[go: up one dir, main page]

WO2009034062A1 - Composés qui inhibent le transporteur de glycine et ses utilisations en médecine - Google Patents

Composés qui inhibent le transporteur de glycine et ses utilisations en médecine Download PDF

Info

Publication number
WO2009034062A1
WO2009034062A1 PCT/EP2008/061890 EP2008061890W WO2009034062A1 WO 2009034062 A1 WO2009034062 A1 WO 2009034062A1 EP 2008061890 W EP2008061890 W EP 2008061890W WO 2009034062 A1 WO2009034062 A1 WO 2009034062A1
Authority
WO
WIPO (PCT)
Prior art keywords
disorder
alkyl
compounds
alkoxy
compound
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/EP2008/061890
Other languages
English (en)
Inventor
David Gwyn Cooper
Roderick Alan Porter
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Glaxo Group Ltd
Original Assignee
Glaxo Group Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GB0717703A external-priority patent/GB0717703D0/en
Priority claimed from GB0802587A external-priority patent/GB0802587D0/en
Priority claimed from GB0813416A external-priority patent/GB0813416D0/en
Application filed by Glaxo Group Ltd filed Critical Glaxo Group Ltd
Publication of WO2009034062A1 publication Critical patent/WO2009034062A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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 predominantly in the forebrain and its distribution corresponds to that of glutaminergic pathways and NMDA receptors (Smith, et al., Neuron, 8, 1992: 927-935).
  • 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.
  • 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).
  • 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
  • NMDA receptors are critically involved in memory and learning (Rison and Staunton, Neurosci. Biobehav. Rev., 1£ 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 (Olnev 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.
  • 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); Lipton and Rosenberg, New Engl. J. of Medicine. 330. 613-622 (1993); Choi, Neuron. 1 , 623-634 (1988).
  • pharmacological agents that increase the activity of GIyTI 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.
  • R 1 , R 2 , R 3 and R 4 are independently selected from hydrogen, C 1-4 alkyl, C 1-4 alkoxy, cyano, halo, haloCi- 4 alkoxy, Ci -4 alkylthio, C 3-6 cycloalkyl, C 3- C 3-6 cycloalkylCi -4 alkoxy, Ci -4 alkylsulfonyl, CONR a R b (wherein R a and R b are independently selected from hydrogen and C 1-4 alkyl, or R a and R b , together with the nitrogen atom to which they are attached, form a 4- to
  • R 2 and R 3 together form a group selected from -0-CH 2 -O- and -0-CH 2 -CH 2 -O-;
  • R 5 is selected from hydrogen, chloro, fluoro, and CF 3 ;
  • R 6 and R 7 are selected from the group consisting of: o hydrogen, C 1-4 alkyl, C 1-4 alkoxy, haloC 1-4 alkyl, haloC 1-4 alkoxy, halo, cyano,
  • • and the other is selected from the group consisting of: o a 5 to 7 membered heteroaryl ring, optionally substituted by C 1-4 alkyl, C 1- 4 alkoxy, haloCi -4 alkoxy, halo or cyano; o a 9 to 10 membered bicyclic heterocyclic ring, optionally substituted by Ci- 4 alkyl, C 1-4 alkoxy, haloC 1-4 alkyl, haloC 1-4 alkoxy, halo or cyano; and o a 5 to 7 membered heterocyclic ring, optionally substituted by Ci -4 alkyl, Ci- 4 alkoxy, haloCi -4 alkoxy, halo or cyano;
  • R 6 and R 7 together form a 5 to 7 membered heterocyclic ring fused to the phenyl ring, or a 5 to 7 membered heteroaryl ring fused to the phenyl ring; wherein the heterocyclic ring or the heteroaryl ring is optionally substituted by d ⁇ alkyl, haloC 1-4 alkyl, haloC 1-4 alkoxy, halo or cyano;
  • m is selected from 0, 1 and 2;
  • R 8 is selected from hydrogen and CrC 4 alkyl; and • R 21 is selected from hydrogen and fluoro.
  • Cr 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 ⁇ 4 alkoxy refers to the group -O-C 1-4 alkyl wherein C 1-4 alkyl is as defined above.
  • C 1-4 alkoxyC 1-4 alkyl refers to the group -(C 1-4 alkyl)-O-(C 1-4 alkyl), wherein is as defined above.
  • C 1-4 alkoxyC 1-4 alkyoxy refers to the group -OC 1-4 alkyl-O-C"
  • C 3-6 cycloalkyr 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 1-4 alkyl refers to a C 1-4 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 group may, for example contain 1 , 2 or 3 halogen atoms.
  • a haloC 1-4 alkyl group may have all hydrogen atoms replaced with halogen atoms.
  • haloCi -4 alkyl groups include fluoromethyl, difluoromethyl and trifluoromethyl.
  • haloC 1-4 alkoxy group may, for example contain 1 , 2 or 3 halogen atoms.
  • a haloCi -4 alkoxy group may have all hydrogen atoms replaced with halogen atoms. Examples of groups include fluoromethyloxy, difluoromethyloxy and trifluoromethyloxy.
  • cyano refers to a group -CN.
  • C 1-4 alkylsulfonyl refers to a group -SO 2 (Ci- 4 alkyl).
  • An example is -SO 2 CH 3 .
  • C 1-4 alkylthio refers to a group -S
  • An example is - SCH 3 .
  • the term "5 to 7 membered heteroaryl” refers to an aromatic ring consisting of 5, 6 or 7 carbon atoms, wherein 1 to 4 carbon atoms are replaced by a heteroatom selected from oxygen, nitrogen and sulphur.
  • aromatic rings include thienyl, furyl, pyrrolyl, triazolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyridazyl, triazinyl and tetrazolyl.
  • the heteroaryl ring may be linked to the remainder of the molecule via a carbon atom, or when present, a suitable nitrogen atom.
  • 9 to 10 membered bicyclic heterocyclic ring refers to a bicyclic aromatic or non-aromatic system consisting of 9 or 10 carbon atoms, wherein 1 to 4 carbon atoms are replaced by a heteroatom selected from oxygen, nitrogen and sulphur.
  • bicyclic heterocyclic rings examples include quinolinyl, isoquinolinyl, indolyl, benzofuryl, benzothienyl, benzoimidazolyl, benzoxazolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolinyl, dihydrobenzofuranyl and dihydrobenzothiophenyl.
  • the bicyclic system may be linked to the remainder of the molecule via a carbon atom, or when present, a suitable nitrogen atom.
  • the term "5 to 7 membered heterocyclic ring” refers to a non-aromatic ring consisting of 5, 6 or 7 carbon atoms, wherein 1 to 4 carbon atoms are replaced by a heteroatom selected from oxygen, nitrogen and sulphur.
  • non-aromatic rings include piperidinyl, piperazinyl, pyrrolidinyl and morpholinyl.
  • the heterocyclic ring may be linked to the remainder of the molecule via a carbon atom, or when present, a suitable nitrogen atom.
  • examples of the resulting fused system include tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolinyl, dihydrobenzofuranyl and dihydrobenzothiophenyl.
  • examples of the resulting fused ring system include quinolinyl, isoquinolinyl, indolyl, benzofuryl, benzothienyl, benzoimidazolyla and benzoxazolyl.
  • X is -CH 2 -.
  • R 1 is selected from H, Ci -2 alkyl, Ci -2 alkoxy, halo, haloCi -2 alkyl, haloCi. 2 alkoxy, Ci -2 alkylthio, Ci -2 alkylsulfonyl, Ci -2 alkoxyCi -2 alkyl, and cyano.
  • R 1 is H.
  • R 2 is selected from H, Ci -2 alkyl, Ci -2 alkoxy, halo, haloCi -2 alkyl, haloC-i. 2 alkoxy, C 1-2 alkylthio, C 1-2 alkylsulfonyl, C 1-2 alkoxyC 1-2 alkyl, and cyano.
  • R 2 is H or halo.
  • R 2 is H or F.
  • R 2 is CF 3 .
  • R 3 is selected from R 3 is selected from H, C 1-2 alkyl, C 1-2 alkoxy, halo, haloCi_ 2 alkyl, haloCi -2 alkoxy, Ci -2 alkylthio, Ci -2 alkylsulfonyl, Ci -2 alkoxyCi -2 alkyl, and cyano.
  • R 3 is H or halo.
  • R 3 is H or F.
  • R 4 is selected from H, Ci -2 alkyl, Ci -2 alkoxy, halo, haloCi -2 alkyl, haloCi. 2 alkoxy, Ci -2 alkylthio, Ci -2 alkylsulfonyl, Ci -2 alkoxyCi -2 alkyl, and cyano.
  • R 4 is H or halo.
  • R 4 is F.
  • R 5 is H.
  • R 6 is imidazolyl, optionally substituted by Ci-C 6 alkyl such as methyl. In one embodiment R 6 is pyridyl.
  • R 7 is selected from H, Ci -2 alkyl, Ci -2 alkoxy, haloCi -2 alkyl, haloCi. 2 alkoxy, halo, cyano, Ci -2 alkoxyCi -2 alkoxy and Ci -2 alkoxyCi -2 alkyl. In a further embodiment R 7 is Cl or H.
  • n 1
  • R 8 is H.
  • Example compounds of the invention include:
  • 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. Most preferably the solvent used is water.
  • pro-drug forms for certain compounds of the present invention are described in Drugs of Today, Volume 19, Number 9, 1983, pp 499 - 538 and in Topics in Chemistry, Chapter 31 , pp 306 - 316 and in "Design of Prodrugs" by H. Bundgaard, Elsevier, 1985, Chapter 1 (the disclosures in which documents are incorporated herein by reference). It will further be appreciated by those skilled in the art, that certain moieties, known to those skilled in the art as “pro-moieties”, for example as described by H. Bundgaard in “Design of Prodrugs” (the disclosure in which document is incorporated herein by reference) may be placed on appropriate functionalities when such functionalities are present within compounds of the invention.
  • prodrugs for certain compounds of the invention include: esters, carbonate esters, hemi-esters, phosphate esters, nitro esters, sulfate esters, sulfoxides, amides, carbamates, azo-compounds, phosphamides, glycosides, ethers, acetals and ketals.
  • 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, 13 C, 11 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 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.
  • Stereoisomers may be separated by high-performance liquid chromatography or other appropriate means. 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. ENeI, S. H. Wilen, and L. N. Mander (Wiley-lnterscience, 1994). Likewise, it is understood that 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.
  • Compounds of formula (II) may be prepared by reduction of compounds of formula (V) using a reducing agent such as lithium aluminium hydride combined with aluminium trichloride in an inert solvent such as tetrahydrofuran at ambient or elevated temperature, preferably ambient temperature as shown for example in Scheme 3.
  • a reducing agent such as lithium aluminium hydride combined with aluminium trichloride in an inert solvent such as tetrahydrofuran at ambient or elevated temperature, preferably ambient temperature as shown for example in Scheme 3.
  • urea esters (Vl) shown as a methyl ester but could conveniently be any of CrCealkyl ester
  • a base such as lithium hydroxide in aqueous tetrahydrofuran below ambient, ambient or elevated temperature, for example reflux as shown in scheme 4.
  • Urea esters of formula (Vl) can be prepared in, for example, two steps, from the corresponding amino ester (VII) as in scheme 5.
  • step (i) Treatment of amino esters (VII), step (i) with, for example, triphosgene or phosgene in an inert solvent such as dichloromethane or toluene in the presence of a base such as triethylamine. preferably at ambient temperature generates isocyanates (VIII). Treatment of isocyanate (VIII), step (ii) with the appropriate substituted aniline (IX) generates the required urea esters of formula (Vl).
  • a compound of structure (IX) treatment of a compound of structure (IX) 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 carbon
  • 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 (IX) treatment of a compound of structure (IX) 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(diphenyl
  • 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 (IX) 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
  • 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
  • compounds of formula (II) can be prepared as shown in scheme 7 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 (X) or R 6 is a cyano group (Xl) 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 (Xl) can be prepared from (IX) by treatment with a cyanide source such as copper (I) cyanide, in a solvent such as N,N-dimethylformamide or N-methylpyrrolidinone at elevated temperature.
  • Carboxylic acid (X) may be prepared by acidic hydrolysis of nitrile (Xl) or directly from (IX) by treatment with 2 equivalents of alkyllithium at reduced temperature followed by addition of carbon dioxide, or through palladium mediated carbonylation methodology.
  • R 1 , R 2 , R 3 , R 4 , R 5 R 6 R 7 , R 8 , R 21 and m are as defined for compounds of formula (I)-
  • Compounds of formula (XII) 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
  • step (iv) Removal of the ester group R from compounds of formula (XII) to afford the acids of formula (XIII), step (iv), can be achieved by known methods, for example by use of a base, such as sodium hydroxide, in an inert solvent, such as aqueous methanol or aqueous ethanol, with or without heating as appropriate.
  • a base such as sodium hydroxide
  • an inert solvent such as aqueous methanol or aqueous ethanol
  • acylation step (v) can be achieved by reaction of the acid (XIII) 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 , R 21 and m are as defined in formula (I) and L represents a suitable leaving group.
  • L may be halogen and acylation in step (vi) may be carried out in an inert solvent such as dichloromethane, in the presence of a base, such as triethylamine.
  • compounds of formula (II) can be prepared according to scheme 10. Treating compounds of formula (VII) (shown as a methyl ester but could conveniently be any of Cr C 6 alkyl ester) with an isocyanate of formula (XVIII) in an inert solvent such as dichloromethane, tetrahydrofuran or dimethylsulphoxide preferably in the presence of a base such as sodium carbonate as described in Tetrahedron Lett. 2005.46.8555-8558 can form compounds of formula (V). This reaction may be carried out at a range of temperature including ambient and elevated temeperatures.
  • Compounds of formula (II) may be prepared by reduction of compounds of formula (V) using a reducing agent such as lithium aluminium hydride combined with aluminium trichloride in an inert solvent such as tetrahydrofuran at ambient or elevated temperature, preferably ambient temperature as shown for example as indicated in Scheme 3.
  • a reducing agent such as lithium aluminium hydride combined with aluminium trichloride in an inert solvent such as tetrahydrofuran at ambient or elevated temperature, preferably ambient temperature as shown for example as indicated in Scheme 3.
  • 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 6.
  • 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 7.
  • 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.
  • 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 .
  • Cells grown to 70-80% confluency in T175 flasks were harvested and resuspended at 4x10 5 cells/mL in assay buffer [14OmM NaCI, 5.4mM KCI, 1.8mM CaCI 2 , 0.8mM MgSO 4 , 2OmM HEPES, 5mM glucose and 5mM alanine, pH 7.4].
  • Compounds are considered to have activity at the the GIyTI transporter if they have a PlCB 50B of 5.0 or above.
  • the example compounds below and the individually named compounds above were found to have a PIC50 at the GIyTI transporter of equal to or greater than 5.4.
  • 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 Diagnostic and Statistical Manual of Mental Disorders
  • ICD-10 International Classification of Diseases
  • 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
  • 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 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 of use in the treatment of neuropathic pain, for example in diabetic neuropathy, sciatica, non-specific lower back pain, multiple sclerosis pain, fibromyalgia, HIV-related neuropathy, neuralgia such as post-herpetic neuralgia and trigeminal neuralgia and pain resulting from physical trauma, amputation, cancer, toxins or chronic inflammatory conditions.
  • neuropathic pain for example in diabetic neuropathy, sciatica, non-specific lower back pain, multiple sclerosis pain, fibromyalgia, HIV-related neuropathy, neuralgia such as post-herpetic neuralgia and trigeminal neuralgia and pain resulting from physical trauma, amputation, cancer, toxins or chronic inflammatory conditions.
  • treatment refers to the alleviation and/or cure of established symptoms as well as prophylaxis.
  • the invention thus provides compounds of formula (I) and salts thereof for use in therapy.
  • the invention also provides compounds of formula (I) and 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 salt thereof.
  • 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.
  • the present invention also provides a pharmaceutical composition, which comprises a compound of formula (I) or a 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 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.
  • 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, 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 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 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) 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) a method of treatment or prevention
  • 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 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 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 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 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 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 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 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 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 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 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 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 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 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 salt thereof and at least one mood stabilising or antimanic agent, a pharmaceutical composition comprising compounds of formula (I) or a salt thereof and at least one mood stabilising or antimanic agent, the use of a pharmaceutical composition comprising compounds of formula (I) or a 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 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
  • tradenames and suppliers of selected antipsychotic drugs are as follows: 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); thiothixene (available under the tradename
  • 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 VESPRI N®), 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 VESPRI N®
  • chlorprothixene available under the tradename TARACTAN®
  • droperidol
  • 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, 5HT1 B antagonists, 5HT1 D antagonists, D1 agonists, M1 agonists and/or anticonvulsant agents, as well as cognitive enhancers.
  • 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, 5HT1 B antagonists, 5HT1 D antagonists, D1 agonists, M1 agonists and/or anticonvulsant agents,
  • 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.
  • H-Y Zeolites was purchased from Zeolyst International as product CBV400. Chromatography was carried out using pre-packed lsolute FlashTM or BiotageTM silica-gel columns as the stationary phase and analytical grade solvents as the eluent unless otherwise stated.
  • SCX cartridge refers to Varian Bond ElutTM MEGA BE_SCX cartridges.
  • Aminopropyl-silica cartridge refers to Biotage lsoluteTM SPE cartridges (part no. 470-1000-F).
  • Phase separation cartridge or hydrophobic frit refers to Biotage lsolute Phase Separator.
  • UV wavelength range 220 -330 nm
  • Mass-directed HPLC refers to methods where the material was purified by HPLC wherein fraction collection is triggered by detection of the programmed mass ion for the compound of interest.
  • the resulting solution was then heated in the microwave (high absorbance) at 1 10 0 C for a further 2 hours. The temperature was increased to 150 0 C and the solution was heated in the microwave (high absorbance) for a further 4 hours.
  • the resulting solution was filtered through Kieselguhr, washed with DCM and evaporated to dryness to give a brown solid. This was purified using 5Og SCX-2 cartridge which was pre conditioned with DCM. The cartridge was washed with DCM (2CV), and MeOH (3CV). The compound was eluted with 0.5M NH 3 /MeOH and the NH 3 eluant was evaporated to dryness under reduced pressure to give a brown solid. The residue was purified via Biotage (0-5% MeOH / DCM, 25+M column) and the desired fractions were evaporated to dryness to give the title compound as a light brown solid (87mg).
  • the title compound is prepared from 3-[3-(2-pyridinyl)phenyl]-1 ,3-diazaspiro[4.5]decan-2- one (D6) using a similar procedure to Example 1.
  • a second fraction was also obtained (32mg) containing the title compound and approximately 18% of 2- ⁇ 3- [4-(5-methyl-1 H-imidazol-1 -yl)phenyl]-2-oxo-1 ,3-diazaspiro[4.5]dec-1-yl ⁇ -N-[3- (trifluoromethyl)phenyl]acetamide.

Landscapes

  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Psychiatry (AREA)
  • Hospice & Palliative Care (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des composés de formule (I) et leurs sels : dans laquelle les groupes sont tels que définis dans la description. L'invention concerne également les utilisations des composés en tant que médicaments et pour la fabrication d'un médicament pour le traitement de troubles neurologiques et neuropsychiatriques, notamment de psychoses, de la démence et de l'hyperactivité avec déficit de l'attention. L'invention concerne également des procédés de fabrication de ces composés et leurs formulations pharmaceutiques.
PCT/EP2008/061890 2007-09-11 2008-09-09 Composés qui inhibent le transporteur de glycine et ses utilisations en médecine Ceased WO2009034062A1 (fr)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
GB0717703A GB0717703D0 (en) 2007-09-11 2007-09-11 Compounds
GB0717703.3 2007-09-11
GB0802587A GB0802587D0 (en) 2008-02-12 2008-02-12 Compounds
GB0802587.6 2008-02-12
GB0813416A GB0813416D0 (en) 2008-07-22 2008-07-22 Compounds
GB0813416.5 2008-07-22

Publications (1)

Publication Number Publication Date
WO2009034062A1 true WO2009034062A1 (fr) 2009-03-19

Family

ID=40223742

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2008/061890 Ceased WO2009034062A1 (fr) 2007-09-11 2008-09-09 Composés qui inhibent le transporteur de glycine et ses utilisations en médecine

Country Status (1)

Country Link
WO (1) WO2009034062A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012081665A1 (fr) * 2010-12-15 2012-06-21 大正製薬株式会社 Substance apte à inhiber un transporteur de la glycine
WO2012115097A1 (fr) 2011-02-21 2012-08-30 大正製薬株式会社 Inhibiteur de transport de glycine
WO2012115066A1 (fr) * 2011-02-21 2012-08-30 大正製薬株式会社 Inhibiteur du transport de la glycine
WO2013187503A1 (fr) * 2012-06-14 2013-12-19 大正製薬株式会社 Inhibiteur de transporteur de glycine
WO2014146995A1 (fr) * 2013-03-20 2014-09-25 F. Hoffmann-La Roche Ag Dérivés d'urée et leurs utilisations en tant qu'inhibiteurs de la protéine de liaison à un acide gras (fabp)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005040166A1 (fr) * 2003-10-23 2005-05-06 F.Hoffmann-La Roche Ag Derives de triaza-spiropiperidine a utiliser comme inhibiteurs de glyt-1 dans le traitement de troubles neurologiques et neuropsychiatriques
WO2007014762A2 (fr) * 2005-08-02 2007-02-08 Glaxo Group Limited Inhibiteurs de transporteurs glyt1 et leurs utilisations dans le traitement de troubles neurologiques et neuropsychiatriques
WO2008046758A2 (fr) * 2006-10-19 2008-04-24 F. Hoffmann-La Roche Ag Dérivés d'imidazolone et d'imidazolidinone utilisés en tant qu'inhibiteurs de l'enzyme 11b-hsd1 pour le diabète
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

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005040166A1 (fr) * 2003-10-23 2005-05-06 F.Hoffmann-La Roche Ag Derives de triaza-spiropiperidine a utiliser comme inhibiteurs de glyt-1 dans le traitement de troubles neurologiques et neuropsychiatriques
WO2007014762A2 (fr) * 2005-08-02 2007-02-08 Glaxo Group Limited Inhibiteurs de transporteurs glyt1 et leurs utilisations dans le traitement de troubles neurologiques et neuropsychiatriques
WO2008046758A2 (fr) * 2006-10-19 2008-04-24 F. Hoffmann-La Roche Ag Dérivés d'imidazolone et d'imidazolidinone utilisés en tant qu'inhibiteurs de l'enzyme 11b-hsd1 pour le diabète
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

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012081665A1 (fr) * 2010-12-15 2012-06-21 大正製薬株式会社 Substance apte à inhiber un transporteur de la glycine
CN103459379B (zh) * 2011-02-21 2015-04-01 大正制药株式会社 甘氨酸转运体抑制物质
WO2012115097A1 (fr) 2011-02-21 2012-08-30 大正製薬株式会社 Inhibiteur de transport de glycine
WO2012115066A1 (fr) * 2011-02-21 2012-08-30 大正製薬株式会社 Inhibiteur du transport de la glycine
CN103459379A (zh) * 2011-02-21 2013-12-18 大正制药株式会社 甘氨酸转运体抑制物质
US8796272B2 (en) 2011-02-21 2014-08-05 Taisho Pharmaceutical Co., Ltd Glycine transporter-inhibiting substances
WO2013187503A1 (fr) * 2012-06-14 2013-12-19 大正製薬株式会社 Inhibiteur de transporteur de glycine
WO2014146995A1 (fr) * 2013-03-20 2014-09-25 F. Hoffmann-La Roche Ag Dérivés d'urée et leurs utilisations en tant qu'inhibiteurs de la protéine de liaison à un acide gras (fabp)
CN105308020A (zh) * 2013-03-20 2016-02-03 豪夫迈·罗氏有限公司 脲衍生物及其作为脂肪酸结合蛋白(fabp)抑制剂的用途
US9278918B2 (en) * 2013-03-20 2016-03-08 Hoffmann-La Roche Inc. Urea derivatives and their use as fatty-acid binding protein (FABP) inhibitors
JP2016514106A (ja) * 2013-03-20 2016-05-19 エフ．ホフマン−ラ ロシュ アーゲーＦ． Ｈｏｆｆｍａｎｎ−Ｌａ Ｒｏｃｈｅ Ａｋｔｉｅｎｇｅｓｅｌｌｓｃｈａｆｔ 尿素誘導体及びその脂肪酸結合タンパク質（ｆａｂｐ）阻害剤としての使用
KR101804650B1 (ko) 2013-03-20 2018-01-10 에프. 호프만-라 로슈 아게 우레아 유도체 및 이의 지방산 결합 단백질(fabp) 억제제로서의 용도
RU2642454C2 (ru) * 2013-03-20 2018-01-25 Ф. Хоффманн-Ля Рош Аг Производные мочевины и их применение в качестве ингибиторов белка, связывающего жирные кислоты

Similar Documents

Publication Publication Date Title
US20120004273A1 (en) Glyt1 transporter inhibitors and uses thereof in treatment of neurological and neuropsychiatric disorders
US20090326027A1 (en) N-Phenyl-2-0X0-1,4-Diazaspiro [4.5] Dec-3-EN-1-YL Acetamide Derivatives And Their Use As Glycine Transporter Inhibitors
US20100029700A1 (en) 1-(2-aryl-2-oxoethyl)-3-phenyl-1, 4-diazaspiro [4.5]dec-3-en-2-one derivatives and their use as glycine transporter inhibitors
WO2007104775A1 (fr) Composés inhibiteurs du transporteur de glycine et applications
US20090325993A1 (en) GLYT1 Transporter Inhibitors and Uses Thereof in Treatment of Neurological and Neuropsychiatric Disorders
WO2009034062A1 (fr) Composés qui inhibent le transporteur de glycine et ses utilisations en médecine
EP1910311A2 (fr) Inhibiteurs de transporteurs glyt1 et leurs utilisations dans le traitement de troubles neurologiques et neuropsychiatriques
EP1833811B1 (fr) Hétérocycles oxygénés en tant que composés inhibiteurs de transporteurs de glycine
US20100113545A1 (en) Glyt1 transporter inhibitors and uses thereof in treatment of neurological and neuropsychiatric disorders
EP1838663A1 (fr) Inhibiteurs du transport de la glycine
US20100048656A1 (en) Glyt1 transporter inhibitors and uses thereof in treatment of neurological and neuropsychiatric disorders
WO2010010133A1 (fr) Phénylacétamides à substitution 2-thia-1,3-diazaspirocyclique utilisés comme médiateurs glt1 dans les maladies neurologiques
US20100105713A1 (en) GLYT1 Transporter Inhibitors and Uses Thereof in Treatment of Neurological and Neuropsychiatric Disorders
US20090227629A1 (en) Compounds having activity at the glycine transporter glyt1 and uses thereof
EP2001831A2 (fr) Composés qui inhibent le transporteur de glycine et utilisations de ceux-ci
US20100016399A1 (en) GLYT1 Transporter Inhibitors and Uses Thereof in Treatment of Neurological and Neuropsychiatric Disorders
WO2007147836A1 (fr) Composés inhibant le transporteur de la glycine et utilisations en médecine
EP2197852A1 (fr) Dérivés de spiro-imidazolone condensés inhibant le transporteur de la glycine
WO2008092879A1 (fr) Inhibiteurs du transporteur glyt1 et utilisations de ceux-ci dans le traitement de troubles neurologiques et neuropsychiatriques
WO2007147839A1 (fr) Composés inhibant le transporteur de la glycine et utilisations de ceux-ci en médecine
WO2010018214A1 (fr) Dérivés de pyrrolidinone utiles pour le traitement de troubles psychotiques et neurologiques

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 08803858

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 08803858

Country of ref document: EP

Kind code of ref document: A1