WO2010057865A1 - N- inden- 2 -yl- isopropylsulfonamides as ampa receptor potentiators - Google Patents

Abstract

A compound of formula (I) and salts thereof are provided: Wherein n and R¹ are defined in the specification. Processes for preparation, pharmaceutical compositions, and uses thereof as a medicament, for example in the treatment of a disease or condition mediated by a reduction or imbalance in glutamate receptor function, such as schizophrenia or cognition impairment, are also disclosed.

Description

N-INDEN-2-YL-ISOPROPYLSULFONAMIDES AS AMPA RECEPTOR POTENTIATORS

This invention relates to novel compounds which potentiate the AMPA receptor. The invention also relates to the use of the compounds in treating diseases and conditions mediated by potentiation of the AMPA receptor, compositions containing the derivatives and processes for their preparation.

Glutamate receptors, which mediate the majority of fast excitatory neurotransmission in the mammalian central nervous system (CNS), are activated by the excitatory amino acid, L-glutamate (for review see Watkins JC, Krogsgaard-Larsen P, Honore T (1990) Trends Pharmacol Sci 11 : 25-33).

Glutamate receptors can be divided into two distinct families. The G-protein or second messenger-linked "metabotropic" glutamate receptor family which can be subdivided into three groups (Group I, mGlui and mGlu5; Group II, mGlu2 and mGlu3; Group III, mGlu4, mGluθ, mGlu7, mGluδ) based on sequence homology and intracellular transduction mechanisms (for review see Conn PJ and Pinn JP (1997) Ann Rev Pharmacol Toxicol 37: 205-237). The "ionotropic" glutamate receptor family, which directly couple to ligand-gated cation channels, can be subdivided into at least three subtypes based on depolarizing activation by selective agonists, N-methyl-D-aspartate (NMDA), α-amino-3-hydroxy-5- methylisoxazole-4-propionic acid (AMPA) and kainic acid (KA) (for review see Dingledine R, Borges K, Bowie, Traynelis S (1999) 51 : 7-61 ).

Native AMPA receptors (AMPAR) exist as heterotetramers consisting of combinations of four different protein subunits (GIuRI -4) (for review see Bettler B and Muller C (1995) 34:

123-139.). Receptor subunit diversity is increased further as each subunit can undergo alternative splicing of a 38 amino acid sequence in the extracellular region just before the fourth membrane spanning domain M4. Such editing results in so-called 'flip' and 'flop' receptor isoforms which differ in kinetic and pharmacological properties (Sommer B, Keinanen K, Verdoon TA, Wisden W, Burnashev N, Herb A, Kohler M, Takagi T,

Sakmann B, Seeburg PH (1990) Science 249: 1580-1585).

Additionally, post-transcriptional editing of GluR2 mRNA changes a neutral glutamine to a positively charged arginine within M2. In normal humans >99% GluR2 is edited in this way. AMPAR containing such edited GluR2 subunit exhibit low calcium permeability (Burnachev N, Monyer H, Seeburg PH, Sakmann B (1992) Neuron 8: 189-198). There is a suggestion, however, that the number of AMPAR with high calcium permeability is elevated in certain disease-associated conditions (Weiss JH, and Sensi SL (2000) Trends in Neurosci 23: 365-371 ).

AMPAR depolarization removes voltage dependent Mg ²⁺ block of NMDA receptors which in turn leads to NMDA receptor activation, an integral stage in the induction of Long Term Potentiation ("LTP") (Bliss TVP, Collingridge GL (1993) Nature 361 : 31-9). LTP is a physiological measure of increased synaptic strength following a repetitive stimulus or activity, such as occurs during learning.

It has been reported that direct activation of glutamate receptors by agonists, in conditions where glutamate receptor function is reduced, increases the risk of excitotoxicity and additional neuronal damage. AMPAR positive allosteric modulators do not activate the receptor directly. However, when the ligand (L-glutamate or AMPA) is present AMPAR modulators increase receptor activity. Thus, AMPA receptor modulators enhance synaptic function when glutamate is released and is able to bind at post-synaptic receptor sites.

Compounds which act as AMPAR positive allosteric modulators have been shown to increase ligand affinity for the receptor (Arai A, Guidotti A, Costa E, Lynch G (1996) Neuroreport. 7: 221 1-5.); reduce receptor desensitization and reduce receptor deactivation (Arai AC, Kessler M, Rogers G, Lynch G (2000) 58: 802-813) and facilitate the induction of LTP both in vitro (Arai A, Guidotti A, Costa E, Lynch G (1996) 7: 2211-5.) and in vivo (Staubli U, Perez Y, Xu F, Rogers G, Ingvar M, Stone-Elander S, Lynch G (1994) Proc Natl Acad Sci 91 : 1 1158-1 1162). Such compounds also enhance the learning and performance of various cognitive tasks in rodent (Zivkovic I, Thompson DM, Bertolino M, Uzunov D, DiBeIIa M, Costa E, Guidotti A (1995) JPET 272: 300-309, Lebrun C, Pilliere E, Lestage P (2000) Eu J Pharmacol 401 : 205-212), sub-human primate (Thompson DM, Guidotti A, DiBeIIa M, Costa E (1995) Proc Natl Acad Sci 92: 7667-7671 ) and man (Ingvar M, Ambros-lngerson J, Davis M, Granger R, Kessler M, Rogers GA, Schehr RS, Lynch G (1997) Exp Neurol 146: 553-559). The efficacy of various AMPAR positive allosteric modulators in pre-clinical and clinical models of psychiatric disorders, such as schizophrenia, have been investigated (Morrow J A, Maclean J KF, Jamieson C (2006) Current Opinion in Drug Discovery and Development 9(5) 571-579)

Compounds which act as AMPAR positive allosteric modulators are known, for example in international patent application WO2006/015828.

We have discovered novel compounds which potentiate the AMPA receptor.

In the first aspect, the present invention provides a compound of formula (I) or a salt thereof:

(I) wherein: • n is 0 or 1 ; and

• R¹ is selected from phenyl and pyridyl, each of which is optionally substituted by one or two groups independently selected from Ci_-4alkyl and halogen.

The term "halogen" refers to fluoro, chloro, bromo or iodo.

The term "C_1-4alkyl" refers to an alkyl group having from one to four carbon atoms. Unless otherwise indicated, C_1-4alkyl may be a straight chain or branched alkyl group. For example, a

group may be selected from the group consisting of methyl, ethyl, n- propyl, i-propyl, n-butyl, i-butyl and t-butyl. For example,

is methyl.

In one embodiment, the present invention provides a compound of formula (Ia) or a salt thereof:

(Ia) wherein:

• n is 0 or 1 ; and

• R¹ is pyridyl, optionally substituted by a group selected from

and halogen.

In one embodiment, the compound is selected from the group consisting of:: • Λ/-[2-methyl-5-(2-pyridinyloxy)-2,3-dihydro-1 H-inden-2-yl]-2-propanesulfonamide;

• Λ/-[2-methyl-5-(2-pyridinyloxy)-2,3-dihydro-1 H-inden-2-yl]-2-propanesulfonamide (S enantiomer);

• Λ/-[2-methyl-5-(2-pyridinyloxy)-2,3-dihydro-1 H-inden-2-yl]-2-propanesulfonamide (R enantiomer); and salts thereof.

It will be appreciated that the present invention is intended to include compounds having any combination of the groups listed hereinbefore. It will be understood that, where appropriate, an embodiment described above for one part of the invention may be combined with an embodiment of another part of the invention.

For the avoidance of doubt, unless otherwise indicated, the term "substituted" means substituted by one or more defined groups. In the case where groups may be selected from a number of alternative groups, the selected groups may be the same or different. For the avoidance of doubt, the term "independently" means that where more than one substituent is selected from a number of possible substituents, those substituents may be the same or different. In one embodiment the salt is a pharmaceutically acceptable salt.

In an embodiment there is provided a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof.

Salts of compounds of formula (I) which are suitable for use in medicine are those wherein the counterion is pharmaceutically acceptable. However, salts having non- pharmaceutically acceptable counterions are within the scope of the present invention, for example, for use as intermediates in the preparation of other compounds of formula (I) and their pharmaceutically acceptable salts and/or for use in non-therapeutic, for example, in vitro, situations.

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. Pharmaceutically acceptable salts are particularly suitable for medical applications because of their greater aqueous solubility relative to the parent compounds. Such salts must clearly have a pharmaceutically acceptable anion or cation. Suitably pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts formed with inorganic acids such as hydrochloric, hydrobromic, hydroiodic, phosphoric, metaphosphoric, nitric and sulfuric acids, and with organic acids, such as tartaric, acetic, trifluoroacetic, citric, malic, lactic, fumaric, benzoic, formic, propionic, glycolic, gluconic, maleic, succinic, (1 R)-(-)-10-camphorsulphonic, (1 S)-(+)-10- camphorsulphonic, 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 naphthalene-1 ,5-disulphonic, naphthalene-1 ,3-disulphonic, 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. The salts may have any suitable stoichiometry. For example, a salt may have 1 :1 or 2:1 stoichiometry. Non-integral stoichiometry ratios are also possible.

Solvates of the compounds of formula (I) and solvates of the salts of the compounds of formula (I) are included within the scope of the present invention. As used herein, the term "solvate" refers to a complex of variable stoichiometry formed by a solute (in this invention, a compound of formula (I) or a salt thereof) and a solvent. Those skilled in the art of organic chemistry will appreciate that many organic compounds can form such complexes with solvents in which they are reacted or from which they are precipitated or crystallized. 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, without limitation, water, ethanol and acetic acid. Most preferably the solvent used is water. Where the solvent used is water such a solvate may then also be referred to as a hydrate.

It will be appreciated by those skilled in the art that certain protected derivatives of compounds of formula (I), which may be made prior to a final deprotection stage, may not possess pharmacological activity as such, but may, in certain instances, be administered orally or parenterally and thereafter metabolised in the body to form compounds of the invention which are pharmacologically active. Such derivatives may therefore be described as "prodrugs". Further, certain compounds of the invention may be administered as prodrugs. Examples of pro-drug forms for certain compounds of the present invention are described in Drugs of Today, Volume 19, Number 9, 1983, pp 499 - 538 and in Topics in Chemistry, Chapter 31 , pp 306 - 316 and in "Design of Prodrugs" by H. Bundgaard, Elsevier, 1985, Chapter 1. It will further be appreciated by those skilled in the art, that certain moieties, known to those skilled in the art as "pro-moieties", for example as described by H. Bundgaard in "Design of Prodrugs" may be placed on appropriate functionalities when such functionalities are present within compounds of the invention. Examples of prodrugs for certain compounds of the invention may include: amides, carbamates, azo-compounds, phosphamides, and glycosides.

Hereinafter, compounds of formula (I) (whether in solvated or unsolvated form) or their pharmaceutically acceptable salts (whether in solvated or unsolvated form) or prodrugs thereof defined in any aspect of the invention (except intermediate compounds in chemical processes) are referred to as "compounds of the invention".

Also included within the scope of the invention are polymorphs of a compound of the invention.

The invention also includes all suitable isotopic variations of a compound of the invention. An isotopic variation of a compound of the invention is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine and chlorine such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁷O, ¹⁸O, ³¹P, ³²P, ³⁵S, ¹⁸F and ³⁶CI, respectively. Certain isotopic variations of the invention, for example, those in which a radioactive isotope such as ³H or ¹⁴C is incorporated, are useful in drug and/or substrate tissue distribution studies. Tritiated, i.e., ³H, and carbon-14, i.e., ¹⁴C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with isotopes such as deuterium, i.e., ²H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements and hence may be preferred in some circumstances. Isotopic variations of the compounds of the invention can generally be prepared by conventional procedures such as by the illustrative methods or by the preparations described in the Examples hereafter using appropriate isotopic variations of suitable reagents.

Compounds of the present invention exist in the S and R enantiomeric forms:

The invention includes all such forms, in particular the pure isomeric forms. The different forms (R and S) may be separated or resolved one from the other by conventional methods, or any given isomer may be obtained by conventional synthetic methods or by stereospecific or asymmetric syntheses. It will also be appreciated, in common with most biologically active molecules that the level of biological activity may vary between the individual stereoisomers of a given molecule. It is intended that the scope of the invention includes all individual stereoisomers (diastereoisomers and enantiomers) and all mixtures thereof, including but not limited to racemic mixtures, which demonstrate appropriate biological activity with reference to the procedures described herein.

In one embodiment, the present invention provides a compound of formula (I) or a salt thereof which is enriched in configuration S. In another embodiment, the present invention provides a compound of formula (I) or a salt thereof which is enriched in configuration R. In one embodiment, the isomers correspond to at least 90% enantiomeric excess. In another embodiment the isomers correspond to at least 95% enantiomeric excess. In another embodiment the isomers correspond to at least 99% enantiomeric excess.

Since the compounds of the invention are intended for use in pharmaceutical compositions it will readily be understood that they are each optionally provided in substantially pure form, for example at least 60% pure, for example at least 75% pure or at least 85%, or at least 98% pure (% are on a weight for weight basis). Impure preparations of the compounds may be used for preparing the more pure forms used in the pharmaceutical compositions; these less pure preparations of the compounds should contain at least 1%, or at least 5% or from 10 to 59% of a compound of the invention.

Compounds of the invention may be prepared by methods known in the art of organic synthesis as set forth in part by the following synthesis schemes. In the following reaction schemes and hereafter, unless otherwise stated, all the groups are as defined in the first aspect. 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 the invention.

Scheme 1 below illustrates the preparation of a compound of formula (Ib) by reaction with the appropriate alcohol ArOH Typical reaction conditions comprise microwaving at a suitable temperature, for example 190 ⁰C, a mixture of a compound of formula (II) and the required alcohol in the presence of a suitable copper reagent such as copper (I) iodide, a suitable ligand such as Λ/,Λ/-dimethylglycine, and a suitable base such as caesium carbonate in a suitable solvent such as dimethylsulphoxide for the required time, for example 30 minutes. Alternatively, the above mixture may be heated under argon using a heating block or oil bath for the appropriate time and temperature, for example 30 hours at 130 ⁰C. The preparation of a compound of formula (II) where X=Br is detailed in the experimental section.

Scheme 1

ArOH / Cu reagent / ligand / base / solvent

X = leaving group such as Br Ar = phenyl or pyridyl system

Alternatively, a compound of formula (Ib) may be prepared from a compound of formula (III) by reaction with the appropriate halide ArX according to scheme 2. Typical reaction conditions comprise microwaving at a suitable temperature, for example 190 ⁰C, a mixture of a compound of formula (III) and the required halide, for example 2-bromopyridine, in the presence of a suitable copper reagent such as copper (I) iodide, a suitable ligand such as Λ/,Λ/-dimethylglycine, and a suitable base such as caesium carbonate in a suitable solvent such as dimethylsulphoxide for the required time, for example 30 minutes. Alternatively, the above mixture may be heated under argon using a heating block or oil bath for the appropriate time and temperature, for example 30 hours at 130 ⁰C. The preparation of a compound of formula (III) is detailed in the experimental section.

Scheme 2 group

Ar = phenyl or pyridyl system

A compound of formula (Ic) below may be prepared from a compound of formula (III) by the Mitsunobu reaction with the appropriate alcohol ArCH₂OH according to scheme 3. Typical reaction conditions comprise adding a phosphine reagent such as triphenylphosphine then a suitable azodicarboxylate reagent such as diisopropyl azodicarboxylate to a mixture of a compound of formula (III) and the appropriate alcohol in a suitable solvent such as dichloromethane at a suitable temperature such as ambient under argon and mixing for the required time, such as 16 hours. The preparation of a compound of formula (III) is detailed in the experimental section.

Scheme 3

1 . ArCH₂OH / phosphine

Ar = phenyl or pyridyl system

Salts may be prepared conventionally by reaction with the appropriate acid or acid derivative.

Further details for the preparation of compounds of formula (I) are found in the Examples section hereinafter.

The compounds of the present invention potentiate the AMPA receptor, as measured by the assay below. Compounds which potentiate the AMPA receptor are potentially useful for treating diseases and conditions which are mediated by the potentiation of the glutamate receptor.

The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in medicine.

In one embodiment, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in treating a disease or condition mediated by a reduction or imbalance in glutamate receptor function in a mammal. The present invention also provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one carrier, diluent or excipient.

It will be appreciated that the invention includes the following further aspects. The embodiments described in respect of the first aspect apply equally to each of these further aspects:

i) the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a disease or condition mediated by a reduction or imbalance in glutamate receptor function in a mammal; ii) a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in treating a disease or condition mediated by a reduction or imbalance in glutamate receptor function in a mammal; iii) a method of treatment of a disease or condition mediated by a reduction or imbalance in glutamate receptor function in a mammal comprising administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof; iv) a combination product of a compound of formula (I) or a pharmaceutically acceptable salt thereof with an antipsychotic; v) a pharmaceutical composition comprising a combination product as defined in iv) above and at least one carrier, diluent or excipient; vi) the use of a combination product as defined in iv) above in the manufacture of a medicament for treating a disease or condition mediated by a reduction or imbalance in glutamate receptor function in a mammal; vii) a combination product as defined in iv) above for use in treating a disease or condition mediated by a reduction or imbalance in glutamate receptor function in a mammal; viii) a combination product as defined in iv) above for use as a medicament; ix) a method of treatment of a disease or condition mediated by a reduction or imbalance in glutamate receptor function in a mammal comprising administering an effective amount of a combination product as defined in iv) above.

Relevant diseases or conditions are: psychosis and psychotic disorders (including schizophrenia, schizo-affective disorder, schizophreniform diseases, brief reactive psychosis, child onset schizophrenia, "schizophrenia-spectrum" disorders such as schizoid or schizotypal personality disorders, acute psychosis, alcohol psychosis, drug- induced psychosis, autism, delerium, mania (including acute mania), manic depressive psychosis, hallucination, endogenous psychosis, organic psychosyndrome, paranoid and delusional disorders, puerperal psychosis, and psychosis associated with neurodegenerative diseases such as Alzheimer's disease); substance related disorders (including alcohol-related disorders and nicotine-related disorders); cognitive impairment (e.g. the treatment of impairment of cognitive functions including attention, orientation, memory (i.e. memory disorders, amnesia, amnesic disorders and age-associated memory impairment) and language function, and including cognitive impairment as a result of stroke, Alzheimer's disease, Aids-related dementia or other dementia states, as well as other acute or sub-acute conditions that may cause cognitive decline such as delirium or depression (pseudodementia states) trauma, aging, 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, post-electroconvulsive treatment related cognitive disorders; anxiety disorders (including generalised anxiety disorder, social anxiety disorder, agitation, tension, social or emotional withdrawal in psychotic patients, panic disorder, and obsessive compulsive disorder); neurodegenerative diseases (such as Alzheimer's disease, amyotrophic lateral sclerosis, motor neurone disease and other motor disorders such as Parkinson's disease (including relief from locomotor deficits and/or motor disability, including slowly increasing disability in purposeful movement, tremors, bradykinesia, hyperkinesia (moderate and severe), akinesia, rigidity, disturbance of balance and co-ordination, and a disturbance of posture), dementia in Parkinson's disease, dementia in Huntington's disease, neuroleptic-induced Parkinsonism and tardive dyskinesias, neurodegeneration following stroke, cardiac arrest, pulmonary bypass, traumatic brain injury, spinal cord injury or the like, and demyelinating diseases such as multiple sclerosis and amyotrophic lateral sclerosis); depression (which term includes bipolar (manic) depression (including type I and type II), unipolar depression, single or recurrent major depressive episodes with or without psychotic features, catatonic features, melancholic features, atypical features (e.g. lethargy, over-eating/obesity, hypersomnia) or postpartum onset, seasonal affective disorder and dysthymia, depression-related anxiety, psychotic depression, and depressive disorders resulting from a general medical condition including, but not limited to, myocardial infarction, diabetes, miscarriage or abortion); posttraumatic stress syndrome; attention deficit disorder; attention deficit hyperactivity disorder; drug-induced (phencyclidine, ketamine and other dissociative anaesthetics, amphetamine and other psychostimulants and cocaine) disorders; Huntingdon's chorea; tardive dyskinesia; dystonia; myoclonus; spasticity; obesity; stroke; sexual dysfunction; sleep disorders and some forms of epilepsy.

Within the context of the present invention, the terms describing the indications 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). Treatment of the various subtypes of the disorders mentioned herein using a compound of the present invention is contemplated as part of the present invention. Numbers in brackets after the listed diseases below refer to the classification code in DSM-IV.

Within the context of the present invention, the term "psychotic disorder" includes :- 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).

Compounds of the invention may also be of use in the treatment of the following disorders:-

Depression and 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 (31 1 ); 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):

Anxiety disorders including Panic Attack; Panic Disorder including Panic Disorder without Agoraphobia (300.01 ) and Panic Disorder with Agoraphobia (300.21 ); Agoraphobia; Agoraphobia Without History of Panic Disorder (300.22), Specific Phobia (300.29, formerly Simple Phobia) including the subtypes Animal Type, Natural Environment Type, Blood-lnjection-lnjury Type, Situational Type and Other Type), Social Phobia (Social Anxiety Disorder, 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, Separation Anxiety Disorder (309.21 ), Adjustment Disorders with Anxiety (309.24) and Anxiety Disorder Not Otherwise Specified (300.00):

Substance-related disorders including Substance Use Disorders such as Substance Dependence, Substance Craving and Substance Abuse; Substance-Induced Disorders such as Substance Intoxication, Substance Withdrawal, Substance-Induced Delirium,

Substance-Induced Persisting Dementia, Substance-Induced Persisting Amnestic Disorder, Substance-Induced Psychotic Disorder, Substance-Induced Mood Disorder, Substance-Induced Anxiety Disorder, Substance-Induced Sexual Dysfunction, Substance- Induced Sleep Disorder and Hallucinogen Persisting Perception Disorder (Flashbacks); Alcohol-Related Disorders such as Alcohol Dependence (303.90), Alcohol Abuse (305.00), Alcohol Intoxication (303.00), Alcohol Withdrawal (291.81 ), Alcohol Intoxication Delirium, Alcohol Withdrawal Delirium, Alcohol-Induced Persisting Dementia, Alcohol- Induced Persisting Amnestic Disorder, Alcohol-Induced Psychotic Disorder, Alcohol- Induced Mood Disorder, Alcohol-Induced Anxiety Disorder, Alcohol-Induced Sexual Dysfunction, Alcohol-Induced Sleep Disorder and Alcohol-Related Disorder Not Otherwise Specified (291.9); Amphetamine (or Amphetamine-I_ike)-Related Disorders such as Amphetamine Dependence (304.40), Amphetamine Abuse (305.70), Amphetamine Intoxication (292.89), Amphetamine Withdrawal (292.0), Amphetamine Intoxication Delirium, Amphetamine Induced Psychotic Disorder, Amphetamine-Induced Mood Disorder, Amphetamine-Induced Anxiety Disorder, Amphetamine-Induced Sexual Dysfunction, Amphetamine-Induced Sleep Disorder and Amphetamine-Related Disorder Not Otherwise Specified (292.9); Caffeine Related Disorders such as Caffeine Intoxication (305.90), Caffeine-Induced Anxiety Disorder, Caffeine-Induced Sleep Disorder and Caffeine-Related Disorder Not Otherwise Specified (292.9); Cannabis-Related Disorders such as Cannabis Dependence (304.30), Cannabis Abuse (305.20), Cannabis Intoxication (292.89), Cannabis Intoxication Delirium, Cannabis-lnduced Psychotic Disorder, Cannabis-lnduced Anxiety Disorder and Cannabis-Related Disorder Not Otherwise Specified (292.9); Cocaine-Related Disorders such as Cocaine Dependence (304.20), Cocaine Abuse (305.60), Cocaine Intoxication (292.89), Cocaine Withdrawal (292.0), Cocaine Intoxication Delirium, Cocaine-Induced Psychotic Disorder, Cocaine-Induced Mood Disorder, Cocaine-Induced Anxiety Disorder, Cocaine-Induced Sexual Dysfunction, Cocaine-Induced Sleep Disorder and Cocaine-Related Disorder Not Otherwise Specified (292.9); Hallucinogen-Related Disorders such as Hallucinogen Dependence (304.50), Hallucinogen Abuse (305.30), Hallucinogen Intoxication (292.89), Hallucinogen Persisting Perception Disorder (Flashbacks) (292.89), Hallucinogen Intoxication Delirium, Hallucinogen-Induced Psychotic Disorder, Hallucinogen-Induced Mood Disorder, Hallucinogen-Induced Anxiety Disorder and Hallucinogen-Related Disorder Not Otherwise Specified (292.9); Inhalant-Related Disorders such as Inhalant Dependence (304.60), Inhalant Abuse (305.90), Inhalant Intoxication (292.89), Inhalant Intoxication Delirium, Inhalant-Induced Persisting Dementia, Inhalant-Induced Psychotic Disorder, Inhalant- Induced Mood Disorder, Inhalant-Induced Anxiety Disorder and Inhalant-Related Disorder Not Otherwise Specified (292.9); Nicotine-Related Disorders such as Nicotine Dependence (305.1 ), Nicotine Withdrawal (292.0) and Nicotine-Related Disorder Not Otherwise Specified (292.9); Opioid-Related Disorders such as Opioid Dependence (304.00), Opioid Abuse (305.50), Opioid Intoxication (292.89), Opioid Withdrawal (292.0), Opioid Intoxication Delirium, Opioid-lnduced Psychotic Disorder, Opioid-lnduced Mood Disorder, Opioid-lnduced Sexual Dysfunction, Opioid-lnduced Sleep Disorder and Opioid- Related Disorder Not Otherwise Specified (292.9); Phencyclidine (or Phencyclidine-Like)- Related Disorders such as Phencyclidine Dependence (304.60), Phencyclidine Abuse (305.90), Phencyclidine Intoxication (292.89), Phencyclidine Intoxication Delirium, Phencyclidine-lnduced Psychotic Disorder, Phencyclidine-lnduced Mood Disorder, Phencyclidine-lnduced Anxiety Disorder and Phencyclidine-Related Disorder Not Otherwise Specified (292.9); Sedative-, Hypnotic-, or Anxiolytic-Related Disorders such as Sedative, Hypnotic, or Anxiolytic Dependence (304.10), Sedative, Hypnotic, or Anxiolytic Abuse (305.40), Sedative, Hypnotic, or Anxiolytic Intoxication (292.89), Sedative, Hypnotic, or Anxiolytic Withdrawal (292.0), Sedative, Hypnotic, or Anxiolytic Intoxication Delirium, Sedative, Hypnotic, or Anxiolytic Withdrawal Delirium, Sedative-, Hypnotic-, or Anxiolytic-Persisting Dementia, Sedative-, Hypnotic-, or Anxiolytic- Persisting Amnestic Disorder, Sedative-, Hypnotic-, or Anxiolytic-lnduced Psychotic Disorder, Sedative-, Hypnotic-, or Anxiolytic-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:

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, in particular sleep disturbances associated with such diseases as neurological disorders, neuropathic pain, restless leg syndrome, heart and lung diseases; and Substance-Induced Sleep Disorder including the subtypes Insomnia Type, Hypersomnia Type, Parasomnia Type and Mixed Type; sleep apnea and jet-lag syndrome:

Autism Spectrum Disorders including Autistic Disorder (299.00), Asperger's Disorder (299.80), Rett's Disorder (299.80), Childhood Disintegrative Disorder (299.10) and Pervasive Disorder Not Otherwise Specified (299.80, including Atypical Autism).

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):

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):

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, e.g. Alzheimer's disease: and

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).

All of the various forms and sub-forms of the disorders mentioned herein are contemplated as part of the present invention.

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.

In one embodiment, the present invention provides a compound of the invention for use in treating schizophrenia or impairment of cognition.

In one embodiment, the present invention provides a use of a compound of the invention in the manufacture of a medicament for treating schizophrenia or impairment of cognition.

In one embodiment, the present invention provides a method of treating schizophrenia or impairment of cognition in a human, comprising administering an therapeutically effective amount of a compound of the present invention, alone or combined with a pharmaceutically acceptable carrier, dilutent or excipient.

The compounds of the invention may be used in combination with one or more of the following agents to treat psychotic disorders: i) antipsychotics (such as olanzapine, risperidone, clozapine, ziprazidone, talnetant); ii) drugs for extrapyramidal side effects, for example anticholinergics (such as benztropine, biperiden, procyclidine, trihexyphenidyl), antihistamines (such as diphenhydramine), dopaminergics (such as amantadine); iii) antidepressants; iv) anxiolytics; v) cognitive enhancers for example cholinesterase inhibitors (such as tacrine, donepezil, rivastigmine,galantamine).

The compounds of the invention may be used in combination with antidepressants to treat depression and mood disorders.

The compounds of the invention may be used in combination with one or more of the following agents to treat bipolar disease: i) mood stabilisers; ii) antipsychotics; iii) antidepressants.

The compounds of the invention may be used in combination with one or more of the following agents to treat anxiety disorders: i) anxiolytics; ii) antidepressants.

The compounds of the invention may be used in combination with one or more of the following agents to improve nicotine withdrawal and reduce nicotine craving: i) nicotine replacement therapy, for example a sublingual formulation of nicotine beta-cyclodextrin and nicotine patches; ii) drugs for treating nicotine addition, for example bupropion. The compounds of the invention may be used in combination with one or more of the following agents to improve alcohol withdrawal and reduce alcohol craving: i) NMDA receptor antagonists for example acamprosate; ii) GABA receptor agonists for example tetrabamate; iii) Opioid receptor antagonists for example naltrexone.

The compounds of the invention may be used in combination with one or more of the following agents to improve opiate withdrawal and reduce opiate craving: i) opioid mu receptor agonist/opioid kappa receptor antagonist for example buprenorphine; ii) opioid receptor antagonists for example naltrexone; iii) vasodilatory antihypertensives for example lofexidine.

The compounds of the invention may be used in combination with one or more of the following agents to treat sleeping disorders: i) benzodiazepines for example temazepam, lormetazepam, estazolam, triazolam; ii) non-benzodiazepine hypnotics for example Zolpidem, zopiclone, zaleplon, indiplon; iii) barbiturates for example aprobarbital, butabarbital, pentobarbital, secobarbita, phenobarbital; iv) antidepressants; v) other sedative-hypnotics for example chloral hydrate, chlormethiazole.

The compounds of the invention may be used in combination with one or more of the following agents to treat anorexia: i) appetite stimulants for example cyproheptidine; ii) antidepressants; iii) antipsychotics; iv) zinc; v) premenstrual agents for example pyridoxine and progesterones.

The compounds of the invention may be used in combination with one or more of the following agents to treat bulimia: i) antidepressants; ii) opioid receptor antagonists; iii) antiemetics for example ondansetron; iv) testosterone receptor antagonists for example flutamide; v) mood stabilisers; vi) zinc; vii) premenstrual agents.

The compounds of the invention may be used in combination with one or more of the following agents to treat autism: i) antipsychotics; ii) antidepressants; iii) anxiolytics; iv) stimulants for example methylphenidate, amphetamine formulations, pemoline.

The compounds of the invention may be used in combination with one or more of the following agents to treat Attention Deficit Hyperactivity Disorder: i) stimulants for example methylphenidate, amphetamine formulations, pemoline; ii) non-stimulants for example norepinephrine reuptake inhibitors (such as atomoxetine), alpha 2 adrenoceptor agonists (such as clonidine), antidepressants, modafinil, cholinesterase inhibitors (such as galantamine and donezepil).

The compounds of the invention may be used in combination with one or more of the following agents to treat personality disorders: i) antipsychotics; ii) antidepressants; iii) mood stabilisers; iv) anxiolytics. The compounds of the invention may be used in combination with one or more of the following agents to treat male sexual dysfunction: i) phosphodiesterase V inhibitors, for example vardenafil, sildenafil; ii) dopamine agonists/dopamine transport inhibitors for example apomorphine, buproprion; iii) alpha adrenoceptor antagonists for example phentolamine; iv) prostaglandin agonists for example alprostadil; v) testosterone agonists such as testosterone; vi) serotonin transport inhibitors for example serotonin reuptake inhibitors; v) noradrenaline transport inhibitors for example reboxetine; vii) 5-HT1A agonists, for example flibanserine.

The compounds of the invention may be used in combination with one or more of the following agents to treat female sexual dysfunction: i) the same agents specified for male sexual dysfunction, ii) an estrogen agonist such as estradiol.

Antipsychotic drugs include Typical Antipsychotics (for example chlorpromazine, thioridazine, mesoridazine, fluphenazine, perphenazine, prochlorperazine, trifluoperazine, thiothixine, haloperidol, molindone and loxapine); and Atypical Antipsychotics (for example clozapine, olanzapine, risperidone, quetiapine, aripirazole, ziprasidone, amisulpride, ziprazidone and talnetant).

Antidepressant drugs include serotonin reuptake inhibitors (such as citalopram, escitalopram, fluoxetine, paroxetine and sertraline); dual serotonin/noradrenaline reuptake inhibitors (such as venlafaxine, duloxetine and milnacipran); Noradrenaline reuptake inhibitors (such as reboxetine); tricyclic antidepressants (such as amitriptyline, clomipramine, imipramine, maprotiline, nortriptyline and trimipramine); monoamine oxidase inhibitors (such as isocarboxazide, moclobemide, phenelzine and tranylcypromine); and others (such as bupropion, mianserin, mirtazapine, nefazodone and trazodone).

Mood stabiliser drugs include lithium, sodium valproate/valproic acid/divalproex, carbamazepine, lamotrigine, gabapentin, topiramate and tiagabine.

Anxiolytics include benzodiazepines such as alprazolam and lorazepam.

The compounds of the invention may be administered in conventional dosage forms prepared by combining a compound of the invention with standard pharmaceutical carriers or diluents according to conventional procedures well known in the art. These procedures may involve mixing, granulating and compressing or dissolving the ingredients as appropriate to the desired preparation.

The pharmaceutical compositions of the invention may be formulated for administration to mammals including humans. The compositions may be formulated for administration by any route. The compositions may be formulated for oral, topical, or parenteral administration, and may be in the form of tablets, capsules, powders, granules, lozenges, creams or liquid preparations, such as oral or sterile parenteral solutions or suspensions.

The topical formulations of the present invention may be presented as, for instance, ointments, creams or lotions, eye ointments and eye or ear drops, impregnated dressings and aerosols, and may contain appropriate conventional additives such as preservatives, solvents to assist drug penetration and emollients in ointments and creams.

The formulations may also contain compatible conventional carriers, such as cream or ointment bases and ethanol or oleyl alcohol for lotions. Such carriers may be present as from about 1 % up to about 98% of the formulation. More usually they will form up to about 80% of the formulation.

Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants, for example potato starch; or acceptable wetting agents such as sodium lauryl sulphate. The tablets may be coated according to methods well known in normal pharmaceutical practice. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives, such as suspending agents, for example sorbitol, methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and, if desired, conventional flavouring or colouring agents.

Suppositories will contain conventional suppository bases, e.g. cocoa-butter or other glyceride.

For parenteral administration, fluid unit dosage forms are prepared utilising the compound and a sterile vehicle, for example water. The compound, depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions the compound can be dissolved in water for injection and filter sterilised before filling into a suitable vial or ampoule and sealing. Agents such as a local anaesthetic, preservative and buffering agents can be dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum. The dry lyophilised powder is then sealed in the vial and an accompanying vial of water for injection may be supplied to reconstitute the liquid prior to use. Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilisation cannot be accomplished by filtration. The compound can be sterilised by exposure to ethylene oxide before suspending in the sterile vehicle. A surfactant or wetting agent may be included in the composition to facilitate uniform distribution of the compound.

It will be recognised by one of skill in the art that the optimal quantity and spacing of individual dosages of a compound of the invention will be determined by the nature and extent of the condition being treated, the form, route and site of administration, and the particular mammal being treated, and that such optimums can be determined by conventional techniques. It will also be appreciated by one of skill in the art that the optimal course of treatment, i.e. the number of doses of a compound of the invention given per day for a defined number of days, can be ascertained by those skilled in the art using conventional course of treatment determination tests.

It is to be understood that "treatment" as used herein includes prophylaxis as well as alleviation of established symptoms. In one embodiment, the mammal to be treated is a human.

The invention is illustrated by the Examples described below.

Starting materials were obtained from commercial suppliers and used without further purification unless otherwise stated. Flash chromatography was carried out using prepacked lsolute Flash™ or Biotage™ silica-gel columns as the stationary phase and analytical grade solvents as the eluent unless otherwise stated.

NMR spectra were obtained at 298K, 303.2K or 300K, at the frequency stated using either a Bruker™ DPX400 or AV400 machine and run as a dilute solution of CDCI₃ unless otherwise stated. All NMR spectra were referenced to tetramethylsilane (TMS 5_H 0, δc 0). All coupling constants are reported in hertz (Hz), and multiplicities are labelled s (singlet), bs (broad singlet), d (doublet), t (triplet), q (quartet), dd (doublet of doublets), dt (doublet of triplets), td (triplet of doublets), ddd (double-double-doublet) and m (multiplet).

All quoted retention times are as measured using LC/MS (Liquid Chromatography/Mass Spectrometry). Where appropriate, these retention times were used as a guide for purification using mass-directed auto-purification (MDAP), which refers to purification by HPLC, wherein fraction collection is triggered by detection of the programmed mass ion for the compound of interest.

Total ion current traces were obtained for electrospray positive and negative ionisation (ES+ / ES-) and/or atmospheric pressure chemical positive and negative ionisation (AP+ / AP-).

Where reactions are described as having been carried out in a similar manner to earlier, more completely described reactions, the general reaction conditions used were essentially the same. Work up conditions used were of the types standard in the art, but may have been adapted from one reaction to another. The starting material may not necessarily have been prepared from the batch referred to. Unless otherwise stated, all compounds with chiral centre(s) are racemic.

Abbreviations

TEA Triethylamine

TMS-CI Trimethylsilyl chloride ss saturated solution

TFA Trifluoroacetic acid

DAD Diode Array Detector

CD Circular dichroism a/a% percentage by area unde the curve

LC/MS Liquid Chromatography / Mass Spectrometry

NMR Nuclear Magnetic Resonance

SCX strong cationic exchange

THF Tetrahydrofuran

DMSO Dimethylsulfoxide

DMF Dimethylformamide

DCM / MDC Dichloromethane / Methylene dichloride

CDI 1 ,1 '-Carbonyldiimidazole

LDA Lithium diisopropylamide

EDC 1-ethyl-3-(dimethylaminopropyl)carbodiimide

MsCI Methanesulfonyl chloride

AcOH Acetic acid

HOAt 1 -hydroxy-7-azabenzotriazole

HOBt 1 -hydroxybenzotriazole

Pd on C Palladium on Charcoal

MeCN Acetonitrile

MDAP Mass-directed auto-purification

DBU 1 ,8-diazabicyclo[5.4.0]undec-7-ene

ES electrospray min(s) minute(s) PdCI₂(dppf) 1 ,1'-bis(diphenylphosphino)ferrocene palladium dichloride ppm parts per million degC degrees Celsius

Analytical chromatographic conditions

One of the following methods were used for the LC/MS analysis:

Method 1

Column: Waters Atlantis, 4.6mm x 50mm. The stationary phase particle size is

3um. Solvents: A : Aqueous solvent = Water + 0.05% Formic Acid;

B : Organic solvent = Acetonitrile + 0.05% Formic Acid Methods: 5 minute runtime.

Time / min %B

0 3

0.1 3

4 97

4.8 97

4.9 3

5.0 3

Flow rate: 3ml/min

Injection volume: 5μl

Column temperature: 30 degC

UV wavelenqth ranqe : 220-330 nm

Method 1 - high pH version - as above, except:

- Column: Waters X-Bridge 4.6mm x 50mm. The stationary phase particle size is

3.5μm.

A : Aqueous solvent = 1OmM Ammonium Bicarbonate solution adjusted to pH 10 with ammonia solution.

B : Organic solvent = Acetonitrile.

Method 2

Column: Waters Acquity BEH UPLC C18, 2.1 mm x 50mm. The stationary phase particle size is 1.7μm.

Solvents

A : Aqueous solvent = Water + 0.05% Formic Acid

B : Organic solvent = Acetonitrile + 0.05% Formic Acid

Weak Wash = 1 :1 Methanol : Water

Strong Wash = Water

The generic method used has a 2 minute runtime.

• The above method has a flow rate of 1 ml/min.

• The injection volume for the generic method is 0.5ul

• The column temperature is 40degC

• The UV detection range is from 220 to 330nm

MDAP conditions

Column: Waters Atlantis, 19mm x 100mm (small scale) and 30mm x 100mm

(large scale). Stationary phase particle size = 5um.

Solvents: A : Aqueous solvent = Water + 0.1% Formic Acid; B : Organic solvent = Acetonitrile + 0.1% Formic Acid. Make up solvent =

Methanol : Water 80:20. Needle rinse solvent = Methanol

Methods: There are five methods used depending on the analytical retention time of the compound of interest. They have a 13.5-minute runtime, which comprises of a 10-minute gradient followed by a 3.5 minute column flush and re-equilibration step.

Large/Small Scale 1.0-1.5 = 5-30% B

Large/Small Scale 1.5-2.2 = 15-55% B

Large/Small Scale 2.2-2.9 = 30-85% B

Large/Small Scale 2.9-3.6 = 50-99% B

Large/Small Scale 3.6-5.0 = 80-99% B (in 6 minutes followed by 7.5 minutes flush and re-equilibration)

Flow rate: 20mls/min (Small Scale) or 40mls/min (Large Scale).

High pH MDAP - as above, except for:

Column: Waters X-bridge, 30mm x 100mm. The stationary phase particle size is

5μm.

A : Aqueous solvent = 1OmM Ammonium Bicarbonate solution adjusted to pH 10 with ammonia solution.

B : Organic solvent = Acetonitrile.

Make up solvent = Methanol : Water 80:20

Needle rinse solvent = Methanol

Description 1 : Methyl 2-[3-(methyloxy)-3-oxopropyl]benzoate

A suspension of 2-carboxycinnamic acid (1.Og, 5.21 mmol) in methanol (70ml) was stirred at 50 ⁰C and treated with concentrated sulphuric acid (5 drops). After 1.5 hours a solution had been obtained and this was then hydrogenated at standard temperature and pressure over 10% palladium on charcoal (0.2Og, wet paste) for 3 days. The catalyst was removed by filtration and the filtrate evaporated to afford an oil which was shown to be mainly the mono-ester by LC/MS. This material was redissolved in methanol (70ml) and saturated with HCI gas with ice-cooling. After standing at room temperature overnight the solvent was removed under reduced pressure and the residue partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate solution. The aqueous layer was extracted with ethyl acetate and the combined organic layers dried over MgSO₄ and evaporated to give methyl 2-[3-(methyloxy)-3-oxopropyl]benzoate as a yellow oil (1.15g, 100%).

¹H-NMR (400MHz, CDCI₃): δ 7.92 (1 H, d, J = 8.0 Hz), 7.44 (1 H, dd, J = 8.0 and 8.0 Hz), 7.29 (2H, d, J = 8.0 Hz), 3.90 (3H, s), 3.67 (3H, s), 3.28 (2H, t, J = 7.6 Hz), 2.68 (2H, t, J = 7.6 Hz).

Description 2: Methyl 1-oxo-2,3-dihydro-1H-indene-2-carboxylate

A solution of methyl 2-[3-(methyloxy)-3-oxopropyl]benzoate (3.77g, 16.98mmol, Description 1 ) in dry THF (75 ml) under argon was stirred during the addition of sodium hydride (2.04g of 60% suspension in oil, 50.9mmol) over 2 minutes. The mixture was then slowly heated to reflux. After 1 hour at reflux a thick paste had formed. This was cooled to room temperature and treated dropwise with water (1 ml) added over 5 minutes. The resulting slurry was acidified with 5M hydrochloric acid (20ml) and extracted twice with ethyl acetate. The combined organics were dried over MgSO₄ and evaporated to afford an oil which was chromatographed on silica gel (7Og). Elution with 0-50% ethyl acetate in pentane gave methyl 1-oxo-2,3-dihydro-1 H-indene-2-carboxylate as a yellow oil (2.14g, 66%), which solidified on standing. ¹H-NMR (400MHz, CDCI₃): δ 7.79 (1 H, d, J = 7.6 Hz), 7.63 (1 H, dd, J = 7.6 and 7.6 Hz), 7.50 (1 H, d, J = 7.6 Hz), 7.42 (1 H, dd, J = 7.6 and 7.6 Hz), 3.80 (3H, s), 3.75 (1 H, m), 3.60 (1 H, m), 3.40 (1 H, m).

Description 3: Methyl 2-methyl-1-oxo-2,3-dihydro-1H-indene-2-carboxylate

A solution of methyl 1-oxo-2,3-dihydro-1 H-indene-2-carboxylate (2.14g, 11.26mmol, Description 2) in dry THF (40ml) was stirred under argon and cooled in a water bath. Sodium hydride (496mg of a 60% suspension in oil, 12.39mmol) was now added in portions over 2 minutes and the resulting suspension stirred for a further 45 minutes, lodomethane (772 ul, 12.39mmol) was added over 5 minutes and the mixture stirred for 18 hours. The solvent was removed under reduced pressure and the residue partitioned between ethyl acetate and excess dilute aqueous hydrochloric acid. The organic layer was dried and evaporated to give a dark oil which was chromatographed on silica gel (5Og). Elution with 0-40% ethyl acetate in pentane gave methyl 2-methyl-1-oxo-2,3- dihydro-1 H-indene-2-carboxylate as a yellow oil (2.19g, 95%).

¹H-NMR (400MHz, CDCI₃): δ 7.80 (1 H, d, J = 7.6 Hz), 7.64 (1 H, dd, J = 7.6 and 7.6 Hz), 7.49 (1 H, d, J = 7.6 Hz), 7.40 (1 H, dd, J = 7.6 and 7.6 Hz), 3.72 (1 H, d, J = 17.3 Hz), 3.69 (3H, s), 3.00 (1 H, d, J = 17.3 Hz), 1.53 (3H, s).

Description 4: Methyl 1 -hydroxy-2-methyl-2,3-dihydro-1H-indene-2-carboxylate

A solution of methyl 2-methyl-1-oxo-2,3-dihydro-1H-indene-2-carboxylate (2.19g, 10.74mmol, Description 3) in methanol (15ml) was stirred under argon and treated with sodium borohydride (245mg, 6.44mmol) added portionwise over 10 minutes. The reaction mixture was stirred at room temperature overnight and the solvent removed under reduced pressure. The residue was partitioned between ethyl acetate and water and the organic layer dried over MgSO₄ and evaporated under reduced pressure to afford methyl 1-hydroxy-2-methyl-2,3-dihydro-1 H-indene-2-carboxylate as a yellow oil (2.14g, 100%). ¹H-NMR (400MHz, CDCI₃): major diastereomer δ 7.38 - 7.18 (4H, d, overlapping m), 5.48 (1 H, d, J = 4.8 Hz), 3.78 (3H, s), 3.32 (1 H, d, J = 15.6 Hz), 2.85 (1 H, d, J = 15.6 Hz), 2.26 (1 H, d, J = 4.8 Hz), 1.25 (3H, s).

Description 5: 2-Methyl-2,3-dihydro-1H-indene-2-carboxylic acid

A solution of methyl 1-hydroxy-2-methyl-2,3-dihydro-1H-indene-2-carboxylate (2.14g, 10.39mmol, Description 4) in acetic acid (100ml), containing concentrated hydrochloric acid (20ml), was hydrogenated at 3 atmospheres and room temperature for 3 days. The reaction mixture was filtered through kieselguhr and evaporated under reduced pressure to give a white solid. This material was chromatographed on silica gel (5Og), eluting with

0-80% ethyl acetate in pentane, to give 2-methyl-2,3-dihydro-1H-indene-2-carboxylic acid as a white solid (1.63g, 89%).

¹H-NMR (400MHz, CDCI₃): δ 7.18 (4H, overlapping m), 3.52 (2H, d, J = 15.6 Hz), 2.85 (2H, d, J = 15.6 Hz), 1.41 (3H, s).

Description 6: 2-Methyl-2,3-dihydro-1H-inden-2-amine hydrochloride

A stirred solution of 2-methyl-2,3-dihydro-1 H-indene-2-carboxylic acid (1.63g, 9.26mmol, Description 5) in acetone (15ml) was cooled to O⁰C and treated with triethylamine (1.47ml, 10.46mmol) followed by the dropwise addition of ethyl chloroformate (1.00ml, 10.46mmol). The reaction mixture was stirred for 40 minutes at O⁰C. A solution of sodium azide (903mg, 13.89mmol) in water (5ml) was then added dropwise over 1 minute and stirring at O⁰C continued for a further 1 hour. The cooled suspension was then partitioned between ethyl acetate and saturated brine and the aqueous layer extracted with further ethyl acetate. The combined organic layers were dried over MgSO₄ and evaporated to give an oil. A solution of this oil in toluene (10ml) was heated to 100⁰C for 20 minutes beyond the point at which nitrogen evolution ceased. The solvent was then removed and the residue heated to reflux in 5M hydrochloric acid (20ml) overnight. On cooling the reaction mixture was diluted with water and the insoluble material extracted with ethyl acetate. The organic layer was dried over MgSO₄ and evaporated to afford recovered starting material (550mg, 34%). The aqueous reaction mixture was evaporated to dryness under reduced pressure to afford 2-methyl-2,3-dihydro-1 H-inden-2-amine hydrochloride as a white powder (870mg, 51%). ¹H-NMR (400MHz, DMSO-d₆): δ 8.42 (3H, broad s), 7.26 (2H, overlapping m), 7.19 (2H, overlapping m), 3.20 (2H, d, J = 16.4 Hz), 2.99 (2H, d, J = 16.4 Hz), 1.44 (3H, s).

Description 7: 5-Bromo-2-methyl-2,3-dihydro-1H-inden-2-amine

A stirred solution of 2-methyl-2,3-dihydro-1 H-inden-2-amine hydrochloride (0.93g, 5.07mmol, Description 6) in water (9ml) was heated to 6O⁰C and treated dropwise with bromine (286ul, 5.57mmol) over 10 minutes. The reaction mixture was then stirred at 6O⁰C for 1 hour and at room temperature for a further 1 hour. The solution was basified by the addition of 2M aqueous sodium hydroxide solution (4ml) and then extracted twice with ethyl acetate. The combined extracts were dried over MgSO₄ and evaporated to give crude 5-bromo-2-methyl-2,3-dihydro-1H-inden-2-amine as a pale oil (0.92g, 80%).

¹H-NMR (400MHz, CDCI₃): δ 7.32 (1 H, s), 7.16 (1 H, m), 7.05 (1 H, d, J = 8.0 Hz), 3.00 - 2.76 (4H, overlapping m), 1.70 (2H, broad s), 1.37 (3H, s).

Description 8: Λ/-(5-bromo-2-methyl-2,3-dihydro-1H-inden-2-yl)-2- propanesulfonamide

A solution of 5-bromo-2-methyl-2,3-dihydro-1 H-inden-2-amine (0.92g, 4.07mmol, Description 7) in dry DCM (15ml) under argon was cooled to O⁰C and stirred during the dropwise addition of DBU (1.82ml, 12.21 mmol) followed by isopropylsulphonyl chloride

(909ul, 8.14mmol). The reaction mixture was stirred at room temperature overnight, washed twice with water, and dried over MgSO₄. Removal of the solvent under reduced pressure gave a crude product which was chromatographed on silica gel (5Og). Elution with 0-50% ethyl acetate in pentane gave Λ/-(5-bromo-2-methyl-2,3-dihydro-1 H-inden-2- yl)-2-propanesulfonamide as a pale solid (1.09g, 81 %).

LC/MS (ES): Found 332 & 330 (M-H⁺), retention time 3.19mins. C₁₃H₁₈NO₂SBr requires 333 & 331. 1H-NMR (400MHz, CDCI₃): δ 7.33 (1 H, s), 7.29 (1 H, d, J = 8.4 Hz), 7.06 (1 H, d, J = 8.4 Hz), 4.14 (1 H, broad s), 3.26 -2.94 (5H, overlapping m), 1.56 (3H, s), 1.32 (6H, m). Description 9: Λ/-[2-methyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-2,3- dihydro-1H-inden-2-yl]-2-propanesulfonamide

A stirred suspension of /V-(5-bromo-2-methyl-2,3-dihydro-1 H-inden-2-yl)-2- propanesulfonamide (97mg, 0.29mmol, Description 8), bis-(pinacolato)diboron (89mg, 0.35mmol), Pd(dppf)CI₂ (12mg, 5 mol%) and potassium acetate (85mg, 0.87mmol) in dry DMSO was kept at 9O⁰C overnight. LC/MS showed about 50% conversion to product so further bis-(pinacolato)diboron (89mg, 0.35mmol) and Pd(dppf)CI₂ (12mg, 5 mol%)was added and heating continued at 9O⁰C for a further 3 hours. LC/MS indicated that reaction was essentially complete so the cooled reaction was partitioned between ethyl acetate (50ml) and water (30ml). The aqueous layer was extracted with further ethyl acetate and the combined organic layers were washed three times with water, dried over MgSO₄ and evaporated to give the crude product as a black oil. Chromatography on silica gel (1Og) eluting with 0-50% ethyl acetate in pentane gave Λ/-[2-methyl-5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-2,3-dihydro-1 H-inden-2-yl]-2-propanesulfonamide (91 mg, 83%).

¹H-NMR (400MHz, CDCI₃): δ 7.64 (1 H, s), 7.63 (1 H, m), 7.17 (1 H, m), 4.10 (1 H, broad s), 3.28 (1 H, d, J = 16.0 Hz), 3.20 (1 H, d, J = 16.2 Hz), 3.05 (3H, overlapping m), 1.56 (3H, s), 1.34 - 1.21 (18H, overlapping m).

Description 10: Λ/-(5-hydroxy-2-methyl-2,3-dihydro-1H-inden-2-yl)-2- propanesulfonamide

Λ/-[2-methyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-2,3-dihydro-1 H-inden-2-yl]-2- propanesulfonamide (1.07g, 2.82mmol, Description 9) in methanol (20ml) was stirred at room temperature and a solution of 30% hydrogen peroxide in water (0.58ml, 5.64mmol) was added. The reaction was stirred under argon at room temperature for 18 hours. The volatile components were removed under reduced pressure and the residue partitioned between DCM and water. The aqueous layer was extracted with further DCM and the combined organics dried over MgSO₄ and evaporated to afford the crude product as a solid. This material was chromatographed on silica gel (7Og), eluting with 0-50% ethyl acetate/pentane, to afford Λ/-(5-hydroxy-2-methyl-2,3-dihydro-1 H-inden-2-yl)-2- propanesulfonamide as a white solid (383mg, 50%).

¹H-NMR (400MHz, CDCI₃): δ 7.02 (1 H, d, J = 8.0 Hz), 6.68 (1 H, d, J = 2 Hz), 6.64 (1 H, dd, J = 8.0 and 2 Hz), 4.82 (1 H, s), 4.17 (1 H, s), 3.22 - 3.05 (3H, overlapping m), 2.95 (2H, overlapping m), 1.60 (3H, s), 1.31 (6H, m).

Example 1 : rac-Λ/-[2-methyl-5-(2-pyridinyloxy)-2,3-dihydro-1H-inden-2-yl]-2- propanesulfonamide

A mixture of Λ/-(5-hydroxy-2-methyl-2,3-dihydro-1 H-inden-2-yl)-2-propanesulfonamide (228 mg, 0.846 mmol, Description 10), 2-bromopyridine (134 mg, 0.846 mmol), copper iodide (177 mg, 0.931 mmol), cesium carbonate (827 mg, 2.54 mmol) and N, N- dimethylglycine (105 mg, 1.016 mmol) in DMSO (3ml) was heated at 13O⁰C on a heating block for 30 hours and cooled. The reaction mixture was diluted with DCM and water and filtered through kieselguhr. The filtrate was separated and the organic layer washed with water (2x), dried over MgSO₄ and evaporated to provide crude product (208mg). This was purified by MDAP to give rac-Λ/-[2-methyl-5-(2-pyridinyloxy)-2,3-dihydro-1 H-inden-2-yl]-2- propanesulfonamide as an oil (92 mg, 28%).

LC/MS (ES): Found 347 (MH⁺), retention time 2.93mins. Ci₈H₂₂N₂O₃S requires 346.

¹H-NMR (400MHz, CDCI₃): δ 8.18 (1 H, m), 7.68 (1 H, m), 7.20 (1 H, d, J= 8.0Hz), 6.98 (3H, overlapping m), 6.90 (1 H, d, J = 8.0 Hz), 4.20 (1 H, s), 3.24 (2H, overlapping d), 3.10 (1 H, m), 3.00 (2H, overlapping d), 1.63 (3H, s), 1.33 (6H, d, J = 6.8 Hz).

Example 2: Λ/-[2-methyl-5-(2-pyridinyloxy)-2,3-dihydro-1 H-inden-2-yl]-2- propanesulfonamide (faster running enantiomer)

The racemic Λ/-[2-methyl-5-(2-pyridinyloxy)-2,3-dihydro-1 H-inden-2-yl]-2- propanesulfonamide (128 mg) was submitted for chiral resolution on a chiralcel OD column eluting with methanol : carbon dioxide (10:90) to give the fast running enantiomer (26 mg).

LC/MS (ES): Found 347 (MH⁺), retention time 2.91 mins. Ci₈H₂₂N₂O₃S requires 346. 1H-NMR (400MHz, CDCI₃): δ 8.18 (1 H, m), 7.68 (1 H, m), 7.20 (1 H, d, J= 8.0Hz), 6.98 (3H, overlapping m), 6.90 (1 H, d, J = 8.0 Hz), 4.20 (1 H, s), 3.24 (2H, overlapping d), 3.10 (1 H, m), 3.00 (2H, overlapping d), 1.63 (3H, s), 1.33 (6H, d, J = 6.8 Hz).

Example 3: Λ/-[2-methyl-5-(2-pyridinyloxy)-2,3-dihydro-1 H-inden-2-yl]-2- propanesulfonamide (slower running enantiomer)

The racemic Λ/-[2-methyl-5-(2-pyridinyloxy)-2,3-dihydro-1 H-inden-2-yl]-2- propanesulfonamide (128 mg) was submitted for chiral resolution on a chiralcel OD column eluting with methanol : carbon dioxide (10:90) to give the slow running enantiomer (25 mg).

LC/MS (ES): Found 347 (MH⁺), retention time 2.91 mins. Ci₈H₂₂N₂O₃S requires 346. 1H-NMR (400MHz, CDCI₃): δ 8.18 (1 H, m), 7.68 (1 H, m), 7.20 (1 H, d, J= 8.0Hz), 6.98 (3H, overlapping m), 6.90 (1 H, d, J = 8.0 Hz), 4.20 (1 H, s), 3.24 (2H, overlapping d), 3.10 (1 H, m), 3.00 (2H, overlapping d), 1.63 (3H, s), 1.33 (6H, d, J = 6.8 Hz).

The ability of the compounds of the invention to potentiate AMPA may be determined by the assays below. In the assays used and described herein, the compounds of the present invention were not necessarily from the same batch described above. A test compound from one batch may have been combined with other batch(es) for the assay(s).

Calcium Influx Fluorescence Assay

384 well plates are prepared containing confluent monolayer of HEK 293 cells stably expressing human GluR2 flip (unedited) AMPA receptor subunit.

On the day of the experiment, culture medium are discarded and the cells washed three times with standard buffer (145 mM NaCI, 5 mM KCI, 1 mM MgCI2, 2 mM CaCI2, 20 mM N-[2-hydroxyethyl]-piperazine-N-[2-ethanesulfonic acid (HEPES), 5.5 mM glucose, pH 7.3) and 20 μl_ of buffer remained in each well after washing. The plates are then incubated at room temperature for 60 minutes in the dark with 2 μM FLUO-4AM dye to allow cell uptake of the FLUO-4AM, which is then converted to FLUO-4 by intracellular esterases which is unable to leave the cells. After incubation cells are washed three times with buffer and 30 μl_ of buffer remained in each well after washing. Compounds of the invention are tested in a final assay concentration range from 50 μM to 50 nM.

Compounds of the invention (or a reference compound such as Λ/-[(2/?)-2-(4'-cyano-4- biphenylyl)propyl]-2-propanesulfonamide) are dissolved in dimethylsulfoxide (DMSO) at a stock concentration of 10 mM. These solutions are further diluted with DMSO in a 384 compound plate and 1 μl_ of each dilution is transferred to another compound plate. Just prior compounds addition to the cells, 50 μl_ pluronic buffer (standard buffer with 0.05% pluronic-F127 acid) is added to the 1 μl_ compound copy plate.

An agonist stimulus 384-well plate containing 50μl_/well of 500 μM glutamate is prepared by diluting with pluronic buffer (standard buffer with 0.05% pluronic-F127 acid) a 100 mM sodium glutamate stock solution prepared in water.

10 μl_ from each plate containing a compound of the invention made up in compound buffer solution is added and incubated with the loaded cells for 10 minute in the dark at room temperature.

The cell plate is then transferred into a fluorescence imaging plate based reader (such as the FLIPR384 - Molecular Devices). A baseline fluorescence reading is taken over a 5 to 10 second period, and then 10 μL of 500 μM glutamate solution is added (to give a final concentration of 100 μM). The fluorescence is then read over a 4-5 minute period.

The activities of the compounds of the invention and reference compounds are determined by measuring peak fluorescence after the last addition. The activity is also expressed relative to the fluorescence increase induced by 5μM Λ/-[(2/?)-2-(4'-cyano-4- biphenylyl)propyl]-2-propanesulfonamide at their maximum response.

The assay described above is believed to have an effective limit of detection of a pEC₅₀ in the region of 3.5-4.0 due to the limitations of compound solubility. The pEC₅o result is generally considered to be accurate +/- 0.3.

All the Example compounds were screened using the assay described above and gave a pEC₅₀ equal to or greater than 4.0 and/or demonstrated an activity of on average at least 10% that of Λ/-[(2/?)-2-(4'-cyano-4-biphenylyl)propyl]-2-propanesulfonamide (at its maximal response).

Claims

Claims

1. A compound of formula (I) or a salt thereof:

(I) wherein:

• n is 0 or 1 ; and

• R¹ is selected from phenyl and pyridyl, each of which is optionally substituted by one or two groups independently selected from C_1-4alkyl and halogen.

2. A compound as claimed in claim 1 , which is:

• Λ/-[2-methyl-5-(2-pyridinyloxy)-2,3-dihydro-1 H-inden-2-yl]-2-propanesulfonamide

• Λ/-[2-methyl-5-(2-pyridinyloxy)-2,3-dihydro-1 H-inden-2-yl]-2-propanesulfonamide (S enantiomer) • Λ/-[2-methyl-5-(2-pyridinyloxy)-2,3-dihydro-1 H-inden-2-yl]-2-propanesulfonamide (R enantiomer) or a salt thereof.

3. A compound as claimed in claim 1 or claim 2 wherein the salt is a pharmaceutically acceptable salt.

4. A compound as claimed in claim 3 for use as a medicament.

5. A compound as claimed in claim 3 for use in the treatment of a disease or condition caused by a reduction or imbalance in glutamate receptor function in a mammal.

6. A compound as claimed in claim 3 for use in the treatment of schizophrenia.

7. A pharmaceutical composition comprising a compound as defined in claim 3 and at least one pharmaceutically acceptable carrier or diluent.

8. A combination product comprising a compound as defined in claim 3 and an antipsychotic.

9. Use of a compound as defined in claim 3, or a composition as defined in claim 7, or a product as defined in claim 8, in the manufacture of a medicament for treating or preventing a disease or a condition caused by a reduction or imbalance in glutamate receptor function.

10. Use as claimed in claim 9 wherein the disease is schizophrenia.

11. A method of treating a disease or condition caused by a reduction or imbalance in glutamate receptor function in a mammal comprising administering an effective amount of a compound as defined in claim 3, or a composition as defined in claim 7, or a product as defined in claim 8.

12. A method as claimed in claim 1 1 wherein the disease is schizophrenia.