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WO2010018214A1 - Dérivés de pyrrolidinone utiles pour le traitement de troubles psychotiques et neurologiques - Google Patents

Dérivés de pyrrolidinone utiles pour le traitement de troubles psychotiques et neurologiques Download PDF

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WO2010018214A1
WO2010018214A1 PCT/EP2009/060515 EP2009060515W WO2010018214A1 WO 2010018214 A1 WO2010018214 A1 WO 2010018214A1 EP 2009060515 W EP2009060515 W EP 2009060515W WO 2010018214 A1 WO2010018214 A1 WO 2010018214A1
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disorder
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Roderick Alan Porter
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Glaxo Group Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/54—Spiro-condensed
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings

Definitions

  • the present invention relates to compounds, processes for their preparation, pharmaceutical compositions and medicaments containing them and to their use in the treatment of a condition wherein inhibition of GIyTI would be beneficial, including neurological and neuropsychiatric disorders, in particular psychoses, dementia or attention deficit disorder.
  • GIyTI is found throughout the brain and may be located at NMDA glutamate receptor synapses as well as in areas containing inhibitory glycine receptors (Cubelos et al., Cerebral Cortex, 15, 2005: 448-459; Zafra et al., Eur. J. Neurosci. 7, 1995: 1342-1352).
  • GIyT-Ia three variants of GIyTI , termed GIyT-Ia, GIyT-I b and GIyT-I c (Kim et al., Molecular Pharmacology, 45, 1994: 608-617), each of which displays a unique distribution in the brain and peripheral tissues.
  • the variants arise by differential splicing and exon usage, and differ in their N-terminal regions.
  • GlyT2 in contrast, is found predominantly in the brain stem and spinal cord, and its distribution corresponds closely to that of inhibitory glycine receptors (Liu et al., J. Biological Chemistry, 268, 1993: 22802-22808; Jursky and Nelson, J.
  • GlyT2 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 GIyTL.
  • GIyTI the role of GIyTI is to regulate glycine levels at both NMDA glutamate receptors and inhibitory glycine receptors, whereas the main role of GlyT2 may be to replenish glycine in presynaptic terminals of inhibitory glycinergic synapses (Gomeza et al., Neuron 40, 2003, 785-796 & 797-806).
  • 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 contribute to the symptoms of schizophrenia (Lisman et al., Trends Neurosci. 31 , 234-242 (2008); Olney and Farber, Archives General Psychiatry, 52, 998-1007 (1996)).
  • agents that inhibit GIyTI 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.
  • Glycine transport inhibitors are already known in the art, for example as disclosed in published international patent application WO03/055478 (SmithKline Beecham).
  • R 1 is selected from H, C 1 -C 4 alkyl, C 1 -C 4 BIkOXy, halo, haloCi-C 4 alkyl, haloCr ⁇ alkoxy, C 1 - C 4 alkylthio, C 3 -C 6 cycloalkyl, C r C 4 alkylsulfonyl, Ci-C 4 alkoxyCrC 4 alkyl, CONR a R b (wherein R a and R b are independently selected from H and C ⁇ C 4 alkyl, or R a and R b , together with the nitrogen atom to which they are attached, form a 4- to 7-membered ring) and cyano;
  • R 2 is selected from H, Ci-C 4 alkyl, CrC 4 alkoxy, halo, haloCi-C 4 alkyl, haloCi-C 4 alkoxy, C 1 - C 4 alkylthio, C 3 -C 6 cycloalkyl, C r C 4 alkylsulfonyl, Ci-C 4 alkoxyCrC 4 alkyl , CONR c R d (wherein R c and R d are independently selected from H and Ci-C 4 alkyl, or R c and R d , together with the nitrogen atom to which they are attached, form a 4- to 7-membered ring) and cyano;
  • R 3 is selected from H, Ci -4 alkyl, CrC 4 alkoxy, halo, haloCrC 4 alkyl, haloCrC 4 alkoxy, d- C 4 alkylthio, C 3 -C 6 cycloalkyl, C r C
  • R 2 and R 3 together form a group selected from -0-CH 2 -O- and -0-CH 2 -CH 2 -O-;
  • R 4 is selected from H, C ⁇ C 4 alkyl, Ci-C 4 alkoxy, halo, haloCi-C 4 alkyl, haloCi-C 4 alkoxy, C 1 - C 4 alkylthio, C 3 -C 6 cycloalkyl, C r C 4 alkylsulfonyl, Ci-C 4 alkoxyCi-C 4 alkyl, C0NR 9 R h (wherein R 9 and R h are independently selected from H and C ⁇ C 4 alkyl, or R 9 and R h , together with the nitrogen atom to which they are attached, form a 4- to 7-membered ring) and cyano;
  • R 5 is selected from hydrogen, chloro, fluoro, Ci-C 4 alkyl and CF 3 ;
  • R 6 is selected from a 5-7 membered heteroaryl or 5 to 7 membered heterocyclic ring optionally substituted by Ci -4 alkyl, Ci -4 alkoxy, haloalkyl, haloalkoxy, halo or cyano;
  • R 7 is selected from H, Ci-C 4 alkyl, Ci-C 4 alkoxy, haloCi-C 4 alkyl, haloCi-C 4 alkoxy, halo, cyano, Ci -4 alkoxyCi -4 alkyl and Ci-C 4 alkoxyCrC 4 alkoxy;
  • n 0, 1 and 2;
  • R 8 is selected from hydrogen and Ci-C 4 alkyl
  • R 21 is selected from H and fluoro.
  • Ci-C 4 alkyl refers to a straight or branched alkyl group of 1-4 carbon atoms in all isomeric forms. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl.
  • C r C 4 alkoxy refers to the group -O-Ci-C 4 alkyl wherein C r C 4 alkyl is as defined above.
  • C r C 4 alkoxyCi-C 4 alkyl refers to the group (Ci -4 alkyl)-O-(Ci_ 4 alkyl), wherein Ci-C 4 alkyl is as defined above.
  • CrC 4 alkoxyCrC 4 alkyoxy refers to the group 4alkyl, wherein d-C 4 alkyl is as defined above.
  • C 3 -C 6 cycloalkyl refers to a cycloalkyl group consisting of from 3 to 6 carbon atoms, ie cyclopropane, cyclobutane, cyclopentane or cyclohexane.
  • halogen and its abbreviation “halo” refer to fluorine, chlorine, bromine, or iodine.
  • haloC 1 -C 4 alkyl refers to a C 1 -C 4 alkyl group as defined above which is substituted with any number of fluorine, chlorine, bromine, or iodine atoms, including with mixtures of those atoms.
  • a haloC 1 -C 4 alkyl group may, for example contain 1 , 2 or 3 halogen atoms.
  • a haloC 1 -C 4 alkyl group may have all hydrogen atoms replaced with halogen atoms.
  • Examples of haloC 1 -C 4 alkyl groups include fluoromethyl, difluoromethyl and trifluoromethyl.
  • haloCi-C 4 alkoxy refers to a CrC 4 alkoxy group as defined above which is substituted with any number of fluorine, chlorine, bromine, or iodine atoms, including with mixtures of those atoms.
  • a haloCrC 4 alkoxy group may, for example contain 1 , 2 or 3 halogen atoms.
  • a haloCrC 4 alkoxy group may have all hydrogen atoms replaced with halogen atoms.
  • Examples of haloCrC 4 alkoxy groups include fluoromethyloxy, difluoromethyloxy and trifluoromethyloxy.
  • cyano refers to a group -CN.
  • C 1 -C 4 alkylsulfonyl refers to a group -SO 2 (C 1 -C 4 alkyl).
  • An example is -SO 2 CH 3 .
  • C 1 -C 4 alkylthio refers to a group -S -(C 1 -C 4 alkyl).
  • An example is -SCH 3 .
  • 5-7 membered heteroaryl refers to an aromatic or a benzofused aromatic ring containing 1 to 4 heteroatoms selected from oxygen, nitrogen and sulphur.
  • aromatic rings include thienyl, furyl, pyrrolyl, triazolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyridazyl, triazinyl and tetrazolyl.
  • Suitable examples of benzofused aromatic rings include quinolinyl, isoquinolinyl, indolyl, benzofuryl, benzothienyl, benzoimidazolyl and benzoxazolyl.
  • 5-7 membered heterocyclic ring refers to a non aromatic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulphur.
  • non aromatic rings include piperidinyl, piperazinyl, pyrrolidinyl and morpholinyl.
  • heteroaryl and 5-7 membered heterocyclic rings may be linked to the remainder of the molecule via a carbon atom, or when present, a suitable nitrogen atom.
  • R 1 is selected from H, C 1 -C 2 alkyl, C 1 -C 2 BIkOXy, halo, haloC 1 -C 2 alkyl, haloCrC ⁇ lkoxy, CrC ⁇ lkylthio, CrC ⁇ lkylsulfonyl, Ci-C 2 alkoxyCi-C 2 alkyl and cyano.
  • R 1 is H.
  • R 2 is selected from H, Ci-C 2 alkyl, Ci-C 2 alkoxy, halo, haloCrC 2 alkyl, haloCi-C 2 alkoxy, Ci-C 2 alkylthio, Ci-C 2 alkylsulfonyl, Ci-C 2 alkoxyCrC 2 alkyl, and cyano.
  • R 2 is halo.
  • R 2 is F.
  • R 3 is selected from H, Ci-C 2 alkyl, Ci-C 2 alkoxy, halo, haloCrC 2 alkyl, haloCi-C 2 alkoxy, Ci-C 2 alkylthio, Ci-C 2 alkylsulfonyl, Ci-C 2 alkoxyCrC 2 alkyl, and cyano. In a further embodiment R 3 is H.
  • R 4 is selected from H, Ci-C 2 alkyl, Ci-C 2 alkoxy, halo, haloCrC 2 alkyl, haloCrC ⁇ lkoxy, CrC ⁇ lkylthio, CrC ⁇ lkylsulfonyl, C ⁇ C 2 alkoxyCi-C 2 alkyl, and cyano.
  • R 4 is halo.
  • R 4 is F.
  • R 5 is selected from hydrogen, chloro, fluoro, C-rC 4 alkyl and CF 3 . In a further embodiment R 5 is H.
  • R 6 is imidazole.
  • R 7 is selected from H, d-C 2 alkyl, CrC 2 alkoxy, haloCi-C 2 alkyl, haloCi-C 2 alkoxy, halo, cyano, Ci-C 2 alkoxyCrC 2 alkyl and Ci-C 2 alkoxyCi-C 2 alkoxy.
  • R 7 is H.
  • m is 1.
  • R 8 is H.
  • R 21 is H.
  • substituted means substituted by one or more defined groups.
  • groups may be selected from a number of alternative groups, the selected groups may be the same or different.
  • independently means that where more than one substituent is selected from a number of possible substituents, those substituents may be the same or different.
  • Salts of compounds of formula (I) which are suitable for use in medicine are those wherein the counterion is pharmaceutically acceptable.
  • salts having non- pharmaceutically acceptable counterions are within the scope of the present invention, for example, for use as intermediates in the preparation of other compounds of formula (I) and their pharmaceutically acceptable salts and/or for use in non-therapeutic, for example, in vitro, situations.
  • 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.
  • Pharmaceutically 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 pharmaceutically acceptable anion or cation.
  • Suitably pharmaceutically 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, (1 R)-(-)-10-camphorsulphonic, (1S)-(+)-10- camphorsulphonic, isothionic, mucic, gentisic, isonicotinic, saccharic, glucuronic, furoic, glutamic, ascorbic, anthranilic, salicylic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, pantothenic, stearic, sulfinilic, alg
  • solvate refers to a complex of variable stoichiometry formed by a solute (in this invention, a compound of formula (I) or a salt thereof) and a solvent.
  • solvents include, but are not limited to, water, methanol, ethanol and acetic acid.
  • 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, without limitation, water, ethanol and acetic acid.
  • the solvent used is water. Where the solvent used is water such a solvate may then also be referred to as a hydrate.
  • polymorphs of a compound of the invention are also included within the scope of the invention.
  • the invention also includes all suitable isotopic variations of a compound of the invention.
  • An isotopic variation of a compound of the invention is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine and chlorine such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F and 36 CI, respectively.
  • isotopic variations of the invention for example, those in which a radioactive isotope such as 3 H or 14 C is incorporated, are useful in drug and/or substrate tissue distribution studies. Tritiated, i.e., 3 H, and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with isotopes such as deuterium, i.e., 2 H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements and hence may be preferred in some circumstances.
  • Isotopic variations of the compounds of the invention can generally be prepared by conventional procedures such as by the illustrative methods or by the preparations described in the Examples hereafter using appropriate isotopic variations of suitable reagents.
  • 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 formula (I) may exist in tautomeric forms other than that shown in the formula and these are also included within the scope of the present invention.
  • an optically pure enantiomer of a compound of the present invention is provided.
  • optically pure enantiomer means that the compound contains greater than about 90 % of the desired isomer by weight, such as greater than about 95 % of the desired isomer by weight, or 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 amido alcohol (V) is treated with an oxidising agent, for example, IBX, DMSO/acetic anhydride or DMSO/oxalyl chloride step (i) in the presence of a base such as triethylamine to give the intermediate aldehyde (Vl).
  • an oxidising agent for example, IBX, DMSO/acetic anhydride or DMSO/oxalyl chloride step (i) in the presence of a base such as triethylamine to give the intermediate aldehyde (Vl).
  • the intermediate aldehyde is subsequently submitted to intramolecular condensation step (ii) in the presence of for example, sodium hydroxide in ethanol or ammonium acetate in an inert solvent such as toluene.
  • compounds (V) may be prepared from aryl; acetic acids (IX) as shown in scheme 5 by treating the amino alcohol (VII) with acid (IX) in an inert solvent, such as dichloromethane in the presence of a coupling reagent, for example a diimide reagent such as N, N dicyclohexylcarbodiimide (DCC), N-(3-(dimethylamino)propyl)-N- ethylcarbodiimide hydrochloride (EDC), or O-(7-azabenzotriazol-1-yl)-1 , 1 ,3,3- tetramethyluronium hexafluoro phosphate (HATU).
  • a coupling reagent for example a diimide reagent such as N, N dicyclohexylcarbodiimide (DCC), N-(3-(dimethylamino)propyl)-N- ethylcarbodiimide hydro
  • Amino alcohols (VII), and arylacetic acids (IX) and activated aryl acetic acids such as acid chlorides (VIII) L Cl are either known compounds or readily prepared by standard methods.
  • a compound of structure (X) treatment of a compound of structure (X) with an appropriate palladium catalyst such as tetrakis(triphenylphosphine)palladium[0] or palladium acetate in conjunction with a phosphine ligand such as 1 ,3-(bis)triphenylphosphino)propane, a base such as sodium carbonate, triethylamine or diisopropylamine and a heteroaryl boronic acid or heteroaryl trialkyltin reagent may undergo palladium mediated coupling to give a compound of formula (II) where R 6 is a carbon linked heteroaryl group.
  • an appropriate palladium catalyst such as tetrakis(triphenylphosphine)palladium[0] or palladium acetate
  • a phosphine ligand such as 1 ,3-(bis)triphenylphosphino)propane
  • a base such as sodium carbonate,
  • reaction may be performed in a range of solvents including tetrahydrofuran, dimethylformamide, dioxan or toluene, or combinations of solvents, optionally in the presence of an ionic liquid such as 1-butyl-3-imidazolium tetrafluoroborate either at ambient or preferably elevated temperatures.
  • solvents including tetrahydrofuran, dimethylformamide, dioxan or toluene, or combinations of solvents, optionally in the presence of an ionic liquid such as 1-butyl-3-imidazolium tetrafluoroborate either at ambient or preferably elevated temperatures.
  • a compound of structure (X) with an appropriate palladium catalyst such as tetrakis(triphenylphosphine)palladium[0] or palladium acetate in conjunction with a phosphine ligand such as 2,2'-bis(diphenylphosphino)-1 ,1 '- binaphthalene (BINAP), a base such as cesium carbonate or potassium phosphate, and a 5 to 7 membered heterocyclic ring containing a secondary amine, such as piperidine or morpholine, may undergo palladium mediated coupling to give a compound of formula (II) where R 6 is a nitrogen linked 5-7 membered heterocyclic group.
  • an appropriate palladium catalyst such as tetrakis(triphenylphosphine)palladium[0] or palladium acetate
  • a phosphine ligand such as 2,2'-bis(diphenylphosphino)-1 ,1 '-
  • reaction may be performed in a range of solvents including tetrahydrofuran, dimethylformamide, dioxan or toluene, or combinations of solvents, optionally in the presence of an ionic liquid such as 1 -butyl-3-imidazolium tetrafluoroborate either at ambient or preferably elevated temperatures.
  • solvents including tetrahydrofuran, dimethylformamide, dioxan or toluene, or combinations of solvents, optionally in the presence of an ionic liquid such as 1 -butyl-3-imidazolium tetrafluoroborate either at ambient or preferably elevated temperatures.
  • a compound of structure (X) with an appropriate copper catalyst such as copper (I) bromide or copper (I) iodide, in conjunction with a ⁇ -ketoester ligand such as ethyl 2-oxocyclohexanecarboxylate or diamine ligand such as trans-1 ,2- diaminocylohexane, a base such as cesium carbonate or potassium phosphate and a heteroaryl or 2-oxo substituted 5-7 membered heterocyclic ring containing a free NH, may undergo copper mediated coupling to give a compound of formula (II) where R 6 is a nitrogen linked heteroaromatic or 2-oxo substituted 5-7 membered heterocyclic ring.
  • an appropriate copper catalyst such as copper (I) bromide or copper (I) iodide
  • a ⁇ -ketoester ligand such as ethyl 2-oxocyclohexanecarboxylate or diamine ligand such as
  • reaction may be performed in a range of solvents such as dimethyl sulphoxide, N,N-dimethylformamide, N-methylpyrrolidinone, acetonitrile or dioxan or combinations of solvents, optionally in the presence of an ionic liquid such as 1 -butyl-3-imidazolium tetrafluoroborate either at ambient or preferably elevated temperatures.
  • solvents such as dimethyl sulphoxide, N,N-dimethylformamide, N-methylpyrrolidinone, acetonitrile or dioxan or combinations of solvents
  • an ionic liquid such as 1 -butyl-3-imidazolium tetrafluoroborate either at ambient or preferably elevated temperatures.
  • compounds of formula (II) can be prepared as shown in scheme 8 wherein R 7 , R 8 and R 21 are as defined in formula (I) and R 6 is a carbon linked heteroaryl group from intermediates such as where R 6 is a carboxylic acid (XIX) or R 6 is a cyano group (XX) using standard methods for preparation of heterocyclic systems such as those described in series such as Organic Syntheses, The Chemistry of Heterocycles or Comprehensive Heterocyclic Chemistry.
  • Nitrile (XII) can be prepared from (X) by treatment with a cyanide such as copper (I) cyanide, in a solvent such as N,N-dimethylformamide or N-methylpyrrolidinone at elevated temperature.
  • Carboxylic acid (Xl) may be prepared by acidic hydrolysis of nitrile (XII) or directly from (X) by treatment with 2 equivalents of alkyllithium at reduced temperature followed by addition of carbon dioxide, or through palladium mediated carbonylation methodology.
  • R , R , R , R R , R , R and R are as defined for compounds of formula (I).
  • Compounds of formula (XIII) can be prepared using standard methods from compounds of formula (II), step (iii), for example, by reaction with an appropriate haloester in the presence of a base, such as sodium hydride or potassium carbonate, in a suitable inert solvent, such as dimethylformamide, at room temperature or elevated temperature as appropriate.
  • a base such as sodium hydride or potassium carbonate
  • a suitable inert solvent such as dimethylformamide
  • acylation step (v) can be achieved by reaction of the acid (XIV) with an aniline of formula (IV), in an inert solvent, such as dichloromethane in the presence of a coupling reagent, for example a diimide reagent such as N, N dicyclohexylcarbodiimide
  • DCC N-(3-(dimethylamino)propyl)-N-ethylcarbodiimide hydrochloride
  • HATU O-(7- azabenzotriazol-1-yl)-1 ,1 ,3,3-tetramethyluronium hexafluoro phosphate
  • R 6 , R 7 , R 8 and R 21 are as defined in formula (I) and L represents a suitable leaving group.
  • L may be halogen and acylation in step (v) may be carried out in an inert solvent such as dichloromethane, in the presence of a base, such as triethylamine.
  • a compound of formula (I) where R 6 is bromo may be converted to compounds of formula (I) wherein R 6 is heteroaryl or a 5-7 membered heterocyclic ring using either palladium or copper mediated coupling using methods as indicated in Scheme 7.
  • a heterocycle may be constructed from a compound of formula (I) where R 6 is bromo via a carboxylic acid or cyano intermediate using procedures as indicated in Scheme 8.
  • Compounds of formula (I) can be converted into further compounds of formula (I) using standard techniques. Salts may be prepared conventionally by reaction with the appropriate acid or acid derivative.
  • the compounds of the present invention inhibit the GIyTI transporter.
  • the compounds may selectively inhibit the GIyTI transporter over the GlyT2 transporter.
  • Some compounds of the invention may have mixed GlyT-1/GlyT-2 activity.
  • treatment and “treating” refer to the alleviation and/or cure of established symptoms as well as prophylaxis.
  • affinities of the compounds of this invention for the GIyTI transporter can be determined by the following assay.
  • HEK293 cells expressing the Glycine (Type 1 ) transporter were grown in cell culture medium [DMEM/NUT mix F12 containing 2mM L-Glutamine, 0.8mg/ml_ G418 and 10% heat inactivated fetal calf serum] at 37°C and 5% CO 2 .
  • Compounds are considered to have activity at the the GIyTI transporter if they have a plC 50 of 5.0 or above in the above assay.
  • the example compounds below and the individually named compounds above were found to have an average plC 5 o at the GIyTI transporter of greater than or equal to 5.6.
  • the compounds of the present invention were not necessarily from the same batch described below. A test compound from one batch may have been combined with other batch(es) for the assay(s).
  • the compounds of the present invention inhibit the GIyTI transporter, as measured by the assay above. Such compounds are therefore of potential utility for the treatment of certain neurological and neuropsychiatric disorders.
  • the compounds may selectively inhibit the GIyTI transporter over the GlyT2 transporter.
  • Some compounds of the invention may have mixed GlyT1/GlyT2 activity.
  • the disorder to be treated by the use or method as hereinbefore described is a psychosis, including schizophrenia, dementia and attention deficit disorders.
  • the disorder is schizophrenia.
  • DSM-IV American Psychiatric Association
  • ICD-10 International Classification of Diseases, 10 th Edition
  • the compounds of the invention be 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 the invention may be 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 Il 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 the invention may also be 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).
  • 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), Obsess
  • the compounds of the invention may also be 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 the invention may also be 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
  • primary sleep disorders such as Dyssomnias such as Primary Insomnia (307.42), Primary Hypersomnia (307.44), Narcolepsy (347), Breathing-Related Sleep
  • the compounds of the invention may also be 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 the invention may also be 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
  • the compounds of the invention may also be 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 the invention may also be of use in the treatment of cognitive impairment.
  • cognitive impairment includes for example the treatment of impairment of cognitive functions including attention, orientation, learning disorders, memory (i.e. memory disorders, amnesia, amnesic disorders, transient global amnesia syndrome and age-associated memory impairment) and language function; cognitive impairment as a result of stroke, Alzheimer's disease, Huntington's disease, Pick disease, Aids-related dementia or other dementia states such as 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- electrostatic impairment
  • the compounds of the present invention may also be of use for the treatment of cognition impairment which arises in association or as a result of other diseases such as schizophrenia, bipolar disorder, depression, other psychiatric disorders and psychotic conditions associated with cognitive impairment.
  • the compounds of the invention may also be 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 compounds of the invention may also be of use as anticonvulsants.
  • the compounds of the invention are thus useful in the treatment of convulsions in mammals, and particularly epilepsy in humans.
  • "Epilepsy” is intended to include the following seizures: simple partial seizures, complex partial seizures, secondary generalised seizures, generalised seizures including absence seizures, myoclonic seizures, clonic seizures, tonic seizures, tonic clonic seizures and atonic seizures.
  • the invention also provides a method of treating convulsions, which comprises administering to a mammal in need thereof an effective amount of a compound of the invention as hereinbefore described or a salt thereof.
  • Treatment of epilepsy may be carried out by the administration of a nontoxic anticonvulsant effective amount of a compound of the formula (I) or a salt thereof.
  • the compounds of the invention may also be useful in the treatment or prophylaxis of pain, including acute pain, chronic pain, chronic articular pain, musculoskeletal pain, neuropathic pain, inflammatory pain, visceral pain, pain associated with cancer, pain associated with migraine, tension headache and cluster headaches, pain associated with functional bowel disorders, lower back and neck pain, pain associated with sprains and strains, sympathetically maintained pain; myositis, pain associated with influenza or other viral infections such as the common cold, pain associated with rheumatic fever, pain associated with myocardial ischemia, post operative pain, cancer chemotherapy, headache, toothache and dysmenorrhea.
  • 'Chronic articular pain' conditions include rheumatoid arthritis, osteoarthritis, rheumatoid spondylitis, gouty arthritis and juvenile arthritis.
  • 'Pain associated with functional bowel disorders' includes non-ulcer dyspepsia, non- cardiac chest pain and irritable bowel syndrome.
  • 'Neuropathic pain' syndromes include: diabetic neuropathy, sciatica, non-specific lower back pain, trigeminal neuralgia, multiple sclerosis pain, fibromyalgia, HIV-related neuropathy, post-herpetic neuralgia, trigeminal neuralgia, and pain resulting from physical trauma, amputation, phantom limb syndrome, spinal surgery, cancer, toxins or chronic inflammatory conditions.
  • neuropathic pain conditions include pain associated with normally non-painful sensations such as "pins and needles" (paraesthesias and dysesthesias), increased sensitivity to touch (hyperesthesia), painful sensation following innocuous stimulation (dynamic, static, thermal or cold allodynia), increased sensitivity to noxious stimuli (thermal, cold, mechanical hyperalgesia), continuing pain sensation after removal of the stimulation (hyperpathia) or an absence of or deficit in selective sensory pathways (hypoalgesia).
  • Other conditions which could potentially be treated by compounds of the invention include neurodegenerative diseases and neurodegeneration, neurodegeneration following trauma, tinnitus, dependence on a dependence-inducing agent such as opioids (e.g. morphine), CNS depressants (e.g. ethanol), psychostimulants (e.g. cocaine) and nicotine.
  • opioids e.g. morphine
  • CNS depressants e.g. ethanol
  • psychostimulants e.g. cocaine
  • Neurodegenerative diseases include dementia, particularly degenerative dementia (including senile dementia, dementia with Lewy bodies, Alzheimer's disease, Pick's disease, Huntingdon's chorea, Parkinson's disease and Creutzfeldt-Jakob disease, ALS, motor neuron disease); vascular dementia (including multi-infarct dementia); as well as dementia associated with intracranial space occupying lesions; trauma; infections and related conditions (including HIV infection, meningitis and shingles); metabolism; toxins; anoxia and vitamin deficiency; and mild cognitive impairment associated with ageing, particularly Age Associated Memory Impairment.
  • degenerative dementia including senile dementia, dementia with Lewy bodies, Alzheimer's disease, Pick's disease, Huntingdon's chorea, Parkinson's disease and Creutzfeldt-Jakob disease, ALS, motor neuron disease
  • vascular dementia including multi-infarct dementia
  • dementia associated with intracranial space occupying lesions trauma
  • infections and related conditions including HIV infection, meningitis and shingles
  • Another condition which could potentially be treated by compounds of the invention is spasticity or muscular hypertonicity.
  • disorders include benign forgetfulness, childhood learning disorders and closed head injury, Parkinson's disease, dyskinetic disorders, cognitive impairment, emesis, movement disorders, amnesia, circadian rhythm disorders, aggression and vertigo.
  • treatment refers to the alleviation and/or cure of established symptoms as well as prophylaxis.
  • the invention thus provides compounds of formula (I) and pharmaceutically acceptable salts thereof for use in therapy.
  • the invention also provides compounds of formula (I) and pharmaceutically acceptable salts thereof for use in the treatment of a disorder wherein inhibition of GIyTI would be beneficial.
  • a method of treating a disorder wherein inhibition of GIyTI would be beneficial comprising administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • 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 a pharmaceutical composition, which comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.
  • the present invention provides a process for preparing a pharmaceutical composition, the process comprising mixing a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.
  • a pharmaceutical composition of the invention is usually adapted 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.
  • oral administration is provided.
  • compositions 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.
  • compositions 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.
  • a flavoured base such as sugar and acacia or tragacanth
  • pastilles comprising the active compound in an inert base, such as gelatin and glycerin or sucrose and acacia.
  • compositions suitable for parenteral administration typically comprise sterile aqueous solutions containing a predetermined concentration of the active compound; the solution may be isotonic with the blood of the intended recipient. Such solutions may be administered intravenously or by subcutaneous or intramuscular injection.
  • compositions suitable for rectal administration may be provided as unit-dose suppositories comprising the active ingredient and one or more solid carriers forming the suppository base, for example, cocoa butter.
  • compositions suitable for topical or intranasal application include ointments, creams, lotions, pastes, gels, sprays, aerosols and oils.
  • Suitable carriers for such compositions include petroleum jelly, lanolin, polyethylene glycols, alcohols, and combinations thereof.
  • compositions 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, sublingual, 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 GIyTI inhibitor, including schizophrenia, may be about 0.1 to about 1000 mg, for example about 0.5 mg to about 1000mg, or about 1 mg to about 1000 mg, or about 5 mg to about 500 mg, or about 10 mg to about 100 mg of the active ingredient per unit dose, which could be administered, for example, 1 to 4 times per day.
  • the compounds of formula (I) and their pharmaceutically acceptable salts thereof may also be suitable for combination with other therapeutic agents, such as typical and atypical antipsychotics.
  • the present invention also provides:
  • a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof with one or more further therapeutic agents such an one or more antipsychotic; ii) a pharmaceutical composition comprising a combination product as defined in i) above and at least one carrier, diluent or excipient; iii) the use of a combination as defined in i) above in the manufacture of a medicament for treating or preventing a disease or condition caused by a reduction or imbalance in glutamate receptor function in a mammal; iv) a combination as defined in i) above for use in treating or preventing a disease or condition caused by a reduction or imbalance in glutamate receptor function in a mammal; v) a kit-of-parts for use in the treatment of a psychotic disorder comprising a first dosage form comprising a compound of the invention and one or more further dosage forms each comprising a antipsychotic agent for simultaneous therapeutic administration, vi) a combination as defined in i) above for use in therapy; vii
  • 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 thereof and at least one antipsychotic 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 thereof may be administered as adjunctive therapeutic treatment to patients who are receiving administration of at least one antipsychotic agent, but the scope of the invention also includes the adjunctive therapeutic administration of at least one antipsychotic agent to patients who are receiving administration of compounds of formula (I) or a pharmaceutically acceptable salt 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 thereof to a patient receiving therapeutic administration of at least one antipsychotic agent.
  • the invention provides the use of compounds of formula (I) or a pharmaceutically acceptable salt 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 antipsychotic agent.
  • the invention further provides compounds of formula (I) or a pharmaceutically acceptable salt thereof for use for adjunctive therapeutic administration for the treatment of a psychotic disorder in a patient receiving therapeutic administration of at least one antipsychotic agent.
  • the invention provides a method of treatment of a psychotic disorder by adjunctive therapeutic administration of at least one antipsychotic agent to a patient receiving therapeutic administration of compounds of formula (I) or a pharmaceutically acceptable salt thereof.
  • the invention provides the use of at least one antipsychotic 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 thereof.
  • the invention further provides at least one antipsychotic agent for adjunctive therapeutic administration for the treatment of a psychotic disorder in a patient receiving therapeutic administration of compounds of formula (I) or pharmaceutically acceptable a salt 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 thereof in combination with at least one antipsychotic agent.
  • the invention further provides the use of a combination of compounds of formula (I) or a salt thereof and at least one antipsychotic 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 antipsychotic 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 antipsychotic agent in the treatment of a psychotic disorder.
  • the invention further provides the use of at least one antipsychotic 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 thereof and at least one mood stabilising or antimanic agent, a pharmaceutical composition comprising compounds of formula (I) or a pharmaceutically acceptable salt 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 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 thereof and at least one mood stabilising or antimanic agent for use in the treatment of a psychotic disorder.
  • 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; benziso- thiazolyl-piperazines; triazine such as lamotrigine; dibenzoxazepines, such as loxapine; dihydroindolones, such as molindone; aripiprazole
  • Examples of tradenames and suppliers of selected antipsychotic drugs are as follows: amisulpride (SOLIAN(D), 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);
  • benperidol (Glianimon®), perazine (Taxilan®) or melperone (Eunerpan®)) may be used.
  • Other antipsychotic 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(D), pipotiazine (available under the tradename PIPOTRIL(D), ziprasidone, and hoperidone.
  • promazine available under the tradename SPARINE®
  • triflurpromazine available under the tradename VESPRIN®
  • chlorprothixene available under the tradename TARACTAN®
  • antidepressant agents such as 5HT3 antagonists, serotonin agonists, NK1 antagonists, NK3 antagonists, AMPA modulators, alpha7 positive modulators, 5HT6 antagonists, 5HT2A antagonists, selective serotonin reuptake inhibitors (SSRI), noradrenaline re- uptake inhibitors (SNRI), tricyclic antidepressants, dopaminergic antidepressants, H3 antagonists, 5HT1A antagonists, 5HT1 B antagonists, 5HT1 D antagonists, D1 agonists, M1 and M1/4 muscarinic agonists and/or anticonvulsant agents, as well as cognitive enhancers.
  • antidepressant agents such as 5HT3 antagonists, serotonin agonists, NK1 antagonists, NK3 antagonists, AMPA modulators, alpha7 positive modulators, 5HT6 antagonists, 5HT2A antagonists, selective serotonin reuptake inhibitors (SSRI), noradrenaline re- up
  • 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.
  • the compound of the invention or a pharmaceutically acceptable salt thereof may be used in combination with other medicaments indicated to be useful in the treatment or prophylaxis of pain of neuropathic origin including neuralgias, neuritis and back pain, and inflammatory pain including osteoarthritis, rheumatoid arthritis, acute inflammatory pain, back pain and migraine.
  • Such therapeutic agents include for Compound COX-2 (cyclooxygenase-2 ) inhibitors, such as celecoxib, deracoxib, rofecoxib, valdecoxib, parecoxib, COX-189 or 2-(4-ethoxy-phenyl)- 3-(4-methanesulfonyl-phenyl)-pyrazolo[1 ,5-b]pyridazine (WO99/012930); 5-lipoxygenase inhibitors; NSAIDs (non-steroidal anti-inflammatory drugs) such as diclofenac, indomethacin, nabumetone or ibuprofen; bisphosphonates, leukotriene receptor antagonists; DMARDs (disease modifying anti-rheumatic drugs) such as methotrexate; adenosine A1 receptor agonists; sodium channel blockers, such as lamotrigine; NMDA (N-methyl-D-aspartate) receptor
  • the compound as defined in the first to fourth aspect or a pharmaceutically acceptable salt thereof may be used in combination with other medicaments indicated to be useful as either disease modifying or symptomatic treatments of Alzheimer's disease.
  • suitable examples of such other therapeutic agents may be agents known to modify cholinergic transmission such as 5-HT 1A antagonists, (e.g.
  • 5-HT6 antagonists M1 muscarinic agonists, M2 muscarinic antagonist, acetylcholinesterase inhibitors (e.g tetrahydroaminoacridine, donepezil or rivastigmine), or allosteric modulators, nicotinic receptor agonists or allosteric modulators, symptomatic agents such as 5-HT6 receptor antagonists, e.g. SB742457, H3 receptor antagonists e.g.
  • GSK189254 and GSK239512 5-HT4 receptor agonist, PPAR agonists, also NMDA receptor antagonists or modulators, also disease modifying agents such as ⁇ or ⁇ -secretase inhibitors (e.g. R-flurbiprofen), also AMPA positive modulators.

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Abstract

La présente invention concerne des composés, des procédés pour leur préparation, des compositions pharmaceutiques et des médicaments les contenant et leur utilisation dans le traitement d'un état dans lequel l'inhibition du GlyTI peut être bénéfique, y compris des troubles neurologiques et neuropsychiatriques, en particulier les psychoses, la démence ou un trouble de déficit de l’attention.
PCT/EP2009/060515 2008-08-15 2009-08-13 Dérivés de pyrrolidinone utiles pour le traitement de troubles psychotiques et neurologiques Ceased WO2010018214A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2679585A4 (fr) * 2011-02-21 2014-08-06 Taisho Pharmaceutical Co Ltd Inhibiteur de transport de glycine

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Publication number Priority date Publication date Assignee Title
WO2008092873A1 (fr) * 2007-02-01 2008-08-07 Glaxo Group Limited Inhibiteurs du transporteur de glyt1 et leurs utilisations pour traiter des troubles neurologiques et neuropsychiatriques
WO2008092878A1 (fr) * 2007-02-01 2008-08-07 Glaxo Group Limited Inhibiteurs du transporteur de glyt1 et leurs utilisations pour le traitement de troubles neurologiques et neuropsychiatriques
WO2008092872A1 (fr) * 2007-02-01 2008-08-07 Glaxo Group Limited Inhibiteurs du transporteur glyt1 et leurs utilisations dans le traitement de troubles neurologiques et neuropsychiatriques

Patent Citations (3)

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Publication number Priority date Publication date Assignee Title
WO2008092873A1 (fr) * 2007-02-01 2008-08-07 Glaxo Group Limited Inhibiteurs du transporteur de glyt1 et leurs utilisations pour traiter des troubles neurologiques et neuropsychiatriques
WO2008092878A1 (fr) * 2007-02-01 2008-08-07 Glaxo Group Limited Inhibiteurs du transporteur de glyt1 et leurs utilisations pour le traitement de troubles neurologiques et neuropsychiatriques
WO2008092872A1 (fr) * 2007-02-01 2008-08-07 Glaxo Group Limited Inhibiteurs du transporteur glyt1 et leurs utilisations dans le traitement de troubles neurologiques et neuropsychiatriques

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2679585A4 (fr) * 2011-02-21 2014-08-06 Taisho Pharmaceutical Co Ltd Inhibiteur de transport de glycine

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