl)-1 H-indole
900 mg (74%) of the mentioned compound were obtained from 770 mg (3.12 mMol) of 5-chloro-3-(1 -methyl-1 , 2, 3,6-tetrahydropyridine-4-yl)-1 H-indole, and 1.7 g (9.36 mMol) of cyclohexanesulfonyl chloride by means of the process described in Example 1h, as a yellow solid.
Example 3h.- 5-amino-1-cyclohexanesulfonyl-3-(1 -methyl-1 , 2,3,6- tetrahydropyridine-4-yl)-1 H-indole 200 mg of 50% Pd/C with a humidity of 5% were added to a solution of 403 mg (1 mMol) of 1-cyclohexanesulfonyl-3-(1 -methyl-1 ,2, 3,6-tetrahydropyridine-4-yl)- 5-nitro-1 H-indole in 200 ml of ethanol. The resulting suspension was hydrogenized at 25 psi of overpressure for 20 hours. Then the catalyst was filtered and evaporated to drying. The resulting crude was purified by chromatography and 150 mg (40%) of the mentioned compound were obtained as a solid cream. Example 4h.- Preparation of 1-cyclohexanesulfonyl-5-fluoro-3-(1 ,2,3,5,8,8a- hexahydro-indolizine-7-yl)-1 H-indole
1.95 g (78%) of 1-cyclohexanesulfonyl-5-fluoro-3-(1 ,2,3,5,8,8a-hexahydro- indolizine-7-yl)-1 H-indole were obtained as an oil from 1.6 g (6.25 mMol) of 5- fluoro-3-(1 ,2,3,5,8,8a-hexahydro-indolizine-7-yl)-1 H-indole and 3.42 g (18.76 mMol) of cyclohexanesulfonyl chloride by means of the process described in Example 1. Then 2 ml of a 6N ethanol/HCI solution were added to a solution of 1.95 g (4.85 mMol) of 1-cyclohexanesulfonyl-5-fluoro-3-(1 ,2,3,5,8,8a- hexahydro-indolizine-7-yl)-1 H-indole in 20 ml of ethanol, precipitating a solid which was recrystallized from ethanol, obtaining 1.5 g (71 %) of the mentioned compound as a white 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 object of the present invention are indicated in the following table.
Figure imgf000412_0001
Figure imgf000412_0002
Figure imgf000413_0001
Pharmacological Data:
(Compounds according to the general formula (la))
(a) According to methods I and III Neuropeptide Y5 and Y2 Binding of the benzoxazine- derived compounds of general formula (la) has been determined. Some of the obtained values are given in the following table 1.
Table 1:
Figure imgf000414_0001
(b)
According to method II Neuropeptide Y5 Binding of the benzoxazine-derived compounds of general formula (la) has been determined. Some of the values are given in the following table 2.
Table 2:
Figure imgf000415_0001
(Compounds of general formula lb)
The binding of the benzoxazinone derived sulphonamide compounds of general formula (lb) was determined as described above.
The binding results of some these compounds are given in the following table 2b:
Figure imgf000416_0001
(Compounds of general formula Ic)
The binding of the inventively used sulphonamide derivatives of general formula (Ic) used inventively was determined as described above.
The binding results of some sulphonamide derivatives are given in the following table 1c:
Table 1c:
Compound % Inhibition K, (nM) according to 106 M example:
1c 98.1 ± 4.0 0.28 3c 96.6 ± 5.2 3.5 4c 96.2 ± 0.6 9.3 5c 101.2 ± 0.1 1.0 6c 97.6 ± 1.8 8.7 7c 103.0 ± 7.9 0J3 8c 94.5 ± 7.0 0.76 9c 96.8 ± 3.7 2.2 11c 101.3 0.98 13c 98.3 4.7 14c 95.7 ± 3.4 24.3 15c 97.4 ± 0.8 6.8 16c 94.4 ± 8.6 21.2 17c 102.0 5.3 (Compounds of general formula Id)
Binding of the new compounds of general Formula (Id) to the 5-HTβ receptor was determined as previously described.
The binding results for some of the compounds object of the present invention are indicated in the following table 1d:
Table 1d Examp )llee % Inhibition 10"6 M 1d 83.9 2d 104.3 3d 94.8 4d 46.6 5d 98.1 6d 55.8 7 72.3
(Compounds of general formula Ie)
Binding of the new compounds of general formula (Ie) to the 5-HT6 receptor was determined as previously described.
The binding results for some of the compounds object of the present invention are indicated in the following table 1e:
Table 1e Example Ki (nM) 3e 94,2 4e 112,4 11e 1,89 12e 104,6 13e 82,5 20e 84,8
(Compounds of general formula If)
Pharmacological data:
Binding of the new compounds of general Formula (If) to the 5-HT6 receptor was determined as previously described.
The binding results for some of the compounds object of the present invention are indicated in the following table 1f: Table 1f Examp )llee %% IInnhhiibbiittiioonn Kj (nM) 106 M 1f 98.6 90.2 2f 97.7 41.2 3f 95.3 19.8 4f 90.8 55.2 5f 93.4 129 4 6f 94.5 74.5 7f 95.1 118.6 8f 86.9 159.1
(Compounds of general formula Ih)
Pharmacological data:
Binding of the new compounds of general Formula (Ih) to the 5-HT6 receptor was determined as previously described.
The binding results for some of the compounds object of the present invention are indicated in the following table 1h:
Table 1h Example % Inhibition Ki (nM) 106 M 1h 59.8 + 3.0 2h 98.2 3h 55.1 4h 191
Two active substance combinations,
I)
[23] N-[3-(2-dimethylaminoethyl)-1H-indol-5-yl]-5-chloronaphthalene-2-sulphonamide,
2-[4-(2-oxo-4H-benzo[d][1 ,3]oxazin-1 -yl)-piperidin-1 -yl]-N-(9-oxo-9H-fluoren-2-yl)- acetamide,
and
II)
[23] N-[3-(2-dimethylaminoethyl)-1 --indol-5-yl]-5-chloronaphthalene-2-sulphonamide,
2-[4-(8-Methyl-2-oxo-4H-benzo[d][1 ,3]oxazin-1-yl)-piperidin-1-yl]-N-(9-oxo-9H- fluoren-3-yl)-acetamide hydrochloride
have been investigated according to the method of measurement of food ingestion described above.
Both combinations show a synergic effect in their pharmacological activities compared with the individual pharmacological activity for each compound.

Claims

Claims
An active substance combination, characterized in that it comprises: (A) at least one compound with neuropeptide Y (NPY) -receptor affinity, and (B) at least one compound with 5- T6 receptor affinity
The combination according to claim 1 , characterized in that as component (A) at least one compound with neuropeptide Y5 (NPY5) -receptor affinity is present.
The combination according to claim 1 or 2, characterized in that as component (A) at least one compound ist present, which is selected from the group consisting of the compounds of general formula (la)
Figure imgf000423_0001
(la) wherein R1a, R2a, R3a, R4a are each independently selected from the group consisting of hydrogen, halogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, an optionally at least mono-substituted aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ringsystem, a nitro, cyano, -OR12a, -OC(=0)R13a, -SR14a, -SOR14a, -S02R14a, -NH-S02R14a, -SO2NH2 and -NR15aR16a moiety,
R5a represents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical or a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic radical,
R6a, R7a, Rδa, R9a are each independently selected from the group consisting of hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic radical, a cyano and a COOR17a moiety,
Aa represents a bridge member -CHR18a- or -CHR18a-CH2-,
R10a represents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic radical or an optionally at least mono-substituted aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, R11a represents an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ringsystem, or an optionally at least mono substituted aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono- substituted mono- or polycyclic ringsystem, or
R10a and R11a together with the bridging nitrogen atom form an optionally at least mono-substituted, saturated, unsaturated or aromatic heterocyclic ring that may contain at least one further heteroatom as a ring member and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ringsystem,
R1 a represents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, or an optionally at least mono-substituted aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono- substituted mono- or polycyclic ring-system,
R13a represents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, or an optionally at least mono-substituted aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono- substituted mono- or polycyclic ring-system,
R14a represents an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, or an optionally at least mono-substituted aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono- substituted mono- or polycyclic ring-system,
R15a and R16a each are independently selected from the group consisting of hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, or an optionally at least mono-substituted aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,
or R15a and R16a together with the bridging nitrogen atom form a saturated, unsaturated or aromatic heterocyclic ring, which may be at least mono- substituted and/or contain at least one further heteroatom as a ring member, R17a represents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic radical or an optionally at least mono-substituted aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,
R18a represents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic radical or an optionally at least mono-substituted aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,
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 physiologically acceptable salt thereof, or a solvate, respectively.
The combination according to any one of the claims 1 to 3, characterized in that as component (B) at least one compound ist present, which is selected from the group consisting of the benzoxazinone-derived sulfonamide compounds of general formula (lb)
Figure imgf000428_0001
(lb)
wherein
R1b, R2b, R3b, R4b are each independently selected from the group consisting of hydrogen, halogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, an optionally at least mono-substituted aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ringsystem, a nitro, cyano, -OR10b, -0(C=0)R11b, - (C=O)OR11b, -SR12b, -SOR12b, -S02R12b, -NH-S02R12b, -S02NH2 and a - NR13bR14b moiety, R5b represents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical or a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic radical,
R6b, R7b, R8b, R9b are each independently selected from the group consisting of hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic radical, a cyano group and a COOR15b moiety,
Wb represents an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical,
a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic radical, which may be bonded via an optionally mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,
an optionally at least mono-substituted aryl or heteroaryl radical, which may be bonded via an optionally at least mono-substituted alkylene or alkenylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,
a NR16bR17b-moiety, or
a COR18b-moiety, R10b represents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, or an optionally at least mono-substituted aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono- substituted mono- or polycyclic ring-system,
R11b represents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, or an optionally at least mono-substituted aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono- substituted mono- or polycyclic ring-system,
R12b represents an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, or an optionally at least mono-substituted aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono- substituted mono- or polycyclic ring-system, R13b and R14b each are independently selected from the group consisting of hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, or an optionally at least mono-substituted aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,
or R13b and R14b together with the bridging nitrogen atom form a saturated, unsaturated or aromatic heterocyclic ring, which may be at least mono- substituted and/or contain at least one further heteroatom as a ring member,
R15b represents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic radical or an optionally at least mono-substituted aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,
R16b represents an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical,
R17b represents an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, and
R >18 represents an optionally at least mono-substituted aryl radical 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 physiologically acceptable salt thereof, or a solvate, respectively, and. compounds derived from sulfonamide of general formula (Ic),
Figure imgf000432_0001
(Ic)
wherein
R1c represents hydrogen, an optionally at least mono-substituted, linear or branched alkyl radical, an optionally at least mono-substituted phenyl radical or an optionally at least mono-substituted benzyl radical,
R2c represents a -NR4cR5c moiety or a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic radical, which may be condensed with a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing mono- or bicyclic cycloaliphatic ringsystem,
R3c represents hydrogen or an optionally at least mono- substituted, linear or branched alkyl radical, R4c and R5c, identical or different, represent hydrogen or an optionally at least mono-substituted, linear or branched alkyl radical, or
R4c and R5c together with the bridging nitrogen atom form an optionally at least mono-substituted, saturated or unsaturated heterocyclic ring, which may contain at least one further heteroatom as a ring member and/or may be condensed with a saturated or unsaturated, optionally at least mono- substituted, optionally at least one heteroatom as ring member containing mono- or bicyclic cycloaliphatic ringsystem,
Ac represents an optionally at least mono-substituted mono- or polycyclic aromatic ringsystem, which may be bonded via an optionally at least mono- substituted alkylene-, an optionally at least mono-substituted alkenylene- or an optionally at least mono-substituted alkynylene group and/or may contain at least one heteroatom as a ring member in one or more of its rings,
nc represents 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 corresponding physiologically acceptable salt or a corresponding solvate,
and compounds of the general formula (Id)
Figure imgf000433_0001
(Id)
R1d represents a -NR8dR9d radical or a saturated or unsaturated, optionally at least mono-substituted cycloaliphatic radical, which may 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, optionally at least one heteroatom as a ring member containing mono- or bicyclic cycloaliphatic ring system,
R2d, R3d, R5d, R6d and R7d, 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 heteroaryl radical,
R4d is hydrogen or a saturated or unsaturated, linear or branched, optionally at least mono-substituted aliphatic radical,
R8d and R9d, identical or different, each represent hydrogen or a saturated or unsaturated, linear or branched, optionally at least mono-substituted aliphatic radical,
or
R8d and R9d together with 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 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,
Ad 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
nd is O, 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,
and sulphonamide-derived compounds of general formula (Ie),
Figure imgf000435_0001
(Ie) wherein
R1e represents a -NR8eR9e 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,
R2e, R3e, R4e, R6e and R7e, 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,
R5e represents hydrogen or a saturated or unsaturated, linear or branched, optionally at least mono-substituted aliphatic radical,
R8e and R9e, identical or different, each represent hydrogen or a saturated or unsaturated, linear or branched, optionally at least mono-substituted aliphatic radical,
or
R8e and R9e 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,
Ae 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
ne is 0, 1 , 2, 3 or 4;
optionally in the form of one of its stereoisomers, preferably enantiomers or diastereomers, its racemate or in the form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, at any mixture ratio, or a corresponding, physiologically acceptable salt, or a corresponding solvate and sulphonamide-derived compounds of general formula (If),
(If)
wherein
R1f represents a -NR8fR9f radical or a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as a ring member containing cycloaliphatic radical, which may be condensed with a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as a ring member containing mono- or bicyclic cycloaliphatic ring system,
R2f, R3f, R4f, R5f and R7f, 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 optionally at least mono-substituted heteroaryl radical,
R6f represents hydrogen or a saturated or unsaturated, linear or branched, optionally at least mono-substituted aliphatic radical,
R and R , identical or different, each represent hydrogen or a saturated or unsaturated, linear or branched, optionally at least mono-substituted aliphatic radical, or
R8f and R9f, 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 may be condensed with a saturated or unsaturated, optionally at least mono- substituted, optionally at least one heteroatom as a ring member containing mono- or bicyclic cycloaliphatic ring system,
Af 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
nf is O, 1 , 2, 3 or 4;
optionally in the form of one of its stereoisomers, preferably enantiomers or diastereomers, its racemate or in the form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, at any mixture ratio, or a corresponding, physiologically acceptable salt, or a corresponding solvate
and sulphonamide-derived compounds of general formula (Ig).
Figure imgf000438_0001
(ig)
wherein
R1g is a -NR8gR9g 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 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,
R2g, R3g, R4g, R5g and R6g, 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 radical or an optionally at least mono-substituted heteroaryl radical,
R7g represents hydrogen or a saturated or unsaturated, linear or branched, optionally at least mono-substituted aliphatic radical,
R8g and R9g, identical or different, represent hydrogen or a saturated or unsaturated, linear or branched, optionally at least mono-substituted aliphatic radical,
or
R8g and R9g 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, A9 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,
ng is O, 1 , 2, 3 or 4;
optionally in the form of one of its stereoisomers, preferably enantiomers or diastereomers, its racemate or in the form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, at any mixture ratio, or a corresponding, physiologically acceptable salt, or a corresponding solvate,
and sulphonamide-derived compounds of general formula (Ih)
Figure imgf000440_0001
(In)
wherein
R1h represents a -NR7hR8h radical or a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as a ring member containing cycloaliphatic radical, which may be condensed with a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as a ring member containing mono- or bicyclic cycloaliphatic ring system, R2h, R3h, R4h, R5h and R6h, identical or different, each represent hydrogen, halogen, cyano, nitro, a saturated or unsaturated, linear or branched aliphatic radical, a linear or branched alkoxy radical, a linear or branched alkylthio radical, hydroxy, trifluoromethyl, a saturated or unsaturated cycloaliphatic radical, an alkylcarbonyl radical, a phenylcarbonyl or a -NR9hR10h group,
R7h and R8h, identical or different, each represent hydrogen or a saturated or unsaturated, optionally at least mono-substituted linear or branched aliphatic radical,
or
R and R8h, together with the bridging nitrogen atom form a saturated or unsaturated, optionally at least mono-substituted, optionally at least one further heteroatom as a ring member containing heterocyclic ring which may be condensed with a saturated or unsaturated, optionally at least mono- substituted, optionally at least one heteroatom as a ring member containing mono- or bicyclic cycloaliphatic ring system,
R9h and R10h, identical or different, each represent hydrogen or a saturated or unsaturated, linear or branched, optionally at least mono-substituted aliphatic radical,
or
R9h and R10h, together with the bridging nitrogen atom form a saturated or unsaturated, optionally at least mono-substituted, optionally at least one further heteroatom as a ring member containing heterocyclic ring which may be condensed with a saturated or unsaturated, optionally at least mono- substituted, optionally at least one heteroatom as a ring member containing mono- or bicyclic cycloaliphatic ring system, Ah and Bh, identical or different, each represent a saturated or unsaturated, linear or branched, optionally at least mono-substituted aliphatic radical or
Ah and Bh, together with the carbon atom to which they are bonded, form a saturated or unsaturated, but not aromatic, optionally at least mono- substituted cycloalkyl ring, and nh is O, 1 , 2, 3, or 4, 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.
5. The combination according to any one of the claims 1 to 4, characterized in that it comprises 1-99% by weight of component (A) and 99-1 % by weight of component (B), more preferably 10-80% by weight of component (A) and 90- 20% by weight of component (B), referring those percentages to the total weight of both components (A) and (B).
6. A medicament comprising an active substance combination acording to any one of the claims 1 to 5 and optionally one or more pharmacologically acceptable adjuvants.
7. A medicament according to claim 6, for simultaneous neuropeptide Y- and 5- HTβ - receptor regulation, for regulation of appetite, for maintenance, increase or reduction of body weight, for prophylaxis and/or treatment of disorders related to food ingestion, preferably for prophylaxis and/or treatment of obesity, anorexia, cachexia, bulimia, diabetes, preferably type II diabetes (non- insulin-dependent diabetes mellitus), or for prophylaxis and/or treatment of gastrointestinal tract disorders, preferably of the irritable bowel syndrome, for prophylaxis and/or treatment of Peripheral Nervous System Disorders, Central Nervous System Disorders, arthritis, epilepsy, anxiety, panic, depression, cognitive disorders, memory disorders, cardiovascular diseases, senile dementia processes, such as Alzheimer's, Parkinson's and/or Huntington's Disease, schizophrenia, psychosis, infantile hyperkinesia (ADHD, attention deficit / hyperactivity disorder), pain, hypertensive syndrome, inflammatoric diseases, immunologic diseases or for improvement of cognition.
8. Use of the combination according to any one of claims 1 to 5 for manufacture of a medicament for simultaneous neuropeptide Y5- and 5-HT6 - receptor regulation.
9. Use of the combination according to any one of claims 1 to 5, for the manufacture of a medicament for regulation of appetite.
10. Use of the combination according to any one of claims 1 to 5, for the manufacture of a medicament for maintenance, increase or reduction of body weight.
11. Use of the combination according to any one of claims 1 to 5, for the manufacture of a medicament for prophylaxis and/or treatment of disorders related to food ingestion, preferably for prophylaxis and/or treatment of obesity, anorexia, cachexia, bulimia, diabetes, preferably type II diabetes (non- insulin-dependent diabetes mellitus).
12. Use of the combination according to any one of claims 1 to 5, for the manufacture of a medicament for prophylaxis and/or treatment of gastrointestinal tract disorders, preferably of the irritable bowel syndrome.
13. Use of the combination according to any one of claims 1 to 5, for the manufacture of a medicament for prophylaxis and/or treatment of Peripheral Nervous System Disorders.
14. Use of the combination according to any one of claims 1 to 5, for the manufacture of a medicament for prophylaxis and/or treatment of Central Nervous System Disorders.
15. Use of the combination according to any one of claims 1 to 5, for the manufacture of a medicament for prophylaxis and/or treatment arthritis.
16. Use of the combination according to any one of claims 1 to 5, for the manufacture of a medicament for prophylaxis and/or treatment of epilepsy.
17. Use of the combination according to any one of claims 1 to 5, for the manufacture of a medicament for prophylaxis and/or treatment of anxiety.
18. Use of the combination according to any one of claims 1 to 5, for the manufacture of a medicament for prophylaxis and/or treatment of panic.
19. Use of the combination according to any one of claims 1 to 5, for the manufacture of a medicament for prophylaxis and/or treatment of depression.
20. Use of the combination according to any one of claims 1 to 5, for the manufacture of a medicament for prophylaxis and/or treatment of bipolar disordes.
21. Use of the combination according to any one of claims 1 to 5, for the manufacture of a medicament for prophylaxis and/or treatment of cognitive disorders.
22. Use of the combination according to any one of claims 1 to 5, for the manufacture of a medicament for prophylaxis and/or treatment of memory disorders.
23. Use of the combination according to any one of claims 1 to 5, for the manufacture of a medicament for prophylaxis and/or treatment of cardiovascular diseases.
24. Use of the combination according to any one of claims 1 to 5, for the manufacture of a medicament for prophylaxis and/or treatment of senile dementia processes.
25. Use of the combination according to any one of claims 1 to 5, for the manufacture of a medicament for prophylaxis and/or treatment of neurodegenerative diseases, preferably Parkinson's disease, Alzheimer's disease, Huntington's disease and Multiple Sklerosis.
26. Use of the combination according to any one of claims 1 to 5, for the manufacture of a medicament for prophylaxis and/or treatment of schizophrenia.
27. The use of the combination according to any one of claims 1 to 5, for the manufacture of a medicament for prophylaxis and/or treatment of psychosis.
28. Use of the combination according to any one of claims 1 to 5, for the manufacture of a medicament for prophylaxis and/or treatment of infantile hyperkinesia (ADHD, attention deficit / hyperactivity disorder).
29. The use of the combination according to any one of claims 1 to 5, for the manufacture of a medicament for prophylaxis and/or treatment of pain.
30. Use of the combination according to any one of claims 1 to 5, for the manufacture of a medicament for prophylaxis and/or treatment of hypertensive syndrome.
31. Use of the combination according to any one of claims 1 to 5, for the manufacture of a medicament for prophylaxis and/or treatment of inflammatoric diseases.
32. Use of the combination according to any one of claims 1 to 5, for the manufacture of a medicament for prophylaxis and/or treatment of immunologic diseases.
33. The use of the combination according to any one of claims 1 to 5, for the manufacture of a medicament for improvement of cognition.
34. A pharmaceutical formulation, characterized in that it comprises an active substance combination according to any one of claims 1 to 5 and optionally one or more pharmacologically acceptable adjuvants.
35. The pharmaceutical formulation according to claim 34, characterized in that it is present in solid pharmaceutical forms such as tablets, tablets, chewing tablets, chewing gums, dragees, capsules, suppositories, powder preparations, transdermal therapeutic systems, transmucosal therapeutic systems, or in liquid and semi-liquid pharmaceutical forms such as drops or such as juice, sirup, solution, emulsion, suspension, preferably in form of tablets, capsules, drops or solution.
36. The pharmaceutical formulation according to claim 34, characterized in that it is present in form of of multiple particles, preferably microtablets, microcapsules, microspheroids, granules, crystals or pellets, optionally compacted in a tablet, filled in a capsule or suspended in a suitable liquid.
37. The pharmaceutical formulation according to one or more of claims 34-36, characterized in that it is for oral, intravenous, intramuscular, subcutaneous, intrathecal, epidural, buccal, sublingual, pulmonal, rectal, transdermal, nasal or intracerebroventricular application, preferably oral or intravenous.
38. The pharmaceutical formulation according to one or more of claims 34-37, characterized in that at least one of the components of the active substance combination (A) or (B) is present at least partially in sustained-release form.
39. The pharmaceutical formulation according to claim 38, characterized in that the medicament has at least one coating or one matrix comprising at least one material, which sustains active substance release.
40. The pharmaceutical formulation according to claim 39, characterized in that the sustained-release material is based on optionally modified, water- insoluble, natural, semisynthetic or synthetic polymer, or a natural wax or fat or fatty alcohol or semisynthetic or synthetic fatty acid, or on a mixture of at least two of these afore mentioned components.
41. The pharmaceutical formulation according to claim 40, characterized in that the water-insoluble polymer is based on an acrylic resin, which is preferably selected from the group of poly(meth)acrylates, poly(Ci-4)dialkylamino(Ci- 4)alkyl (meth)acrylates and/or copolymers thereof or a mixture of at least two of the afore-mentioned polymers.
42. The pharmaceutical formulation according to claim 40, characterized in that the water-insoluble polymers are cellulose derivatives, preferably alkyl cellulose and even more preferably ethyl cellulose, or cellulose esters.
43. The pharmaceutical formulation according to claim 40, characterized in that the wax is carnauba wax, beeswax, glycerol monostearate, glycerol monobehenate, glycerol ditripalmitostearate, microcrystalline wax or a mixture of at least two of these components.
44. The pharmaceutical formulation according to one or more of claims 40 to 43, characterized in that polymers have been used in combination with one or more plasticizers.
45. The pharmaceutical formulation according to one or more of claims 34 to 44, characterized in that besides the sustained-release form, at least one of the active substance components (A) or (B) is present in a non-sustained-release form.
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CA2534100A1 (en) 2005-02-17
EP1648468A1 (en) 2006-04-26
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EP1648468B1 (en) 2008-09-24
ES2315685T3 (en) 2009-04-01
MXPA06001232A (en) 2006-05-15
DE602004016752D1 (en) 2008-11-06
US20070059364A1 (en) 2007-03-15
US20120128768A1 (en) 2012-05-24
ES2228267B1 (en) 2006-07-01
ES2228267A1 (en) 2005-04-01
AU2004262489A1 (en) 2005-02-17

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