US20110172270A1 - 2-'4(phenylamino)-piperidin-1-yl!-n-phenyl-acetamine derivatives and related compounds as neuropeptide y5 (npy5) ligands for the treatment of obesity - Google Patents

2-'4(phenylamino)-piperidin-1-yl!-n-phenyl-acetamine derivatives and related compounds as neuropeptide y5 (npy5) ligands for the treatment of obesity Download PDF

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US20110172270A1
US20110172270A1 US12/985,646 US98564611A US2011172270A1 US 20110172270 A1 US20110172270 A1 US 20110172270A1 US 98564611 A US98564611 A US 98564611A US 2011172270 A1 US2011172270 A1 US 2011172270A1
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mono
optionally
phenylamino
piperidin
hydroxymethyl
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Antoni Jover Torrens
Josep Mas Prio
Alberto Dordal Zueras
Maria Angeles Fisas Escasany
Helmut-Heinrich Buschmann
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Esteve Pharmaceuticals SA
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Laboratorios del Dr Esteve SA
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Assigned to LABORATORIOS DEL DR. ESTEVE S.A. reassignment LABORATORIOS DEL DR. ESTEVE S.A. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: BUSCHMANN, HELMUT-HEINRICH
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    • C04B35/622—Forming processes; Processing powders of inorganic compounds preparatory to the manufacturing of ceramic products
    • C04B35/626—Preparing or treating the powders individually or as batches ; preparing or treating macroscopic reinforcing agents for ceramic products, e.g. fibres; mechanical aspects section B
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    • A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/56—Nitrogen atoms
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    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to 1,4-disubstituted piperidine compounds of general formula (I), methods for their preparation, medicaments comprising these compounds as well as their use for the preparation of a medicament for the treatment of humans or animals.
  • 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.
  • NPY5 neuropeptide Y 5
  • NPY5 neuropeptide Y 5
  • disorders of food ingestion such as obesity, anorexia, cachexia, bulimia or type II (non insulin dependent) diabetes
  • prophylaxis and/or treatment of disorders of the peripheral nervous system disorders of the central nervous system
  • anxiety, depression, cognitive disorders preferably memory disorders
  • cardiovascular diseases pain, epilepsy, arthritis, hypertensive syndrom, inflammatory diseases, immune diseases and other NPY5 mediated disorders in animals and mammals, including man.
  • R 1 , R 2 , R 3 , R 4 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, —OR 12 , —OC( ⁇ O
  • R P represents —OCO—C 1-3 -Alkyl, —CH 2 —N(C 1-4 -Alkyl) 2 or
  • R 1 , R 2 , R 3 , R 4 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, —OR 12 , —OC( ⁇ O)
  • R P represents ortho —OCO—C 1-3 -Alkyl, —CH 2 —N(C 1-4 -Alkyl) 2 in the meta or para position of the phenyl ring or
  • 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.
  • 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.
  • the polycyclic ring-system may comprise two rings that are condensed.
  • the rings of the mono- or polycyclic ring-system are preferably 5- or 6-membered.
  • each of these substituents may preferably be selected from the group consisting of hydroxy, halogen, branched or unbranched C 1-4 -alkoxy, branched or unbranched C 1-4 -perfluoroalkoxy, branched or unbranched C 1-4 -perfluoroalkyl, amino, carboxy, amido, cyano, nitro, —SO 2 NH 2 , —CO—C 1-4 -alkyl, —SO—C 1-4 -alkyl, —SO 2 —C 1-4 -alkyl, —NH—SO 2 —C 1-4 -alkyl, wherein the C 1-4 -alkyl may in each case be branched or unbranched, an unsubstituted or at least mono-substituted phenyl or naphthyl radical
  • each of these substituents may preferably be selected from the group consisting of hydroxy, halogen, branched or unbranched C 1-4 -alkyl, branched or unbranched C 1-4 -alkoxy, branched or unbranched C 1-4 -perfluoroalkoxy, phenoxy, benzoyl, cyclohexyl, branched or unbranched C 1-4 -perfluoroalkyl, —NR A R B wherein R A , R B are each independently selected from the group consisting of H, a branched or unbranched C 1-4 -alkyl-radical, —CH 2 —CH 2 —OH and phenyl, carboxy, amido, cyano, nitro, —SO 2 NH 2 , —CO—C 1-4 -al
  • each of these substituents may preferably be selected from the group consisting of hydroxy, halogen, branched or unbranched C 1-4 -alkoxy, branched or unbranched C 1-4 -perfluoroalkoxy, branched or unbranched C 1-4 -perfluoroalkyl, amino, carboxy, amido, cyano, nitro, —SO 2 NH 2 , —CO—C 1-4 -alkyl, —SO—C 1-4 -alkyl, —SO 2 —C 1-4 -alkyl, —NH—SO 2 —C 1-4 -alkyl, wherein C 1-4 -alkyl may be branched or unbranched, an unsubstituted or at least mono-substituted phenyl or naphthyl radical
  • each of these substituents may preferably be selected from the group consisting of hydroxy, halogen, branched or unbranched C 1-4 -alkyl, branched or unbranched C 1-4 -alkoxy, branched or unbranched C 1-4 -perfluoroalkoxy, branched or unbranched C 1-4 -perfluoroalkyl, amino, carboxy, amido, cyano, keto, nitro, —SO 2 NH 2 , —CO—C 1-4 -alkyl, —SO—C 1-4 -alkyl, —SO 2 —C 1-4 -alkyl, —NH—SO 2 —C 1-4 -alkyl wherein C 1-4 -alkyl may be branched or unbranched, an unsubstit
  • each of these substituents may preferably be selected from the group consisting of hydroxy, halogen, branched or unbranched C 1-4 -alkoxy, branched or unbranched C 1-4 -alkyl, branched or unbranched C 1-4 -perfluoroalkoxy, unsubstituted or at least mono-substituted phenoxy, unsubstituted or at least mono-substituted benzoyl, cyclohexyl, branched or unbranched C 1-4 -perfluoroalkyl, NR A R B wherein R A , R B are each independently selected from the group consisting of H, a branched or unbranched C 1-4 -alkyl-radical, —CH 2 —CH 2 —OH and phenyl,
  • each of these substituents may preferably be selected from the group consisting of hydroxy, halogen, branched or unbranched C 1-4 -alkoxy, branched or unbranched C 1-4 -alkyl, branched or unbranched C 1-4 -perfluoroalkoxy, unsubstituted or at least mono-substituted phenoxy, unsubstituted or at least mono-substituted benzoyl, cyclohexyl, branched or unbranched C 1-4 -perfluoroalkyl, NR A R B wherein R A , R B are each independently selected from the group consisting of H, a branched or unbranched C 1-4 -alkyl-radical, —CH 2 —CH 2 —OH and phenyl
  • each of these substituents may preferably be selected from the group consisting of hydroxy, halogen, branched or unbranched C 1-4 -alkoxy, branched or unbranched C 1-4 -alkyl, branched or unbranched C 1-4 -perfluoroalkoxy, branched or unbranched C 1-4 -perfluoroalkyl, amino, carboxy, amido, cyano, nitro, —SO 2 NH 2 , —CO—C 1-4 -alkyl, —SO—C 1-4 -alkyl, —SO 2 —C 1-4 -alkyl, —NH—SO 2 —C 1-4 -alkyl, wherein C 1-4 -alkyl may be branched or unbranched, an unsubstituted or at least mono-substituted
  • 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.
  • 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 23 represents an aliphatic radical, which comprises at least one heteroatom as a chain member, each of these heteroatoms may preferably be O or S, more preferably O.
  • R 1 , R 2 , R 3 , R 4 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 1-6 -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 1-6 -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 1-6 -alkylene group and/or may be condensed with an optionally
  • R 5 represents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C 1-6 -aliphatic radical, or a saturated or unsaturated, optionally at least mono-substituted C 3-8 -cycloaliphatic radical,
  • R 6 , R 7 , R 8 , R 9 are each independently selected from the group consisting of hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C 1-6 -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-moiety and a COOR 17 moiety,
  • A represents a bridge member —CHR 18 — or —CHR 18 —CH 2 —
  • B represents an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C 1-6 -aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted C 3-8 -cycloaliphatic radical, a COOR 19 -moiety, a COR 20 -moiety, or a —C 2 —OR 23 -moiety,
  • R 10 represents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C 1-6 -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 1-6 -alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,
  • R 11 represents an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C 1-6 -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 1-6 -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 C 1-6 -alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ringsystem, or
  • R 10 and R 11 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 12 represents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C 1-6 -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 C 1-6 -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 1-6 -alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,
  • R 13 represents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C 1-6 -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 1-6 -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 1-6 -alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,
  • R 14 represents an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C 1-6 -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 1-6 -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 1-6 -alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,
  • R 15 and R 16 each are independently selected from the group consisting of hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C 1-6 -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 1-6 -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 1-6 -alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,
  • R 15 and R 16 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 17 represents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C 1-6 -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 1-6 -alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,
  • R 18 represents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C 1-6 -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 1-6 -alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,
  • R 19 represents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C 1-6 -aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted C 3-8 cycloaliphatic radical, or an optionally at least mono-substituted, 5- or 6-membered aryl- or heteroaryl radical, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,
  • R 20 represents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C 1-6 -aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted C 3-8 cycloaliphatic radical, an optionally at least mono-substituted, 5- or 6-membered aryl- or heteroaryl radical, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, or a NR 21 R 22 -moiety,
  • R 21 represents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C 1-6 -aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted C 3-8 cycloaliphatic radical, or an optionally at least mono-substituted, 5- or 6-membered aryl- or heteroaryl radical, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,
  • R 22 represents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C 1-6 -aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted C 3-8 cycloaliphatic radical, or an optionally at least mono-substituted, 5- or 6-membered aryl- or heteroaryl radical, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,
  • R 23 represents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C 1-6 -aliphatic radical, which may comprise at least one heteroatom as a chain member, or a —(C ⁇ O)R 13 -moiety,
  • 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 corresponding solvates, respectively.
  • R 1 , R 2 , R 3 , R 4 are each independently selected from the group consisting of H, F, Cl, Br, a saturated, branched or unbranched, optionally at least mono-substituted C 1-3 -aliphatic radical, a saturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing C 5 - or C 6 -cycloaliphatic radical, which may be bonded via an optionally at least mono-substituted C 1 - or C 2 -alkylene group, a nitro, cyano, —OR 12 , —OC( ⁇ O)R 13 , —SR 14 and —NR 15 R 16 moiety, preferably are each independently selected from the group consisting of H, F, Cl, Br, CH 3 , CH 2 CH 3 , CF 3 , CF 2 CF 3 , cyclopentyl, cyclohexyl, nitro
  • R 5 represents H or a branched or unbranched C 1-3 -alkyl radical, preferably H, CH 3 or CH 2 CH 3 , and the remaining residues R 1 -R 4 , R 6 -R 23 , A and 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 salts, preferably physiologically acceptable salts thereof, or corresponding solvates, respectively.
  • R 6 , R 7 , R 8 , R 9 are each independently selected from the group consisting of H, a branched or unbranched C 1-3 -alkyl radical, a cyano and a COOR 17 moiety, preferably selected from the group consisting of H, CH 3 , CH 2 CH 3 and a cyano moiety, more preferably all represent H, and the remaining residues R 1 -R 5 , R 10 -R 23 , A and 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 salts, preferably physiologically acceptable salts thereof, or corresponding solvates, respectively.
  • B represents an optionally branched, optionally at least mono-substituted C 1-3 -alkyl radical, a COOR 19 -moiety, or a CH 2 OR 23 -moiety, preferably a COOR 19 -moiety, a CH 2 OR 23 -moiety or a C 1-2 -alkyl radical, more preferably a COOR 19 -moiety or a CH 2 OR 23 -moiety, and the remaining residues R 1 -R 23 and 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 salts, preferably physiologically acceptable salts thereof, or corresponding solvates, respectively.
  • R 10 represents hydrogen or a branched or unbranched C 1-4 -alkyl radical, more preferably hydrogen, and the remaining residues R 1 -R 9 , R 11 -R 23 , A and 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 salts, preferably physiologically acceptable salts thereof, or solvates, respectively.
  • R 11 is selected from the group consisting of an unsubstituted phenyl radical, a phenyl radical that is optionally at least mono-substituted with a substituent selected from the group consisting of branched or unbranched C 1-4 -alkyl-radical, a branched or unbranched C 1-4 -alkoxy-radical, a branched or unbranched C 1-4 -perfluoroalkyl-radical, a branched or unbranched C 1-4 -perfluoroalkoxy-radical, F, Cl, Br, cyclohexyl, phenyl, phenoxy, phenylthio, benzoyl, cyano, —C( ⁇ O)C 1-2 -alkyl, —C( ⁇ O)OC 1-2 -alkyl, -carboxy, —C(H)(OH)(phenyl), —C(H)
  • n 1 or 2
  • X represents CH or N
  • Y represents CH 2 , O, N—R c , CH—OH or C( ⁇ O)
  • R c is H or a branched or unbranched C 1-4 -alkyl radical, a group of formula (B),
  • R D is H or a branched or unbranched C 1-4 -alkyl radical and a group of general formula (E),
  • R E represents H, a branched or unbranched C 1-4 -alkyl radical or a branched or unbranched C 1-4 -alkoxy radical
  • W represents a bond between the two aromatic rings, CH 2 , CH—OH or C( ⁇ O),
  • Z represents CH 2 , O, S, CH—OH, C( ⁇ O) or N—R F
  • R F represents H or a branched or unbranched C 1-4 -alkyl-radical
  • the remaining residues R 1 -R 10 , R 12 -R 23 , A and 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 salts, preferably physiologically acceptable salts thereof, or corresponding solvates, respectively.
  • groups (A)-(E) may be bonded via any suitable ring member of any ring, for example group (B) may also be bonded via the ring containing the nitrogen atom.
  • R 10 and R 11 together with the bridging nitrogen atom form a saturated, 6-membered heterocyclic ring, which is optionally 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 1 -R 9 , R 12 -R 23 , A and 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 salts, preferably physiologically acceptable salts thereof, or corresponding
  • R 12 represents H, a C 1-4 -alkyl radical, a cyclohexyl radical or a phenyl radical, preferably H, CH 3 , C 2 H 5 or a phenyl radical, and the remaining residues R 1 -R 11 , R 13 -R 23 , A and 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 salts, preferably physiologically acceptable salts thereof, or corresponding solvates, respectively.
  • R 13 represents H, a C 1-4 -alkyl radical, cyclohexyl or a phenyl radical, preferably H, CH 3 , C 2 H 5 or phenyl, and the remaining residues R 1 -R 12 , R 14 -R 23 , A and 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 salts, preferably physiologically acceptable salts thereof, or corresponding solvates, respectively.
  • R 14 represents H, a C 1-4 -alkyl radical, cyclohexyl or a phenyl radical, preferably H, CH 3 , C 2 H 5 or phenyl, and the remaining residues R 1 -R 13 , R 15 -R 23 , A and 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 salts, preferably physiologically acceptable salts thereof, or corresponding solvates, respectively.
  • R 15 and R 16 are each independently selected from the group consisting of H, a C 1-4 -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 1 -R 14 , R 17 -R 23 , A and 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 salts, preferably physiologically acceptable salts thereof, or corresponding solvates, respectively.
  • R 17 represents H, a C 1-4 -alkyl radical, cyclohexyl or a phenyl radical, preferably H, C 2 H 5 or phenyl
  • R 1 -R 16 , R 18 -R 23 , A and 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 salts, preferably physiologically acceptable salts thereof, or corresponding solvates, respectively.
  • R 18 represents H, a C 1-4 -alkyl radical or a phenyl radical, preferably H, CH 3 or phenyl
  • R 1 -R 17 , R 19 -R 23 , A and 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 salts, preferably physiologically acceptable salts thereof, or corresponding solvates, respectively.
  • R 19 represents H or an unbranched or branched C 1-4 alkyl radical, preferably H or a C 1-2 alkyl radical and the remaining residues R 1 -R 18 , R 20 -R 23 , A and 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 salts, preferably physiologically acceptable salts thereof, or corresponding solvates, respectively.
  • R 20 represents H, an unbranched or branched C 1-4 alkyl radical or a NR 21 R 22 -moiety, preferably H, a C 1-2 alkyl radical or a NR 21 R 22 -moiety and the remaining residues R 1 -R 19 , R 21 -R 23 , A and 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 salts, preferably physiologically acceptable salts thereof, or corresponding solvates, respectively.
  • R 21 represents H or an unbranched or branched C 1-4 alkyl radical, preferably H or a C 1-2 alkyl radical and the remaining residues R 1 -R 20 , R 22 , R 23 , A and 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 salts, preferably physiologically acceptable salts thereof, or corresponding solvates, respectively.
  • R 22 represents H or an unbranched or branched C 1-4 alkyl radical, preferably H or a C 1-2 alkyl radical and the remaining residues R 1 -R 21 , R 23 A and 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 salts, preferably physiologically acceptable salts thereof, or corresponding solvates, respectively.
  • R 23 represents H or an unbranched or branched C 1-4 alkyl radical, preferably H or a C 1-2 alkyl radical and the remaining residues R 1 -R 22 , A and 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 salts, preferably physiologically acceptable salts thereof, or corresponding solvates, respectively.
  • A represents a —CH 2 -group and the remaining residues R 1 -R 23 and 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 salts, preferably physiologically acceptable salts thereof, or corresponding solvates, respectively.
  • R 1 , R 2 , R 3 , R 4 are each independently selected from the group consisting of H, F, Cl, Br, OH, CH 3 and OCH 3
  • R 5 represents hydrogen
  • R 6 , R 7 , R 3 , R 9 all represent H
  • A represents —CH 2 —
  • B represents a —CH 2 —OH or —(C ⁇ O)—O—CH 3 group
  • R 10 represents hydrogen
  • R 11 is selected from the group consisting of unsubstituted phenyl, phenyl that is optionally at least mono-substituted with one or more substituents independently selected from the group consisting cyclohexyl, phenyl, phenoxy, benzoyl, —C( ⁇ O)—C 1-2 -alkyl, —C(H)(OH)(phenyl) and —C(H)(OH)(CH 3 ), a group of general formula (A)
  • n 1 or 2
  • X represents CH
  • Y represents CH—OH or C( ⁇ O)
  • R E represents H, a branched or unbranched C 1-4 -alkyl radical or a branched or unbranched C 1-4 -alkoxy radical
  • Z represents CH 2 , O, S, CH—OH, C( ⁇ O) or N—R F
  • R F represents H or an alkyl-radical selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and tert.-butyl, 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, preferably a physiologically acceptable salt thereof, or a corresponding solvate, respectively.
  • 1,4-disubstituted piperidine compounds of general formula (I) selected from the list B of the examples section given below.
  • the present invention also provides a process for the preparation of 1,4-disubstituted piperidine compounds of general formula (I), wherein R 1 -R 23 , A and B have the meaning given above, according to which at least one compound of general formula (II),
  • F represents halogen, hydroxy or an O-acyl group and G represents halogen, preferably chlorine, in a suitable reaction medium and preferably in the presence of at least one base and/or optionally at least one auxiliary agent, and reacting the so obtained compound of general (IV)
  • A, G, R 10 and R 11 have the above defined meaning, is reacted with at least one piperidine compound of general formula (V) and/or a salt, preferably hydrochloride salt, thereof,
  • R 1 to R 9 and B have the meaning as defined 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 I.
  • reaction scheme A the process may be illustrated as an example by the following reaction scheme A:
  • R 1 to R 11 , A and B have the meaning as given above.
  • the present invention also provides a process for the preparation of 1,4 disubstituted piperidine compounds of general formula (I), wherein R 1 -R 23 and A have the meaning given above and B represents a substituted aliphatic radical or a —CH 2 OR 23 -moiety, according to which at least one compound of general formula (II),
  • F represents halogen, hydroxy or an O-acyl group and G represents halogen, preferably chlorine, in a suitable reaction medium and preferably in the presence of at least one base and/or at least one auxiliary agent, and reacting the so obtained compound of general (IV)
  • A, G, R 10 and R 11 have the above defined meaning, with at least one piperidin compound of general formula (V) and/or a salt, preferably hydrochloride, thereof,
  • R 1 to R 9 have the meaning as defined above and R x represents any substituent including hydrogen, preferably hydrogen, 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 (VI),
  • 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,
  • 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.
  • alkali metal hydroxides e.g. sodium hydroxyde or potassium hydroxyde
  • other metals such as barium hydroxyde or different carbonates
  • alkoxides e.g. sodium methoxide, potassium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide or potassium ter
  • 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.
  • 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 amounts from 0.5 to 5 mol versus 1 mol of the corresponding reactands.
  • bases are generally used in amounts from 0.05 to 10 mol versus 1 mol of the corresponding reactands.
  • 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. The protective groups may also be eliminated as convenient by means well-known to those skilled in the art.
  • the compounds of general formulas (II), (III), (IV) and (V) 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 (IV) and (V) to yield 1,4-disubstituted piperidine compounds of general formula (I) may also be facilitated by conventional methods known to those skilled in the art.
  • the compounds of general formula (IV) are commercially available or may be produced according to scheme I by conventional methods known to those skilled in the art. Essentially the respective compound of general formula (II) is reacted with chloroacetyl chloride or the respective compound of general formula (III) 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 present invention also provides a process for the preparation of salts of 1,4-disubstituted piperidine compounds of general formula (I), wherein at least one compound of general formula (I) having at least one basic group is reacted with an inorganic and/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 present invention also provides a process for the preparation of salts of 1,4-disubstituted piperidine compounds of general formula (I), wherein at least one compound of general formula (I) 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 R 4-n ] + , wherein n is 0, 1, 2, 3 or 4 and R represents a branched or unbranched C 1-4 -alkyl-radical.
  • Solvates preferably hydrates, of the 1,4-disubstituted piperidine compounds of general formula (I), or corresponding stereoisomers, or corresponding salts may also be obtained by standard procedures known to those skilled in the art.
  • 1,4-disubstituted piperidine compounds of general formula (I) 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.
  • 1,4-disubstituted piperidine compounds of general formula (I), their stereoisomers or the respective salts or solvates are toxicologically acceptable and are therefore suitable as pharmaceutical active substances for the preparation of medicaments.
  • the present invention therefore also provides for a medicament comprising at least one 1,4-disubstituted piperidine compound of general formula (I), optionally in form of one of its stereoisomers, preferably enantiomers or diastereomers, its racemate or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or a physiologically acceptable salt thereof, or a solvate, respectively, and optionally one or more pharmaceutically acceptable adjuvants.
  • a medicament comprising at least one 1,4-disubstituted piperidine compound of general formula (I), optionally in form of one of its stereoisomers, preferably enantiomers or diastereomers, its racemate or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or a physiologically acceptable salt thereof, or a solvate, respectively, and optionally one or
  • the present invention also provides for a pharmaceutical composition
  • a pharmaceutical composition comprising at least one 1,4-disubstituted piperidine compound of general formula (I), optionally in form of one of its stereoisomers, preferably enantiomers or diastereomers, its racemate or in form of a mixture of at least two of its stereoisomers in any mixing ratio, or a physiologically acceptable salt thereof, or a solvate, respectively, and optionally one or more pharmaceutically acceptable adjuvants, which is not yet formulated into a medicament.
  • the medicament is suitable for the regulation of neuropeptide Y receptors, preferably of neuropeptide Y 5 (NPY5) receptor, for improvement of cognition, regulation of appetite, regulation of body weight, for the regulation of food ingestion (food intake), preferably for the prophylaxis and/or treatment of disorders of food ingestion, preferably obesity, anorexia, bulimia, cachexia or type II diabetes (non insuline dependent diabetes), for the prophylaxis and/or treatment of disorders of the peripheral nervous system, disorders of the central nervous system, diabetes, arthritis, epilepsy, anxiety, depression, cognitive disorders, preferably memory disorders, cardiovascular diseases, pain, hypertensive syndrom, inflammatory diseases or immune diseases.
  • NPY5 neuropeptide Y 5
  • the present invention also provides for the use of at least one 1,4-disubstituted piperidine compound of general formula (I), optionally in form of one of its stereoisomers, preferably enantiomers or diastereomers, its racemate or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or a physiologically acceptable salt thereof, or a solvate, respectively, for the manufacture of a medicament for the regulation of neuropeptide Y receptors, preferably of neuropeptide Y 5 (NPY5) receptor, for improvement of cognition, for regulation of appetite, regulation of body weight, for the regulation of food ingestion (food intake), preferably for the prophylaxis and/or treatment of disorders of food ingestion, preferably obesity, anorexia, bulimia, cachexia or type II diabetes (non insuline dependent diabetes), for the prophylaxis and/or treatment of disorders of the peripheral nervous system, disorders of the central nervous system, diabetes,
  • the medicament may be in any form suitable for the application to humans and/or animals, preferably mammals, and can be produced by standard procedures known to those skilled in the art.
  • the composition of the medicament may vary depending on the route of administration.
  • the medicament of the present invention may e.g. be administered parentally in combination with conventional injectable liquid carriers, such as water or suitable alcohols.
  • conventional injectable liquid carriers such as water or suitable alcohols.
  • Conventional pharmaceutical adjuvants for injection such as stabilizing agents, solubilizing agents, and buffers, may be included in such injectable compositions.
  • These medicaments may preferably be injected intramuscularly, intraperitoneally, or intravenously.
  • Medicaments according to the present invention may also be formulated into orally administrable compositions containing one or more physiologically compatible carriers or excipients, in solid or liquid form.
  • These compositions may contain conventional ingredients such as binding agents, fillers, lubricants, and acceptable wetting agents.
  • the compositions may take any convenient form, such as tablets, pellets, capsules, lozenges, multiparticulates such as granules or pellets, optionally compressed into a tablet or filled into a capsule, aqueous or oily solutions, suspensions, emulsions, or dry powdered form suitable for reconstitution with water or other suitable liquid medium before use, for immediate or controlled release.
  • liquid oral forms for administration may also contain certain additives such as sweeteners, flavoring, preservatives, and emulsifying agents.
  • Non-aqueous liquid compositions for oral administration may also be formulated, containing e.g. edible oils. Such liquid compositions may be conveniently encapsulated in e.g., gelatin capsules in a unit dosage amount.
  • compositions of the present invention may also be administered topically or via a suppository.
  • compositions include preferably 1 to 60% by weight of one or more of the 1,4-disubstituted piperidine compound of general formula (I), optionally in form of one of its stereoisomers, preferably enantiomers or diastereomers, its racemate or in form of a mixture of at least two of its stereoisomers in any mixing ratio, or a physiologically acceptable salt thereof, or a solvate, respectively, and 40 to 99% by weight of the appropriate pharmaceutical vehicle(s).
  • the 1,4-disubstituted piperidine compound of general formula (I) optionally in form of one of its stereoisomers, preferably enantiomers or diastereomers, its racemate or in form of a mixture of at least two of its stereoisomers in any mixing ratio, or a physiologically acceptable salt thereof, or a solvate, respectively, and 40 to 99% by weight of the appropriate pharmaceutical vehicle(s).
  • the daily dosage for humans and animals may vary depending on factors that have their basis in the respective species or other factors, such as age, weight or degree of illness and so forth.
  • the daily dosage for mammals including humans usually ranges from 1 milligram to 2000 milligram, preferably 1 to 1500 mg, more preferably 1 to 1000 mg of substance to be administered during one or several intakes.
  • 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 48,000 g for 20 min (4° C.).
  • the pellet was resuspended in 8 ml membrane buffer (Tris-HCl 25 mM, NaCl 120 mM, KCl 5 mM, KH 2 PO 4 1.2 mM, CaCl 2 2.5 mM, MgSO 4 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 in the incubation was 40 ⁇ g/ml.
  • the radioligand was [ 125 I]-PYY (100 pM) in a total incubation volume of 200 ⁇ l.
  • the reaction was stopped by addition of 5 ml ice-cold buffer (Tris-HCl 25 mM, NaCl-120 mM, KCl 5 mM, KH 2 PO 4 1.2 mM, CaCl 2 2.5 mM, MgSO 4 1.2 mM, pH 7.4) and rapid filtration in a Harvester Brandell Cell using filters (Schleicher & Schuell GF 3362) pretreated for two hours with 0.5% polyethyleneimine.
  • 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 [ 125 I][Leu 31 , Pro 34 ]Peptide YY and [ 125 I]Peptide YY 3-36 as Selective Y1 and Y2 Radioligands, The Journal of Pharmacology and Experimental Therapeutics, 1995, 272, 673-680, with slight modifications. Said literature description is herewith incorporated by reference and forms part of the disclosure.
  • 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 KCl, 2.2 mM CaCl 2 , 1.2 mM KH 2 PO 4 , 1.2 mM MgSO 4 , 25 mM NaHCO 3 , 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 [ 125 I]-PYY 3-36 at the concentration of 28 pM.
  • Incubation volume 500 ⁇ l. Incubation is performed at 25° C.
  • rats Male W, 200-270 g, obtained from Harlan, S.A were used.
  • the rats are acclimatized to the animal facility for at least 5 days before being subjected to any experimental procedure.
  • animals were housed in groups of five in translucid cages and provided with food and water ad libitum. At least 24 hours before the tests, animals are adapted to single-housing conditions.
  • Food intake is measured in home cages in order to minimize non-specific stress effects on food intake resulting from changes in housing conditions. Food and water is available. ad libitum. Immediately before lights turn off, rats are weighed, randomized and dosed (orally or intraperitoneally), either with vehicle or selected 1,4-disubstituted piperidine compounds of general formula (I). Thereafter, rats are returned to home cages and food left on top covers is measured. Remaining food and animal's weight is measured next morning.
  • Rats were fasted for 23 hours in home cages, and after this period dosed (orally or intraperitoneally), either with vehicle or 1,4-disubstituted piperidine compound of general formula (I).
  • One hour later preweighed food is left on top covers, and cumulative food intake is measured after 1, 2, 4 and 6 hours.
  • the methods are described in Ants Kask et al., European Journal of Pharmacology 414 (2001) 215-224 and Turnbull et al., Diabetes, Vol. 51, August 2002, which are hereby incorporated by reference and form part of the disclosure.
  • haloamides used for obtaining the compounds of the present invention are either commercially available or have been prepared according to the scheme 2, employing conventional methods. Essentially the corresponding amines are reacted with chloroacetyl chloride or with a derivative of the general formula (IIIa), the reaction is carried out using an organic solvent, usually dichloromethane, and a base, usually triethylamine.
  • the reaction mixture was added to 50 mL water and 100 mL ethyl acetate, the organic phase was decanted and washed with water (3 ⁇ 50 mL), dried over sodium sulfate and a 2.8 M hydrogen chloride solution in absolute ethanol (1.80 mL) was added, to precipitate the hydrochloride, which was filtered off and washed with ethyl acetate. 1840 mg of a white solid were obtained. Yield: 77%.

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Abstract

1,4-disubstituted piperidine compounds of general formula (I) wherein the substituents are defined in claim 1 that are suitable in particular as active substances in medicaments, preferably in medicaments for the regulation of neuropeptide Y receptors, particularly preferably of neuropeptide Y5 (NPY5) receptor, for the regulation of food ingestion (food intake), preferably for the prophylaxis and/or treatment of disorders of food ingestion, such as obesity, anorexia, cachexia, bulimia or type II (non insulin dependent) diabetes, for the prophylaxis and/or treatment of disorders of the peripheral nervous system, disorders of the central nervous system, anxiety, depression, cognitive disorders, preferably memory disorders, cardiovascular diseases, pain, epilepsy, arthritis, hypertensive syndrome, inflammatory diseases, immune diseases and other NPY5 mediated disorders in animals and mammals, including man.

Description

  • The present invention relates to 1,4-disubstituted piperidine compounds of general formula (I), methods for their preparation, medicaments comprising these compounds as well as their use for the preparation of a medicament for the treatment of humans or animals.
  • 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.
  • Several NPY5 non-peptidic antagonists have been described. Thus, 2-aminoquinazoline derivatives [PCT Int. Appl. WO 9720823, 1997 (Novartis AG)], sulfonamides [PCT Int. Appl. WO 9719682, 1997 (Synaptic Pharmaceutical Corp.)], pyrazoles [PCT Int. Appl. WO 9824768, 1998 (Banyu Pharmaceutical Co., Ltd)], aminopyridines [PCT Int. Appl. WO 9840356, 1998 (Banyu Pharmaceutical Co., Ltd)], N-aralkyl-2-tetralinamines [PCT Int. Appl. WO 0020376, 2000 (Ortho McNeil Pharmaceutical Inc.)], several amides [PCT Int. Appl. WO 9835957, 1998 (Bayer Corp.)], pyridine and pyrimidine derivatives [PCT Int. Appl. WO 9940091, 1999 (Amgen Inc.)], carbazoles [PCT Int. Appl. WO 0107409, 2001 (Astra Zeneca AB.)], and spiroisoquinolinones [PCT Int. Appl. WO 0113917, 2001 (Bristol-Myers Squibb Co.)], have been prepared.
  • Thus, it was an object of the present invention to provide novel compounds that are suitable in particular as active substances in medicaments, preferably in medicaments for the regulation of neuropeptide Y receptors, particularly preferably of neuropeptide Y 5 (NPY5) receptor, for the regulation of food ingestion (food intake), preferably for the prophylaxis and/or treatment of disorders of food ingestion, such as obesity, anorexia, cachexia, bulimia or type II (non insulin dependent) diabetes, for the prophylaxis and/or treatment of disorders of the peripheral nervous system, disorders of the central nervous system, anxiety, depression, cognitive disorders, preferably memory disorders, cardiovascular diseases, pain, epilepsy, arthritis, hypertensive syndrom, inflammatory diseases, immune diseases and other NPY5 mediated disorders in animals and mammals, including man.
  • Said object was achieved by providing 1,4-disubstituted piperidine compounds of general formula (I),
  • Figure US20110172270A1-20110714-C00001
  • wherein
    R1, R2, R3, R4 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, —OR12, —OC(═O)R13, —SR14, —SOR14, —SO2R14, —NH—SO2R14, —SO2NH2, —NR15R16 moiety and —O—P,
    R5 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 cycloaliphatic radical,
    R6, R7, R8, R9 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 COOR17 moiety,
    A represents a bridge member —CHR18— or —CHR18—CH2—,
    B represents an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted cycloaliphatic radical, a COOR19-moiety, a —(C═O)R20-moiety, or a —CH2OR23-moiety,
    R10 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,
    R11 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
    R10 and R11 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,
    R12 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,
    R13 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,
    R14 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,
    R15 and R16 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 R15 and R16 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,
    R17 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,
    R18 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,
    R19 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 cycloaliphatic radical, or an optionally at least mono-substituted aryl- or heteroaryl radical, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,
    R20 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 cycloaliphatic radical, an optionally at least mono-substituted aryl- or heteroaryl radical, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, or a NR21R22-moiety,
    R21 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 cycloaliphatic radical, or an optionally at least mono-substituted aryl- or heteroaryl radical, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,
    R22 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 cycloaliphatic radical, or an optionally at least mono-substituted aryl- or heteroaryl radical, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,
    R23 represents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, which may comprise at least one heteroatom as a chain member, or a —(C═O)R13-moiety,
    P represents hydrogen, a linear or branched C1-3 alkyl radical, —PO(O—C1-4-Alkyl), —CO(OC1-5-Alkyl),
  • Figure US20110172270A1-20110714-C00002
  • and RP represents —OCO—C1-3-Alkyl, —CH2—N(C1-4-Alkyl)2 or
  • Figure US20110172270A1-20110714-C00003
  • 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, preferably a physiologically acceptable salt thereof, or a corresponding solvate, respectively.
  • Preferred are 1,4-disubstituted piperidine compounds of general formula (I) given above, wherein
  • R1, R2, R3, R4 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, —OR12, —OC(═O)R13, —SR14, —SOR14, —SO2R14, —NH—SO2R14, —SO2NH2, —NR15R16 moiety and —O—P,
    R5 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 cycloaliphatic radical,
    R6, R7, R8, R9 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-moiety and a —COOR17 moiety,
    A represents a bridge member —CHR18— or —CHR19—CH2—,
    B represents an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted cycloaliphatic radical, a COOR19-moiety, a —(C═O)R20-moiety, or a —CH2OR23-moiety,
    R10 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,
    R11 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
    R10 and R11 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,
    R12 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,
    R13 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,
    R14 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,
    R15 and R16 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 R15 and R16 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,
    R17 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,
    R18 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,
    R19 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 cycloaliphatic radical, or an optionally at least mono-substituted aryl- or heteroaryl radical, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,
    R20 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 cycloaliphatic radical, an optionally at least mono-substituted aryl- or heteroaryl radical, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, or a NR21R22-moiety,
    R21 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 cycloaliphatic radical, or an optionally at least mono-substituted aryl- or heteroaryl radical, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,
    R22 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 cycloaliphatic radical, or an optionally at least mono-substituted aryl- or heteroaryl radical, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,
    R23 represents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, which may comprise at least one heteroatom as a chain member, or a —(C═O)R13-moiety,
    P represents hydrogen, a linear or branched C1-3 alkyl radical, —PO(O—C1-4-Alkyl), —CO(OC1-5-Alkyl),
  • Figure US20110172270A1-20110714-C00004
  • and RP represents ortho —OCO—C1-3-Alkyl, —CH2—N(C1-4-Alkyl)2 in the meta or para position of the phenyl ring or
  • Figure US20110172270A1-20110714-C00005
  • in the meta or para position of the phenyl ring,
    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 salts thereof, preferably physiologically acceptable salts thereof, or corresponding solvates.
  • 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-system are preferably 5- or 6-membered.
  • If one or more of the residues R1-R23 and B 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 C1-4-alkoxy, branched or unbranched C1-4-perfluoroalkoxy, branched or unbranched C1-4-perfluoroalkyl, amino, carboxy, amido, cyano, nitro, —SO2NH2, —CO—C1-4-alkyl, —SO—C1-4-alkyl, —SO2—C1-4-alkyl, —NH—SO2—C1-4-alkyl, wherein the C1-4-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 these substituents 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 R1-R22 and B 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 C1-4-alkyl, branched or unbranched C1-4-alkoxy, branched or unbranched C1-4-perfluoroalkoxy, phenoxy, benzoyl, cyclohexyl, branched or unbranched C1-4-perfluoroalkyl, —NRARB wherein RA, RB are each independently selected from the group consisting of H, a branched or unbranched C1-4-alkyl-radical, —CH2—CH2—OH and phenyl, carboxy, amido, cyano, nitro, —SO2NH2, —CO—C1-4-alkyl, —CO—OC1-4-alkyl, —SO—C1-4-alkyl, —SO2—C1-4-alkyl, —NH—SO2—C1-4-alkyl, wherein C1-4-alkyl may in each case be branched or unbranched, unsubstituted or at least mono-substituted phenyl or naphthyl 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, methoxy, ethoxy, benzoyl, 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 C1-4-alkyl-radical, —CH2—CH2—OH and phenyl, and an unsubstituted phenyl radical. If any one of these substituents 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 R1-R4 and R10-R18 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 C1-4-alkoxy, branched or unbranched C1-4-perfluoroalkoxy, branched or unbranched C1-4-perfluoroalkyl, amino, carboxy, amido, cyano, nitro, —SO2NH2, —CO—C1-4-alkyl, —SO—C1-4-alkyl, —SO2—C1-4-alkyl, —NH—SO2—C1-4-alkyl, wherein C1-4-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 these substituents 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 R1-R4 and R10-R22 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 C1-4-alkyl, branched or unbranched C1-4-alkoxy, branched or unbranched C1-4-perfluoroalkoxy, branched or unbranched C1-4-perfluoroalkyl, amino, carboxy, amido, cyano, keto, nitro, —SO2NH2, —CO—C1-4-alkyl, —SO—C1-4-alkyl, —SO2—C1-4-alkyl, —NH—SO2—C1-4-alkyl wherein C1-4-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, keto (═O), cyano and an unsubstituted phenyl radical. If any one of these substituents 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 R1-R4 and R10-R22 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 C1-4-alkoxy, branched or unbranched C1-4-alkyl, branched or unbranched C1-4-perfluoroalkoxy, unsubstituted or at least mono-substituted phenoxy, unsubstituted or at least mono-substituted benzoyl, cyclohexyl, branched or unbranched C1-4-perfluoroalkyl, NRARB wherein RA, RB are each independently selected from the group consisting of H, a branched or unbranched C1-4-alkyl-radical, —CH2—CH2—OH and phenyl, carboxy, amido, cyano, —C(H)(OH)(phenyl), —C(H)(OH)(CH3), nitro, —SO2NH2, —CO—C1-4-alkyl, —CO—OC1-4-alkyl, —SO—C1-4-alkyl, —SO2—C1-4-alkyl, —NH—SO2—C1-4-alkyl, wherein C1-4-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 radical, more preferably be selected from the group consisting of hydroxy, F, Cl, Br, methyl, ethyl, cyano, —C(H)(OH)(phenyl), —C(H)(OH)(CH3), 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 C1-4-alkyl-radical, —CH2—CH2—OH and phenyl, and an unsubstituted phenyl radical. If any of these substituents 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 R1-R4 and R10-R22 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 C1-4-alkoxy, branched or unbranched C1-4-alkyl, branched or unbranched C1-4-perfluoroalkoxy, unsubstituted or at least mono-substituted phenoxy, unsubstituted or at least mono-substituted benzoyl, cyclohexyl, branched or unbranched C1-4-perfluoroalkyl, NRARB wherein RA, RB are each independently selected from the group consisting of H, a branched or unbranched C1-4-alkyl-radical, —CH2—CH2—OH and phenyl, carboxy, amido, cyano, nitro, —C(H)(OH)(phenyl), —C(H)(OH)(CH3), —SO2NH2, —CO—C1-4-alkyl, —CO—OC1-4-alkyl, SO—C1-4-alkyl, SO2—C1-4-alkyl, —NH—SO2—C1-4-alkyl, wherein C1-4-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, —C(H)(OH)(phenyl), —C(H)(OH)(CH3), —CO—CH3, —CO—OCH3, —NRARB wherein RA, RB are each independently selected from the group consisting of H, a branched or unbranched —CH2—CH2—OH and phenyl, and an unsubstituted phenyl radical. If any one of these substituents itself is at least mono-substituted, said substituents may preferably be selected from the group consisting of F, Cl, methyl and methoxy.
  • If R10 and R11 and/or R15 and R16 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 C1-4-alkoxy, branched or unbranched C1-4-alkyl, branched or unbranched C1-4-perfluoroalkoxy, branched or unbranched C1-4-perfluoroalkyl, amino, carboxy, amido, cyano, nitro, —SO2NH2, —CO—C1-4-alkyl, —SO—C1-4-alkyl, —SO2—C1-4-alkyl, —NH—SO2—C1-4-alkyl, wherein C1-4-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 these substituents itself is at least mono-substituted, said substituents may preferably be selected from the group consisting of F, Cl, methyl and methoxy.
  • If R10 and R11 and/or R15 and R16 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 R1-R22 and B represents 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 R1-R4 and R10-R22 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 R23 represents an aliphatic radical, which comprises at least one heteroatom as a chain member, each of these heteroatoms may preferably be O or S, more preferably O.
  • Preferred compounds of general formula (I) are also those, wherein R1, R2, R3, R4 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 C1-6-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 C1-6-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 C1-6-alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ringsystem a nitro, cyano, —OR12, —OC(═O)R13, —SR14, —SOR14, —SO2R14, —NH—SO2R14, —SO2NH2 and —NR15R16 moiety,
  • R5 represents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C1-6-aliphatic radical, or a saturated or unsaturated, optionally at least mono-substituted C3-8-cycloaliphatic radical,
  • R6, R7, R8, R9 are each independently selected from the group consisting of hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C1-6-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-moiety and a COOR17 moiety,
  • A represents a bridge member —CHR18— or —CHR18—CH2—,
  • B represents an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C1-6-aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted C3-8-cycloaliphatic radical, a COOR19-moiety, a COR20-moiety, or a —C2—OR23-moiety,
  • R10 represents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C1-6-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 C1-6-alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,
  • R11 represents an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C1-6-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 C1-6-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 C1-6-alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ringsystem, or
  • R10 and R11 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,
  • R12 represents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C1-6-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 C1-6-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 C1-6-alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,
  • R13 represents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C1-6-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 C1-6-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 C1-6-alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,
  • R14 represents an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C1-6-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 C1-6-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 C1-6-alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,
  • R15 and R16 each are independently selected from the group consisting of hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C1-6-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 C1-6-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 C1-6-alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,
  • or R15 and R16 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,
  • R17 represents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C1-6-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 C1-6-alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,
  • R18 represents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C1-6-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 C1-6-alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,
  • R19 represents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C1-6-aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted C3-8 cycloaliphatic radical, or an optionally at least mono-substituted, 5- or 6-membered aryl- or heteroaryl radical, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,
  • R20 represents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C1-6-aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted C3-8 cycloaliphatic radical, an optionally at least mono-substituted, 5- or 6-membered aryl- or heteroaryl radical, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, or a NR21R22-moiety,
  • R21 represents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C1-6-aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted C3-8 cycloaliphatic radical, or an optionally at least mono-substituted, 5- or 6-membered aryl- or heteroaryl radical, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,
  • R22 represents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C1-6-aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted C3-8 cycloaliphatic radical, or an optionally at least mono-substituted, 5- or 6-membered aryl- or heteroaryl radical, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,
  • R23 represents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C1-6-aliphatic radical, which may comprise at least one heteroatom as a chain member, or a —(C═O)R13-moiety,
  • 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 corresponding solvates, respectively.
  • Particularly preferred are compounds of general formula (I), wherein R1, R2, R3, R4 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 C1- or C2-alkylene group, a nitro, cyano, —OR12, —OC(═O)R13, —SR14 and —NR15R16 moiety, preferably are each independently selected from the group consisting of H, F, Cl, Br, CH3, CH2CH3, CF3, CF2CF3, cyclopentyl, cyclohexyl, nitro, cyano and —OR12 and the remaining residues R5-R23, A and 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 salts, preferably physiologically acceptable salts thereof, or corresponding solvates, respectively.
  • Also particularly preferred are compounds of general formula (I), wherein R5 represents H or a branched or unbranched C1-3-alkyl radical, preferably H, CH3 or CH2CH3, and the remaining residues R1-R4, R6-R23, A and 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 salts, preferably physiologically acceptable salts thereof, or corresponding solvates, respectively.
  • Also particularly preferred are compounds of general formula (I), wherein R6, R7, R8, R9 are each independently selected from the group consisting of H, a branched or unbranched C1-3-alkyl radical, a cyano and a COOR17 moiety, preferably selected from the group consisting of H, CH3, CH2CH3 and a cyano moiety, more preferably all represent H, and the remaining residues R1-R5, R10-R23, A and 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 salts, preferably physiologically acceptable salts thereof, or corresponding solvates, respectively.
  • Also particularly preferred are compounds of general formula (I), wherein B represents an optionally branched, optionally at least mono-substituted C1-3-alkyl radical, a COOR19-moiety, or a CH2OR23-moiety, preferably a COOR19-moiety, a CH2OR23-moiety or a C1-2-alkyl radical, more preferably a COOR19-moiety or a CH2OR23-moiety, and the remaining residues R1-R23 and 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 salts, preferably physiologically acceptable salts thereof, or corresponding solvates, respectively.
  • Also particularly preferred are compounds of general formula (I), wherein R10 represents hydrogen or a branched or unbranched C1-4-alkyl radical, more preferably hydrogen, and the remaining residues R1-R9, R11-R23, A and 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 salts, preferably physiologically acceptable salts thereof, or solvates, respectively.
  • Also particularly preferred are compounds of general formula (I), wherein R11 is selected from the group consisting of an unsubstituted phenyl radical, a phenyl radical that is optionally at least mono-substituted with a substituent selected from the group consisting of branched or unbranched C1-4-alkyl-radical, a branched or unbranched C1-4-alkoxy-radical, a branched or unbranched C1-4-perfluoroalkyl-radical, a branched or unbranched C1-4-perfluoroalkoxy-radical, F, Cl, Br, cyclohexyl, phenyl, phenoxy, phenylthio, benzoyl, cyano, —C(═O)C1-2-alkyl, —C(═O)OC1-2-alkyl, -carboxy, —C(H)(OH)(phenyl), —C(H)(OH)(CH3) and —NRARB wherein RA, RB are each independently selected from the group consisting of H, a branched or unbranched C1-4-alkyl-radical, —CH2—CH2—OH and an unsubstituted phenyl radical,
  • an unsubstituted thiazole radical,
  • a group of general formula (A)
  • Figure US20110172270A1-20110714-C00006
  • 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 C1-4-alkyl radical,
    a group of formula (B),
  • Figure US20110172270A1-20110714-C00007
  • a group of formula (C),
  • Figure US20110172270A1-20110714-C00008
  • a group of general formula (D),
  • Figure US20110172270A1-20110714-C00009
  • wherein RD is H or a branched or unbranched C1-4-alkyl radical and a group of general formula (E),
  • Figure US20110172270A1-20110714-C00010
  • wherein
  • RE represents H, a branched or unbranched C1-4-alkyl radical or a branched or unbranched C1-4-alkoxy radical,
  • W represents a bond between the two aromatic rings, CH2, CH—OH or C(═O),
  • Z represents CH2, O, S, CH—OH, C(═O) or N—RF where RF represents H or a branched or unbranched C1-4-alkyl-radical, and the remaining residues R1-R10, R12-R23, A and 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 salts, preferably physiologically acceptable salts thereof, or corresponding solvates, respectively.
  • Those skilled in the art understand that the afore mentioned groups (A)-(E) may be bonded via any suitable ring member of any ring, for example group (B) may also be bonded via the ring containing the nitrogen atom.
  • Also particularly preferred are compounds of general formula (I), wherein R10 and R11 together with the bridging nitrogen atom form a saturated, 6-membered heterocyclic ring, which is optionally 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 R1-R9, R12-R23, A and 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 salts, preferably physiologically acceptable salts thereof, or corresponding solvates, respectively.
  • Also particularly preferred are compounds of general formula (I), wherein R12 represents H, a C1-4-alkyl radical, a cyclohexyl radical or a phenyl radical, preferably H, CH3, C2H5 or a phenyl radical, and the remaining residues R1-R11, R13-R23, A and 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 salts, preferably physiologically acceptable salts thereof, or corresponding solvates, respectively.
  • Also particularly preferred are compounds of general formula (I), wherein R13 represents H, a C1-4-alkyl radical, cyclohexyl or a phenyl radical, preferably H, CH3, C2H5 or phenyl, and the remaining residues R1-R12, R14-R23, A and 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 salts, preferably physiologically acceptable salts thereof, or corresponding solvates, respectively.
  • Also particularly preferred are compounds of general formula (I), wherein R14 represents H, a C1-4-alkyl radical, cyclohexyl or a phenyl radical, preferably H, CH3, C2H5 or phenyl, and the remaining residues R1-R13, R15-R23, A and 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 salts, preferably physiologically acceptable salts thereof, or corresponding solvates, respectively.
  • Also particularly preferred are compounds of general formula (I), wherein R15 and R16 are each independently selected from the group consisting of H, a C1-4-alkyl radical, cyclohexyl and a phenyl radical, preferably from the group consisting of H, CH3, C2H5 and phenyl, and the remaining residues R1-R14, R17-R23, A and 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 salts, preferably physiologically acceptable salts thereof, or corresponding solvates, respectively.
  • Also particularly preferred are compounds of general formula (I), wherein R17 represents H, a C1-4-alkyl radical, cyclohexyl or a phenyl radical, preferably H, C2H5 or phenyl, and the remaining residues R1-R16, R18-R23, A and 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 salts, preferably physiologically acceptable salts thereof, or corresponding solvates, respectively.
  • Also particularly preferred are compounds of general formula (I), wherein R18 represents H, a C1-4-alkyl radical or a phenyl radical, preferably H, CH3 or phenyl, and the remaining residues R1-R17, R19-R23, A and 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 salts, preferably physiologically acceptable salts thereof, or corresponding solvates, respectively.
  • Also particularly preferred are compounds of general formula (I), wherein R19 represents H or an unbranched or branched C1-4 alkyl radical, preferably H or a C1-2 alkyl radical and the remaining residues R1-R18, R20-R23, A and 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 salts, preferably physiologically acceptable salts thereof, or corresponding solvates, respectively.
  • Also particularly preferred are compounds of general formula (I), wherein R20 represents H, an unbranched or branched C1-4 alkyl radical or a NR21R22-moiety, preferably H, a C1-2 alkyl radical or a NR21R22-moiety and the remaining residues R1-R19, R21-R23, A and 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 salts, preferably physiologically acceptable salts thereof, or corresponding solvates, respectively.
  • Also particularly preferred are compounds of general formula (I), wherein R21 represents H or an unbranched or branched C1-4 alkyl radical, preferably H or a C1-2 alkyl radical and the remaining residues R1-R20, R22, R23, A and 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 salts, preferably physiologically acceptable salts thereof, or corresponding solvates, respectively.
  • Also particularly preferred are compounds of general formula (I), wherein R22 represents H or an unbranched or branched C1-4 alkyl radical, preferably H or a C1-2 alkyl radical and the remaining residues R1-R21, R23 A and 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 salts, preferably physiologically acceptable salts thereof, or corresponding solvates, respectively.
  • Also particularly preferred are compounds of general formula (I), wherein R23 represents H or an unbranched or branched C1-4 alkyl radical, preferably H or a C1-2 alkyl radical and the remaining residues R1-R22, A and 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 salts, preferably physiologically acceptable salts thereof, or corresponding solvates, respectively.
  • Also particularly preferred are compounds of general formula (I), wherein A represents a —CH2-group and the remaining residues R1-R23 and 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 salts, preferably physiologically acceptable salts thereof, or corresponding solvates, respectively.
  • Also particularly preferred are 1,4-disubstituted piperidine compounds of general formula (I) given above, wherein
  • R1, R2, R3, R4 are each independently selected from the group consisting of H, F, Cl, Br, OH, CH3 and OCH3,
    R5 represents hydrogen,
    R6, R7, R3, R9 all represent H,
    A represents —CH2—,
    B represents a —CH2—OH or —(C═O)—O—CH3 group,
    R10 represents hydrogen,
    R11 is selected from the group consisting of unsubstituted phenyl, phenyl that is optionally at least mono-substituted with one or more substituents independently selected from the group consisting cyclohexyl, phenyl, phenoxy, benzoyl, —C(═O)—C1-2-alkyl, —C(H)(OH)(phenyl) and —C(H)(OH)(CH3),
    a group of general formula (A)
  • Figure US20110172270A1-20110714-C00011
  • wherein
    n is 1 or 2,
    X represents CH,
    Y represents CH—OH or C(═O),
    a group of formula (B),
  • Figure US20110172270A1-20110714-C00012
  • a group of formula (C),
  • Figure US20110172270A1-20110714-C00013
  • and a group of general formula (E),
  • Figure US20110172270A1-20110714-C00014
  • wherein
    RE represents H, a branched or unbranched C1-4-alkyl radical or a branched or unbranched C1-4-alkoxy radical,
    Z represents CH2, O, S, CH—OH, C(═O) or N—RF where RF represents H or an alkyl-radical selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and tert.-butyl,
    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, preferably a physiologically acceptable salt thereof, or a corresponding solvate, respectively.
  • Most preferred are 1,4-disubstituted piperidine compounds of general formula (I) selected from the list B of the examples section given below.
  • Most preferred are also the following 1,4-disubstituted piperidine compounds of general formula (I):
    • [1] N-(9-Ethyl-9H-carbazol-3-yl)-2-[4-(2-hydroxymethyl-6-methyl-phenylamino)-piperidine-yl]acetamide;
    • [2] 2-[4-(2-Hydroxymethyl-4-methyl-phenylamino)-piperidine-1-yl]-N-(9-oxo-9H-fluoren-3-yl)-acetamide;
    • [3] 2-[4-(2-Hydroxymethyl-6-methyl-phenylamino)-piperidine-1-yl-]-N-(9-oxo-9H -fluoren-3-yl)-acetamide;
    • [4] N-(9-Hydroxy-9H-fluoren-3-yl)-2-[4-(2-hydroxymethyl-4-methyl-phenylamino)-piperidine-1-yl]-acetamide;
    • [5] N-(9-Hydroxy-9H-fluoren-3-yl)-2-[4-(2-hydroxymethyl-6-methyl-phenylamino)-piperidine-1-yl]-acetamide;
    • [6] 2-{1-[(9-Oxo-9H-fluoren-3ylcarbamoyl)-methyl]-piperidin-4-ylamino}benzoic acid methyl ester and
    • [7] 2-[4-(2-Hydroxymethyl-4-methyl-phenylamino)-piperidin-1-yl]-N-phenyl-acetamide,
    • [8] 2-[4-(2-Hydroxymethyl-phenylamino)-piperidin-1-yl]-N-(1-oxo-indan-5-yl)-acetamide,
      optionally in form of a salt, preferably a physiologically acceptable salt, particularly preferably in form of a physiologically acceptable acid addition salt, most preferably a hydrochloride salt, or a corresponding solvate.
  • In a further aspect the present invention also provides a process for the preparation of 1,4-disubstituted piperidine compounds of general formula (I), wherein R1-R23, A and B have the meaning given above, according to which at least one compound of general formula (II),
  • Figure US20110172270A1-20110714-C00015
  • wherein R10 and R11 have the meaning given above, is reacted with at least one compound of general formula (III),
  • Figure US20110172270A1-20110714-C00016
  • wherein A has the meaning given above, F represents halogen, hydroxy or an O-acyl group and G represents halogen, preferably chlorine, in a suitable reaction medium and preferably in the presence of at least one base and/or optionally at least one auxiliary agent, and reacting the so obtained compound of general (IV)
  • Figure US20110172270A1-20110714-C00017
  • wherein A, G, R10 and R11 have the above defined meaning, is reacted with at least one piperidine compound of general formula (V) and/or a salt, preferably hydrochloride salt, thereof,
  • Figure US20110172270A1-20110714-C00018
  • wherein R1 to R9 and B have the meaning as defined 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 I.
  • According to the invention, the process may be illustrated as an example by the following reaction scheme A:
  • Figure US20110172270A1-20110714-C00019
  • wherein R1 to R11, A and B have the meaning as given above.
  • In yet a further aspect the present invention also provides a process for the preparation of 1,4 disubstituted piperidine compounds of general formula (I), wherein R1-R23 and A have the meaning given above and B represents a substituted aliphatic radical or a —CH2OR23-moiety, according to which at least one compound of general formula (II),
  • Figure US20110172270A1-20110714-C00020
  • wherein R10 and R11 have the meaning given above, is reacted with at least one compound of general formula (III),
  • Figure US20110172270A1-20110714-C00021
  • wherein A has the meaning given above, F represents halogen, hydroxy or an O-acyl group and G represents halogen, preferably chlorine, in a suitable reaction medium and preferably in the presence of at least one base and/or at least one auxiliary agent, and reacting the so obtained compound of general (IV)
  • Figure US20110172270A1-20110714-C00022
  • wherein A, G, R10 and R11 have the above defined meaning, with at least one piperidin compound of general formula (V) and/or a salt, preferably hydrochloride, thereof,
  • Figure US20110172270A1-20110714-C00023
  • wherein R1 to R9 have the meaning as defined above and Rx represents any substituent including hydrogen, preferably hydrogen, 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 (VI),
  • Figure US20110172270A1-20110714-C00024
  • which is reacted with a base, preferably in a suitable reaction medium, more preferably in a mixture of water and ethanol, to yield a compound of general formula (I), wherein R1-R4 and R6-R23 and A have the meaning as defined above, R5 represents H and B represents a substituted aliphatic radical or a —CH2OR23-moiety.
  • According to the invention, said process may be illustrated as an example by the following reaction scheme B:
  • Figure US20110172270A1-20110714-C00025
  • 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 amounts from 0.5 to 5 mol versus 1 mol of the corresponding reactands. These bases are generally used in amounts from 0.05 to 10 mol versus 1 mol of the corresponding reactands.
  • During some of the synthetic reactions described or while preparing the compounds of general formulas (I), (II), (III), (IV), (V) and (VI), 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. The protective groups may also be eliminated as convenient by means well-known to those skilled in the art.
  • The compounds of general formulas (II), (III), (IV) and (V) 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 (IV) and (V) to yield 1,4-disubstituted piperidine compounds of general formula (I) may also be facilitated by conventional methods known to those skilled in the art.
  • The compounds of general formula (IV) are commercially available or may be produced according to scheme I by conventional methods known to those skilled in the art. Essentially the respective compound of general formula (II) is reacted with chloroacetyl chloride or the respective compound of general formula (III) in the presence of an organic reaction medium, preferably dichloromethane and a base, preferably triethylamine and/or diisopropylethylamine.
  • The preparation of compounds of general formula (V) and their use for the preparation of compounds of general formula (I) is illustrated in schemes 1 and 2 given below:
  • Figure US20110172270A1-20110714-C00026
    Figure US20110172270A1-20110714-C00027
    Figure US20110172270A1-20110714-C00028
  • Figure US20110172270A1-20110714-C00029
    Figure US20110172270A1-20110714-C00030
  • In a further aspect the present invention also provides a process for the preparation of salts of 1,4-disubstituted piperidine compounds of general formula (I), wherein at least one compound of general formula (I) having at least one basic group is reacted with an inorganic and/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.
  • In yet a further aspect the present invention also provides a process for the preparation of salts of 1,4-disubstituted piperidine compounds of general formula (I), wherein at least one compound of general formula (I) 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 C1-4-alkyl-radical.
  • Solvates, preferably hydrates, of the 1,4-disubstituted piperidine compounds of general formula (I), or corresponding stereoisomers, or corresponding salts may also be obtained by standard procedures known to those skilled in the art.
  • If the 1,4-disubstituted piperidine compounds of general formula (I) 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 1,4-disubstituted piperidine compounds of general formula (I) or a corresponding stereoisomer, or a corresponding salt, or corresponding 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 1,4-disubstituted piperidine compounds of general formula (I), their stereoisomers or the respective salts or solvates are toxicologically acceptable and are therefore suitable as pharmaceutical active substances for the preparation of medicaments.
  • The present invention therefore also provides for a medicament comprising at least one 1,4-disubstituted piperidine compound of general formula (I), optionally in form of one of its stereoisomers, preferably enantiomers or diastereomers, its racemate or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or a physiologically acceptable salt thereof, or a solvate, respectively, and optionally one or more pharmaceutically acceptable adjuvants.
  • Furthermore, the present invention also provides for a pharmaceutical composition comprising at least one 1,4-disubstituted piperidine compound of general formula (I), optionally in form of one of its stereoisomers, preferably enantiomers or diastereomers, its racemate or in form of a mixture of at least two of its stereoisomers in any mixing ratio, or a physiologically acceptable salt thereof, or a solvate, respectively, and optionally one or more pharmaceutically acceptable adjuvants, which is not yet formulated into a medicament.
  • Preferably the medicament is suitable for the regulation of neuropeptide Y receptors, preferably of neuropeptide Y 5 (NPY5) receptor, for improvement of cognition, regulation of appetite, regulation of body weight, for the regulation of food ingestion (food intake), preferably for the prophylaxis and/or treatment of disorders of food ingestion, preferably obesity, anorexia, bulimia, cachexia or type II diabetes (non insuline dependent diabetes), for the prophylaxis and/or treatment of disorders of the peripheral nervous system, disorders of the central nervous system, diabetes, arthritis, epilepsy, anxiety, depression, cognitive disorders, preferably memory disorders, cardiovascular diseases, pain, hypertensive syndrom, inflammatory diseases or immune diseases.
  • The present invention also provides for the use of at least one 1,4-disubstituted piperidine compound of general formula (I), optionally in form of one of its stereoisomers, preferably enantiomers or diastereomers, its racemate or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or a physiologically acceptable salt thereof, or a solvate, respectively, for the manufacture of a medicament for the regulation of neuropeptide Y receptors, preferably of neuropeptide Y 5 (NPY5) receptor, for improvement of cognition, for regulation of appetite, regulation of body weight, for the regulation of food ingestion (food intake), preferably for the prophylaxis and/or treatment of disorders of food ingestion, preferably obesity, anorexia, bulimia, cachexia or type II diabetes (non insuline dependent diabetes), for the prophylaxis and/or treatment of disorders of the peripheral nervous system, disorders of the central nervous system, diabetes, arthritis, epilepsy, anxiety, depression, cognitive disorders, preferably memory disorders, cardiovascular diseases, pain, hypertensive syndrom, inflammatory diseases or immune diseases.
  • The medicament may be in any form suitable for the application to humans and/or animals, preferably mammals, and can be produced by standard procedures known to those skilled in the art. The composition of the medicament may vary depending on the route of administration.
  • The medicament of the present invention may e.g. be administered parentally in combination with conventional injectable liquid carriers, such as water or suitable alcohols. Conventional pharmaceutical adjuvants for injection, such as stabilizing agents, solubilizing agents, and buffers, may be included in such injectable compositions. These medicaments may preferably be injected intramuscularly, intraperitoneally, or intravenously.
  • Medicaments according to the present invention may also be formulated into orally administrable compositions containing one or more physiologically compatible carriers or excipients, in solid or liquid form. These compositions may contain conventional ingredients such as binding agents, fillers, lubricants, and acceptable wetting agents. The compositions may take any convenient form, such as tablets, pellets, capsules, lozenges, multiparticulates such as granules or pellets, optionally compressed into a tablet or filled into a capsule, aqueous or oily solutions, suspensions, emulsions, or dry powdered form suitable for reconstitution with water or other suitable liquid medium before use, for immediate or controlled release.
  • The liquid oral forms for administration may also contain certain additives such as sweeteners, flavoring, preservatives, and emulsifying agents. Non-aqueous liquid compositions for oral administration may also be formulated, containing e.g. edible oils. Such liquid compositions may be conveniently encapsulated in e.g., gelatin capsules in a unit dosage amount.
  • The compositions of the present invention may also be administered topically or via a suppository.
  • The above mentioned compositions include preferably 1 to 60% by weight of one or more of the 1,4-disubstituted piperidine compound of general formula (I), optionally in form of one of its stereoisomers, preferably enantiomers or diastereomers, its racemate or in form of a mixture of at least two of its stereoisomers in any mixing ratio, or a physiologically acceptable salt thereof, or a solvate, respectively, and 40 to 99% by weight of the appropriate pharmaceutical vehicle(s).
  • The daily dosage for humans and animals may vary depending on factors that have their basis in the respective species or other factors, such as age, weight or degree of illness and so forth. The daily dosage for mammals including humans usually ranges from 1 milligram to 2000 milligram, preferably 1 to 1500 mg, more preferably 1 to 1000 mg of substance to be administered during one or several intakes.
    • Pharmacological Methods: Neuropeptide Y5 Receptor Binding Studies:
  • The methods used for membrane preparation and binding are similar to those 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. Said literature description is herewith incorporated by reference and forms part of the disclosure. 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 (4° C.). 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 48,000 g for 20 min (4° C.). The pellet was resuspended in 8 ml membrane buffer (Tris-HCl 25 mM, NaCl 120 mM, KCl 5 mM, KH2PO4 1.2 mM, CaCl2 2.5 mM, MgSO4 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 in the incubation was 40 μg/ml. The radioligand was [125I]-PYY (100 pM) in a total incubation volume of 200 μl. Following incubation at 25° C. for 2 h, the reaction was stopped by addition of 5 ml ice-cold buffer (Tris-HCl 25 mM, NaCl-120 mM, KCl 5 mM, KH2PO4 1.2 mM, CaCl2 2.5 mM, MgSO4 1.2 mM, pH 7.4) and rapid filtration in a Harvester Brandell Cell using filters (Schleicher & Schuell GF 3362) pretreated for two hours with 0.5% polyethyleneimine. Filters were washed one time with 5 ml ice-cold buffer. The filters were placed into plastic scintilation vials and 5 ml scintilation cocktail Ecoscint H were added. The quantity of radioactivity present was determined in a Wallac Winspectral 1414 counter. Non specific binding was determined in the presence of 1 μM de pNPY. All binding assays were done in triplicate.
    • Binding to Neuropeptide Y2
  • 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 [125I][Leu31, Pro34]Peptide YY and [125I]Peptide YY3-36 as Selective Y1 and Y2 Radioligands, The Journal of Pharmacology and Experimental Therapeutics, 1995, 272, 673-680, with slight modifications. Said literature description is herewith incorporated by reference and forms part of the disclosure.
  • 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 KCl, 2.2 mM CaCl2, 1.2 mM KH2PO4, 1.2 mM MgSO4, 25 mM NaHCO3, 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 KCl, 2.2 mM CaCl2, 1.2 mM KH2PO4, 1.2 mM MgSO4, 25 mM NaHCO3, 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 [125I]-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.
    • Behavioural Models (Food Intake Measurements)
  • In both test, animals rats (Male W, 200-270 g, obtained from Harlan, S.A) were used. The rats are acclimatized to the animal facility for at least 5 days before being subjected to any experimental procedure. During this period, animals were housed in groups of five in translucid cages and provided with food and water ad libitum. At least 24 hours before the tests, animals are adapted to single-housing conditions.
    • Nocturnal Feeding:
  • Food intake is measured in home cages in order to minimize non-specific stress effects on food intake resulting from changes in housing conditions. Food and water is available. ad libitum. Immediately before lights turn off, rats are weighed, randomized and dosed (orally or intraperitoneally), either with vehicle or selected 1,4-disubstituted piperidine compounds of general formula (I). Thereafter, rats are returned to home cages and food left on top covers is measured. Remaining food and animal's weight is measured next morning.
  • The above mentioned methods are described in Ants Kask et al., European Journal of Pharmacology 414 (2001) 215-224 and Turnbull et al., Diabetes, Vol. 51, August 2002, which are hereby incorporated by reference and form part of the disclosure.
    • Acute Effects of Selected Compounds on Food Intake in Fasted Rats:
  • Rats were fasted for 23 hours in home cages, and after this period dosed (orally or intraperitoneally), either with vehicle or 1,4-disubstituted piperidine compound of general formula (I). One hour later preweighed food is left on top covers, and cumulative food intake is measured after 1, 2, 4 and 6 hours. The methods are described in Ants Kask et al., European Journal of Pharmacology 414 (2001) 215-224 and Turnbull et al., Diabetes, Vol. 51, August 2002, which are hereby incorporated by reference and form part of the disclosure.
  • The following examples are given to illustrate the present invention, but they do not limit the scope of the present invention.
    • EXAMPLES General Method for Obtaining Haloamides Derivatives of the General Formula (Iv)
  • Figure US20110172270A1-20110714-C00031
  • The haloamides used for obtaining the compounds of the present invention are either commercially available or have been prepared according to the scheme 2, employing conventional methods. Essentially the corresponding amines are reacted with chloroacetyl chloride or with a derivative of the general formula (IIIa), the reaction is carried out using an organic solvent, usually dichloromethane, and a base, usually triethylamine.
    • Example A 2-Chloro-N-(9-oxo-9H-fluoren-3-yl)-acetamide
  • Figure US20110172270A1-20110714-C00032
  • A solution of 3-amino-9-fluorenone (1.95 g, 10 mmols), triethylamine (2.07 ml, 15 mmols), in 25 ml of dried dichloromethane, is cooled to 10° C. and a solution of chloroacetyl chloride (1.18 g, 10.5 mmoles) in 10 ml of dried dichloromethane is then added drop by drop. The resulting mixture is kept stirring for 1 hour at room temperature overnight. The mixture is washed with 2×30 ml of water, dried over sodium sulfate and evaporated. 2.63 g 2-Chloro-N-(9-oxo-9H-fluoren-3-yl)-acetamide (97%) are obtained.
  • 1H RMN (d6-DMSO): 10.7 (s, 1H), 7.98 (s, 1H), 7.66 (d, 1H), 7.57 (m, 3H), 7.50 (d, 1H), 7.37 (t, 1H), 4.32 (s, 2H)
    • Example 6a 2-{1-[(9-Oxo-9H-fluoren-3-yl-carbamoyl)-methyl]-piperidin-4-yl-amino}benzoic acid methyl ester chlorohydrate
  • Figure US20110172270A1-20110714-C00033
    • a) 4-(2-metoxycarbonyl-phenylamino)-piperidine-1-tert-butylcarboxylate
  • A solution of 1-(tert-butyloxycarbonyl)-4-piperidinone (2 g, 0.01 mol), methyl anthranylate (1.66 g, 0.011 mol) y acetic acid (1.4 ml, 0.022 mol) in dried toluene (50 mL) were heated to reflux, removing the water by means of azeotropic distillation with a Dean-Stark, over 30 hours. Then, the mixture was cooled and concentrated under vacuum to the half of the volume. NaBH3CN (2 g, 0.032 mol) and dried THF (30 mL) is added to a resulting solution.
  • Afterwards, acetic acid (1 mL, 0.017 mol) was added drop by drop over one hour (1 mL, 0.017 mol). The reaction mixture was stirred at room temperature over 24 hours. The mixture was concentrated under vacuum and the residue was dissolved in ethyl acetate (75 mL), washed with a saturated NaHCO3 (4×25 mL) and a saturated NaCl solution (25 mL), dried and evaporated to dryness. This raw material was used in the following step.
    • b) 2-(Piperidine-4-yl-amino)-methyl benzoate
  • A solution of 3.2 g of the raw material obtained in the previous step in 40 mL of dried ethyl acetate, was cooled to 0° C. Then a 5 M hydrogen chloride solution in ethyl ether (40 mL) was added and the resulting mixture was keeped at 0° C. over 4 hours. The solvent was evaporated and the residue was suspended in water and was alcalinized with sodium hydroxyde, and was extracted with chloroform (3×20 mL), the combined organic extracts were washed with water, dried over sodium sulfate and evaporated. The raw material was purified via column cromatography by eluting with chloroform:methanol 9:1 (vol/vol). In this way 1.45 g of a yellow solid is obtained.
  • IR (cm−1) KBr.: 3349, 3232, 2941, 2812, 1686, 1578, 1518, 1436, 1253, 1162, 1079, 742.
  • M.P.: 113-115° C.
    • c) 2-{1-[(9-Oxo-9H-fluoren-3-yl-carbamoyl)-methyl]-piperidine-4-yl-amino}benzoic acid methyl ester chlorhidrate
  • A mixture of 2-(Piperidine-4-yl-amino)-methyl benzoate (1100 mg, 4.70 mmol), 2-Chloro-N-(9-oxo-9H-fluoren-3-yl)-acetamide (1358 mg, 5 mmol) and K2CO3 (1380 mg, 10 mmol) in DMF (40 mL) was stirred at 10° C. for 2 hours and then at room temperature overnight. The reaction mixture was added to 50 mL water and 100 mL ethyl acetate, the organic phase was decanted and washed with water (3×50 mL), dried over sodium sulfate and a 2.8 M hydrogen chloride solution in absolute ethanol (1.80 mL) was added, to precipitate the hydrochloride, which was filtered off and washed with ethyl acetate. 1840 mg of a white solid were obtained. Yield: 77%.
    • Example 7a Preparation of: 2-[4-2(2-Hydroxymethyl-4-methyl-phenylamino)-piperidine-1-yl]-N-phenyl-acetamide.
  • Figure US20110172270A1-20110714-C00034
  • A mixture of 4-methyl-(2-hidroxymethylphenylamino)piperidine dihydrochloride (234 mg, 0.80 mmol), 2-chloro-N-phenylacetamide (149 mg, 0.88 mmol) and K2CO3 (440 mg, 3.20 mmol) in DMF (10 mL) was stirred at room temperature overnight. The solvent is evaporated and H2O (15 mL) are added and the formed precipitate is extracted with ethyl acetate. The resulting phase is washed with water, dried and evaporated to dryness. The raw material was crystallized from ethyl acetate, filtered off and dried to give 178 mg of a white solid. Yield: 63%.
    • Example 8a Preparation of 2-[4-(2-Hydroxymethyl-phenylamino)-piperidine-1-yl](1-oxo-indan-5-yl)-acetamide.:
  • Figure US20110172270A1-20110714-C00035
  • 5 mL 10% sodium hydroxide were added to a suspension of 2-[4-(2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidine-1-yl]-N-(1-oxo-indan-5-yl)-acetamide (25 mg, 0.06 mmols) in 5 mL ethanol. The resulting mixture was heated to 50° C. for 2 hours, cooled, the ethanol was evaporated and the aqueous phase was neutralized and extracted with methylene chloride (2×15 mL). The combined organic extracts were washed with water, dried over sodium sulfate and evaporated to dryness. The crude material was purified via a silica gel column, eluting with ethyl acetate. 15 mg of a white solid were obtained, i.e. a yield of 64%.
  •
    Ex. 1a N-(9-Ethyl-9H-carbazol-3-yl)-2-[4-(2-hydroxymethyl-6-methyl-phenylamino)-piperidin-yl]acetamide dihydrochloride
    Figure US20110172270A1-20110714-C00036
         		1H NMR (300 MHz, DMSO-d6) δ ppm: 1.3 (t, J = 7.0 Hz, 3 H) 2.1 (s, 4 H) 2.4 (s, 3 H) 3.2 (m, 2H) 3.5-4.1 (4 H) 4.2 (s, 2 H) 4.4 (m, 2 H) 4.7 (s, 2 H) 7.2 (m, 4 H) 7.4 (t, J = 7.7 Hz, 1 H) 7.6 (d, J = 8.2 Hz, 3 H) 8.0 (d, J = 7.7 Hz, 1 H) 8.4 (s, 1 H) 10.3 (s,1 H) 11.0 (s, 1 H) IR (KBr/cm−1): 3398, 2974, 1685, 1597, 1560, 1491, 1471, 1230, 749. Melting point: 218-222° C.
    Ex. 2a 2-[4-(2-Hydroxymethyl-4-methyl-phenylamino)-piperidin-1-yl]-N-(9-oxo-9H-fluoren-3-yl)-acetamide
    Figure US20110172270A1-20110714-C00037
         		1H NMR (300 MHz, CDCl3-d) δ ppm: 1.6 (m, 2 H) 2.2 (d, J = 13.9 Hz, 2 H) 2.2 (s, 3 H) 2.5 (t, J = 10.2 Hz, 2 H) 2.9 (d, J = 10.6 Hz, 2 H) 3.2 (s, 2 H) 3.4 (m, 1 H) 4.7 (s, 2 H) 6.6 (d, J = 8.2 Hz, 1 H) 6.9 (d, J = 1.6 Hz, 1 H) 7.0 (dd, J = 8.1, 1.7 Hz, 1 H) 7.3 (m, 2 H) 7.5 (td, J = 7.4, 1.1 Hz, 1 H) 7.6 (m, 3 H) 8.0 (d, J = 1.6 Hz, 1 H) 9.5 (s, 1 H) IR (KBr/cm−1): 3330, 3148, 1710, 1590, 1516, 1291, 1109, 980, 772 Melting point: 152° C.
    Ex. 3a 2-[4-(2-Hydroxymethyl-6-methyl-phenylamino)-piperidin-1-yl]-N-(9-oxo-9H-fluoren-3-yl)-acetamide
    Figure US20110172270A1-20110714-C00038
         		1H NMR (300 MHz, CDCl3-d) δ ppm: 1.6 (d, J = 11.8, 2 H) 2.0 (d, J = 12.3 Hz, 2 H) 2.3 (s, 3 H) 2.4 (m, 2 H) 2.9 (d, J = 7.0 Hz, 2 H) 3.1 (m, 1 H) 3.2 (s, 2 H) 4.7 (s, 2 H) 6.9 (t, J = 7.4 Hz, 1 H) 7.0 (m, 1 H) 7.1 (d, J = 9.2 Hz, 1 H) 7.3 (m, 2 H) 7.5 (td, J = 7.4, 1.1 Hz, 1 H) 7.6 (m, 3 H) 8.0 (d, J = 1.8 Hz, 1 H) 9.4 (s, 1 H) IR (KBr/cm−1): 3414, 3269, 2920, 1710, 1692, 1609, 1508, 1230, 1101, 1002, 737. Melting point: 113° C.
    Ex. 4a N-(9-Hydroxy-9H-fluoren-3-yl)-2-[4-(2-hydroxymethyl-4-methyl-phenylamino)-piperidin-1-yl]-acetamide
    Figure US20110172270A1-20110714-C00039
         		1H NMR (300 MHz, CDCl3-d) δ ppm: 1.6 (m, 2 H) 2.1 (d, J = 14.3 Hz, 2 H) 2.2 (s, 3 H) 2.5 (m, 2 H) 2.9 (d, J = 12.5 Hz, 2 H) 3.1 (s, 2 H) 3.4 (m, 1 H) 4.6 (s, 2 H) 5.6 (s, 1 H) 6.6 (d, J = 8.2 Hz, 1 H) 6.9 (d, J = 1.8 Hz, 1 H) 7.0 (dd, J = 8.1, 1.9 Hz, 1 H) 7.4 (m, 3 H) 7.6 (m, 3 H) 8.0 (d, J = 1.8 Hz, 1 H) 9.3 (s, 1 H) IR (KBr/cm−1): 3300, 2920, 1670, 1613, 1521, 1025, 767. Melting point: 124° C.
    Ex. 5a N-(9-Hydroxy-9H-fluoren-3-yl)-2-[4-(2-hydroxymethyl-6-methyl-phenylamino)-piperidin-1-yl]-acetamide
    Figure US20110172270A1-20110714-C00040
         		1H NMR (300 MHz, CDCl3-d) δ ppm: 1.6 (m, 2 H) 2.0 (d, J = 10.4 Hz, 2 H) 2.3 (m, 5 H) 2.9 (d, J = 11.9 Hz, 2 H) 3.0 (m, 1 H) 3.1 (s, 2 H) 4.7 (s, 2 H) 5.6 (s, 1 H) 6.9 (t, J = 7.4 Hz, 1 H) 7.0 (m, 1 H) 7.1 (d, J = 9.0 Hz, 1 H) 7.4 (m, 3 H) 7.6 (m, 3 H) 8.0 (d, J = 2.0 Hz, 1 H) 9.2 (s, 1 H) IR (KBr/cm−1): 3315, 2927, 1676, 1527, 1097, 1025, 771, 737. Melting point: 133° C.
    Ex. 6a 2-{1-[(9-Oxo-9H-fluoren-3-ylcarbamoyl)-methyl]-piperidin-4-ylamino}benzoic acid methyl ester hydrochloride
    Figure US20110172270A1-20110714-C00041
         		1H NMR (300 MHz, DMSO-d6) δ ppm: 1.8 (m, 2 H) 2.2 (d, J = 13.8 Hz, 2 H) 3.3 (m, 2 H) 3.6 (d, J = 10.8 Hz, 2 H) 3.8 (s, 3 H) 3.8 (m, 1 H) 4.2 (s, 2 H) 6.6 (t, J = 7.8 Hz, 1 H) 6.9 (d, J = 8.6 Hz, 1 H) 7.3 (m, 2 H) 7.5 (m, 4 H) 7.6 (m, 1 H) 7.8 (dd, J = 8.0, 1.6 Hz, 1 H) 8.0 (d, J = 1.3 Hz, 1 H) 10.1 (s, 1 H) 11.1 (s, 1 H) IR (KBr/cm−1): 2946, 2539, 1700, 1684, 1603, 1560, 1255, 748. Melting point: 258° C.
    Ex. 7a 2-[4-(2-Hydroxymethyl-4-methyl-phenylamino)-piperidin-1-yl]-N-phenyl-acetamide
    Figure US20110172270A1-20110714-C00042
         		1H NMR (300 MHz, CDCl3-d) δ ppm: 1.6 (m, 2 H) 2.1 (d, J = 13.0 Hz, 2 H) 2.2 (s, 3 H) 2.4 (t, J = 10.3 Hz, 2 H) 2.9 (d, J = 11.9 Hz, 2 H) 3.1 (s, 2 H) 3.4 (m, 1 H) 4.6 (s, 2 H) 6.6 (d, J = 8.2 Hz, 1 H) 6.9 (s, 1 H) 7.0 (dd, J = 8.2, 1.5 Hz, 1 H) 7.1 (t, J = 7.4 Hz, 1 H) 7.3 (t, J = 7.9 Hz, 2 H) 7.6 (d, J = 7.7 Hz, 2 H) 9.2 (s, 1 H) IR (KBr/cm−1): 3346, 1691, 1598, 1543, 1438, 1317, 748. Melting point: 128° C.
    Ex. 8 2-[4-(2-Hydroxymethyl-phenylamino)-piperidin-1-yl]-N-phenyl-acetamide
    Figure US20110172270A1-20110714-C00043
         		IR (KBr): 3398, 2923, 1710, 1655, 1590, 1541, 1425, 1287, 1126, 1013 Melting point: 138-140° C.
    • Example 9a Example of a Tablet Formulation
  • Compound according to example 6a 5 mg
    Lactose 60 mg
    Crystalline cellulose 25 mg
    Povidone K 90 5 mg
    Pregelanitized starch 3 mg
    Colloidal silica dioxide 1 mg
    Magnesium stearate 1 mg
    Total weight per tablet 100 mg
  • The above mentioned ingredients were mixed and compressed into a tablet by conventional methods known to those skilled in the art.
  • The compounds according to the following list B have also been prepared by the methods described above:
    • List B:
  • MS
    Name APCI
    No Structure Autonom ® M + H+ NMR
     1
    Figure US20110172270A1-20110714-C00044
         		2-[4-(2- ydroxymethyl- phenylamino)- piperidin-1-yl]- N-quinolin-3-yl- acetamide 391 1H NMR (300 MHz, DMSO-D6) δ ppm 1.56 (m, 2 H), 1.96 (d, J = 11.71 Hz, 2 H), 2.38 (m, 2 H), 2.87 (m, 2 H), 3.22 (s, 2 H), 4.41 (m, 2 H), 4.97 (d, J = 7.32 Hz, 1 H), 5.20 (s, 1 H), 6.51 (t, J = 7.17 Hz, 1 H), 6.63 (d, J = 7.76 Hz, 1 H), 7.04 (m, 2 H), 7.59 (m, 2 H), 7.93 (t, J = 8.20 Hz, 2 H), 8.71 (d, J = 2.49 Hz, 1 H), 9.00 (d, J = 2.49 Hz, 1 H), 10.19 (s, 1 H)
     2
    Figure US20110172270A1-20110714-C00045
         		2-[4-(2- Hydroxymethyl- phenylamino)- piperidin-1-yl]- N-quinolin-5-yl- acetamide 391 1H NMR (300 MHz, DMSO-D6) δ ppm 1.59 (q, J = 9.32 Hz, 2 H), 2.01 (m, 2 H), 2.44 (m, 2 H), 2.94 (d, J = 10.69 Hz, 2 H), 3.27 (s, 2 H), 4.42 (d, J = 5.27 Hz, 2 H), 4.99 (d, J = 7.61 Hz, 1 H), 5.17 (t, J = 5.27 Hz, 1 H), 6.52 (t, J = 7.25 Hz, 1 H), 6.64 (d, J = 7.91 Hz, 1 H), 7.04 (m, 2 H), 7.58 (dd, J = 8.49, 4.25 Hz, 1 H), 7.73 (m, 1 H), 7.84 (m, 2 H), 8.31 (d, J = 8.20 Hz, 1 H), 8.91 (d, J = 4.39 Hz, 1 H), 10.07 (s, 1 H)
     3
    Figure US20110172270A1-20110714-C00046
         		2-[4-(2- Hydroxymethyl- phenylamino)- piperidin-1-yl]- N-quinolin-6-yl- acetamide 391 1H NMR (300 MHz, DMSO-D6) δ ppm 1.55 (m, 2 H), 1.96 (d, J = 10.84 Hz, 2 H), 2.38 (t, J = 10.10 Hz, 2 H), 2.86 (d, J = 9.08 Hz, 2 H), 3.20 (s, 2 H), 4.41 (d, J = 5.12 Hz, 2 H), 4.97 (d, J = 7.32 Hz, 1 H), 5.16 (t, J = 5.27 Hz, 1 H), 6.51 (t J = 7.32 Hz, 1 H), 6.62 (d, J = 8.05 Hz, 1 H), 7.05 (m, 2 H), 7.46 (dd, J = 8.27, 4.32 Hz, 1 H), 7.91 (m, 2 H), 8.27 (m, 1 H), 8.39 (d, J = 2.20 Hz, 1 H), 8.77 (dd, J = 4.17, 1.68 Hz, 1 H), 10.03 (s, 1 H)
     4
    Figure US20110172270A1-20110714-C00047
         		2-[4-(2- Hydroxymethyl- phenylamino)- piperidin-1-yl]- N-quinolin-8-yl- acetamide 391
     5
    Figure US20110172270A1-20110714-C00048
         		2-[4-(2- Hydroxymethyl- 4-methyl- phenylamino)- piperidin-1-yl]- N-quinolin-3-yl- acetamide 405 1H NMR (300 MHz, DMSO-D6) δ ppm 1.54 (m, 2 H), 1.95 (d, J = 11.42 Hz, 2 H), 2.13 (s, 3 H), 2.36 (m, 2 H), 2.86 (d, J = 9.37 Hz, 2 H), 3.22 (s, 2 H), 4.38 (d, J = 5.27 Hz, 2 H), 4.75 (m, 1 H), 5.11 (m, 1 H), 6.53 (d, J = 7.91 Hz, 1 H), 6.87 (m, 2 H), 7.60 (m, 2 H), 7.92 (t, J = 8.42 Hz, 2 H), 8.71 (d, J = 2.34 Hz, 1 H), 9.00 (d, J = 2.49 Hz, 1 H), 10.16 (s, 1 H)
     6
    Figure US20110172270A1-20110714-C00049
         		2-[4-(2- Hydroxymethyl- 4-methyl- phenylamino)- piperidin-1-yl]- N-quinolin-5-yl- acetamide 405 1H NMR (300 MHz, DMSO-D6) δ ppm 1.57 (m, 2 H), 2.00 (m, 2 H), 2.14 (s, 3 H), 2.41 (m, 2 H), 2.93 (d, J = 9.08 Hz, 2 H), 3.26 (s, 2 H), 4.38 (d, J = 5.12 Hz, 2 H), 4.78 (d, J = 7.76 Hz, 1 H), 5.12 (t, J = 5.20 Hz, 1 H), 6.55 (d, J = 7.61 Hz, 1 H), 6.86 (s, 2 H), 7.58 (dd, J = 8.57, 4.17 Hz, 1 H), 7.73 (m, 1 H), 7.84 (m, 2 H), 8.31 (m, 1 H), 8.91 (dd, J = 4.10, 1.46 Hz, 1H), 10.07 (s, 1H)
     7
    Figure US20110172270A1-20110714-C00050
         		2-[4-(2- Hydroxymethyl- 4-methyl- phenylamino)- piperidin-1-yl]- N-quinolin-6-yl- acetamide 405 1H NMR (300 MHz, DMSO-D6) δ ppm 1.52 (m, 2 H), 1.94 (d, J = 9.81 Hz, 2 H), 2.13 (s, 3 H), 2.36 (t, J = 10.91 Hz, 2 H), 2.87 (m, 2 H), 3.19 (s, 2 H), 4.37 (d, J = 4.98 Hz, 2 H), 4.76 (d, J = 7.76 Hz, 1 H), 5.12 (t, J = 5.34 Hz, 1 H), 6.53 (d, J = 8.20 Hz, 1 H), 6.87 (m, 2 H), 7.46 (m, 1 H), 7.92 (m, 2 H), 8.26 (s, 1 H), 8.38 (s, 1 H), 8.77 (d, J = 4.25 Hz, 1 H), 10.03 (s, 1 H)
     8
    Figure US20110172270A1-20110714-C00051
         		2-[4-(2- Hydroxymethyl- 4-methyl- phenylamino)- piperidin-1-yl]- N-quinolin-8-yl- acetamide 405 1H NMR (300 MHz, DMSO-D6) δ ppm 1.63 (m, 2 H), 2.03 (m, 2 H), 2.14 (s, 3 H), 2.42 (m, 2 H), 2.89 (m, 2 H), 3.25 (s, 2 H), 4.42 (d, J = 5.42 Hz, 2 H), 4.86 (d, J = 7.61 Hz, 1 H), 5.18 (t, J = 5.20 Hz, 1 H), 6.56 (d, J = 8.79 Hz, 1 H), 6.88 (m, 2 H), 7.62 (m, 3 H), 8.40 (dd, J = 8.35, 1.61 Hz, 1 H), 8.64 (dd, J = 7.47, 1.46 Hz, 1 H), 8.92 (dd, J = 4.25, 1.61 Hz, 1 H), 11.38 (s, 1 H)
     9
    Figure US20110172270A1-20110714-C00052
         		2-[4-(2- Hydroxymethyl- 6-methyl- phenylamino)- piperidin-1-yl]- N-quinolin-3-yl- acetamide 405 1H NMR (300 MHz, DMSO-D6) δ ppm 1.55 (m, 2 H), 1.76 (d, J = 10.40 Hz, 2 H), 2.20 (m, 5 H), 2.87 (m, 2 H), 3.19 (s, 2 H), 4.12 (d, J = 10.40 Hz, 1 H), 4.48 (d, J = 5.27 Hz, 2 H), 5.19 (t, J = 5.20 Hz, 1 H), 6.75 (t, J = 7.39 Hz, 1 H), 7.00 (d, J = 6.88 Hz, 2 H), 7.56 (m, 1 H), 7.61 (s, 1 H), 7.92 (t, J = 8.86 Hz, 2 H), 8.69 (d, J = 2.34 Hz, 1 H), 8.98 (d, J = 2.34 Hz, 1 H), 10.15 (s, 1 H)
     10
    Figure US20110172270A1-20110714-C00053
         		2-[4-(2- Hydroxymethyl- 6-methyl- phenylamino)- piperidin-1-yl]- N-quinolin-5-yl- acetamide 405 1H NMR (300 MHz, DMSO-D6) δ ppm 1.58 (m, 2 H), 1.80 (d, J = 10.10 Hz, 2 H), 2.22 (s, 3 H), 2.26 (m, 2 H), 2.94 (d, J = 11.13 Hz, 2 H), 3.23 (s, 2 H), 4.14 (d, J = 10.40 Hz, 1 H), 4.49 (d, J = 5.27 Hz, 2 H), 5.19 (t, J = 5.27 Hz, 1 H), 6.76 (t, J = 7.47 Hz, 1 H), 7.01 (d, J = 14.35 Hz, 1 H), 7.59 (dd, J = 8.49, 4.10 Hz, 1 H), 7.78 (m, 3 H), 8.31 (dd, J = 7.76, 0.73 Hz, 1 H), 8.92 (dd, J = 4.17, 1.39 Hz, 1 H), 10.05 (s, 1 H)
     11
    Figure US20110172270A1-20110714-C00054
         		2-[4-(2- Hydroxymethyl- 6-methyl- phenylamino)- piperidin-1-yl]- N-quinolin-6-yl- acetamide 405 1H NMR (300 MHz, DMSO-D6) δ ppm 1.54 (m, 2 H), 1.76 (d, J = 10.69 Hz, 2 H), 2.20 (m, 5 H), 2.86 (d, J = 10.98 Hz, 3 H), 3.16 (s, 2 H), 4.11 (d, J = 10.40 Hz, 1 H), 4.48 (d, J = 5.42 Hz, 2 H), 5.19 (t, J = 5.27 Hz, 1 H), 6.75 (t, J = 7.39 Hz, 1 H), 7.02 (m, 2 H), 7.46 (dd, J = 8.20, 4.25 Hz, 1 H), 7.87 (m, 1 H), 7.95 (m, 1 H), 8.28 (m, 1 H), 8.37 (d, J = 2.20 Hz, 1 H), 8.77 (m, 1 H), 10.00 (s, 1 H)
     12
    Figure US20110172270A1-20110714-C00055
         		2-[4-(2- Hydroxymethyl- 6-methyl- phenylamino)- piperidin-1-yl]- N-quinolin-8-yl- acetamide 405 1H NMR (300 MHz, DMSO-D6) δ ppm 1.65 (m, 2 H), 1.83 (d, J = 9.52 Hz, 2 H), 2.24 (s, 3 H), 2.28 (m, 2 H), 2.89 (d, J = 10.25 Hz, 2 H), 3.22 (s, 2 H), 4.26 (d, J = 9.96 Hz, 1 H), 4.54 (d, J = 4.83 Hz, 2 H), 5.29 (t, J = 5.20 Hz, 1 H), 6.77 (t, J = 7.39 Hz, 1 H), 7.05 (m, 2 H), 7.57 (t, J = 7.91 Hz, 1 H), 7.66 (m, 2 H), 8.41 (dd, J = 8.20, 1.32 Hz, 1 H), 8.63 (d, J = 7.03 Hz, 1 H), 8.98 (m, 1 H), 11.40 (s, 1 H)
     13
    Figure US20110172270A1-20110714-C00056
         		N-(4-Benzoyl- phenyl)-2-[4-(2- hydroxymethyl- phenylamino)- piperidin-1-yl]- acetamide 444 1H NMR (300 MHz, DMSO-D6) δ ppm 1.53 (m, 2 H), 1.95 (m, 2 H), 2.35 (t, J = 10.32 Hz, 2 H), 2.84 (m, 2 H), 3.18 (s, 2 H), 4.40 (d, J = 5.27 Hz, 2 H), 4.95 (d, J = 7.61 Hz, 1 H), 5.16 (t, J = 5.34 Hz, 1 H), 6.51 (t, J = 7.25 Hz, 1 H), 6.62 (d, J = 7.91 Hz, 1 H), 7.05 (m, 2 H), 7.53 (m, 2 H), 7.68 (m, 5 H), 7.84 (m, 2 H), 10.09 (s, 1 H)
     14
    Figure US20110172270A1-20110714-C00057
         		N-(4-Benzoyl- phenyl)-2-[4-(2- hydroxymethyl- 4-methyl- phenylamino)- piperidin-1-yl]- acetamide 458 1H NMR (300 MHz, DMSO-D6) δ ppm 1.50 (m, 2 H), 1.93 (d, J = 10.54 Hz, 2 H), 2.13 (s, 3 H), 2.34 (m, 2 H), 2.81 (m, 2 H), 3.17 (s, 2 H), 4.37 (d, J = 5.27 Hz, 2 H), 4.75 (d, J = 7.76 Hz, 1 H), 5.10 (m, 1 H), 6.52 (d, J = 7.91 Hz, 1 H), 6.87 (m, 2 H), 7.53 (m, 2 H), 7.68 (m, 5 H), 7.83 (m, 2 H), 10.09 (s, 1 H)
     15
    Figure US20110172270A1-20110714-C00058
         		N-(4-Benzoyl- phenyl)-2-[4-(2- hydroxymethyl- 6-methyl- phenylamino)- piperidin-1-yl]- acetamide 458 1H NMR (300 MHz, DMSO-D6) δ ppm 1.51 (m, 2 H), 1.75 (d, J = 11.13 Hz, 2 H), 2.17 (m, 2 H), 2.20 (s, 3 H), 2.83 (m, 3 H), 3.14 (s, 2 H), 4.11 (d, J = 10.69 Hz, 1 H), 4.47 (d, J = 5.12 Hz, 2 H), 5.18 (t, J = 5.20 Hz, 1 H), 6.75 (t, J = 7.39 Hz, 1 H), 7.02 (dd, J = 14.42, 7.39 Hz, 2 H), 7.54 (t, J = 7.39 Hz, 2 H), 7.68 (m, 5 H), 7.82 (m, 2 H), 10.06 (s, 1 H)
     16
    Figure US20110172270A1-20110714-C00059
         		N-Benzo[1,3] dioxol-5-yl-2- [4-(2- hydroxymethyl- phenylamino)- piperidin-1-yl]- acetamide 384
     17
    Figure US20110172270A1-20110714-C00060
         		N-Benzo[1,3] dioxol-5-yl-2- [4-(2- hydroxymethyl- 4-methyl- phenylamino)- piperidin-1-yl]- acetamide 398 1H NMR (300 MHz, DMSO-D6) δ ppm 1.49 (q, J = 9.71 Hz, 2 H), 1.92 (d, J = 10.69 Hz, 2 H), 2.13 (s, 3 H), 2.30 (t, J = 10.84 Hz, 2 H), 2.79 (d, J = 11.27 Hz, 2 H), 3.07 (s, 2 H), 3.26 (m, 1 H), 4.36 (d, J = 5.42 Hz, 2 H), 4.74 (d, J = 7.61 Hz, 1 H), 5.11 (t, J = 5.34 Hz, 1 H), 5.96 (s, 2 H), 6.52 (d, J = 7.76 Hz, 1 H), 6.83 (m, 3 H), 7.03 (dd, J = 8.49, 2.05 Hz, 1 H), 7.33 (d, J = 1.90 Hz, 1 H), 9.58 (s, 1 H)
     18
    Figure US20110172270A1-20110714-C00061
         		N-Benzo[1,3] dioxol-5-yl-2- [4-(2- hydroxymethyl- 6-methyl- phenylamino)- piperidin-1-yl]- acetamide hydrochloride
     19
    Figure US20110172270A1-20110714-C00062
         		2-[4-(4-Chloro-2- hydroxymethyl- phenylamino)- piperidin-1-yl]- N-quinolin-3-yl- acetamide
     20
    Figure US20110172270A1-20110714-C00063
         		2-[4-(4-Fluoro-2- hydroxymethyl- phenylamino)- piperidin-1-yl]- N-quinolin-3-yl- acetamide
     21
    Figure US20110172270A1-20110714-C00064
         		2-[4-(3-Chloro-2- hydroxymethyl- phenylamino)- piperidin-1-yl]- N-quinolin-3-yl- acetamide
     22
    Figure US20110172270A1-20110714-C00065
         		2-[4-(4-Chloro-2- hydroxymethyl- phenylamino)- piperidin-1-yl]- N-quinolin-5-yl- acetamide
     23
    Figure US20110172270A1-20110714-C00066
         		2-[4-(4-Fluoro-2- hydroxymethyl- phenylamino)- piperidin-1-yl]- N-quinolin-5-yl- acetamide
     24
    Figure US20110172270A1-20110714-C00067
         		2-[4-(3-Chloro-2- hydroxymethyl- phenylamino)- piperidin-1-yl]- N-quinolin-5-yl- acetamide
     25
    Figure US20110172270A1-20110714-C00068
         		2-[4-(4-Chloro-2- hydroxymethyl- phenylamino)- piperidin-1-yl]- N-quinolin-6-yl- acetamide
     26
    Figure US20110172270A1-20110714-C00069
         		2-[4-(4-Fluoro-2- hydroxymethyl- phenylamino)- piperidin-1-yl]- N-quinolin-6-yl- acetamide
     27
    Figure US20110172270A1-20110714-C00070
         		2-[4-(3-Chloro-2- hydroxymethyl- phenylamino)- piperidin-1-yl]- N-quinolin-6-yl- acetamide
     28
    Figure US20110172270A1-20110714-C00071
         		2-[4-(2- Hydroxymethyl- 6-methoxy- phenylamino)- piperidin-1-yl]- N-quinolin-6-yl- acetamide
     29
    Figure US20110172270A1-20110714-C00072
         		2-[4-(4,5- Difluoro-2- hydroxymethyl- phenylamino)- piperidin-1-yl]- N-quinolin-6-yl- acetamide
     30
    Figure US20110172270A1-20110714-C00073
         		2-[4-(4-Chloro-2- hydroxymethyl- phenylamino)- piperidin-1-yl]- N-quinolin-8-yl- acetamide
     31
    Figure US20110172270A1-20110714-C00074
         		2-[4-(4-Fluoro-2- hydroxymethyl- phenylamino)- piperidin-1-yl]- N-quinolin-8-yl- acetamide
     32
    Figure US20110172270A1-20110714-C00075
         		2-[4-(3-Chloro-2- hydroxymethyl- phenylamino)- piperidin-1-yl]- N-quinolin-8-yl- acetamide
     33
    Figure US20110172270A1-20110714-C00076
         		N-(4-Benzoyl- phenyl)-2-[4-(4- chloro-2- hydroxymethyl- phenylamino)- piperidin-1-yl]- acetamide
     34
    Figure US20110172270A1-20110714-C00077
         		N-(4-Benzoyl- phenyl)-2-[4-(4- fIuoro-2- hydroxymethyl- phenylamino)- piperidin-1-yl]- acetamide
     35
    Figure US20110172270A1-20110714-C00078
         		N-(4-Benzoyl- phenyl)-2-[4-(2- hydroxymethyl- 6-methoxy- phenylamino)- piperidin-1-yl]- acetamide
     36
    Figure US20110172270A1-20110714-C00079
         		N-(4-Benzoyl- phenyl)-2-[4-(3- chloro-2- hydroxymethyl- phenylamino)- piperidin-1-yl]- acetamide
     37
    Figure US20110172270A1-20110714-C00080
         		2-[4-(2- Hydroxymethyl- phenylamino)- piperidin-1-yl]- N-[4-(hydroxy- phenyl-methyl)- phenyl]- acetamide
     38
    Figure US20110172270A1-20110714-C00081
         		2-[4-(2- Hydroxymethyl- 6-methyl- phenylamino)- piperidin-1-yl]- N-[4-(hydroxy- phenyl-methyl)- phenyl]- acetamide
     39
    Figure US20110172270A1-20110714-C00082
         		2-[4-(4-Chloro-2- hydroxymethyl- phenylamino)- piperidin-1-yl]- N-[4-(hydroxy- phenyl-methyl)- phenyl]- acetamide
     40
    Figure US20110172270A1-20110714-C00083
         		2-[4-(2- Hydroxymethyl- 4-methyl- phenylamino)- piperidin-1-yl]- N-[4-(hydroxy- phenyl-methyl)- phenyl]- acetamide
     41
    Figure US20110172270A1-20110714-C00084
         		2-[4-(4-Fluoro-2- hydroxymethyl- phenylamino)- piperidin-1-yl]- N-[4-(hydroxy- phenyl-methyl)- phenyl]- acetamide
     42
    Figure US20110172270A1-20110714-C00085
         		2-[4-(2- Hydroxymethyl- 6-methoxy- phenylamino)- piperidin-1-yl]- N-[4-(hydroxy- phenyl-methyl)- phenyl]- acetamide
     43
    Figure US20110172270A1-20110714-C00086
         		2-[4-(3-Chloro-2- hydroxymethyl- phenylamino)- piperidin-1-yl]- N-[4-(hydroxy- phenyl-methyl)- phenyl]- acetamide
     44
    Figure US20110172270A1-20110714-C00087
         		2-[4-(2- Hydroxymethyl- phenylamino)- piperidin-1-yl]- N-(9-oxo-9H- fluoren-3-yl)- acetamide
     45
    Figure US20110172270A1-20110714-C00088
         		2-[4-(4-Chloro-2- hydroxymethyl- phenylamino)- piperidin-1-yl]- N-(9-oxo-9H- fluoren-3-yl)- acetamide
     46
    Figure US20110172270A1-20110714-C00089
         		2-[4-(4-Fluoro-2- hydroxymethyl- phenylamino)- piperidin-1-yl]- N-(9-oxo-9H- fluoren-3-yl)- acetamide
     47
    Figure US20110172270A1-20110714-C00090
         		2-[4-(2- Hydroxymethyl- 6-methoxy- phenylamino)- piperidin-1-yl]- N-(9-oxo-9H- fluoren-3-yl)- acetamide
     48
    Figure US20110172270A1-20110714-C00091
         		2-[4-(4,5- Difluoro-2- hydroxymethyl- phenylamino)- piperidin-1-yl]- N-(9-oxo-9H- fluoren-3-yl)- acetamide
     49
    Figure US20110172270A1-20110714-C00092
         		2-[4-(3-Chloro-2- hydroxymethyl- phenylamino)- piperidin-1-yl]- N-(9-oxo-9H- fluoren-3-yl)- acetamide
     50
    Figure US20110172270A1-20110714-C00093
         		N-(9-Hydroxy- 9H-fluoren-3- yl)-2-[4-(2- hydroxymethyl- phenylamino)- piperidin-1-yl]- acetamide
     51
    Figure US20110172270A1-20110714-C00094
         		2-[4-(4-Chloro-2- hydroxymethyl- phenylamino)- piperidin-1-yl]- N-(9-hydroxy- 9H-fluoren-3- yl)-acetamide
     52
    Figure US20110172270A1-20110714-C00095
         		2-[4-(4-Fluoro-2- hydroxymethyl- phenylamino)- piperidin-1-yl]- N-(9-hydroxy- 9H-fluoren-3- yl)-acetamide
     53
    Figure US20110172270A1-20110714-C00096
         		N-(9-Hydroxy- 9H-fluoren-3- yl)-2-[4-(2- hydroxymethyl- 6-methoxy- phenylamino)- piperidin-1-yl]- acetamide
     54
    Figure US20110172270A1-20110714-C00097
         		2-[4-(4,5- Difluoro-2- hydroxymethyl- phenylamino)- piperidin-1-yl]- N-(9-hydroxy- 9H-fluoren-3- yl)-acetamide
     55
    Figure US20110172270A1-20110714-C00098
         		2-[4-(3-Chloro-2- hydroxymethyl- phenylamino)- piperidin-1-yl]- N-(9-hydroxy 9H-fluoren-3- yl)-acetamide
     56
    Figure US20110172270A1-20110714-C00099
         		N-(3-Acetyl- phenyl)-2-[4-(2- hydroxymethyl- phenylamino)- piperidin-1-yl]- acetamide
     57
    Figure US20110172270A1-20110714-C00100
         		N-(3-Acetyl- phenyl)-2-[4-(2- hydroxymethyl- 6-methyl- phenylamino)- piperidin-1-yl]- acetamide
     58
    Figure US20110172270A1-20110714-C00101
         		N-(3-Acetyl- phenyl)-2-[4-(4- chloro-2- hydroxymethyl- phenylamino)- piperidin-1-yl]- acetamide
     59
    Figure US20110172270A1-20110714-C00102
         		N-(3-Acetyl- phenyl)-2-[4-(2- hydroxymethyl- 4-methyl- phenylamino)- piperidin-1-yl]- acetamide
     60
    Figure US20110172270A1-20110714-C00103
         		N-[3-(1- Hydroxy-ethyl)- phenyl]-2-[4-(2- hydroxymethyl- phenylamino)- piperidin-1-yl]- acetamide
     61
    Figure US20110172270A1-20110714-C00104
         		N-[3-(1- Hydroxy-ethyl)- phenyl]-2-[4-(2- hydroxymethyl- 6-methyl- phenylamino)- piperidin-1-yl]- acetamide
     62
    Figure US20110172270A1-20110714-C00105
         		2-[4-(4-Chloro-2- hydroxymethyl- phenylamino)- piperidin-1-yl]- N-[3-(1- hydroxy-ethyl)- phenyl]- acetamide
     63
    Figure US20110172270A1-20110714-C00106
         		N-[3-(1- Hydroxy-ethyl)- phenyl]-2-[4-(2- hydroxymethyl- 4-methyl- phenylamino)- piperidin-1-yl]- acetamide
     64
    Figure US20110172270A1-20110714-C00107
         		N-Benzo[1,3] dioxol-5-yl-2- [4-(4-chloro-2- hydroxymethyl- phenylamino)- piperidin-1-yl]- acetamide
     65
    Figure US20110172270A1-20110714-C00108
         		N-Benzo[1,3] dioxol-5-yl-2- [4-(4-fluoro-2- hydroxymethyl- phenylamino)- piperidin-1-yl]- acetamide
     66
    Figure US20110172270A1-20110714-C00109
         		N-Benzo[1,3] dioxol-5-yl-2- [4-(2- hydroxymethyl- 6-methoxy- phenylamino)- piperidin-1-yl]- acetamide
     67
    Figure US20110172270A1-20110714-C00110
         		N-Benzo[1,3] dioxol-5-yl-2-[4- (4,5-difluoro-2- hydroxymethyl- phenylamino)- piperidin-1-yl]- acetamide
     68
    Figure US20110172270A1-20110714-C00111
         		N-Benzo[1,3] dioxol-5-yl-2-[4- (3-chloro-2- hydroxymethyl- phenylamino)- piperidin-1-yl]- acetamide
     69
    Figure US20110172270A1-20110714-C00112
         		N-(4-Acetyl- phenyl)-2-[4-(2- hydroxymethyl- phenylamino)- piperidin-1-yl]- acetamide
     70
    Figure US20110172270A1-20110714-C00113
         		N-(4-Acetyl- phenyl)-2-[4-(2- hydroxymethyl- 6-methyl- phenylamino)- piperidin-1-yl]- acetamide
     71
    Figure US20110172270A1-20110714-C00114
         		N-(4-Acetyl- phenyl)-2-[4-(4- chloro-2- hydroxymethyl- phenylamino)- piperidin-1-yl]- acetamide
     72
    Figure US20110172270A1-20110714-C00115
         		N-(4-Acetyl- phenyl)-2-[4-(2- hydroxymethyl- 4-methyl- phenylamino)- piperidin-1-yl]- acetamide
     73
    Figure US20110172270A1-20110714-C00116
         		N-(4-Acetyl- phenyl)-2-[4-(4- fluoro-2- hydroxymethyl- phenylamino)- piperidin-1-yl]- acetamide
     74
    Figure US20110172270A1-20110714-C00117
         		N-(4-Acetyl- phenyl)-2-[4-(2- hydroxymethyl- 6-methoxy- phenylamino)- piperidin-1-yl]- acetamide
     75
    Figure US20110172270A1-20110714-C00118
         		N-(4-Acetyl- phenyl)-2-[4-(3- chloro-2- hydroxymethyl- phenylamino)- piperidin-1-yl]- acetamide
     76
    Figure US20110172270A1-20110714-C00119
         		N-[4-(1- Hydroxy-ethyl)- phenyl]-2-[4-(2- hydroxymethyl- phenylamino)- piperidin-1-yl]- acetamide
     77
    Figure US20110172270A1-20110714-C00120
         		N-[4-(1- Hydroxy-ethyl)- phenyl]-2-[4-(2- hydroxymethyl- 6-methyl- phenylamino)- piperidin-1-yl]- acetamide
     78
    Figure US20110172270A1-20110714-C00121
         		2-[4-(4-Chloro-2- hydroxymethyl- phenylamino)- piperidin-1-yl]- N-[4-(1- hydroxy-ethyl)- phenyl]- acetamide
     79
    Figure US20110172270A1-20110714-C00122
         		N-[4-(1- Hydroxy-ethyl)- phenyl]-2-[4-(2- hydroxymethyl- 4-methyl- phenylamino)- piperidin-1-yl]- acetamide
     80
    Figure US20110172270A1-20110714-C00123
         		2-[4-(4-Fluoro-2- hydroxymethyl- phenylamino)- piperidin-1-yl]- N-[4-(1- hydroxy-ethyl)- phenyl]- acetamide
     81
    Figure US20110172270A1-20110714-C00124
         		N-[4-(1- Hydroxy-ethyl)- phenyl]-2-[4-(2- hydroxymethyl- 6-methoxy- phenylamino)- piperidin-1-yl]- acetamide
     82
    Figure US20110172270A1-20110714-C00125
         		2-[4-(3-Chloro-2- hydroxymethyl- phenylamino)- piperidin-1-yl]- N-[4-(1- hydroxy-ethyl)- phenyl]- acetamide
     83
    Figure US20110172270A1-20110714-C00126
         		N-(9-Ethyl-9H- carbazol-3-yl)- 2-[4-(2- hydroxymethyl- phenylamino)- piperidin-1-yl]- acetamide
     84
    Figure US20110172270A1-20110714-C00127
         		2-[4-(4-Chloro-2- hydroxymethyl- phenylamino)- piperidin-1-yl]- N-(9-ethyl-9H- carbazol-3-yl)- acetamide
     85
    Figure US20110172270A1-20110714-C00128
         		N-(9-Ethyl-9H- carbazol-3-yl)- 2-[4-(2- hydroxymethyl- 4-methyl- phenylamino)- piperidin-1-yl]- acetamide
     86
    Figure US20110172270A1-20110714-C00129
         		N-(9-Ethyl-9H- carbazol-3-yl)- 2-[4-(4-fluoro-2- hydroxymethyl- phenylamino)- piperidin-1-yl]- acetamide
     87
    Figure US20110172270A1-20110714-C00130
         		N-(9-Ethyl-9H- carbazol-3-yl)- 2-[4-(2- hydroxymethyl- 6-methoxy- phenylamino)- piperidin-1-yl]- acetamide
     88
    Figure US20110172270A1-20110714-C00131
         		2-[4-(4,5- Difluoro-2- hydroxymethyl- phenylamino)- piperidin-1-yl]- N-(9-ethyl-9H- carbazol-3-yl)- acetamide
     89
    Figure US20110172270A1-20110714-C00132
         		2-[4-(3-Chloro-2- hydroxymethyl- phenylamino)- piperidin-1-yl]- N-(9-ethyl-9H- carbazol-3-yl)- acetamide
     90
    Figure US20110172270A1-20110714-C00133
         		2-[4-(2- Hydroxymethyl- phenylamino)- piperidin-1-yl]- N-(9-methyl- 9H-carbazol-3- yl)-acetamide
     91
    Figure US20110172270A1-20110714-C00134
         		2-[4-(2- Hydroxymethyl- 6-methyl- phenylamino)- piperidin-1-yl]- N-(9-methyl- 9H-carbazol-3- yl)-acetamide
     92
    Figure US20110172270A1-20110714-C00135
         		2-[4-(4-Chloro-2- hydroxymethyl- phenylamino)- piperidin-1-yl]- N-(9-methyl- 9H-carbazol-3- yl)-acetamide
     93
    Figure US20110172270A1-20110714-C00136
         		2-[4-(2- Hydroxymethyl- methyl- phenylamino)- piperidin-1-yl]- N-(9-methyl- 9H-carbazol-3- yl)-acetamide
     94
    Figure US20110172270A1-20110714-C00137
         		2-[4-(2- Hydroxymethyl- phenylamino)- piperidin-1-yl]- N-(5-oxo- 5,6,7,8- tetrahydro- naphthalen-2- yl)-acetamide
     95
    Figure US20110172270A1-20110714-C00138
         		2-[4-(2- Hydroxymethyl- 6-methyl- phenylamino)- piperidin-1-yl]- N-(5-oxo- 5,6,7,8- tetrahydro- naphthalen-2- yl)-acetamide
     96
    Figure US20110172270A1-20110714-C00139
         		2-[4-(4-Chloro-2- hydroxymethyl- phenylamino)- piperidin-1-yl]- N-(5-oxo- 5,6,7,8- tetrahydro- naphthalen-2- yl)-acetamide
     97
    Figure US20110172270A1-20110714-C00140
         		2-[4-(2- Hydroxymethyl- 4-methyl- phenylamino)- piperidin-1-yl]- N-(5-oxo- 5,6,7,8- tetrahydro- naphthalen-2- yl)-acetamide
     98
    Figure US20110172270A1-20110714-C00141
         		2-[4-(4-Fluoro-2- hydroxymethyl- phenylamino)- piperidin-1-yl]- N-(5-oxo- 5,6,7,8- tetrahydro- naphthalen-2- yl)-acetamide
     99
    Figure US20110172270A1-20110714-C00142
         		2-[4-(2- Hydroxymethyl- phenylamino)- piperidin-1-yl]- N-(5-hydroxy- 5,6,7,8- tetrahydro- naphthalen-2- yl)-acetamide
    100
    Figure US20110172270A1-20110714-C00143
         		2-[4-(2- Hydroxymethyl- 6-methyl- phenylamino)- piperidin-1-yl]- N-(5-hydroxy- 5,6,7,8- tetrahydro- naphthalen-2- yl)-acetamide
    101
    Figure US20110172270A1-20110714-C00144
         		2-[4-(4-Chloro-2- hydroxymethyl- phenylamino)- piperidin-1-yl]- N-(5-hydroxy- 5,6,7,8- tetrahydro- naphthalen-2- yl)-acetamide
    102
    Figure US20110172270A1-20110714-C00145
         		2-[4-(2- Hydroxymethyl- 4-methyl- phenylamino)- piperidin-1-yl]- N-(5-hydroxy- 5,6,7,8- tetrahydro- naphthalen-2- yl)-acetamide
    103
    Figure US20110172270A1-20110714-C00146
         		2-[4-(4-Fluoro-2- hydroxymethyl- phenylamino)- piperidin-1-yl]- N-(5-hydroxy- 5,6,7,8- tetrahydro- naphthalen-2- yl)-acetamide
    104
    Figure US20110172270A1-20110714-C00147
         		2-[4-(2- Hydroxymethyl- 6-methyl- phenylamino)- piperidin-1-yl]- N-(1-oxo- indan-5-yl)- acetamide
    105
    Figure US20110172270A1-20110714-C00148
         		2-[4-(4-Chloro-2- hydroxymethyl- phenylamino)- piperidin-1-yl]- N-(1-oxo- indan-5-yl)- acetamide
    106
    Figure US20110172270A1-20110714-C00149
         		2-[4-(2- Hydroxymethyl- 4-methyl- phenylamino)- piperidin-1-yl]- N-(1-oxo- indan-5-yl)- acetamide
    107
    Figure US20110172270A1-20110714-C00150
         		N-(1-Hydroxy- indan-5-yl)-2- [4-(2- hydroxymethyl- phenylamino)- piperidin-1-yl]- acetamide
    108
    Figure US20110172270A1-20110714-C00151
         		N-(1-Hydroxy- indan-5-yl)-2- [4-(2- hydroxymethyl- 6-methyl- phenylamino)- piperidin-1-yl]- acetamide
    109
    Figure US20110172270A1-20110714-C00152
         		2-[4-(4-Chloro-2- hydroxymethyl- phenylamino)- piperidin-1-yl]- N-(1-hydroxy- indan-5-yl)- acetamide
    110
    Figure US20110172270A1-20110714-C00153
         		N-(1-Hydroxy- indan-5-yl)-2- [4-(2- hydroxymethyl- 4-methyl- phenylamino)- piperidin-1-yl]- acetamide
    111
    Figure US20110172270A1-20110714-C00154
         		2-[4-(4-Bromo-2- hydroxymethyl- phenylamino)- piperidin-1-yl]- N-(9-ethyl-9H- carbazol-3-yl)- acetamide
    112
    Figure US20110172270A1-20110714-C00155
         		2-[4-(2- Hydroxymethyl- 6-methyl- phenylamino)- piperidin-1-yl]- N-(9-oxo-9H- fluoren-2-yl)- acetamide
    113
    Figure US20110172270A1-20110714-C00156
         		2-[4-(2- Hydroxymethyl- 4-methyl- phenylamino)- piperidin-1-yl]- N-(9-oxo-9H- fluoren-2-yl)- acetamide
    114
    Figure US20110172270A1-20110714-C00157
         		N-Dibenzofuran- 2-yl-2-[4-(2- hydroxymethyl- 4-methyl- phenylamino)- piperidin-1-yl]- acetamide
    115
    Figure US20110172270A1-20110714-C00158
         		N-Dibenzofuran- 2-yl-2-[4-(2- hydroxymethyl- 6-methyl- phenylamino)- piperidin-1-yl]- acetamide
    116
    Figure US20110172270A1-20110714-C00159
         		2-[4-(2- Hydroxymethyl- 6-methoxy- phenylamino)- piperidin-1-yl]- N-quinolin-3-yl- acetamide
    117
    Figure US20110172270A1-20110714-C00160
         		2-[4-(4,5- Difluoro-2- hydroxymethyl- phenylamino)- piperidin-1-yl]- N-quinolin-3-yl- acetamide
    118
    Figure US20110172270A1-20110714-C00161
         		N-(9-Hydroxy- 9H-fluoren-2- yl)-2-[4-(2- hydroxymethyl- 6-methyl- phenylamino)- piperidin-1-yl]- acetamide
    119
    Figure US20110172270A1-20110714-C00162
         		N-(9-Hydroxy- 9H-fluoren-2- yl)-2-[4-(2- hydroxymethyl- 4-methyl- phenylamino)- piperidin-1-yl]- acetamide
    120
    Figure US20110172270A1-20110714-C00163
         		2-[4-(2- Hydroxymethyl- phenylamino)- piperidin-1-yl]- N-(4-phenoxy- phenyl)- acetamide
    121
    Figure US20110172270A1-20110714-C00164
         		2-[4-(2- Hydroxymethyl- 6-methyl- phenylamino)- piperidin-1-yl]- N-(4-phenoxy- phenyl)- acetamide
    122
    Figure US20110172270A1-20110714-C00165
         		2-[4-(4-Chloro-2- hydroxymethyl- phenylamino)- piperidin-1-yl]- N-(4-phenoxy- phenyl)- acetamide
    123
    Figure US20110172270A1-20110714-C00166
         		2-[4-(2- Hydroxymethyl- 4-methyl- phenylamino)- piperidin-1-yl]- N-(4-phenoxy- phenyl)- acetamide
    124
    Figure US20110172270A1-20110714-C00167
         		N-(4- Cyclohexyl- pheny)-2-[4-(2- hydroxymethyl- phenylamino)- piperidin-1-yl]- acetamide
    125
    Figure US20110172270A1-20110714-C00168
         		2-[4-(2- Hydroxymethyl- 3-methoxy- phenylamino)- piperidin-1-yl]- N-quinolin-3-yl- acetamide
    126
    Figure US20110172270A1-20110714-C00169
         		2-[4-(3-Hydroxy- 2-hydroxymethyl- phenylamino)- piperidin-1-yl]- N-quinolin-3-yl- acetamide
    127
    Figure US20110172270A1-20110714-C00170
         		2-[4-(4-Hydroxy- 2-hydroxymethyl- phenylamino)- piperidin-1-yl]- N-quinolin-3-yl- acetamide
    128
    Figure US20110172270A1-20110714-C00171
         		2-[4-(2-Hydroxy- 6-hydroxymethyl- phenylamino)- piperidin-1-yl]- N-quinoline-3- yl-acetamide
    129
    Figure US20110172270A1-20110714-C00172
         		2-[4-(2- Hydroxymethyl- 3-methoxy- phenylamino)- piperidin-1-yl]-N- quinolin-6-yl- acetamide
    130
    Figure US20110172270A1-20110714-C00173
         		2-[4-(3-Hydroxy- 2-hydroxymethyl- phenylamino)- piperidin-1-yl]-N- quinolin-6-yl- acetamide
    131
    Figure US20110172270A1-20110714-C00174
         		2-[4-(4-Hydroxy- 2-hydroxymethyl- phenylamino)- piperidin-1-yl]-N- quinolin-6-yl- acetamide
    132
    Figure US20110172270A1-20110714-C00175
         		2-[4-(2-Hydroxy- 6-hydroxymethyl- phenylamino)- piperidin-1-yl]-N- quinolin-6-yl- acetamide
    133
    Figure US20110172270A1-20110714-C00176
         		N-(4-Benzoyl- phenyl)-2-[4-(2- hydroxymethyl- 3-methoxy- phenylamino)- piperidin-1-yl]- acetamide
    134
    Figure US20110172270A1-20110714-C00177
         		N-(4-Benzoyl- phenyl)-2-[4-(3- hydroxy-2- hydroxymethyl- phenylamino)- piperidin-1-yl]- acetamide
    135
    Figure US20110172270A1-20110714-C00178
         		N-(4-Benzoyl- phenyl)-2-[4-(4- hydroxy-2- hydroxymethyl- phenylamino)- piperidin-1-yl]- acetamide
    136
    Figure US20110172270A1-20110714-C00179
         		N-(4-Benzoyl- phenyl)-2-[4-(2- hydroxy-6- hydroxymethyl- phenylamino)- piperidin-1-yl]- acetamide
    137
    Figure US20110172270A1-20110714-C00180
         		2-[4-(2- Hydroxymethyl- 3-methoxy- phenylamino)- piperidin-1-yl]-N- [4-(hydroxy- phenyl-methyl)- phenyl]- acetamide
    138
    Figure US20110172270A1-20110714-C00181
         		2-[4-(3-Hydroxy- 2-hydroxymethyl- phenylamino)- piperidin-1-yl]-N- [4-(hydroxy- phenyl-methyl)- phenyl]- acetamide
    139
    Figure US20110172270A1-20110714-C00182
         		2-[4-(4-Hydroxy- 2-hydroxymethyl- phenylamino)- piperidin-1-yl]-N- [4-(hydroxy- phenyl-methyl)- phenyl]- acetamide
    140
    Figure US20110172270A1-20110714-C00183
         		2-[4-(2-Hydroxy- 6-hydroxymethyl- phenylamino)- piperidin-1-yl]-N- [4-(hydroxy- phenyl-methyl)- phenyl]- acetamide
    141
    Figure US20110172270A1-20110714-C00184
         		2-[4-(2- Hydroxymethyl- 3-methoxy- phenylamino)- piperidin-1-yl]-N- (9-oxo-9H- fluoren-3-yl)- acetamide
    142
    Figure US20110172270A1-20110714-C00185
         		2-[4-(3-Hydroxy- 2-hydroxymethyl- phenylamino)- piperidin-1-yl]-N- (9-oxo-9H- fluoren-3-yl)- acetamide
    143
    Figure US20110172270A1-20110714-C00186
         		2-[4-(4-Hydroxy- 2-hydroxymethyl- phenylamino)- piperidin-1-yl]-N- (9-oxo-9H- fluoren-3-yl)- acetamide
    144
    Figure US20110172270A1-20110714-C00187
         		2-[4-(2-Hydroxy- 6-hydroxymethyl- phenylamino)- piperidin-1-yl]-N- (9-oxo-9H- fluoren-3-yl)- acetamide
    145
    Figure US20110172270A1-20110714-C00188
         		N-(9-Hydroxy- 9H-fluoren-3-yl)- 2-[4-(2- hydroxymethyl- 3-methoxy- phenylamino)- piperidin-1-yl]- acetamide
    146
    Figure US20110172270A1-20110714-C00189
         		N-(9-Hydroxy- 9H-fluoren-3-yl)- 2-[4-(3-hydroxy- 2-hydroxymethyl- phenylamino)- piperidin-1-yl]- acetamide
    147
    Figure US20110172270A1-20110714-C00190
         		N-(9-Hydroxy- 9H-fluoren-3-yl)- 2-[4-(4-hydroxy- 2-hydroxymethyl- phenylamino)- piperidin-1-yl]- acetamide
    148
    Figure US20110172270A1-20110714-C00191
         		N-(9-Hydroxy- 9H-fluoren-3-yl)- 2-[4-(2-hydroxy- 6-hydroxymethyl- phenylamino)- piperidin-1-yl]- acetamide
    149
    Figure US20110172270A1-20110714-C00192
         		N-(3-Acetyl- phenyl)-2-[4-(2- hydroxymethyl- 3-methoxy- phenylamino)- piperidin-1-yl]- acetamide
    150
    Figure US20110172270A1-20110714-C00193
         		N-(3-Acetyl- phenyl)-2-[4-(3- hydroxy-2- hydroxymethyl- phenylamino)- piperidin-1-yl]- acetamide
    151
    Figure US20110172270A1-20110714-C00194
         		N-(3-Acetyl- phenyl)-2-[4-(4- hydroxy-2- hydroxymethyl- phenylamino)- piperidin-1-yl]- acetamide
    152
    Figure US20110172270A1-20110714-C00195
         		N-(3-Acetyl- phenyl)-2-[4-(2- hydroxy-6- hydroxymethyl- phenylamino)- piperidin-1-yl]- acetamide
    153
    Figure US20110172270A1-20110714-C00196
         		N-[3-(1-Hydroxy- ethyl)-phenyl]-2- [4-(2- hydroxymethyl- 3-methoxy- phenylamino)- piperidin-1-yl]- acetamide
    154
    Figure US20110172270A1-20110714-C00197
         		N-[3-(1-Hydroxy- ethyl)-phenyl]-2- [4-(3-hydroxy-2- hydroxymethyl- phenylamino)- piperidin-1-yl]- acetamide
    155
    Figure US20110172270A1-20110714-C00198
         		N-[3-(1-Hydroxy- ethyl)-phenyl]-2- [4-(4-hydroxy-2- hydroxymethyl- phenylamino)- piperidin-1-yl]- acetamide
    156
    Figure US20110172270A1-20110714-C00199
         		N-[3-(1-Hydroxy- ethyl)-phenyl]-2- [4-(2-hydroxy-6- hydroxymethyl- phenylamino)- piperidin-1-yl]- acetamide
    157
    Figure US20110172270A1-20110714-C00200
         		N-(4-Acetyl- phenyl)-2-[4-(2- hydroxymethyl- 3-methoxy- phenylamino)- piperidin-1-yl]- acetamide
    158
    Figure US20110172270A1-20110714-C00201
         		N-(4-Acetyl- phenyl)-2-[4-(3- hydroxy-2- hydroxymethyl- phenylamino)- piperidin-1-yl]- acetamide
    159
    Figure US20110172270A1-20110714-C00202
         		N-(4-Acetyl- phenyl)-2-[4-(4- hydroxy-2- hydroxymethyl- phenylamino)- piperidin-1-yl]- acetamide
    160
    Figure US20110172270A1-20110714-C00203
         		N-(4-Acetyl- phenyl)-2-[4-(2- hydroxy-6- hydroxymethyl- phenylamino)- piperidin-1-yl]- acetamide
    161
    Figure US20110172270A1-20110714-C00204
         		N-[4-(1-Hydroxy- ethyl)-phenyl]-2- [4-(2- hydroxymethyl- 3-methoxy- phenylamino)- piperidin-1-yl]- acetamide
    162
    Figure US20110172270A1-20110714-C00205
         		N-[4-(1-Hydroxy- ethyl)-phenyl]-2- [4-(3-hydroxy-2- hydroxymethyl- phenylamino)- piperidin-1-yl]- acetamide
    163
    Figure US20110172270A1-20110714-C00206
         		N-[4-(1-Hydroxy- ethyl)-phenyl]-2- [4-(4-hydroxy-2- hydroxymethyl- phenylamino)- piperidin-1-yl]- acetamide
    164
    Figure US20110172270A1-20110714-C00207
         		N-[4-(1-Hydroxy- ethyl)-phenyl]-2- [4-(2-hydroxy-6- hydroxymethyl- phenylamino)- piperidin-1-yl]- acetamide
    165
    Figure US20110172270A1-20110714-C00208
         		N-(9-Ethyl-9H- carbazol-3-yl)-2- [4-(2- hydroxymethyl- 3-methoxy- phenylamino)- piperidin-1-yl]- acetamide
    166
    Figure US20110172270A1-20110714-C00209
         		N-(9-Ethyl-9H- carbazol-3-yl)-2- [4-(3-hydroxy-2- hydroxymethyl- phenylamino)- piperidin-1-yl]- acetamide
    167
    Figure US20110172270A1-20110714-C00210
         		N-(9-Ethyl-9H- carbazol-3-yl)-2- [4-(4-hydroxy-2- hydroxymethyl- phenylamino)- piperidin-1-yl]- acetamide
    168
    Figure US20110172270A1-20110714-C00211
         		N-(9-Ethyl-9H- carbazol-3-yl)-2- [4-(2-hydroxy-6- hydroxymethyl- phenylamino)- piperidin-1-yl]- acetamide
    169
    Figure US20110172270A1-20110714-C00212
         		2-[4-(2- Hydroxymethyl- 3-methoxy- phenylamino)- piperidin-1-yl]-N- (5-oxo-5,6,7,8- tetrahydro- naphthalen-2-yl)- acetamide
    170
    Figure US20110172270A1-20110714-C00213
         		2-[4-(3-Hydroxy- 2-hydroxymethyl- phenylamino)- piperidin-1-yl]-N- (5-oxo-5,6,7,8- tetrahdyro- naphthalen-2-yl)- acetamide
    171
    Figure US20110172270A1-20110714-C00214
         		2-[4-(4-Hydroxy- 2-hydroxymethyl- phenylamino)- piperidin-1-yl]-N- (5-oxo-5,6,7,8- tetrahydro- naphthalen-2-yl)- acetamide
    172
    Figure US20110172270A1-20110714-C00215
         		2-[4-(2-Hydroxy- 6-hydroxymethyl- phenylamino)- piperidin-1-yl]-N- (5-oxo-5,6,7,8- tetrahydro- naphthalen-2-yl)- acetamide
    173
    Figure US20110172270A1-20110714-C00216
         		2-[4-(2- Hydroxymethyl- 3-methoxy- phenylamino)- piperidin-1-yl]-N- (5-hydroxy- 5,6,7,8- tetrahydro- naphthalen-2-yl)- acetamide
    174
    Figure US20110172270A1-20110714-C00217
         		2-[4-(3-Hydroxy- 2-hydroxymethyl- phenylamino)- piperidin-1-yl]-N- (5-hydroxy- 5,6,7,8- tetrahydro- naphthalen-2-yl)- acetamide
    175
    Figure US20110172270A1-20110714-C00218
         		2-[4-(4-Hydroxy- 2-hydroxymethyl- phenylamino)- piperidin-1-yl]-N- (5-hydroxy- 5,6,7,8- tetrahydro- naphthalen-2-yl)- acetamide
    176
    Figure US20110172270A1-20110714-C00219
         		2-[4-(2-Hydroxy- 6-hydroxymethyl- phenylamino)- piperidin-1-yl]-N- (5-hydroxy- 5,6,7,8- tetrahydro- naphthalen-2-yl)- acetamide
    177
    Figure US20110172270A1-20110714-C00220
         		2-[4-(2- Hydroxymethyl- 3-methoxy- phenylamino)- piperidin-1-yl]-N- (4-phenoxy- phenyl)- acetamide
    178
    Figure US20110172270A1-20110714-C00221
         		2-[4-(3-Hydroxy- 2-hydroxymethyl- phenylamino)- piperidin-1-yl]-N- (4-phenoxy- phenyl)- acetamide
    179
    Figure US20110172270A1-20110714-C00222
         		2-[4-(4-Hydroxy- 2-hydroxymethyl- phenylamino)- piperidin-1-yl]-N- (4-phenoxy- phenyl)- acetamide
    180
    Figure US20110172270A1-20110714-C00223
         		2-[4-(2-Hydroxy- 6-hydroxymethyl- phenylamino)- piperidin-1-yl]-N- (4-phenoxy- phenyl)- acetamide
    • Pharmacological Data:
  • (a)
  • According to the methods given above Neuropeptide Y5 and Y2 Binding of the 1,4-disubstituted piperidine compounds of general formula (I) has been determined. Some of the Y5 values are given in the following tables 1 and 2.
  • TABLE 1
    Compound according Neuropeptide Y5 Binding
    to Example IC50 (nm)
    1a 50
    2a 80.9
    3a 36.3
    5a 40.1
  • TABLE 2
    Compound according Binding of Neuropeptide Y5
    to example % Inhibition 10−6 M
    5 86.2
    7 82.3
    9 80.4
    11 73.9
    13 81.5
    14 88.9
    15 93.2

Claims (13)

1-24. (canceled)
25. A process for preparing a 1,4-disubstituted piperidine compounds of formula (I)
Figure US20110172270A1-20110714-C00224
the process comprising,
reacting at least one compound of general formula (II),
Figure US20110172270A1-20110714-C00225
with at least one compound of general formula (III),
Figure US20110172270A1-20110714-C00226
F represents halogen, hydroxy or an O-acyl group and G represents halogen, in a suitable reaction medium and optionally in the presence of at least one base and/or at least one auxiliary agent, and reacting the so obtained compound of general (IV)
Figure US20110172270A1-20110714-C00227
with at least one piperidine compound of general formula (V) and/or a salt, thereof,
Figure US20110172270A1-20110714-C00228
in a suitable reaction medium, optionally in the presence of at least one base and/or at least one auxiliary agent,
wherein
R1, R2, R3, R4 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, —OR12, —OC(═O)R13, —SR14, —SOR14, —SO2R14, —NH—SO2R14, —SO2NH2, —NR15R15 moiety and —O—P,
R5 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 cycloaliphatic radical,
R6, R7, R8, R9 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 COOR17 moiety,
A represents a bridge member —CHR18— or —CHR18—CH2—,
B represents an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted cycloaliphatic radical, a COOR19-moiety, a —(C═O)R20-moiety, or a —CH7OR23-moiety,
R10 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,
R11 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
R10 and R11 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,
R12 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,
R13 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,
R14 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,
R15 and R16 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 R15 and R16 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,
R17 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,
R18 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,
R19 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 cycloaliphatic radical, or an optionally at least mono-substituted aryl- or heteroaryl radical, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,
R20 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 cycloaliphatic radical, an optionally at least mono-substituted aryl- or heteroaryl radical, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, or a NR21R22-moiety,
R21 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 cycloaliphatic radical, or an optionally at least mono-substituted aryl- or heteroaryl radical, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,
R22 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 cycloaliphatic radical, or an optionally at least mono-substituted aryl- or heteroaryl radical, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,
R23 represents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, which may comprise at least one heteroatom as a chain member, or a —(C═O)R13-moiety,
P represents hydrogen, a linear or branched C1-3 alkyl radical,
—PO(O—C1-4-Alkyl), —CO(OC1-5-Alkyl),
Figure US20110172270A1-20110714-C00229
and RP represents —OCO—C1-3-Alkyl, —CH2—N(C1-4-Alkyl)2 or
Figure US20110172270A1-20110714-C00230
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.
26. A process for preparing a 1,4 disubstituted piperidine compound of general formula (I)
Figure US20110172270A1-20110714-C00231
wherein B represents a substituted aliphatic radical or a —CH2OR23-moiety, the process comprising,
reacting at least one compound of general formula (II),
Figure US20110172270A1-20110714-C00232
with at least one compound of general formula (III),
Figure US20110172270A1-20110714-C00233
wherein F represents halogen, hydroxy or an O-acyl group and G represents halogen in a suitable reaction medium and optionally in the presence of at least one base and/or at least one auxiliary agent, and reacting the so obtained compound of general formula (IV)
Figure US20110172270A1-20110714-C00234
with at least one piperidine compound of general formula (V) and/or a salt thereof,
Figure US20110172270A1-20110714-C00235
wherein Rx represents any substituent including hydrogen 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 (VI),
Figure US20110172270A1-20110714-C00236
which is reacted with a base in a suitable reaction medium to yield a compound of general formula (I), wherein
R1, R2, R3, R4 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, —OR12, —OC(═O)R13, —SR14, —SOR14, —SO2R14, —NH—SO2R14, —SO2NH2, —NR15R16 moiety and —O—P,
R5 represents H;
R6, R7, R8, R9 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 COOR17 moiety,
A represents a bridge member —CHR18— or —CHR18—CH2—,
B represents a substituted aliphatic radical or a —CH2OR23-moiety.
R10 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,
R11 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
R10 and R11 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,
R12 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,
R13 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,
R14 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,
R15 and R16 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 R15 and R16 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,
R17 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,
R18 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,
R19 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 cycloaliphatic radical, or an optionally at least mono-substituted aryl- or heteroaryl radical, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,
R20 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 cycloaliphatic radical, an optionally at least mono-substituted aryl- or heteroaryl radical, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, or a NR21R22-moiety,
R21 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 cycloaliphatic radical, or an optionally at least mono-substituted aryl- or heteroaryl radical, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,
R22 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 cycloaliphatic radical, or an optionally at least mono-substituted aryl- or heteroaryl radical, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,
R23 represents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, which may comprise at least one heteroatom as a chain member, or a —(C═O)R13-moiety,
P represents hydrogen, a linear or branched C1-3 alkyl radical,
—PO(O—C1-4-Alkyl), —CO(OC1-5-Alkyl),
Figure US20110172270A1-20110714-C00237
and RP represents —OCO—C1-3-Alkyl, —CH2—N(C1-4-Alkyl)2 or
Figure US20110172270A1-20110714-C00238
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.
27. A process for the preparing a physiologically acceptable salt of a 1,4-disubstituted piperidine compound of general formula (I), the process comprising reacting at least one compound of general formula (I) having at least one basic group with at least one acid in the presence of a suitable reaction medium
Figure US20110172270A1-20110714-C00239
wherein
R1, R2, R3, R4 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, —OR12, —OC(═O)R13, —SR14, —SOR14, —SO2R14, —NH—SO2R14, —SO2NH2, —NR15R16 moiety and —O—P,
R5 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 cycloaliphatic radical,
R6, R7, R8, R9 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 COOR17 moiety,
A represents a bridge member —CHR18— or —CHR18—CH2—,
B represents an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted cycloaliphatic radical, a COOR19-moiety, a —(C═O)R20-moiety, or a —CH2OR23-moiety,
R10 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,
R11 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
R10 and R11 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,
R12 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,
R13 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,
R14 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,
R15 and R16 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 R15 and R16 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,
R17 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,
R18 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,
R19 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 cycloaliphatic radical, or an optionally at least mono-substituted aryl- or heteroaryl radical, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,
R20 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 cycloaliphatic radical, an optionally at least mono-substituted aryl- or heteroaryl radical, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, or a NR21R22-moiety,
R21 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 cycloaliphatic radical, or an optionally at least mono-substituted aryl- or heteroaryl radical, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,
R22 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 cycloaliphatic radical, or an optionally at least mono-substituted aryl- or heteroaryl radical, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,
R23 represents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, which may comprise at least one heteroatom as a chain member, or a —(C═O)R13-moiety,
P represents hydrogen, a linear or branched C1-3 alkyl radical,
—PO(O—C1-4-Alkyl), —CO(OC1-5-Alkyl),
Figure US20110172270A1-20110714-C00240
and RP represents —OCO—C1-3-Alkyl, —CH2—N(C1-4-Alkyl), or
Figure US20110172270A1-20110714-C00241
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.
28. A process for the preparing a physiologically acceptable salt of a 1,4-disubstituted piperidine compound, the method comprising reacting at least one compound of general formula (I) having at least one acidic group with at least one base in the presence of a suitable reaction medium
Figure US20110172270A1-20110714-C00242
wherein
R1, R2, R3, R4 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, —OR12, —OC(═O)R13, —SR14, —SOR14, —SO2R14, —NH—SO2R14, —SO2NH2, —NR15R16 moiety and —O—P,
R5 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 cycloaliphatic radical,
R6, R7, R8, R9 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 COOR17 moiety,
A represents a bridge member —CHR18— or —CHR18—CH2—,
B represents an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted cycloaliphatic radical, a COOR19-moiety, a —(C═O)R20-moiety, or a —CH2OR23-moiety,
R10 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,
R11 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
R10 and R11 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,
R12 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,
R13 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,
R14 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,
R15 and R16 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 R15 and R16 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,
R17 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,
R18 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,
R19 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 cycloaliphatic radical, or an optionally at least mono-substituted aryl- or heteroaryl radical, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,
R20 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 cycloaliphatic radical, an optionally at least mono-substituted aryl- or heteroaryl radical, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, or a NR21R22-moiety,
R21 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 cycloaliphatic radical, or an optionally at least mono-substituted aryl- or heteroaryl radical, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,
R22 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 cycloaliphatic radical, or an optionally at least mono-substituted aryl- or heteroaryl radical, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,
R23 represents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, which may comprise at least one heteroatom as a chain member, or a —(C═O)R13-moiety,
P represents hydrogen, a linear or branched C1-3 alkyl radical,
—PO(O—C1-4-Alkyl), —CO(OC1-5-Alkyl),
Figure US20110172270A1-20110714-C00243
and RP represents —OCO—C1-3-Alkyl, —CH, —N(C1-4-Alkyl), or
Figure US20110172270A1-20110714-C00244
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.
29-56. (canceled)
57. A method for regulating a neuropeptide Y receptor in a subject in need thereof, the method comprising administering an effective amount of at least one 1,4-disubstituted piperidine compound according to general formula (I):
Figure US20110172270A1-20110714-C00245
wherein
R1, R2, R3, R4 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, —OR12, —OC(═O)R13, —SR14, —SOR14, —SO2R14, —NH—SO2R14, —SO2NH2, —NR15R16 moiety and —O—P,
R5 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 cycloaliphatic radical,
R6, R7, R8, R9 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 COOR17 moiety,
A represents a bridge member —CHR18— or —CHR18—CH2—,
B represents an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted cycloaliphatic radical, a COOR19-moiety, a —(C═O)R20-moiety, or a —CH2OR23-moiety,
R10 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,
R11 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
R10 and R11 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,
R12 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,
R13 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,
R14 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,
R15 and R16 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 R15 and R16 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,
R17 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,
R18 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,
R19 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 cycloaliphatic radical, or an optionally at least mono-substituted aryl- or heteroaryl radical, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,
R20 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 cycloaliphatic radical, an optionally at least mono-substituted aryl- or heteroaryl radical, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, or a NR21R22-moiety,
R21 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 cycloaliphatic radical, or an optionally at least mono-substituted aryl- or heteroaryl radical, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,
R22 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 cycloaliphatic radical, or an optionally at least mono-substituted aryl- or heteroaryl radical, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,
R23 represents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, which may comprise at least one heteroatom as a chain member, or a —(C═O)R13-moiety,
P represents hydrogen, a linear or branched C1-3 alkyl radical,
—PO(O—C1-4-Alkyl), —CO(OC1-5-Alkyl),
Figure US20110172270A1-20110714-C00246
and RP represents —OCO—C1-3-Alkyl, —CH2—N(C1-4-Alkyl)2 or
Figure US20110172270A1-20110714-C00247
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.
58. The method of claim 57, wherein the neuropeptide Y receptor is a neuropeptide Y 5 (NPY5) receptor.
59. The method of claim 56, wherein the administering treats at least one condition in the subject selected from the group consisting of appetite, body weight, food ingestion (food intake), obesity, anorexia, cachexia, bulimia, type (II) diabetes, a disorder of the peripheral nervous system, a disorder of the central nervous system, arthritis, epilepsy, anxiety, depression, cognitive disorders, cardiovascular disease, pain, hypertensive syndrome, an inflammatory disease, an immune disease, a panic attack, a bipolar disorder, diabetes, and improvement of cognition.
60. The process of claim 25, wherein R1, R2, R3, R4 are each independently selected from the group consisting of H, F, Cl, Br, OH, CH3, and OCH3, B represents a —CH2—OH or —(C═O)—O—CH3 group,
R11 is selected from the group consisting of unsubstituted phenyl, phenyl that is optionally at least mono-substituted with one or more substituents independently selected from the group consisting of cyclohexyl, phenyl, phenoxy, benzoyl, —C(═O)—C1-2-alkyl, —C(H)(OH)(phenyl) and —C(H)(OH)(CH3),
a group of formula (A)
Figure US20110172270A1-20110714-C00248
wherein
n is 1 or 2,
X represents CH,
Y represents CH—OH or C(═O),
a group of formula (B),
Figure US20110172270A1-20110714-C00249
a group of formula (C),
Figure US20110172270A1-20110714-C00250
and a group of formula (E),
Figure US20110172270A1-20110714-C00251
wherein
RE represents H, a branched or unbranched C1-4-alkyl radical or a branched or unbranched C1-4-alkoxy radical,
Z represents CH2, O, S, CH—OH, C(═O) or N—RF where RF represents H or a branched or unbranched C1-4-alkyl-radical,
optionally in form of one of its stereoisomers, its racemate or in form of a mixture of at least two of its stereoisomers, or a salt.
61. The process according to claim 25, wherein the 1,4-disubstituted compound of general formula (I) is selected from the group consisting of:
1 2-[4-(2-Hydroxymethyl-phenylamino)-piperidin-1-yl]-N-quinolin-3-yl-acetamide 2 2-[4-(2-Hydroxymethyl-phenylamino)-piperidin-1-yl]-N-quinolin-5-yl-acetamide 3 2-[4-(2-Hydroxymethyl-phenylamino)-piperidin-1-yl]-N-quinolin-6-yl-acetamide 4 2-[4-(2-Hydroxymethyl-phenylamino)-piperidin-1-yl]-N-quinolin-8-yl-acetamide 5 2-[4-(2-Hydroxymethyl-4-methyl-phenylamino)-piperidin-1-yl]-N-quinolin-3-yl-acetamide 6 2-[4-(2-Hydroxymethyl-4-methyl-phenylamino)-piperidin-1-yl]-N-quinolin-5-yl-acetamide 7 2-[4-(2-Hydroxymethyl-4-methyl-phenylamino)-piperidin-1-yl]-N-quinolin-6-yl-acetamide 8 2-[4-(2-Hydroxymethyl-4-methyl-phenylamino)-piperidin-1-yl]-N-quinolin-8-yl-acetamide 9 2-[4-(2-Hydroxymethyl-6-methyl-phenylamino)-piperidin-1-yl]-N-quinolin-3-yl-acetamide 10 2-[4-(2-Hydroxymethyl-6-methyl-phenylamino)-piperidin-1-yl]-N-quinolin-5-yl-acetamide 11 2-[4-(2-Hydroxymethyl-6-methyl-phenylamino)-piperidin-1-yl]-N-quinolin-6-yl-acetamide 12 2-[4-(2-Hydroxymethyl-6-methyl-phenylamino)-piperidin-1-yl]-N-quinolin-8-yl-acetamide 13 N-(4-Benzoyl-phenyl)-2-[4-(2-hydroxymethyl-phenylamino)-piperidin-1-yl]-acetamide 14 N-(4-Benzoyl-phenyl)-2-[4-(2-hydroxymethyl-4-methyl-phenylamino)-piperidin-1-yl]-acetamide 15 N-(4-Benzoyl-phenyl)-2-[4-(2-hydroxymethyl-6-methyl-phenylamino)-piperidin-1-yl]-acetamide 16 N-Benzo[1,3] dioxol-5-yl-2-[4-(2-hydroxymethyl-phenylamino)-piperidin-1-yl]-acetamide 17 N-Benzo[1,3]dioxol-5-yl-2-[4-(2-hydroxymethyl-4-methyl-phenylamino)-piperidin-1-yl]-acetamide 18 N-Benzo[1,3]dioxol-5-yl-2-[4-(2-hydroxymethyl-6-methyl-phenylamino)-piperidin-1-yl]-acetamide hydrochloride 19 2-[4-(4-Chioro-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-quinolin-3-yl-acetamide 20 2-[4-(4-Fluoro-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-quinolin-3-yl-acetamide 21 2-[4-(3-Chloro-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-quinolin-3-yl-acetamide 22 2-[4-(4-Chloro-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-quinolin-5-yl-acetamide 23 2-[4-(4-Fluoro-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-quinolin-5-yl-acetamide 24 2-[4-(3-Chloro-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-quinolin-5-yl-acetamide 25 2-[4-(4-Chloro-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-quinolin-6-yl-acetamide 26 2-[4-(4-Fluoro-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-quinolin-6-yl-acetamide 27 2-[4-(3-Chloro-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-quinolin-6-yl-acetamide 28 2-[4-(2-Hydroxymethyl-6-methoxy-phenylamino)-piperidin-1-yl]-N-quinolin-6-yl-acetamide 29 2-[4-(4,5-Difluoro-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-quinolin-6-yl-acetamide 30 2-[4-(4-Chloro-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-quinolin-8-yl-acetamide 31 2-[4-(4-Fluoro-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-quinolin-8-yl-acetamide 32 2-[4-(3-Chloro-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-quinolin-8-yl-acetamide 33 N-(4-Benzoyl-phenyl)-2-[4-(4-chloro-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-acetamide 34 N-(4-Benzoyl-phenyl)-2-[4-(4-fluoro-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-acetamide 35 N-(4-Benzoyl-phenyl)-2-[4-(2-hydroxymethyl-6-methoxy-phenylamino)-piperidin-1-yl]-acetamide 36 N-(4-Benzoyl-phenyl)-2-14-(3-chloro-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-acetamide 37 2-[4-(2-Hydroxymethyl-phenylamino)-piperidin-1-yl]-N-[4-(hydroxy-phenyl-methyl)-phenyl]-acetamide 38 2-[4-(2-Hydroxymethyl-6-methyl-phenylamino)-piperidin-1-yl]-N-[4-(hydroxy-phenyl-methyl)-phenyl]-acetamide 39 2-[4-(4-Chloro-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-[4-(hydroxy-phenyl-methyl)-phenyl]-acetamide 40 2-[4-(2-Hydroxymethyl-4-methyl-phenylamino)-piperidin-1-yl]-N-[4-(hydroxy-phenyl-methyl)-phenyl]-acetamide 41 2-[4-(4-Fluoro-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-[4-(hydroxy-phenyl-methyl)-phenyl]-acetamide 42 2-[4-(2-Hydroxymethyl-6-methoxy-phenylamino)-piperidin-1-yl]-N-[4-(hydroxy-phenyl-methyl)-phenyl]-acetamide 43 2-[4-(3-Chloro-2-hydroxytnethyl-phenylamino)-piperidin-1-yl]-N-[4-(hydroxy-phenyl-methyl)-phenyl]-acetamide 44 2-[4-(2-Hydroxymethyl-phenylamino)-piperidin-1-yl]-N-(9-oxo-9H-fluoren-3-yl)-acetamide 45 2-[4-(4-Chloro-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-(9-oxo-9H-fluoren-3-yl)-acetamide 46 2-[4-(4-Fluoro-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-(9-oxo-9H-fluoren-3-yl)-acetamide 47 2-[4-(2-Hydroxymethyl-6-methoxy-phenylamino)-piperidin-1-yl]-N-(9-oxo-9H-fluoren-3-yl)-acetamide 48 2-[4-(4,5-Difluoro-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-(9-oxo-9H-fluoren-3-yl)-acetamide 49 2-[4-(3-Chloro-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-(9-oxo-9H-fluoren-3-yl)-acetamide 50 N-(9-Hydroxy-9H-fluoren-3-yl)-2-[4-(2-hydroxymethyl-phenylamino)-piperidin-1-yl]-acetamide 51 2-[4-(4-Chloro-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-(9-hydroxy-9H-fluoren-3-yl)-acetamide 52 2-[4-(4-Fiuoro-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-(9-hydroxy-9H-fluoren-3-yl)-acetamide 53 N-(9-Hydroxy-9H-fluoren-3-yl)-2-[4-(2-hydroxymethyl-6-methoxy-phenylamino)-piperidin-1-yl]-acetamide 54 2-[4-(4,5-Difluoro-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-(9-hydroxy-9H-fluoren-3-yl)-acetamide 55 2-[4-(3-Chloro-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-(9-hydroxy-9H-fluoren-3-yl)-acetamide 56 N-(3-Acetyl-phenyl)-2-[4-(2-hydroxymethyl-phenylamino)-piperidin-1-yl]-acetamide 57 N-(3-Acetyl-phenyl)-2-[4-(2-hydroxymethyi-6-methyl-phenylamino)-piperidin-1-yl]-acetamide 58 N-(3-Acetyl-phenyl)-2-[4-(4-chloro-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-acetamide 59 N-(3-Acetyl-phenyl)-2-[4-(2-hydroxymethyl-4-methyl-phenylamino)-piperidin-1-yl]-acetamide 60 N-[3-(1-Hydroxy-ethyl)-phenyl]-2-[4-(2-hydroxymethyl-phenylamino)-piperidin-1-yl]-acetamide 61 N-[3-(1-Hydroxy-ethyl)-phenyl]-2-[4-(2-hydroxymethyl-6-methyl-phenylamino)-piperidin-1-yl]-acetamide 62 2-[4-(4-Chloro-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-[3-(1-hydroxy-ethyl)-phenyl]-acetamide 63 N-[3-(1-Hydroxy-ethyl)-phenyl]-2-[4-(2-hydroxymethyl-4-methyl-phenylamino)-piperidin-1-yl]-acetamide 64 N-Benzo[1,3]dioxol-5-yl-2-[4-(4-chloro-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-acetamide 65 N-Benzo[1,3]dioxol-5-yl-2-[4-(4-fluoro-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-acetamide 66 N-Benzo[1,3] dioxol-5-yl-2-[4-(2-hydroxymethyl-6-methoxy-phenylamino)-piperidin-1-yl]-acetamide 67 N-Benzo[1,3]dioxol-5-yl-2-[4-(4,5-difluoro-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-acetamide 68 N-Benzo[1,3]dioxol-5-yl-2-[4-(3-chloro-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-acetamide 69 N-(4-Acetyl-phenyl)-2-[4-(2-hydroxymethyl-phenylamino)-piperidin-1-yl]-acetamide 70 N-(4-Acetyl-phenyl)-2-[4-(2-hydroxymethyl-6-methyl-phenylamino)-piperidin-1-yl]-acetamide 71 N-(4-Acetyl-phenyl)-2-[4-(4-chloro-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-acetamide 72 N-(4-Acetyl-phenyl)-2-[4-(2-hydroxymethyl-4-methyl-phenylamino)-piperidin-1-yl]-acetamide 73 N-(4-Acetyl-phenyl)-2-[4-(4-fluoro-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-acetamide 74 N-(4-Acetyl-phenyl)-2-[4-(2-hydroxymethyl-6-methoxy-phenylamino)-piperidin-1-yl]-acetamide 75 N-(4-Acetyl-phenyl)-2-[4-(3-chloro-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-acetamide 76 N-[4-(1-Hydroxy-ethyl)-phenyl]-2-[4-(2-hydroxymethyl-phenylamino)-piperidin-1-yl]-acetamide 77 N-[4-(1-Hydroxy-ethyl)-phenyl]-2-[4-(2-hydroxymethyl-6-methyl-phenylamino)-piperidin-1-yl]-acetamide 78 2-[4-(4-Chloro-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-[4-(1-hydroxy-ethyl)-phenyl]-acetamide 79 N-[4-(1-Hydroxy-ethyl)-phenyl]-2-[4-(2-hydroxymethyl-4-methyl-phenylamino)-piperidin-1-yl]-acetamide 80 2-[4-(4-Fluoro-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-[4-(1-hydroxy-ethyl)-phenyl]-acetamide 81 N-[4-(1-Hydroxy-ethyl)-phenyl]-2-[4-(2-hydroxymethyl-6-methOxy-phenylamino)-piperidin-1-yl]-acetamide 82 2-[4-(3-Chloro-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-[4-(1-hydroxy-ethyl)-phenyl-acetamide 83 N-(9-Ethyl-9H-carbazol-3-yl)-2-[4-(2-hydroxymethyl-phenylamino)-piperidin-1-yl]-acetamide 84 2-[4-(4-Chloro-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-(9-ethyl-9H-carbazol-3-yl)-acetamide 85 N-(9-Ethyl-9H-carbazol-3-yl)-2-[4-(2-hydroxymethyl-4-methyl-phenylamino)-piperidin-1-yl]-acetamide 86 N-(9-Ethyl-9H-carbazol-3-yl)-2-[4-(4-fluoro-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-acetamide 87 N-(9-Ethyl-9H-carbazol-3-yl)-2-[4-(2-hydroxymethyl-6-methoxy-phenylamino)-piperidin-1-yl]-acetamide 88 2-[4-(4,5-Difluoro-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-(9-ethyl-9H-carbazol-3-yl)-acetamide 89 2-[4-(3-Chloro-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-(9-ethyl-9H-carbazol-3-yl)-acetamide 90 2-[4-(2-Hydroxymethyl-phenylamino)-piperidin-1-yl]-N-(9-methyl-9H-carbazol-3-yl)-acetamide 91 2-[4-(2-Hydroxymethyl-6-methyl-phenylamino)-piperidin-1-yl]-N-(9-methyl-9H-carbazol-3-yl)-acetamide 92 2-[4-(4-Chloro-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-(9-methyl-9H-carbazol-3-yl)-acetamide 93 2-[4-(2-Hydroxymethyl-4-methyl-phenylamino)-piperidin-1-yl]-N-(9-methyl-9H-carbazol-3-yl)-acetamide 94 2-[4-(2-Hydroxymethyl-phenylamino)-piperidin-1-yl]-N-(5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yl)-acetamide 95 2-[4-(2-Hydroxymethyl-6-methyl-phenylamino)-piperidin-1-yl]-N-(5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yl)acetamide 96 2-[4-(4-Chloro-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-(5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yl)acetamde 97 2-[4-(2-Hydroxymethyl-4-methyl-phenylamino)-piperidin-1-yl]-N-(5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yl)acetamide 98 2-[4-(4-Fluoro-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-(5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yl)acetamide 99 2-[4-(2-Hydroxymethyl-phenylamino)-piperidin-1-yl]-N-(5-hydroxy-5,6,7,8-tetrahydro-naphthalen-2-yl)-acetamide 100 2-[4-(2-Hydroxymethyl-6-methyl-phenylamino)-piperidin-1-yl]-N-(5-hydroxy-5,6,7,8-tetrahydro-naphthalen-2-yl)acetamde 101 2-[4-(4-Chloro-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-(5-hydroxy-5,6,7,8-tetrahydro-naphthalen-2-yl)acetamide 102 2-[4-(2-Hydroxymethyl-4-methyl-phenylamino)-piperidin-1-yl]-N-(5-hydroxy-5,6,7,8-tetrahydro-naphthalen-2-yl)acetamide 103 2-[4-(4-Fluoro-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-(5-hydroxy-5,6,7,8-tetrahydro-naphthalen-2-yl) 104 2-[4-(2-Hydroxymethyl-6-methyl-phenylamino)-piperidin-1-yl]-N-(1-oxo-indan-5-yl)-acetamide 105 2-[4-(4-Chloro-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-(1-oxo-indan-5-yl)-acetamide 106 2-[4-(2-Hydroxymethyl-4-methyl-phenylamino)-piperidin-1-yl]-N-(1-oxo-indan-5-yl)-acetamide 107 N-(1-Hydroxy-indan-5-yl)-2-[4-(2-hydroxymethyl-phenylamino)-piperidin-1-yl]-acetamide 108 N-(1-Hydroxy-indan-5-yl)-2-[4-(2-hydroxymethyl-6-methyl-phenylamino)-piperidin-1-yl]-acetamide 109 2-[4-(4-Chloro-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-(1-hydroxy-indan-5-yl)-acetamide 110 N-(1-Hydroxy-indan-5-yl)-2-[4-(2-hydroxymethyl-4-methyl-phenylamino)-piperidin-1-yl]-acetamide 111 2-[4-(4-Bromo-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-(9-ethYl-9H-carbazol-3-yl)-acetamide 112 2-[4-(2-Hydroxymethyl-6-methyl-phenylamino)-piperidin-1-yl]-N-(9-oxo-9H-fluoren-2-yl)-acetamide 113 2-[4-(2-Hydroxymethyl-4-methyl-phenylamino)-piperidin-1-yl]-N-(9-oxo-9H-fluoren-2-YI)-acetamide 114 N-Dibenzofuran-2-yl-2-[4-(2-hydroxymethyl-4-methyl-phenylamino)-piperidin-1-yl]-acetamide 115 N-Dibenzofuran-2-yl-2-[4-(2-hydroxymethyl-6-methyl-phenylamino)-piperidin-1-yl]-acetamide 116 2-[4-(2-Hydroxymethyl-6-methoxy-phenylamino)-piperidin-1-yl]-N-quinolin-3-yl-acetamide 117 2-[4-(4,5-Difluoro-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-quinolin-3-yl-acetamide 118 N-(9-Hydroxy-9H-fluoren-2-yl)-2-[4-(2-hydroxymethyl-6-methyl-phenylamino)-piperidin-1-yl]-acetamide 119 N-(9-Hydroxy-9H-fluoren-2-yl)-2-[4-(2-hydroxymethyl-4-methyl-phenylamino)-piperidin-1-yl]-acetamide 120 2-[4-(2-Hydroxymethyl-phenylamino)-piperidin-1-yl]-N-(4-phenoxy-phenyl)-acetamide 121 2-[4-(2-Hydroxymethyl-6-methyl-phenylamino)-piperidin-1-yl]-N-(4-phenoxy-phenyl)-acetamide 122 2-[4-(4-Chloro-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-(4-phenoxy-phenyl)-acetamide 123 2-[4-(2-Hydroxymethyl-4-methyl-phenylamino)-piperidin-1-yl]-N-(4-phenoxy-phenyl)-acetamide 124 N-(4-Cyclohexyl-phenyl)-2-[4-(2-hydroxymethyl-phenylamino)-piperidin-1-yl]-acetamide 125 2-[4-(2-Hydroxymethyl-3-methoxy-phenylamino)-piperidin-1-yl]-N-quinolin-3-yl-acetamide 126 2-[4-(3-Hydroxy-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-quinolin-3-yl-acetamide 127 2-[4-(4-Hydroxy-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-quinolin-3-yl-acetamide 128 2-[4-(2-Hydroxy-6-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-quinolin-3-yl-acetamide 129 2-[4-(2-Hydroxymethyl-3-methoxy-phenylamino)-piperidin-1-yl]-N-quinolin-6-yl-acetamide 130 2-[4-(3-Hydroxy-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-quinolin-6-yl-acetamide 131 2-[4-(4-Hydroxy-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-quinolin-6-yl-acetamide 132 2-[4-(2-Hydroxy-6-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-quinolin-6-yl-acetamide 133 N-(4-Benzoyl-phenyl)-2-[4-(2-hydroxymethyl-3-methoxy-phenylamino)-piperidin-1-yl]-acetamide 134 N-(4-Benzoyl-phenyl)-2-[4-(3-hydroxy-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-acetamide 135 N-(4-Benzoyl-phenyl)-2-[4-(4-hydroxy-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-acetamide 136 N-(4-Benzoyl-phenyl)-2-[4-(2-hydroxy-6-hydroxymethyl-phenylamino)-piperidin-1-yl]-acetamide 137 2-[4-(2-Hydroxymethyl-3-methoxy-phenylamino)-piperidin-1-yl]-N-[4-(hydroxy-phenyl-methyl)-phenyl]-acetamide 138 2-[4-(3-Hydroxy-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-[4-(hydroxy-phenyl-methyl)-phenyl]-acetamide 139 2-[4-(4-Hydroxy-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-[4-(hydroxy-phenyl-methyl)-phenyl-acetamide 140 2-[4-(2-Hydroxy-6-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-[4-(hydroxy-phenyl-methyl)-phenyl]-acetamide 141 2-[4-(2-Hydroxymethyl-3-methoxy-phenylamino)-piperidin-1-yl]-N-(9-oxo-9H-fluoren-3-yl)-acetamide 142 2-[4-(3-Hydroxy-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-(9-oxo-9H-fluoren-3-yl)-acetamide 143 2-[4-(4-Hydroxy-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-(9-oxo-9H-fluoren-3-yl)-acetamide 144 2-[4-(2-Hydroxy-6-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-(9-oxo-9H-fluoren-3-yl)-acetamide 145 N-(9-Hydroxy-9H-fluoren-3-yl)-2-[4-(2-hydroxymethyl-3-methoxy-phenylamino)-piperidin-1-yl]-acetamide 146 N-(9-Hydroxy-9H-fluoren-3-yl)-2-[4-(3-hydroxy-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-acetamide 147 N-(9-Hydroxy-9H-fluoren-3-yl)-2-[4-(4-hydroxy-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-acetamide 148 N-(9-Hydroxy-9H-fluoren-3-yl)-2-[4-(2-hydroxy-6-hydroxymethyl-phenylamino)-piperidin-1-yl]-acetamide 149 N-(3-Acetyl-phenyl)-2-[4-(2-hydroxymethyl-3-methoxy-phenylamino)-piperidin-1-yl]-acetamide 150 N-(3-Acetyl-phenyl)-2-[4-(3-hydroxy-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-acetamide 151 N-(3-Acetyl-phenyl)-2-[4-(4-hydroxy-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-acetamide 152 N-(3-Acetyl-phenyl)-2-[4-(2-hydroxy-6-hydroxymethyl-phenylamino)-piperidin-1-yl]-acetamide 153 N-[3-(1-Hydroxy-ethyl)-phenyl]-2-[4-(2-hydroxymethyl-3-methoxy-phenylamino)-piperidin-1-yl]-acetamide 154 N-[3-(1-Hydroxy-ethyl)-phenyl]-2-[4-(3-hydroxy-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-acetamide 155 N-3-(1-Hydroxy-ethyl)-phenyl]-2-[4-(4-hydroxy-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-acetamide 156 N-[3-(1-Hydroxy-ethyl)-phenyl]-2-[4-(2-hydroxy-6-hydroxymethyl-phenylamino)-piperidin-1-yl]-acetamide 157 N-(4-Acetyl-phenyl)-2-[4-(2-hydroxymethyl-3-methoxy-phenylamino)-piperidin-1-yl]-acetamide 158 N-(4-Acetyl-phenyl)-2-[4-(3-hydroxy-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-acetamide 159 N-(4-Acetyl-phenyl)-2-[4-(4-hydroxy-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-acetamide 160 N-(4-Acetyl-phenyl)-2-[4-(2-hydroxy-6-hydroxymethyl-phenylamino)-piperidin-1-yl]-acetamide 161 N-[4-(1-Hydroxy-ethyl)-phenyl]-2-[4-(2-hydroxymethyl-3-methoxy-phenylamino)-piperidin-1-yl]-acetamide 162 N-[4-(1-Hydroxy-ethyl)-phenyl]-2-[4-(3-hydroxy-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-acetamide 163 N-[4-(1-Hydroxy-ethyl)-phenyl]-2-[4-(4-hydroxy-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-acetamide 164 N-[4-(1-Hydroxy-ethyl)-phenyl]-2-[4-(2-hydroxy-6-hydroxymethyl-phenylamino)-piperidin-1-yl]-acetamide 165 N-(9-Ethyl-9H-carbazol-3-yl)-2-[4-(2-hydroxymethyl-3-methoxy-phenylamino)-piperidin-1-yl]-acetamide 166 N-(9-Ethyl-9H-carbazol-3-yl)-2-[4-(3-hydroxy-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-acetamide 167 N-(9-Ethyl-9H-carbazol-3-yl)-2-[4-(4-hydroxy-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-acetamide 168 N-(9-Ethyl-9H-carbazol-3-yl)-2-[4-(2-hydroxy-6-hydroxymethyl-phenylamino)-piperidin-1-yl]-acetamide 169 2-[4-(2-Hydroxymethyl-3-methoxy-phenylamino)-piperidin-1-yl]-N-(5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yl)acetamide 170 2-[4-(3-Hydroxy-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-(5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yl)acetamde 171 2-[4-(4-Hydroxy-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-(5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yl)acetamide 172 2-[4-(2-Hydroxy-6-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-(5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yl)acetamide 173 2-[4-(2-Hydroxymethyl-3-methoxy-phenylamino)-piperidin-1-yl]-N-(5-hydroxy-5,6,7,8-tetrahydro-naphthalen-2-yl)acetamide 174 2-[4-(3-Hydroxy-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-(5-hydroxy-5,6,7,8-tetrahydro-naphthalen-2-yl)acetamide 175 2-[4-(4-Hydroxy-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-(5-hydroxy-5,6,7,8-tetrahydro-naphthalen-2-yl)acetamide 176 2-[4-(2-Hydroxy-6-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-(5-hydroxy-5,6,7,8-tetrahydro-naphthalen-2-yl)acetamide 177 2-[4-(2-Hydroxymethyl-3-methoxy-phenylamino)-piperidin-1-yl]-N-(4-phenoxy-phenyl)-acetamide 178 2-[4-(3-Hydroxy-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-(4-phenoxy-phenyl)-acetamide 179 2-[4-(4-Hydroxy-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-(4-phenoxy-phenyl)-acetamide 180 2-[4-(2-Hydroxy-6-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-(4-phenoxy-phenyl)-acetamide
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.
62. The process of claim 57, wherein R1, R2, R3, R4 are each independently selected from the group consisting of H, F, Cl, Br, OH, CH3, and OCH3, B represents a —CH2—OH or —(C═O)—O—CH3 group,
R11 is selected from the group consisting of unsubstituted phenyl, phenyl that is optionally at least mono-substituted with one or more substituents independently selected from the group consisting of cyclohexyl, phenyl, phenoxy, benzoyl, —C(═O)—C1-2-alkyl, —C(H)(OH)(phenyl) and —C(H)(OH)(CH3),
a group of formula (A)
Figure US20110172270A1-20110714-C00252
wherein
n is 1 or 2,
X represents CH,
Y represents CH—OH or C(═O),
a group of formula (B),
Figure US20110172270A1-20110714-C00253
a group of formula (C),
Figure US20110172270A1-20110714-C00254
and a group of formula (E),
Figure US20110172270A1-20110714-C00255
wherein
RE represents H, a branched or unbranched C1-4-alkyl radical or a branched or unbranched C1-4-alkoxy radical,
Z represents CH2, O, S, CH—OH, C(═O) or N—RF where RF represents H or a branched or unbranched C1-4-alkyl-radical,
optionally in form of one of its stereoisomers, its racemate or in form of a mixture of at least two of its stereoisomers, or a salt.
63. The process according to claim 57, wherein the 1,4-disubstituted compound of general formula (I) is selected from the group consisting of:
1 2-[4-(2-Hydroxymethyl-phenylamino)-piperidin-1-yl]-N-quinolin-3-yl-acetamide 2 2-[4-(2-Hydroxymethyl-phenylamino)-piperidin-1-yl]-N-quinolin-5-yl-acetamide 3 2-[4-(2-Hydroxymethyl-phenylamino)-piperidin-1-yl]-N-quinolin-6-yl-acetamide 4 2-[4-(2-Hydroxymethyl-phenylamino)-piperidin-1-yl]-N-quinolin-8-yl-acetamide 5 2-[4-(2-Hydroxymethyl-4-methyl-phenylamino)-piperidin-1-yl]-N-quinolin-3-yl-acetamide 6 2-[4-(2-Hydroxymethyl-4-methyl-phenylamino)-piperidin-1-yl]-N-quinolin-5-yl-acetamide 7 2-[4-(2-Hydroxymethyl-4-methyl-phenylamino)-piperidin-1-yl]-N-quinolin-6-yl-acetamide 8 2-[4-(2-Hydroxymethyl-4-methyl-phenylamino)-piperidin-1-yl]-N-quinolin-8-yl-acetamide 9 2-[4-(2-Hydroxymethyl-6-methyl-phenylamino)-piperidin-1-yl]-N-quinolin-3-yl-acetamide 10 2-[4-(2-Hydroxymethyl-6-methyl-phenylamino)-piperidin-1-yl]-N-quinolin-5-yl-acetamide 11 2-[4-(2-Hydroxymethyl-6-methyl-phenylamino)-piperidin-1-yl]-N-quinolin-6-yl-acetamide 12 2-[4-(2-Hydroxymethyl-6-methyl-phenylamino)-piperidin-1-yl]-N-quinolin-8-yl-acetamide 13 N-(4-Benzoyl-phenyl)-2-[4-(2-hydroxymethyl-phenylamino)-piperidin-1-yl]-acetamide 14 N-(4-Benzoyl-phenyl)-2-[4-(2-hydroxymethyl-4-methyl-phenylamino)-piperidin-1-yl]-acetamide 15 N-(4-Benzoyl-phenyl)-2-[4-(2-hydroxymethyl-6-methyl-phenylamino)-piperidin-1-yl]-acetamide 16 N-Benzo[1,3] dioxol-5-yl-2-[4-(2-hydroxymethyl-phenylamino)-piperidin-1-yl]-acetamide 17 N-Benzo[1,3]dioxol-5-yl-2-[4-(2-hydroxymethyl-4-methyl-phenylamino)-piperidin-1-yl]- acetamide 18 N-Benzo[1,3]dioxol-5-yl-2-[4-(2-hydroxymethyl-6-methyl-phenylamino)-piperidin-1-yl]- acetamide hydrochloride 19 2-[4-(4-Chioro-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-quinolin-3-yl-acetamide 20 2-[4-(4-Fluoro-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-quinolin-3-yl-acetamide 21 2-[4-(3-Chloro-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-quinolin-3-yl-acetamide 22 2-[4-(4-Chloro-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-quinolin-5-yl-acetamide 23 2-[4-(4-Fluoro-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-quinolin-5-yl-acetamide 24 2-[4-(3-Chloro-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-quinolin-5-yl-acetamide 25 2-[4-(4-Chloro-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-quinolin-6-yl-acetamide 26 2-[4-(4-Fluoro-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-quinolin-6-yl-acetamide 27 2-[4-(3-Chloro-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-quinolin-6-yl-acetamide 28 2-[4-(2-Hydroxymethyl-6-methoxy-phenylamino)-piperidin-1-yl]-N-quinolin-6-yl-acetamide 29 2-[4-(4,5-Difluoro-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-quinolin-6-yl-acetamide 30 2-[4-(4-Chloro-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-quinolin-8-yl-acetamide 31 2-[4-(4-Fluoro-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-quinolin-8-yl-acetamide 32 2-[4-(3-Chloro-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-quinolin-8-yl-acetamide 33 N-(4-Benzoyl-phenyl)-2-[4-(4-chloro-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-acetamide 34 N-(4-Benzoyl-phenyl)-2-[4-(4-fluoro-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-acetamide 35 N-(4-Benzoyl-phenyl)-2-[4-(2-hydroxymethyl-6-methoxy-phenylamino)-piperidin-1-yl]-acetamide 36 N-(4-Benzoyl-phenyl)-2-14-(3-chloro-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-acetamide 37 2-[4-(2-Hydroxymethyl-phenylamino)-piperidin-1-yl]-N-[4-(hydroxy-phenyl-methyl)- phenyl]-acetamide 38 2-[4-(2-Hydroxymethyl-6-methyl-phenylamino)-piperidin-1-yl]-N-[4-(hydroxy-phenyl- methyl)-phenyl]-acetamide 39 2-[4-(4-Chloro-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-[4-(hydroxy-phenyl- methyl)-phenyl]-acetamide 40 2-[4-(2-Hydroxymethyl-4-methyl-phenylamino)-piperidin-1-yl]-N-[4-(hydroxy-phenyl- methyl)-phenyl]-acetamide 41 2-[4-(4-Fluoro-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-[4-(hydroxy-phenyl- methyl)-phenyl]-acetamide 42 2-[4-(2-Hydroxymethyl-6-methoxy-phenylamino)-piperidin-1-yl]-N-[4-(hydroxy-phenyl- methyl)-phenyl]-acetamide 43 2-[4-(3-Chloro-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-[4-(hydroxy-phenyl- methyl)-phenyl]-acetamide 44 2-[4-(2-Hydroxymethyl-phenylamino)-piperidin-1-yl]-N-(9-oxo-9H-fluoren-3-yl)-acetamide 45 2-[4-(4-Chloro-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-(9-oxo-9H-fluoren-3- yl)-acetamide 46 2-[4-(4-Fluoro-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-(9-oxo-9H-fluoren-3- yl)-acetamide 47 2-[4-(2-Hydroxymethyl-6-methoxy-phenylamino)-piperidin-1-yl]-N-(9-oxo-9H-fluoren-3- yl)-acetamide 48 2-[4-(4,5-Difluoro-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-(9-oxo-9H-fluoren- 3-yl)-acetamide 49 2-[4-(3-Chloro-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-(9-oxo-9H-fluoren-3- yl)-acetamide 50 N-(9-Hydroxy-9H-fluoren-3-yl)-2-[4-(2-hydroxymethyl-phenylamino)-piperidin-1-yl]-acetamide 51 2-[4-(4-Chloro-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-(9-hydroxy-9H-fluoren- 3-yl)-acetamide 52 2-[4-(4-Fiuoro-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-(9-hydroxy-9H-fluoren- 3-yl)-acetamide 53 N-(9-Hydroxy-9H-fluoren-3-yl)-2-[4-(2-hydroxymethyl-6-methoxy-phenylamino)- piperidin-1-yl]-acetamide 54 2-[4-(4,5-Difluoro-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-(9-hydroxy-9H- fluoren-3-yl)-acetamide 55 2-[4-(3-Chloro-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-(9-hydroxy-9H-fluoren- 3-yl)-acetamide 56 N-(3-Acetyl-phenyl)-2-[4-(2-hydroxymethyl-phenylamino)-piperidin-1-yl]-acetamide 57 N-(3-Acetyl-phenyl)-2-[4-(2-hydroxymethyi-6-methyl-phenylamino)-piperidin-1-yl]-acetamide 58 N-(3-Acetyl-phenyl)-2-[4-(4-chloro-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-acetamide 59 N-(3-Acetyl-phenyl)-2-[4-(2-hydroxymethyl-4-methyl-phenylamino)-piperidin-1-yl]-acetamide 60 N-[3-(1-Hydroxy-ethyl)-phenyl]-2-[4-(2-hydroxymethyl-phenylamino)-piperidin-1-yl]- acetamide 61 N-[3-(1-Hydroxy-ethyl)-phenyl]-2-[4-(2-hydroxymethyl-6-methyl-phenylamino)- piperidin-1-yl]-acetamide 62 2-[4-(4-Chloro-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-[3-(1-hydroxy-ethyl)- phenyl]-acetamide 63 N-[3-(1-Hydroxy-ethyl)-phenyl]-2-[4-(2-hydroxymethyl-4-methyl-phenylamino)- piperidin-1-yl]-acetamide 64 N-Benzo[1,3]dioxol-5-yl-2-[4-(4-chloro-2-hydroxymethyl-phenylamino)-piperidin-1-yl]- acetamide 65 N-Benzo[1,3]dioxol-5-yl-2-[4-(4-fluoro-2-hydroxymethyl-phenylamino)-piperidin-1-yl]- acetamide 66 N-Benzo[1,3] dioxol-5-yl-2-[4-(2-hydroxymethyl-6-methoxy-phenylamino)-piperidin-1- yl]-acetamide 67 N-Benzo[1,3]dioxol-5-yl-2-[4-(4,5-difluoro-2-hydroxymethyl-phenylamino)-piperidin-1- yl]-acetamide 68 N-Benzo[1,3]dioxol-5-yl-2-[4-(3-chloro-2-hydroxymethyl-phenylamino)-piperidin-1-yl]- acetamide 69 N-(4-Acetyl-phenyl)-2-[4-(2-hydroxymethyl-phenylamino)-piperidin-1-yl]-acetamide 70 N-(4-Acetyl-phenyl)-2-[4-(2-hydroxymethyl-6-methyl-phenylamino)-piperidin-1-yl]-acetamide 71 N-(4-Acetyl-phenyl)-2-[4-(4-chloro-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-acetamide 72 N-(4-Acetyl-phenyl)-2-[4-(2-hydroxymethyl-4-methyl-phenylamino)-piperidin-1-yl]-acetamide 73 N-(4-Acetyl-phenyl)-2-[4-(4-fluoro-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-acetamide 74 N-(4-Acetyl-phenyl)-2-[4-(2-hydroxymethyl-6-methoxy-phenylamino)-piperidin-1-yl]-acetamide 75 N-(4-Acetyl-phenyl)-2-[4-(3-chloro-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-acetamide 76 N-[4-(1-Hydroxy-ethyl)-phenyl]-2-[4-(2-hydroxymethyl-phenylamino)-piperidin-1-yl]- acetamide 77 N-[4-(1-Hydroxy-ethyl)-phenyl]-2-[4-(2-hydroxymethyl-6-methyl-phenylamino)- piperidin-1-yl]-acetamide 78 2-[4-(4-Chloro-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-[4-(1-hydroxy-ethyl)- phenyl]-acetamide 79 N-[4-(1-Hydroxy-ethyl)-phenyl]-2-[4-(2-hydroxymethyl-4-methyl-phenylamino)- piperidin-1-yl]-acetamide 80 2-[4-(4-Fluoro-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-[4-(1-hydroxy-ethyl)- phenyl]-acetamide 81 N-[4-(1-Hydroxy-ethyl)-phenyl]-2-[4-(2-hydroxymethyl-6-methOxy-phenylamino)-pipe ridin-1-yl]-acetamide 82 2-[4-(3-Chloro-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-[4-(1-hydroxy-ethyl)- phenyl-acetamide 83 N-(9-Ethyl-9H-carbazol-3-yl)-2-[4-(2-hydroxymethyl-phenylamino)-piperidin-1-yl]- acetamide 84 2-[4-(4-Chloro-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-(9-ethyl-9H-carbazol-3- yl)-acetamide 85 N-(9-Ethyl-9H-carbazol-3-yl)-2-[4-(2-hydroxymethyl-4-methyl-phenylamino)-piperidin- 1-yl]-acetamide 86 N-(9-Ethyl-9H-carbazol-3-yl)-2-[4-(4-fluoro-2-hydroxymethyl-phenylamino)-piperidin-1- yl]-acetamide 87 N-(9-Ethyl-9H-carbazol-3-yl)-2-[4-(2-hydroxymethyl-6-methoxy-phenylamino)- piperidin-1-yl]-acetamide 88 2-[4-(4,5-Difluoro-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-(9-ethyl-9H- carbazol-3-yl)-acetamide 89 2-[4-(3-Chloro-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-(9-ethyl-9H-carbazol-3- yl)-acetamide 90 2-[4-(2-Hydroxymethyl-phenylamino)-piperidin-1-yl]-N-(9-methyl-9H-carbazol-3-yl)-acetamide 91 2-[4-(2-Hydroxymethyl-6-methyl-phenylamino)-piperidin-1-yl]-N-(9-methyl-9H- carbazol-3-yl)-acetamide 92 2-[4-(4-Chloro-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-(9-methyl-9H-carbazol- 3-yl)-acetamide 93 2-[4-(2-Hydroxymethyl-4-methyl-phenylamino)-piperidin-1-yl]-N-(9-methyl-9H- carbazol-3-yl)-acetamide 94 2-[4-(2-Hydroxymethyl-phenylamino)-piperidin-1-yl]-N-(5-oxo-5,6,7,8-tetrahydro- naphthalen-2-yl)-acetamide 95 2-[4-(2-Hydroxymethyl-6-methyl-phenylamino)-piperidin-1-yl]-N-(5-oxo-5,6,7,8- tetrahydro-naphthalen-2-yl)acetamide 96 2-[4-(4-Chloro-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-(5-oxo-5,6,7,8- tetrahydro-naphthalen-2-yl)acetamde 97 2-[4-(2-Hydroxymethyl-4-methyl-phenylamino)-piperidin-1-yl]-N-(5-oxo-5,6,7,8- tetrahydro-naphthalen-2-yl)acetamide 98 2-[4-(4-Fluoro-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-(5-oxo-5,6,7,8- tetrahydro-naphthalen-2-yl)acetamide 99 2-[4-(2-Hydroxymethyl-phenylamino)-piperidin-1-yl]-N-(5-hydroxy-5,6,7,8-tetrahydro- naphthalen-2-yl)-acetamide 100 2-[4-(2-Hydroxymethyl-6-methyl-phenylamino)-piperidin-1-yl]-N-(5-hydroxy-5,6,7,8- tetrahydro-naphthalen-2-yl)acetamde 101 2-[4-(4-Chloro-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-(5-hydroxy-5,6,7,8- tetrahydro-naphthalen-2-yl)acetamide 102 2-[4-(2-Hydroxymethyl-4-methyl-phenylamino)-piperidin-1-yl]-N-(5-hydroxy-5,6,7,8- tetrahydro-naphthalen-2-yl)acetamide 103 2-[4-(4-Fluoro-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-(5-hydroxy-5,6,7,8- tetrahydro-naphthalen-2-yl) 104 2-[4-(2-Hydroxymethyl-6-methyl-phenylamino)-piperidin-1-yl]-N-(1-oxo-indan-5-yl)- acetamide 105 2-[4-(4-Chloro-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-(1-oxo-indan-5-yl)- acetamide 106 2-[4-(2-Hydroxymethyl-4-methyl-phenylamino)-piperidin-1-yl]-N-(1-oxo-indan-5-yl)- acetamide 107 N-(1-Hydroxy-indan-5-yl)-2-[4-(2-hydroxymethyl-phenylamino)-piperidin-1-yl]-acetamide 108 N-(1-Hydroxy-indan-5-yl)-2-[4-(2-hydroxymethyl-6-methyl-phenylamino)-piperidin-1- yl]-acetamide 109 2-[4-(4-Chloro-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-(1-hydroxy-indan-5- yl)-acetamide 110 N-(1-Hydroxy-indan-5-yl)-2-[4-(2-hydroxymethyl-4-methyl-phenylamino)-piperidin-1- yl]-acetamide 111 2-[4-(4-Bromo-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-(9-ethYl-9H-carbazol- 3-yl)-acetamide 112 2-[4-(2-Hydroxymethyl-6-methyl-phenylamino)-piperidin-1-yl]-N-(9-oxo-9H-fluoren-2- yl)-acetamide 113 2-[4-(2-Hydroxymethyl-4-methyl-phenylamino)-piperidin-1-yl]-N-(9-oxo-9H-fluoren-2- YI)-acetamide 114 N-Dibenzofuran-2-yl-2-[4-(2-hydroxymethyl-4-methyl-phenylamino)-piperidin-1-yl]- acetamide 115 N-Dibenzofuran-2-yl-2-[4-(2-hydroxymethyl-6-methyl-phenylamino)-piperidin-1-yl]- acetamide 116 2-[4-(2-Hydroxymethyl-6-methoxy-phenylamino)-piperidin-1-yl]-N-quinolin-3-yl-acetamide 117 2-[4-(4,5-Difluoro-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-quinolin-3-yl-acetamide 118 N-(9-Hydroxy-9H-fluoren-2-yl)-2-[4-(2-hydroxymethyl-6-methyl-phenylamino)- piperidin-1-yl]-acetamide 119 N-(9-Hydroxy-9H-fluoren-2-yl)-2-[4-(2-hydroxymethyl-4-methyl-phenylamino)- piperidin-1-yl]-acetamide 120 2-[4-(2-Hydroxymethyl-phenylamino)-piperidin-1-yl]-N-(4-phenoxy-phenyl)-acetamide 121 2-[4-(2-Hydroxymethyl-6-methyl-phenylamino)-piperidin-1-yl]-N-(4-phenoxy-phenyl)-acetamide 122 2-[4-(4-Chloro-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-(4-phenoxy-phenyl)-acetamide 123 2-[4-(2-Hydroxymethyl-4-methyl-phenylamino)-piperidin-1-yl]-N-(4-phenoxy-phenyl)-acetamide 124 N-(4-Cyclohexyl-phenyl)-2-[4-(2-hydroxymethyl-phenylamino)-piperidin-1-yl]-acetamide 125 2-[4-(2-Hydroxymethyl-3-methoxy-phenylamino)-piperidin-1-yl]-N-quinolin-3-yl-acetamide 126 2-[4-(3-Hydroxy-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-quinolin-3-yl-acetamide 127 2-[4-(4-Hydroxy-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-quinolin-3-yl-acetamide 128 2-[4-(2-Hydroxy-6-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-quinolin-3-yl-acetamide 129 2-[4-(2-Hydroxymethyl-3-methoxy-phenylamino)-piperidin-1-yl]-N-quinolin-6-yl-acetamide 130 2-[4-(3-Hydroxy-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-quinolin-6-yl-acetamide 131 2-[4-(4-Hydroxy-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-quinolin-6-yl-acetamide 132 2-[4-(2-Hydroxy-6-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-quinolin-6-yl-acetamide 133 N-(4-Benzoyl-phenyl)-2-[4-(2-hydroxymethyl-3-methoxy-phenylamino)-piperidin-1-yl]-acetamide 134 N-(4-Benzoyl-phenyl)-2-[4-(3-hydroxy-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-acetamide 135 N-(4-Benzoyl-phenyl)-2-[4-(4-hydroxy-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-acetamide 136 N-(4-Benzoyl-phenyl)-2-[4-(2-hydroxy-6-hydroxymethyl-phenylamino)-piperidin-1-yl]-acetamide 137 2-[4-(2-Hydroxymethyl-3-methoxy-phenylamino)-piperidin-1-yl]-N-[4-(hydroxy-phenyl- methyl)-phenyl]-acetamide 138 2-[4-(3-Hydroxy-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-[4-(hydroxy-phenyl- methyl)-phenyl]-acetamide 139 2-[4-(4-Hydroxy-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-[4-(hydroxy-phenyl- methyl)-phenyl-acetamide 140 2-[4-(2-Hydroxy-6-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-[4-(hydroxy-phenyl- methyl)-phenyl]-acetamide 141 2-[4-(2-Hydroxymethyl-3-methoxy-phenylamino)-piperidin-1-yl]-N-(9-oxo-9H-fluoren-3- yl)-acetamide 142 2-[4-(3-Hydroxy-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-(9-oxo-9H-fluoren-3- yl)-acetamide 143 2-[4-(4-Hydroxy-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-(9-oxo-9H-fluoren-3- yl)-acetamide 144 2-[4-(2-Hydroxy-6-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-(9-oxo-9H-fluoren-3- yl)-acetamide 145 N-(9-Hydroxy-9H-fluoren-3-yl)-2-[4-(2-hydroxymethyl-3-methoxy-phenylamino)- piperidin-1-yl]-acetamide 146 N-(9-Hydroxy-9H-fluoren-3-yl)-2-[4-(3-hydroxy-2-hydroxymethyl-phenylamino)- piperidin-1-yl]-acetamide 147 N-(9-Hydroxy-9H-fluoren-3-yl)-2-[4-(4-hydroxy-2-hydroxymethyl-phenylamino)- piperidin-1-yl]-acetamide 148 N-(9-Hydroxy-9H-fluoren-3-yl)-2-[4-(2-hydroxy-6-hydroxymethyl-phenylamino)- piperidin-1-yl]-acetamide 149 N-(3-Acetyl-phenyl)-2-[4-(2-hydroxymethyl-3-methoxy-phenylamino)-piperidin-1-yl]-acetamide 150 N-(3-Acetyl-phenyl)-2-[4-(3-hydroxy-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-acetamide 151 N-(3-Acetyl-phenyl)-2-[4-(4-hydroxy-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-acetamide 152 N-(3-Acetyl-phenyl)-2-[4-(2-hydroxy-6-hydroxymethyl-phenylamino)-piperidin-1-yl]-acetamide 153 N-[3-(1-Hydroxy-ethyl)-phenyl]-2-[4-(2-hydroxymethyl-3-methoxy-phenylamino)- piperidin-1-yl]-acetamide 154 N-[3-(1-Hydroxy-ethyl)-phenyl]-2-[4-(3-hydroxy-2-hydroxymethyl-phenylamino)- piperidin-1-yl]-acetamide 155 N-3-(1-Hydroxy-ethyl)-phenyl]-2-[4-(4-hydroxy-2-hydroxymethyl-phenylamino)- piperidin-1-yl]-acetamide 156 N-[3-(1-Hydroxy-ethyl)-phenyl]-2-[4-(2-hydroxy-6-hydroxymethyl-phenylamino)- piperidin-1-yl]-acetamide 157 N-(4-Acetyl-phenyl)-2-[4-(2-hydroxymethyl-3-methoxy-phenylamino)-piperidin-1-yl]-acetamide 158 N-(4-Acetyl-phenyl)-2-[4-(3-hydroxy-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-acetamide 159 N-(4-Acetyl-phenyl)-2-[4-(4-hydroxy-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-acetamide 160 N-(4-Acetyl-phenyl)-2-[4-(2-hydroxy-6-hydroxymethyl-phenylamino)-piperidin-1-yl]-acetamide 161 N-[4-(1-Hydroxy-ethyl)-phenyl]-2-[4-(2-hydroxymethyl-3-methoxy-phenylamino)- piperidin-1-yl]-acetamide 162 N-[4-(1-Hydroxy-ethyl)-phenyl]-2-[4-(3-hydroxy-2-hydroxymethyl-phenylamino)- piperidin-1-yl]-acetamide 163 N-[4-(1-Hydroxy-ethyl)-phenyl]-2-[4-(4-hydroxy-2-hydroxymethyl-phenylamino)- piperidin-1-yl]-acetamide 164 N-[4-(1-Hydroxy-ethyl)-phenyl]-2-[4-(2-hydroxy-6-hydroxymethyl-phenylamino)- piperidin-1-yl]-acetamide 165 N-(9-Ethyl-9H-carbazol-3-yl)-2-[4-(2-hydroxymethyl-3-methoxy-phenylamino)- piperidin-1-yl]-acetamide 166 N-(9-Ethyl-9H-carbazol-3-yl)-2-[4-(3-hydroxy-2-hydroxymethyl-phenylamino)-piperidin- 1-yl]-acetamide 167 N-(9-Ethyl-9H-carbazol-3-yl)-2-[4-(4-hydroxy-2-hydroxymethyl-phenylamino)-piperidin- 1-yl]-acetamide 168 N-(9-Ethyl-9H-carbazol-3-yl)-2-[4-(2-hydroxy-6-hydroxymethyl-phenylamino)-piperidin- 1-yl]-acetamide 169 2-[4-(2-Hydroxymethyl-3-methoxy-phenylamino)-piperidin-1-yl]-N-(5-oxo-5,6,7,8- tetrahydro-naphthalen-2-yl)acetamide 170 2-[4-(3-Hydroxy-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-(5-oxo-5,6,7,8- tetrahydro-naphthalen-2-yl)acetamde 171 2-[4-(4-Hydroxy-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-(5-oxo-5,6,7,8- tetrahydro-naphthalen-2-yl)acetamide 172 2-[4-(2-Hydroxy-6-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-(5-oxo-5,6,7,8- tetrahydro-naphthalen-2-yl)acetamide 173 2-[4-(2-Hydroxymethyl-3-methoxy-phenylamino)-piperidin-1-yl]-N-(5-hydroxy-5,6,7,8- tetrahydro-naphthalen-2-yl)acetamide 174 2-[4-(3-Hydroxy-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-(5-hydroxy-5,6,7,8- tetrahydro-naphthalen-2-yl)acetamide 175 2-[4-(4-Hydroxy-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-(5-hydroxy-5,6,7,8- tetrahydro-naphthalen-2-yl)acetamide 176 2-[4-(2-Hydroxy-6-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-(5-hydroxy-5,6,7,8- tetrahydro-naphthalen-2-yl)acetamide 177 2-[4-(2-Hydroxymethyl-3-methoxy-phenylamino)-piperidin-1-yl]-N-(4-phenoxy-phenyl)- acetamide 178 2-[4-(3-Hydroxy-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-(4-phenoxy-phenyl)- acetamide 179 2-[4-(4-Hydroxy-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-(4-phenoxy-phenyl)- acetamide 180 2-[4-(2-Hydroxy-6-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-(4-phenoxy-phenyl)- acetamide
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, preferably a physiologically acceptable salt thereof
US12/985,646 2003-07-30 2011-01-06 2-'4(phenylamino)-piperidin-1-yl!-n-phenyl-acetamine derivatives and related compounds as neuropeptide y5 (npy5) ligands for the treatment of obesity Abandoned US20110172270A1 (en)

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PCT/EP2004/008508 WO2005013988A1 (en) 2003-07-30 2004-07-29 2-`4(phenylamino)-piperidin-1-yl!-n-phenyl-acetamine derivatives and related compounds as neuropeptide y5 (npy5) ligands for the treatement of obesity
US56597907A 2007-11-05 2007-11-05
US12/985,646 US20110172270A1 (en) 2003-07-30 2011-01-06 2-'4(phenylamino)-piperidin-1-yl!-n-phenyl-acetamine derivatives and related compounds as neuropeptide y5 (npy5) ligands for the treatment of obesity

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US10/566,399 Abandoned US20070105853A1 (en) 2003-07-30 2004-07-29 2-'4-(Hydroxymethyl-phenylamino)-piperidine-1-yl!-n-(9h-carbazol-3-yl) - acetamine derivatives and related compounds as neuropeptide y5 (npy5) ligands for the treatment of obesity
US10/565,979 Expired - Fee Related US7888510B2 (en) 2003-07-30 2004-07-29 2-′4(phenylamino)-piperidin-1-yl!-n-phenyl-acetamine derivatives and related compounds as neuropeptide Y5 (NPY5) ligands for the treatment of obesity
US12/834,211 Abandoned US20100280072A1 (en) 2003-07-30 2010-07-12 2-'4-(hydroxymethyl-phenylamino) -piperidine-1-yl!-n- (9h-carbazol-3yl) - acetamine derivatives and related compounds as neuropeptide y5 (npy5) ligands for the treatment of obesity
US12/985,646 Abandoned US20110172270A1 (en) 2003-07-30 2011-01-06 2-'4(phenylamino)-piperidin-1-yl!-n-phenyl-acetamine derivatives and related compounds as neuropeptide y5 (npy5) ligands for the treatment of obesity

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US10/565,979 Expired - Fee Related US7888510B2 (en) 2003-07-30 2004-07-29 2-′4(phenylamino)-piperidin-1-yl!-n-phenyl-acetamine derivatives and related compounds as neuropeptide Y5 (NPY5) ligands for the treatment of obesity
US12/834,211 Abandoned US20100280072A1 (en) 2003-07-30 2010-07-12 2-'4-(hydroxymethyl-phenylamino) -piperidine-1-yl!-n- (9h-carbazol-3yl) - acetamine derivatives and related compounds as neuropeptide y5 (npy5) ligands for the treatment of obesity

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022035898A1 (en) * 2020-08-11 2022-02-17 Board Of Trustees Of Michigan State University Proteasome enhancers and uses thereof

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9560804B1 (en) 2010-12-15 2017-02-07 Marion Calmer Stalk roll with flutes defining a recess
ES2222833B1 (en) * 2003-07-30 2006-03-01 Laboratorios Del Dr. Esteve, S.A. 1,4-DISPOSED PIPERIDINIC COMPOUNDS, THEIR PREPARATION AND THEIR USE AS MEDICINES.
EP1918281A1 (en) * 2006-11-02 2008-05-07 Laboratorios del Dr. Esteve S.A. Phenylamino-substituted piperidine compounds, their preparation and use as medicaments
CA2678615A1 (en) * 2007-02-16 2008-08-28 Synta Pharmaceutical Corp. Substituted fused-ring compounds for inflammation and immune-related uses
CN102272120B (en) * 2008-11-07 2013-12-25 H.隆德贝克有限公司 Biologically active amides

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6399631B1 (en) * 1999-07-23 2002-06-04 Pfizer Inc. Carbazole neuropeptide Y5 antagonists
US20040058920A1 (en) * 2002-04-09 2004-03-25 Jover Antoni Torrens Benzoxazinone-derived compounds, their preparation and use as medicaments
US20070009567A1 (en) * 1997-12-19 2007-01-11 Naomi Balaban Methods and compositions for the treatment and prevention of staphylococcal infections
US20070059364A1 (en) * 2003-07-30 2007-03-15 Laboratorios Del Dr. Esteve S.A. Active substance combination comprising a compound with npy receptor affinity and a compound with 5-ht6 receptor affinity
US7435744B2 (en) * 2001-07-24 2008-10-14 Gedeon Richter Vegyeszeti Gyar Rt Piperidine derivatives as NMDA receptor antagonists

Family Cites Families (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU7692996A (en) 1995-12-01 1997-06-27 Ciba-Geigy Ag Receptor antagonists
WO1997019682A1 (en) 1995-12-01 1997-06-05 Synaptic Pharmaceutical Corporation Aryl sulfonamide and sulfamide derivatives and uses thereof
WO1998024768A1 (en) 1996-12-03 1998-06-11 Banyu Pharmaceutical Co., Ltd. Novel urea derivatives
EP0910565A1 (en) * 1997-02-14 1999-04-28 Bayer Corporation Amide derivatives as selective neuropeptide y receptor antagonists
US6048900A (en) * 1998-02-13 2000-04-11 Bayer Corporation Amide derivatives and methods for using the same as selective neuropeptide Y receptor antagonists
WO1998040356A1 (en) 1997-03-12 1998-09-17 Banyu Pharmaceutical Co., Ltd. Drugs containing aminopyridine derivatives as the active ingredient
US6187777B1 (en) 1998-02-06 2001-02-13 Amgen Inc. Compounds and methods which modulate feeding behavior and related diseases
NZ510988A (en) 1998-10-07 2005-01-28 Ortho Mcneil Pharm Inc N-aralkylaminotetralins useful as ligands for the neuropeptide Y5 receptor
WO2001007409A1 (en) * 1999-07-23 2001-02-01 Astrazeneca Uk Limited Carbazole derivatives and their use as neuropeptide y5 receptor ligands
RU2228927C2 (en) * 1999-07-28 2004-05-20 Орто-Макнейл Фармасьютикал, Инк. Derivatives of amines or amides, pharmaceutical composition based on thereof and method for antagonizing receptor y5 of neuropeptide npy
AU769081B2 (en) 1999-08-26 2004-01-15 Bristol-Myers Squibb Company NPY antagonists: spiroisoquinolinone derivatives
US7067549B2 (en) * 2001-12-31 2006-06-27 Actelion Pharmaceuticals Ag Pyrrolidone carboxamides
ES2222833B1 (en) * 2003-07-30 2006-03-01 Laboratorios Del Dr. Esteve, S.A. 1,4-DISPOSED PIPERIDINIC COMPOUNDS, THEIR PREPARATION AND THEIR USE AS MEDICINES.

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070009567A1 (en) * 1997-12-19 2007-01-11 Naomi Balaban Methods and compositions for the treatment and prevention of staphylococcal infections
US6399631B1 (en) * 1999-07-23 2002-06-04 Pfizer Inc. Carbazole neuropeptide Y5 antagonists
US7435744B2 (en) * 2001-07-24 2008-10-14 Gedeon Richter Vegyeszeti Gyar Rt Piperidine derivatives as NMDA receptor antagonists
US20040058920A1 (en) * 2002-04-09 2004-03-25 Jover Antoni Torrens Benzoxazinone-derived compounds, their preparation and use as medicaments
US20040067941A1 (en) * 2002-04-09 2004-04-08 Antonio Torrens-Jover Benzoxazinone derivatives, their preparation and use as medicaments
US20070059364A1 (en) * 2003-07-30 2007-03-15 Laboratorios Del Dr. Esteve S.A. Active substance combination comprising a compound with npy receptor affinity and a compound with 5-ht6 receptor affinity

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022035898A1 (en) * 2020-08-11 2022-02-17 Board Of Trustees Of Michigan State University Proteasome enhancers and uses thereof

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