WO2005049023A1 - Inhibiteurs du transporteur glyt1 - Google Patents

Inhibiteurs du transporteur glyt1 Download PDF

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WO2005049023A1
WO2005049023A1 PCT/EP2004/013052 EP2004013052W WO2005049023A1 WO 2005049023 A1 WO2005049023 A1 WO 2005049023A1 EP 2004013052 W EP2004013052 W EP 2004013052W WO 2005049023 A1 WO2005049023 A1 WO 2005049023A1
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alkyl
piperidin
dimethyl
methyl
compound
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PCT/EP2004/013052
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Steven Coulton
Martin Leonard Gilpin
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Glaxo Group Limited
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    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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    • C07D207/06—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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 radicals, containing only hydrogen and carbon atoms, attached to ring carbon atoms
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    • C07D213/06—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
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    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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
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    • C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
    • C07D295/027—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring
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    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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    • C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
    • C07D303/02—Compounds containing oxirane rings
    • C07D303/36—Compounds containing oxirane rings with hydrocarbon radicals, substituted by nitrogen atoms
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    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
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    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/62—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring 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 atoms of the carbocyclic ring
    • C07D317/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom 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
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    • 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
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    • C07D405/06—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 carbon chain containing only aliphatic carbon atoms

Definitions

  • the present invention relates to glycine transporter inhibiting compounds, their use in the manufacture of medicaments for treating neurological and neuropsychiatric disorders, in particular psychoses, dementia or attention deficit disorder.
  • the invention further comprises processes to make these compounds and pharmaceutical formulations thereof.
  • GlyT1 is found predominantly in the forebrain and its distribution corresponds to that of glutaminergic pathways and NMDA receptors (Smith, et. al., Neuron, 8, 1992: 927-935).
  • GlyT-la is found predominantly in the forebrain and its distribution corresponds to that of glutaminergic pathways and NMDA receptors (Smith, et. al., Neuron, 8, 1992: 927-935).
  • GlyT-la three variants of GlyT1 , termed GlyT-la, GlyT-1 b and GlyT-1 c (Kim et al., Molecular Pharmacology, 45, 1994: 608-617), each of which displays a unique distribution in the brain and peripheral tissues.
  • GlyT2 in contrast, is found predominantly in the brain stem and spinal cord, and its distribution corresponds closely to that of strychnine-sensitive glycine receptors (Liu et al., J. Biological Chemistry, 268, 1993: 22802-22808; Jursky and Nelson, J. Neurochemistry, 64, 1995 : 1026-1033).
  • Another distinguishing feature of glycine transport mediated by GlyT2 is that it is not inhibited by sarcosine as is the case for glycine transport mediated by GlyT1.
  • NMDA receptors are critically involved in memory and learning (Rison and Staunton, Neurosci. Biobehav. Rev.. 19 533-552 (1995); Danysz et al, Behavioral Pharmacol.. 6 455-474 (1995)); and, furthermore, decreased function of NMDA-mediated neurotransmission appears to underlie, or contribute to, the symptoms of schizophrenia (Olney and Farber, Archives General Psychiatry, 52, 998-1007 (1996).
  • agents that inhibit GlyT1 and thereby increase glycine activation of NMDA receptors can be used as novel antipsychotics and anti-dementia agents, and to treat other diseases in which cognitive processes are impaired, such as attention deficit disorders and organic brain syndromes.
  • NMDA receptors have been implicated in a number of disease states, in particular the neuronal death associated with stroke and possibly neurodegenerative diseases, such as Alzheimer's disease, multi-infarct dementia, AIDS dementia, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis or other conditions in which neuronal cell death occurs, such as stroke or head trauma.
  • neurodegenerative diseases such as Alzheimer's disease, multi-infarct dementia, AIDS dementia, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis or other conditions in which neuronal cell death occurs, such as stroke or head trauma.
  • Coyle & Puttfarcken Science. 262. 689-695 (1993); Upton and Rosenberg, New En ⁇ l. J. of Medicine. 330. 613-622 (1993); Choi, Neuron. 1 , 623-634 (1988).
  • pharmacological agents that increase the activity of GlyT1 will result in decreased glycine- activation of NMDA receptors, which activity can be used to treat these and related disease states.
  • drugs that directly block the glycine site of the NMDA receptors can be used to treat these and related disease states.
  • Glycine transport inhibitors are already known in the art, for example as disclosed in published International Applications WO97/45423 (Trophix Pharmaceuticals, Inc.), and WO97/45115 (Trophix Pharmaceuticals Inc.).
  • the classes of compounds disclosed in these applications inhibit glycine transport via the GlyTI or GlyT2 transporters.
  • glycine transport inhibitors include published International Applications WO99/45011 (Janssen Pharmaceutica N.V.), WO00/07978 (Akzo Nobel N.V.) and WO01/87855 (Yamanouchi Pharmaceutical Co. Ltd.).
  • Published International Applications WO01/32602 and WO01/81308 disclose classes of compounds which inhibit glycine transport (or reuptake) via the GlyTI transporter.
  • Published International Applications WO01/36423 (Akzo Nobel N.V.) and WO03/55478 (SmithKline Beecham pic) disclose compounds that inhibit glycine transport by the human GlyTI transporter .
  • GlyTI transporters include those that inhibit GlyTI transporters selectively over GlyT2 transporters.
  • Such compounds would thus be suitable for the treatment of certain neurological and neuropsychiatric disorders, including psychoses such as schizophrenia, dementia and other forms of impaired cognition such as attention deficit disorders and organic brain syndromes.
  • neuropsychiatric disorders include drug-induced (phencyclidine, ketamine and other dissociative anaesthetics, amphetamine and other psychostimulants and cocaine) psychosis, psychosis associated with affective disorders, brief reactive psychosis, schizoaffective psychosis, and psychosis NOS, "schizophrenia- spectrum” disorders such as schizoid or schizotypal personality disorders, or illness associated with psychosis (such as major depression, manic depressive (bipolar) disorder, Alzheimer's disease and post-traumatic stress syndrome), and NMDA receptor- related disorders such as autism, depression, benign forgetfulness, childhood learning disorders and closed head injury.
  • drug-induced phencyclidine, ketamine and other dissociative anaesthetics, amphetamine and other psychostimulants and cocaine
  • psychosis psychosis associated with affective disorders
  • brief reactive psychosis schizoaffective psychosis
  • psychosis NOS "schizophrenia- spectrum” disorders such as schizo
  • R 1 and R 2 are independently:
  • Q is an optionally substituted 4-, 5-, 6- or 7-membered saturated ring, wherein one or more of the carbon atoms of the saturated ring is optionally replaced by a heteroatom independently selected from N, O and S, and R 15 , R 16 , R 17 and R 18 are independently hydrogen or d-Ce alkyl; R 3 is
  • Y is C-
  • R 4 and R 5 are both hydrogen, or one of R 4 and R 5 is hydrogen and the other is: (a) -SO2R 19 wherein R 19 is a 5- to 7- membered optionally substituted monocyclic aromatic ring system or a 6- to 11- membered optionally substituted bicyclic aromatic ring system; or (b) -XR 20 wherein X is -CO(CH2)r- (wherein r is 0, 1 , 2, 3 or 4) or -CONH- wherein R 20 is hydrogen, C ⁇ -C 6 alkyl or a 5- to 7- membered optionally substituted monocyclic aromatic ring system or a 6- to 11- membered optionally substituted bicyclic aromatic ring system;
  • R 6 is independently selected from hydrogen, C ⁇ -C 6 alkyl, C 3 -C 6 cycloalkyl, C 3 - Cecycloalkyld-C ⁇ alkyl, aryl and arylC- ⁇ -C 4 alkyl; and
  • R 7 , R 8 , R 9 and R 10 are independently selected from hydrogen, C.
  • d.Ce alkyl refers to a straight or branched chain hydrocarbon which contains at least 1 , and at most 6, carbon atoms.
  • C C 6 alkyl groups useful in the present invention include, but are not limited to, methyl, ethyl, n-propyl, i- propyl, n-butyl, i-butyl, t-butyl, n-pentyl and n-hexyl.
  • C 4 alkyl refers to a straight or branched chain hydrocarbon which contains at least 1 , and at most 4, carbon atoms.
  • C C 4 alkyl groups useful in the present invention include, but are not limited to, methyl, ethyl, n-propyl, i- propyl, n-butyl, i-propyl and t-butyl.
  • C 3- C 6 cycloalkyl refers to a non-aromatic cyclic hydrocarbon ring having from three to six carbon atoms. Examples of “C 3 -C 6 cycloalkyl” groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • C 3 -C 6 cycloalkylC 1 -C 4 alkyl refers to a C 3- C 6 cycloalkyl group, as hereinbefore defined, attached through a C- ⁇ -C 4 alkylene linker, wherein C- ⁇ -C 4 alkylene is as defined herein.
  • Examples of "C 3 -C 6 cycloalkylC 1 -C 4 alkyl” include, but are not limited to, cyclohexylmethyl.
  • aryl refers to a 5- to 7-membered aromatic or heteroaromatic ring system wherein the heteroatomic ring contains at least one heteroatom selected from nitrogen, oxygen and sulphur.
  • aryl groups include phenyl, pyrrolyl, pyrrolinyl, pyrazolinyl, imidazolyl, pyrazolyl, oxadiazolyl, isothiazolyl, thiazolyl, furyl, thienyl, pyridyl, thiazinyl, pyridazinyl, pyrimidinyl, pyrazinyl and azepinyl.
  • arylC C 4 alkyl refers to an aryl group, as hereinbefore defined, attached through a C C 4 alkylene linker, wherein C C 4 alkylene is as defined herein.
  • Examples of “arylC C 4 alkyl” include, but are not limited to, benzyl, phenethyl, pyridylmethyl and phenylpropyl.
  • C ⁇ .C 2 alkylene As used herein, the terms “C ⁇ .C 2 alkylene”, “C-i.Cs alkylene” and “C ⁇ ,C 4 alkylene” refer to a straight or branched chain divalent hydrocarbon radical, which contains at least 1 , and at most 2, 3 or 4, carbon atoms respectively.
  • Examples of “d-C 2 alkylene”, “C ⁇ _C 3 alkylene” and “d.d alkylene” groups useful in the present invention include methylene, ethylene, n- propylene and n-butylene.
  • C 2 alkenylene refers to a divalent hydrocarbon radical with a double bond, which contains 2 carbon atoms.
  • C 2 alkynylene refers to a divalent hydrocarbon radical with a triple bond, which contains 2 carbon atoms.
  • hal and halo are abbreviations for "halogen” and refers to fluorine, chlorine, bromine, or iodine.
  • 5- to 7- membered monocyclic aromatic ring system refers to a monocyclic aromatic ring system consisting of 5, 6 or 7 carbon atoms, wherein one or more of the carbon atoms is optionally replaced by a heteroatom independently selected from nitrogen, oxygen and sulfur.
  • Examples of such groups include: phenyl, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyrazolyl, isothiazolyl, thiazolyl, isoxazolyl, furazanyl, oxazolyl, furyl, thienyl, pyridyl, pyridazinyl, pyrimidinyl, oxadiazolyl, triazolyl, thiadiazolyl, pyrazinyl, triazinyl, azepinyl and pyranyl.
  • 6- to 11- membered bicyclic aromatic ring system refers to a bicyclic aromatic ring system consisting of 6, 7, 8, 9, 10 or 11 carbon atoms, wherein one or more of the carbon atoms is optionally replaced by a heteroatom independently selected from nitrogen, oxygen and sulfur.
  • the term includes bicyclic aromatic ring systems wherein both rings are aromatic, as well as bicyclic aromatic ring systems wherein one of the rings is partially or fully saturated.
  • bicyclic aromatic ring systems in which both rings are aromatic include: naphthyl, indenyl, indolyl, isoindolyl, indazolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzothienyl, benzofuranyl, naphthridinyl, quinolyl, quinoxalinyl, quinazolinyl and isoquinolyl.
  • bicyclic aryl groups in which one of the rings is partially or fully saturated includes dihydrobenzofuranyl, indanyl, tetrahydronaphthyl, indolinyl, isoindolinyl, tetrahydroisoquinolinyl, tetrahydroquinolyl, benzoxazinyl and benzoazepinyl.
  • All of these ring systems may be attached to the rest of the molecule via any available atom on the ring system, such as carbon or nitrogen.
  • salt refers to any salt of a compound according to the present invention prepared from an inorganic or organic acid or base, quaternary ammonium salts and internally formed salts.
  • Physiologically acceptable salts are particularly suitable for medical applications because of their greater aqueous solubility relative to the parent compounds. Such salts must clearly have a physiologically acceptable anion or cation.
  • physiologically acceptable salts of the compounds of the present invention include acid addition salts formed with inorganic acids such as hydrochloric, hydrobromic, hydroiodic, phosphoric, metaphosphoric, nitric and sulfuric acids, and with organic acids, such as tartaric, acetic, trifluoroacetic, citric, malic, lactic, fumaric, benzoic, formic, propionic, glycolic, gluconic, maleic, succinic, camphorsulfuric, isothionic, mucic, gentisic, isonicotinic, saccharic, glucuronic, furoic, glutamic, ascorbic, anthranilic, salicylic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, pantothenic, stearic, sulfinilic, alginic, galacturonic and arylsulfonic, for example benzenesul, in
  • solvate refers to a complex of variable stoichiometry formed by a solute (in this invention, a compound of formula (I) or formula (la), or a salt or physiologically functional derivative thereof) and a solvent.
  • solvents for the purpose of the invention may not interfere with the biological activity of the solute.
  • suitable solvents include, but are not limited to, water, methanol, ethanol and acetic acid.
  • the solvent used is a pharmaceutically acceptable solvent.
  • suitable pharmaceutically acceptable solvents include water, ethanol and acetic acid. Most preferably the solvent used is water.
  • physiologically functional derivative refers to any pharmaceutically acceptable derivative of a compound of the present invention, for example, an ester or an amide, which upon administration to a mammal is capable of providing (directly or indirectly) a compound of the present invention or an active metabolite thereof.
  • physiologically functional derivatives are clear to those skilled in the art, without undue experimentation, and with reference to the teaching of Burger's Medicinal Chemistry And Drug Discovery, 5 th Edition, Vol 1 : Principles and Practice, which is incorporated herein by reference to the extent that it teaches physiologically functional derivatives.
  • Suitable substituents for groups in formula (I) which are optionally substituted include one or more groups selected from: halogen, hydroxy, oxo, cyano, nitro, C-j. alkyl, C-] ⁇ alkoxy, haloci-4alkyl.
  • substituents may be different or the same. If substituent(s) is/are present, preferably the number of substituent(s) is 1 , 2, 3 or 4.
  • substituent(s) is/are present, preferably the number of substituent(s) is 1 , 2, 3 or 4.
  • Certain of the compounds described herein may exist in stereoisomeric forms (i.e. they may contain one or more asymmetric carbon atoms or may exhibit cis-trans isomerism). The individual stereoisomers (enantiomers and diastereoisomers) and mixtures of these are included within the scope of the present invention.
  • compounds of formulae (I) and (la) may exist in tautomeric forms other than that shown in the formulae and these are also included within the scope of the present invention.
  • optically pure enantiomer means that the compound contains greater than about 90 % of the desired isomer by weight, preferably greater than about 95 % of the desired isomer by weight, and most preferably greater than about 99 % of the desired isomer by weight, said weight percent based upon the total weight of the isomer(s) of the compound.
  • the compound of formula (I) as hereinbefore described has the following stereochemical configuration:
  • R 1 and R 2 are independently selected from optionally substituted d-C 6 alkyl, preferably C 3 -C 6 alkyl such as isopropyl.
  • the optional substituents for the d-C 6 alkyl may be one, two or three groups selected from: halogen, C-
  • R 1 and R 2 together with the nitrogen atom to which they are attached are linked to form a 4-, 5-, 6- or 7-membered heterocyclic ring, wherein the sole heteroatom is the nitrogen atom to which R 1 and R 2 are attached, said ring being optionally substituted by one, two or three groups selected from: halogen, Chalky!, C-j. 4alkoxy, haloci-4alky[, haloC ⁇ alkoxy, C ⁇ alkylsulfonamidoC- ⁇ alkyl, C-
  • R 1 and R 2 together with the nitrogen atom to which they are attached are linked to form a 5- or 6-membered ring, wherein one or more of the carbon atoms is optionally replaced by a heteroatom independently selected from N, O and S, said ring being optionally substituted by one, two or three groups selected from: halogen,
  • R 21 R 22 forms part of a C3_ ⁇ azacyloalkane or C3_6(2-oxo)azacycloalkane ring and r represents zero or an integer from 1 to 4), said ring being further optionally fused to a C 5 -
  • R 1 and R 2 together with the nitrogen atom to which they are attached are linked to form a 5- or 6-membered heterocyclic ring, wherein the sole heteroatom is the nitrogen atom to which R 1 and R 2 are attached, said ring being optionally substituted by one, two or three groups selected from: halogen, C- ⁇ _galkyl, C-
  • the 4-, 5-, 6- or 7-membered saturated ring formed by R 1 and R 2 together with the nitrogen atom to which they are linked is selected from the group comprising: azetidine, azepine, pyrrolidine, imidazolidine, piperidine, morpholine, thiomorpholine, piperazine, all of which being optionally substituted by one, two or three groups selected from: halogen, C ⁇ .galkyl, C-j ⁇ alkoxy, haloci-4.alkyl, haloC-] ⁇ alkoxy, C ⁇ _
  • R 1 and R 2 together with the nitrogen atom to which they are attached are linked to form a pyrrolidinyl ring, said ring being optionally substituted by one or more groups independently selected from optionally substituted C 1 -C 4 alkyl, preferably methyl, ethyl or isopropyl.
  • the pyrrolidinyl ring formed by R 1 and R 2 together with the nitrogen atom to which they are attached is substituted by one or more d-C 4 alkyl groups, preferably methyl, ethyl or isopropyl groups, preferably at the 2- and/or 5- positions, more preferably at the 2-position.
  • R 1 and R 2 together with the nitrogen atom to which they are attached are linked to form a piperidinyl ring, said ring being optionally substituted by one or more groups independently selected from optionally substituted C 1 -C 4 alkyl , preferably methyl or ethyl.
  • the piperidinyl ring formed by R 1 and R 2 together with the nitrogen atom to which they are attached is substituted by one or more methyl or ethyl groups, preferably at the 2- and 6-positions. More preferably, the piperidinyl ring formed by R 1 and R 2 together with the nitrogen atom to which they are attached is substituted by two methyl groups, preferably at the 2- and 6- positions.
  • q is 0.
  • Z is substituted by 1 , 2 or 3 groups independently selected from: - hal, -R 23 , -OR 24 , -C(O)OR 25 , -CN, -NO 2 , -NR 26 R 27 , -C(O)NR 28 R 29 , -NR 30 C(O)R 31 , - C(O)R 32 , -C(NR 33 )NR 34 R 35 , -C(NOR 36 )R 37 , or C ⁇
  • Z is a 5- to 7-membered optionally substituted monocyclic aromatic ring system as hereinbefore described.
  • Z is a 5- or 6-membered optionally substituted monocyclic ring system as hereinbefore described.
  • Z is phenyl optionally substituted as hereinbefore described, preferably by one or more groups independently selected from -hal, -R 10 , -CF3, -C-
  • Z is a 6- to 11 -membered optionally substituted bicyclic aromatic ring system as hereinbefore described.
  • Z is a 8- to 10- membered optionally substituted bicyclic aromatic ring system as hereinbefore described.
  • Z is selected from the group comprising: naphthyl, naphthyridinyl, quinolinyl, isoquinolyl, benzothienyl, chromanyl, chromenyl, imidazoleisothiazolyl, benzothiadiazolyl, benzofuryl, all of which being optionally substituted as hereinbefore described.
  • Z is quinolinyl (preferably 5-quinolinyl), optionally substituted as hereinbefore described, preferably by one or more groups independently selected from -hal, -R 23 , -OR 24 , - COOR 25 , -CF3, -Ci-C ⁇ alkylsulphonyl, -CN, -NO 2 , and -NR 26 R 27 , wherein hal, R 23 , R 24 , R 25 , R 26 and R 27 are as hereinbefore defined, preferably hal, d-C 6 alkyl, Ci-Ce alkoxy, CF3, -CN and C 3 -C 6 cycloalkyl.
  • Z is 5-quinolinyl optionally substituted by one or more groups independently selected from -hal, d-C 6 alkyl, d-C 6 alkoxy, - CF3, -CN and C 3 -C 6 cycloalkyl.
  • R 3 is phenyl or 5-quinolinyl.
  • one of R 4 and R 5 is hydrogen and the other is a group -COCH2R 38 , - COR 38 or -CONHR 38 wherein R 38 is a 5- to 7- membered monocylic aromatic ring system or a 6- to 11- membered bicyclic aromatic ring system, said ring system being optionally substituted by one or two groups independently selected from hal, CF3, d-C 6 alkyl, d- C 6 alkoxy,-CN, d-Cealkylamido, d-C 6 alkanoyl and d-C 6 alkylsulphonyl.
  • R 6 is selected from hydrogen, d-C 6 alkyl, aryl and benzyl, wherein the d ⁇ C 6 alkyl, aryl and benzyl are optionally substituted by one or more groups independently selected from hal, d-C 6 alkyl, hydroxy and d-C 6 alkoxy.
  • R 6 is hydrogen.
  • R 7 , R 8 , R 9 and R 10 are independently selected from hydrogen and Ci- Ce alkyl, preferably hydrogen.
  • R 39 and R 40 are independently selected from C 3 -C 6 alkyl, or
  • R 39 and R 40 together with the nitrogen atom to which they are attached, are linked to form a 5-, 6-, or 7- membered heterocyclic ring, wherein the sole heteroatom is the nitrogen atom to which R 39 and R 40 are attached, said heterocyclic ring being optionally substituted by one or more groups independently selected from C 1 -C 4 alkyl and C 3 -C 6 cycloalkyl, and said heterocyclic ring being further optionally fused to a C 6 alicyclic or aromatic ring, and said heterocyclic ring being further optionally bridged by a methylene group;
  • R 42 and R 43 is hydrogen and the other is a group -X 1 R 49 , wherein X-, is CONH- or - CO(CH2)b- wherein b is 0, 1 or 2, and R 49 is a 5- to 6-membered monocylic aromatic ring system or a 6- to 10- membered bicyclic aromatic ring system, said ring system being optionally substituted by one, two or three groups independently selected from -hal, -R 50 , -OR 51 , -C(O)OR 52 , -CN, -NO 2 , -NR 53 R 54 , -C(O)NR 55 R 56 , -NR 57 C(O)R 58 , -C(O)R 59 , - C(NR 60 )NR 6 R 62 , -C(NOR 63 )R 64 , or C-
  • X- is CONH- or - CO(CH2)b- wherein b is 0, 1 or 2
  • R 49 is a
  • R 50 is d-C 6 alkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkylC 1 -C 4 alkyl, aryl, aryloxy or arylC 1 -C 4 alkyl, all of which being optionally substituted by one or more groups independently selected from hal, C
  • the C 2 alkenylene group may be in the cis or trans configuration, preferably the trans configuration.
  • a is 0.
  • the compound of formula (la) as hereinbefore described has the following stereochemical configuration:
  • Examples of preferred compounds of the invention include Examples 1 to 42 shown below, as well as salts, solvates and physiologically functional derivatives thereof:
  • the compounds of formulae (I) and (la) have the ability to crystallise in more than one form, a characteristic, which is known as polymorphism, and it is understood that such polymorphic forms (“polymorphs”) are within the scope of formulae (I) and (la).
  • Polymorphism generally can occur as a response to changes in temperature or pressure or both and can also result from variations in the crystallisation process. Polymorphs can be distinguished by various physical characteristics known in the art such as x-ray diffraction patterns, solubility, and melting point.
  • the compounds of this invention may be made by a variety of methods, including standard chemistry. Any previously defined variable will continue to have the previously defined meaning unless otherwise indicated. Illustrative general synthetic methods are set out below and then specific compounds of the invention are prepared in the working
  • a compound When a compound is desired as a single enantiomer, it may be obtained by stereospecific synthesis or by resolution of the final product or any convenient intermediate. Resolution of the final product, an intermediate, or a starting material may be effected by any suitable method known in the art. See, for example, Stereochemistry of Organic Compounds by E. L. Eliel, S. H. Wilen, and L. N. Mander (Wiley-lnterscience, 1994).
  • the compounds of formula (A) may be prepared using methodology similar to that described by Gutcait A. et. al., Tetrahedron Asymmetry, 1996, 7(6), 1641-1648.
  • Compounds of formula (A) may be converted to compounds of formula (I) above by displacement of the hydroxyl with azide, as shown above.
  • the reduction of the azide may be carried out using all methods known to those skilled in the art, for example, hydrogenation in the presence of catalyst such as palladium on carbon, Pd(OH) 2 and those known in the art, see for example March, Advanced Organic Chemistry, 4 th edition, Wiley Interscience.
  • the reduction of the azide is preferably carried out by hydrogenation in the presence of a catalyst such as palladium on carbon.
  • Schemes 1 and 2 can be adapted to prepare compounds wherein R 6 , R 7 , R 8 , R 9 and R 10 are other than hydrogen.
  • R 3 is as hereinbefore defined and L is a suitable leaving group, such as, for example, a halogen, preferably chlorine; or
  • the present invention provides a compound of formula (I) or formula (1a) as hereinbefore described and salts, solvates and physiologically functional derivatives thereof, for use in therapy.
  • the present invention provides a compound of formula (I) or formula (1a) as hereinbefore described and salts, solvates and physiologically functional derivatives thereof, for use in treating a disorder mediated by GlyTI .
  • a method of treating a mammal including a human, suffering from or susceptible to a disorder mediated by GlyTI , which comprises administering an effective amount of a GlyTI inhibiting compound of formula (I) or (la) as hereinbefore defined or a salt, solvate or a physiologically functional derivative thereof.
  • the terms “therapy” and “treatment” refer to alleviation and/or cure of established symptoms as well as prophylaxis.
  • an effective amount means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher or clinician.
  • the present invention also provides the use of a compound of formula (I) or formula (la) as hereinbefore defined or a salt, solvate or a physiologically functional derivative thereof in the preparation of a medicament for the treatment of a disorder mediated by GlyTI .
  • a disorder mediated by GlyTI refers to a disorder that may be treated by the administration of a medicament that alters the activity of the GlyTI transporter.
  • the action of GlyTI transporters affects the local concentration of glycine around NMDA receptors.
  • any change to that local concentration can affect NMDA-mediated neurotransmission.
  • changes in NMDA-mediated neurotransmission have been implicated in certain neuropsychiatric disorders such as dementia, depression and psychoses, for example schizophrenia, and learning and memory disorders, for example attention deficit disorders and autism.
  • alterations in the activity of the GlyTI transporter are expected to influence such disorders.
  • the disorders mediated by GlyTI referred to herein include neurological and neuropsychiatric disorders, including psychoses such as schizophrenia, dementia and other forms of impaired cognition such as attention deficit disorders and organic brain syndromes.
  • Other neuropsychiatric disorders include drug-induced (phencyclidine, ketamine and other dissociative anesthetics, amphetamine and other psychostimulants and cocaine) psychosis, psychosis associated with affective disorders, brief reactive psychosis, schizoaffective psychosis, and psychosis NOS, "schizophrenia-spectrum" disorders such as schizoid or schizotypal personality disorders, or illness associated with psychosis (such as major depression, manic depressive (bipolar) disorder, Alzheimer's disease and post-traumatic stress syndrome), and NMDA receptor-related disorders such as autism, depression, benign forgetfulness, childhood learning disorders and closed head injury.
  • NMDA receptor-related disorders such as autism, depression, benign forgetfulness, childhood learning disorders and closed head injury.
  • the disorders mediated by GlyTI to be treated by the use or method as hereinbefore described are psychoses, including schizophrenia, dementia and attention deficit disorders, particularly schizophrenia.
  • Compounds for use according to the invention may be administered as the raw material but the active ingredients are preferably provided in the form of pharmaceutical compositions.
  • a pharmaceutical composition comprising as active ingredient the compound of formula (I) or formula (la) as hereinbefore described, or a salt, solvate or a physiologically functional derivative thereof, and at least one pharmaceutically acceptable carrier, diluent or excipient.
  • compositions may be used in the treatment of clinical conditions for which a GlyTI inhibitor is indicated such as, for example, schizophrenia.
  • the carrier must be pharmaceutically acceptable to the recipient and must be compatible with, i.e. not have a deleterious effect upon, the other ingredients in the composition.
  • the carrier may be a solid or a liquid and is preferably formulated with at least one compound of formula (I) or (la) as hereinbefore described as a unit dose formulation. If desired, other physiologically active ingredients may also be incorporated in the pharmaceutical compositions of the invention.
  • DSM-IV American Psychiatric Association
  • the compounds of formula (I) are of use in the treatment of schizophrenia including the subtypes Paranoid Type (295.30), Disorganised Type (295.10), Catatonic Type (295.20), Undifferentiated Type (295.90) and Residual Type (295.60); Schizophreniform Disorder (295.40); Schizoaffective Disorder (295.70) including the subtypes Bipolar Type and Depressive Type; Delusional Disorder (297.1) including the subtypes Erotomanic Type, Grandiose Type, Jealous Type, Persecutory Type, Somatic Type, Mixed Type and Unspecified Type; Brief Psychotic Disorder (298.8); Shared Psychotic Disorder (297.3); Psychotic Disorder Due to a General Medical Condition including the subtypes With Delusions and With Hallucinations; Substance-Induced Psychotic Disorder including the subtypes With Delusions (293.81) and With Hallucinations (293.82); and Psychotic Disorder Not Otherwise Specified (298.9).
  • the compounds of formula (I) are also of use in the treatment of mood disorders including Major Depressive Episode, Manic Episode, Mixed Episode and Hypomanic Episode; Depressive Disorders including Major Depressive Disorder, Dysthymic Disorder (300.4), Depressive Disorder Not Otherwise Specified (311); Bipolar Disorders including Bipolar I Disorder, Bipolar II Disorder (Recurrent Major Depressive Episodes with Hypomanic Episodes) (296.89), Cyclothymic Disorder (301.13) and Bipolar Disorder Not Otherwise Specified (296.80); Other Mood Disorders including Mood Disorder Due to a General Medical Condition (293.83) which includes the subtypes With Depressive Features, With Major Depressive-like Episode, With Manic Features and With Mixed Features), Substance-Induced Mood Disorder (including the subtypes With Depressive Features, With Manic Features and With Mixed Features) and Mood Disorder Not Otherwise Specified (296.90).
  • the compounds of formula (I) are also of use in the treatment of anxiety disorders including Panic Attack, Agoraphobia, Panic Disorder, Agoraphobia Without History of Panic Disorder (300.22), Specific Phobia (300.29) including the subtypes Animal Type, Natural Environment Type, Blood-lnjection-lnjury Type, Situational Type and Other Type), Social Phobia (300.23), Obsessive-Compulsive Disorder (300.3), Posttraumatic Stress Disorder (309.81), Acute Stress Disorder (308.3), Generalized Anxiety Disorder (300.02), Anxiety Disorder Due to a General Medical Condition (293.84), Substance-Induced Anxiety Disorder and Anxiety Disorder Not Otherwise Specified (300.00).
  • the compounds of formula (I) are also of use in the treatment of substance-related disorders including Substance Use Disorders such as Substance Dependence and Substance Abuse; Substance-Induced Disorders such as Substance Intoxication, Substance Withdrawal, Substance-Induced Delirium, Substance-Induced Persisting Dementia, Substance-Induced Persisting Amnestic Disorder, Substance-Induced Psychotic Disorder, Substance-Induced Mood Disorder, Substance-Induced Anxiety Disorder, Substance-Induced sexual Dysfunction, Substance-Induced Sleep Disorder and Hallucinogen Persisting Perception Disorder (Flashbacks); Alcohol-Related Disorders such as Alcohol Dependence (303.90), Alcohol Abuse (305.00), Alcohol Intoxication (303.00), Alcohol Withdrawal (291.81), Alcohol Intoxication Delirium, Alcohol Withdrawal Delirium, Alcohol-Induced Persisting Dementia, Alcohol-Induced Persisting Amnestic Disorder, Alcohol-
  • the compounds of formula (I) are also of use in the treatment of sleep disorders including primary sleep disorders such as Dyssomnias such as Primary Insomnia (307.42), Primary Hypersomnia (307.44), Narcolepsy (347), Breathing-Related Sleep Disorders (780.59), Circadian Rhythm Sleep Disorder (307.45) and Dyssomnia Not Otherwise Specified (307.47); primary sleep disorders such as Parasomnias such as Nightmare Disorder (307.47), Sleep Terror Disorder (307.46), Sleepwalking Disorder (307.46) and Parasomnia Not Otherwise Specified (307.47); Sleep Disorders Related to Another Mental Disorder such as Insomnia Related to Another Mental Disorder (307.42) and Hypersomnia Related to Another Mental Disorder (307.44); Sleep Disorder Due to a General Medical Condition; and Substance-Induced Sleep Disorder including the subtypes Insomnia Type, Hypersomnia Type, Parasomnia Type and Mixed Type.
  • the compounds of formula (I) are also of use in the treatment of eating disorders such as Anorexia Nervosa (307.1 ) including the subtypes Restricting Type and Binge- Eating/Purging Type; Bulimia Nervosa (307.51 ) including the subtypes Purging Type and Nonpurging Type; Obesity; Compulsive Eating Disorder; and Eating Disorder Not Otherwise Specified (307.50).
  • eating disorders such as Anorexia Nervosa (307.1 ) including the subtypes Restricting Type and Binge- Eating/Purging Type; Bulimia Nervosa (307.51 ) including the subtypes Purging Type and Nonpurging Type; Obesity; Compulsive Eating Disorder; and Eating Disorder Not Otherwise Specified (307.50).
  • the compounds of formula (I) are also of use in the treatment of Autistic Disorder (299.00); Attention-Deficit /Hyperactivity Disorder including the subtypes Attention-Deficit /Hyperactivity Disorder Combined Type (314.01), Attention-Deficit /Hyperactivity Disorder Predominantly Inattentive Type (314.00), Attention-Deficit /Hyperactivity Disorder Hyperactive-Impulse Type (314.01 ) and Attention-Deficit /Hyperactivity Disorder Not Otherwise Specified (314.9); Hyperkinetic Disorder; Disruptive Behaviour Disorders such as Conduct Disorder including the subtypes childhood-onset type (321.81), Adolescent- Onset Type (312.82) and Unspecified Onset (312.89), Oppositional Defiant Disorder (313.81) and Disruptive Behaviour Disorder Not Otherwise Specified; and Tic Disorders such as Tourette's Disorder (307.23).
  • Attention-Deficit /Hyperactivity Disorder including the subtypes Attention-Defici
  • the compounds of formula (I) are also of use in the treatment of Personality Disorders including the subtypes Paranoid Personality Disorder (301.0), Schizoid Personality Disorder (301.20), Schizotypal Personality Disorder (301 ,22), Antisocial Personality Disorder (301.7), Borderline Personality Disorder (301 ,83), Histrionic Personality Disorder (301.50), Narcissistic Personality Disorder (301,81), Avoidant Personality Disorder (301.82), Dependent Personality Disorder. (301.6), Obsessive-Compulsive Personality Disorder (301.4) and Personality Disorder Not Otherwise Specified (301.9).
  • Paranoid Personality Disorder (301.0
  • Schizoid Personality Disorder 301.20
  • Schizotypal Personality Disorder 301 ,22
  • Antisocial Personality Disorder (301.7
  • Borderline Personality Disorder 301 ,83
  • Histrionic Personality Disorder 301.50
  • Narcissistic Personality Disorder 301,81
  • Avoidant Personality Disorder (301.82)
  • Dependent Personality Disorder (301.6
  • the compounds of Formula (I) are also of use in the enhancement of cognition including the treatment of cognition impairment in other diseases such as schizophrenia, bipolar disorder, depression, other psychiatric disorders and psychotic conditions associated with cognitive impairment.
  • cognitive impairment includes for example the treatment of impairment of cognitive functions including attention, orientation, learning disorders, memory (i.e.
  • Alzheimer's disease Huntington's disease, Pick disease, Aids-related dementia or other dementia states
  • Multiinfarct dementia alcoholic dementia, hypotiroidism-related dementia, and dementia associated to other degenerative disorders such as cerebellar atrophy and amyotropic lateral sclerosis
  • other acute or sub-acute conditions that may cause cognitive decline such as delirium or depression (pseudodementia states) trauma, head trauma, age related cognitive decline, stroke, neurodegeneration, drug-induced states, neurotoxic agents, mild cognitive impairment, age related cognitive impairment, autism related cognitive impairment, Down's syndrome, cognitive deficit related to psychosis, and post-electroconvulsive treatment related cognitive disorders
  • dyskinetic disorders such as Parkinson's disease, neuroleptic-induced parkinsonism, and tardive dyskinesias.
  • the compounds of formula (I) are also of use in the treatment of sexual dysfunctions including Sexual Desire Disorders such as Hypoactive Sexual Desire Disorder (302.71), and Sexual Aversion Disorder (302.79); sexual arousal disorders such as Female sexual Arousal Disorder (302.72) and Male Erectile Disorder (302.72); orgasmic disorders such as Female Orgasmic Disorder (302.73), Male Orgasmic Disorder (302.74) and Premature Ejaculation (302.75); sexual pain disorder such as Dyspareunia (302.76) and Vaginismus (306.51); sexual Dysfunction Not Otherwise Specified (302.70); paraphilias such as Exhibitionism (302.4), Fetishism (302.81), Frotteurism (302.89), Pedophilia (302.2), sexual Masochism (302.83), Sexual Sadism (302.84), Transvestic Fetishism (302.3), - Voyeurism (302.82) and Paraphilia Not Otherwise Specified (302.9); gender identity disorders such as Gender Identity Disorder in Children (302.6) and Gender Identity Disorder
  • the invention also provides a compound of formula (I) as hereinbefore described or a pharmaceutically acceptable salt or solvate thereof for use in the treatment of schizophrenia, mood disorders, anxiety disorders, substance-related disorders, sleep disorders, eating disorders, autistic disorder, attention-deficit/hyperactivity disorder, disruptive behaviour disorder, tic disorders, personality disorders, cognition impairment in other diseases, sexual dysfunction, Parkinson's disease, dyskinetic disorders, depression, bipolar disorder, cognitive impairment, obesity, emesis, movement disorders, obsessive- compulsive disorders, amnesia, aggression, vertigo, dementia and circadian rhythm disorders.
  • the invention also provides a compound of formula (I) as hereinbefore described or a pharmaceutically acceptable salt or solvate thereof for use in the treatment of psychotic disorders, schizophrenia, Parkinson's disease, substance abuse, dyskinetic disorders, depression, bipolar disorder, anxiety, cognitive impairment, eating disorders, obesity, sexual dysfunction, sleep disorders, emesis, movement disorders, obsessive-compulsive disorders, amnesia, aggression, autism, vertigo, dementia, circadian rhythm disorders and gastric motility disorders.
  • psychotic disorders schizophrenia, Parkinson's disease, substance abuse, dyskinetic disorders, depression, bipolar disorder, anxiety, cognitive impairment, eating disorders, obesity, sexual dysfunction, sleep disorders, emesis, movement disorders, obsessive-compulsive disorders, amnesia, aggression, autism, vertigo, dementia, circadian rhythm disorders and gastric motility disorders.
  • a method of treating a mammal including a human, suffering from or susceptible to a disorder mediated by GlyTI , which comprises administering an effective amount of a compound of formula (I) as hereinbefore defined or a salt or solvate thereof.
  • the invention also provides a method of treating schizophrenia, mood disorders, anxiety disorders, substance-related disorders, sleep disorders, eating disorders, autistic disorder, attention-deficit/hyperactivity disorder, disruptive behaviour disorder, tic disorders, personality disorders, cognition impairment in other diseases, sexual dysfunction, Parkinson's disease, dyskinetic disorders, depression, bipolar disorder, cognitive impairment, obesity, emesis, movement disorders, obsessive-compulsive disorders, amnesia, aggression, vertigo, dementia and circadian rhythm disorders which comprises administering to a mammal in need thereof an effective amount of a compound of formula (I) as hereinbefore described or a pharmaceutically acceptable salt or solvate thereof.
  • the invention also provides a method of treating psychotic disorders, schizophrenia, Parkinson's disease, substance abuse, dyskinetic disorders, depression, bipolar disorder, anxiety, cognitive impairment, eating disorders, obesity, sexual dysfunction, sleep disorders, emesis, movement disorders, obsessive-compulsive disorders, amnesia, aggression, autism, vertigo, dementia, circadian rhythm disorders and gastric motility disorders which comprises administering to a mammal in need thereof an effective amount of a compound of formula (I) as hereinbefore described or a pharmaceutically acceptable salt or solvate thereof.
  • the disorder mediated by GlyTI to be treated by the use or method as hereinbefore described is a psychosis, including schizophrenia, dementia and attention deficit disorders, particularly schizophrenia.
  • the invention also provides the use of a compound of formula (I) as hereinbefore described or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for the treatment of schizophrenia, mood disorders, anxiety disorders, substance-related disorders, sleep disorders, eating disorders, autistic disorder, attention- deficit/hyperactivity disorder, disruptive behaviour disorder, tic disorders, personality disorders, cognition impairment in other diseases, sexual dysfunction, Parkinson's disease, dyskinetic disorders, depression, bipolar disorder, cognitive impairment, obesity, emesis, movement disorders, obsessive-compulsive disorders, amnesia, aggression, vertigo, dementia and circadian rhythm disorders.
  • the invention also provides the use of a compound of formula (I) as hereinbefore described or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for the treatment of psychotic disorders, schizophrenia, Parkinson's disease, substance abuse, dyskinetic disorders, depression, bipolar disorder, anxiety, cognitive impairment, eating disorders, obesity, sexual dysfunction, sleep disorders, emesis, movement disorders, obsessive-compulsive disorders, amnesia, aggression, autism, vertigo, dementia, circadian rhythm disorders and gastric motility disorders.
  • psychotic disorders schizophrenia, Parkinson's disease, substance abuse, dyskinetic disorders, depression, bipolar disorder, anxiety, cognitive impairment, eating disorders, obesity, sexual dysfunction, sleep disorders, emesis, movement disorders, obsessive-compulsive disorders, amnesia, aggression, autism, vertigo, dementia, circadian rhythm disorders and gastric motility disorders.
  • the term "effective amount” means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher or clinician.
  • Compounds for use according to the invention may be administered as the raw material but the active ingredients are preferably provided in the form of pharmaceutical compositions.
  • a pharmaceutical composition comprising a compound of formula (I) as hereinbefore described or a salt or solvate thereof, and at least one pharmaceutically acceptable carrier, diluent or excipient.
  • These pharmaceutical compositions may be used in the treatment of clinical conditions for which a GlyTI inhibitor is indicated such as, for example, schizophrenia.
  • the carrier must be pharmaceutically acceptable to the recipient and must be compatible with, i.e. not have a deleterious effect upon, the other ingredients in the composition.
  • the carrier may be a solid or a liquid and is preferably formulated with at least one compound of formula (I) or a salt or solvate thereof as a unit dose formulation. If desired, other physiologically active ingredients may also be incorporated in the pharmaceutical compositions of the invention.
  • the compounds according to the invention may advantageously be used in conjunction with one or more other therapeutic agents, for instance, different antidepressant agents such as 5HT3 antagonists, serotonin agonists, NK-1 antagonists, selective serotonin reuptake inhibitors (SSRI), noradrenaline re-uptake inhibitors (SNRI), tricyclic antidepressants, dopaminergic antidepressants, H3 antagonists, 5HT1A antagonists, 5HT1B antagonists, 5HT1D antagonists, D1 agonists, M1 agonists and/or anticonvulsant agents, as well as atypical antipsychotic drugs and cognitive enhancers.
  • different antidepressant agents such as 5HT3 antagonists, serotonin agonists, NK-1 antagonists, selective serotonin reuptake inhibitors (SSRI), noradrenaline re-uptake inhibitors (SNRI), tricyclic antidepressants, dopaminergic antidepressants, H3 antagonists, 5HT1A antagonists, 5
  • Suitable 5HT3 antagonists which may be used in combination of the compounds of the inventions include for example ondansetron, granisetron, metoclopramide.
  • Suitable serotonin agonists which may be used in combination with the compounds of the invention include sumatriptan, rauwolscine, yohimbine, metoclopramide.
  • Suitable SSRIs which may be used in combination with the compounds of the invention include fluoxetine, citalopram, femoxetine, fluvoxamine, paroxetine, indalpine, sertraline, zimeldine.
  • Suitable SNRIs which may be used in combination with the compounds of the invention include venlafaxine and reboxetine.
  • Suitable tricyclic antidepressants which may be used in combination with a compound of the invention include imipramine, amitriptiline, chlomipramine and nortriptiline.
  • Suitable dopaminergic antidepressants which may be used in combination with a compound of the invention include bupropion and amineptine.
  • Suitable anticonvulsant agents which may be used in combination of the compounds of the invention include for example divalproex, carbamazepine and diazepam.
  • Suitable atypical antipsychotic drugs which which may be used in combination of the compounds of the invention include for example risperidone, olanzapine, ziprasidone, aripiprazole and clozapine. It will be appreciated that the compounds of the combination or composition may be administered simultaneously (either in the same or different pharmaceutical formulations), separately or sequentially.
  • the compounds of formula (I) and their pharmaceutically acceptable salts and solvates thereof are also suitable for combination with other typical and atypical antipsychotics to provide improved treatment of psychotic disorders.
  • Particular advantages associated with the combinations, uses and methods of treatment of compounds of formula (I) and their pharmaceutically acceptable salts and solvates thereof include equivalent or improved efficacy at doses of administration which are lower than those commonly used for the individual components. Improved treatments of positive symptoms and/or negative symptoms and/or cognitive symptoms of the psychotic disorder may also be observed.
  • the combinations, uses and methods of treatment of the invention may also provide advantages in treatment of patients who fail to respond adequately or who are resistant to treatment with certain neuroleptic agents.
  • adjunctive administration is meant the coterminous or overlapping administration of each of the components in the form of separate pharmaceutical compositions or devices.
  • This regime of therapeutic administration of two or more therapeutic agents is referred to generally by those skilled in the art and herein as adjunctive therapeutic administration; it is also known as add-on therapeutic administration.
  • Any and all treatment regimes in which a patient receives separate but coterminous or overlapping therapeutic administration of the compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof and at least one neuroleptic agent are within the scope of .the current invention.
  • a patient is typically stabilised on a therapeutic administration of one or more of the of the components for a period of time and then receives administration of another component.
  • the compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof is administered as adjunctive therapeutic treatment to patients who are receiving administration of at least one neuroleptic agent, but the scope of the invention also includes the adjunctive therapeutic administration of at least one neuroleptic agent to patients who are receiving administration of compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof.
  • the combination therapies of the invention may also be administered simultaneously.
  • simultaneous administration is meant a treatment regime wherein the individual components are administered together, either in the form of a single pharmaceutical composition or device comprising or containing both components, or as separate compositions or devices, each comprising one of the components, administered simultaneously.
  • Such combinations of the separate individual components for simultaneous combination may be provided in the form of a kit-of-parts.
  • the invention provides a method of treatment of a psychotic disorder by adjunctive therapeutic administration of compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof to a patient receiving therapeutic administration of at least one neuroleptic agent.
  • the invention provides the use of compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for adjunctive therapeutic administration for the treatment of a psychotic disorder in a patient receiving therapeutic administration of at least one neuroleptic agent.
  • the invention further provides compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use for adjunctive therapeutic administration for the treatment of a psychotic disorder in a patient receiving therapeutic administration of at least one neuroleptic agent.
  • the invention provides a method of treatment of a psychotic disorder by adjunctive therapeutic administration of at least one neuroleptic agent to a patient receiving therapeutic administration of compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof.
  • the invention provides the use of at least one neuroleptic agent in the manufacture of a medicament for adjunctive therapeutic administration for the treatment of a psychotic disorder in a patient receiving therapeutic administration of compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof.
  • the invention further provides at least one neuroleptic agent for adjunctive therapeutic administration for the treatment of a psychotic disorder in a patient receiving therapeutic administration of compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof.
  • the invention provides a method of treatment of a psychotic disorder by simultaneous therapeutic administration of compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof in combination with at least one neuroleptic agent.
  • the invention further provides the use of a combination of compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof and at least one neuroleptic agent in the manufacture of a medicament for simultaneous therapeutic administration in the treatment of a psychotic disorder.
  • the invention further provides the use of compounds of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for simultaneous therapeutic administration with at least one neuroleptic agent in the treatment of a psychotic disorder.
  • the invention further provides compounds of formula (I) or a pharmaceutically acceptable salt thereof for use for simultaneous therapeutic administration with at least one neuroleptic agent in the treatment of a psychotic disorder.
  • the invention further provides the use of at least one neuroleptic agent in the manufacture of a medicament for simultaneous therapeutic administration with compounds of formula (I) or a pharmaceutically acceptable salt thereof in the treatment of a psychotic disorder.
  • the invention provides a method of treatment of a psychotic disorder by simultaneous therapeutic administration of a pharmaceutical composition comprising compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof and at least one mood stabilising or antimanic agent, a pharmaceutical composition comprising compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof and at least one mood stabilising or antimanic agent, the use of a pharmaceutical composition comprising compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof and at least one mood stabilising or antimanic agent in the manufacture of a medicament for the treatment of a psychotic disorder, and a pharmaceutical composition comprising compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof and at least one mood stabilising or antimanic agent for use in the treatment of a psychotic disorder.
  • the invention provides a kit-of-parts for use in the treatment of a psychotic disorder comprising a first dosage form comprising compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof and one or more further dosage forms each comprising a neuroleptic agent for simultaneous therapeutic administration.
  • psychotic disorder includes those disorders mentioned above, such as schizophrenia, mood disorders, anxiety disorders, substance-related disorders, sleep disorders, eating disorders, autistic disorder, attention- deficit/hyperactivity disorder, disruptive behaviour disorder, tic disorders, personality disorders, cognition impairment in other diseases, sexual dysfunction, dyskinetic disorders, depression, bipolar disorder, cognitive impairment and obsessive-compulsive disorders and all the various forms of the disorders as mentioned herein.- which are contemplated as part of the present invention.
  • neuroleptic/antipsychotic drugs examples include, but are not limited to: butyrophenones, such as haloperidol, pimozide, and droperidol; phenothiazines, such as chlorpromazine, thioridazine, mesoridazine, trifluoperazine, perphenazine, fluphenazine, thiflupromazine, prochlorperazine, and acetophenazine; thioxanthenes, such as thiothixene and chlorprothixene thienobenzodiazepines; dibenzodiazepines; benzisoxazoles; dibenzothiazepines imidazolidinones ; benzisothiazolyl-piperazines; triazine such as lamotrigine dibenzoxazepines, such as loxapine; dihydroindolones, such as molindone; aripiprazole
  • neuroleptic drugs that are preferred for use in the present invention are shown in Table 1.
  • clozapine available under the tradename CLOZARIL®, from Mylan, Zenith Goldline, UDL, Novartis
  • olanzapine available under the tradename ZYPREX®, from Lilly
  • ziprasidone available under the tradename GEODON®, from Pfizer
  • risperidone available under the tradename RISPERDAL®, from Janssen
  • quetiapine fumarate available under the tradename SEROQUEL®, from AstraZeneca
  • haloperidol available under the tradename HALDOL®, from Ortho-McNeil
  • chlorpromazine available under the tradename THORAZINE®, from SmithKline Beecham (GSK); fluphenazine (available under the tradename PROLIXIN®, from Apothecon, Copley, Schering, Teva, and American Pharmaceutical Partners, Pasadena); thioth
  • neuroleptic drugs include promazine (available under the tradename SPARINE®), triflurpromazine (available under the tradename VESPRIN®), chlorprothixene (available under the tradename TARACTAN®), droperidol (available under the tradename INAPSINE®), acetophenazine (available under the tradename TINDAL®;), prochlorperazine (available under the tradename COMPAZINE®), methotrimeprazine (available under the tradename NOZINAN®), pipotiazine (available under the tradename PIPOTRIL®), ziprasidone, and hoperidone.
  • promazine available under the tradename SPARINE®
  • triflurpromazine available under the tradename VESPRIN®
  • chlorprothixene available under the tradename TARACTAN®
  • droperidol available under the tradename INAPSINE®
  • acetophenazine available under the tradename TINDAL®
  • prochlorperazine available under the tradename COMP
  • Particularly preferred neuroleptic agents for use in the invention are olanzapine, risperidone, quetiapine, aripiprazole, haloperidol, clozapine, ziprasidone and osanetant.
  • Possible formulations include those suitable for oral, sub-lingual, buccal, parenteral (for example, subcutaneous, intramuscular, or intravenous), rectal, topical and intranasal administration and in forms suitable for administration by inhalation or insufflation (either through the mouth or nose).
  • parenteral for example, subcutaneous, intramuscular, or intravenous
  • rectal topical and intranasal administration and in forms suitable for administration by inhalation or insufflation (either through the mouth or nose).
  • inhalation or insufflation either through the mouth or nose.
  • Formulations suitable for oral administration may be provided as discrete units, such as tablets, capsules, cachets, or lozenges, each containing a predetermined amount of the active compound; as powders or granules; as solutions or suspensions in aqueous or non-aqueous liquids; or as oil-in-water or water-in-oil emulsions.
  • Formulations suitable for sublingual or buccal administration include lozenges comprising the active compound and, typically, a flavoured base, such as sugar and acacia or tragacanth and pastilles comprising the active compound in an inert base, such as gelatin and glycerin or sucrose and acacia.
  • Formulations suitable for parenteral administration typically comprise sterile aqueous solutions containing a predetermined concentration of the active compound; the solution is preferably isotonic with the blood of the intended recipient. Although such solutions are preferably administered intraveneously, they may also be administered by subcutaneous or intramuscular injection.
  • Formulations suitable for rectal administration are preferably provided as unit-dose suppositories comprising the active ingredient and one or more solid carriers forming the suppository base, for example, cocoa butter.
  • Formulations suitable for topical or intranasal application include ointments, creams, lotions, pastes, gels, sprays, aerosols and oils.
  • Suitable carriers for such formulations include petroleum jelly, lanolin, polyethylene glycols, alcohols, and combinations thereof.
  • the formulations of the invention may be prepared by any suitable method, typically by uniformly and intimately admixing the active compound(s) with liquids or finely divided solid carriers, or both, in the required proportions and then, if necessary, shaping the resulting mixture into the desired shape.
  • a tablet may be prepared by compressing an intimate mixture comprising a powder or granules of the active ingredient and one or more optional ingredients, such as a binder, lubricant, inert diluent, or surface active dispersing agent, or by moulding an intimate mixture of powdered active ingredient and inert liquid diluent.
  • one or more optional ingredients such as a binder, lubricant, inert diluent, or surface active dispersing agent, or by moulding an intimate mixture of powdered active ingredient and inert liquid diluent.
  • Aqueous solutions for parenteral administration are typically prepared by dissolving the active compound in sufficient water to give the desired concentration and then rendering the resulting solution sterile and isotonic.
  • the compound may be administered in single or divided doses and may be administered one or more times, for example 1 to 4 times per day.
  • a proposed dose of the active ingredient for use according to the invention for oral, sub- lingual, parenteral, buccal, rectal, intranasal or topical administration to a human (of approximately 70 kg bodyweight) for the treatment of neurological and neuropsychiatric disorders mediated by a GlyTI inhibitor, including schizophrenia, may be about 1 to about 1000 mg, preferably about 5 to about 500 mg, more preferably about 10 to about 100 mg of the active ingredient per unit dose which could be administered, for example, 1 to 4 times per day.
  • M molar
  • mM millimolar
  • i. v. intravenous
  • Hz Hertz
  • T r retention time
  • RP reverse phase
  • TEA triethylamine
  • TFA trifluoroacetic acid
  • TFAA trifluoroacetic anhydride
  • THF tetrahydrofuran
  • DCE dichloroethane
  • DMF N./V-dimethylformamide
  • DMPU ⁇ /, ⁇ /'-dimethyIpropyleneurea
  • GDI 1,1-carbonyldiimidazole
  • IBCF isobutyl chloroformate
  • HOAc acetic acid
  • HOSu ⁇ /-hydroxysuccinimide
  • HOBT 1-hydroxybenzotriazole
  • mCPBA metal-chloroperbenzoic acid
  • EDC ethylcarbodiimide hydrochloride
  • BOC ife/ -butyloxycarbonyl
  • FMOC 9-fluorenylmethoxycarbonyl
  • DCC (dicyclohexylcarbodiimide); CBZ (benzyloxycarbonyl);
  • TIPS triisopropylsilyl
  • TBS f-butyldimethylsilyl
  • Me methyl
  • HPLC high pressure liquid chromatography
  • MS mass spectra
  • MS and liquid chromatography MS were recorded on a Micromass MS2 Platform LC spectrometer. All mass spectra were taken under electrospray ionisation (ESI), chemical ionisation (Cl), electron impact (El) or by fast atom bombardment (FAB) methods. All reactions were monitored by thin-layer chromatography on 0.25 mm E. Merck silica gel plates (60F-254), visualised with UV light, 5% ethanolic phosphomolybdic acid or p- anisaldehyde solution. Flash column chromatography was performed on silica gel (230- 400 mesh, Merck).
  • the title compound was prepared by the method of DeJong and Wibaut, Reel. Trav. Chim. Pays-Bas., 49 p.237-46 (1930).
  • a solution of 2,4-dimethylpyrroie (10g; 0.105mol) in glacial acetic acid (500ml) was hydrogenated at atmospheric pressure and ambient temperature over platinum oxide (2g). After 4h, a further 2g platinum oxide was added and the reaction continued overnight.
  • the catalyst was removed by filtration, and the resulting filtrate was basified strongly with potassium hydroxide pellets (with addition of ice and external card-ice/acetone cooling).
  • the product was obtained by steam distillation of the basic solution, followed by extraction with diethyl ether.
  • the title compound was prepared from fert-butylpropylamine (D36) (632mg; 5.5mmol) using the method outlined in Description 1 (40mg; 4% over 2 steps).
  • Potassium hydride (860mg; 30% in oil) was weighed into an oven dried 3-necked flask and stirred in THF (5ml) under an inert atmosphere during the addition of (2R.6S)- dimethylpiperidine (0.75ml) as a solution in THF (5ml). The suspension was stirred at room temperature for 2 hrs. S-(-)-Glycidyl nosylate (1.13g) was then added dropwise as a solution in THF (5ml) and the reaction mixture stirred at room temperature overnight. The reaction mixture was filtered under an inert atmosphere through CeliteTM and the organic solution evaporated to half volume at reduced pressure, m/z 170 (API + ) [MH + ].
  • 2,6-Diacetylpyridine (2g) was dissolved in diethyleneglycol (50ml) with hydrazine monohydrate (3.6ml). The reaction mixture was heated at 170°C for 30 min. The reaction mixture was then cooled to room temperature for the addition of potassium hydroxide (3.1g), then heated at 200°C for 2h when the reaction mixtue lost all colour. The reaction mixture was then cooled to room temperature and poured onto water.
  • Naphthalene-1 -sulfonic acid [(R)-3-((2S,6R)-2,6-dimethyl-piperidin-1-yl)-2-hydroxy- propylj-amide was prepared by the following procedure: (S)-1-Amino-3-piperidin-1- ylpropan-2-ol (D50; 117mg) was dissolved in dichloromethane (6ml) and 1- naphthylsulfonylchloride (185mg) and triethylamine (0.11ml) were added. The reaction mixture was stirred overnight, diluted with dichloromethane and washed with NaHCO 3 solution and brine. The organic solution was dried (MgSO 4 ), and evaporated.

Abstract

L'invention concerne un composé de formule générale (I), ou un sel, un solvate ou un dérivé fonctionnel sur le plan physiologique de celui-ci, dans laquelle R1 à R10 ont la signification indiquée dans la description ; ainsi que des utilisations desdits composés. Ces composés inhibent les transporteurs GlyT1 et sont utiles dans le traitement de certains troubles neurologiques et neuropsychiatriques, notamment la schizophrénie.
PCT/EP2004/013052 2003-11-18 2004-11-16 Inhibiteurs du transporteur glyt1 WO2005049023A1 (fr)

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WO2006000222A2 (fr) * 2004-06-24 2006-01-05 H. Lundbeck A/S Combinaison d'un antipsychotique et d'un inhibiteur de type 1 transporteur de glycine pour le traitement de la schizophrenie
US8420670B2 (en) 2007-08-22 2013-04-16 Abbott Laboratories 4-benzylaminoquinolines, pharmaceutical compositions containing them, and their use in therapy
CN103209964A (zh) * 2010-08-13 2013-07-17 Abbvie德国有限责任两合公司 苯烷基胺衍生物、含其的药物组合物及其在治疗中的用途
US8563617B2 (en) 2009-02-16 2013-10-22 AbbVie Deutschland GmbH & Co. KG Aminotetraline derivatives, pharmaceutical compositions containing them, and their use in therapy
US8642587B2 (en) 2009-02-16 2014-02-04 AbbVie Deutschland GmbH & Co. KG Heterocyclic compounds, pharmaceutical compositions containing them, and their use in therapy
US8653100B2 (en) 2008-04-01 2014-02-18 Abbvie Inc. Tetrahydroisoquinolines, pharmaceutical compositions containing them, and their use in therapy
US8846741B2 (en) 2011-11-18 2014-09-30 Abbvie Inc. N-substituted aminobenzocycloheptene, aminotetraline, aminoindane and phenalkylamine derivatives, pharmaceutical compositions containing them, and their use in therapy
US8846743B2 (en) 2010-08-13 2014-09-30 Abbott Laboratories Aminoindane derivatives, pharmaceutical compositions containing them, and their use in therapy
US8853196B2 (en) 2011-08-05 2014-10-07 AbbVie Deutschland GmbH & Co. KG Aminochromane, aminothiochromane and amino-1,2,3,4-tetrahydroquinoline derivatives, pharmaceutical compositions containing them, and their use in therapy
US8877794B2 (en) 2010-08-13 2014-11-04 Abbott Laboratories Phenalkylamine derivatives, pharmaceutical compositions containing them, and their use in therapy
US8883839B2 (en) 2010-08-13 2014-11-11 Abbott Laboratories Tetraline and indane derivatives, pharmaceutical compositions containing them, and their use in therapy
US9051280B2 (en) 2010-08-13 2015-06-09 AbbVie Deutschland GmbH & Co. KG Tetraline and indane derivatives, pharmaceutical compositions containing them, and their use in therapy
US9309200B2 (en) 2011-05-12 2016-04-12 AbbVie Deutschland GmbH & Co. KG Benzazepine derivatives, pharmaceutical compositions containing them, and their use in therapy
US9365512B2 (en) 2012-02-13 2016-06-14 AbbVie Deutschland GmbH & Co. KG Isoindoline derivatives, pharmaceutical compositions containing them, and their use in therapy
US9550754B2 (en) 2014-09-11 2017-01-24 AbbVie Deutschland GmbH & Co. KG 4,5-dihydropyrazole derivatives, pharmaceutical compositions containing them, and their use in therapy
US9586942B2 (en) 2013-10-17 2017-03-07 AbbVie Deutschland GmbH & Co. KG Aminotetraline and aminoindane derivatives, pharmaceutical compositions containing them, and their use in therapy
US9586945B2 (en) 2013-10-17 2017-03-07 AbbVie Deutschland GmbH & Co. KG Aminochromane, aminothiochromane and amino-1,2,3,4-tetrahydroquinoline derivatives, pharmaceutical compositions containing them, and their use in therapy
US9650334B2 (en) 2013-03-15 2017-05-16 Abbvie Inc. Pyrrolidine derivatives, pharmaceutical compositions containing them, and their use in therapy
US9656955B2 (en) 2013-03-15 2017-05-23 Abbvie Inc. Pyrrolidine derivatives, pharmaceutical compositions containing them, and their use in therapy
CN107805223A (zh) * 2017-10-30 2018-03-16 广东莱佛士制药技术有限公司 一种喹喔啉‑5‑磺酰氯的合成方法

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Cited By (27)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006000222A2 (fr) * 2004-06-24 2006-01-05 H. Lundbeck A/S Combinaison d'un antipsychotique et d'un inhibiteur de type 1 transporteur de glycine pour le traitement de la schizophrenie
WO2006000222A3 (fr) * 2004-06-24 2006-06-29 Lundbeck & Co As H Combinaison d'un antipsychotique et d'un inhibiteur de type 1 transporteur de glycine pour le traitement de la schizophrenie
US8420670B2 (en) 2007-08-22 2013-04-16 Abbott Laboratories 4-benzylaminoquinolines, pharmaceutical compositions containing them, and their use in therapy
US8957089B2 (en) 2008-04-01 2015-02-17 AbbVie Deutschland GmbH & Co. KG Tetrahydroisoquinolines, pharmaceutical compositions containing them, and their use in therapy
US8653100B2 (en) 2008-04-01 2014-02-18 Abbvie Inc. Tetrahydroisoquinolines, pharmaceutical compositions containing them, and their use in therapy
US9067871B2 (en) 2009-02-16 2015-06-30 AbbVie Deutschland GmbH & Co. KG Aminotetraline derivatives, pharmaceutical compositions containing them, and their use in therapy
US8642587B2 (en) 2009-02-16 2014-02-04 AbbVie Deutschland GmbH & Co. KG Heterocyclic compounds, pharmaceutical compositions containing them, and their use in therapy
US8563617B2 (en) 2009-02-16 2013-10-22 AbbVie Deutschland GmbH & Co. KG Aminotetraline derivatives, pharmaceutical compositions containing them, and their use in therapy
US9096619B2 (en) 2009-02-16 2015-08-04 AbbVie Deutschland GmbH & Co. KG Aminotetraline derivatives, pharmaceutical compositions containing them, and their use in therapy
US8877794B2 (en) 2010-08-13 2014-11-04 Abbott Laboratories Phenalkylamine derivatives, pharmaceutical compositions containing them, and their use in therapy
US9227930B2 (en) 2010-08-13 2016-01-05 Abbvie Inc. Aminoindane derivatives, pharmaceutical compositions containing them, and their use in therapy
US8883839B2 (en) 2010-08-13 2014-11-11 Abbott Laboratories Tetraline and indane derivatives, pharmaceutical compositions containing them, and their use in therapy
CN103209964A (zh) * 2010-08-13 2013-07-17 Abbvie德国有限责任两合公司 苯烷基胺衍生物、含其的药物组合物及其在治疗中的用途
US9045459B2 (en) 2010-08-13 2015-06-02 AbbVie Deutschland GmbH & Co. KG Phenalkylamine derivatives, pharmaceutical compositions containing them, and their use in therapy
US9051280B2 (en) 2010-08-13 2015-06-09 AbbVie Deutschland GmbH & Co. KG Tetraline and indane derivatives, pharmaceutical compositions containing them, and their use in therapy
US9238619B2 (en) 2010-08-13 2016-01-19 AbbVie Deutschland GmbH & Co. KG Phenalkylamine derivatives, pharmaceutical compositions containing them, and their use in therapy
US8846743B2 (en) 2010-08-13 2014-09-30 Abbott Laboratories Aminoindane derivatives, pharmaceutical compositions containing them, and their use in therapy
US9309200B2 (en) 2011-05-12 2016-04-12 AbbVie Deutschland GmbH & Co. KG Benzazepine derivatives, pharmaceutical compositions containing them, and their use in therapy
US8853196B2 (en) 2011-08-05 2014-10-07 AbbVie Deutschland GmbH & Co. KG Aminochromane, aminothiochromane and amino-1,2,3,4-tetrahydroquinoline derivatives, pharmaceutical compositions containing them, and their use in therapy
US8846741B2 (en) 2011-11-18 2014-09-30 Abbvie Inc. N-substituted aminobenzocycloheptene, aminotetraline, aminoindane and phenalkylamine derivatives, pharmaceutical compositions containing them, and their use in therapy
US9365512B2 (en) 2012-02-13 2016-06-14 AbbVie Deutschland GmbH & Co. KG Isoindoline derivatives, pharmaceutical compositions containing them, and their use in therapy
US9650334B2 (en) 2013-03-15 2017-05-16 Abbvie Inc. Pyrrolidine derivatives, pharmaceutical compositions containing them, and their use in therapy
US9656955B2 (en) 2013-03-15 2017-05-23 Abbvie Inc. Pyrrolidine derivatives, pharmaceutical compositions containing them, and their use in therapy
US9586942B2 (en) 2013-10-17 2017-03-07 AbbVie Deutschland GmbH & Co. KG Aminotetraline and aminoindane derivatives, pharmaceutical compositions containing them, and their use in therapy
US9586945B2 (en) 2013-10-17 2017-03-07 AbbVie Deutschland GmbH & Co. KG Aminochromane, aminothiochromane and amino-1,2,3,4-tetrahydroquinoline derivatives, pharmaceutical compositions containing them, and their use in therapy
US9550754B2 (en) 2014-09-11 2017-01-24 AbbVie Deutschland GmbH & Co. KG 4,5-dihydropyrazole derivatives, pharmaceutical compositions containing them, and their use in therapy
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