WO2008148836A1 - Compounds which potentiate ampa receptor and uses thereof in medicine - Google Patents

Abstract

Compound of formula (I) and salts thereof are provided: Wherein R1, R2, R4 and R5 are as 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

Compounds which potentiate AMPA receptor and uses thereof in medicine

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 wherein the potentiation of the AMPA receptor would be beneficial, 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), -amino-3-hydroxy-5- methylisoxazole-4-propionic acid (AMPA) and kainic acid (KA) (for review see Dingledine R, Borges K, Bowie, Traynelis S (1999) Pharmacol Rev. 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 MuIIe C (1995) Neuropharmacology 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 WO/2007/107539. 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:

R¹ is methyl and R² is halogen; or R¹ is selected from cyclopropyl and haloC_1-4alkyl, and R² is selected from hydrogen and halogen; R₄ and R₅ are:

(i) independently C_1-4alkyl, wherein one of the alkyl is optionally substituted by hydroxy; or

(ii) R₄ is hydrogen and R₅ is Ci_-4alkylsulfonyl; or

(iii) R₄ and R₅, together with the nitrogen atom to which they are attached, form a 4, 5 or 6-membered saturated or unsaturated heterocyclic ring, wherein one of the carbon atoms is optionally replaced by sulphur, and which ring is optionally substituted by one or two groups selected from C_1-4alkyl, C(O)C_{1- 4}alkyl, halo, haloC_1-4alkyl, hydroxy and oxo.

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. An atom may be substituted by more than one substituent. 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. It will be appreciated that the present invention is intended to include compounds having any combination of the groups listed hereinbefore.

The term "halogen", "halo" and "Hal" are interchangeable and refer to fluoro, chloro, bromo or iodo.

The term "C_1-6alkyl" refers to an alkyl group having from one to six carbon atoms; and the term "C_1-4alkyl" refers to an alkyl group having from one to four carbon atoms. Unless otherwise indicated, Ci_-4alkyl or

may be a straight chain or branched alkyl group. For example, a C_1-4alkyl group may be selected from the group consisting of methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl or t-butyl. A C_1-6alkyl group may be selected from the group consisting of a Ci_-4alkyl group, sec-pentyl, n-pentyl, isopentyl, tert-pentyl and hexyl. For example, C_1-4alkyl is methyl. "Me" refers to methyl. The terms "haloC_1-6alkyl" and "haloC_1-4alkyl" refer to a C_1-6alkyl or C_1-4alkyl group as defined above which is substituted with any number of fluorine, chlorine, bromine, or iodine atoms, including with mixtures of those atoms. A haloalkyl group may, for example contain 1 , 2 or 3 halogen atoms. For example, a haloC_1-6alkyl or a haloC_1-4alkyl group may have all hydrogen atoms replaced with halogen atoms. Examples of haloalkyl groups include fluoromethyl, difluoromethyl and trifluoromethyl.

The term "C_1-4alkylsulfonyl" refers to a Ci_-4alkyl group linked by a sulfonyl group.

The term "4, 5 or 6-membered saturated or unsaturated heterocyclic ring wherein one of the carbon atoms in the ring is optionally replaced by sulfur" as used in the definition of R₄ and R₅ refers to a saturated or unsaturated ring formed by 4, 5 or 6 atoms, including the nitrogen atom to which R₄ and R₅ are attached, wherein one of the other atoms in the ring may be sulfur. Examples of 4, 5 or 6-membered saturated or unsaturated heterocyclic ring wherein one of the carbon atoms in the ring is optionally replaced by sulfur include azetidinyl, pyrrolidinyl, piperidinyl, thiazolidinyl, isothiazolidinyl, and thiomorpholinyl.

"CO" and "C(=O)" are interchangeable and represent a carbonyl group. The term "oxo" refers to the group "=O".

In one embodiment, R¹ is methyl and R² is halogen. In one embodiment, R¹ is methyl and R² is chloro.

In one embodiment, R¹ is selected from cyclopropyl and haloC_1-4alkyl, and R² is selected from hydrogen and halogen. In one embodiment, R¹ is cyclopropyl or CF₃, and R² is hydrogen, fluoro or chloro.

In one embodiment, R₄ and R₅ are independently C_1-4alkyl, wherein one of the alkyl is optionally substituted by hydroxy.

In one embodiment, R₄ is hydrogen and R₅ is C_1-4alkylsulfonyl. In one embodiment, R₄ is hydrogen and R₅ is methylsulfonyl.

In one embodiment, R₄ and R₅, together with the nitrogen atom to which they are attached, form a 4, 5 or 6-membered saturated or unsaturated heterocyclic ring wherein one of the carbon atoms in the ring is optionally replaced by sulfur, and which ring is optionally substituted by one or two groups selected from C_1-4alkyl, C(O)C_1-4alkyl, halo, haloCi_₄alkyl, hydroxy and oxo. In one embodiment, R₄ and R₅, together with the nitrogen atom to which they are attached, form a pyrrolidinyl group optionally substituted by oxo; azetidinyl group optionally substituted by oxo; and isothiazolidinyl, optionally substituted by two oxo groups. 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.

Examples of compounds of formula (I) include:

1-({4-[5-cyclopropyl-3-(trifluoromethyl)-1 /-/-pyrazol-1-yl]phenyl}methyl)-2-pyrrolidinone 1-({4-[3,5-bis(trifluoromethyl)-1 H-pyrazol-1-yl]phenyl}methyl)-2-pyrrolidinone 2-({4-[4-chloro-5-methyl-3-(trifluoromethyl)-1 H-pyrazol-1-yl]phenyl}methyl)cyclopentanone and salts thereof.

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, (1S)-(+)-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 (the disclosures in which documents are incorporated herein by reference). It will further be appreciated by those skilled in the art, that certain moieties, known to those skilled in the art as "pro-moieties", for example as described by H. Bundgaard in "Design of Prodrugs" (the disclosure in which document is incorporated herein by reference) may be placed on appropriate functionalities when such functionalities are present within compounds of the invention. Examples of prodrugs for certain compounds of the invention include: esters, carbonate esters, hemi-esters, phosphate esters, nitro esters, sulfate esters, sulfoxides, amides, carbamates, azo-compounds, phosphamides, glycosides, ethers, acetals and ketals.

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.

Certain compounds of formula (I) are capable of existing in stereoisomeric forms (e.g. geometric (or "cis-trans") isomers, diastereomers and enantiomers) and the invention extends to each of these stereoisomeric forms and to mixtures thereof including racemates. The different stereoisomeric forms may be separated one from the other by the usual methods, or any given isomer may be obtained by stereospecific or asymmetric synthesis. The invention also extends to any tautomeric forms and mixtures thereof. The present invention includes within its scope all such isomers, including mixtures. It will be appreciated, in common with most biologically active molecules that the level of biological activity may vary between the enantiomers of a given molecule.

In one embodiment a compound of the invention in chiral form has at least 80% e.e. In another embodiment, a compound of the invention in chiral form has at least 90% e.e., for example at least 95% e.e. In another embodiment the isomers correspond to at least 98% e.e, for example at least 99% e.e.

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.

Compounds of the invention may be prepared in a variety of ways. These processes form further aspects of the invention. In the following schemes, unless otherwise stated, the substituents in the compounds shown have the same definition as for formula (I). 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.

The present invention also provides a process for the manufacture of a compound of formula (I) or a salt or solvate thereof, which process comprises coupling a compound of formula (II):

(H)

wherein L is a leaving group and R₄ and R₅ are as defined for formula (I); with a compound of formula (III):

wherein R₁ and R₂ are as defined for formula (I); and thereafter optionally: - removing any protecting groups; and/or

- forming a salt or solvate; and/or

- converting a compound of formula (I) or a salt or solvate thereof to another compound of formula (I) or a salt or solvate thereof.

In the above reaction, L is a leaving group such as iodine. Typical coupling conditions comprise heating a compound of formula (II), a compound of formula (III), a base (such as potassium carbonate), copper (I) iodide with N,N-dimethylglycine in dimethylsulfoxide at 180degC in a microwave reactor for 40 minutes. Compounds of formula (II) can be prepared in a manner similar to that described below in scheme 3. Compounds of formula (III) are commercially available.

A compound of formula (IV), wherein Z is a carbonyl or a sulfonyl group and R¹ and R² are as defined in formula (I), can be prepared by the sulfonylation or acylation of a compound of formula (V) followed by base mediated cyclisation according to reaction scheme 2. Typical reaction conditions comprise addition of a compound of formula (Vl) to a solution of a compound of formula (V) and triethylamine in dimethylformamide. Sodium hydride (available as a 60% suspension in mineral oil) is added in excess and the whole mix stirred until cyclisation is complete. Compounds of formula (V) can be prepared in a manner similar to that described below in scheme 4. Compounds of formula (Vl) are either commercially available or may be made using conventional chemistry.

Scheme 2

An intermediate compound of formula (VII) can be prepared by alkylation of a secondary amide of formula HNR₄R₅ with an alkylhalide compound of formula (VIII) according to reaction scheme 3. Typical alkylation conditions comprise treatment of a compound of formula HNR₄R₅ with a suitable base such as sodium hydride (available as a 60% suspension in mineral oil) in dimethylformamide, followed by the addition of the alkylating agent (VIII). In one embodiment, R₄ and R₅ together with the nitrogen atom to which they are attached form a 4, 5, or 6-membered heterocyclic ring wherein one of the carbon atoms is substituted by oxo. Compounds of formula (VIII) are commercially available.

Scheme 3

(VIII) (VII)

An intermediate compound of formula (V) can be prepared by the reduction of a compound of formula (IX) according to reaction scheme 4. Typical reduction conditions comprise treating a solution of lithium aluminium hydride [LiAIH₄] in tetrahydrofuran (THF) with a compound of formula (IX) in THF solution and stirring at ambient temperature until complete reduction. Compounds of formula (IX) can be prepared in a manner similar to that described below in scheme 5.

Scheme 4 LiAIH. / THF

An intermediate compound of formula (X) can be prepared by the condensation of a compound of formula (Xl) with hexafluoroacetylacetone (XII) according to reaction scheme 5. Typical condensation conditions comprise the vigorous heating of a compound of formula (Xl) with hexafluoroacetylacetone (XII) and concentrated sulphuric acid in ethanol at 1 10-160degC using conventional or microwave methods. The compounds of formula (Xl) and (XII) are commercially available.

Scheme 5

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

The compounds of the invention may be prepared singly or as compound libraries comprising at least 2, for example 5 to 1 ,000 compounds, for example 10 to 100 compounds. Libraries of compounds of the invention may be prepared by a combinatorial 'split and mix' approach or by multiple parallel synthesis using either solution phase or solid phase chemistry, by procedures known to those skilled in the art. Thus according to a further aspect there is provided a compound library comprising at least 2 compounds of the invention.

The compounds of the present invention potentiate the AMPA receptor. Compounds which potentiate the AMPA receptor may be useful for treating diseases and conditions which are mediated by or caused by a reduction or imbalance in glutamate receptor function, and which therefore benefit from the potentiation of the AMPA receptor.

Thus the present invention provides a compound of the invention for use as a medicament.

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 the invention 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 the invention 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 the invention; iv) a combination product of a compound of formulathe invention 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.

In the case of aspects i), ii), iii), vi), vii), viii) and ix), 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); post-traumatic 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 are 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 (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):

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).

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 treatment of schizophrenia or impairment of cognition, comprising administering an effective amount of a compound of the invention.

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 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.

The invention is illustrated by the Examples described below.

Starting materials, reagents and solvents were obtained from commercial suppliers and used without further purification unless otherwise stated. Flash chromatography was carried out using pre-packed lsolute Flash™ or Biotage™ silica-gel columns as the stationary phase and analytical grade solvents as the eluent. Unless otherwise stated, all compounds with chiral centre(s) are racemates.

NMR spectra were obtained at 298K, at the frequency stated using either a Bruker™ DPX400 or an Oxford Instruments™ 250 MHz machine and run as a dilute solution of CDCI3 unless otherwise stated. All NMR spectra were reference to tetramethylsilane (TMS δ_H 0, δ_c 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) and m (multiplet).

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

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-preparation (MDAP), which refers to purification by HPLC, wherein fraction collection is triggered by detection of the programmed mass ion for the compound of interest.

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. All reactions were either carried out under argon or may be carried out under argon, unless otherwise stated. Compounds synthesised may have various purities ranging from for example 85% to 98%. However, calculations of number of moles and yield are generally not adjusted for this. 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).

LC/MS conditions

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: The generic method used has a 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: 5ul

Column temperature: 30 degC

UV wavelenqth ranqe : 220-330 nm

MDAP conditions

Column: Waters Atlantis, 19mrr

(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 5

Abbreviations

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 Chromatography column supplied by Varian™

THF Tetrahydrofuran

DMSO Dimethylsulfoxide

DMF Dimethylformamide

DCM / MDC Dichloromethane / Methylene dichloride

AcOH Acetic acid

MeCN Acetonitrile

MDAP Mass-directed auto-preparation

In the procedures that follow, the starting material may not necessarily have been prepared from the batch referred to. All reactions were either carried out under argon or may be carried out under argon, unless otherwise stated.

Description 1 : 1-[(4-iodophenyl)methyl]-2-pyrrolidinone

A solution of 2-pyrrolidinone (3.15g, 37.1 mmol) in dimethylformamide (130ml) was cooled in an ice/methanol bath with stirring under an atmosphere of argon. Then a solid suspension of sodium hydride (60% in mineral oil, 1.48g, 37.0mmol) was added portionwise over 10 minutes. The reaction mix was allowed to stir with cooling for 30 minutes, then 4-iodobenzyl bromide (10g, 33.7mmol) was added portionwise over 10 minutes. The whole mix was allowed to warm slowly up to room temperature then stirred for a further 3 hours. The reaction mixture was partitioned between dichloromethane (150ml) and water (100ml), the aqueous layer was washed a second time with dichloromethane (100ml), the combined organic layers were removed and washed with water (3 x 100ml) then brine (100ml). The organic layer was dried over sodium sulphate and evaporated under reduced pressure to give the title compound as a yellow solid (9.98g, 98%).

¹ H-NMR (400MHz, CDCI₃) δ: 7.65 (2H, m), 7.00 (2H, m), 4.39 (2H, s), 3.25 (2H, m), 2.44 (2H, m), 2.00 (2H, m); LC/MS Retention time 2.57mins/(ES+) 302 (M+H, C₁₁H₁₂INO requires 301 ).

Description 2: 4-[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]benzonitrile

To a round bottom flask fitted with a reflux condenser was added hexafluoroacetylacetone (2.45g, 11.8mmol) and concentrated sulphuric acid (0.3ml) in ethanol (15ml), then 4- cyanophenyl hydrazine hydrochloride was added portionwise. The reaction mixture was heated at 11 O⁰C for 24 hours and then heated in a microwave reactor at 16O⁰C for 5 minutes. Reaction mixture was neutralized with saturated sodium bicarbonate, extracted with dichloromethane, the organic layer dried over sodium sulphate and the solvent was removed by rotary evaporation. The desired product was isolated by column chromatography on silica using 5-70% ethyl acetate in n-pentane to give the title compound as a crude product (3.37g, 93% yield).

¹ H-NMR (400MHz, CDCI₃) δ: 7.85 (2H, m), 7.69 (2H, m), 7.13 (1 H, s); LC/MS Retention time 3.27mins/(ES+) 306 (M+H, C₁₂H₅F₆N₃ requires 305).

Description 3: ({4-[3,5-bis(trifluoromethyl)-1H-pyrazol-1 -yl]phenyl}methyl)amine

Tetrahydrofuran (THF) (30ml) and lithium aluminium hydride (22ml, 22mmol, 1 M solution in THF) were stirred in an ice bath under argon. A solution of 4-[3,5-bis(trifluoromethyl)- 1H-pyrazol-1-yl]benzonitrile (3.359g, 11 mmol) in THF (40ml) was added dropwise over 15 minutes. The ice bath was removed and the reaction mixture was allowed to stir at room temperature for 1.5 hr. The reaction mixture was cooled in an ice bath and quenched with water dropwise. The solvent was removed by rotary evaporation and residual material was diluted with dichloromethane and water. Insoluble solid was filtered and the organic layer was separated, washed with brine, dried over sodium sulphate and evaporated. The desired product was isolated by SCX column, eluted initially with dichloromethane, methanol and then the desired product was eluted with 1 M ammonia solution in methanol. Solvent was removed by rotary evaporation to give the title compound as a yellow oil (2.22g, 65%).

¹ H-NMR (400MHz, CDCI₃) δ: 7.45 (4H, m), 7.06 (1 H, s), 3.98 (2H, s); LC/MS Retention time 2.01 mins/(ES+) 310 (M+H, C₁₂H₉F₆N₃ requires 309).

Example 1 : 1 -({4-[5-cyclopropyl-3-(trifluoromethyl)-1 H-pyrazol-1 -yl]phenyl}methyl)- 2-pyrrolidinone

A mixture of copper (I) iodide (27mg, 10mol%), 5-cyclopropyl-3-(trifluoromethyl)-1 H- pyrazole (250mg, 1.42mmol), potassium carbonate (392mg, 2.84mmol) in DMSO (2ml) was prepared, then 1-[(4-iodophenyl)methyl]-2-pyrrolidinone (427mg, 1.42mmol) and N, N- dimethylglycine (29mg, 20mol%) was successively added. The reaction tube was quickly sealed and the contents were heated in a microwave reactor at 18O⁰C for 40 minutes. The reaction mixture was diluted with ethyl acetate and filtered through kieselguhr to remove catalyst. The filtrate was washed with brine then dried over sodium sulphate. The solvent was removed by rotary evaporation and the desired product was isolated by MDAP to give the title compound as a white solid (289mg, 58%).

¹ H-NMR (400MHz, CDCI₃) δ: 7.58 (2H, m), 7.37 (2H, m), 6.20 (1 H, s), 4.52 (2H, s), 3.29 (2H, m), 2.47 (2H, m), 2.03( 2H, m), 1.79 (1 H, m), 1.04 ( 2H, m) 0.80 (2H, m); LC/MS Retention time 3.05mins/(ES+) 350 (M+H, Ci₈H₁₈F₃N₃O requires 349).

Example 2: 1 -({4-[3,5-bis(trifluoromethyl)-1 H-pyrazol-1 -yl]phenyl}methyl)-2- pyrrolidinone

A solution of ({4-[3,5-bis(trifluoromethyl)-1 /-/-pyrazol-1-yl]phenyl}methyl)amine (400mg, 1.29mmol) and triethylamine (0.36ml, 2.59mmol) in dimethylformamide (10ml) was treated with 4-chlorobutyryl chloride (182mg, 1.29mmol) dropwise over 10 minutes with stirring under argon. This mixture was stirred for 30minut.es before being treated with sodium hydride (60% in mineral oil; 155mg, 3.88mmol) portionwise and the whole mixture stirred at room temperature for a long weekend. Then further sodium hydride (60% in mineral oil; 155mg, 3.88mmol) was added portionwise and the whole mixture stirred at room temperature overnight. The reaction mixture was partitioned between water and dichloromethane. The organic layer was dried over sodium sulphate and evaporated. The desired product was isolated by MDAP to give the title compound as a white solid (82mg, 17%).

¹ H-NMR (400MHz, CDCI₃) δ: 7.47 (2H, d, J=8Hz ), 7.39 (2H, d, J=8Hz), 7.07 (1 H, s), 4.54 (2H, s), 3.29 (2H, m), 2.47 (2H, m), 2.03( 2H, m); LC/MS Retention time 3.08mins/(ES+) 378 (M+H, C₁₆H₁₃F₆N₃O requires 377).

Example 3: 2-({4-[4-chloro-5-methyl-3-(trifluoromethyl)-1 H-pyrazol-1 - yl]phenyl}methyl)cyclopentanone

A mixture of copper (I) iodide (13mg, 10mol%), 4-chloro-5-methyl-3-(trifluoromethyl)-1 H- pyrazole (123mg, 0.66mmol), potassium carbonate (184mg, 1.33mmol) in DMSO (3ml) was prepared, then 1-[(4-iodophenyl)methyl]-2-pyrrolidinone (200mg, 0.66mmol) and N, N- dimethylglycine (13mg, 20mol%) was successively added. The reaction tube was quickly sealed and the contents were heated in a microwave reactor at 18O⁰C for 40 minutes. The reaction mixture was diluted with ethyl acetate and filtered through kieselguhr to remove catalyst. The filtrate was washed with brine then dried over sodium sulphate. The solvent was removed by rotary evaporation and the desired product was isolated by MDAP to give the title compound as an oil (49mg, 21%). ¹ H-NMR (400MHz, CDCI3) δ:7.39 (4H, appr s), 4.52 (2H, s ), 3.29 (2H, m), 2.47 (2H, m), 2.32 (3H, s), 2.03( 2H, m); LC/MS Retention time 3.00mins/(ES+) 358 (M+H, C₁₆H₁₅ ³⁵CIF₃N₃O requires 357).

Biological Assay

The ability of the compounds of the invention to potentiate AMPA was determined by the assay below. In the assay 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).

384 well plates were prepared containing confluent monolayer of HEK 293 cells either stably expressing or transiently transfected with human GluR2 flip (unedited) AMPA receptor subunit. These cells formed functional homotetrameric AMPA receptors. The tissue culture medium in the wells were discarded and the wells each washed three times with standard buffer (80 μl_) for the stable cell line (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) or with a Na-free buffer for the transient transfected cells (145 mM N-methyl-glucamine instead of NaCI). The plates were then incubated for 60 minutes in the dark with 2 μM FLUO4-AM dye (20 μl_) (Molecular Probes, Netherlands) at room temperature to allow cell uptake of the FLUO-4AM, which was then converted to FLUO-4 by intracellular esterases which is unable to leave the cell. After incubation each well was washed three times with buffer (80 μl_) (30 μl_ of buffer remained in each well after washing).

Compounds of the invention (or the reference compound, cyclothiazide) were dissolved in dimethylsulfoxide (DMSO) at a stock concentration of 10 mM. These solutions were further diluted with DMSO using a Biomek FX (Beckman Coulter) in a 384 compound plate. Each dilution (1 μl_) was transferred to another compound plate and buffer (50 μl_) was added. An agonist stimulus (glutamate) plate was prepared by dissolving sodium glutamate in water to give a concentration of 100 mM. This solution was diluted with buffer to give a final concentration of 500 μM and dispensed into another 384-well plate (50μl_/well) using a Multidrop (Thermolabsystems).

The cell plate was then transferred into a fluorescence imaging plate based reader [such as the FLIPR384 (Molecular Devices)]. A baseline fluorescence reading was taken over a 10 to 240 second period, and then 10 μL from each plate containing a compound of the invention made up in standard buffer solution (in a concentration range from 100 μM to 10 pM) is added (to give a final concentration in the range 30 μM to 3 pM). The fluorescence was read over 5 minute period. 500 μM glutamate solution (10μl_) was added (to give a final concentration of 100 μM). The fluorescence was then read over a 4 minute period. The activities of the compounds of the invention and reference compounds were determined by measuring peak fluorescence after the last addition. The activity was also expressed relative to the fluorescence increase induced by cyclothiazide at their maximum response (i.e. greater than 30 μM).

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. Accordingly, a compound exhibiting a pEC₅₀ value within this range from such an assay may indeed have a reasonable affinity for the receptor, but equally it may also have a lower affinity, including a considerably lower affinity. For each compound, more than one reading was taken.

All the Example compounds were screened using the assay as described above and the average of the measurable pEC₅₀s were taken. All compounds gave an average pEC₅₀ equal to or greater than 4.0 and/or demonstrated an activity of on average at least 10% that of cyclothiazide (at its maximal response).

Claims

Claims

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

O wherein:

R¹ is methyl and R² is halogen; or R¹ is selected from cyclopropyl and haloC_1-4alkyl, and R² is selected from hydrogen and halogen; R₄ and R₅ are: (i) independently C_1-4alkyl, wherein one of the alkyl is optionally substituted by hydroxy; or

(ii) R₄ is hydrogen and R₅ is C_1-4alkylsulfonyl; or

(iii) R₄ and R₅, together with the nitrogen atom to which they are attached, form a

4, 5 or 6-membered saturated or unsaturated heterocyclic ring, wherein one of the carbon atoms is optionally replaced by sulphur, and which ring is optionally substituted by one or two groups selected from C_1-4alkyl, C(O)C_{1- 4}alkyl, halo,

hydroxy and oxo.

2. A compound of formula (I) as defined in claim 1 or a pharmaceutically acceptable salt thereof.

3. A compound as claimed in claim 1 wherein the compound is selected from: 1-({4-[5-cyclopropyl-3-(trifluoromethyl)-1 H-pyrazol-1-yl]phenyl}methyl)-2-pyrrolidinone 1-({4-[3,5-bis(trifluoromethyl)-1 H-pyrazol-1-yl]phenyl}methyl)-2-pyrrolidinone 2-({4-[4-chloro-5-methyl-3-(trifluoromethyl)-1 H-pyrazol-1-yl]phenyl}methyl)cyclopentanone and salts thereof.

4. A compound as claimed in any of claims 1 , 2, or 3 for use in medicine.

5. A compound as claimed in any of claims 1 , 2 or 3 for use in treating a disease or condition mediated by a reduction or imbalance in glutamate receptor function in a mammal.

6. A compound as claimed in claim 5, wherein the disease or condition is schizophrenia or impairment of cognition.

7. A pharmaceutical composition comprising a compound as claimed in any of claims 1 , 2 or 3 and at least one carrier, diluent or excipient.

8. Use of a compound as defined in any of claims 1 , 2 or 3 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.

9. The use as claimed in claim 8, wherein the disease or condition is schizophrenia or impairment of cognition.

10. 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 as defined in any of claims 1 , 2 or 3.

11. The method as claimed in claim 10, wherein the disease or condition is schizophrenia or impairment of cognition.

12. A combination product comprising a compound as claimed in claim 1 or claim 2 with an antipsychotic.