EP1858868A1 - Compounds - Google Patents

Compounds

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Publication number
EP1858868A1
EP1858868A1 EP06723516A EP06723516A EP1858868A1 EP 1858868 A1 EP1858868 A1 EP 1858868A1 EP 06723516 A EP06723516 A EP 06723516A EP 06723516 A EP06723516 A EP 06723516A EP 1858868 A1 EP1858868 A1 EP 1858868A1
Authority
EP
European Patent Office
Prior art keywords
alkyl
alkoxy
compound
independently selected
alkanoyl
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.)
Withdrawn
Application number
EP06723516A
Other languages
German (de)
French (fr)
Inventor
Daniel Marcus GlaxoSmithKline BRADLEY
Clive Leslie GlaxoSmithKline BRANCH
Bethany Joy GlaxoSmithKline BROWN
Wai Ngor GlaxoSmithKline CHAN
Steven GlaxoSmithKline COULTON
Anthony William GlaxoSmithKline DEAN
Paul Martin BioFocus DPI Ltd DOYLE
Brian GlaxoSmithKline EVANS
Martin Leonard GlaxoSmithKline GILPIN
Sharon Lisa GlaxoSmithKline GOUGH
Jacqueline Anne BioFocus DPI Ltd MACRITCHIE
Howard Robert GlaxoSmithKline MARSHALL
David John GlaxoSmithKline NASH
Roderick Alan GlaxoSmithKline PORTER
Luigi Piero GlaxoSmithKline SpA STASI
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
Application filed by Glaxo Group Ltd filed Critical Glaxo Group Ltd
Publication of EP1858868A1 publication Critical patent/EP1858868A1/en
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/192—Radicals derived from carboxylic acids from aromatic carboxylic acids
    • 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
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to glycine transporter inhibiting compounds, their use in the manufacture of medicaments for treating neurological and neuropsychiatric disorders, in particular psychoses, dementia or attention deficit disorder.
  • the invention further comprises processes to make these compounds and pharmaceutical formulations thereof.
  • GIyTI is found predominantly in the forebrain and its distribution corresponds to that of glycinergic pathways and NMDA receptors (Smith, et a/., Neuron, 8, 1992: 927-935).
  • GIyT-Ia 1 GIyT-Ib and GIyT-Ic 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 a/., J. Biological Chemistry, 268, 1993: 22802-22808; Jursky and Nelson, J. Neurochemistry, 64, 1995 : 1026-1033).
  • Another distinguishing feature of glycine transport mediated by GlyT2 is that it is not inhibited by sarcosine as is the case for glycine transport mediated by GIyTI .
  • NMDA receptors are critically involved in memory and learning (Rison and Staunton, Neurosci. Biobehav. Rev., 19 533-552 (1995); Danysz et a/, Behavioral Pharmacol., 6 455-474 (1995)); and, furthermore, decreased function of NMDA-mediated neurotransmission appears to underlie, or contribute to, the symptoms of schizophrenia (Olney and Farber, Archives General Psychiatry, 52, 998-1007 (1996).
  • agents that inhibit 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.
  • Glycine transport inhibitors are already known in the art, for example as disclosed in published international patent application WO03/055478 (SmithKline Beecham).
  • X is -SR 2 , wherein - R 2 is selected from C 1-6 alkyl and C 3-7 cycloalkyl, which C 1-6 alkyl or C 3-7 cycloalkyl group is optionally substituted with one or more groups selected from C 3-7 cycloalkyl, C 1-4 alkyl, Ci -4 haloalkyl, C- ⁇ -4 alkoxy, Ci. 4 haloalkoxy, C 1-4 alkylthio, halo and hydroxy;
  • Y is S(O) m R 5 or -SO 2 NHR 6 wherein - m is 1 or 2;
  • R 5 is selected from C 1-6 alkyl, C 3-7 cycioalkyl, C 5-11 aryl and C 4-10 heteroaryl, which C 1-6 alkyl, C ⁇ cycloalkyl, C 5-11 aryl or C 4-10 heteroaryl is optionally substituted with one or two groups selected from halo, C 1-4 alkoxy and C 1-4 haloalkoxy;
  • Ci_ 6 alkyl is Ci_ 6 alkyl; which C 1-6 alkyl is optionally substituted with one or more groups selected from halo, C- ⁇ alkoxy and C 1-4 haloalkoxy;
  • n 0, 1 or 2
  • each R 1 is independently selected from C 1-6 alkyl, halo, C 1-6 haloalkyl C 1-4 alkoxy and C 1-4 haloalkoxy;
  • each Ri 3 is independently selected from hydrogen, halogen, hydroxy, cyano, amino, nitro, C 1-6 alkyl, haloCi -4 alkyl, haloC 1-4 alkoxy, C 6 -iiarylC 1 . 4 alkoxy, C 1-4 alkylthio, hydroxyC 1-4 alkyl, C 1-4 alkoxyC 1-4 alkyl, C 3-6 cycloalkylC 1-4 alkyl, C 3-6 cycloalkyl,
  • R 9 .R 10 .NSO 2 (CH 2 ) p or R 9 .SO 2 NR 10 .(CH 2 ) p , -CR 9 . CH(CN), R 9 .R 10 'N(CH 2 ) q - and R 9 .R 10' N(CH 2 ) q O-,wherein
  • each R 9 and R 10 is independently C 1-4 alkyl, or where appropriate R 9 R 10 forms part of a C 3-6 azacyloalkane or C 3-6 (2-, 3- or 4-oxo)azacycloalkane ring
  • each R 9' and Ri 0 - is independently selected from R 9 and R 10 and hydrogen;
  • each R 9 » and Ri 0" is independently selected from Rg' and R 10 ' and - p is selected from 0, 1 , 2, 3 or 4;
  • - q is selected from 2, 3 or 4;
  • each Ri 4 is independently selected from hydrogen, halogen, hydroxy, cyano, amino, nitro, C 1- ⁇ alkyl, C 1-4 alkoxy, haloC 1-4 alkyl, haloC 1-4 alkoxy, Ce-narylC ⁇ alkoxy,
  • 0 is independently C ⁇ alkyl, or where appropriate R 9 Ri 0 forms part of a C 3-6 azacyloalkane or C 3 . 6 (2-, 3- or 4-oxo)azacycloalkane ring
  • each R 9' and R 10' is independently selected from R 9 and R 10 and hydrogen;
  • each Rg " and R 10 » is independently selected from R 9' and R 10' and C 1-4 alkanoyl;
  • - p is selected from 0, 1 , 2, 3 or 4;
  • - q is selected from 2, 3 or 4;
  • each R 15 is independently selected from hydrogen, halogen, hydroxy, cyano, amino, nitro, C 1-6 alkyl, C 1-4 alkoxy, haloC 1-4 alkyl, haloC 1 . 4 alkoxy, Ce-narylC- ⁇ alkoxy, C 1-4 alkylthio, hydroxyC 1-4 alkyl, C- t ⁇ alkoxyC ⁇ alkyl, C 1-4 haloalkoxyC 1-4 alkyl, C 3 - 6 cycloalkylC 1-4 alkyl, C 3 .
  • each R 9 . and R 10 - is independently selected from R 9 and R 10 and hydrogen;
  • each R 9" and Ri O » is independently selected from R 9 . and R 10 . and C 1-4 alkanoyl;
  • - p is selected from 0, 1 , 2, 3 or 4;
  • - q is selected from 2, 3 or 4;
  • Z is selected from a monocyclic or bicyclic heteroaryl group, which monocyclic heteroaryi group is or which bicyclic heteroaryl group optionally is substituted by one or more groups selected from amino, halogen, hydroxy, cyano, nitro, C 2-4 alkyl, C 1-4 alkoxy, haloC 1-4 alkyl, haloC 1-4 alkoxy, C 6-11 arylC 1-4 alkoxy, C 1-4 alkylthio, hydroxyC 1-4 alkyl, C 1-4 alkoxyC 1-4 alkyl, C 1-4 haloalkoxyC 1-4 alkyl, Cs. 6 cycloalkylC 1-4 alkyl, C 3-6 cycloalkyl, C 3 .
  • each R 9 > and Rw is independently selected from R 9 and Ri 0 and hydrogen;
  • each R 9" and Ri 0" is independently selected from R 9' and R 10' and C 1-4 alkanoyl;
  • - p is selected from 0, 1 , 2, 3 or 4;
  • - q is selected from 2, 3 or 4;
  • C 1-6 alkyl refers to a straight or branched alkyl which contains from one to six carbon atoms in all isomeric forms. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl, sec-pentyl, n-pentyl, isopentyl, tert-pentyl and hexyl.
  • C 3-7 cycloaikyr refers to a non-aromatic cyclic saturated hydrocarbon ring having from three to seven carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl .
  • N-linked 3- to 7-membered monocyclic heterocyclic ring refers to a 3, 4, 5, 6 or 7 membered non-aromatic cyclic group containing one to three heteroatom(s) independently selected from N, O and S, which is linked to the rest of the molecule via a nitrogen atom.
  • Examples of N-linked 3- to 7-membered monocyclic heterocyclic rings include aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl and azepanyl.
  • 8- to 11 -membered bicyclic heterocyclic ring refers to a 8, 9, 10 or 11 -membered bicyclic group containing one to three heteroatom(s) independently selected from N, O and S, wherein at least one of the rings is non-aromatic.
  • 8- to 11 -membered bicyclic heterocyclic rings in which one of the rings is non-aromatic include dihydrobenzofuranyl, indanyl, indolinyl, isoindolinyl, tetrahydroisoquinolinyl, tetrahydroquinolyl and benzoazepanyl.
  • the term refers to a straight or branched chain divalent hydrocarbon radical, which contains 1 , 2, 3 or 4 carbon atoms. Examples include methylene, ethylene, n-propylene and n-butylene.
  • aryl refers to phenyl or a 8- to 11- membered bicyclic aromatic group in which at least one of the rings is aromatic.
  • 8- to 11- membered bicyclic aromatic groups include indenyl, azulenyl, naphthyl and tetrahydronaphthyl.
  • heteroaryl and “heteroaromatic group” refer to a 5- or 6- membered monocyclic aromatic group wherein one, two or three carbon atoms are replaced by a heteroatom independently selected from N, O and S, or to a 8- to 11- membered bicyclic aromatic group in which at least one of the rings is aromatic and wherein one to four carbon atoms in total are replaced by a heteroatom independently selected from N, O and S.
  • Examples of 5- or 6-membered monocyclic heteroaromatic groups include furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyridyl, triazolyl, triazinyl, pyridazyl, pyrimidinyl, isothiazolyl, isoxazolyl, pyrazinyl, pyrazolyl and pyrimidinyl;
  • examples of 8- to 11-membered bicyclic heteroaromatic groups include quinoxalinyl, quinazolinyl, pyridopyrazinyl, benzoxazolyl, benzothiophenyl, benzimidazolyl, naphthyridinyl, quinolinyl, benzofuranyl, indolyl, benzothiazolyl, oxazolyl[4,5-b]pyridiy
  • halogen and its abbreviation “hal” refer to fluorine, chlorine, bromine, or iodine.
  • salt refers to any salt of a compound according to the present invention prepared from an inorganic or organic acid or base, quaternary ammonium salts and internally formed salts.
  • Physiologically acceptable salts are particularly suitable for medical applications because of their greater aqueous solubility relative to the parent compounds. Such salts must clearly have a physiologically acceptable anion or cation.
  • physiologically acceptable salts of the compounds of the present invention include acid addition salts formed with inorganic acids such as hydrochloric, hydrobromic, hydroiodic, phosphoric, metaphosphoric, nitric and sulfuric acids, and with organic acids, such as tartaric, acetic, trifluoroacetic, citric, malic, lactic, fumaric, benzoic, formic, propionic, glycolic, gluconic, maleic, succinic, camphorsulfuric, isothionic, mucic, gentisic, isonicotinic, saccharic, glucuronic, furoic, glutamic, ascorbic, anthranilic, salicylic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, pantothenic, stearic, sulfinilic, alginic, galacturonic and arylsulfonic, for example benzenesul, in
  • solvate refers to a complex of variable stoichiometry formed by a solute (in this invention, a compound of formula (I) or a salt thereof) and a solvent.
  • solvents for the purpose of the invention may not interfere with the biological activity of the solute.
  • suitable solvents include, but are not limited to, water, methanol, ethanol and acetic acid.
  • the solvent used is a pharmaceutically acceptable solvent.
  • suitable pharmaceutically acceptable solvents include water, ethanol and acetic acid. Most preferably the solvent used is water.
  • X is -SR 2 ; and R 2 is selected from C 1-6 alkyl and C 3-7 cycloalkyl, which C 1-6 alkyl or C 3-7 cycloalkyl group is optionally substituted with one or more groups selected from C 3-7 cycloalkyl, C 1-4 alkyl, C- ⁇ -4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1 . 4 alkylthio, halo and hydroxyl.
  • X may be C 1-6 alkylthio, optionally substituted by one or two groups selected from C 3-7 cycloalkyl, C 1-4 alkyl, C 1-4 haloalkyl, Ci -4 alkoxy, C 1-4 haloalkoxy, C 1-4 alkylthio, halo and hydroxyl.
  • R 2 may, for example, be unsubstituted.
  • Y is S(O) m R 5 where m is 1 or 2 and R 5 is as defined above.
  • R 5 is preferably Ci -8 alkyl, for example methyl.
  • n 0.
  • n is 1 or 2 and R 1 is independently hydrogen or C 1-4 alkyl.
  • Z is a phenyl group Z' as set out above.
  • each R 13 is independently selected from hydrogen, halogen, cyano and Ci -4 alkoxyCi. 4 alkyl.
  • each R 14 is independently selected from hydrogen, halogen, cyano, nitro, C 1-6 alkyl, C 1-4 alkoxy and haloC 1-4 alkyl.
  • each R 15 is independently selected from hydrogen, halogen, cyano, amino, nitro, C ⁇ alkyl, C- ⁇ -4 alkoxy, haloC 1-4 alkyl, for example trifluoromethyl, C 1-4 alkylthio, hydroxyC 1-4 alkyl, Ci -4 alkoxyC 1-4 alkyl, C 1 .
  • each R 9 and R 10 is independently C ⁇ alkyl, or where appropriate R 9 R 10 forms part of a C 3-6 azacyloalkane or C 3 . 6 (2-, 3- or 4-oxo)azacycloalkane ring
  • each R 9' and R 10' is independently selected from R 9 and Ri 0 and hydrogen;
  • - p is selected from 0, 1 , 2, 3 or 4;
  • Z is a phenyl group Z 1 as described herein, and is substituted, and one or more of R 13 , R 14 and R 15 is SO 2 C 1-4 alkyl, with the other groups R 13 , R 14 and R 15 being selected from hydrogen or halogen for example from hydrogen, chloro or fluoro.
  • one or more of R 13 , R 14 and R 15 is C 1-4 alkoxyC 1-4 alkyl with the other groups Ri 3 , R 14 and R 15 being selected from hydrogen or halo, for example, F or Cl.
  • one or more of R 13 , R 14 and R 15 is C 1-4 alkanoyl with the other groups R 13 , Ri 4 and R 15 being selected from hydrogen and halo, for example, F or Cl.
  • one or more of Ri 3 , R 14 and Ri 5 is Ci -4 alkoxy, for example methoxy, with the other groups R 13 , R 14 and R 15 being selected from hydrogen and halo, for example, F or Cl.
  • one or more of Ri 3 , R 14 and Ri 5 is haloC 1-4 alkyl, for example trifluoromethyl, with the other groups R 13 , R 14 and R 15 being selected from hydrogen and halo, for example F or Cl.
  • Z is selected from the group consisting of, pyridyl, pyrimidinyl, 1 Hpyrrole[2,3-ib]pyridine, pyridazinyl, pyrazinyl, triazolyl, triazinyl, pyrrolyl, imidazolyl, thienyl, furanyl, thiadiazolyl, isoxazolyl, isothiazolyl, thiazolyl, oxadiazolyl and oxazolyl, benzothiazolyl, 1 ,4-benzodioxinyl, 2,3-dihydro-1,4-benzodioxinyl, benzoxazolyl, indolyl, quinolyl, isoquinolinyl, 1-benzopyranyl, 2-benzopyranyl, dihyrdo-1-benzopyranyl, dihydro-2-benzopyranyl, quinoxalinyl and quinazolinyl
  • Such groups Z may optionally be substituted with one or more groups selected from amino, cyano, nitro, haloC 1-4 alkyl, Ci -4 alkoxy, Ci -4 alkoxycarbonyl, C 4- gheteroarylsulfonyl, and R g »R 10" N-, wherein each R 9 - and R 10 - is independently selected from hydrogen, C ⁇ alkyl and C 1-4 alkanoyl.
  • Z is an optionally substituted pyrrolopyridine or an optionally substituted 1 H-pyrrolo[2,3-b]piperidine.
  • Preferred optional substituents are arylsulfonyl and heteroarylsulfonyl, most preferably heteroarylsulfonyl.
  • the compounds of formula (I) may have the ability to crystallise in more than one form. This is a characteristic known as polymorphism, and it is understood that such polymorphic forms (“polymorphs”) are within the scope of formula (I). Polymorphism generally can occur as a response to changes in temperature or pressure or both and can also result from variations in the crystallisation process. Polymorphs can be distinguished by various physical characteristics known in the art such as x-ray diffraction patterns, solubility, and melting point. Certain of the compounds described herein may exist in stereoisomer ⁇ forms (i.e. they may contain one or more asymmetric carbon atoms or may exhibit cis-trans isomerism).
  • optically pure enantiomer means that the compound contains greater than about 90 % of the desired isomer by weight, preferably greater than about 95 % of the desired isomer by weight, and most preferably greater than about 99 % of the desired isomer by weight, said weight percent based upon the total weight of the isomer(s) of the compound.
  • the compounds of this invention may be made by a variety of methods, including standard chemistry. Any previously defined variable will continue to have the previously defined meaning unless otherwise indicated. Illustrative general synthetic methods are set out below and then specific compounds of the invention are prepared in the working Examples.
  • the present invention includes both possible stereoisomers and includes not only racemic compounds but the individual enantiomers as well.
  • stereochemistry is indicated as being variable at certain positions, a mixture of stereoisomers may be obtained, this mixture having been separated where indicated.
  • Stereoisomers may be separated by high-performance liquid chromatography or other appropriate means.
  • a compound is desired as a single enantiomer, it may be obtained by stereospecific synthesis or by resolution of the final product or any convenient intermediate. Resolution of the final product, an intermediate, or a starting material may be effected by any suitable method known in the art. See, for example, Stereochemistry of Organic Compounds by E. L. Eliel, S. H. Wilen, and L. N. Mander (Wiley-lnterscience, 1994).
  • Typical reaction routes for the preparation of a compound of formula (I) as hereinbefore defined are shown in the following schemes. It should be noted that, while the schemes illustrate cases wherein Y is -SO 2 Me and n is zero, the schemes are applicable for other cases wherein n and Y are as defined for formula (I) above. Similarly, the schemes illustrate cases where the leaving group is chlorine, but the leaving group may be any other suitable group.
  • Scheme 5 illustrates methodology for preparing compounds in which Z is phenyl substituted with an alkoxyalkyl group. The methodology is also suitable for the preparation of other molecules of the invention that comprise alkoxyalkyl groups. Starting materials and reagents are known to the skilled person in the art and/or can be prepared using methods known in the art.
  • R 1 H 1 Me, Alkyl
  • Route A Route B. NaH, DMF, R 11 OH, toluene, R"l or R"Br ptsa.H 2 0, reflux
  • the present invention provides a method of preparing a compound of formula (I), comprising the step of: (a) reacting a compound of formula (II):
  • X is as defined for formula (I) and H is hydrogen, in the presence of a suitable base, for example sodium hydride; or
  • X, Y, n and R 1 are as defined for formula (I), with a group Z-L wherein Z is as defined for formula (I) and L is a leaving group such as halogen or triflate, under basic conditions with a suitable catalyst such as palladium acetate, and a suitable ligand such as 2,2'-bis(diphenylphosphino)-1 ,1-binaphthyl; or by heating a compound of formula (Vl) with a group Z-L to 180 0 C, with or without diisopropylamine as solvent, in a microwave reactor;
  • Step (c) may be carried out under suitable reaction conditions known in the literature, for example in J P Wolfe, H Tomori, J P Sadighi, J Yin and S L Buchwald, J. Org. Chem. (2000), 65, 1158; Org. Lett. (2003), 5(14), 2413; or J P Wolfe and S L Buchwald, J. Org. Chem. (2000), 65, 1144.
  • Compounds of formula (I) can be converted into further compounds of formula (I) using standard techniques.
  • possible conversion reactions include acylation with an appropriate acylating agent such as acetyl chloride, alkylation using an appropriate alkylating reagent such as methyl iodide, and sulfonylation using a sulfonylating agent such as methanesulfonic anhydride.
  • compositions 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.
  • 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 medium (DMEM/NUT mix F12) containing 2 mM L-Glutamine, 0.8 mg/mL G418 and 10% heat inactivated fetal calf serum (Gibco BRL) at 37 0 C in 5% CO 2 .
  • Cells grown to 70-80% confluency in T175 flasks were harvested and resuspended at 1.6x10 6 cells/ml in assay buffer [NaC!
  • HEK293 cells expressing the Glycine (Type 1) transporter were grown in cell medium (DMEM/NUT mix F12) containing 2 mM L-Glutamine, 0.8 mg/mL G418 and 10% heat inactivated fetal calf serum (Gibco BRL) at 37 0 C in 5% CO 2 .
  • Cells grown to 70-80% confluency in T175 flasks were harvested and resuspended at 4x10 5 cells/ml in assay buffer [NaCI (140 mM), KCI (5.4 mM), CaCI 2 (1.8 mM), MgSO 4 (0.8 mM), HEPES (2OmM), glucose (5 mM) and alanine (5 mM), pH 7.4].
  • Electrode SPA beads (12.5mg/ml suspended in assay buffer) was added to the cell suspension.
  • Compounds were prepared as 1OmM stocks in DMSO. 2.5 fold serial dilutions of the compounds were made in DMSO from a top cone of 2.5 mM. 100 nL of compound at each concentration was added to the assay plate (384-well white solid bottom plate) using the hummingbird dispenser. 5uL of the cell/bead mix was then added on top of the compound using a multidrop dispenser.
  • Compounds are considered to have activity at the the GIyTI transporter if they have a plC 50 of 5.0 or above.
  • the example compounds below were found to have a PIC50 at the GIyTI transporter of greater than 5.0.
  • Preferred compounds of the invention were found to have a plC 50 at the GIyTI transporter of greater than 6.0.
  • compositions comprising a compound of formula (I) as hereinbefore described or a salt or solvate thereof, and at least one pharmaceutically acceptable carrier, diluent or excipient.
  • a pharmaceutical composition comprising a compound of formula (I) as hereinbefore described or a salt or solvate thereof, and at least one pharmaceutically acceptable carrier, diluent or excipient.
  • a GIyTI inhibitor is indicated such as, for example, schizophrenia.
  • the carrier must be pharmaceutically acceptable to the recipient and must be compatible with, i.e. not have a deleterious effect upon, the other ingredients in the composition.
  • the carrier may be a solid or a liquid and is preferably formulated with at least one compound of formula (I) or a salt or solvate thereof as a unit dose formulation. If desired, other physiologically active ingredients may also be incorporated in the pharmaceutical compositions of the invention.
  • compositions may be used in the treatment of clinical conditions for which a GIyTI inhibitor is indicated such as, for example, schizophrenia.
  • the carrier must be pharmaceutically acceptable to the recipient and must be compatible with, i.e. not have a deleterious effect upon, the other ingredients in the composition.
  • the carrier may be a solid or a liquid and is preferably formulated with at least one compound of formula (I) or a salt or solvate thereof as a unit dose formulation. If desired, other physiologically active ingredients may also be incorporated in the pharmaceutical compositions of the invention.
  • DSM-IV Diagnostic and Statistical Manual of Mental Disorders
  • ICD-10 International Classification of Diseases
  • the compounds of formula (I) are of use in the treatment of schizophrenia including the subtypes Paranoid Type (295.30), Disorganised Type (295.10), Catatonic Type (295.20), Undifferentiated Type (295.90) and Residual Type (295.60); Schizophreniform Disorder (295.40); Schizoaffective Disorder (295.70) including the subtypes Bipolar Type and Depressive Type; Delusional Disorder (297.1) including the subtypes Erotomanic Type, Grandiose Type, Jealous Type, Persecutory Type, Somatic Type, Mixed Type and Unspecified Type; Brief Psychotic Disorder (298.8); Shared Psychotic Disorder (297.3); Psychotic Disorder Due to a General Medical Condition including the subtypes With Delusions and With Hallucinations; Substance-Induced Psychotic Disorder including the subtypes With Delusions (293.81) and With Hallucinations (293.82); and Psychotic Disorder Not Otherwise Specified (298.9).
  • the compounds of formula (I) are also of use in the treatment of mood disorders including Major Depressive Episode, Manic Episode, Mixed Episode and Hypomanic Episode;
  • Depressive Disorders including Major Depressive Disorder, Dysthymic Disorder (300.4),
  • 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 formula (I) are also of use in the treatment of anxiety disorders including Panic Attack, Agoraphobia, Panic Disorder, Agoraphobia Without History of Panic Disorder (300.22), Specific Phobia (300.29) including the subtypes Animal Type, Natural Environment Type, Blood-lnjection-lnjury Type, Situational Type and Other Type), Social Phobia (300.23), Obsessive-Compulsive Disorder (300.3), Posttraumatic Stress Disorder (309.81), Acute Stress Disorder (308.3), Generalized Anxiety Disorder (300.02), Anxiety Disorder Due to a General Medical Condition (293.84), Substance-Induced Anxiety Disorder and Anxiety Disorder Not Otherwise Specified (300.00).
  • the compounds of formula (I) are also of use in the treatment of substance-related disorders including Substance Use Disorders such as Substance Dependence and Substance Abuse; Substance-Induced Disorders such as Substance Intoxication, Substance Withdrawal, Substance-Induced Delirium, Substance-Induced Persisting Dementia, Substance-Induced Persisting Amnestic Disorder, Substance-Induced Psychotic Disorder, Substance-Induced Mood Disorder, Substance-Induced Anxiety Disorder, Substance-Induced sexual Dysfunction, Substance-Induced Sleep Disorder and Hallucinogen Persisting Perception Disorder (Flashbacks); Alcohol-Related Disorders such as Alcohol Dependence (303.90), Alcohol Abuse (305.00), Alcohol Intoxication (303.00), Alcohol Withdrawal (291.81), Alcohol Intoxication Delirium, Alcohol Withdrawal Delirium, Alcohol-Induced Persisting Dementia, Alcohol-Induced Persisting Amnestic Disorder, Alcohol-
  • the compounds of formula (I) are also of use in the treatment of sleep disorders including primary sleep disorders such as Dyssomnias such as Primary Insomnia (307.42), Primary Hypersomnia (307.44), Narcolepsy (347), Breathing-Related Sleep Disorders (780.59), Circadian Rhythm Sleep Disorder (307.45) and Dyssomnia Not Otherwise Specified (307.47); primary sleep disorders such as Parasomnias such as Nightmare Disorder (307.47), Sleep Terror Disorder (307.46), Sleepwalking Disorder (307.46) and Parasomnia Not Otherwise Specified (307.47); Sleep Disorders Related to Another Mental Disorder such as Insomnia Related to Another Mental Disorder (307.42) and Hypersomnia Related to Another Mental Disorder (307.44); Sleep Disorder Due to a General Medical Condition; and Substance-Induced Sleep Disorder including the subtypes Insomnia Type, Hypersomnia Type, Parasomnia Type and Mixed Type.
  • the compounds of formula (I) are also of use in the treatment of eating disorders such as Anorexia Nervosa (307.1) including the subtypes Restricting Type and Binge- Eating/Purging Type; Bulimia Nervosa (307.51 ) including the subtypes Purging Type and Nonpurging Type; Obesity; Compulsive Eating Disorder; and Eating Disorder Not Otherwise Specified (307.50).
  • eating disorders such as Anorexia Nervosa (307.1) including the subtypes Restricting Type and Binge- Eating/Purging Type; Bulimia Nervosa (307.51 ) including the subtypes Purging Type and Nonpurging Type; Obesity; Compulsive Eating Disorder; and Eating Disorder Not Otherwise Specified (307.50).
  • the compounds of formula (I) are also of use in the treatment of Autistic Disorder (299.00); Attention-Deficit /Hyperactivity Disorder including the subtypes Attention-Deficit /Hyperactivity Disorder Combined Type (314.01), Attention-Deficit /Hyperactivity Disorder Predominantly Inattentive Type (314.00), Attention-Deficit /Hyperactivity Disorder Hyperactive-Impulse Type (314.01) and Attention-Deficit /Hyperactivity Disorder Not Otherwise Specified (314.9); Hyperkinetic Disorder; Disruptive Behaviour Disorders such as Conduct Disorder including the subtypes childhood-onset type (321.81), Adolescent- Onset Type (312.82) and Unspecified Onset (312.89), Oppositional Defiant Disorder (313.81) and Disruptive Behaviour Disorder Not Otherwise Specified; and Tic Disorders such as Tourette's Disorder (307.23).
  • Attention-Deficit /Hyperactivity Disorder including the subtypes Attention-Deficit
  • the compounds of formula (I) are also of use in the treatment of Personality Disorders including the subtypes Paranoid Personality Disorder (301.0), Schizoid Personality Disorder (301.20), Schizotypal Personality Disorder (301 ,22), Antisocial Personality Disorder (301.7), Borderline Personality Disorder (301 ,83), Histrionic Personality Disorder (301.50), Narcissistic Personality Disorder (301,81), Avoidant Personality Disorder (301.82), Dependent Personality Disorder (301.6), Obsessive-Compulsive Personality Disorder (301.4) and Personality Disorder Not Otherwise Specified (301.9).
  • Paranoid Personality Disorder (301.0
  • Schizoid Personality Disorder 301.20
  • Schizotypal Personality Disorder 301 ,22
  • Antisocial Personality Disorder (301.7
  • Borderline Personality Disorder 301 ,83
  • Histrionic Personality Disorder 301.50
  • Narcissistic Personality Disorder 301,81
  • Avoidant Personality Disorder (301.82)
  • Dependent Personality Disorder (301.6
  • the compounds of Formula (I) are also of use in the enhancement of cognition including the treatment of cognition impairment in other diseases such as schizophrenia, bipolar disorder, depression, other psychiatric disorders and psychotic conditions associated with cognitive impairment.
  • cognitive impairment includes for example the treatment of impairment of cognitive functions including attention, orientation, learning disorders, memory (i.e.
  • Alzheimer's disease Huntington's disease, Pick disease, Aids-related dementia or other dementia states
  • Multiinfarct dementia alcoholic dementia, hypotiroidism-related dementia, and dementia associated to other degenerative disorders such as cerebellar atrophy and amyotropic lateral sclerosis
  • other acute or sub-acute conditions that may cause cognitive decline such as delirium or depression (pseudodementia states) trauma, head trauma, age related cognitive decline, stroke, neurodegeneration, drug-induced states, neurotoxic agents, mild cognitive impairment, age related cognitive impairment, autism related cognitive impairment, Down's syndrome, cognitive deficit related to psychosis, and post-electroconvulsive treatment related cognitive disorders
  • dyskinetic disorders such as Parkinson's disease, neuroleptic-induced parkinsonism, and tardive dyskinesias.
  • the compounds of formula (I) are also of use in the treatment of sexual dysfunctions including Sexual Desire Disorders such as Hypoactive Sexual Desire Disorder (302.71), and Sexual Aversion Disorder (302.79); sexual arousal disorders such as Female sexual Arousal Disorder (302.72) and Male Erectile Disorder (302.72); orgasmic disorders such as Female Orgasmic Disorder (302.73), Male Orgasmic Disorder (302.74) and Premature Ejaculation (302.75); sexual pain disorder such as Dyspareunia (302.76) and Vaginismus (306.51); sexual Dysfunction Not Otherwise Specified (302.70); paraphilias such as Exhibitionism (302.4), Fetishism (302.81), Frotteurism (302.89), Pedophilia (302.2), sexual Masochism (302.83), Sexual Sadism (302.84), Transvestic Fetishism (302.3), Voyeurism (302.82) and Paraphilia Not Otherwise Specified (302.9); gender identity disorders such as Gender Identity Disorder in Children (302.6) and Gender Identity Disorder in Ad
  • the invention also provides a compound of formula (I) as hereinbefore described or a pharmaceutically acceptable salt or solvate thereof for use in the treatment of schizophrenia, mood disorders, anxiety disorders, substance-related disorders, sleep disorders, eating disorders, autistic disorder, attention-deficit/hyperactivity disorder, disruptive behaviour disorder, tic disorders, personality disorders, cognition impairment in other diseases, sexual dysfunction, Parkinson's disease, dyskinetic disorders, depression, bipolar disorder, cognitive impairment, obesity, emesis, movement disorders, obsessive- compulsive disorders, amnesia, aggression, vertigo, dementia and arcadian rhythm disorders.
  • the invention also provides a compound of formula (I) as hereinbefore described or a pharmaceutically acceptable salt or solvate thereof for use in the treatment of psychotic disorders, schizophrenia, Parkinson's disease, substance abuse, dyskinetic disorders, depression, bipolar disorder, anxiety, cognitive impairment, eating disorders, obesity, sexual dysfunction, sleep disorders, emesis, movement disorders, obsessive-compulsive disorders, amnesia, aggression, autism, vertigo, dementia, circadian rhythm disorders and gastric motility disorders.
  • psychotic disorders schizophrenia, Parkinson's disease, substance abuse, dyskinetic disorders, depression, bipolar disorder, anxiety, cognitive impairment, eating disorders, obesity, sexual dysfunction, sleep disorders, emesis, movement disorders, obsessive-compulsive disorders, amnesia, aggression, autism, vertigo, dementia, circadian rhythm disorders and gastric motility disorders.
  • a method of treating a mammal including a human, suffering from or susceptible to a disorder mediated by GIyTI , which comprises administering an effective amount of a compound of formula (I) as hereinbefore defined or a salt or solvate thereof.
  • the invention also provides a method of treating schizophrenia, mood disorders, anxiety disorders, substance-related disorders, sleep disorders, eating disorders, autistic disorder, attention-deficit/hyperactivity disorder, disruptive behaviour disorder, tic disorders, personality disorders, cognition impairment in other diseases, sexual dysfunction, Parkinson's disease, dyskinetic disorders, depression, bipolar disorder, cognitive impairment, obesity, emesis, movement disorders, obsessive-compulsive disorders, amnesia, aggression, vertigo, dementia and circadian rhythm disorders which comprises administering to a mammal in need thereof an effective amount of a compound of formula (I) as hereinbefore described or a pharmaceutically acceptable salt or solvate thereof.
  • the invention also provides a method of treating psychotic disorders, schizophrenia, Parkinson's disease, substance abuse, dyskinetic disorders, depression, bipolar disorder, anxiety, cognitive impairment, eating disorders, obesity, sexual dysfunction, sleep disorders, emesis, movement disorders, obsessive-compulsive disorders, amnesia, aggression, autism, vertigo, dementia, circadian rhythm disorders and gastric motility disorders which comprises administering to a mammal in need thereof an effective amount of a compound of formula (I) as hereinbefore described or a pharmaceutically acceptable salt or solvate thereof.
  • the disorder mediated by GIyTI to be treated by the use or method as hereinbefore described is a psychosis, including schizophrenia, dementia and attention deficit disorders, particularly schizophrenia.
  • the invention also provides the use of a compound of formula (I) as hereinbefore described or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for the treatment of schizophrenia, mood disorders, anxiety disorders, substance-related disorders, sleep disorders, eating disorders, autistic disorder, attention- deficit/hyperactivity disorder, disruptive behaviour disorder, tic disorders, personality disorders, cognition impairment in other diseases, sexual dysfunction, Parkinson's disease, dyskinetic disorders, depression, bipolar disorder, cognitive impairment, obesity, emesis, movement disorders, obsessive-compulsive disorders, amnesia, aggression, vertigo, dementia and circadian rhythm disorders.
  • the invention also provides the use of a compound of formula (I) as hereinbefore described or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for the treatment of psychotic disorders, schizophrenia, Parkinson's disease, substance abuse, dyskinetic disorders, depression, bipolar disorder, anxiety, cognitive impairment, eating disorders, obesity, sexual dysfunction, sleep disorders, emesis, movement disorders, obsessive-compulsive disorders, amnesia, aggression, autism, vertigo, dementia, circadian rhythm disorders and gastric motility disorders.
  • psychotic disorders schizophrenia, Parkinson's disease, substance abuse, dyskinetic disorders, depression, bipolar disorder, anxiety, cognitive impairment, eating disorders, obesity, sexual dysfunction, sleep disorders, emesis, movement disorders, obsessive-compulsive disorders, amnesia, aggression, autism, vertigo, dementia, circadian rhythm disorders and gastric motility disorders.
  • the term "effective amount” means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher or clinician.
  • Compounds for use according to the invention may be administered as the raw material but the active ingredients are preferably provided in the form of pharmaceutical compositions.
  • a pharmaceutical composition comprising a compound of formula (I) as hereinbefore described or a salt or solvate thereof, and at least one pharmaceutically acceptable carrier, diluent or excipient.
  • compositions may be used in the treatment of clinical conditions for which a GIyTI inhibitor is indicated such as, for example, schizophrenia.
  • the carrier must be pharmaceutically acceptable to the recipient and must be compatible with, i.e. not have a deleterious effect upon, the other ingredients in the composition.
  • the carrier may be a solid or a liquid and is preferably formulated with at least one compound of formula (I) or a salt or solvate thereof as a unit dose formulation. If desired, other physiologically active ingredients may also be incorporated in the pharmaceutical compositions of the invention.
  • the compounds according to the invention may advantageously be used in conjunction with one or more other therapeutic agents, for instance, different antidepressant agents such as 5HT3 antagonists, serotonin agonists, NK-1 antagonists, selective serotonin reuptake inhibitors (SSRI), noradrenaline re-uptake inhibitors (SNRI), tricyclic antidepressants, dopaminergic antidepressants, H3 antagonists, 5HT1A antagonists, 5HT1B antagonists, 5HT1D antagonists, D1 agonists, M1 agonists and/or anticonvulsant agents, as well as atypical antipsychotic drugs and cognitive enhancers.
  • Suitable 5HT3 antagonists which may be used in combination of the compounds of the inventions include for example ondansetron, granisetron, metoclopramide.
  • Suitable serotonin agonists which may be used in combination with the compounds of the invention include sumatriptan, rauwolscine, yohimbine, metoclopramide.
  • Suitable SSRIs which may be used in combination with the compounds of the invention include fluoxetine, citalopram, femoxetine, fluvoxamine, paroxetine, indalpine, sertraline, zimeldine.
  • Suitable SNRIs which may be used in combination with the compounds of the invention include venlafaxine and reboxetine.
  • Suitable tricyclic antidepressants which may be used in combination with a compound of the invention include imipramine, amitriptiline, chlomipramine and nortriptiline.
  • Suitable dopaminergic antidepressants which may be used in combination with a compound of the invention include bupropion and amineptine.
  • Suitable anticonvulsant agents which may be used in combination of the compounds of the invention include for example divalproex, carbamazepine and diazepam.
  • Suitable atypical antipsychotic drugs which which may be used in combination of the compounds of the invention include for example risperidone, olanzapine, ziprasidone, aripiprazole and clozapine.
  • the compounds of the combination or composition may be administered simultaneously (either in the same or different pharmaceutical formulations), separately or sequentially.
  • the compounds of formula (I) and their pharmaceutically acceptable salts and solvates thereof are also suitable for combination with other typical and atypical antipsychotics to provide improved treatment of psychotic disorders.
  • Particular advantages associated with the combinations, uses and methods of treatment of compounds of formula (I) and their pharmaceutically acceptable salts and solvates thereof include equivalent or improved efficacy at doses of administration which are lower than those commonly used for the individual components. Improved treatments of positive symptoms and/or negative symptoms and/or cognitive symptoms of the psychotic disorder may also be observed.
  • the combinations, uses and methods of treatment of the invention may also provide advantages in treatment of patients who fail to respond adequately or who are resistant to treatment with certain neuroleptic agents.
  • the combination therapies of the invention are preferably administered adjunctively.
  • adjunctive administration is meant the coterminous or overlapping administration of each of the components in the form of separate pharmaceutical compositions or devices.
  • This regime of therapeutic administration of two or more therapeutic agents is referred to generally by those skilled in the art and herein as adjunctive therapeutic administration; it is also known as add-on therapeutic administration.
  • Any and all treatment regimes in which a patient receives separate but coterminous or overlapping therapeutic administration of the compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof and at least one neuroleptic agent are within the scope of the current invention.
  • a patient is typically stabilised on a therapeutic administration of one or more of the of the components for a period of time and then receives administration of another component.
  • the compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof is administered as adjunctive therapeutic treatment to patients who are receiving administration of at least one neuroleptic agent, but the scope of the invention also includes the adjunctive therapeutic administration of at least one neuroleptic agent to patients who are receiving administration of compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof.
  • the combination therapies of the invention may also be administered simultaneously.
  • simultaneous administration is meant a treatment regime wherein the individual components are administered together, either in the form of a single pharmaceutical composition or device comprising or containing both components, or as separate compositions or devices, each comprising one of the components, administered simultaneously.
  • Such combinations of the separate individual components for simultaneous combination may be provided in the form of a kit-of-parts.
  • the invention provides a method of treatment of a psychotic disorder by adjunctive therapeutic administration of compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof to a patient receiving therapeutic administration of at least one neuroleptic agent.
  • the invention provides the use of compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for adjunctive therapeutic administration for the treatment of a psychotic disorder in a patient receiving therapeutic administration of at least one neuroleptic agent.
  • the invention further provides compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use for adjunctive therapeutic administration for the treatment of a psychotic disorder in a patient receiving therapeutic administration of at least one neuroleptic agent.
  • the invention provides a method of treatment of a psychotic disorder by adjunctive therapeutic administration of at least one neuroleptic agent to a patient receiving therapeutic administration of compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof.
  • the invention provides the use of at least one neuroleptic agent in the manufacture of a medicament for adjunctive therapeutic administration for the treatment of a psychotic disorder in a patient receiving therapeutic administration of compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof.
  • the invention further provides at least one neuroleptic agent for adjunctive therapeutic administration for the treatment of a psychotic disorder in a patient receiving therapeutic administration of compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof.
  • the invention provides a method of treatment of a psychotic disorder by simultaneous therapeutic administration of compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof in combination with at least one neuroleptic agent.
  • the invention further provides the use of a combination of compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof and at least one neuroleptic agent in the manufacture of a medicament for simultaneous therapeutic administration in the treatment of a psychotic disorder.
  • the invention further provides the use of compounds of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for simultaneous therapeutic administration with at least one neuroleptic agent in the treatment of a psychotic disorder.
  • the invention further provides compounds of formula (I) or a pharmaceutically acceptable salt thereof for use for simultaneous therapeutic administration with at least one neuroleptic agent in the treatment of a psychotic disorder.
  • the invention further provides the use of at least one neuroleptic agent in the manufacture of a medicament for simultaneous therapeutic administration with compounds of formula (I) or a pharmaceutically acceptable salt thereof in the treatment of a psychotic disorder.
  • the invention provides a method of treatment of a psychotic disorder by simultaneous therapeutic administration of a pharmaceutical composition comprising compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof and at least one mood stabilising or antimanic agent, a pharmaceutical composition comprising compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof and at least one mood stabilising or antimanic agent, the use of a pharmaceutical composition comprising compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof and at least one mood stabilising or antimanic agent in the manufacture of a medicament for the treatment of a psychotic disorder, and a pharmaceutical composition comprising compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof and at least one mood stabilising or antimanic agent for use in the treatment of a psychotic disorder.
  • the invention provides a kit-of-parts for use in the treatment of a psychotic disorder comprising a first dosage form comprising compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof and one or more further dosage forms each comprising a neuroleptic agent for simultaneous therapeutic administration.
  • psychotic disorder includes those disorders mentioned above, such as schizophrenia, mood disorders, anxiety disorders, substance-related disorders, sleep disorders, eating disorders, autistic disorder, attention- deficit/hyperactivity disorder, disruptive behaviour disorder, tic disorders, personality disorders, cognition impairment in other diseases, sexual dysfunction, dyskinetic disorders, depression, bipolar disorder, cognitive impairment and obsessive-compulsive disorders and all the various forms of the disorders as mentioned herein, which are contemplated as part of the present invention.
  • neuroleptic/antipsychotic drugs examples include, but are not limited to: butyrophenones, such as haloperidol, pimozide, and droperidol; phenothiazines, such as chlorpromazine, thioridazine, mesoridazine, trifluoperazine, perphenazine, fluphenazine, thiflupromazine, prochlorperazine, and acetophenazine; thioxanthenes, such as thiothixene and chlorprothixene ; thienobenzodiazepines; dibenzodiazepines; benzisoxazoles; dibenzothiazepines; imidazolidinones ; benzisothiazolyl-piperazines; triazine such as lamotrigine; dibenzoxazepines, such as loxapine; dihydroindolones, such as molindone; arip
  • neuroleptic drugs that are preferred for use in the present invention are shown in Table 1.
  • clozapine available under the tradename CLOZARIL®, from Mylan, Zenith Goldline, UDL 1 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
  • neuroleptic drugs include promazine (available under the tradename SPARINE®), triflurpromazine (available under the tradename VESPRIN®), chlorprothixene (available under the tradename TARACT AN®), droperidol (available under the tradename INAPSINE®), acetophenazine (available under the tradename TINDAL®;), prochlorperazine (available under the tradename COMPAZINE®), methotrimeprazine (available under the tradename NOZINAN®), pipotiazine (available under the tradename PIPOTRIL®), ziprasidone, and hoperidone.
  • promazine available under the tradename SPARINE®
  • triflurpromazine available under the tradename VESPRIN®
  • chlorprothixene available under the tradename TARACT AN®
  • droperidol available under the tradename INAPSINE®
  • acetophenazine available under the tradename TINDAL®
  • prochlorperazine available under the trade
  • Particularly preferred neuroleptic agents for use in the invention are olanzapine, risperidone, quetiapine, aripiprazole, haloperidol, clozapine, ziprasidone and osanetant.
  • the compounds according to the invention may advantageously be used in conjunction with one or more other therapeutic agents, for instance, different antidepressant agents such as 5HT3 antagonists, serotonin agonists, NK-1 antagonists, selective serotonin reuptake inhibitors (SSRI), noradrenaline re-uptake inhibitors (SNRI), tricyclic antidepressants, dopaminergic antidepressants, H3 antagonists, 5HT1A antagonists, 5HT1B antagonists, 5HT1 D antagonists, D1 agonists, M1 agonists and/or anticonvulsant agents, as well as atypical antipsychotic drugs and cognitive enhancers.
  • different antidepressant agents such as 5HT3 antagonists, serotonin agonists, NK-1 antagonists, selective serotonin reuptake inhibitors (SSRI), noradrenaline re-uptake inhibitors (SNRI), tricyclic antidepressants, dopaminergic antidepressants, H3 antagonists, 5HT1A antagonists, 5
  • Suitable 5HT3 antagonists which may be used in combination of the compounds of the inventions include for example ondansetron, granisetron, metoclopramide.
  • Suitable serotonin agonists which may be used in combination with the compounds of the invention include sumatriptan, rauwolscine, yohimbine, metoclopramide.
  • Suitable SSRIs which may be used in combination with the compounds of the invention include fluoxetine, citalopram, femoxetine, fluvoxamine, paroxetine, indalpine, sertraline, zimeldine.
  • Suitable SNRIs which may be used in combination with the compounds of the invention include venlafaxine and reboxetine.
  • Suitable tricyclic antidepressants which may be used in combination with a compound of the invention include imipramine, amitriptiline, chlomipramine and nortriptiline.
  • Suitable dopaminergic antidepressants which may be used in combination with a compound of the invention include bupropion and amineptine.
  • Suitable anticonvulsant agents which may be used in combination of the compounds of the invention include for example divalproex, carbamazepine and diazepam.
  • Suitable atypical antipsychotic drugs which which may be used in combination of the compounds of the invention include for example risperidone, olanzapine, ziprasidone, aripiprazole and clozapine.
  • the compounds of the combination or composition may be administered simultaneously (either in the same or different pharmaceutical formulations), separately or sequentially.
  • a disorder mediated by GIyTI refers to a disorder that may be treated by the administration of a medicament that alters the activity of the GIyTI transporter.
  • the action of GIyTI transporters affects the local concentration of glycine around NMDA receptors. As a certain amount of glycine is needed for the efficient functioning of NMDA receptors, any change to that local concentration can affect NMDA-mediated neurotransmission.
  • changes in NMDA-mediated neurotransmission have been implicated in certain neuropsychiatric disorders such as dementia, depression and psychoses, for example schizophrenia, and learning and memory disorders, for example attention deficit disorders and autism.
  • alterations in the activity of the GIyTI transporter are expected to influence such disorders.
  • the disorders mediated by GIyTI referred to herein include neurological and neuropsychiatric disorders, including psychoses such as schizophrenia, dementia and other forms of impaired cognition such as attention deficit disorders and organic brain syndromes.
  • Other neuropsychiatric disorders include drug-induced (phencyclidine, ketamine and other dissociative anesthetics, amphetamine and other psychostimulants and cocaine) psychosis, psychosis associated with affective disorders, brief reactive psychosis, schizoaffective psychosis, and psychosis NOS, "schizophrenia-spectrum” disorders such as schizoid or schizotypal personality disorders, or illness associated with psychosis (such as major depression, manic depressive (bipolar) disorder, Alzheimer's disease and post-traumatic stress syndrome), and NMDA receptor-related disorders such as autism, depression, benign forgetfulness, childhood learning disorders and closed head injury.
  • NMDA receptor-related disorders such as autism, depression, benign forgetfulness, childhood learning disorders and closed head injury.
  • a method of treating a mammal including a human, suffering from or susceptible to a disorder mediated by GIyTI , which comprises administering an effective amount of a compound of formula (Ib) or a salt or solvate thereof:
  • X is -SR 2 , wherein - R 2 is selected from C-
  • Y is S(O) 171 R 5 or -SO 2 NR 6 R 7 wherein
  • R 5 is selected from C 1-6 alkyl, C 3-7 cycloalkyl, G ⁇ aryl and C 4-10 heteroaryl, which C 1-6 alkyl, C 3-7 cycloalkyl, C 5-H aryl or C 4-10 heteroaryl is optionally substituted with one or two groups selected from halo, C 1-4 alkoxy and Ci -4 haloalkoxy;
  • - R 6 and R 7 are independently selected from hydrogen and C 1-6 alkyl but are not both simultaneously C 1-6 alkyl; which Ci. 6 alkyl is optionally substituted with one or more groups selected from halo, C-i -4 alkoxy and C 1-4 haloalkoxy;
  • n 0, 1 or 2
  • each Ri is independently selected from C 1-6 alkyl, halo, C 1-6 haloalkyl C 1-4 alkoxy and C 1-4 haloalkoxy;
  • each Ri 3 is independently selected from hydrogen, halogen, hydroxy, cyano, amino, nitro, C 1-6 alkyl, haloC ⁇ alkyl, haloC 1-4 alkoxy, C 6- narylC 1-4 alkoxy, C 1-4 alkylthio, hydroxyC 1-4 alkyl, C 3 . 6 cycloalkylC 1-4 alkyl, C 3 .
  • Ce.-narylcarboxamidoC ⁇ lkyl C 6-11 aroyl, C 6- naroylC 1-4 alkyl, C 6-11 arylC 1-4 alkanoyl, C 1-4 acyl, C 6- iiarylCi -4 alkyl, Ci -4 alkylaminoCi.
  • each R 9 and Ri 0 is independently C 1-4 alkyl, or where appropriate RgR 10 forms part of a C 3-6 azacyloalkane or C 3 . 6 (2-, 3- or 4-oxo)azacycloalkane ring
  • each R 9 . and R 10 . is independently selected from R 9 and R 10 and hydrogen; - each R 9" and R 10" is independently selected from R 9 . and R 10 . and C 1-4 alkanoyl;
  • - p is selected from 0, 1 , 2, 3 or 4;
  • - q is selected from 2, 3 or 4;
  • each Ri 4 is independently selected from hydrogen, halogen, hydroxy, cyano, amino, nitro, C 1-6 alkyl, Ci -4 alkoxy, haloCi. 4 alkyl, haloCi -4 alkoxy, C 6-1 iarylCi -4 alkoxy, Ci -4 alkylthio, 6 cycloalkyl, C 3-6 cycloalkylCi -4 alkoxy, Ci -4 alkoxycarbony Ci -4 alkylsulfonyl, Ci -4 alkylsulfonyloxy, Ci -4 alkylsulfonylC 1-4 alkyl, C 6- narylsulfonyl, C 6 -narylsulfonyloxy, Ci -4 alkylsulfonamido, C 1-4 alkylamido, C 1-4 alkylsulfonamidoC-i -4 alkyl, C- ⁇ _ 4 alkylsuIfinyl, C C
  • each R 9 - and Ri 0' is independently selected from R 9 and R 10 and hydrogen;
  • each Rg» and R 10" is independently selected from R 9 ' and R 10 - and C 1-4 alkanoyl; - p is selected from 0, 1 , 2, 3 or 4;
  • - q is selected from 2, 3 or 4;
  • each R 15 is independently selected from hydrogen, halogen, hydroxy, cyano, amino, nitro, C 1-6 alkyl, Ci -4 alkoxy, haloC 1 . 4 alkyl, haloC 1 . 4 alkoxy, C 6 -i 1 arylC 1-4 alkoxy, C 1-4 alkylthio, hydroxyC 1-4 alkyl, C 1-4 alkoxyC 1-4 alkyl, C 1-4 haloalkoxyC 1-4 alkyl, C 3-6 cycloalkylC 1-4 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl, C 3-6 cycloalkylCi -4 alkoxy, C 1-4 alkanoyl, Ci -4 haloalkanoyl, C 1-4 alkoxycarbonyl, C 1-4 alkoxycarbonylCi -4 alkyl, C 1 .
  • each R 9 and R 10 is independently C 1-4 alkyl, or where appropriate R 9 Ri 0 forms part of a C 3-6 azacyloalkane or C 3-6 (2-, 3- or 4-oxo)azacycloalkane ring
  • each R 9 ' and Rw is independently selected from R 9 and R 10 and hydrogen; - each R 9 - and R 10 - is independently selected from R 9' and R 10 ' and C 1-4 alkanoyl;
  • - p is selected from 0, 1 , 2, 3 or 4;
  • - q is selected from 2, 3 or 4;
  • Z is selected from a monocyclic or bicyclic heteroaryl group, which monocyclic heteroaryl group is or which bicyclic heteroaryl group optionally is substituted by one or more groups selected from amino, halogen, hydroxy, cyano, nitro, C 2-4 alkyl, C 1-4 alkoxy, haloC 1-4 alkyl, haloC 1-4 alkoxy, C 6- i 1 arylC 1 . 4 alkoxy, C 1-4 alkylthio, hydroxyCi -4 alkyl,
  • Ci -4 haloalkylsulfinyl, C ⁇ alkylsulfonyloxy, C 1-4 alkylsulfonylCi -4 alkyl, C 6- iiarylsulfonyl,
  • each Rg and Ri 0 is independently C 1-4 alkyl, or where appropriate R 9 R 10 forms part of a C 3-6 azacyloalkane or C 3 . 6 (2-, 3- or 4-oxo)azacyc!oalkane ring - each R 9' and R 10 - is independently selected from R 9 and R-
  • each Rg- and R 10" is independently selected from R 3 - and R 10' and C 1-4 alkanoyl;
  • - p is selected from 0, 1 , 2, 3 or 4;
  • - q is selected from 2, 3 or 4;
  • the disorder mediated by GIyTI to be treated by the use or method as hereinbefore described is a psychosis, including schizophrenia, dementia and attention deficit disorders, particularly schizophrenia.
  • 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.
  • Possible formulations include those suitable for oral, sub-lingual, buccal, parenteral (for example, subcutaneous, intramuscular, or intravenous), rectal, topical and intranasal administration and in forms suitable for administration by inhalation or insufflation (either through the mouth or nose).
  • parenteral for example, subcutaneous, intramuscular, or intravenous
  • rectal topical and intranasal administration and in forms suitable for administration by inhalation or insufflation (either through the mouth or nose).
  • inhalation or insufflation either through the mouth or nose.
  • Formulations suitable for oral administration may be provided as discrete units, such as tablets, capsules, cachets, or lozenges, each containing a predetermined amount of the active compound; as powders or granules; as solutions or suspensions in aqueous or non-aqueous liquids; or as oil-in-water or water-in-oil emulsions.
  • Formulations suitable for sublingual or buccal administration include lozenges comprising the active compound and, typically, a flavoured base, such as sugar and acacia or tragacanth and pastilles comprising the active compound in an inert base, such as gelatin and glycerin or sucrose and acacia.
  • 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.
  • Formulations suitable for parenteral administration typically comprise sterile aqueous solutions containing a predetermined concentration of the active compound; the solution is preferably isotonic with the blood of the intended recipient. Although such solutions are preferably administered intraveneously, they may also be administered by subcutaneous or intramuscular injection.
  • Formulations suitable for rectal administration are preferably provided as unit-dose suppositories comprising the active ingredient and one or more solid carriers forming the suppository base, for example, cocoa butter.
  • Formulations suitable for topical or intranasal application include ointments, creams, lotions, pastes, gels, sprays, aerosols and oils.
  • Suitable carriers for such formulations include petroleum jelly, lanolin, polyethylene glycols, alcohols, and combinations thereof.
  • the formulations of the invention may be prepared by any suitable method, typically by uniformly and intimately admixing the active compound(s) with liquids or finely divided solid carriers, or both, in the required proportions and then, if necessary, shaping the resulting mixture into the desired shape.
  • a tablet may be prepared by compressing an intimate mixture comprising a powder or granules of the active ingredient and one or more optional ingredients, such as a binder, lubricant, inert diluent, or surface active dispersing agent, or by moulding an intimate mixture of powdered active ingredient and inert liquid diluent.
  • one or more optional ingredients such as a binder, lubricant, inert diluent, or surface active dispersing agent, or by moulding an intimate mixture of powdered active ingredient and inert liquid diluent.
  • Aqueous solutions for parenteral administration are typically prepared by dissolving the active compound in sufficient water to give the desired concentration and then rendering the resulting solution sterile and isotonic.
  • the compound may be administered in single or divided doses and may be administered one or more times, for example 1 to 4 times per day.
  • a proposed dose of the active ingredient for use according to the invention for oral, sublingual, parenteral, buccal, rectal, intranasal or topical administration to a human (of approximately 70 kg bodyweight) for the treatment of neurological and neuropsychiatry disorders mediated by a GIyTI inhibitor, including schizophrenia, may be about 1 to about 1000 mg, preferably about 5 to about 500 mg, more preferably about 10 to about 100 mg of the active ingredient per unit dose which could be administered, for example, 1 to 4 times per day.
  • a reaction mixture of the ester (2.2mrnol), methanol (10ml) and aqueous sodium hydroxide (10ml, 2M) was heated to 70 0 C for 18 hrs.
  • the cooled reaction mixture was then diluted with water and ethyl acetate.
  • the aqueous layer was acidified to pH 1 with aqueous hydrochloric acid (1 M) and extracted with ethyl acetate.
  • the organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give the crude product. Purification by trituration gave the pure title compound.
  • Trifluoroacetic acid 200 ⁇ l_; 2.69 mmol was added in one portion to a room temperature stirring solution of carbamate 4-[4-(methylthio)phenyl]piperazine-1-carboxylic acid-ferf- butylester (79 mg; 0.26 mmol) in dichloromethane (1 mL). The reaction was stirred for 15 hours and purified using an SCX ion exchange column, giving 1-[4- (methylthio)phenyl]piperazine as a pale yellow solid (42.9 mg; 79%).
  • me.a-Chloroperoxybenzoic acid (approx. 77%; 191 mg; 0.85 mmol) was added in one portion to a cool (O 0 C) stirring solution of 4-[4-(methylthio)phenyl]piperazine-1-carboxylic acid-te/t-butylester (179 mg; 0.58 mmol) in dichloromethane (3 mL).
  • the mixture was stirred at O 0 C for 1% hours, quenched with saturated aqueous sodium hydrogen carbonate (5 ml_) and diluted with water (1 ml_) and dichloromethane (2 ml_).
  • the separated aqueous phase was extracted with dichloromethane (10 mL), and the combined organic phase dried (MgSO 4 ).
  • Trifluoroacetic acid 250 ⁇ l_; 3.37 mmol was added in one portion to a room temperature stirring solution of 4-[4-(methylsulfinyl)phenyi]piperazine-1-carboxylic acid-terf-butylester (141 mg; 0.436 mmol) in dichloromethane (1.7 mL). The reaction was stirred for 18 hours and purified using an SCX ion exchange column, giving 4-[4- (methylsulfinyl)phenyl]piperazine-1-carboxylic acid-te/if-butylester as a white solid (92.9 mg; 93%).
  • LC/MS Ammonium bicarbonate ES+
  • N-BOC piperazine (0.5g) and 2-chloro-5-nitropyridine (0.424g) in DMF (16ml) were treated with potassium carbonate (0.744g) and DIPEA (1.41ml).
  • the resulting mixture was heated at 120 0 C for 4 hours.
  • the solvent was removed in vacuo and the residue partitioned between ethyl acetate and water.
  • Organic layer washed again with water then dried over anhydrous magnesium sulphate. After filtration, the solvent evaporated to dryness in vacuo to afford the title compound as a pale brown solid in 95%.

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Abstract

The invention provides a compound of formula (I) or a salt or solvate thereof: wherein R1, n, X, Y and Z are as defined in the specification, and uses of such compounds. The compounds inhibit GlyT1 transporters and are useful in the treatment of certain neurological and neuropsychiatric disorders, including schizophrenia.

Description

PIPERAZINE DERIVATIVES AS GLYTl INHIBITORS
The present invention relates to glycine transporter inhibiting compounds, their use in the manufacture of medicaments for treating neurological and neuropsychiatric disorders, in particular psychoses, dementia or attention deficit disorder. The invention further comprises processes to make these compounds and pharmaceutical formulations thereof.
Molecular cloning has revealed the existence in mammalian brains of two classes of glycine transporters, termed GIyTI and GlyT2. GIyTI is found predominantly in the forebrain and its distribution corresponds to that of glycinergic pathways and NMDA receptors (Smith, et a/., Neuron, 8, 1992: 927-935). Molecular cloning has. further revealed the existence of three variants of GIyTI , termed GIyT-Ia1 GIyT-Ib and GIyT-Ic (Kim et a/., 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 strychnine-sensitive glycine receptors (Liu et a/., J. Biological Chemistry, 268, 1993: 22802-22808; Jursky and Nelson, J. Neurochemistry, 64, 1995 : 1026-1033). Another distinguishing feature of glycine transport mediated by GlyT2 is that it is not inhibited by sarcosine as is the case for glycine transport mediated by GIyTI . These data are consistent with the view that, by regulating the synaptic levels of glycine, GIyTI and GlyT2 selectively influence the activity of NMDA receptors and strychnine-sensitive glycine receptors, respectively.
NMDA receptors are critically involved in memory and learning (Rison and Staunton, Neurosci. Biobehav. Rev., 19 533-552 (1995); Danysz et a/, Behavioral Pharmacol., 6 455-474 (1995)); and, furthermore, decreased function of NMDA-mediated neurotransmission appears to underlie, or contribute to, the symptoms of schizophrenia (Olney and Farber, Archives General Psychiatry, 52, 998-1007 (1996). Thus, 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. Conversely, over-activation of NMDA receptors has 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. 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). Thus, 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. Similarly, drugs that directly block the glycine site of the NMDA receptors can be used to treat these and related disease states.
Glycine transport inhibitors are already known in the art, for example as disclosed in published international patent application WO03/055478 (SmithKline Beecham).
However, there still remains the need to identify further compounds that can inhibit GIyTI transporters, including those that inhibit GIyTI transporters selectively over GlyT2 transporters.
International patent application WO97/28128 (Zeneca Limited) discloses certain pyridinyl, pyridazinyl, pyrimidinyl and triazinyl derivatives which are claimed to inhibit the enzyme oxido squalene cyclase. European patent application EP1247809 (Pfizer Products Inc) discloses certain triazine derivatives as being useful as sorbitol dehydrogenase inhibitors.
It has now been found that a novel class of compounds inhibit GIyTI transporters and are thus useful in the treatment of certain neurological and neuropsychiatry disorders, including schizophrenia.
Thus, in the first aspect, there is provided a compound of formula (I) or a salt or solvate thereof: :
(I) wherein
• X is -SR2, wherein - R2 is selected from C1-6alkyl and C3-7cycloalkyl, which C1-6alkyl or C3-7cycloalkyl group is optionally substituted with one or more groups selected from C3-7cycloalkyl, C1-4alkyl, Ci-4haloalkyl, C-ι-4alkoxy, Ci.4haloalkoxy, C1-4alkylthio, halo and hydroxy;
• Y is S(O)mR5 or -SO2NHR6 wherein - m is 1 or 2; and
- R5 is selected from C1-6alkyl, C3-7cycioalkyl, C5-11aryl and C4-10heteroaryl, which C1-6alkyl, C^cycloalkyl, C5-11aryl or C4-10heteroaryl is optionally substituted with one or two groups selected from halo, C1-4alkoxy and C1-4haloalkoxy;
- R6 is Ci_6alkyl; which C1-6alkyl is optionally substituted with one or more groups selected from halo, C-^alkoxy and C1-4haloalkoxy;
• n is 0, 1 or 2, • each R1 is independently selected from C1-6alkyl, halo, C1-6haloalkyl C1-4alkoxy and C1-4haloalkoxy;
• Z is an optionally substituted phenyl group 71:
71
wherein each Ri3 is independently selected from hydrogen, halogen, hydroxy, cyano, amino, nitro, C1-6alkyl, haloCi-4alkyl, haloC1-4alkoxy, C6-iiarylC1.4alkoxy, C1-4alkylthio, hydroxyC1-4alkyl, C1-4alkoxyC1-4alkyl, C3-6cycloalkylC1-4alkyl, C3-6cycloalkyl,
C3-6cycloalkylC1-4alkoxy, d-4alkanoyl, C1-4alkoxycarbonyl, C1-4alkoxycarbonylCi-4alkyl,
C1-4alkylsulfonyl, Ci-4alkylsulfonyloxy, Ci-4alkylsulfonylC1-4alkyl, C6.narylsulfonyl,
C6-11arylsulfonyloxy, C6-narylsulfonylC1-4alkyl, C-Malkylsulfonamido, C4-9heteroarylsulfonyl, C1-4alkylamido, C1-4alkylsulfonamidoCi-4alkyl, C1-4alkylamidoC1-4alkyl,
C6-11arylsulfonamido, C6-narylcarboxamido,
C6-11arylcarboxamidoC1-4alkyl, C6-naroyl, C6-naroylC1-4alkyl, C6-narylC1-4alkanoyl, C1-4acyl,
C6-1iarylC1-4alkyl, Ci-4alkylaminoC1-4alkyl, a group R^R10-N-, R9R10NCO(CI-I2)P,
R9.R10.NSO2(CH2)p or R9.SO2NR10.(CH2)p, -CR9.=CH(CN), R9.R10'N(CH2)q- and R9.R10'N(CH2)qO-,wherein
- each R9 and R10 is independently C1-4alkyl, or where appropriate R9R10 forms part of a C3-6azacyloalkane or C3-6(2-, 3- or 4-oxo)azacycloalkane ring
- each R9' and Ri0- is independently selected from R9 and R10 and hydrogen;
- each R9» and Ri0" is independently selected from Rg' and R10' and - p is selected from 0, 1 , 2, 3 or 4;
- q is selected from 2, 3 or 4;
wherein each Ri4 is independently selected from hydrogen, halogen, hydroxy, cyano, amino, nitro, C1-βalkyl, C1-4alkoxy, haloC1-4alkyl, haloC1-4alkoxy, Ce-narylC^alkoxy,
Ci-4alkylthio, C3-6cycloalkylC1-4alkyl, C3.6cycloalkyl, C3-6cycloalkylCi-4alkoxy,
C1-4alkoxycarbonyl, Ci-4alkoxycarbonylC1-4alkyl, C1-4alkylsulfonyl, Ci-4alkylsulfonyloxy,
C1-4alkylsulfonylC.,.4alkyl, C6-11arylsulfonyl, C6-I 1 arylsulfonyloxy,
C1-4alkylsulfonamido, C1-4alkylamido, C1-4alkylsulfonamidoCi-4alkyl, C1-4alkylsulfinyl, Ci-4haloalkylsulfinyl, C1-4alkylamidoC1-4alkyl, C6-narylsulfonamido, C4_gheteroarylsulfonyl,
C6-iiarylcarboxamido, C6-11arylsulfonamidoC1-4alkyl, C6-11arylcarboxamidoC1-4alkyl,
Ce-naroyl, C6-11arylC1-4alkanoyl, C1-4acyl, C6-iiaryl, Ce^aryld^alkyl, C1-4alkylaminoC1-4alkyl, a group R9-R1CrN-, R9R10NCO(CH2)P, R9.R10'NSO2(CH2)p or Re-SO2NR101(CH2)P, -CR9.=NR10', -CR9-NOR10., -CR91=C(CN)21 -CR9.=CH(CN), R9.R10'N(CH2)q- and R9.R10'N(CH2)qO-,wherein
- each R9 and R-|0 is independently C^alkyl, or where appropriate R9Ri0 forms part of a C3-6azacyloalkane or C3.6(2-, 3- or 4-oxo)azacycloalkane ring
- each R9' and R10' is independently selected from R9 and R10 and hydrogen;
- each Rg" and R10» is independently selected from R9' and R10' and C1-4alkanoyl;
- p is selected from 0, 1 , 2, 3 or 4;
- q is selected from 2, 3 or 4;
wherein each R15 is independently selected from hydrogen, halogen, hydroxy, cyano, amino, nitro, C1-6alkyl, C1-4alkoxy, haloC1-4alkyl, haloC1.4alkoxy, Ce-narylC-^alkoxy, C1-4alkylthio, hydroxyC1-4alkyl, C-t^alkoxyC^alkyl, C1-4haloalkoxyC1-4alkyl, C3-6cycloalkylC1-4alkyl, C3.6cycloalkyl, C3-6cycloalkylC1-4alkoxy, C1-4alkanoyl, C1-4haloalkanoyl, C1-4alkoxycarbonyl, C1-4alkylsulfonyl, C1-4haloalkylsulfonyl, Ci-4alkylsulfinyl, C1.4haloalkylsulfinyl, C1-4alkylsulfonyloxy, C1-4alkylsulfonylC1-4alkyl, Ce-^arylsulfonyl, C6-1iarylsulfonyloxy, C6-iiarylsulfonylC1-4alkyl, C1-4alkylsulfonamido, C4.9heteroarylsulfonyl, C1-4alkylamido, C1-4alkylsulfonamidoCi-4alkyl, C1-4alkylamidoCi-4alkyl, C6-11arylsulfonamido, C6-I 1 arylcarboxamido, Ce.-narylsulfonamidoC^alkyl, C6-11arylcarboxamidoC1-4alkyl, C6-11aroyl, C6-1iaroylC1-4alkyl, Ci-4acyl, C6-11aryl, C6-1iarylC1-4alkyl, C1-4alkylaminoC1-4alkyl, a group R9-RiO-N-, R9R1oNCO(CH2)p, R9.R1o.NS02(CH2)p or R9.SO2NR10.(CH2)P, -CR9-NRi0., -CR9-NOR10., -CR9.=C(CN)2, -CR9.=CH(CN), R9>R10>N(CH2)q- and R9.R10.N(CH2)qO-, wherein - each R9 and R10 is independently C1-4alkyl, or where appropriate RgR10 forms part of a C3-6azacyloalkane or C3-6(2-, 3- or 4-oxo)azacycloalkane ring
- each R9. and R10- is independently selected from R9 and R10 and hydrogen;
- each R9" and RiO» is independently selected from R9. and R10. and C1-4alkanoyl;
- p is selected from 0, 1 , 2, 3 or 4; - q is selected from 2, 3 or 4;
or Z is selected from a monocyclic or bicyclic heteroaryl group, which monocyclic heteroaryi group is or which bicyclic heteroaryl group optionally is substituted by one or more groups selected from amino, halogen, hydroxy, cyano, nitro, C2-4alkyl, C1-4alkoxy, haloC1-4alkyl, haloC1-4alkoxy, C6-11arylC1-4alkoxy, C1-4alkylthio, hydroxyC1-4alkyl, C1-4alkoxyC1-4alkyl, C1-4haloalkoxyC1-4alkyl, Cs.6cycloalkylC1-4alkyl, C3-6cycloalkyl, C3.6cycloalkylC1-4alkoxy, C1-4alkanoyl, Ci-4haloalkanoyl, Ci-4alkoxycarbonyl, C^alkoxycarbonylC^alkyl, C1-4alkylsulfonyl, C1-4haloalkylsulfonyl, C^alkylsulfinyl, C1-4haloalkylsulfinyl, C1-4alkylsulfonyloxy, C^alkylsulfonylC^alkyl, Ce^arylsulfonyl, C6-11arylsulfonyloxy, C6-11arylsulfonylC1-4alkyl, C1-4alkylsulfonamido, C4.9heteroarylsulfonyl, C1-4alkylamido, Ci-4alkylsulfonamidoC-ι^alkyl, C1-4alkylamidoC1-4alkyl,
C6-iiarylsulfonamido, C6-11aryicarboxamido, C6-1iarylsulfonamidoCi-4alkyl, Ce-narylcarboxamidoC^alkyl, C6-11aroyl, Ce-^aroylC-Malkyl, C6-iiarylCi.4alkanoyl, C1-4acyl, C6-11aryl, C6-11arylC1.4alkyl, R9R10NCO(CH2)P, R9.R10.NSO2(CH2)p or R9.SO2NR10'(CH2)p, -CR9>=NR10', -CR9.=NOR10., -CR9-C(CN)2, -CR9=CH(CN), R9.R10'N(CH2)q- and R9.R10'N(CH2)qC-, wherein - each R9 and R10 is independently Ci-4alkyl, or where appropriate R9R10 forms part of a C3-6azacyloalkane or C3-6(2-, 3- or 4-oxo)azacycloalkane ring
- each R9> and Rw is independently selected from R9 and Ri0 and hydrogen;
- each R9" and Ri0" is independently selected from R9' and R10' and C1-4alkanoyl;
- p is selected from 0, 1 , 2, 3 or 4; - q is selected from 2, 3 or 4;
As used herein, the term "C1-6alkyl" refers to a straight or branched alkyl which contains from one to six carbon atoms in all isomeric forms. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl, sec-pentyl, n-pentyl, isopentyl, tert-pentyl and hexyl.
As used herein, the term "C3-7cycloaikyr refers to a non-aromatic cyclic saturated hydrocarbon ring having from three to seven carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl .
As used herein, the term "N-linked 3- to 7-membered monocyclic heterocyclic ring" refers to a 3, 4, 5, 6 or 7 membered non-aromatic cyclic group containing one to three heteroatom(s) independently selected from N, O and S, which is linked to the rest of the molecule via a nitrogen atom. Examples of N-linked 3- to 7-membered monocyclic heterocyclic rings include aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl and azepanyl.
As used herein, the term "8- to 11 -membered bicyclic heterocyclic ring" refers to a 8, 9, 10 or 11 -membered bicyclic group containing one to three heteroatom(s) independently selected from N, O and S, wherein at least one of the rings is non-aromatic. Examples of 8- to 11 -membered bicyclic heterocyclic rings in which one of the rings is non-aromatic include dihydrobenzofuranyl, indanyl, indolinyl, isoindolinyl, tetrahydroisoquinolinyl, tetrahydroquinolyl and benzoazepanyl.
As used herein, the term refers to a straight or branched chain divalent hydrocarbon radical, which contains 1 , 2, 3 or 4 carbon atoms. Examples include methylene, ethylene, n-propylene and n-butylene.
As used herein, the term "aryl" refers to phenyl or a 8- to 11- membered bicyclic aromatic group in which at least one of the rings is aromatic. Examples of 8- to 11- membered bicyclic aromatic groups include indenyl, azulenyl, naphthyl and tetrahydronaphthyl. As used herein, the terms "heteroaryl" and "heteroaromatic group" refer to a 5- or 6- membered monocyclic aromatic group wherein one, two or three carbon atoms are replaced by a heteroatom independently selected from N, O and S, or to a 8- to 11- membered bicyclic aromatic group in which at least one of the rings is aromatic and wherein one to four carbon atoms in total are replaced by a heteroatom independently selected from N, O and S. Examples of 5- or 6-membered monocyclic heteroaromatic groups include furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyridyl, triazolyl, triazinyl, pyridazyl, pyrimidinyl, isothiazolyl, isoxazolyl, pyrazinyl, pyrazolyl and pyrimidinyl; examples of 8- to 11-membered bicyclic heteroaromatic groups include quinoxalinyl, quinazolinyl, pyridopyrazinyl, benzoxazolyl, benzothiophenyl, benzimidazolyl, naphthyridinyl, quinolinyl, benzofuranyl, indolyl, benzothiazolyl, oxazolyl[4,5-b]pyridiyl, pyridopyrimidinyl, isoquinolinyl and benzodroxazole.
As used herein, the terms "halogen" and its abbreviation "hal" refer to fluorine, chlorine, bromine, or iodine.
As used herein, the term "salt" refers to any salt of a compound according to the present invention prepared from an inorganic or organic acid or base, quaternary ammonium salts and internally formed salts. Physiologically acceptable salts are particularly suitable for medical applications because of their greater aqueous solubility relative to the parent compounds. Such salts must clearly have a physiologically acceptable anion or cation. Suitably physiologically acceptable salts of the compounds of the present invention include acid addition salts formed with inorganic acids such as hydrochloric, hydrobromic, hydroiodic, phosphoric, metaphosphoric, nitric and sulfuric acids, and with organic acids, such as tartaric, acetic, trifluoroacetic, citric, malic, lactic, fumaric, benzoic, formic, propionic, glycolic, gluconic, maleic, succinic, camphorsulfuric, isothionic, mucic, gentisic, isonicotinic, saccharic, glucuronic, furoic, glutamic, ascorbic, anthranilic, salicylic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, pantothenic, stearic, sulfinilic, alginic, galacturonic and arylsulfonic, for example benzenesulfonic and p-toluenesulfonic, acids; base addition salts formed with alkali metals and alkaline earth metals and organic bases such as N,N-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumaine (N-methylglucamine), lysine and procaine; and internally formed salts. Salts having a non-physiologically acceptable anion or cation are within the scope of the invention as useful intermediates for the preparation of physiologically acceptable salts and/or for use in non-therapeutic, for example, in vitro, situations.
As used herein, the term "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. Such solvents for the purpose of the invention may not interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, methanol, ethanol and acetic acid. Preferably the solvent used is a pharmaceutically acceptable solvent. Examples of suitable pharmaceutically acceptable solvents include water, ethanol and acetic acid. Most preferably the solvent used is water.
In one embodiment, wherein X is -SR2; and R2 is selected from C1-6alkyl and C3-7cycloalkyl, which C1-6alkyl or C3-7cycloalkyl group is optionally substituted with one or more groups selected from C3-7cycloalkyl, C1-4alkyl, C-ι-4haloalkyl, C1-4alkoxy, C1-4haloalkoxy, C1.4alkylthio, halo and hydroxyl. For example X may be C1-6alkylthio, optionally substituted by one or two groups selected from C3-7cycloalkyl, C1-4alkyl, C1-4haloalkyl, Ci-4alkoxy, C1-4haloalkoxy, C1-4alkylthio, halo and hydroxyl.
R2 may, for example, be unsubstituted.
In one embodiment, Y is S(O)mR5 where m is 1 or 2 and R5 is as defined above. For example, Y is S(O)mR5 where m is 2. R5 is preferably Ci-8alkyl, for example methyl.
In one embodiment, n is 0.
In another embodiment, n is 1 or 2 and R1 is independently hydrogen or C1-4alkyl.
In one embodiment, Z is a phenyl group Z' as set out above.
In one embodiment, each R13 is independently selected from hydrogen, halogen, cyano and Ci-4alkoxyCi.4alkyl.
In one embodiment, each R14 is independently selected from hydrogen, halogen, cyano, nitro, C1-6alkyl, C1-4alkoxy and haloC1-4alkyl.
In one embodiment, each R15 is independently selected from hydrogen, halogen, cyano, amino, nitro, C^alkyl, C-ι-4alkoxy, haloC1-4alkyl, for example trifluoromethyl, C1-4alkylthio, hydroxyC1-4alkyl, Ci-4alkoxyC1-4alkyl, C1.4haloalkoxyCi-4alkyl, C1- 4haloalkanoyl, C1-4alkylsulfonyl, C1-4alkylsulfinyl, C1-4haloalkylsulfinyl, RgRioNCO(CH2)p, - CR9-NR1O-, -CR9-NOR10', wherein
- each R9 and R10 is independently C^alkyl, or where appropriate R9R10 forms part of a C3-6azacyloalkane or C3.6(2-, 3- or 4-oxo)azacycloalkane ring
- each R9' and R10' is independently selected from R9 and Ri0 and hydrogen;
- p is selected from 0, 1 , 2, 3 or 4;
In a further embodiment, Z is a phenyl group Z1 as described herein, and is substituted, and one or more of R13, R14 and R15 is SO2C1-4alkyl, with the other groups R13, R14 and R15 being selected from hydrogen or halogen for example from hydrogen, chloro or fluoro. In a further embodiment, one or more of R13, R14 and R15 is C1-4alkoxyC1-4alkyl with the other groups Ri3, R14 and R15 being selected from hydrogen or halo, for example, F or Cl. In a further embodiment, one or more of R13, R14 and R15 is C1-4alkanoyl with the other groups R13, Ri4 and R15 being selected from hydrogen and halo, for example, F or Cl. In a further embodiment, one or more of Ri3, R14 and Ri5 is Ci-4alkoxy, for example methoxy, with the other groups R13, R14 and R15 being selected from hydrogen and halo, for example, F or Cl. In a further embodiment, one or more of Ri3, R14 and Ri5 is CR9=C(CN)2 where R9 is hydrogen or C1-4alkyl with the other groups R13, R14 and R15 being selected from hydrogen and halo, for example, F or Cl;
In a further embodiment, one or more of Ri3, R14 and Ri5 is haloC1-4alkyl, for example trifluoromethyl, with the other groups R13, R14 and R15 being selected from hydrogen and halo, for example F or Cl.
In an alternative embodiment, Z is selected from the group consisting of, pyridyl, pyrimidinyl, 1 Hpyrrole[2,3-ib]pyridine, pyridazinyl, pyrazinyl, triazolyl, triazinyl, pyrrolyl, imidazolyl, thienyl, furanyl, thiadiazolyl, isoxazolyl, isothiazolyl, thiazolyl, oxadiazolyl and oxazolyl, benzothiazolyl, 1 ,4-benzodioxinyl, 2,3-dihydro-1,4-benzodioxinyl, benzoxazolyl, indolyl, quinolyl, isoquinolinyl, 1-benzopyranyl, 2-benzopyranyl, dihyrdo-1-benzopyranyl, dihydro-2-benzopyranyl, quinoxalinyl and quinazolinyl, each of which is optionally substituted as set out above. For example, Z may be selected from pyrid-2-yl, pyrimidin-
2-yl , pyrimidin-4-yl , quinoxalinyl, quinolinyl, 1H-pyrrolo[2,3-ib]pyridinyl. Such groups Z may optionally be substituted with one or more groups selected from amino, cyano, nitro, haloC1-4alkyl, Ci-4alkoxy, Ci-4alkoxycarbonyl, C4- gheteroarylsulfonyl, and Rg»R10"N-, wherein each R9- and R10- is independently selected from hydrogen, C^alkyl and C1-4alkanoyl.
In a further embodiment Z is an optionally substituted pyrrolopyridine or an optionally substituted 1 H-pyrrolo[2,3-b]piperidine. Preferred optional substituents are arylsulfonyl and heteroarylsulfonyl, most preferably heteroarylsulfonyl.
Specific examples of compounds of the present invention include compounds of Examples 1 and 2 as out below, and salts and solvates thereof:
The compounds of formula (I) may have the ability to crystallise in more than one form. This is a characteristic known as polymorphism, and it is understood that such polymorphic forms ("polymorphs") are within the scope of formula (I). Polymorphism generally can occur as a response to changes in temperature or pressure or both and can also result from variations in the crystallisation process. Polymorphs can be distinguished by various physical characteristics known in the art such as x-ray diffraction patterns, solubility, and melting point. Certain of the compounds described herein may exist in stereoisomer^ 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. 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.
As referred to above, individual enantiomers of compounds of formula (I) may be prepared and an indication of the preferred stereochemistry for such enantiomers has been given. In a preferred embodiment, an optically pure enantiomer is desired. The term "optically pure enantiomer" means that the compound contains greater than about 90 % of the desired isomer by weight, preferably greater than about 95 % of the desired isomer by weight, and most preferably greater than about 99 % of the desired isomer by weight, said weight percent based upon the total weight of the isomer(s) of the compound.
The compounds of this invention may be made by a variety of methods, including standard chemistry. Any previously defined variable will continue to have the previously defined meaning unless otherwise indicated. Illustrative general synthetic methods are set out below and then specific compounds of the invention are prepared in the working Examples.
Compounds of general formula (I) may be prepared by methods disclosed in the documents hereinbefore referred to and by methods known in the art of organic synthesis as set forth in part by the following synthesis schemes. It is also recognised that in all of the schemes described below, it is well understood that protecting groups for sensitive or reactive groups are employed where necessary in accordance with general principles of chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (T. W. Greene and P. G. M. Wuts (1991) Protecting Groups in Organic Synthesis, John Wiley & Sons). These groups are removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art. The selection of processes as well as the reaction conditions and order of their execution shall be consistent with the preparation of compounds of formula (I). Those skilled in the art will recognise if a stereocentre exists in compounds of formula (I). Accordingly, the present invention includes both possible stereoisomers and includes not only racemic compounds but the individual enantiomers as well. Where the stereochemistry is indicated as being variable at certain positions, a mixture of stereoisomers may be obtained, this mixture having been separated where indicated. 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. Eliel, S. H. Wilen, and L. N. Mander (Wiley-lnterscience, 1994).
Typical reaction routes for the preparation of a compound of formula (I) as hereinbefore defined, are shown in the following schemes. It should be noted that, while the schemes illustrate cases wherein Y is -SO2Me and n is zero, the schemes are applicable for other cases wherein n and Y are as defined for formula (I) above. Similarly, the schemes illustrate cases where the leaving group is chlorine, but the leaving group may be any other suitable group. Scheme 5 illustrates methodology for preparing compounds in which Z is phenyl substituted with an alkoxyalkyl group. The methodology is also suitable for the preparation of other molecules of the invention that comprise alkoxyalkyl groups. Starting materials and reagents are known to the skilled person in the art and/or can be prepared using methods known in the art.
Scheme 1
Scheme 2
Scheme 3
I 1 ) react with R2SH 1 2) deprotect
Scheme 4
R1 = H1 Me, Alkyl
Route A. Route B. NaH, DMF, R11OH, toluene, R"l or R"Br ptsa.H20, reflux
Scheme 5
Accordingly, in a second aspect, the present invention provides a method of preparing a compound of formula (I), comprising the step of: (a) reacting a compound of formula (II):
(H) wherein L is a leaving group such as halogen or triflate, and Y, Ri, n and Z are as defined for formula (I), with a compound of formula (III):
H-X (III)
wherein X is as defined for formula (I) and H is hydrogen, in the presence of a suitable base, for example sodium hydride; or
(b) reacting a compound of formula (IV):
(IV) wherein X and Y are as defined for formula (I), with a compound of formula (V):
w ftln
(V) wherein R1, n and Z are as defined for formula (I); or
(c) reacting a compound of formula (Vl):
wherein X, Y, n and R1 are as defined for formula (I), with a group Z-L wherein Z is as defined for formula (I) and L is a leaving group such as halogen or triflate, under basic conditions with a suitable catalyst such as palladium acetate, and a suitable ligand such as 2,2'-bis(diphenylphosphino)-1 ,1-binaphthyl; or by heating a compound of formula (Vl) with a group Z-L to 180 0C, with or without diisopropylamine as solvent, in a microwave reactor;
and thereafter optionally for step (a), step (b) or step (c),
• removing any protecting groups and/or
• converting a compound of formula (I) into another compound of formula (I) and/or • forming a salt or solvate.
Step (c) may be carried out under suitable reaction conditions known in the literature, for example in J P Wolfe, H Tomori, J P Sadighi, J Yin and S L Buchwald, J. Org. Chem. (2000), 65, 1158; Org. Lett. (2003), 5(14), 2413; or J P Wolfe and S L Buchwald, J. Org. Chem. (2000), 65, 1144.
Compounds of formulae (N)-(VI) are commercially available, or may be made according to known methods available to the skilled person, or may be made according to methods disclosed herein.
Compounds of formula (V) (piperazines) are either commercially available or may be prepared by following literature methods:-
1. D. V. Gardner and A. C. Goudie, Ger. Offen. (1978), DE 2753878 (Becham Group)
2. Hakan V. Wikstrόm,, Marguerite M. Mensonides-Harsema.Thomas I. F. H. Cremers, Ejner K. Moltzen.and Jøm Arnt J Med Chem 2002, 45, 3280-3285
3. Harsha G. Jaisinghani and Bhushan M. Khadilkar Tet Lett 1997, 38, 6875-6876
4. C. Yamato, T. Takahishi, T. Fujita, S. Kuriyama, N. Hirose Xenobiotica 1974, 4, 765- 777.
Compounds of formula (I) can be converted into further compounds of formula (I) using standard techniques. For example, and by way of illustration rather than limitation, possible conversion reactions include acylation with an appropriate acylating agent such as acetyl chloride, alkylation using an appropriate alkylating reagent such as methyl iodide, and sulfonylation using a sulfonylating agent such as methanesulfonic anhydride.
Pharmaceutically acceptable 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.
Such compounds would be suitable for the treatment of certain neurological and neuropsychiatric disorders. As used herein, the terms "treatment" and "treating" refer to the alleviation and/or cure of established symptoms as well as prophylaxis.
The 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 medium (DMEM/NUT mix F12) containing 2 mM L-Glutamine, 0.8 mg/mL G418 and 10% heat inactivated fetal calf serum (Gibco BRL) at 370C in 5% CO2. Cells grown to 70-80% confluency in T175 flasks were harvested and resuspended at 1.6x106 cells/ml in assay buffer [NaC! (140 mM), KCI (5.4 mM), CaCI2 (1.8 mM), MgSO4 (0.8 mM), HEPES (20 mM), glucose (5 mM) and alanine (5 mM), pH 7.4]. An equal volume of LeadseekerTM SPA beads (12.5mg/ml suspended in assay buffer) was added to the cells and 25mL of the cell/bead suspension transferred to each well of a 384-well white solid bottom plate (20,000 cells/well) that contained 14ml_ of assay buffer. Compounds were prepared as 1OmM stocks in DMSO. Two-fold serial dilutions of the compounds were made in DMSO from a top concentration of 5mM. 1 mL of compound at each concentration was added to the assay plate using 384-well parallel dispensing. Substrate (1OmL) was added to each well [1:40 dilution of [3H]-glycine in assay buffer containing 5mM glycine). Final DMSO concentration = 2%. Data was collected using a PerkinElmer Viewlux as 5 minute exposures. IC50 values were determined using Grafit.
The following alternative assay may also be used:
HEK293 cells expressing the Glycine (Type 1) transporter were grown in cell medium (DMEM/NUT mix F12) containing 2 mM L-Glutamine, 0.8 mg/mL G418 and 10% heat inactivated fetal calf serum (Gibco BRL) at 370C in 5% CO2. Cells grown to 70-80% confluency in T175 flasks were harvested and resuspended at 4x105 cells/ml in assay buffer [NaCI (140 mM), KCI (5.4 mM), CaCI2 (1.8 mM), MgSO4 (0.8 mM), HEPES (2OmM), glucose (5 mM) and alanine (5 mM), pH 7.4]. An equal volume of Leadseeker SPA beads (12.5mg/ml suspended in assay buffer) was added to the cell suspension. Compounds were prepared as 1OmM stocks in DMSO. 2.5 fold serial dilutions of the compounds were made in DMSO from a top cone of 2.5 mM. 100 nL of compound at each concentration was added to the assay plate (384-well white solid bottom plate) using the hummingbird dispenser. 5uL of the cell/bead mix was then added on top of the compound using a multidrop dispenser. Substrate (5uL) was then added to each well (1 :100 dilution of H3-glycine in assay buffer containing 2.5 uM glycine) Data was collected using a PerkinElmer Viewlux as 5 minute exposures. plC50 data values were determined using Activity Base.
Compounds are considered to have activity at the the GIyTI transporter if they have a plC50 of 5.0 or above. The example compounds below were found to have a PIC50 at the GIyTI transporter of greater than 5.0. Preferred compounds of the invention were found to have a plC50 at the GIyTI transporter of greater than 6.0.
Compounds for use according to the invention may be administered as the raw material but the active ingredients are preferably provided in the form of pharmaceutical compositions. Accordingly, in a further aspect of the invention, there is provided a pharmaceutical composition comprising a compound of formula (I) as hereinbefore described or a salt or solvate thereof, and at least one pharmaceutically acceptable carrier, diluent or excipient. These pharmaceutical compositions may be used in the treatment of clinical conditions for which a GIyTI inhibitor is indicated such as, for example, schizophrenia. The carrier must be pharmaceutically acceptable to the recipient and must be compatible with, i.e. not have a deleterious effect upon, the other ingredients in the composition. The carrier may be a solid or a liquid and is preferably formulated with at least one compound of formula (I) or a salt or solvate thereof as a unit dose formulation. If desired, other physiologically active ingredients may also be incorporated in the pharmaceutical compositions of the invention.
These pharmaceutical compositions may be used in the treatment of clinical conditions for which a GIyTI inhibitor is indicated such as, for example, schizophrenia. The carrier must be pharmaceutically acceptable to the recipient and must be compatible with, i.e. not have a deleterious effect upon, the other ingredients in the composition. The carrier may be a solid or a liquid and is preferably formulated with at least one compound of formula (I) or a salt or solvate thereof as a unit dose formulation. If desired, other physiologically active ingredients may also be incorporated in the pharmaceutical compositions of the invention.
Within the context of the present invention, the terms used herein are classified in the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, published by the American Psychiatric Association (DSM-IV) and/or the International Classification of Diseases, 10th Edition (ICD-10). The various subtypes of the disorders mentioned herein are contemplated as part of the present invention. Numbers in brackets after the listed diseases below refer to the classification code in DSM-IV.
In particular, the compounds of formula (I) are of use in the treatment of schizophrenia including the subtypes Paranoid Type (295.30), Disorganised Type (295.10), Catatonic Type (295.20), Undifferentiated Type (295.90) and Residual Type (295.60); Schizophreniform Disorder (295.40); Schizoaffective Disorder (295.70) including the subtypes Bipolar Type and Depressive Type; Delusional Disorder (297.1) including the subtypes Erotomanic Type, Grandiose Type, Jealous Type, Persecutory Type, Somatic Type, Mixed Type and Unspecified Type; Brief Psychotic Disorder (298.8); Shared Psychotic Disorder (297.3); Psychotic Disorder Due to a General Medical Condition including the subtypes With Delusions and With Hallucinations; Substance-Induced Psychotic Disorder including the subtypes With Delusions (293.81) and With Hallucinations (293.82); and Psychotic Disorder Not Otherwise Specified (298.9).
The compounds of formula (I) are also of use in the treatment of mood disorders including Major Depressive Episode, Manic Episode, Mixed Episode and Hypomanic Episode;
Depressive Disorders including Major Depressive Disorder, Dysthymic Disorder (300.4),
Depressive Disorder Not Otherwise Specified (311); Bipolar Disorders including Bipolar I Disorder, Bipolar 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 formula (I) are also of use in the treatment of anxiety disorders including Panic Attack, Agoraphobia, Panic Disorder, Agoraphobia Without History of Panic Disorder (300.22), Specific Phobia (300.29) including the subtypes Animal Type, Natural Environment Type, Blood-lnjection-lnjury Type, Situational Type and Other Type), Social Phobia (300.23), Obsessive-Compulsive Disorder (300.3), Posttraumatic Stress Disorder (309.81), Acute Stress Disorder (308.3), Generalized Anxiety Disorder (300.02), Anxiety Disorder Due to a General Medical Condition (293.84), Substance-Induced Anxiety Disorder and Anxiety Disorder Not Otherwise Specified (300.00).
The compounds of formula (I) are also of use in the treatment of substance-related disorders including Substance Use Disorders such as Substance Dependence and Substance Abuse; Substance-Induced Disorders such as Substance Intoxication, Substance Withdrawal, Substance-Induced Delirium, Substance-Induced Persisting Dementia, Substance-Induced Persisting Amnestic Disorder, Substance-Induced Psychotic Disorder, Substance-Induced Mood Disorder, Substance-Induced Anxiety Disorder, Substance-Induced Sexual Dysfunction, Substance-Induced Sleep Disorder and Hallucinogen Persisting Perception Disorder (Flashbacks); Alcohol-Related Disorders such as Alcohol Dependence (303.90), Alcohol Abuse (305.00), Alcohol Intoxication (303.00), Alcohol Withdrawal (291.81), Alcohol Intoxication Delirium, Alcohol Withdrawal Delirium, Alcohol-Induced Persisting Dementia, Alcohol-Induced Persisting Amnestic Disorder, Alcohol-Induced Psychotic Disorder, Alcohol-Induced Mood Disorder, Alcohol- Induced Anxiety Disorder, Alcohol-Induced Sexual Dysfunction, Alcohol-Induced Sleep Disorder and Alcohol-Related Disorder Not Otherwise Specified (291.9); Amphetamine (or Amphetamine-I_ike)-Related Disorders such as Amphetamine Dependence (304.40), Amphetamine Abuse (305.70), Amphetamine Intoxication (292.89), Amphetamine Withdrawal (292.0), Amphetamine Intoxication Delirium, Amphetamine Induced Psychotic Disorder, Amphetamine-Induced Mood Disorder, Amphetamine-Induced Anxiety Disorder, Amphetamine-Induced Sexual Dysfunction, Amphetamine-Induced Sleep Disorder and Amphetamine-Related Disorder Not Otherwise Specified (292.9); Caffeine Related Disorders such as Caffeine Intoxication (305.90), Caffeine-Induced Anxiety Disorder, Caffeine-Induced Sleep Disorder and Caffeine-Related Disorder Not Otherwise Specified (292.9); Cannabis-Related Disorders such as Cannabis Dependence (304.30), Cannabis Abuse (305.20), Cannabis Intoxication (292.89), Cannabis Intoxication Delirium, Cannabis-lnduced Psychotic Disorder, Cannabis-lnduced Anxiety Disorder and Cannabis- Related Disorder Not Otherwise Specified (292.9); Cocaine-Related Disorders such as Cocaine Dependence (304.20), Cocaine Abuse (305.60), Cocaine Intoxication (292.89), Cocaine Withdrawal (292.0), Cocaine Intoxication Delirium, Cocaine-Induced Psychotic Disorder, Cocaine-Induced Mood Disorder, Cocaine-Induced Anxiety Disorder, Cocaine- Induced Sexual Dysfunction, Cocaine-Induced Sleep Disorder and Cocaine-Related Disorder Not Otherwise Specified (292.9); Hallucinogen-Related Disorders such as Hallucinogen Dependence (304.50), Hallucinogen Abuse (305.30), Hallucinogen Intoxication (292.89), Hallucinogen Persisting Perception Disorder (Flashbacks) (292.89), Hallucinogen Intoxication Delirium, Hallucinogen-Induced Psychotic Disorder, Hallucinogen-Induced Mood Disorder, Hallucinogen-Induced Anxiety Disorder and Hallucinogen-Related Disorder Not Otherwise Specified (292.9); Inhalant-Related Disorders such as Inhalant Dependence (304.60), Inhalant Abuse (305.90), Inhalant Intoxication (292.89), Inhalant Intoxication Delirium, Inhalant-Induced Persisting Dementia, Inhalant-Induced Psychotic Disorder, Inhalant-Induced Mood Disorder, Inhalant-Induced Anxiety Disorder and Inhalant-Related Disorder Not Otherwise Specified (292.9); Nicotine-Related Disorders such as Nicotine Dependence (305.1), Nicotine Withdrawal (292.0) and Nicotine-Related Disorder Not Otherwise Specified (292.9); Opioid-Related Disorders such as Opioid Dependence (304.00), Opioid Abuse (305.50), Opioid Intoxication (292.89), Opioid Withdrawal (292.0), Opioid Intoxication Delirium, Opioid-lnduced Psychotic Disorder, Opioid-lnduced Mood Disorder, Opioid-lnduced Sexual Dysfunction, Opioid-lnduced Sleep Disorder and Opioid-Related Disorder Not Otherwise Specified (292.9); Phencyclidine (or Phencyclidine-Like)-Related Disorders such as Phencyclidine Dependence (304.60), Phencyclidine Abuse (305.90), Phencyclidine Intoxication (292.89), Phencyclidine Intoxication Delirium, Phencyclidine- lnduced Psychotic Disorder, Phencyclidine-lnduced Mood Disorder, Phencyclidine- lnduced Anxiety Disorder and Phencyclidine-Related Disorder Not Otherwise Specified (292.9); Sedative-, Hypnotic-, or Anxiolytic-Related Disorders such as Sedative, Hypnotic, or Anxiolytic Dependence (304.10), Sedative, Hypnotic, or Anxiolytic Abuse (305.40), Sedative, Hypnotic, or Anxiolytic Intoxication (292.89), Sedative, Hypnotic, or Anxiolytic Withdrawal (292.0), Sedative, Hypnotic, or Anxiolytic Intoxication Delirium, Sedative, Hypnotic, or Anxiolytic Withdrawal Delirium, Sedative-, Hypnotic-, or Anxiolytic-Persisting Dementia, Sedative-, Hypnotic-, or Anxiolytic- Persisting Amnestic Disorder, Sedative-, Hypnotic-, or Anxiolytic-lnduced Psychotic Disorder, Sedative-, Hypnotic-, or Anxiolytic- Induced Mood Disorder, Sedative-, Hypnotic-, or Anxiolytic-lnduced Anxiety Disorder Sedative-, Hypnotic-, or Anxiolytic-lnduced Sexual Dysfunction, Sedative-, Hypnotic-, or Anxiolytic-lnduced Sleep Disorder and Sedative-, Hypnotic-, or Anxiolytic-Related Disorder Not Otherwise Specified (292.9); Polysubstance-Related Disorder such as Polysubstance Dependence (304.80); and Other (or Unknown) Substance-Related Disorders such as Anabolic Steroids, Nitrate Inhalants and Nitrous Oxide. The compounds of formula (I) are also of use in the treatment of sleep disorders including primary sleep disorders such as Dyssomnias such as Primary Insomnia (307.42), Primary Hypersomnia (307.44), Narcolepsy (347), Breathing-Related Sleep Disorders (780.59), Circadian Rhythm Sleep Disorder (307.45) and Dyssomnia Not Otherwise Specified (307.47); primary sleep disorders such as Parasomnias such as Nightmare Disorder (307.47), Sleep Terror Disorder (307.46), Sleepwalking Disorder (307.46) and Parasomnia Not Otherwise Specified (307.47); Sleep Disorders Related to Another Mental Disorder such as Insomnia Related to Another Mental Disorder (307.42) and Hypersomnia Related to Another Mental Disorder (307.44); Sleep Disorder Due to a General Medical Condition; and Substance-Induced Sleep Disorder including the subtypes Insomnia Type, Hypersomnia Type, Parasomnia Type and Mixed Type.
The compounds of formula (I) are also of use in the treatment of eating disorders such as Anorexia Nervosa (307.1) including the subtypes Restricting Type and Binge- Eating/Purging Type; Bulimia Nervosa (307.51 ) including the subtypes Purging Type and Nonpurging Type; Obesity; Compulsive Eating Disorder; and Eating Disorder Not Otherwise Specified (307.50).
The compounds of formula (I) are also of use in the treatment of Autistic Disorder (299.00); Attention-Deficit /Hyperactivity Disorder including the subtypes Attention-Deficit /Hyperactivity Disorder Combined Type (314.01), Attention-Deficit /Hyperactivity Disorder Predominantly Inattentive Type (314.00), Attention-Deficit /Hyperactivity Disorder Hyperactive-Impulse Type (314.01) and Attention-Deficit /Hyperactivity Disorder Not Otherwise Specified (314.9); Hyperkinetic Disorder; Disruptive Behaviour Disorders such as Conduct Disorder including the subtypes childhood-onset type (321.81), Adolescent- Onset Type (312.82) and Unspecified Onset (312.89), Oppositional Defiant Disorder (313.81) and Disruptive Behaviour Disorder Not Otherwise Specified; and Tic Disorders such as Tourette's Disorder (307.23).
The compounds of formula (I) are also of use in the treatment of Personality Disorders including the subtypes Paranoid Personality Disorder (301.0), Schizoid Personality Disorder (301.20), Schizotypal Personality Disorder (301 ,22), Antisocial Personality Disorder (301.7), Borderline Personality Disorder (301 ,83), Histrionic Personality Disorder (301.50), Narcissistic Personality Disorder (301,81), Avoidant Personality Disorder (301.82), Dependent Personality Disorder (301.6), Obsessive-Compulsive Personality Disorder (301.4) and Personality Disorder Not Otherwise Specified (301.9).
The compounds of Formula (I) are also of use in the enhancement of cognition including the treatment of cognition impairment in other diseases such as schizophrenia, bipolar disorder, depression, other psychiatric disorders and psychotic conditions associated with cognitive impairment. Within the context of the present invention, the term 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-electroconvulsive treatment related cognitive disorders; and dyskinetic disorders such as Parkinson's disease, neuroleptic-induced parkinsonism, and tardive dyskinesias.
The compounds of formula (I) are also of use in the treatment of sexual dysfunctions including Sexual Desire Disorders such as Hypoactive Sexual Desire Disorder (302.71), and Sexual Aversion Disorder (302.79); sexual arousal disorders such as Female Sexual Arousal Disorder (302.72) and Male Erectile Disorder (302.72); orgasmic disorders such as Female Orgasmic Disorder (302.73), Male Orgasmic Disorder (302.74) and Premature Ejaculation (302.75); sexual pain disorder such as Dyspareunia (302.76) and Vaginismus (306.51); Sexual Dysfunction Not Otherwise Specified (302.70); paraphilias such as Exhibitionism (302.4), Fetishism (302.81), Frotteurism (302.89), Pedophilia (302.2), Sexual Masochism (302.83), Sexual Sadism (302.84), Transvestic Fetishism (302.3), Voyeurism (302.82) and Paraphilia Not Otherwise Specified (302.9); gender identity disorders such as Gender Identity Disorder in Children (302.6) and Gender Identity Disorder in Adolescents or Adults (302.85); and Sexual Disorder Not Otherwise Specified (302.9).
The invention also provides a compound of formula (I) as hereinbefore described or a pharmaceutically acceptable salt or solvate thereof for use in the treatment of schizophrenia, mood disorders, anxiety disorders, substance-related disorders, sleep disorders, eating disorders, autistic disorder, attention-deficit/hyperactivity disorder, disruptive behaviour disorder, tic disorders, personality disorders, cognition impairment in other diseases, sexual dysfunction, Parkinson's disease, dyskinetic disorders, depression, bipolar disorder, cognitive impairment, obesity, emesis, movement disorders, obsessive- compulsive disorders, amnesia, aggression, vertigo, dementia and arcadian rhythm disorders.
The invention also provides a compound of formula (I) as hereinbefore described or a pharmaceutically acceptable salt or solvate thereof for use in the treatment of psychotic disorders, schizophrenia, Parkinson's disease, substance abuse, dyskinetic disorders, depression, bipolar disorder, anxiety, cognitive impairment, eating disorders, obesity, sexual dysfunction, sleep disorders, emesis, movement disorders, obsessive-compulsive disorders, amnesia, aggression, autism, vertigo, dementia, circadian rhythm disorders and gastric motility disorders.
In another aspect of the invention, there is provided a method of treating a mammal, including a human, suffering from or susceptible to a disorder mediated by GIyTI , which comprises administering an effective amount of a compound of formula (I) as hereinbefore defined or a salt or solvate thereof.
The invention also provides a method of treating schizophrenia, mood disorders, anxiety disorders, substance-related disorders, sleep disorders, eating disorders, autistic disorder, attention-deficit/hyperactivity disorder, disruptive behaviour disorder, tic disorders, personality disorders, cognition impairment in other diseases, sexual dysfunction, Parkinson's disease, dyskinetic disorders, depression, bipolar disorder, cognitive impairment, obesity, emesis, movement disorders, obsessive-compulsive disorders, amnesia, aggression, vertigo, dementia and circadian rhythm disorders which comprises administering to a mammal in need thereof an effective amount of a compound of formula (I) as hereinbefore described or a pharmaceutically acceptable salt or solvate thereof.
The invention also provides a method of treating psychotic disorders, schizophrenia, Parkinson's disease, substance abuse, dyskinetic disorders, depression, bipolar disorder, anxiety, cognitive impairment, eating disorders, obesity, sexual dysfunction, sleep disorders, emesis, movement disorders, obsessive-compulsive disorders, amnesia, aggression, autism, vertigo, dementia, circadian rhythm disorders and gastric motility disorders which comprises administering to a mammal in need thereof an effective amount of a compound of formula (I) as hereinbefore described or a pharmaceutically acceptable salt or solvate thereof.
In another aspect of the invention, there is provided use of a compound of formula (I) as hereinbefore defined or a salt or solvate thereof in the preparation of a medicament for the treatment of a disorder mediated by GIyTI .
Preferably, the disorder mediated by GIyTI to be treated by the use or method as hereinbefore described is a psychosis, including schizophrenia, dementia and attention deficit disorders, particularly schizophrenia.
The invention also provides the use of a compound of formula (I) as hereinbefore described or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for the treatment of schizophrenia, mood disorders, anxiety disorders, substance-related disorders, sleep disorders, eating disorders, autistic disorder, attention- deficit/hyperactivity disorder, disruptive behaviour disorder, tic disorders, personality disorders, cognition impairment in other diseases, sexual dysfunction, Parkinson's disease, dyskinetic disorders, depression, bipolar disorder, cognitive impairment, obesity, emesis, movement disorders, obsessive-compulsive disorders, amnesia, aggression, vertigo, dementia and circadian rhythm disorders.
The invention also provides the use of a compound of formula (I) as hereinbefore described or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for the treatment of psychotic disorders, schizophrenia, Parkinson's disease, substance abuse, dyskinetic disorders, depression, bipolar disorder, anxiety, cognitive impairment, eating disorders, obesity, sexual dysfunction, sleep disorders, emesis, movement disorders, obsessive-compulsive disorders, amnesia, aggression, autism, vertigo, dementia, circadian rhythm disorders and gastric motility disorders.
As used herein, the term "effective amount" means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher or clinician.
Compounds for use according to the invention may be administered as the raw material but the active ingredients are preferably provided in the form of pharmaceutical compositions.
Accordingly, in a further aspect of the invention, there is provided a pharmaceutical composition comprising a compound of formula (I) as hereinbefore described or a salt or solvate thereof, and at least one pharmaceutically acceptable carrier, diluent or excipient.
These pharmaceutical compositions may be used in the treatment of clinical conditions for which a GIyTI inhibitor is indicated such as, for example, schizophrenia. The carrier must be pharmaceutically acceptable to the recipient and must be compatible with, i.e. not have a deleterious effect upon, the other ingredients in the composition. The carrier may be a solid or a liquid and is preferably formulated with at least one compound of formula (I) or a salt or solvate thereof as a unit dose formulation. If desired, other physiologically active ingredients may also be incorporated in the pharmaceutical compositions of the invention.
It will be appreciated by those skilled in the art that the compounds according to the invention may advantageously be used in conjunction with one or more other therapeutic agents, for instance, different antidepressant agents such as 5HT3 antagonists, serotonin agonists, NK-1 antagonists, selective serotonin reuptake inhibitors (SSRI), noradrenaline re-uptake inhibitors (SNRI), tricyclic antidepressants, dopaminergic antidepressants, H3 antagonists, 5HT1A antagonists, 5HT1B antagonists, 5HT1D antagonists, D1 agonists, M1 agonists and/or anticonvulsant agents, as well as atypical antipsychotic drugs and cognitive enhancers. Suitable 5HT3 antagonists which may be used in combination of the compounds of the inventions include for example ondansetron, granisetron, metoclopramide.
Suitable serotonin agonists which may be used in combination with the compounds of the invention include sumatriptan, rauwolscine, yohimbine, metoclopramide.
Suitable SSRIs which may be used in combination with the compounds of the invention include fluoxetine, citalopram, femoxetine, fluvoxamine, paroxetine, indalpine, sertraline, zimeldine.
Suitable SNRIs which may be used in combination with the compounds of the invention include venlafaxine and reboxetine.
Suitable tricyclic antidepressants which may be used in combination with a compound of the invention include imipramine, amitriptiline, chlomipramine and nortriptiline.
Suitable dopaminergic antidepressants which may be used in combination with a compound of the invention include bupropion and amineptine.
Suitable anticonvulsant agents which may be used in combination of the compounds of the invention include for example divalproex, carbamazepine and diazepam.
Suitable atypical antipsychotic drugs which which may be used in combination of the compounds of the invention include for example risperidone, olanzapine, ziprasidone, aripiprazole and clozapine.
It will be appreciated that the compounds of the combination or composition may be administered simultaneously (either in the same or different pharmaceutical formulations), separately or sequentially.
The compounds of formula (I) and their pharmaceutically acceptable salts and solvates thereof are also suitable for combination with other typical and atypical antipsychotics to provide improved treatment of psychotic disorders. Particular advantages associated with the combinations, uses and methods of treatment of compounds of formula (I) and their pharmaceutically acceptable salts and solvates thereof include equivalent or improved efficacy at doses of administration which are lower than those commonly used for the individual components. Improved treatments of positive symptoms and/or negative symptoms and/or cognitive symptoms of the psychotic disorder may also be observed. The combinations, uses and methods of treatment of the invention may also provide advantages in treatment of patients who fail to respond adequately or who are resistant to treatment with certain neuroleptic agents. The combination therapies of the invention are preferably administered adjunctively. By adjunctive administration is meant the coterminous or overlapping administration of each of the components in the form of separate pharmaceutical compositions or devices. This regime of therapeutic administration of two or more therapeutic agents is referred to generally by those skilled in the art and herein as adjunctive therapeutic administration; it is also known as add-on therapeutic administration. Any and all treatment regimes in which a patient receives separate but coterminous or overlapping therapeutic administration of the compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof and at least one neuroleptic agent are within the scope of the current invention. In one embodiment of adjunctive therapeutic administration as described herein, 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. Within the scope of this invention, it is preferred that the compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof is administered as adjunctive therapeutic treatment to patients who are receiving administration of at least one neuroleptic agent, but the scope of the invention also includes the adjunctive therapeutic administration of at least one neuroleptic agent to patients who are receiving administration of compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof.
The combination therapies of the invention may also be administered simultaneously. By 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.
In a further aspect therefore, the invention provides a method of treatment of a psychotic disorder by adjunctive therapeutic administration of compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof to a patient receiving therapeutic administration of at least one neuroleptic agent. In a further aspect, the invention provides the use of compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for adjunctive therapeutic administration for the treatment of a psychotic disorder in a patient receiving therapeutic administration of at least one neuroleptic agent. The invention further provides compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use for adjunctive therapeutic administration for the treatment of a psychotic disorder in a patient receiving therapeutic administration of at least one neuroleptic agent.
In a further aspect, the invention provides a method of treatment of a psychotic disorder by adjunctive therapeutic administration of at least one neuroleptic agent to a patient receiving therapeutic administration of compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof. In a further aspect, the invention provides the use of at least one neuroleptic agent in the manufacture of a medicament for adjunctive therapeutic administration for the treatment of a psychotic disorder in a patient receiving therapeutic administration of compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof. The invention further provides at least one neuroleptic agent for adjunctive therapeutic administration for the treatment of a psychotic disorder in a patient receiving therapeutic administration of compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof.
In a further aspect, the invention provides a method of treatment of a psychotic disorder by simultaneous therapeutic administration of compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof in combination with at least one neuroleptic agent. The invention further provides the use of a combination of compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof and at least one neuroleptic agent in the manufacture of a medicament for simultaneous therapeutic administration in the treatment of a psychotic disorder. The invention further provides the use of compounds of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for simultaneous therapeutic administration with at least one neuroleptic agent in the treatment of a psychotic disorder. The invention further provides compounds of formula (I) or a pharmaceutically acceptable salt thereof for use for simultaneous therapeutic administration with at least one neuroleptic agent in the treatment of a psychotic disorder. The invention further provides the use of at least one neuroleptic agent in the manufacture of a medicament for simultaneous therapeutic administration with compounds of formula (I) or a pharmaceutically acceptable salt thereof in the treatment of a psychotic disorder.
In further aspects, the invention provides a method of treatment of a psychotic disorder by simultaneous therapeutic administration of a pharmaceutical composition comprising compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof and at least one mood stabilising or antimanic agent, a pharmaceutical composition comprising compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof and at least one mood stabilising or antimanic agent, the use of a pharmaceutical composition comprising compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof and at least one mood stabilising or antimanic agent in the manufacture of a medicament for the treatment of a psychotic disorder, and a pharmaceutical composition comprising compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof and at least one mood stabilising or antimanic agent for use in the treatment of a psychotic disorder.
In a further aspect, the invention provides a kit-of-parts for use in the treatment of a psychotic disorder comprising a first dosage form comprising compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof and one or more further dosage forms each comprising a neuroleptic agent for simultaneous therapeutic administration. Within the context of the present invention, the term psychotic disorder includes those disorders mentioned above, such as schizophrenia, mood disorders, anxiety disorders, substance-related disorders, sleep disorders, eating disorders, autistic disorder, attention- deficit/hyperactivity disorder, disruptive behaviour disorder, tic disorders, personality disorders, cognition impairment in other diseases, sexual dysfunction, dyskinetic disorders, depression, bipolar disorder, cognitive impairment and obsessive-compulsive disorders and all the various forms of the disorders as mentioned herein, which are contemplated as part of the present invention.
Examples of neuroleptic/antipsychotic drugs that are useful in the present invention include, but are not limited to: butyrophenones, such as haloperidol, pimozide, and droperidol; phenothiazines, such as chlorpromazine, thioridazine, mesoridazine, trifluoperazine, perphenazine, fluphenazine, thiflupromazine, prochlorperazine, and acetophenazine; thioxanthenes, such as thiothixene and chlorprothixene ; thienobenzodiazepines; dibenzodiazepines; benzisoxazoles; dibenzothiazepines; imidazolidinones ; benzisothiazolyl-piperazines; triazine such as lamotrigine; dibenzoxazepines, such as loxapine; dihydroindolones, such as molindone; aripiprazole; and derivatives thereof that have antipsychotic activity.
Examples of neuroleptic drugs that are preferred for use in the present invention are shown in Table 1.
Table 1 Neuroleptic drugs
Examples of tradenames and suppliers of selected neuroleptic drugs are as follows : clozapine (available under the tradename CLOZARIL®, from Mylan, Zenith Goldline, UDL1 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 NAVANE®;, from Pfizer); trifluoperazine (10-[3-(4-methyl-1-piperazinyl)propyl]- 2-(trifluoromethyl)phenothiazine dihydrochloride, available under the tradename STELAZINE®, from Smith Klein Beckman; perphenazine (available under the tradename TRILAFON®; from Schering); thioridazine (available under the tradename MELLARIL®; from Novartis, Roxane, HiTech, Teva, and Alpharma) ; molindone (available under the tradename MOBAN®, from Endo); and loxapine (available under the tradename LOXITANE®; from Watson). Furthermore, benperidol (Glianimon®), perazine (Taxilan®) or melperone (Eunerpan®)) may be used.
Other preferred neuroleptic drugs include promazine (available under the tradename SPARINE®), triflurpromazine (available under the tradename VESPRIN®), chlorprothixene (available under the tradename TARACT AN®), 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.
Particularly preferred neuroleptic agents for use in the invention are olanzapine, risperidone, quetiapine, aripiprazole, haloperidol, clozapine, ziprasidone and osanetant.
It will be appreciated by those skilled in the art that the compounds according to the invention may advantageously be used in conjunction with one or more other therapeutic agents, for instance, different antidepressant agents such as 5HT3 antagonists, serotonin agonists, NK-1 antagonists, selective serotonin reuptake inhibitors (SSRI), noradrenaline re-uptake inhibitors (SNRI), tricyclic antidepressants, dopaminergic antidepressants, H3 antagonists, 5HT1A antagonists, 5HT1B antagonists, 5HT1 D antagonists, D1 agonists, M1 agonists and/or anticonvulsant agents, as well as atypical antipsychotic drugs and cognitive enhancers.
Suitable 5HT3 antagonists which may be used in combination of the compounds of the inventions include for example ondansetron, granisetron, metoclopramide.
Suitable serotonin agonists which may be used in combination with the compounds of the invention include sumatriptan, rauwolscine, yohimbine, metoclopramide.
Suitable SSRIs which may be used in combination with the compounds of the invention include fluoxetine, citalopram, femoxetine, fluvoxamine, paroxetine, indalpine, sertraline, zimeldine.
Suitable SNRIs which may be used in combination with the compounds of the invention include venlafaxine and reboxetine.
Suitable tricyclic antidepressants which may be used in combination with a compound of the invention include imipramine, amitriptiline, chlomipramine and nortriptiline. Suitable dopaminergic antidepressants which may be used in combination with a compound of the invention include bupropion and amineptine.
Suitable anticonvulsant agents which may be used in combination of the compounds of the invention include for example divalproex, carbamazepine and diazepam.
Suitable atypical antipsychotic drugs which which may be used in combination of the compounds of the invention include for example risperidone, olanzapine, ziprasidone, aripiprazole and clozapine.
It will be appreciated that the compounds of the combination or composition may be administered simultaneously (either in the same or different pharmaceutical formulations), separately or sequentially.
In a further aspect of the invention, there is provided a compound of formula (I) as hereinbefore described or a salt or solvate thereof, for use in therapy.
In another aspect of the invention, there is provided a compound of formula (I) as hereinbefore described or a salt or solvate thereof, for use in the treatment of a disorder mediated by GIyTI .
As used herein, the term "a disorder mediated by GIyTI" refers to a disorder that may be treated by the administration of a medicament that alters the activity of the GIyTI transporter. As hereinbefore described, the action of GIyTI transporters affects the local concentration of glycine around NMDA receptors. As a certain amount of glycine is needed for the efficient functioning of NMDA receptors, any change to that local concentration can affect NMDA-mediated neurotransmission. As hereinbefore described, changes in NMDA-mediated neurotransmission have been implicated in certain neuropsychiatric disorders such as dementia, depression and psychoses, for example schizophrenia, and learning and memory disorders, for example attention deficit disorders and autism. Thus, alterations in the activity of the GIyTI transporter are expected to influence such disorders.
The disorders mediated by GIyTI referred to herein include neurological and neuropsychiatric disorders, including psychoses such as schizophrenia, dementia and other forms of impaired cognition such as attention deficit disorders and organic brain syndromes. Other neuropsychiatric disorders include drug-induced (phencyclidine, ketamine and other dissociative anesthetics, amphetamine and other psychostimulants and cocaine) psychosis, psychosis associated with affective disorders, brief reactive psychosis, schizoaffective psychosis, and psychosis NOS, "schizophrenia-spectrum" disorders such as schizoid or schizotypal personality disorders, or illness associated with psychosis (such as major depression, manic depressive (bipolar) disorder, Alzheimer's disease and post-traumatic stress syndrome), and NMDA receptor-related disorders such as autism, depression, benign forgetfulness, childhood learning disorders and closed head injury.
In a further aspect of the invention, there is provided a method of treating a mammal, including a human, suffering from or susceptible to a disorder mediated by GIyTI , which comprises administering an effective amount of a compound of formula (Ib) or a salt or solvate thereof:
(Ib) wherein
• X is -SR2, wherein - R2 is selected from C-|.6alkyl and C3-7cycloalkyl, which C1-6alkyl or C3.7cycloalkyl group is optionally substituted with one or more groups selected from C3-7cycloalkyl, C1.4alkyl, C1-4haloalkyl, C1-4alkoxy, d-4haloalkoxy, Ci-4alkylthio, halo and hydroxy;
• Y is S(O)171R5 or -SO2NR6R7 wherein
- m is 1 or 2; and
- R5 is selected from C1-6alkyl, C3-7cycloalkyl, G^aryl and C4-10heteroaryl, which C1-6alkyl, C3-7cycloalkyl, C5-H aryl or C4-10heteroaryl is optionally substituted with one or two groups selected from halo, C1-4alkoxy and Ci-4haloalkoxy; - R6 and R7 are independently selected from hydrogen and C1-6alkyl but are not both simultaneously C1-6alkyl; which Ci.6alkyl is optionally substituted with one or more groups selected from halo, C-i-4alkoxy and C1-4haloalkoxy;
• n is 0, 1 or 2,
• each Ri is independently selected from C1-6alkyl, halo, C1-6haloalkyl C1-4alkoxy and C1-4haloalkoxy;
• Z is an optionally substituted phenyl group 2':
Z'
wherein each Ri3 is independently selected from hydrogen, halogen, hydroxy, cyano, amino, nitro, C1-6alkyl, haloC^alkyl, haloC1-4alkoxy, C6-narylC1-4alkoxy, C1-4alkylthio, hydroxyC1-4alkyl, C3.6cycloalkylC1-4alkyl, C3.6cycloalkyl, Cs-ecycloalkylCT^alkoxy, Ci-4alkanoyl, C1-4alkoxycarbonyl, C^alkoxycarbonylC^alkyl, C1-4alkylsulfonyl, C1-4alkylsulfonyloxy, Ci-4alkylsulfonylC1-4alkyl, C6.narylsulfonyl, C6--I -larylsulfonyloxy, C6-11arylsulfonylC1-4alkyl, Ci-4alkylsulfonamido, C4-9heteroarylsulfonyl, C1-4alkylamido, Ci-4alkylsulfonamidoCi-4alkyl, C1-4alkylamidoCi-4alkyl,
C6-narylsulfonamido, C6-narylcarboxamido,
Ce.-narylcarboxamidoC^^lkyl, C6-11aroyl, C6-naroylC1-4alkyl, C6-11arylC1-4alkanoyl, C1-4acyl, C6-iiarylCi-4alkyl, Ci-4alkylaminoCi.4alkyl, a group R9»R10»N-, R9R10NCO(CH2)P, R9.R10.NSO2(CH2)p or R9.SO2NR10.(CH2)p, -CR9=NR10., -CR9.=NOR1o., -CR9.=C(CN)2, -CR9.=CH(CN), R9.R10.N(CH2)q- and R9>Ri0.N(CH2)qO-,wherein
- each R9 and Ri0 is independently C1-4alkyl, or where appropriate RgR10 forms part of a C3-6azacyloalkane or C3.6(2-, 3- or 4-oxo)azacycloalkane ring
- each R9. and R10. is independently selected from R9 and R10 and hydrogen; - each R9" and R10" is independently selected from R9. and R10. and C1-4alkanoyl;
- p is selected from 0, 1 , 2, 3 or 4;
- q is selected from 2, 3 or 4;
wherein each Ri4 is independently selected from hydrogen, halogen, hydroxy, cyano, amino, nitro, C1-6alkyl, Ci-4alkoxy, haloCi.4alkyl, haloCi-4alkoxy, C6-1iarylCi-4alkoxy, Ci-4alkylthio, 6cycloalkyl, C3-6cycloalkylCi-4alkoxy, Ci-4alkoxycarbony Ci-4alkylsulfonyl, Ci-4alkylsulfonyloxy, Ci-4alkylsulfonylC1-4alkyl, C6-narylsulfonyl, C6-narylsulfonyloxy, Ci-4alkylsulfonamido, C1-4alkylamido, C1-4alkylsulfonamidoC-i-4alkyl, C-ι_4alkylsuIfinyl, C1-4haloalkylsulfinyl, C1-4alkylamidoC1-4alkyl, C6-narylsulfonamido, C4.gheteroarylsulfonyl, C6-iiarylcarboxamido, C6-narylsulfonamidoC1-4alkyl, C6-naroyl, C6-iiaryl, C6-narylC1-4alkyl, a group R9-Ri0-N-, R9Ri0NCO(CH2)p, R9.Ri0.NSO2(CH2)p or R9.SO2NRi0.(CH2)p, -CR9.=NORi0., -CR9-C(CN)2, -CR9.=CH(CN), R9.Ri0.N(CH2)q- and R9.R1o.N(CH2)qO-,wherein - each R9 and R10 is independently C1-4alkyl, or where appropriate R9R10 forms part of a C3-6azacyloalkane or C3.6(2-, 3- or 4-oxo)azacycloaIkane ring
- each R9- and Ri0' is independently selected from R9 and R10 and hydrogen;
- each Rg» and R10" is independently selected from R9' and R10- and C1-4alkanoyl; - p is selected from 0, 1 , 2, 3 or 4;
- q is selected from 2, 3 or 4;
wherein each R15 is independently selected from hydrogen, halogen, hydroxy, cyano, amino, nitro, C1-6alkyl, Ci-4alkoxy, haloC1.4alkyl, haloC1.4alkoxy, C6-i1arylC1-4alkoxy, C1-4alkylthio, hydroxyC1-4alkyl, C1-4alkoxyC1-4alkyl, C1-4haloalkoxyC1-4alkyl, C3-6cycloalkylC1-4alkyl, C3-6cycloalkyl, C3-6cycloalkylCi-4alkoxy, C1-4alkanoyl, Ci-4haloalkanoyl, C1-4alkoxycarbonyl, C1-4alkoxycarbonylCi-4alkyl, C1.4alkylsulfonyl, C1-4haloalkylsulfonyl, C1-4alkylsulfinyl, Ci-4haloalkylsulfinyl, C1-4alkylsulfonyloxy, C1-4alkylsulfonylCMalkyl, C6-11arylsulfonyl, Ce^arylsulfonyloxy, C6-iiarylsulfonylC1-4alkyl, C1-4alkylsulfonamido, C4.9heteroarylsulfonyl, C^alkylamido, Ci.4alkylsulfonamidoCi-4alkyl, C1-4alkylamidoCi-4alkyl, C6-11arylsulfonamido, C6-iiarylcarboxamido,
C6-11arylsulfonamidoC1-4alkyl, C6-11arylcarboxamidoC1-4alkyl, C6-11aroyl, C6-1iaroylC1-4alkyl, C6-i.|arylCi-4alkanoyl, C1-4acyl, C6-1iaryl, C6.narylC-ι^alkyl, Ci.4alkylaminoC1-4alkyl, a group R9-R10-N-, R9R10NCO(CH2)p, R9.R10.NSO2(CH2)P or R9'SO2NR10.(CH2)p, -CR9.=NR10', -CR9.=NORiσ, -CR9.=C(CN)2, -CR9=CH(CN), R9.R10>N(CH2)q- and R9.R1o.N(CH2)qO-, wherein
- each R9 and R10 is independently C1-4alkyl, or where appropriate R9Ri0 forms part of a C3-6azacyloalkane or C3-6(2-, 3- or 4-oxo)azacycloalkane ring
- each R9' and Rw is independently selected from R9 and R10 and hydrogen; - each R9- and R10- is independently selected from R9' and R10' and C1-4alkanoyl;
- p is selected from 0, 1 , 2, 3 or 4;
- q is selected from 2, 3 or 4;
or Z is selected from a monocyclic or bicyclic heteroaryl group, which monocyclic heteroaryl group is or which bicyclic heteroaryl group optionally is substituted by one or more groups selected from amino, halogen, hydroxy, cyano, nitro, C2-4alkyl, C1-4alkoxy, haloC1-4alkyl, haloC1-4alkoxy, C6-i1arylC1.4alkoxy, C1-4alkylthio, hydroxyCi-4alkyl,
C1-4alkoxyC1-4alkyl, C^haloalkoxyC^alkyl, Cs-ecycloalkylC^alkyl, C3-6cycloalkyl,
C3-6cycloalkylC1-4alkoxy, C1.4alkanoyl, C1-4haloalkanoyl, C1-4alkoxycarbonyl, C1-4alkoxycarbonylCi-4alkyl, C1-4alkylsulfonyl, C1-4haloalkylsulfonyl, C1-4alkylsulfinyl,
Ci-4haloalkylsulfinyl, C^alkylsulfonyloxy, C1-4alkylsulfonylCi-4alkyl, C6-iiarylsulfonyl,
C6-11arylsulfonyloxy, Ce.-πarylsulfonylC^alkyl, Ci_4alkylsulfonamido, C4-9heteroarylsulfonyl,
C1-4alkylamido, C1-4alkylsulfonamidoC1-4alkyl, C1-4alkylamidoCi-4alkyl,
C6--I ■larylsulfonamido, C6-11arylcarboxamido, Ce-narylsulfonamidoC^alkyl, C6-11aroyl, C6-iiaroylC1-4alkyl, C6-11arylC1-4alkanoyl, C1-4acyl,
Cβ-naryl, Ce.-πarylC^alkyl, C^alkylaminoC-Malkyl, a group R9-R10-N-, R9Ri0NCO(CH2)p, R9.R10.NSO2(CH2)p or R9,SO2NR10.(CH2)p, -CR9-NR10., -CR9-NOR10', -CR9.=C(CN)2, -CR9-CH(CN)1 R9.Rio'N(CH2)q- and R9.R10.N(CH2)qO-, wherein
- each Rg and Ri0 is independently C1-4alkyl, or where appropriate R9R10 forms part of a C3-6azacyloalkane or C3.6(2-, 3- or 4-oxo)azacyc!oalkane ring - each R9' and R10- is independently selected from R9 and R-|0 and hydrogen;
- each Rg- and R10" is independently selected from R3- and R10' and C1-4alkanoyl;
- p is selected from 0, 1 , 2, 3 or 4;
- q is selected from 2, 3 or 4;
In a further aspect of the invention, there is provided a compound of formula (Ib) as hereinbefore defined or a salt or solvate thereof.
All features and preferences for formula (I) as described above apply to compounds of formula (Ib) mutatis mutandis.
In another aspect of the invention, there is provided use of a compound of formula (Ib) as hereinbefore defined or a salt or solvate thereof in the preparation of a medicament for the treatment of a disorder mediated by GIyTI .
Preferably, the disorder mediated by GIyTI to be treated by the use or method as hereinbefore described is a psychosis, including schizophrenia, dementia and attention deficit disorders, particularly schizophrenia.
As used herein, 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.
Possible formulations include those suitable for oral, sub-lingual, buccal, parenteral (for example, subcutaneous, intramuscular, or intravenous), rectal, topical and intranasal administration and in forms suitable for administration by inhalation or insufflation (either through the mouth or nose). The most suitable means of administration for a particular patient will depend on the nature and severity of the conditions being treated and on the nature of the active compound, but, where possible, oral administration is preferred.
Formulations suitable for oral administration may be provided as discrete units, such as tablets, capsules, cachets, or lozenges, each containing a predetermined amount of the active compound; as powders or granules; as solutions or suspensions in aqueous or non-aqueous liquids; or as oil-in-water or water-in-oil emulsions.
Formulations suitable for sublingual or buccal administration include lozenges comprising the active compound and, typically, a flavoured base, such as sugar and acacia or tragacanth and pastilles comprising the active compound in an inert base, such as gelatin and glycerin or sucrose and acacia.
Formulations suitable for parenteral administration typically comprise sterile aqueous solutions containing a predetermined concentration of the active compound; the solution is preferably isotonic with the blood of the intended recipient. Although such solutions are preferably administered intraveneously, they may also be administered by subcutaneous or intramuscular injection.
Formulations suitable for rectal administration are preferably provided as unit-dose suppositories comprising the active ingredient and one or more solid carriers forming the suppository base, for example, cocoa butter.
Formulations suitable for topical or intranasal application include ointments, creams, lotions, pastes, gels, sprays, aerosols and oils. Suitable carriers for such formulations include petroleum jelly, lanolin, polyethylene glycols, alcohols, and combinations thereof.
The formulations of the invention may be prepared by any suitable method, typically by uniformly and intimately admixing the active compound(s) with liquids or finely divided solid carriers, or both, in the required proportions and then, if necessary, shaping the resulting mixture into the desired shape.
For example, 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.
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.
It will be appreciated that the precise dose administered will depend on the age and condition of the patient and the frequency and route of administration and will be at the ultimate discretion of the attendant physician. 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 neuropsychiatry disorders mediated by a GIyTI inhibitor, including schizophrenia, may be about 1 to about 1000 mg, preferably about 5 to about 500 mg, more preferably about 10 to about 100 mg of the active ingredient per unit dose which could be administered, for example, 1 to 4 times per day.
The invention is further illustrated by the following non-limiting examples.
Description 1.
Methyl 2-chloro-5-(methylthio)benzoate
A reaction mixture of 2-chloro-5-(methylthio)benzoic acid (15.01g, 0.07mol) in dry methanol (180ml) was added concentrated sulphuric acid (18ml) at room temperature. The mixture was heated to 8O0C and left stirring at this temperature for 15 hrs. The cooled mixture was then concentrated in vacuo to give a dark brown oil. Purification by flash chromatography (SiO2) using 5% petroleum ether (40-600C) in dichloromethane yielded the pure title compound as a yellow oil (9g, 56%), dH (400MHz, CDCI3) 7.68 (1 H, d, ArH), 7.36 (1 H, d, ArH), 7.29 (1H, dd, ArH), 3.94 (3H, s, OMe), 2.51 (3H, s, SMe).
Description 2.
2-Chloro-5-methanesulfonyl-benzoi l ester
A reaction mixture of 2-chloro-5-methylsulfanyl-benzoic acid methyl ester (5.2g, 0.02mol) in dichloromethane (200ml) was added portion-wise 3-chloroperoxybenzoic acid (50-55%,
24.7g, 3 equiv.), maintaining the temperature at 250C by using an ice-bath. The resulting mixture was then left to stir at room temperature for 18 hrs. The insoluble white precipitate was filtered off and the cake washed with dichloromethane. The filtrate was then washed with aqueous sodium sulfite until all the oxidants have been removed. The organic layer was further washed with saturated sodium bicarbonate, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give the desired compound as a cream solid (4.7g, 79%). dH (400MHz, CDCI3) 7.77 (1 H, d, ArH), 7.46 (1 H, d, ArH), 7.36 (1 H, dd, ArH), 3.92 (3H, s,
OMe) and 2.50 (3H, s, SMe).
Description 3.
2-Chloro-5-(methylsulfonyl)benzoic acid
A reaction mixture of the ester (2.2mrnol), methanol (10ml) and aqueous sodium hydroxide (10ml, 2M) was heated to 700C for 18 hrs. The cooled reaction mixture was then diluted with water and ethyl acetate. The aqueous layer was acidified to pH 1 with aqueous hydrochloric acid (1 M) and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give the crude product. Purification by trituration gave the pure title compound.
Description 19. 1 -[3-Fluoro-4-(1 -piperazinyl)phenyl]ethanone
A solution of 3',4'-difluoroacetophenone (14.3 g, 0.092 mol) in acetonitrile (150 ml) was treated with piperazine (27.6 g, 0.32 mol) and heated at reflux for 18 h. The mixture was allowed to cool and partitioned between EtOAc and water. The organics were further washed with water (x2), dried (Na2SO4) and evaporated in vacuo to the title compound (17.6 g, 86%). LC/MS Found 223 (ESI) (M+1 )
Description 23. 2-Chloro-5-(chlorosulfonyl)benzoic acid
Chlorosulphonic acid (10ml) was stirred at 0° during the addition of o-chlorobenzoic acid (4.69g) added portionwise over 5 mins. Stirred at ambient temperature overnight. The reaction mixture was added dropwise to stirred ice and the resulting white solid collected by filtration. Dried to give the desired compound (6.1g, 79%).
Description 24. 2-Chloro-5-(dioxidosulfanyl)benzoic acid
2-Chloro-5-(chlorosulfonyl)benzoic acid (3.Og) was added in portions to a stirred suspension of sodium sulphite (3.24g) in water (6ml). The pH was then adjusted to 9 by addition of 50% sodium hydroxide solution and stirred for 18 hours at room temperature. The solution was acidified to pH 1 by addition of 5M HCI and after 10 minutes the suspension was cooled in ice and the solid collected by filtration. Obtained desired product as a white solid (2.43g, 94%).
Description 25.
Ethyl 2-chloro-5-(ethylsulfonyl)benzoate
2-Chloro-5-(dioxidosulfanyl)benzoic acid (1.Og) in DMF (3ml) was treated with potassium carbonate (1.86g) and iodoethane (1.1ml) and stirred for 18 hours. The reaction mixture was then diluted with ethyl acetate and washed 6 times with water, dried and evaporated to afford crude product. Chromatography on silica gel eluting with 5-50% ethyl acetate in pentane afforded the diethyl derivative as a colourless oil (1.0g, 80%). LC/MS Found 249 (ESI) (MH-28).
Description 29.
Methyl 2-chloro-5-(methylsulfinyl)benzoate
A solution of methyl 2-chloro-5-(methylthio)benzoate (0.4Og) in DCM (10ml) at 0° was treated with 75% m-chloroperbenzoic acid (420mg), Stirred at ambient temperature for 4 hours. The reaction mixture was washed with 10% sodium carbonate solution, dried and evaporated to afford crude sulphoxide as a yellow solid (406mg, 96%). LC/MS Found 233 (ESI) (M+1).
Description 32.
1 ,1 -Dimethylethyl 4-(4-acetyl-3,5-dichlorophenyl)-1 -piperazinecarboxylate
A solution of 1.4M methylmagnesium bromide in THF (29ml) was stirred under argon at 50° and a solution of 2,4,6-trichlorobenzoyl chloride (2.0Og) in dry toluene (2ml) was added over 15 minutes. Stirring was continued for a further 30 minutes and the cooled (0°) reaction mixture was then treated with ice and diluted with ether and 2M hydrochloric acid. Organic layer dried and evaporated to afford 2,4,6-trichloroacetophenone as an oil (1.78g). This material (1.0g), N-Boc piperazine (0.83g), caesium carbonate (2.18g), palladium acetate (101mg) and BINAP (418mg) were heated in 1,4-dioxane (30ml) at 100° under argon for 24 hours. After cooling, the precipitate was removed by filtration and the filtrate evaporated at reduced pressure. The residue was partitioned between ethyl acetate and water and the aqueous layer extracted with further ethyl acetate. The combined organic layers were dried and evaporated. Chromatography on silica gel eluting with 0-50% ethyl acetate/pentane gave desired product as a yellow gum (81 mg). LC/MS (ESI) found 273 (MH-100).
Description 33.
1 -[2,6-Dichloro-4-(1 -piperazinyl)phenyl]ethanone
1 ,1-dimethylethyl 4-(4-acetyl-3,5-dichlorophenyl)-1-piperazinecarboxylate (81mg) was treated with trifluoroacetic acid (0.9ml) and water (0.1ml) and stirred for 1 hour. The volatile components were removed under reduced pressure to afford the desired product as a brown gum.
Description 34.
1 -[4-(1 -Piperazinyl)-2-(trifluoromethyl)phenyl]ethanone
A solution of 1-[4-fluoro-2-(trifluoromethyl)phenyl]ethanone (4.83 g, 0.023 mol) in acetonitrile (150 ml) was treated with piperazine (7.1 g, 0.082 mol) and the mixture heated at reflux under argon for 20 h. On cooling the mixture was partitioned between water and EtOAc. The organics were washed further with water (x2), dried (Na2SO4) and evaporated in vacuo to a yellow solid 5.8 g, 93%. δH (400MHz, CDCI3) 7.55 (1H1 d), 7.18 (1H, d), 6.96 (1H, dd), 3.30 (4H, m), 3.03 (4H, m), 2.54 (3H, s). LC/MS (ESI) Found 273 (M+1)
Description 35. 1 -[2-Chloro-4-(1 -piperazinyl)phenyl]ethanone
The compound was prepared from 1-(2-chloro-4-fluorophenyl)ethanone (4.8 g, 0.028 mol) by the procedure described in Description 34 to afford the title compound 6.4 g, 96%. LC/MS (ESI) Found 239/241 (M+1 )
Description 37.
1 -[6-(1 -Piperazinyl)-3-pyridinyl]ethanone
The title compound was prepared from 1-(6-chloro-3-pyridinyl)ethanone and piperazine according to the procedure described in J. Med. Chem.1999, VoI 42, No:14 p.2577 . (90% yield) LC/MS (ESI) Found 206.2 (M+1)
Description 38.
1-{[2-Chloro-5-(methylsulfonyl)phenyl]carbonyl}-4-[3,5-dichloro-4-
(methyloxy)phenyl]piperazine
2-Chloro-5-(methylsulfonyl)benzoic acid and 1 -[3,5-dichloro-4-(methyloxy)phenyl]- piperazine hydrochloride were dissolved in DMF and stirred at room temperature for 16 hours, under an argon atmosphere, with an excess of DIPEA and HATU. The reaction mixture was then partitioned between ethyl acetate and water. The organic solution was dried (Na2SO4) and evaporated to yield the crude product, which was purified by silica gel column chromatography, eluting with a gradient of 0 to 100% ethyl acetate in N-pentane. The title compound was obtained as a white solid (87% yield). LC/MS (ESI) Found 478.9 (M+1 ).
Description 39. 4-[4-(Methylthio)phenyl]piperazine-1-carboxylic acid-terf-butylester
Under an inert atmosphere of argon, sodium ferf-butoxide (200 mg; 2.08 mmol) was added in one portion to a room temperature stirring solution of Λ/-Boc-piperazine (199 mg; 1.07 mmol), 1-bromo-4-(methylthio)benzene (217 mg; 1.07 mmol), 2- dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl (113 mg; 0.29 mmol), and Pd2(dba)2 (57 mg; 62 μmol) in degassed 1 ,4-dioxan (5 ml_). The mixture was sonicated for 1 minute, and stirred under microwave conditions in a sealed tube at 1000C for 5 minutes. The crude mixture was partitioned between ethyl acetate (40 mL) and water (40 ml_), and the separated aqueous extracted with ethyl acetate (40 mL). The combined organic phase was dried (MgSO4), and concentrated in vacuo. The resulting brown oil was purified by column chromatography, giving the title compound 4-[4-(methylthio)phenyl]piperazine-1- carboxylic acid-terf-butylester as a yellow solid (259 mg; 79%). LC/MS (Ammonium bicarbonate ES+) Found 209 (M-Boc+H).
Description 40. 1-[4-(Methylthio)phenyl]piperazine
Trifluoroacetic acid (200 μl_; 2.69 mmol) was added in one portion to a room temperature stirring solution of carbamate 4-[4-(methylthio)phenyl]piperazine-1-carboxylic acid-ferf- butylester (79 mg; 0.26 mmol) in dichloromethane (1 mL). The reaction was stirred for 15 hours and purified using an SCX ion exchange column, giving 1-[4- (methylthio)phenyl]piperazine as a pale yellow solid (42.9 mg; 79%).
Description 41.
4-[4-(Methylsulfinyl)phenyl]piperazine-1-carboxylic acid-terf-biitylester
me.a-Chloroperoxybenzoic acid (approx. 77%; 191 mg; 0.85 mmol) was added in one portion to a cool (O0C) stirring solution of 4-[4-(methylthio)phenyl]piperazine-1-carboxylic acid-te/t-butylester (179 mg; 0.58 mmol) in dichloromethane (3 mL). The mixture was stirred at O0C for 1% hours, quenched with saturated aqueous sodium hydrogen carbonate (5 ml_) and diluted with water (1 ml_) and dichloromethane (2 ml_). The separated aqueous phase was extracted with dichloromethane (10 mL), and the combined organic phase dried (MgSO4). Concentration in vacuo gave a yellow solid (189 mg) which was purified by column chromatography giving 4-[4- (methylsulfinyl)phenyl]piperazine-1-carboxylic acid-ferf-butylester (141 mg; 75%) as a pale yellow solid. LC/MS (Ammonium bicarbonate ES+) Found 347 (M+Na).
Description 42.
4-[4-(methylsulfinyl)phenyl]piperazine-1-carboxylic acid-fert-butylester
Trifluoroacetic acid (250 μl_; 3.37 mmol) was added in one portion to a room temperature stirring solution of 4-[4-(methylsulfinyl)phenyi]piperazine-1-carboxylic acid-terf-butylester (141 mg; 0.436 mmol) in dichloromethane (1.7 mL). The reaction was stirred for 18 hours and purified using an SCX ion exchange column, giving 4-[4- (methylsulfinyl)phenyl]piperazine-1-carboxylic acid-te/if-butylester as a white solid (92.9 mg; 93%). LC/MS (Ammonium bicarbonate ES+) Found 225 (M+H).
Description 43.
1,1-Dimethylethyl 4-(5-nitro oxylate
N-BOC piperazine (0.5g) and 2-chloro-5-nitropyridine (0.424g) in DMF (16ml) were treated with potassium carbonate (0.744g) and DIPEA (1.41ml). The resulting mixture was heated at 1200C for 4 hours.After cooling to room temperarure, the solvent was removed in vacuo and the residue partitioned between ethyl acetate and water. Organic layer washed again with water then dried over anhydrous magnesium sulphate. After filtration, the solvent evaporated to dryness in vacuo to afford the title compound as a pale brown solid in 95%.
LCMS (ES+) 209.05 (MH+-BOC)
Description 44. 1-(5-Nitro-2-pyridinyl)piperazine
Compound from Description 43 (0.78g) was dissolved in dry DCM (18ml), cooled in an ice bath to ~ O0C before adding TFA (2ml) slowly over 5 minutes. The resultant solution was then allowed to warm up to R.T. and was stirred for 4 hours, under argon. The reaction solution was poured slowly onto ice saturated potassium carbonate before extracting with DCM (3x 50ml). The combined extracts were dried over anhydrous magnesium sulphate, filtered and solvent removed in vacuo to afford the title compound as a yellow solid in 71%.
1H NMR ( 400MHz, CDCI3) δ 9.03 ( d, 1H), 8.20 (dd, 1 H), 6.55 (d, 1 H), 3.75 ( m, 4H), 2.98 (m, 4H)
Description 45.
1 ,1 -Dimethylethyl 4-(6-chloro-4-pyrimidinyl)-1 -piperazinecarboxylate
The title compound was prepared by the method as Description 43, heating for 16 hours to afford the title compound as a pale orange solid in 94% yield. LCMS (ES+) 299 (M + H)
Description 46. 4-Chloro-6-(1-piperazinyl)pyrimidine
The title compound, obtained as an orange oil, was prepared in a similar manner to Description 44 (95% yield). LCMS (ES+) 199 (M + H) Description 47. i.i-Dimethylethyl ^S-acetyiphenyO-i-piperazinecarboxylate
N-BOC piperazine (372mg), 3-bromoacetophenone (398mg), palladium acetate ( 45mg), rac-BINAP (79mg), and sodium t-butoxide ( 288mg) were heated in THF (7ml) at 850C for 28 hours. After cooling to rt, the reaction mixture was filtered through Kieselguhr, washing well with water and ethyl acetate. The layers were separated. The organic layer was dried over anhydrous magnesium sulphate. The solution was filtered and the solvent was removed in vacuo. The residue purified by silica gel chromatography, eluting with ethyl acetate/pentane mixtures. The desired fractions were combined and solvent removed in vacuo to afford the title compound as a yellow gum in 7% yield. LCMS (ES+) 205 (M+H-BOC)
Description 48.
1-[3-(1-Piperazinyl)phenyl]ethanone
The BOC piperazine derivative from Description 47 (100mg), was dissolved in methanol (3ml) and treated with 4M HCI in dioxane (1ml). the resulting solution was stirred for 18 hours at rt under an atmosphere of argon. The solvent removed in vacuo to afford the title compound as an orange gummy solid in quantitative yield. LCMS (ES+) 205 (M + H)
Description 49. 1,1-Dimethylethyl 4-(1W-pyrrolo[2,3-)b]pyridin-4-yl)-1-piperazinecarboxylate
A solution of 4-bromo-1H-pyrrolo[2,3-ib]pyridine (6.1g) and N-butyloxycarbony)piperazine (29.8g) in N-methylpyrrolidine (20ml) was heated on an oil bath at 135° under argon for 3 days. The mixture was dissolved in DCM (500ml) and washed with water (6 x 250ml), dried and concentrated under reduced pressure. Treatment with ether (200ml) afforded a cream solid (7.1g).
Description 50. 1-(Phenylsulfonyl)-4-(1-pipe lo[2,3-Jb]pyridine
A solution of 1 ,1-dimethylethyl 4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1-piperazinecarboxylate (100mg) in THF (1 ml) and DMF (1 ml) was treated with BEMP (0.19ml). A solution of phenylsulphonyl chloride (76mg) in THF (1ml) was then added and the solution stirred under argon for 2.5 hours. After dilution with ethyl acetate, the reaction mixture was washed with 2M HCI and brine, dried and concentrated to a yellow oil. This was chromatographed on silica gel eluting with 10-50% ethyl acetate in pentane to give an oil (34mg). This was treated with trifluoroacetic acid for 1 hour and the volatile components removed under reduced pressure to give the desired product as an oil (30mg).
Description 51. 1-(2-Furanylsulfonyl)-4-(1-piperazinyl)-1H-pyrrolo[2,3-jb]pyridine
Prepared as described for 1-(phenylsulfonyl)-4-(1-piperazinyl)-1H-pyrrolo[2,3-jfc>]pyridine (Description 50).
Description 52.
(2-Chloro-5-methanesulfonyl-phenyl)-[4-(3,4-dichloro-phenyl)-piperazin-1-yl]- methanone
A reaction mixture of 2-chloro-5-methanesulfonylbenzoic acid (0.12mmoi), 1-(3,4- dichlorophenyl)piperazine (0.14mmol), and EDCI (52mg, 0.27mmol) in dry dichloromethane (6ml) was stirred at room temperature for 2 hrs. TLC indicated no reaction. The reaction mixture was therefore heated to 350C for 4 hrs. TLC indicated consumption of starting materials. The reaction mixture was then diluted with dichloromethane and washed with saturated aqueous potassium bicarbonate followed by aqueous hydrochloric acid (1M). The organic layer was then dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to provide the title compound, isolated as a beige solid. Purification was not necessary
Example 1.
[4-(3,4-Dichloro-phenyl)-piperazin-1-yl]-(5-methanesulfonyl-2-ethylthio-phenyl)- methanone
A reaction mixture of (2-chloro-5-methanesulfonyl-phenyl)-[4-(3,4-dichloro-phenyl)- piperazin-1-yl]-methanone (1 equiv.), 60% sodium hydride (1.5 equiv.) and ethyl mercaptan (0.2ml, excess) in dry 1-methyl-2-pyrrolidinone (50ml), after the gas evolution had ceased, was heated to 140-1600C for 3 hrs and then left to cool overnight. The mixture was carefully poured into water, left to stir for 1 hr and then extracted with diethyl ether. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered and then concentrated in vacuo to give the crude product. Purification by flash chromatography (SiO2) afforded the pure title compound, isolated as a pale yellow oil (56%). dH (400MHz, CDCI3) 7.88 (1H, dd, ArH), 7.75 (1H, d, ArH), 7.45 (1H, d, ArH), 7.30 (1H, d, ArH), 6.96 (1 H, d, ArH), 6.74 (1 H, dd, ArH), 3.96 (2H, br s), 3.37 (2H, br s), 3.27 (2H, br t), 3.14 (2H, br s), 3.06 (2H, t), 3.05 (3H, s, SO2Me) and 1.37 (3H, t) LC/MS (Ammonium bicarbonate APCI) Found 473/475 (M+1 , TR 2.25 min)
Example 2.
[4-(3,4-Dichloro-phenyl)-piperazin-1-yl]-(5-methanesulfonyl-2-propylthio-phenyl)- methanone
A reaction mixture of (2-chloro-5-methanesulfonyl-phenyl)-[4-(3,4-dichloro-phenyl)- piperazin-1-yl]-methanone (1 equiv.), 60% sodium hydride (10 equiv.) and 1 -propanediol (25ml) was heated at reflux under nitrogen atmosphere until completion of reaction. The cooled reaction mixture was acidified to pH 4 with glacial acetic acid and then concentrated in vacuo to give the crude product. Toluene was used to azeotrope out any residual acid. Purification by flash chromatography (SiO2) provided the title compound as a colourless oil. dH (400MHz, CDCI3) 7.87 (1H, dd, ArH), 7.75 (1H, d, ArH), 7.44 (1 H, d, ArH), 7.29 (1 H, d, ArH), 6.96 (1 H, d, ArH), 6.74 (1 H, dd, ArH), 3.96 (2H, br s), 3.37 (2H, br s), 3.27 (2H, br t), 3.14 (2H, br s), 3.05 (3H, s, SO2Me), 3.00 (2H, t) 1.74 (2H, sextet) and 1.08 (3H, t) LC/MS (Ammonium bicarbonate APCl) Found 487/489 (M+1, TR 2.38 min)
Further examples may be prepared by of the methodology outlined in schemes 1 to 5 above, using the appropriate intermediate (described in the "descriptions section" above) and an appropriate thiol.

Claims

1. A compound of formula (I) or a salt or solvate thereof:
(I) wherein
• X is -SR2, wherein
- R2 is selected from Ci.6alkyl and C3-7CyClOaIRyI, which C1-6alkyl or C3-7cycloalkyl group is optionally substituted with one or more groups selected from C3- 7cycloalkyl, C1-4alkyl, Ci-4haloalkyl, Ci-4alkoxy, C1-4haloalkoxy, C1-4alkylthio, halo and hydroxy;
Y is S(O)mR5 or -SO2NHR6 wherein
- m is 1 or 2; and
- R5 is selected from C1-6alkyl, C3-7cycloalkyl, C5--πaryl and C4-10heteroaryl, which Ci-Balkyl, C3-7cycloalkyl, C5-11aryl or C4.10heteroaryl is optionally substituted with one or two groups selected from halo, C1^aIkOXy and C^haloalkoxy;
- R6 is C-i-6alkyl; which C1-6alkyl is optionally substituted with one or more groups selected from halo, C1-4alkoxy and C1-4haloalkoxy; n is O, 1 or 2, each R-i is independently selected from C1-6alkyl, halo, C1-6haloalkyl C1^aIkOXy and
C1-4haloalkoxy;
Z is an optionally substituted phenyl group Z':
T
wherein each R13 is independently selected from hydrogen, halogen, hydroxy, cyano, amino, nitro, C1-6alkyl, haloCi-4alkyl, haloC1-4alkoxy, C6-11arylC1-4alkoxy, C1-4alkylthio, hydroxyC1-4alkyl, C1-4alkoxyC1-4alkyl, C3-6cycloalkylC1-4alkyl, C3-6cycloalkyl, Ca-ecycloalkylC^alkoxy, Ci-4alkanoyl, C1-4alkoxycarbonyl, C1-4alkoxycarbonylC1-4alkyl, C1-4alkylsulfonyl, C1-4alkylsulfonyloxy, C^alkylsulfonylC^alkyl, C6.narylsulfonyl, C6-11arylsulfonyloxy, Ci-4alkylsulfonamido, C4-9heteroarylsulfonyl, C1-4alkylamido, C1-4alkylsulfonamicioC1-4alkyl, C6-1iarylsulfonamido, C6.narylcarboxamido, C6-1iarylsulfonamidoCi-4alkyl, C6-naroyl, C6-iiaroylC1-4alkyl, C6-11arylC1-4alkanoyl, C1-4acyl, C6-11arylC1-4a!kyl, Ci-4alkylaminoC1-4alkyl, a group R9-Ri0-N-, R9R10NCO(CH2)P, R9.R10.NSO2(CH2)p or R9>S02NR1o.(CH2)p, -CR91=NR10-, -CR9-NOR10., -CR9.=C(CN)2, -CR9-CH(CN), R9.R10.N(CH2)q- and R9.R10.N(CH2)qO-,wherein - each R9 and R10 is independently C1-4alkyl, or where appropriate R9R10 forms part of a C3-6azacyloalkane or C3.6(2-, 3- or 4-oxo)azacycloalkane ring
- each R9' and Ri0' is independently selected from R9 and R10 and hydrogen;
- each R9" and R10" is independently selected from R9. and Ri0' and Ci-4alkanoyl;
- p is selected from 0, 1 , 2, 3 or 4; - q is selected from 2, 3 or 4;
wherein each R14 is independently selected from hydrogen, halogen, hydroxy, cyano, amino, nitro, C1-6alkyl, C1-4alkoxy, haloC-i-4alkyl, haloC1-4alkoxy, C6-11arylC-i.4alkoxy, C1-4alkylthio, C^alkoxycarbonyl, Ci-4alkoxycarbonylCi-4alkyl, C1-4alkylsulfonyl, C1-4alkylsulfonyloxy, C1-4alkylsulfonylC1-4alkyl, C6-11arylsulfonyl, C6-11arylsulfonyloxy, C6-11arylsulfonylC1-4alkyl, C1-4alkylsulfonamido, Ci-4alkylamido, Ci-4alkylsulfonamidoC1-4alkyl, C1-4alkylsulfinyl, Ci-4haloalkylsulfinyl, C6.narylsulfonamido, C4-9heteroarylsulfonyl, C6-1iarylcarboxamido, C6-HaTOyI, C6-11aroylC1-4alkyl, C6--i1arylC1-4alkanoyl, C1-4acyl, C6-naryl, Ci-4alkylaminoCi-4alkyl, a group R9-R1^N-, R9R10NCO(CH2)P, R9>Ri0.NSO2(CH2)p or R9'SO2NR10.(CH2)p, -CR9.=NR10., -CR9=NOR10., -CR9.=C(CN)2, -CR9=CH(CN), R9.R10.N(CH2)q- and R9.R10.N(CH2)qO-,wherein - each R9 and R10 is independently C1-4alkyl, or where appropriate R9R10 forms part of a C3-6azacyloalkane or C3-6(2-, 3- or 4-oxo)azacycloalkane ring
- each R9' and R10. is independently selected from R9 and R10 and hydrogen;
- each R9.. and R10- is independently selected from R9. and R10. and
- p is selected from 0, 1 , 2, 3 or 4; - q is selected from 2, 3 or 4;
wherein each R15 is independently selected from hydrogen, halogen, hydroxy, cyano, amino, nitro, C-|.6alkyl, C1-4alkoxy, haloC1-4alkyl, haloC1-4alkoxy, C6-1 iary IC1 -4alkoxy, C1-4alkylthio, hydroxyC1-4alkyl, Ci.4haloalkoxyC1-4alkyl, C3-6cycloalkylC1-4alkyl, C3-6cycloalkyl, Cs-ecycloalkylC^alkoxy, Ci-4alkanoyl, C1-4haloalkanoyl, C1-4alkoxycarbonyl, C^alkoxycarbonylC-Malkyl, C1-4alkylsulfonyl, C1-4haloalkylsulfonyl, C1-4alkylsulfinyl, C1-4haloalkylsulfinyl, Ci-4alkylsulfonyloxy, C1-4alkylsulfonamido, C4,9heteroarylsulfonyl, Ci-4alkylamido, C1-4alkylsulfonamidoC1-4alkyl, C1.4alkylamidoC1-4alkyl, C6-naryisulfonamido, C6-iiarylcarboxamido,
C6-11arylsulfonamidoC1-4alkyl, C6-1iarylcarboxamidoC1-4alkyl, C6-11aroyl, Ce-^aroylC-Malkyl, C6-11arylC1-4alkanoyl, C1-4acyl, C6-11aryl, C6-11arylCi-4alkyl, C1.4alkylaminoC1.4alkyl, a group R9-R10-N-, R9R10NCO(CH2)P, R9>R10'NSO2(CH2)p or Rg.SO2NR10.(CH2)p, -CR9=NR10', -CR9.=NOR10., -CR91=C(CN)2, -CR9.=CH(CN), R9>R10.N(CH2)q- and R9.R10.N(CH2)qO-, wherein
- each R9 and R10 is independently C1-4alkyl, or where appropriate R9R10 forms part of a C3.6azacyloalkane or C3.6(2-, 3- or 4-oxo)azacycloalkane ring
- each R9' and R10' is independently selected from R9 and R10 and hydrogen;
- each R9- and R10" is independently selected from R9' and R10' and C1-4alkanoyl;
- p is selected from 0, 1 , 2, 3 or 4;
- q is selected from 2, 3 or 4;
or Z is selected from a monocyclic or bicyclic heteroaryl group, which monocyclic heteroaryl group is or which bicyclic heteroaryl group optionally is substituted by one or more groups selected from amino, halogen, hydroxy, cyano, nitro, C2-4alkyl, C1-4alkoxy, haloCi-4alkyl, haloC1-4alkoxy, C6-1 ^ a ryl C1^aIkOXy, C1-4alkylthio, hydroxyCi-4alkyl, C1-4alkoxyC1-4alkyl, C3-6cycloalkylC1-4alkyl, C3-6cycloalkyl, C3-6cycloalkylC1-4alkoxy, Ci-4alkanoyl, C1-4haloalkanoyl, C1-4alkoxycarbonyl, C1-4alkoxycarbonylC1-4alkyl, C1-4alkylsulfonyl, Ci-4haloalkylsulfonyl, C1-4alkylsulfinyl, C1-4haloalkylsulfinyl, C1-4alkylsulfonyloxy, C1-4alkylsulfonylCi-4alkyl, C6-11arylsulfonyl, C6-iiarylsulfonyloxy, C1-4alkylsulfonamido, C4-9heteroarylsulfonyl, Ci-4alkylamido,
C6-I1 arylsulfonamido, C6-11arylcarboxamido, C6-iiarylsulfonamidoC1-4alkyl,
Ce-^arylcarboxamidoC^^lkyl, C6-11aroyl, C6-iiaroylCi-4alkyl, C6-11arylC-|.4alkanoyl, C1-4acyl, C6-iiaryl, Ce.-πarylC^alkyl, C^alkylaminoC^alkyl, a group R9-R10-N-, R9R10NCO(CI-I2)P, R9.R10.NSO2(CH2)p or R9SO2NR1 o.(CH2)p, -CR9.=NR1o., -CR9=NOR10., -CR9=C(CN)2, -CR9.=CH(CN), R9'R10'N(CH2)q- and R9'R10.N(CH2)qO-, wherein
- each R9 and R10 is independently C1-4alkyl, or where appropriate RgR10 forms part of a C3.6azacyloalkane or C3-6(2-, 3- or 4-oxo)azacycloalkane ring
- each R9' and R10' is independently selected from R9 and R10 and hydrogen;
- each R9- and R10- is independently selected from R9' and Ri0' and C1-4alkanoyl; - p is selected from 0, 1 , 2, 3 or 4;
- q is selected from 2, 3 or 4;
2. A compound as claimed in claim 1 , wherein X is -SR2; and R2 is selected from C1-6alkyl and C3-7cycloalkyl, which C1-6alkyl or C3-7cycloalkyl group is optionally substituted with one or more groups selected from C3-7cycloalkyl, C1-4alkyl, C1-4haloalkyl, C1-4alkoxy, C1-4haloalkoxy, halo and hydroxyl.
3. A compound as claimed in claim 1 or claim 2, wherein Y is S(O)2R5 and R5 is C1-6alkyl.
4. A compound as claimed in any of claims 1-3 wherein Z is a phenyl group Z'.
5. A compound as claimed in claim 4 wherein each R13 is independently selected from hydrogen, halogen, cyano and C1-4alkoxyC1.4alkyl.
6. A compound as claimed in claim 4 or claim 5 wherein each R14 is independently selected from hydrogen, halogen, cyano, nitro, C1-6alkyl, C1-4alkoxy and haloC1-4alkyl.
7. A compound as claimed in any one of claims 4, 5 or 6 wherein each Ri5 is independently selected from hydrogen, halogen, cyano, amino, nitro, C1-6alkyl, C1-4alkoxy, haloCi-4alkyl, Ci-4alkylthio, hydroxyC1-4alkyl, C1-4alkoxyC1-4alkyl, C1-4alkanoyl, C1-4haloalkanoyl, C1-4alkylsulfonyl, C1.4alkylsulfinyl, C1-4haloalkylsulfinyl, R9R10NCO(CH2)P, -CR9.=NR10', -CR9-NOR10., wherein
- each R9 and Ri0 is independently C1-4alkyl, or where appropriate R9R10 forms part of a C3.6azacyloalkane or C3-6(2-, 3- or 4-oxo)azacycloalkane ring - each R9. and R10. is independently selected from R9 and R10 and hydrogen;
- p is selected from 0, 1 , 2, 3 or 4;
8. A compound as claimed in any one of claims 1 to 3 wherein Z is selected from the group consisting of, pyridyl, pyrimidinyl, 1H-pyrrolo[2,3-ib]pyridinyl, pyridazinyl, pyrazinyl, triazolyl, triazinyl, pyrrolyl, imidazolyl, thienyl, furanyl, thiadiazolyi, isoxazolyl, isothiazolyl, thiazolyl, oxadiazolyl and oxazolyl, benzothiazolyl, 1 ,4-benzodioxinyl, 2,3-dihydro-1 ,4- benzodioxinyl, benzoxazolyl, indolyl, quinolyl, isoquinolinyl, 1-benzopyranyl, 2-benzopyranyl, dihyrdo-1-benzopyranyl, dihydro-2-benzopyranyl, quinoxalinyl and quinazolinyl, each of which is optionally is substituted set out in claim 1.
9. A compound as claimed in claim 8 in which the group Z is selected from pyrid-2-yl, pyrimidin-2-yl , pyrimidin-4-yl , quinoxalinyl, quinolinyl and 1 H-pyrrolo[2,3-ό]pyridinyl.
10. A compound as claimed in claim 8 or claim 9 which is optionally substituted with one or more groups selected from amino, cyano, nitro, haloC-i.4alkyl, C1-4alkanoyl, hydroxyCi-4alkyl, C^alkoxy, C^alkoxycarbonyl, C4-9heteroarylsulfonyl, and R9"R10"N-, wherein each R9.. and R10- is independently selected from hydrogen, C^alkyl and Ci-4alkanoyl.
11. A compound as claimed in claim 1, which is Example 1 or Example 2, or a salt or solvate thereof.
12. A method of preparing a compound of formula (I) as defined in claim 1 or a salt or solvate thereof, comprising the step of:
(a) reacting a compound of formul
(H)
wherein L is a leaving group such as halogen or triflate, and Y, R1, n and Z are as defined in claim 1 , with a compound of formula (III):
H-X (III)
wherein X is as defined in claim 1 and H is hydrogen in the presence of a suitable base, for example sodium hydride; or
(b) reacting a compound of formula (IV):
(IV)
wherein X and Y are as defined in claim 1 , with a compound of formula (V):
(V) wherein R1, n and Z are as defined in claim 1; or
(c) reacting a compound of formula (Vl):
(Vl)
wherein X, Y, n and Ri are as defined for formula (I), with a group Z-L wherein Z is as defined for formula (I) and L is a leaving group, under basic conditions with a suitable catalyst, and a suitable ligand; or by heating a compound of formula (Vl) with a group Z-L to 180 degC, with or without diisopropylamine as solvent, in a microwave reactor;
and thereafter optionally for step (a), step (b) or step (c),
• removing any protecting groups and/or
• converting a compound of formula (I) into another compound of formula (I) and/or
• forming a salt or solvate.
13. A pharmaceutical composition comprising a compound as defined in any of claims 1-15 and at least one pharmaceutically acceptable carrier, diluent or excipient.
14. A compound as defined in any of claims 1-11 for use in therapy.
15. A compound as defined in any of claims 1-11 for use in the treatment of a disorder mediated by GIyTI .
16. A compound as claimed in claim 15 wherein the disorder is a psychosis, such as schizophrenia, dementia or an attention deficit disorder.
17. A method of treating a mammal, including a human, suffering from or susceptible to a disorder mediated by GIyTI , which comprises administering an effective amount of a compound of formula (Ib) or a salt or solvate thereof:
(Ib) wherein
• X is -SR2, wherein - R2 is selected from C1-6alkyl and C3-7cycloalkyl, which C1-6alkyl or C3.7cycloalkyl group is optionally substituted with one or more groups selected from C3- ycycloalkyl, C1-4alkyl, C1-4haloalkyl, Ci-4alkoxy, C1-4haloalkoxy, C1-4alkylthio, halo and hydroxy;
• Y is S(O)mR5 or -SO2NR6R7 wherein
- m is 1 or 2; and
- R5 is selected from Ci-6alkyl, C3-7cycloalkyl, C5.naryl and C4-i0heteroaryl, which Ci-6alkyl, C3-7cycloalkyl, C5-11 aryl or C4-10heteroaryl is optionally substituted with one or two groups selected from halo, C^alkoxy and C1-4haloalkoxy;
- R6 and R7 are independently selected from hydrogen and C1-6alkyl but are not both simultaneously C1-6alkyl; which Ci-6alkyl is optionally substituted with one or more groups selected from halo, C1-4alkoxy and C^haloalkoxy;
• n is 0, 1 or 2, • each R1 is independently selected from C1-6alkyl, halo, Ci-6haloalkyl C1-4alkoxy and C1-4haloalkoxy;
• Z is an optionally substituted phenyl group Z':
T
wherein each R13 is independently selected from hydrogen, halogen, hydroxy, cyano, amino, nitro, C1-6alkyl, haloC1-4alkyl, haloC1-4alkoxy, C6-iiarylC1-4alkoxy, C1-4alkylthio, hydroxyC1-4alkyl, C1-4alkoxyC1-4alkyl, C3.6cycloalkyl, C3-6cycloalkylC1-4alkoxy, C1-4alkanoyl, C1-4alkoxycarbonyl, C1-4alkoxycarbonylC1-4alkyl, C1-4alkylsulfonyl, C1-4alkylsulfonyloxy, C1-4alkylsulfonylC1-4alkyl, Ce^arylsulfonyl, C6-11arylsulfonyloxy, C6-11arylsulfonylCi-4alkyl, C1-4alkylsulfonamido, C4-9heteroarylsulfonyl, C1-4alkylamido, C1-4alkylsulfonamidoC1-4alkyl, C1-4alkylamidoCi-4alkyl, Ce-narylsulfonamido, C6-11arylcarboxamido, Ce^arylsulfonamidoC-Malkyl, C6-1iaroyl, C6-iiaroylC-|.4alkyl, C6-1iarylC1-4alkanoyl, Ci-4acyl, C1-4alkylaminoC1-4alkyl, a group R9-R10-N-, R9Ri0NCO(CH2)p, R9-Ri0-NSO2(CH2)P or R9.SO2NR10.(CH2)p, -CR9=CH(CN), R9.R10.N(CH2)q- and R9.R10'N(CH2)qO-,wherein - each R9 and R10 is independently C^alkyl, or where appropriate R9Ri0 forms part of a C3.6azacyloalkane or C3-6(2-, 3- or 4-oxo)azacycloalkane ring - each R9. and R10. is independently selected from R9 and Ri0 and hydrogen; - each R9.. and R10" is independently selected from R9. and Rw and C1-4alkanoyl;
- p is selected from 0, 1 , 2, 3 or 4;
- q is selected from 2, 3 or 4;
wherein each R14 is independently selected from hydrogen, halogen, hydroxy, cyano, amino, nitro, C1-6alkyl, C1-4alkoxy, haloC^aikyl, haioC1-4alkoxy, C6-11arylC1-4alkoxy, C1-4alkylthio, C^cycloalkylC-Malkyl, C3.6cycloalkyl, C3-6cycloalkylC1-4alkoxy, C1-4alkoxycarbonyl, C1-4alkylsulfonyl, C1-4alkylsulfonyloxy, C1-4alkylsulfonylCi-4alkyl, C6-narylsulfonyl, C6-narylsulfonyloxy, C6-narylsulfonylCi-4alkyl, C1-4alkylsulfonamido, Ci-4alkylamido, C1-4alkylsulfonamidoCi-4alkyl, C1-4alkylsulfinyl, C1-4haloalkylsulfinyl, C1-4alkylamidoCi-4alkyl, C6-11arylsulfonamido, C4-9heteroarylsulfonyl, C6-11arylcarboxamido, C6-narylsulfonamidoC1-4alkyl, C6-narylcarboxamidoC1-4alkyl, Ce.naroyl, C6-11aroylC1-4alkyl, C6-11arylC1-4alkanoyl, Ci-4acyl, C6-11aryl, Ce.-πarylC^alkyl, C1-4alkylaminoCi-4alkyl, a group R9-R10-N-, R9R10NCO(CH2)p, R9-R10-NSO2(CH2)P or R9.SO2NR10-(CH2)p> -CR9=NR10-, -CR9=NOR10., -CR9=C(CN)2, -CR9=CH(CN), R9-R10-N(CH2V and R9'Riθ'N(CH2)qO-,wherein
- each R9 and R10 is independently C1-4alkyl, or where appropriate R9R10 forms part of a C3-6azacyloalkane or C3.6(2-, 3- or 4-oxo)azacycloalkane ring - each R9. and R10. is independently selected from R9 and R10 and hydrogen;
- each R9- and Ri0" is independently selected from R9- and R10. and C1-4alkanoyl;
- p is selected from 0, 1 , 2, 3 or 4;
- q is selected from 2, 3 or 4;
wherein each Ri5 is independently selected from hydrogen, halogen, hydroxy, cyano, amino, nitro, C1-6alkyl, C1-4alkoxy, haloC1-4alkyl, C1-4alkylthio, hydroxyC1-4alkyl, Ci-4alkoxyC1-4alkyl, Ci-4haloalkoxyC1-4alkyl, C3-6cycloalkyl, C3-6cycloalkylCi.4alkoxy, C1-4alkanoyl, C1-4haloalkanoyl, C1-4alkoxycarbonyl, C1-4alkoxycarbonylCi-4alkyl, C1-4alkylsulfonyl, C1-4haloalkylsulfonyl, C1-4alkylsulfinyl, Ci-4haloalkylsulfinyl, C1-4alkylsulfonyloxy, C1-4alkylsulfonylC1-4alkyl, C6-11arylsulfonyl, C6--I 1 arylsulfonyloxy, C6-11arylsulfonylC1-4alkyl, C1-4alkylsulfonamido, C4-gheteroarylsulfonyl, C1-4alkylamido, Ci-4alkylsulfonamidoC1-4alkyl, C1-4alkylamidoC1-4alkyl, Ce-^arylsulfonamido, C6-1iarylcarboxamido, C6-11arylsulfonamidoC1-4alkyl, C6-i-iarylcarboxamidoC1-4alkyl, C6-11aroyl, C6-11aroylC1-4alkyl, C6-11arylC1-4alkanoyl, C1-4acyl, C6-iiaryl, C6-11arylC1.4alkyl, C-MalkylaminoC^alkyl, a group R9-R10-N-, R9R10NCO(CH2)p, R9.R10-NSO2(CH2)p or R9.SO2NR10.(CH2)p, -CR9=NR10., -CR91=NOR10-, -CR9=C(CN)2, -CR9-=CH(CN), R9-R10-N(CH2)q- and R9-R10.N(CH2)qO-, wherein - each R9 and R10 is independently C1-4alkyl, or where appropriate R9R10 forms part of a C3-6azacyloalkane or C3-6(2-, 3- or 4-oxo)azacycloalkane ring
- each R9. and R10- is independently selected from R9 and R10 and hydrogen; - each R9" and R10" is independently selected from R9- and R10' and C1-4alkanoyl;
- p is selected from 0, 1 , 2, 3 or 4;
- q is selected from 2, 3 or 4;
or Z is selected from a monocyclic or bicyclic heteroaryl group, which monocyclic heteroaryl group is or which bicyclic heteroaryl group optionally is substituted by one or more groups selected from amino, halogen, hydroxy, cyano, nitro, C2-4alkyl, C1^aIkOXy, haloC1-4alkyl, haloCi-4alkoxy, C6-iiarylC1-4alkoxy, C1-4alkylthio, hydroxyC^alkyl, C1-4alkoxyC1.4alkyl, C1-4haloalkoxyCMalkyl, C3.6cycloalkylC1-4alkyl, C3-6cycloalkyl, C3.6cycloalkylC1-4alkoxy, C-|.4alkanoyl, Ci-4haloalkanoyl, C1-4alkoxycarbonyl, C1-4alkoxycarbonylC1-4alkyl, Ci-4alkylsulfonyl, Ci-4haloalkylsulfonyl, Ci-4alkylsulfinyl, C1-4haloalkylsulfinyl, C1-4alkylsulfonyloxy, C1-4alkylsulfonylC1-4alkyl, CVπarylsulfonyl, C6.iiarylsulfonyloxy, C6-1iarylsulfonylCi-4alkyl, C4-gheteroarylsulfonyl, C-i-4alkylamido, C6-iiarylsulfonamido, C6-narylcarboxamido, C6-11arylsulfonamidoCi-4alkyl,
C6-11arylcarboxamidoC1-4alkyl, C6-11aroyl, C6-naroylC1-4alkyl, C6-iiarylCi-4alkanoyl, C1-4acyl, C6-11aryl, C6.11arylC1-4alkyl, C1-4alkylaminoC1-4alkyl, a group R9"R10"N-, R9R10NCO(CH2)P, R9.R10.NSO2(CH2)p or R9.SO2NR1ff(CH2)p, -CR9.=NR1ff, -CR9.=NOR10>, -CR9.=C(CN)2, -CR9.=CH(CN), R9>R10.N(CH2)q- and R9'Ri0'N(CH2)qO-, wherein - each R9 and Ri0 is independently C^alkyl, or where appropriate R9R10 forms part of a C3.6azacyloalkane or C3-6(2-, 3- or 4-oxo)azacycloalkane ring
- each Rg' and R10' is independently selected from R9 and R10 and hydrogen;
- each Rg" and R10" is independently selected from Rg> and R10' and Ci-4alkanoyl;
- p is selected from 0, 1 , 2, 3 or 4; - q is selected from 2, 3 or 4;
18. A method as claimed in claim 17 wherein the disorder is a psychosis, such as schizophrenia, dementia or an attention deficit disorder.
19. Use of a compound of formula (Ib) or a salt or solvate thereof as defined in claim 17 in the preparation of a medicament for the treatment of a disorder mediated by GIyTI .
20. Use as claimed in claim 19 wherein the disorder is a psychosis, such as schizophrenia, dementia or an attention deficit disorder.
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