WO2006002956A1 - Piperidine derivatives and their use as glycine transporter inhibitors - Google Patents

Piperidine derivatives and their use as glycine transporter inhibitors Download PDF

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Publication number
WO2006002956A1
WO2006002956A1 PCT/EP2005/007136 EP2005007136W WO2006002956A1 WO 2006002956 A1 WO2006002956 A1 WO 2006002956A1 EP 2005007136 W EP2005007136 W EP 2005007136W WO 2006002956 A1 WO2006002956 A1 WO 2006002956A1
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phenyl
methyl
morpholinyl
fluoro
piperidinecarboxamide
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PCT/EP2005/007136
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French (fr)
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Andrea Bozzoli
Clive Leslie Branch
Howard Marshall
David John Nash
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Glaxo Group Limited
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Publication of WO2006002956A1 publication Critical patent/WO2006002956A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to 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 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 glutaminergic pathways and NMDA receptors (Smith, et al., Neuron, 8, 1992: 927-935).
  • Molecular cloning has further revealed the existence of three variants of GIyTI , termed GIyT-Ia, GIyT-I b and GIyT-Ic (Kim et al., Molecular Pharmacology, 45, 1994: 608-617), each of which displays a unique distribution in the brain and peripheral tissues.
  • GlyT2 in contrast, is found predominantly in the brain stem and spinal cord, and its distribution corresponds closely to that of strychnine-sensitive glycine receptors (Liu et al., J. Biological Chemistry, 268, 1993: 22802-22808; Jursky and Nelson, J. Neurochemistry, 64, 1995 : 1026-1033).
  • GlyT2 Another distinguishing feature of glycine transport mediated by GlyT2 is that it is not inhibited by sarcosine as is the case for glycine transport mediated by GIyTL
  • NMDA receptors are critically involved in memory and learning (Rison and Staunton, Neurosci. Biobehav. Rev., 19 533-552 (1995); Danysz et al, Behavioral Pharmacol.. 6 455-474 (1995)); and, furthermore, decreased function of NMDA-mediated neurotransmission appears to underlie, or contribute to, the symptoms of schizophrenia (Olney and Farber, Archives General Psychiatry, 52, 998-1007 (1996).
  • agents that inhibit 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); Upton and Rosenberg, New En ⁇ l. J. of Medicine. 330, 613-622 (1993); Choi, Neuron. 1 , 623-634 (1988).
  • pharmacological agents that increase the activity of 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).
  • R is hydrogen or C 1-8 alkyl, or R is a group
  • R 1 is selected from the group consisting of optionally substituted C 3 . scycloalkyl, optionally substituted C 3-8 heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl, and R 2 and R 3 are independently hydrogen or C 1 . 8 alkyl;
  • X is nitrogen or a group -CR 4 wherein R 4 is hydrogen or halogen; • R 5 , R 6 and R 7 are independently selected from hydrogen and halogen;
  • R 8 and R 9 are independently selected from the group consisting of hydrogen, halogen and C 1-4 alkyl, or R 8 and R 9 together form a C 3-4 cycloalkyl;
  • Ar is an optionally substituted aryl or an optionally substituted heteroaryl
  • alkyl refers to a straight or branched alkyl in all isomeric forms.
  • Examples of C 1 ⁇ aIRyI include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl.
  • Examples of C 1-8 alkyl include, for example, in addition to C 1-4 alkyl, pentyl, neopentyl, sec-pentyl, n-pentyl, isopentyl, tert-pentyl, hexyl, heptyl and octyl.
  • cycloalkyl refers to a non-aromatic cyclic saturated hydrocarbon ring.
  • Examples of C 3-4 cycloalkyl include cyclopropyl and cyclobutyl.
  • Examples of C 3-8 cycloalkyl include, in addition, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
  • C 3-8 heterocyclyl refers to a C 3 . 8 cycloalkyl group wherein one to three of the carbon atoms are replaced by heteroatom(s) independently selected from N, O and S.
  • Examples include aziridinyl, oxetanyl, oxiranyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, tetrahydrofuranyl, dioxolanyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydrothienyl, tetrahydropyranyl, dioxanyl, dithianyl, azepanyl and octahydroazocinyl.
  • aryl refers to a 5- or 6- membered monocyclic aromatic group or a 8- to 11- membered bicyclic aromatic group. Examples include phenyl, indenyl, azulenyl and naphthyl.
  • heteroaryl refers to a 5- or 6-membered monocyclic aromatic group wherein one, two, three or four carbon atoms are replaced by a heteroatom independently selected from N, O and S, or a 8- to 11- membered bicyclic aromatic group wherein one to four carbon atoms are replaced by a heteroatom independently selected from N, O and S.
  • Examples of 5- or 6-membered monocyclic heteroaryls include furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, triazolyl, triazinyl, pyridazinyl, pyrimidinyl, isothiazolyl, isoxazolyl, pyrazinyl, pyrazolyl and pyrimidinyl;
  • examples of 8- to 11- membered bicyclic heteroaryls include quinoxalinyl, quinazolinyl, pyridopyrazinyl, benzoxazolyl, benzothiophenyl, benzimidazolyl, naphthyridinyl, quinolinyl, benzofuranyl, indolyl, benzothiazolyl, oxazolyl[4,5-b]pyridiyl
  • 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 (1) 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.
  • R 1 is an optionally substituted C 3-8 cycloalkyl or an optionally substituted Q ⁇ heterocyclyl
  • the optionally substituted cycloalkyl or heterocyclyl group may be additionally optionally bridged by a Ci -3 alkylene group.
  • substituents may be different or the same. If substituent(s) is/are present, preferably the number of substituent(s) is 1 , 2, 3 or 4.
  • R is hydrogen. In another embodiment, R is a group
  • R 1 is C 3-8 cycloalkyl (such as cyclopentyl or cyclohexyl), C 3- eheterocyclyl (such as tetrahydropyranyl)or aryl (such as phenyl optionally substituted by one or two groups selected from halogen, C 1-4 alkyl and C-i -4 alkoxy).
  • R 2 and R 3 are both hydrogen.
  • X is a group -CR 4 .
  • R 4 , R 5 and R 6 are hydrogen and R 7 is fluorine.
  • Ar is an optionally substituted aryl, such as phenyl optionally substituted by one or two groups selected from C ⁇ alkyl, haloC 1-4 alkyl such as CF 3 , halogen and C 3-6 cycloalkyl.
  • Ar is an optionally substituted heteroaryl such as quinolinyl or benzimidazolyl, each of which is optionally substituted by one or two C 1-4 alkyl or halod. 4 alkyl such as CF 3 .
  • Ar is optionally substituted by one, two or three substituents selected from the group consisting of: halogen, oxo, cyano, C-]_Qalkyl, C-
  • n 1
  • R 8 and R 9 are both hydrogen.
  • the present invention provides a compound of formula (1a) or a salt or solvate thereof:
  • R 1 is selected from the group consisting of C 3-8 cycloalkyl, C 3-8 heterocyclyl, aryl and heteroaryl; each of which is optionally substituted by one, two or three substituents selected from the group consisting of halogen, oxo, cyano, C ⁇ galkyl, C ⁇
  • R 12 R 13 NCO(CH 2 ) m (where each of R 12 and R 13 is independently selected from hydrogen or Ci_4alkyl, or where appropriate R 12 R 13 forms part of a C ⁇ . gazacycloalkane ring and m is 0, 1 , 2, 3 or 4);
  • Ar is phenyl or heteroaryl, each of which is optionally substituted by one, two or three substituents selected from the group consisting of halogen, cyano, C-
  • Examples of compounds of the invention include:
  • the compounds of formula (1 ) 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 (1). 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 stereoisomeric forms (i.e. they may contain one or more asymmetric carbon atoms or may exhibit cis-trans isomerism). The individual stereoisomers (enantiomers and diastereoisomers) and mixtures of these are included within the scope of the present invention. Likewise, it is understood that compounds of formula (1) may exist in tautomeric forms other than that shown in the formula and these are also included within the scope of the present invention.
  • optically pure enantiomer means that the compound contains greater than about 90 % of the desired isomer by weight, preferably greater than about 95 % of the desired isomer by weight, and most preferably greater than about 99 % of the desired isomer by weight, said weight percent based upon the total weight of the isomer(s) of the compound.
  • the 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. ENeI, S. H. Wilen, and L. N. Mander (Wiley-lnterscience, 1994).
  • Scheme 1 Typical reaction routes for the preparation of a compound of formula (1 ) as hereinbefore defined, are shown in Scheme 1.
  • Scheme 1 shows compounds wherein X is - CR 4 and R is a group -C(R 1 )(R 2 )(R 3 ), the scheme is also applicable to cases wherein X is nitrogen and R is hydrogen or d -8 alkyl.
  • R 1 - R 9 , n and Ar are as defined above for (1) and L and W are leaving groups.
  • L is halogen and acylation in steps (ii), (iv) and (vii) may be carried out in an inert solvent such as dichloromethane, in the presence of a base such as triethylamine.
  • L represents hydroxy
  • the reaction takes place in an inert solvent such as dichloromethane in the presence of a diimide reagent such as [O-(7- azabenzotriazol-1-yl)-1 ,1,3,3-tetramethyluronium hexafluoro phosphate].
  • a diimide reagent such as [O-(7- azabenzotriazol-1-yl)-1 ,1,3,3-tetramethyluronium hexafluoro phosphate].
  • examples of leaving groups include chlorine, bromine and iodine.
  • L is bromine or iodine and alkylation in step (iii) may be carried out in a suitable solvent such as dimethylformamide in the presence of a base such as sodium hydride.
  • Reduction step (i) can be accomplished using known methods, such as catalytic hydrogenolysis in an inert solvent (e.g. using palladium on charcoal in a lower alcohol or ethyl acetate), catalytic transfer hydrogenolysis (e.g. using palladium black and formic acid in methanol) or chemical reduction (e.g. iron and acetic acid).
  • the reductive amination step (vi) can be carried out using known methods e.g. reaction of (3) with an aldehyde (10) in the presence of a reducing agent such as sodium triacetoxyborohydride in an inert solvent such as 1 ,2-dichloroethane or dichoromethane.
  • the reduction step (v) can be carried out in an inert solvent such as tetrahydrofuran, in the presence of lithium aluminium hydride.
  • the present invention provides a method of preparing a compound of formula (1 ), comprising the step of:
  • R , R , R and X are as defined for formula (1), with a compound of formula (4):
  • R 5 8 , O R9 , n and Ar are as defined for formula (1) and L is a leaving group;
  • R 1 to R 7 are as defined for formula (1), with a compound of formula (4) as defined above;
  • Compounds of formula (1) can be converted into further compounds of formula (1) 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.
  • acylation with an appropriate acylating agent such as acetyl chloride
  • alkylation using an appropriate alkylating reagent such as methyl iodide
  • sulfonylation such as methanesulfonic anhydride
  • a compound of formula (1) wherein R is hydrogen may be reacted with a compound of formula (6):
  • R 1 , R 2 and R 3 are as defined for formula (1) and W is a leaving group, to form compounds wherein R is -C(R 1 )(R 2 )(R 3 ).
  • Appropriate leaving groups for W are described above.
  • 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 culture medium [DMEM/NUT mix F12 containing 2mM L-Glutamine, 0.8mg/ml_ G418 and 10% heat inactivated fetal calf serum] at 37°C and 5% CO 2 .
  • Cells grown to 70-80% confluency in T175 flasks were harvested and resuspended at 1.6x10 6 cells/mL in assay buffer [14OmM NaCI, 5.4mM KCI, 1.8mM CaCI 2 , 0.8mM MgSO 4 , 2OmM HEPES, 5mM glucose and 5mM alanine, pH 7.4].
  • HEK293 cells expressing the Glycine (Type 1) transporter were grown in cell culture medium [DMEM/NUT mix F12 containing 2mM L-Glutamine, 0.8mg/ml_ G418 and 10% heat inactivated fetal calf serum] at 37°C and 5% CO 2 .
  • Cells grown to 70-80% confluency in T175 flasks were harvested and resuspended at 4x10 5 cells/mL in assay buffer [14OmM NaCI, 5.4mM KCI, 1.8mM CaCI 2 , 0.8mM MgSO 4 , 2OmM HEPES, 5mM glucose and 5mM alanine, pH 7.4].
  • Compounds are considered to have activity at the the GIyTI transporter if they have a plC 50 of 5.0 or above.
  • the example compounds below were found to have a PIC50 at the GIyTI transporter of greater than 6.0.
  • Preferred compounds of the invention were found to have a plC 50 at the GIyTI transporter of greater than 6.0.
  • a compound of formula (1) as hereinbefore described or a salt or solvate thereof for use in the treatment of a disorder mediated by GIyTI .
  • 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 forgetful ness, childhood learning disorders and closed head injury.
  • NMDA receptor-related disorders such as autism, depression, benign forgetful ness, 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 (1) as hereinbefore defined or a 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 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.
  • compositions comprising a compound of formula (1 ) 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 (1) 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), 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 anxiety disorders including Panic Attack, Agoraphobia, Panic Disorder, Agoraphobia Without History of anxiety disorders including Panic Attack, Agoraphobia, Panic Disorder, Agoraphobia Without History of anxiety disorders including Panic Attack, Agoraphobia, Panic Disorder, Agoraphobia Without History of anxiety disorders including Panic Attack, Agoraphobia, Panic Disorder, Agoraphobia Without History of anxiety disorders including Panic Attack, Agoraphobia, Panic Disorder, Agoraphobia Without History of anxiety disorders including Panic Attack, Agoraphobia, Panic Disorder, Agoraphobia Without History of anxiety disorders including Panic Attack, Agoraphobia, Panic Disorder, Agoraphobia Without History of anxiety disorders including Panic Attack, Agoraphobia, Panic Disorder, Agoraphobia Without History of anxiety disorders including Panic Attack, Agoraphobia, Panic Disorder, Agoraphobia Without History of anxiety disorders
  • Panic Disorder (300.22), Specific Phobia (300.29) including the subtypes Animal Type,
  • 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
  • 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
  • the invention also provides a compound of formula (I) as hereinbefore described or a pharmaceutically acceptable salt or solvate thereof for use in the treatment of schizophrenia, mood disorders, anxiety disorders, substance-related disorders, sleep disorders, eating disorders, autistic disorder, attention-deficit/hyperactivity disorder, disruptive behaviour disorder, tic disorders, personality disorders, cognition impairment in other diseases, sexual dysfunction, Parkinson's disease, dyskinetic disorders, depression, bipolar disorder, cognitive impairment, obesity, emesis, movement disorders, obsessive- compulsive disorders, amnesia, aggression, vertigo, dementia and circadian rhythm disorders.
  • the invention also provides a compound of formula (I) as hereinbefore described or a pharmaceutically acceptable salt or solvate thereof for use in the treatment of psychotic disorders, schizophrenia, Parkinson's disease, substance abuse, dyskinetic disorders, depression, bipolar disorder, anxiety, cognitive impairment, eating disorders, obesity, sexual dysfunction, sleep disorders, emesis, movement disorders, obsessive-compulsive disorders, amnesia, aggression, autism, vertigo, dementia, circadian rhythm disorders and gastric motility disorders.
  • psychotic disorders schizophrenia, Parkinson's disease, substance abuse, dyskinetic disorders, depression, bipolar disorder, anxiety, cognitive impairment, eating disorders, obesity, sexual dysfunction, sleep disorders, emesis, movement disorders, obsessive-compulsive disorders, amnesia, aggression, autism, vertigo, dementia, circadian rhythm disorders and gastric motility disorders.
  • a method of treating a mammal including a human, suffering from or susceptible to a disorder mediated by 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
  • 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, 5HT1 B 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.
  • the compounds of formula (I) and their pharmaceutically acceptable salts and solvates thereof are also suitable for combination with other typical and atypical antipsychotics to provide improved treatment of psychotic disorders.
  • Particular advantages associated with the combinations, uses and methods of treatment of compounds of formula (I) and their pharmaceutically acceptable salts and solvates thereof include equivalent or improved efficacy at doses of administration which are lower than those commonly used for the individual components. Improved treatments of positive symptoms and/or negative symptoms and/or cognitive symptoms of the psychotic disorder may also be observed.
  • the combinations, uses and methods of treatment of the invention may also provide advantages in treatment of patients who fail to respond adequately or who are resistant to treatment with certain neuroleptic agents.
  • adjunctive administration is meant the coterminous or overlapping administration of each of the components in the form of separate pharmaceutical compositions or devices.
  • This regime of therapeutic administration of two or more therapeutic agents is referred to generally by those skilled in the art and herein as adjunctive therapeutic administration; it is also known as add-on therapeutic administration.
  • Any and all treatment regimes in which a patient receives separate but coterminous or overlapping therapeutic administration of the compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof and at least one neuroleptic agent are within the scope of the current invention.
  • a patient is typically stabilised on a therapeutic administration of one or more of the of the components for a period of time and then receives administration of another component.
  • the compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof is administered as adjunctive therapeutic treatment to patients who are receiving administration of at least one neuroleptic agent, but the scope of the invention also includes the adjunctive therapeutic administration of at least one neuroleptic agent to patients who are receiving administration of compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof.
  • the combination therapies of the invention may also be administered simultaneously.
  • simultaneous administration is meant a treatment regime wherein the individual components are administered together, either in the form of a single pharmaceutical composition or device comprising or containing both components, or as separate compositions or devices, each comprising one of the components, administered simultaneously.
  • Such combinations of the separate individual components for simultaneous combination may be provided in the form of a kit-of-parts.
  • the invention provides a method of treatment of a psychotic disorder by adjunctive therapeutic administration of compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof to a patient receiving therapeutic administration of at least one neuroleptic agent.
  • the invention provides the use of compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for adjunctive therapeutic administration for the treatment of a psychotic disorder in a patient receiving therapeutic administration of at least one neuroleptic agent.
  • the invention further provides compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use for adjunctive therapeutic administration for the treatment of a psychotic disorder in a patient receiving therapeutic administration of at least one neuroleptic agent.
  • the invention provides a method of treatment of a psychotic disorder by adjunctive therapeutic administration of at least one neuroleptic agent to a patient receiving therapeutic administration of compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof.
  • the invention provides the use of at least one neuroleptic agent in the manufacture of a medicament for adjunctive therapeutic administration for the treatment of a psychotic disorder in a patient receiving therapeutic administration of compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof.
  • the invention further provides at least one neuroleptic agent for adjunctive therapeutic administration for the treatment of a psychotic disorder in a patient EP2005/007136
  • 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, 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 TARACTAN®), droperidol (available under the tradename INAPSINE®), acetophenazine (available under the tradename TINDAL®;), prochlorperazine (available under the tradename COMPAZINE®), methotrimeprazine (available under the tradename NOZINAN®), pipotiazine (available under the tradename PIPOTRIL®), ziprasidone, and hoperidone.
  • promazine available under the tradename SPARINE®
  • triflurpromazine available under the tradename VESPRIN®
  • chlorprothixene available under the tradename TARACTAN®
  • droperidol available under the tradename INAPSINE®
  • acetophenazine available under the tradename TINDAL®
  • prochlorperazine available under the tradename COMP
  • 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, 5HT1 B antagonists, 5HT1D antagonists, D1 agonists, M1 agonists and/or anticonvulsant agents, as well as atypical antipsychotic drugs and cognitive enhancers.
  • different antidepressant agents such as 5HT3 antagonists, serotonin agonists, NK-1 antagonists, selective serotonin reuptake inhibitors (SSRI), noradrenaline re-uptake inhibitors (SNRI), tricyclic antidepressants, dopaminergic antidepressants, H3 antagonists, 5HT1A antagonists, 5
  • Suitable 5HT3 antagonists which may be used in combination of the compounds of the inventions include for example ondansetron, granisetron, metoclopramide.
  • Suitable serotonin agonists which may be used in combination with the compounds of the invention include sumatriptan, rauwolscine, yohimbine, metoclopramide.
  • Suitable SSRIs which may be used in combination with the compounds of the invention include fluoxetine, citalopram, femoxetine, fluvoxamine, paroxetine, indalpine, sertraline, zimeldine.
  • Suitable SNRIs which may be used in combination with the compounds of the invention include venlafaxine and reboxetine.
  • Suitable tricyclic antidepressants which may be used in combination with a compound of the invention include imipramine, amitriptiline, chlomipramine and nortriptiline.
  • Suitable dopaminergic antidepressants which may be used in combination with a compound of the invention include bupropion and amineptine.
  • Suitable anticonvulsant agents which may be used in combination of the compounds of the invention include for example divalproex, carbamazepine and diazepam.
  • Suitable atypical antipsychotic drugs which which may be used in combination of the compounds of the invention include for example risperidone, olanzapine, ziprasidone, aripiprazole and clozapine.
  • the compounds of the combination or composition may be administered simultaneously (either in the same or different pharmaceutical formulations), separately or sequentially.
  • 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 intravenously, they may also be administered by subcutaneous or intramuscular injection.
  • Formulations suitable for rectal administration are preferably provided as unit-dose suppositories comprising the active ingredient and one or more solid carriers forming the suppository base, for example, cocoa butter.
  • Formulations suitable for topical or intranasal application include ointments, creams, lotions, pastes, gels, sprays, aerosols and oils.
  • Suitable carriers for such formulations include petroleum jelly, lanolin, polyethylene glycols, alcohols, and combinations thereof.
  • the formulations of the invention may be prepared by any suitable method, typically by uniformly and intimately admixing the active compound(s) with liquids or finely divided solid carriers, or both, in the required proportions and then, if necessary, shaping the resulting mixture into the desired shape.
  • a tablet may be prepared by compressing an intimate mixture comprising a powder or granules of the active ingredient and one or more optional ingredients, such as a binder, lubricant, inert diluent, or surface active dispersing agent, or by moulding an intimate mixture of powdered active ingredient and inert liquid diluent.
  • one or more optional ingredients such as a binder, lubricant, inert diluent, or surface active dispersing agent, or by moulding an intimate mixture of powdered active ingredient and inert liquid diluent.
  • Aqueous solutions for parenteral administration are typically prepared by dissolving the active compound in sufficient water to give the desired concentration and then rendering the resulting solution sterile and isotonic.
  • the compound may be administered in single or divided doses and may be administered one or more times, for example 1 to 4 times per day.
  • a proposed dose of the active ingredient for use according to the invention for oral, sub ⁇ lingual, parenteral, buccal, rectal, intranasal or topical administration to a human (of approximately 70 kg bodyweight) for the treatment of neurological and neuropsychiatric disorders mediated by a 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.
  • Methyl tetrahydro-2/-/-pyran-4-carboxylate (667 ul, 0.721 g, 5 mmol) was dissolved in methanol (60 ml) and water (15 ml). Lithium hydroxide was added (1.05 g, 25 mmol) and the resulting solution heated to 80 0 C for 3 h. The solution was cooled and acidified with
  • Tetrahydro-2H-pyran-4-carboxylic acid (D7; 0.248 g, 1.91 mmol) was dissolved in dry DCM (4 ml), two drops of dry DMF were added and the solution was cooled to O 0 C.
  • Oxalyl chloride (246 ul, 2.87 mmol) was added dropwise and the mixture was allowed to reach ambient temperature. The reaction was stirred for 2 h and then cooled again to O 0 C. At that temperature a solution of 3-fluoro-4-morpholin-4-yl-aniline (D2; 0.3 g, 1.53 mmol) and of triethylamine (0.93 ml, 6.68 mmol) in DCM (3 ml) was added dropwise.
  • EtOAc (100 ml) was also sonicated for 45 min. This solution was added to the suspension and the mixture heated at 105 0 C for 24 h. The resultant black suspension was partitioned between diethyl ether (200 ml) and water (200 ml). The aqueous layer was further extracted (diethyl ether, 100 ml), the combined organics dried (Na 2 SO 4 ) and evaporated in vacuo.
  • Example 1 1-(4-Ethylphenylmethyl)- ⁇ /-[3-fluoro-4-(4-morpholinyl)phenyl]- ⁇ /- (benzyI)-4-piperidinecarboxamide
  • Example 4 1 -[4-(1 ,1 -Dimethylethyl)phenyl]methyl- ⁇ /-[3-fIuoro-4-(4- morpholinyl)phenyl]- ⁇ /-(tetrahydro-2W-pyran-4-ylmethyl)-4-piperidinecarboxamide
  • Example 28 N-[3-Fluoro-4-(4-morpholinyl)phenyl]-N-(phenylmethyl)-1 -[4- (trifluoromethyl)phenyl]-4-piperidinecarboxamide

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Abstract

The invention provides a compound of formula (1), or a salt or solvate thereof: wherein R, R5, R6, R7, R8, R9, X, n and Ar 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

PIPERIDINE DERIVATIVES AND THEIR USE AS GLYCINE TRANSPORTER 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 glutaminergic pathways and NMDA receptors (Smith, et al., Neuron, 8, 1992: 927-935). Molecular cloning has further revealed the existence of three variants of GIyTI , termed GIyT-Ia, GIyT-I b and GIyT-Ic (Kim et al., Molecular Pharmacology, 45, 1994: 608-617), each of which displays a unique distribution in the brain and peripheral tissues. The variants arise by differential splicing and exon usage, and differ in their N-terminal regions. GlyT2, in contrast, is found predominantly in the brain stem and spinal cord, and its distribution corresponds closely to that of strychnine-sensitive glycine receptors (Liu et al., J. Biological Chemistry, 268, 1993: 22802-22808; Jursky and Nelson, J. Neurochemistry, 64, 1995 : 1026-1033). Another distinguishing feature of glycine transport mediated by GlyT2 is that it is not inhibited by sarcosine as is the case for glycine transport mediated by GIyTL 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 al, Behavioral Pharmacol.. 6 455-474 (1995)); and, furthermore, decreased function of NMDA-mediated neurotransmission appears to underlie, or contribute to, the symptoms of schizophrenia (Olney and Farber, Archives General Psychiatry, 52, 998-1007 (1996). 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); Upton and Rosenberg, New Enαl. 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.
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 neuropsychiatric disorders, including schizophrenia.
Thus, in the first aspect, there is provided a compound of formula (1) or a salt or solvate thereof:
Figure imgf000004_0001
(D
wherein:
• R is hydrogen or C1-8alkyl, or R is a group
Figure imgf000004_0002
wherein R1 is selected from the group consisting of optionally substituted C3. scycloalkyl, optionally substituted C3-8heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl, and R2 and R3 are independently hydrogen or C1. 8alkyl;
• X is nitrogen or a group -CR4 wherein R4 is hydrogen or halogen; • R5, R6 and R7 are independently selected from hydrogen and halogen;
• R8 and R9 are independently selected from the group consisting of hydrogen, halogen and C1-4alkyl, or R8 and R9 together form a C3-4cycloalkyl;
• Ar is an optionally substituted aryl or an optionally substituted heteroaryl; and
• n is 0, 1, 2 or 3. As used herein, the term "alkyl" refers to a straight or branched alkyl in all isomeric forms. Examples of C1^aIRyI include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl. Examples of C1-8alkyl include, for example, in addition to C1-4alkyl, pentyl, neopentyl, sec-pentyl, n-pentyl, isopentyl, tert-pentyl, hexyl, heptyl and octyl.
As used herein, the term "cycloalkyl" refers to a non-aromatic cyclic saturated hydrocarbon ring. Examples of C3-4cycloalkyl include cyclopropyl and cyclobutyl. Examples of C3-8cycloalkyl include, in addition, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
As used herein, the term "C3-8heterocyclyl" refers to a C3.8cycloalkyl group wherein one to three of the carbon atoms are replaced by heteroatom(s) independently selected from N, O and S. Examples include aziridinyl, oxetanyl, oxiranyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, tetrahydrofuranyl, dioxolanyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydrothienyl, tetrahydropyranyl, dioxanyl, dithianyl, azepanyl and octahydroazocinyl.
As used herein, the term "aryl" refers to a 5- or 6- membered monocyclic aromatic group or a 8- to 11- membered bicyclic aromatic group. Examples include phenyl, indenyl, azulenyl and naphthyl.
■ As used herein, the term "heteroaryl" refers to a 5- or 6-membered monocyclic aromatic group wherein one, two, three or four carbon atoms are replaced by a heteroatom independently selected from N, O and S, or a 8- to 11- membered bicyclic aromatic group wherein one to four carbon atoms are replaced by a heteroatom independently selected from N, O and S. Examples of 5- or 6-membered monocyclic heteroaryls include furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, triazolyl, triazinyl, pyridazinyl, pyrimidinyl, isothiazolyl, isoxazolyl, pyrazinyl, pyrazolyl and pyrimidinyl; examples of 8- to 11- membered bicyclic heteroaryls include quinoxalinyl, quinazolinyl, pyridopyrazinyl, benzoxazolyl, benzothiophenyl, benzimidazolyl, naphthyridinyl, quinolinyl, benzofuranyl, indolyl, benzothiazolyl, oxazolyl[4,5-b]pyridiyl, pyridopyrimidinyl and isoquinolinyl.
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 (1) 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.
As used herein, the term "optionally substituted" refers to substitution by one or more groups selected from:
halogen, hydroxy, oxo, cyano, nitro, C-j.galkyl, C-|_4alkoxy, haloci-4alkyl, haloC-|_ 4alkoxy, arylC-|_4alkoxy, C<|_4alkylthio, hydroxyC^alkyl, C-|_4alkoxyC<|_4alkyl, C3_6cycloalkyl, C3_6cycloalkylC«|_4alkoxy, C-j^alkanoyl, Ci^alkoxycarbonyl, C-] _ 4alkylsulfonyl, C-|_4alkylsulfonyloxy, C1_4alkylsulfonylC-i_4alkyl, arylsulfonyl, arylsulfonyloxy, arylsulfonylC^alkyl, C<|_4alkylsulfonamido, C-|_4alkylamido, C-) _ 4alkylsulfonamidoC-| _4alkyl, C-] _4alkylamidoC-i _4alkyl, arylsulfonamido, arylcarboxamido, arylsulfonamidoC-|_4alkyl, arylcarboxamidoC-|_4alkyl, aroyl, aroylC-i_4alkyl, arylC^alkanoyl, C^acyl, aryl, arylC-^alkyl, Ci_4alkylaminoCi_ 4alkyl, a group R10R11N-, R10OCO(CH2)m, R10CON(R11)(CH2)m, R10R11NCO(CH2)m,
R10R11NSO2(CH2)m or R10SO2NR11(CH2)m (where each of R10 and R11 is independently selected from hydrogen or C-j^alkyl , or where appropriate R10R11 forms part of a C3_6azacyloalkane or C3_6(2-oxo)azacycloalkane ring and m is 0, 1 , 2, 3 or 4), a group R10R11N(CH2)P- or R10R11N(CH2)pO- (wherein p is 1 , 2, 3 or 4); wherein when the substituent is R10R11N(CH2)p- or R10R11N(CH2)pO, R10 with at least one CH2 of the (CH2)p portion of the group may also form a C3., gazacycloalkane and R11 may be hydrogen, C-|_4alkyl or with the nitrogen to which it is attached, form a second C3_6azacycloalkane fused to the first C3_ gazacycloalkane. Furthermore, when R1 is an optionally substituted C3-8cycloalkyl or an optionally substituted Q^heterocyclyl, the optionally substituted cycloalkyl or heterocyclyl group may be additionally optionally bridged by a Ci-3alkylene group.
Where there is more than one substituent, the substituents may be different or the same. If substituent(s) is/are present, preferably the number of substituent(s) is 1 , 2, 3 or 4.
In one embodiment, R is hydrogen. In another embodiment, R is a group
Figure imgf000007_0001
In one embodiment, R1 is C3-8cycloalkyl (such as cyclopentyl or cyclohexyl), C3- eheterocyclyl (such as tetrahydropyranyl)or aryl (such as phenyl optionally substituted by one or two groups selected from halogen, C1-4alkyl and C-i-4alkoxy).
In one embodiment, R2 and R3 are both hydrogen.
In one embodiment, X is a group -CR4.
In one embodiment, R4, R5 and R6 are hydrogen and R7 is fluorine.
In one embodiment, Ar is an optionally substituted aryl, such as phenyl optionally substituted by one or two groups selected from C^alkyl, haloC1-4alkyl such as CF3, halogen and C3-6cycloalkyl.
In another embodiment, Ar is an optionally substituted heteroaryl such as quinolinyl or benzimidazolyl, each of which is optionally substituted by one or two C1-4alkyl or halod. 4alkyl such as CF3.
In one embodiment, Ar is optionally substituted by one, two or three substituents selected from the group consisting of: halogen, oxo, cyano, C-]_Qalkyl, C-|_4alkoxy, haloC-^alkyl, haloC-|_4alkoxy, arylCi_4alkoxy, Ci_4alkoxyCi_4alkyl, C3_gcycloalkyl, C3_6CycloalkylC-|_ 4alkoxy, C<i_4alkanoyl, C-|_4alkylsulfonyl, aroyl, C^acyl, aryl, arylCi_4alkyl, C-] _ 4alkylaminoC<|_4alkyl, a group R12R13N-, R12CON(R13)(CH2)m or R12R13NCO(CH2)m (where each of R12 and R13 is independently selected from hydrogen or C-j^alkyl, or where appropriate R12R13 forms part of a C3_6azacycloalkane ring and m is 0, 1 , 2, 3 or 4).
In one embodiment, n is 1.
In one embodiment, R8 and R9 are both hydrogen. In one embodiment, the present invention provides a compound of formula (1a) or a salt or solvate thereof:
Figure imgf000008_0001
da) wherein • R1 is selected from the group consisting of C3-8cycloalkyl, C3-8heterocyclyl, aryl and heteroaryl; each of which is optionally substituted by one, two or three substituents selected from the group consisting of halogen, oxo, cyano, C^galkyl, C<|_4alkoxy, haloC-|_4alkyl, haloC-|_4alkoxy, arylCi^alkoxy, C-^alkoxyC^alkyl, C3_ρcycloalkyl, C3_6cycloalkylC<|_4alkoxy, C-|_4alkanoyl, C<|_4alkylsulfonyl, Ci_4acyl, aryl, arylCi_ 4alkyl, Ci^alkylaminoC-i^alkyl, a group R12R13N-, R12CON(R13)(CH2)m or
R12R13NCO(CH2)m (where each of R12 and R13 is independently selected from hydrogen or Ci_4alkyl, or where appropriate R12R13 forms part of a C^. gazacycloalkane ring and m is 0, 1 , 2, 3 or 4);
• R2 is hydrogen or methyl; • n is O oM ;
• Z is hydrogen, fluorine or chlorine; and
• Ar is phenyl or heteroaryl, each of which is optionally substituted by one, two or three substituents selected from the group consisting of halogen, cyano, C-|_galkyl, C-j. 4alkoxy, haloC^alkyl, haloC^alkoxy, Ci_4alkoxyC<|_4alkyl, C3_gcycloalkyl, C^. gcycloalkylC-i_4alkoxy, C-|_4acyl and C-|_4alkylaminoC<|_4alkyl.
All embodiments and features of compounds of formula (1) apply to compounds of formula (1a).
Examples of compounds of the invention include:
1. 1 -(4-Ethylphenylmethyl)-Λ/-[3-fluoro-4-(4-morpholinyl)phenyl]-/V-(benzyl)-4- piperidinecarboxamide
2. Λ/-[3-Fluoro-4-(4-morpholinyl)phenyl]-A/-(benzyl)-1-(4-trifluoromethylphenyl)methyl- 4-piperidinecarboxamide Λ/-[3-Fluoro-4-(4-morpholinyl)phenyl]-A/-(1-phenylethyl)-
1-{[4-(trifluoromethyl)phenyl]methyl}-4-piperidinecarboxamide 1-[4-(1,1-
Dimethylethyl)phenyl]methyl-Λ/-[3-fluoro-4-(4-morpholinyl)phenyl]-Λ/-(tetrahydro-
2H-pyran-4-ylmethyl)-4-piperidinecarboxamide 5. 1-[(4-chlorophenyl)methyl]-N-[3-fluoro-4-(4-morpholinyl)phenyll-N-(phenylmethyl)- 4-piperidinecarboxamide
6. 1 -{[4-(1 , 1 -dimethylethyl)phenyl]methyl}-N-[3-fluoro-4-(4-morpholinyl)phenyl]-N- (phenylmethyl)-4-piperidiπecarboxamide 7. N-[3-fluoro-4-(4-morphoiinyl)phenyl]-1 -[(1 -methyl-1 H-benzimidazol-2-yl)methyl]-N-
(phenylmethyl)-4-piperidinecarboxamide
8. N-[3-fluoro-4-(4-morpholinyl)phenyl]-N-(phenylmethyl)-1-(2-quinolinylmethyl)-4- piperidinecarboxamide
9. N, 1 -bis[(4-chlorophenyl)methyl]-N-[3-fluoro-4-(4-morpholinyl)phenyl]-4- piperidinecarboxamide
10. N-[(4-chlorophenyl)methyl]-N-[3-fluσro-4-(4-morpholinyl)phenyl]-1-{[4- (trifluoromethyl)phenyl]methyl}-4-piperidinecarboxamide
11. N-[(4-chlorophenyl)methyl]-1-{[4-(1,1-dimethylethyl)phenyl]methyl}-N-[3-fluoro-4- (4-morpholinyl)phenyl]-4-piperidinecarboxamide 12. N-[(4-chlorophenyl)methyl]-N-[3-fluoro-4-(4-morρholinyl)phenyl]-1 -[(1 -methyl-1 H- benzimidazol-2-yl)methyl]-4-piperidinecarboxamide 13, N-[(4-chlorophenyl)methyl]-N-[3-fluoro-4-(4-morpholinyl)phenyl]-1 -(2- quinolinylmethyl)-4-piperidinecarboxamide
14. 1 -[(4-chlorophenyl)methyl]-N-i;3-f luoro-4-(4-morpholinyl)phenyl]-N-{[4- (methyloxy)phenyl]methyl}-4-piperidinecarboxamide
15. N-[3-fluoro-4-(4-morpholinyl)phenyl]-N-{[4-(methyloxy)phenyl]methyl}-1-{[4-
(trifluoromethyl)phenyl]methyl}-4-piperidinecarboxamide 16. 1-{[4-(1,1-dimethylethyl)phenyl]methyl}-N-[3-fluoro-4-(4-morρholinyl)phenyl]-N-{[4-
(methyloxy)phenyl]methyl}-4-piperidinecarboxamide 17. N-[3-fluoro-4-(4~morphσlinyl)phenyl]~1 -[(1 -methyl-1 H-benzimidazol-2-yl)methyl]-N-
{[4-(methyloxy)phenyl]methyl}-4-piperidinecarboxamide 18. N-[3-fluoro-4-(4-morpholinyl)phenyl]-N-{[4-(methyloxy)phenyl]methyl}-1-(2- quinolinylmethyl)-4-piperidinecarboxamide
19. 1 -[(4-chlorophenyl)methyl]-N-(cyclopentylmethyl)-N-[3-fluoro-4-(4- morpholinyl)phenyl]-4-piperidinecarboxamide
20. N-(cyclopentylmethyl)-N-[3-fluoro-4-(4-morpholinyl)phenyl]-1-{[4- (trifluoromethyl)phenyl]methyl}-4-piperidinecarboxamide
21. N-(cyclopentylmethyl)-1-{[4-(1 ,1-dimethylethyl)phenyl]methyl}-N-[3-fluoro-4-(4- morpholinyl)phenyl]-4-piperidinecarboxamide 22. N-(cyclopentylmethyl)-N-[3-fluoro-4-(4-morpholinyl)phenyl]-1-[(1 -methyl-1 H- benzimidazol-2-yl)methyl]-4-piperidinecarboxamide
23. N-(cyclopentylmethyl)-N-[3-fluoro-4-(4-morpholinyl)phenyl]-1-(2-quinolinylmethyl)- 4-piperidinecarboxamide
24. 1-[(4-chlorophenyl)methyl]-N-[3-fluoro-4-(4-morpholinyl)phenyl]-N-(tetrahydro-2H- pyran-4-ylmethyl)-4-piperidinecarboxamide
25. N-[3-fluoro-4-(4-morpholinyl)phenyl]-N-(tetrahydro-2H-pyran-4-ylmethyl)-1-{[4- (trifluoromethyl)phenyl]methyl}-4-piperidinecarboxamide 26. N-[3-fluoro-4-(4-morpholinyl)phenyl]-1 -[(1 -methyl-1 H-benzimidazol-2-yl)methyl]-N- (tetrahydro-2H-pyran-4-ylmethyl)-4-piperidinecarboxamide
27. N-[3-fluoro-4-(4-morpholinyl)phenyl]-1-(2-quinolinylmethyl)-N-(tetrahydro-2H- pyran-4-ylmethyl)-4-piperidinecarboxamide 28. N-[3-Fluoro-4-(4-morpholinyl)phenyl]-N-(phenylmethyl)-1 -[4-
(trifluoromethyl)phenyl]-4-piperidinecarboxamide 29. N-[3-Fluoro-4-(4-morpholinyl)phenyl]-1-[4-(trifluoromethyl)phenyl]-4- piperidinecarboxamide
and salts and solvates thereof.
The compounds of formula (1 ) 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 (1). 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 stereoisomeric forms (i.e. they may contain one or more asymmetric carbon atoms or may exhibit cis-trans isomerism). The individual stereoisomers (enantiomers and diastereoisomers) and mixtures of these are included within the scope of the present invention. Likewise, it is understood that compounds of formula (1) 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 (1) 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 (1 ) 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 (1). Those skilled in the art will recognise if a stereocentre exists in compounds of formula (1). 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. ENeI, S. H. Wilen, and L. N. Mander (Wiley-lnterscience, 1994).
Typical reaction routes for the preparation of a compound of formula (1 ) as hereinbefore defined, are shown in Scheme 1. Although Scheme 1 shows compounds wherein X is - CR4 and R is a group -C(R1)(R2)(R3), the scheme is also applicable to cases wherein X is nitrogen and R is hydrogen or d-8alkyl.
Starting materials of general structure (2) and (9) and reagents (4), (6), (7) & (10) are known in the literature or can be prepared using methods known in the art.
P2005/007136
Scheme 1
Figure imgf000012_0001
wherein R1 - R9 , n and Ar are as defined above for (1) and L and W are leaving groups. For L, examples of leaving groups include halogen, hydroxy, OC(=O)alkyl, OC(=O)O-alkyl and OSO2Me. Preferably L is halogen and acylation in steps (ii), (iv) and (vii) may be carried out in an inert solvent such as dichloromethane, in the presence of a base such as triethylamine. When L represents hydroxy, the reaction takes place in an inert solvent such as dichloromethane in the presence of a diimide reagent such as [O-(7- azabenzotriazol-1-yl)-1 ,1,3,3-tetramethyluronium hexafluoro phosphate]. For W, examples of leaving groups include chlorine, bromine and iodine. Preferably L is bromine or iodine and alkylation in step (iii) may be carried out in a suitable solvent such as dimethylformamide in the presence of a base such as sodium hydride.
Reduction step (i) can be accomplished using known methods, such as catalytic hydrogenolysis in an inert solvent (e.g. using palladium on charcoal in a lower alcohol or ethyl acetate), catalytic transfer hydrogenolysis (e.g. using palladium black and formic acid in methanol) or chemical reduction (e.g. iron and acetic acid). The reductive amination step (vi) can be carried out using known methods e.g. reaction of (3) with an aldehyde (10) in the presence of a reducing agent such as sodium triacetoxyborohydride in an inert solvent such as 1 ,2-dichloroethane or dichoromethane. The reduction step (v) can be carried out in an inert solvent such as tetrahydrofuran, in the presence of lithium aluminium hydride.
Accordingly, in a second aspect, the present invention provides a method of preparing a compound of formula (1 ), comprising the step of:
(a) reacting a compound of formula (3):
Figure imgf000013_0001
wherein R , R , R and X are as defined for formula (1), with a compound of formula (4):
Figure imgf000013_0002
(4)
wherein R 58 , O R9 , n and Ar are as defined for formula (1) and L is a leaving group; or
(b) for a compound of formula (1) wherein R is a group -C(R1)(R2)(R3), reacting a compound of formula (9):
Figure imgf000013_0003
wherein R1 to R7 are as defined for formula (1), with a compound of formula (4) as defined above;
and thereafter optionally for step (a) or step (b):
• removing any protecting groups and/or
• converting a compound of formula (1 ) into another compound of formula (1 ) and/or
• forming a salt or solvate.
Compounds of formula (1) can be converted into further compounds of formula (1) 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. Also, a compound of formula (1) wherein R is hydrogen may be reacted with a compound of formula (6):
Figure imgf000014_0001
(6)
wherein R1, R2 and R3 are as defined for formula (1) and W is a leaving group, to form compounds wherein R is -C(R1)(R2)(R3). Appropriate leaving groups for W are described above.
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 culture medium [DMEM/NUT mix F12 containing 2mM L-Glutamine, 0.8mg/ml_ G418 and 10% heat inactivated fetal calf serum] at 37°C and 5% CO2. Cells grown to 70-80% confluency in T175 flasks were harvested and resuspended at 1.6x106 cells/mL in assay buffer [14OmM NaCI, 5.4mM KCI, 1.8mM CaCI2, 0.8mM MgSO4, 2OmM HEPES, 5mM glucose and 5mM alanine, pH 7.4]. An equal volume of WGA SPA beads (12.5mg/ml suspended in assay buffer) was added to the cell suspension and 25μl_ of the cell/bead suspension transferred to each well of a 384-well white solid bottom plate (20,000 cells/well) that contained 14μl_ of assay buffer. Compounds were serially diluted 2-fold in DMSO from a top concentration of 5mM with each compound giving a 16 data point dose-response. 1μL of compound at each concentration was added to the assay plate. Substrate (10μl_) was added to each well [1 :40 dilution of [3H]-glycine stock in assay buffer containing 5μM glycine). Final DMSO concentration was 2% v/v. Data was collected using a Wallac Trilux. 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 culture medium [DMEM/NUT mix F12 containing 2mM L-Glutamine, 0.8mg/ml_ G418 and 10% heat inactivated fetal calf serum] at 37°C and 5% CO2. Cells grown to 70-80% confluency in T175 flasks were harvested and resuspended at 4x105 cells/mL in assay buffer [14OmM NaCI, 5.4mM KCI, 1.8mM CaCI2, 0.8mM MgSO4, 2OmM HEPES, 5mM glucose and 5mM alanine, pH 7.4]. Compounds were serially diluted 2.5-fold in DMSO from a top concentration of 2.5mM with each compound giving a 11 data point dose-response. 10OnL of compound at each concentration was added to the assay plate. An equal volume of Leadseeker™ WGA SPA beads (12.5mg/ml suspended in assay buffer) was added to the cell suspension and 5μL of the cell/bead suspension transferred to each well of a 384-well white solid bottom plate (1 ,000 cells/well) containing 10OnL of test compounds. Substrate (5μL) was added to each well [1 :100 dilution of [3H]-glycine stock in assay buffer containing 2.5μM glycine). Final DMSO concentration was 1% v/v. Data was collected using a Perkin Elmer Viewlux. plC50 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 6.0. Preferred compounds of the invention were found to have a plC50 at the GIyTI transporter of greater than 6.0.
Accordingly, in a further aspect of the invention, there is provided a compound of formula (1 ) 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 (1) 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 forgetful ness, childhood learning disorders and closed head injury.
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 (1) as hereinbefore defined or a salt or solvate thereof.
In another aspect of the invention, there is provided use of a compound of formula (1) 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.
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 (1 ) 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 (1) 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-Like)-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-I_ike)-Related Disorders such as Phencyclidine Dependence (304.60), Phencyclidine Abuse (305.90), Phencyclidine Intoxication (292.89), Phencyclidine Intoxication Delirium, Phencyclidine- Induced 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- lnduced 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 circadian rhythm disorders.
The invention also provides a compound of formula (I) as hereinbefore described or a pharmaceutically acceptable salt or solvate thereof for use in the treatment of psychotic disorders, schizophrenia, Parkinson's disease, substance abuse, dyskinetic disorders, depression, bipolar disorder, anxiety, cognitive impairment, eating disorders, obesity, sexual dysfunction, sleep disorders, emesis, movement disorders, obsessive-compulsive disorders, amnesia, aggression, autism, vertigo, dementia, circadian rhythm disorders and gastric motility disorders.
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, 5HT1 B 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.
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 EP2005/007136
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
Figure imgf000027_0001
Figure imgf000028_0001
Figure imgf000029_0001
Examples of tradenames and suppliers of selected neuroleptic drugs are as follows : clozapine (available under the tradename CLOZARIL®, from Mylan, Zenith Goldline, UDL, Novartis); olanzapine (available under the tradename ZYPREX®, from Lilly ; ziprasidone (available under the tradename GEODON®, from Pfizer); risperidone (available under the tradename RISPERDAL®, from Janssen); quetiapine fumarate (available under the tradename SEROQUEL®, from AstraZeneca); haloperidol (available under the tradename HALDOL®, from Ortho-McNeil); chlorpromazine (available under the tradename THORAZINE®, from SmithKline Beecham (GSK); fluphenazine (available under the tradename PROLIXIN®, from Apothecon, Copley, Schering, Teva, and American Pharmaceutical Partners, Pasadena); thiothixene (available under the tradename NAVANE®;, from Pfizer); trifluoperazine (10-[3-(4-methyl-1-piperazinyl)propyl]- 2-(trifluoromethy[)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 TARACTAN®), droperidol (available under the tradename INAPSINE®), acetophenazine (available under the tradename TINDAL®;), prochlorperazine (available under the tradename COMPAZINE®), methotrimeprazine (available under the tradename NOZINAN®), pipotiazine (available under the tradename PIPOTRIL®), ziprasidone, and hoperidone.
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, 5HT1 B 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.
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 intravenously, 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, sub¬ lingual, parenteral, buccal, rectal, intranasal or topical administration to a human (of approximately 70 kg bodyweight) for the treatment of neurological and neuropsychiatric disorders mediated by a GIyTI inhibitor, including schizophrenia, may be about 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.
Abbreviations:
Tetrahydrofuran THF
Dichloromethane DCM
Triethylamine TEA
Ethyl acetate EtOAc
Sodium bicarbonate NaHCO3
Lithium aluminium hydride LAH
Dimethyl sulphoxide DMSO
Trifluoroacetic acid TFA
Ammonium Chloride NH4CI Descriptions and Examples
Description 1: 4-(2-Fluoro-4-nitrophenyl)morpholine
Figure imgf000033_0001
To a solution of morpholine (71.3 ml; 0.82mol) in THF (60ml), chilled in an ice-salt bath, was added dropwise 3,4-difluoro nitrobenzene (3Og; 0.18mol). After the addition, cooling was removed and the reaction mixture warmed to room temperature over 1.25h. The resulting pale yellow suspension was cooled and aqueous citric acid added dropwise over 25 min, followed by stirring for a further 35 min. Toluene (1L) was added and the resulting solution washed with water, dried and evaporated to afford the title product (42.6g; 100%) as a pale yellow solid. 1H NMR (CDCI3) δ: 3.29 (4H, m), 3.88 (4H, m), 6.92 (1 H, t, J = 9Hz), 7.91 (1 H, m), 8.00 (1 H,m).
Description 2: 3-Fluoro-4-(4-morpho!inyl)aniline
Figure imgf000033_0002
4-(2-Fluoro-4-nitrophenyl)morpholine (D1 ; 42.6g, 0.19mol) in ethanol (1.2L) was hydrogenated over 10%Pd/C paste (4g) at NTP for 18h. The resulting mixture was filtered through Kieselguhr and the filtrate evaporated in vacuo to afford the title product (36.9g, 100%) as a colourless solid. 1H NMR (CDCI3) δ: 2.96 (4H, m), 3.55(2H, br s), 3.84 (4H, m), 6.41 (2H1 m), 6.79 (1 H, m).
Description 3: Ethyl 1-[4-(trifluoromethyl)phenyl]methyl-4-piperidinecarboxylate
Figure imgf000033_0003
To a solution of ethyl isonipecotate (7.22 g, 0.046 mol) and 4-trifluoromethylbenzaldehyde (8.0 g, 0.046 mol) in DCM (400 ml) was added sodium triacetoxyborohydride (19.5 g, 0.092 mol) portionwise over 10 mins. The mixture was stirred at room temp, for 70 h. Water (200 ml) was added (with appropriate care) and the mixture stirred for 1 h. The organics were separated, dried (Na2SO4) and evaporated in vacuo to a white solid (14.0 g, 97%).
1H NMR (CDCI3) δ: 1.23 (3H, t), 1.76-1.91 (4H, m), 2.04-2.10 (2H, m), 2.28 (1 H,m), 2.81- 2.85 (2H, m), 3.54 (2H, s), 4.13 (2H, q), 7.43 (2H, d), 7.56 (2H, d).
Description 4: 1-[4-(Trifluoromethyl)phenyl]methyl-4-piperidinecarbonyl chloride
Figure imgf000034_0001
To a solution of ethyl 1-[4-(trifluoromethyl)phenyl]methyl-4-piperidinecarboxylate (D3; 14.Og, 0.044 mol) in methanol (100 ml) and water (25 ml) was added sodium hydroxide (2.0 g, 0.050 mol) and the mixture stirred at room temp, for 16 h. The solvents were removed in vacuo to give a white solid. A portion of the solid (1.69 g, 5.9 mmol) in DCM (50 ml) was treated with oxalyl chloride (0.6 ml, 6.9 mmol) and DMF (1 drop) and the mixture stirred at room temp, for 16 h. To the solution was added ice-cold saturated NaHCO3 solution and the organics separated quickly, dried (Na2SO4) and evaporated in vacuo to a yellow oil (0.95g, 53%).
1H NMR (CDCI3) δ: 1.76-1.86 (2H, m), 1.91-1.96 (2H, m), 2.05-2.11 (2H, m), 2.43 (1 H, m), 2.81-2.86 (2H, m), 3.54 (2H, s), 7.43 (2H1 d), 7.56 (2H, d).
Description 5: Λ/-[3-Fluoro-4-(4-morpholinyl)phenyl]-1-(4- trifluoromethylphenylmethyl)-4-piperidinecarboxamide
Figure imgf000034_0002
A mixture of 3-fluoro-4-(4-morpholinyl)aniline (D2; 608 mg, 3.1 mmol) and 1-[4- (trifluoromethyl)phenyl]methyl-4-piperidinecarbonyl chloride (D4; 948 mg, 3.1 mmol) in DCM was treated with triethylamine and stirred at room temp, for 16 h. The mixture was washed with saturated aqueous NaHCO3, the organics separated, dried (Na2SO4), and evaporated in vacuo. Column chromatography afforded the title compound as a white solid (620 mg, 43%). 1H NMR (CDCI3) δ: 1.85-1.91 (4H, m), 2.03-2.09 (2H, m), 2.23 (1 H, m), 2.94 (2H, m), 3.03 (4H, m), 3.85 (4H, m), 6.87 (1 H, t), 7.09 (2H, m), 7.44 (3H, m inc. NH), 7.57 (2H1 d). Mass Spectrum (Electrospray LC/MS): Found 466 (MH+). C24H27F4N3O2 requires 465.
Description 6: Cyclopentanecarboxylic acid
Figure imgf000035_0001
Chromic anhydride (6 g, 0.06 mol) was added portionwise to water (21 ml) and the resulting solution cooled at 00C. Concentrated sulphuric acid (6 ml) were added dropwise and the solution stirred for 15 minutes. The resulting red solution was added dropwise to a solution of hydroxymethyl cyclopentane (2 g, 0.02 mol) in acetone (150 ml), keeping the temperature lower than 5°C.
At the end of the addition the ice bath was removed and the reaction was stirred for 1h. Water (150 ml) and diethyl ether (200 ml) were added, the phases were separated and the organic layer was extracted with 2M NaOH (3x120 ml). The aqueous phase was then acidified with 2M HCI to pH 2-3 and extracted with diethyl ether.
The organic phase was dried with Na2SO4, filtered and evaporated to afford the crude product, which was filtered through a silica pad to give the title product as a colorless oil (2.2 g, 96% yield).
1HNMR (CDCI3) δ: 1.5-1.9 (8H, m), 2.75 (1H, m).
Description 7: Tetrahydro-2H-pyran-4-carboxylic acid
Figure imgf000035_0002
Methyl tetrahydro-2/-/-pyran-4-carboxylate (667 ul, 0.721 g, 5 mmol) was dissolved in methanol (60 ml) and water (15 ml). Lithium hydroxide was added (1.05 g, 25 mmol) and the resulting solution heated to 800C for 3 h. The solution was cooled and acidified with
2M HCI to pH 2-3. Methanol was removed in vacuo and the residual aqueous phase was extracted with EtOAc (3x10 ml). The organic layer was dried (Na2SO4), filtered and evaporated to afford the title product (0.65 g, 99%).
1HNMR (CDCI3) δ: 1.8 (4H, m), 2.5 (1 H, m), 3.45 (2H, m), 3.9 (2H, m).
Description 8: yV-[3-Fluoro-4-(4-morphoIinyl)phenyl]tetrahydro-2H-pyran-4- carboxamide
Figure imgf000036_0001
Tetrahydro-2H-pyran-4-carboxylic acid (D7; 0.248 g, 1.91 mmol) was dissolved in dry DCM (4 ml), two drops of dry DMF were added and the solution was cooled to O0C. Oxalyl chloride (246 ul, 2.87 mmol) was added dropwise and the mixture was allowed to reach ambient temperature. The reaction was stirred for 2 h and then cooled again to O0C. At that temperature a solution of 3-fluoro-4-morpholin-4-yl-aniline (D2; 0.3 g, 1.53 mmol) and of triethylamine (0.93 ml, 6.68 mmol) in DCM (3 ml) was added dropwise. The mixture was stirred at room temperature overnight. The solution was washed with aqueous satd. NaHCO3 (2x10 ml) and then NH4CI (2x15 ml). The organic layer was dried with Na2SO4, filtered and evaporated, and the residue purified by flash chromatography (100% cyclohexane to 100% EtOAc gradient), giving the title compound (0.252 g, 53% yield) as a yellow solid. 1HNMR (CDCI3) δ: 1.8 (4H, m), 2.45 (1H, m), 3.0 (4H, t), 3.4 (2H1 dt), 3.85 (4H, t), 4.0 (2H, m), 6.85 (1 H, m), 7.05 (2H, m-s broad), 7.4 (1 H, dd).
Mass spectrum (API+): Found 309 (MH+). C16H2IFN2O3 requires 308.
Description 9: 3-Fluoro-4-(4-morphoIinyl)-Λ/-(tetrahydro-2H-pyran-4-ylmethyl)aniline
Figure imgf000036_0002
/V-[3-Fluoro-4-(4-morpholinyl)phenyl]tetrahydro-2H-pyran-4-carboxamide
(D8; 492 mg, 1.60 mmol) was suspended in THF (20 ml) and the mixture was cooled to
O0C. A solution of LAH in ether (2.5 ml of a 1.0M solution in ether, 2.5 mmol) was added dropwise. The reaction was stirred at room temperature for 2h. Further LAH solution (1.6 ml, 1.6 mmol) was added at O0C and the reaction heated to 600C for 30 minutes. After cooling to O0C, water (190 ul), 20% wt aqueous NaOH (230 ul) and water (190 ul) were sequentially added. The mixture was stirred for 1 hour, during which a white precipitate was formed. The solid was separated by filtration and washed with THF and then with EtOAc. The collected liquid phases were evaporated to yield a dark orange oil, which was purified on a 5g Phenomenex Silica cartridge, using a cyclohexane - EtOAc gradient. The title compound was obtained as a yellow solid (390 mg, 82% yield). 1HNMR (DMSO) δ: 1.2 (2H, m), 2.55 (2H, m), 2.7 (1 H1 m), 2.85 (6H, m), 3.25 (2H, m), 3.65 (4H, t), 3.85 (2H, m), 5.6 (1 H1 1 br), 6.3 (1 H, dd), 6.35 (1 H, dd), 6.8 (1 H, dd). Mass spectrum (API+): Found 295 (MH+). C16H23FN2O2 requires 294.
Description 10: i-^i.i-DimethylethyOphenylmethyll^-piperidinecarboxylic acid
Figure imgf000037_0001
lsonipecotic acid (500 mg, 3.87 mmol) was suspended in dry dichloroethane (15 ml), then 4-ferf-butylbenzaldehyde (0.77 ml, 4.46 mmol) was added. The suspension was stirred for 2h and then sodium triacetoxyborohydride (1.64 g, 7.74 mmol) was added portionwise and the suspension stirred overnight. Water (1 ml) was added to quench the reaction and, after 10 minutes, the solvent was removed. The residue was taken up with water and loaded onto a 10g reversed phase C18 cartridge (Waters Sep-Pak), washed with water to remove inorganic salts and eluted with a water-methanol gradient. The fractions containing the product were collected and evaporated in a vacuum centrifuge, yielding the title product as a white crystalline solid (774mg, 72%). 1HNMR (DMSO) δ: 1.2 (9H, s), 1.5 (2H, m), 1.75 (2H, m), 2.95 (2H, dt), 2.15 (1 H, m), 2.7 (2H, m), 3.35 (2H, s), 7.15 (2H, d), 7.3 (2H, d), 12 (1 H, s broad). Mass spectrum (API+): Found 276 (MH+). C17H25NO2 requires 275.
Description 11 : 3-Fluoro-4-(4-morpholinyl)-Λ/-(phenylmethyl)aniline
Figure imgf000037_0002
3-Fluoro-4-morpholin-4-yl-aniline (D2; 313 mg, 1.6 mmol) and benzaldehyde (162 ul, 1.6 mmol) were dissolved in dry THF (0.7 ml) in an 8 ml vial. Dibutyl tin dichloride (97 mg, 0.32 mmol) was added and the mixture agitated for 10 minutes.
Phenylsilane (125 ul, 1.76 mmol) was added and the mixture agitated overnight. The crude material was purified on a 5g Varian SCX cartridge, yielding the title product as a brown solid (400mg, 87%). Mass spectrum (API+): Found 287 (MH+). C17H19FN2O requires 286. Description 12: 1-[(4-Ethylphenyl)methyl]-4-piperidinecarbonyl chloride
Figure imgf000038_0001
The compound was prepared in 3 steps in a similar manner to that of D3 and D4. Mass spectrum (ES+): Found 262 (methyl ester MH+). C15H20 35CINO requires 265.
Description 13: Ethyl 1-[4-(trifluoromethyl)phenyl]-4-piperidinecarboxylate
Figure imgf000038_0002
A suspension of rac-2,2'-bis(diphenylphosphino)-1 ,1'-binaphthyl (3.35 g, 5.37 mmol), cesium carbonate (16.86 g, 52 mmol), and palladium(ll) acetate (0.82 g, 3.65 mmol) in 1 ,4-dioxan (100 ml) under argon was sonicated for 45 min. A solution of ethyl isonipecotate (4.11g, 26.1 mmol) and 4-bromobenzenetrifluoride (6.0 g, 26.1 mmol) in
EtOAc (100 ml) was also sonicated for 45 min. This solution was added to the suspension and the mixture heated at 1050C for 24 h. The resultant black suspension was partitioned between diethyl ether (200 ml) and water (200 ml). The aqueous layer was further extracted (diethyl ether, 100 ml), the combined organics dried (Na2SO4) and evaporated in vacuo. Chromatography (split into 2 x 70 g Argonaut IST columns; eluent 100% pentane-»10% EtOAc/pentane-»15% EtOAc/pentane run on Argonaut Flashmaster II) afforded the title compound (5.3 g, 66%).
1HNMR (CDCI3) δ: 1.26 (3H, t), 1.80-1.89 (2H, m), 2.00-2.05 (2H, m), 2.48 (1 H, m), 2.87- 2.94 (2H, m), 3.72-3.77 (2H, m), 4.16(2H, q), 6.92 (2H, m), 7.46 (2H, m) Mass spectrum (ES+): Found 302 Ci5Hi8F3NO2 requires 301.
Description 14: 1-[4-(Trifluoromethyl)phenyl]-4-piperidinecarbonyl chloride
Figure imgf000038_0003
Ethyl 1-[4-(trifluoromethyl)phenyl]-4-piperidinecarboxylate D13 (5.3g; 17.6mmol) was suspended in methanol (150ml) and water (50ml), 2N NaOH (10.6ml; 21.1 mmol) added and the mixture stirred at room temperature for 18h. The resulting solution was acidified with 5M HCI and the precipitate collected by filtration, washed with water and dried in vacuo to afford 1-[4-(trifluoromethyl)phenyl]-4-piperidinecarboxylic acid (4.6g; 95%). To this acid (1.Og; 3.67 mmol) in DCM (70ml) containing DMF (2 drops) was added oxalyl chloride (0.96ml; 11.01 mmol) at O0C. The reaction was allowed to reach room temperature and after 1 h was heated at 450C for a further 2h. The cooled reaction mixture was evaporated in vacuo and then re-evaporated from DCM (X2) and dried in vacuo to afford the title compound (1.2g) as a pale pink solid. Mass Spectrum (Electrospray LC/MS): Found 288 (methyl ester MH+) C13H13 35CIF3NO requires 291.
Example 1 : 1-(4-Ethylphenylmethyl)-Λ/-[3-fluoro-4-(4-morpholinyl)phenyl]-Λ/- (benzyI)-4-piperidinecarboxamide
Figure imgf000039_0001
A mixture of 3-fluoro-4-(4-morpholinyl)-Λ/-(phenylmethyl)aniline (D11; 100 mg, 0.35 mmol), 1-[(4-ethylphenyl)methyl]-4-piperidinecarbonyl chloride (D12; 111 mg, 0.42 mmol) in DCM (15 ml) was treated with triethylamine (106 mg, 1.05 mmol) and stirred at room temp, for 16 h. The mixture was washed with saturated aqueous NaHCO3, the organics separated (Phase Sep cartridge) and evaporated in vacuo. Column chromatography
(eluent 50% EtOAc/pentane→100% EtOAc→5% MeOH/EtOAc) afforded the title compound as a white foam (58 mg, 32%).
1HNMR (CDCI3) δ: 1.22 (3H, t), 1.55 (2H, m), 1,70-1.76 (2H, m), 1.87-1.96 (2H, m), 2.15
(1 H, m), 2.62 (2H, q), 2.82 (2H, m), 3.09 (4H, m), 3.39 (2H, s), 3.86 (4H, m), 4.80 (2H, s),
6.63-6.66 (2H, m), 6.81 (1 H, t), 7.11-7.25 (9H, m).
Mass spectrum (ES+): Found 516 (MH+). C32H38FN3O2 requires 515.
Example 2: Λ/-[3-Fluoro-4-(4-morpholinyl)phenyl]-Λ/-(benzyl)-1 -(4- trifluoromethylphenyl)methyl-4-piperidinecarboxamide
Figure imgf000039_0002
A solution of Λ/-[3-fluoro-4-(4-morpholinyl)phenyl]-1-(4-trifluoromethylphenylmethyl)-4- piperidinecarboxamide (D5; 100 mg, 0.22 mmol) in DMF (2 ml) was treated with sodium hydride (60% dispersion in oil; 9 mg, 0.23 mmol) and the mixture stirred at room temp, for 30 mins. Benzyl bromide (37 mg, 0.22 mmol) was added and the mixture shaken for 16 h.
Treatment with aqueous saturated NaHCO3, extraction with DCM and column chromatography afforded the title compound as a white solid (86 mg, 70%).
1HNMR (CDCI3) δ: 1.57-1.59 (2H, m), 1.76 (2H, m), 1.89-1.98 (2H, m), 2.17 (1H, m), 2.80
(2H, m), 3.10 (4H, m), 3.46 (2H, s), 3.86 (4H1 m), 4.81 (2H, s), 6.64-6.67 (2H, m), 6.82
(1H, t), 7.14 (2H1 m), 7.24 (3H, m), 7.40 (2H, m), 7.54 (2H, m).
Mass spectrum (ES+): Found 556 (MH+). C31H33F4N3O2 requires 555.
Example 3: Λ/-[3-Fluoro-4-(4-morpholinyl)phenyl]-/V-(1 -phenylethyl)-1 -{[4- (trifluoromethyl)phenyl]methyl}-4-piperidinecarboxamide
Figure imgf000040_0001
The title compound (22 mg, 22%) was made from Λ/-[3-fluoro-4-(4-morpholinyl)phenyl]-1- (4-trifluoromethylphenylmethyl)-4-piperidinecarboxamide (D5; 83 mg, 0.18 mmol) and (1- bromoethyl)benzene (37 mg, 0.2 mmol) in a similar manner to that decribed for E2. Mass spectrum (ES+): Found 570 (MH+). C3IH33F4N3O2 requires 569.
Example 4: 1 -[4-(1 ,1 -Dimethylethyl)phenyl]methyl-Λ/-[3-fIuoro-4-(4- morpholinyl)phenyl]-Λ/-(tetrahydro-2W-pyran-4-ylmethyl)-4-piperidinecarboxamide
Figure imgf000040_0002
1-[4-(1 ,1-Dimethylethyl)phenyl]methyl-4-piperidinecarboxylic acid (D10; 80 mg, 0.29 mmol) was dissolved in dry DCM (2 ml) and dry DMF (2 drops) was added as catalyst.
The solution was cooled to O0C and oxalyl chloride (38 ul, 0.44 mmol) was added. The mixture was stirred at room temperature for 4 h.
The reaction was again cooled at O0C and a solution of 3-fluoro-4-(4-morpholinyl)-Λ/-
(tetrahydro-2H-pyran-4-ylmethyl)aniline (D9; 60 mg, 0.2 mmol) and N,N-diisopropyl- ethylamine (176 ul, 1.01 mmol) in dry DCM (2 ml) was added dropwise.
The mixture was stirred overnight and PS-Trisamine (Argonaut 3 eq). were added. The reaction was shaken for 20 h then the resin was filtered off and the liquid phase washed with satd. aqueous NH4CI (2x4 ml) and NaHCO3 (2x4 ml). The organic layer was evaporated to give a crude oil, which was purified on a 1g Phenomenex silica cartridge with a cyclohexane to EtOAc gradient, to give the title compound (25 mg, 23%).
1HNMR (DMSO) δ: 1.1 (2H, m), 1.3 (9H, s), 1.5 (9H, m), 2.1 (1 H, m), 2.7 (2H, m), 3.05
(4H, m), 3.2 (2H, t), 3.35 (2H, m), 3.5 (2H, d), 3.8 (6H, m), 7.1 (2H, m), 7.15 (2H, d), 7.25
(1 H, d), 7.3 (2H, d).
Mass spectrum (API+): Found 552 (MH+). C33H46FN3O3 requires 551.
The following examples were made in a manner similar to that described in the Examples above.
Figure imgf000041_0001
Figure imgf000041_0002
Figure imgf000042_0001
Figure imgf000043_0001
Example 28: N-[3-Fluoro-4-(4-morpholinyl)phenyl]-N-(phenylmethyl)-1 -[4- (trifluoromethyl)phenyl]-4-piperidinecarboxamide
Figure imgf000044_0001
The title compound (139 mg; 42%) was made from 3-fluoro-4-(4-morpholinyl)-Λ/- (phenylmethyl)aniline (D11; 174 mg, 0.61 mmol) and 1-[4-(trifluoromethyl)phenyl]-4- piperidinecarbonyl chloride (D14; 213 mg, 0.73 mmol) in a similar manner to that described for E1. Mass spectrum (ES+): Found 542 (MH+). C30H31F4N3O2 requires 541.
Example 29: N-[3-Fluoro-4-(4-morpholinyl)phenyl]-1 -[4-(trifluoromethyl)phenyl]-4- piperidinecarboxamide
Figure imgf000044_0002
The title compound (520 mg, 48 %) was made from 3-fluoro-4-(4-morpholinyl)aniline (D2; 478 mg, 2.4 mmol) and 1-[4-(trifluoromethyl)phenyl]-4-piperidinecarbonyl chloride (D14; 843 mg, 2.9 mmol) in a similar manner to that described for D5. Mass spectrum (ES+): Found 452 (MH+). C23H2SF4N3O2 requires 451.

Claims

Claims
1. A compound of formula (1 ) or a salt or solvate thereof:
Figure imgf000045_0001
(1 )
wherein:
• R is hydrogen or C1-8alkyl, or R is a group
Figure imgf000045_0002
wherein R1 is selected from the group consisting of optionally substituted C3- βcycloalkyl, optionally substituted C3.8heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl, and R2 and R3 are independently hydrogen or C1- 8alkyl; • X is nitrogen or a group -CR4 wherein R4 is hydrogen or halogen;
• R5, R6 and R7 are independently selected from hydrogen and halogen;
• R8 and R9 are independently selected from the group consisting of hydrogen, halogen and C1-4alkyl, or R8 and R9 together form a C3-4Cy cloa Iky I;
• Ar is an optionally substituted aryl or an optionally substituted heteroaryl; and • n is 0, 1 , 2 or 3.
2. A compound as claimed in claim 1 , wherein R1 is C3-8cycloalkyl (such as cyclopentyl or cyclohexyl), C3.8heterocyclyl (such as tetrahydropyranyl)or aryl (such as phenyl optionally substituted by one or two groups selected from halogen, C^alkyl and C1-4alkoxy).
3. A compound as claimed in claim 1 or claim 2, wherein R2 and R3 are both hydrogen.
4. A compound as claimed in claim 1 , 2 or 3, wherein X is CR4, and R4, R5 and R6 are hydrogen and R7 is fluorine.
5. A compound as claimed in claim 1 , wherein R is hydrogen.
6. A compound as claimed in any of claims 1-5, wherein Ar is an optionally substituted aryl, such as phenyl optionally substituted by one or two groups selected from C1-4alkyl,
Figure imgf000046_0001
such as CF3, halogen and C3-6cycloalkyl; or Ar is an optionally substituted heteroaryl such as quinolinyl or benzimidazolyl, each of which is optionally substituted by one or two C^alkyl or haloC1-4alkyl such as CF3.
7. A compound as claimed in any of claims 1-6, wherein n is 1.
8. A compound as claimed in any of claims 1-7, wherein R8 and R9 are both hydrogen.
9. A compound as claimed in claim 1, having formula (Ia):
Figure imgf000046_0002
(1a) wherein
• R1 is selected from the group consisting of C3-8cycloalkyl, C3-8heterocyclyl, aryl and heteroaryl; each of which is optionally substituted by one, two or three substituents selected from the group consisting of halogen, oxo, cyano, C-^alkyl, C-|_4alkoxy, haloCi_4alkyl, haloC^alkoxy, arylC<|_4alkoxy, C^alkoxyC^alkyl, C3_6cycloalkyl, Cβ.βcycloalkylC-^alkoxy, C-j_4alkanoyl, C-]_4alkylsulfonyl, C-j^acyl, aryl, arylC-|_ 4alkyl, C^alkylaminoCi^alkyl. a group R12R13N-, R12CON(R13)(CH2)m or R12R13NCO(CH2)m (where each of R12 and R13 is independently selected from hydrogen or C^alkyl, or where appropriate R12R13 forms part of a C3.. βazacycloalkane ring and m is 0, 1 , 2, 3 or 4);
• R2 is hydrogen or methyl;
• n is 0 or 1 ;
• Z is hydrogen, fluorine or chlorine; and
• Ar is phenyl or heteroaryl, each of which is optionally substituted by one, two or three substituents selected from the group consisting of halogen, cyano, Chalky], C-μ 4alkoxy, haloC-|.4alkyl, haloC-|_4alkoxy, Ci_4alkoxyCi_4alkyl, C3_6cycloalkyl, C3. øcycloalkylC-i .43IkOXy1 C-|_4acyl and Ci_4alkylaminoC<|_4alkyl.
10. A compound as claimed in claim 1 , which is: 1. 1-(4-Ethylphenylmethyl)-Λ/-[3-fluoro-4-(4-morpholinyl)phenyl]-/V-(benzyl)-4- piperidinecarboxamide
2. Λ/-[3-Fluoro-4-(4-morpholinyl)phenyl]-Λ/-(benzyl)-1-(4-trifluoromethylphenyl)methyl- 4-piperidinecarboxamide Λ/-[3-Fluoro-4-(4-morpholinyl)phenyl]-Λ/-(1-phenylethyl)-1- {[4-(trifluoromethyl)phenyl]methyl}-4-piperidinecarboxamide 1-[4-(1 ,1- Dimethylethyl)phenyl]methyl-A/-[3-fluoro-4-(4-morpholinyl)phenyl]-Λ/-(tetrahydro-
2H-pyran-4-ylmethyl)-4-piperidinecarboxamide
5. 1-[(4-chlorophenyl)methyl]-N-[3-fluoro-4-(4-morpholinyl)phenyl]-N-(phenylmethyl)- 4-piperidinecarboxamide
6. 1-{[4-(1,1-dimethylethyl)phenyl]methyl}-N-[3-fluoro-4-(4-morpholinyl)phenyl]-N- (phenylmethyl)-4-piperidinecarboxamide
7. N-[3-fluoro-4-(4-morpholinyl)phenyl]-1 -[(1 -methyl-1 H-benzimidazol-2-yl)methyl]-N- (phenylmethyl)-4-piperidinecarboxamide
8. N-[3-fluoro-4-(4-morpholinyl)phenyl]-N-(phenylmethyl)-1-(2-quinolinylmethyl)-4- piperidinecarboxamide 9. N,1-bis[(4-chlorophenyl)methyl]-N-[3-fluoro-4-(4-morpholinyl)phenyl]-4- piperidinecarboxamide
10. N-[(4-chlorophenyl)methyl]-N-[3-fluoro-4-(4-morpholinyl)phenyl]-1 -{[4- (trifluoromethyl)phenyl]methyl}-4-piperidinecarboxamide
11. N-[(4-chlorophenyl)methyl]-1-{[4-(1 ,1-dimethylethyl)phenyl]methyl}-N-[3-fluoro-4- (4-morpholinyl)phenyl]-4-piperidinecarboxamide
12. N-[(4-chlorophenyl)methyl]-N-[3-fluoro-4-(4-morpholinyl)phenyl]-1 -[(1 -methyl-1 H- benzimidazol-2-yl)methyl]-4-piperidinecarboxamide
13. N-[(4-chlorophenyl)methyl]-N-[3-fluoro-4-(4-morpholinyl)phenyl]-1 -(2- quinolinylmethyl)-4-piperidinecarboxamide 14. 1 -[(4-chlorophenyl)methyl]-N-[3-f luoro-4-(4-morpholinyl)phenyl]-N-{[4-
(methyloxy)phenyl]methyl}-4-piperidinecarboxamide 15. N-[3-fluoro-4-(4-morpholinyl)phenyl]-N-{[4-(methyloxy)phenyl]methyl}-1 -{[4-
(trifluoromethyl)phenyl]methyl}-4-piperidinecarboxamide
16. 1-{[4-(1,1-dimethylethyl)phenyl]methyl}-N-[3-fluoro-4-(4-morpholinyl)phenyl]-N-{[4- (methyloxy)phenyl]methyl}-4-piperidinecarboxamide
17. N-[3-fluoro-4-(4-morpholinyl)phenyl]-1 -[(1 -methyl-1 H-benzimidazol-2-yl)methyl]-N- {[4-(methyloxy)phenyl]methyl}-4-piperidinecarboxamide
18. N-[3-fluoro-4-(4-morpholinyl)phenyl]-N-{[4-(methyloxy)phenyl]methyl}-1 -(2- quinolinylmethyl)-4-piperidinecarboxamide
19. 1 -[(4-chlorophenyl)methyl]-N-(cyclopentylmethyl)-N-[3-fluoro-4-(4- morpholinyl)phenyl]-4-piperidinecarboxamide
20. N-(cyclopentylmethyl)-N-[3-fluoro-4-(4-morpholinyl)phenyl]-1-{[4- (trifluoromethyl)phenyl]methyl}-4-piperidinecarboxamide
21. N-(cyclopentylmethyl)-1-{[4-(1 ,1-dimethylethy[)phenyl]methyl}-N-[3-fluoro-4-(4- morpholinyl)phenyl]-4-piperidinecarboxamide
22. N-(cyclopentylmethyl)-N-[3-fluoro-4-(4-morpholinyl)phenyl]-1 -[(1 -methyl-1 H- benzimidazol-2-yl)methyl]-4-piperidinecarboxamide
23. N-(cyclopentylmethyl)-N-[3-fluoro-4-(4-morpholinyl)phenyl]-1-(2-quinolinylmethyl)-
4-piperidinecarboxamide
24. 1-[(4-chlorophenyl)methyl]-N-[3-fluoro-4-(4-morpholinyl)phenyl]-N-(tetrahydro-2H- pyran-4-ylmethyl)-4-piperidinecarboxamide
25. N-[3-fluoro-4-(4-morpholinyl)phenyl]-N-(tetrahydro-2H-pyran-4-ylmethyl)-1-{[4- (trifluoromethyl)phenyl]methyl}-4-piperidinecarboxamide
26. N-[3-fluoro-4-(4-morpholinyl)phenyl]-1 -[(1 -methyl-1 H-benzimidazol-2-yl)methyl]-N- (tetrahydro-2H-pyran-4-ylmethyl)-4-piperidinecarboxamide
27. N-[3-fluoro-4-(4-morpholinyl)phenyl]-1 -(2-quinolinylmethyl)-N-(tetrahydro-2H- pyran-4-ylmethyl)-4-piperidinecarboxamide
28. N-[3-Fluoro-4-(4-morpholinyl)phenyl]-N-(phenylmethyl)-1-[4- (trifluoromethyl)phenyl]-4-piperidinecarboxamide
29. N-[3-Fluoro-4-(4-morpholinyl)phenyl]-1-[4-(trifluoromethyl)phenyl]-4- piperidinecarboxamide or a salt or solvate thereof.
11. A method of preparing a compound as defined in claim 1 , comprising the step of:
(a) reacting a compound of formula (3):
Figure imgf000048_0001
(3)
wherein R5, Rb, R' and X are as defined in claim 1 , with a compound of formula (4):
Figure imgf000049_0001
(4) wherein R8, R9, n and Ar are as defined in claim 1 and L is a leaving group; or
(b) for a compound of formula (1) wherein R is a group -C(R1)(R2)(R3), reacting a compound of formula (9):
Figure imgf000049_0002
wherein R1 to R7 are as defined in claim 1 , with a compound of formula (4) as defined above;
and thereafter optionally for step (a) or step (b):
• removing any protecting groups and/or
• converting a compound of formula (1 ) into another compound of formula (1 ) and/or • forming a salt or solvate.
12. A compound as claimed in any of claims 1-10 for use in therapy.
13. A compound as claimed in any of claims 1-10 for use in the treatment of a disorder mediated by GIyTI . .
14. A compound as claimed in claim 13, wherein the disorder is psychosis, including schizophrenia, dementia or attention deficit disorder.
15. 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 as claimed in any of claims 1-10.
16. A method as claimed in claim 15, wherein the disorder is psychosis, including schizophrenia, dementia or attention deficit disorder. 17. Use of a compound as claimed in any of claims 1-10 in the preparation of a medicament for the treatment of a disorder mediated by GIyTI .
18. Use as claimed in claim 17, wherein the disorder is psychosis, including schizophrenia, dementia or attention deficit disorder.
19. A pharmaceutical composition comprising a compound as claimed in any of claims 1-10, and at least one pharmaceutically acceptable carrier, diluent or excipient.
PCT/EP2005/007136 2004-07-01 2005-06-29 Piperidine derivatives and their use as glycine transporter inhibitors WO2006002956A1 (en)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005058885A2 (en) * 2003-12-18 2005-06-30 Glaxo Group Limited Piperidine derivatives and their use as glycine transporter inhibitors

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005058885A2 (en) * 2003-12-18 2005-06-30 Glaxo Group Limited Piperidine derivatives and their use as glycine transporter inhibitors

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
A. SLASSI, I. EGLE: "Recent progress in the use of glycine transporter-1 inhibitors for the treatment of central and peripheral nervous system diseases", EXPERT OPIN. THER. PATENTS, vol. 14, no. 2, February 2004 (2004-02-01), pages 201-214, XP002345324 *

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