WO2009053449A1 - Thiazoles which potentiate ampa receptor and medicinal uses thereof - Google Patents

Abstract

The invention provides compounds of formula (I) and salts thereof: wherein R1, R2, R3, R4 and X are as defined in the description. 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

THIAZOLES WHICH POTENTIATE AMPA RECEPTOR AND MEDICINAL USES THEREOF

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 1 1 : 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: 2211-5.); 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). The ability of AMPAR positive allosteric modulators to improve pre-clinical and clinical cognitive task performance as well as the potential for efficacy in psychiatric disorders, such as schizophrenia, in man 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.

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

(I) wherein:

• R¹ is selected from C(O)C_1-4alkyl and C(O)NR⁶R⁷, wherein R⁶ and R⁷ are independently selected from hydrogen and Ci_-4alkyl, or R⁶ and R⁷, together with the nitrogen to which they are attached, form a saturated 4- to 7-membered ring;

• R² is C_1-4alkyl;

• R³ is selected from hydrogen and hydroxyl;

• one of Y and Z is CH, and the other is selected from CF and N;

• R⁴ is selected from halogen, C_1-6alkoxy, haloC_1-6alkyl, pyridyl and phenyl, wherein the pyridyl and the phenyl are optionally substituted by one to five groups independently selected from halogen and C_1-6alkyl; and

• R⁵ is selected from hydrogen and halogen.

Halo is selected from fluoro, chloro, bromo and iodo. For example, halo is selected from fluoro and chloro, for example fluoro.

The terms "C_1-4alkyl" and "C_1-6alkyl" refer respectively to an alkyl group having from one to four and one to six carbon atoms. Unless otherwise indicated, alkyl may be a straight chain or branched. For example, a Ci_-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, in addition to

n-pentyl, isopentyl, neopentyl and hexyl.

The term "C_1-4alkoxy" refers to a group

where Ci_-4alkyl is as defined above.

The terms "haloCi_-4alkyl" and "haloCi_-6alkyl" refer to a C-^alkyl group or a Ci_-6alkyl 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 haloCi_-4alkyl group may have all hydrogen atoms replaced with halogen atoms. Examples of haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluroethyl and trifluoroethyl.

"C(O)" and "C(=O)" are interchangeable and represent a carbonyl group.

In one embodiment, R¹ is C(O)Ci_-4alkyl. In one embodiment, R¹ is C(O)CH₃. In one embodiment, R¹ is C(O)NR⁶R⁷, wherein R⁶ and R⁷ are independently selected from hydrogen and C_1-4alkyl.

In one embodiment, R¹ is C(O)N(CH₃)₂.

In one embodiment, R² is methyl.

In one embodiment, R³ is hydrogen. In one embodiment, R³ is hydroxyl.

In one embodiment, Y is CH, and Z is CF. In one embodiment, Y is CH, and Z is N.

In one embodiment, Z is CH, and Y is N. In one embodiment, Z is CH, and Y is CF.

In one embodiment, R⁴ is selected from halogen, C_1-6alkoxy and haloC_1-6alkyl. In one embodiment, R⁴ is selected from halogen, CF₃ and OEt. In one embodiment, R⁴ is selected from bromine, CF₃ and OEt.

In one embodiment, R⁴ is selected from pyridyl and phenyl, wherein the pyridyl and the phenyl are optionally substituted by one to five groups selected from halogen and Ci- ₆alkyl. In one embodiment, R⁴ is selected from pyridyl and phenyl, wherein the pyridyl and the phenyl are optionally substituted by a fluorine or a methyl.

In one embodiment, R⁵ is hydrogen.

In one embodiment, R⁵ is halogen. In one embodiment, R⁵ is fluorine.

In one embodiment, there is provided a compound of formula (Ia) or a salt thereof:

(Ia) wherein:

• R¹ is selected from C(O)C_1-4alkyl and C(O)NR⁶R⁷, wherein R⁶ and R⁷ are independently selected from hydrogen and Ci_-4alkyl;

R³ is selected from hydrogen and hydroxyl;

• one of Y and Z is CH, and the other is selected from CF and N; • R⁴ is selected from halogen, Ci_-6alkoxy, haloCi_-6alkyl, pyridyl and phenyl, wherein the pyridyl and the phenyl are optionally substituted by one to five groups independently selected from halogen and C_1-6alkyl; and • R⁵ is selected from hydrogen and fluoro.

The imine bond in formula (I) (between the central nitrogen atom and the carbon atom in the thiazolyl group) indicates E, Z or a mixture of both E and Z isomers:

In mixtures of E and Z compounds, or compounds in which the E/Z (i.e cis/trans) configuration have not been determined, the imine bond is drawn as a crossed bond as shown in formula (I).

The individual isomers (E and Z) and mixtures of these are included within the scope of the present invention. The isomers may be separated one from the other by the usual methods or by methods detailed for the example compounds below. Any given isomer may also be obtained by stereospecific synthesis. The invention also extends to any tautomeric forms and mixtures thereof.

In one embodiment, the compounds of formula (I) are E isomers.

In another embodiment, the compounds of formula (I) are Z isomers.

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.

Examples of compounds of the present invention include:

1-(2-{[3,5-difluoro-4-(trifluoromethyl)phenyl]imino}-3-ethyl-4-methyl-2,3-dihydro-1 ,3- thiazol-5-yl)ethanone ^(S-ethyl^^-fluoro^-^rifluoromethyOphenyφminoH-methyl^.S-dihydro-I .S-thiazol-S- yl)ethanone

2-{[4-(ethyloxy)-2-fluorophenyl]imino}-3-(2-hydroxyethyl)-N_!N_!4-trimethyl-2_!3-dihydro-1 ,3- thiazole-5-carboxamide 1-{2-[(6-bromo-3-pyridinyl)imino]-3-ethyl-4-methyl-2,3-dihydro-1 ,3-thiazol-5-yl}ethanone i-iS-ethyl^-Ke'-fluoro^.S'-bipyridin-S-yOiminol^-methyl^.S-dihydro-I .S-thiazol-S- yl}ethanone

1-{3-(2-hydroxyethyl)-4-methyl-2-[(6-phenyl-3-pyridinyl)imino]-2_!3-dihydro-1 ,3-thiazol-5- yl}ethanone 1-[2-{[6-(4-fluorophenyl)-3-pyridinyl]imino}-3-(2-hydroxyethyl)-4-methyl-2_!3-dihydro-1 ,3- thiazol-5-yl]ethanone

1-[2-{[6-(2-fluorophenyl)-3-pyridinyl]imino}-3-(2-hydroxyethyl)-4-methyl-2_!3-dihydro-1 ,3- thiazol-5-yl]ethanone

1-[2-{[6-(3-fluorophenyl)-3-pyridinyl]imino}-3-(2-hydroxyethyl)-4-methyl-2_!3-dihydro-1 ,3- thiazol-5-yl]ethanone

1-(3-(2-hydroxyethyl)-4-methyl-2-{[6-(trifluoromethyl)-3-pyridinyl]imino}-2_!3-dihydro-1 ,3- thiazol-5-yl)ethanone

1-[2-[(5-bromo-2-pyridinyl)imino]-3-(2-hydroxyethyl)-4-methyl-2_!3-dihydro-1 ,3-thiazol-5- yl]ethanone 1-(3-(2-hydroxyethyl)-4-methyl-2-{[5-(trifluoromethyl)-2-pyridinyl]imino}-2_!3-dihydro-1 ,3- thiazol-5-yl)ethanone

1-{3-(2-hydroxyethyl)-4-methyl-2-[(5-phenyl-2-pyridinyl)imino]-2_!3-dihydro-1 ,3-thiazol-5- yl}ethanone

1-[2-[(6-bromo-3-pyridinyl)imino]-3-(2-hydroxyethyl)-4-methyl-2_!3-dihydro-1 ,3-thiazol-5- yl]ethanone

1-(3-(2-hydroxyethyl)-4-methyl-2-{[6-(4-methylphenyl)-3-pyridinyl]imino}-2_!3-dihydro-1 ,3- thiazol-5-yl)ethanone and salts thereof.

In one embodiment the salt of the compound of formula (I) is a pharmaceutically acceptable salt. In one embodiment, the invention provides a compound of formula (I) or a pharmaceutically acceptable salt.

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.

Furthermore, some of the crystalline forms of the compounds of structure (I) may exist as polymorphs, which are included in the present invention. Some of the compounds of this invention may be crystallised or recrystallised from solvents such as aqueous and organic solvents. In such cases solvates may be formed. This invention includes within its scope stoichiometric solvates as well as compounds containing variable amounts of solvent, where non-stoichiometric solvates may be produced by processes such as lyophilisation. In one embodiment, the compounds of the present invention are provided in the form of stoichiometric and non-stoichiometric hydrates.

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".

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 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.

Thus, the present invention provides a process for the manufacture of a compound of formula (I), the process comprising: (a) coupling a compound of formula (II):

(H) wherein R³, R⁴, R⁵, Y and Z are as defined for formula (I), with a compound of formula

(III) wherein R¹ and R² are as defined for formula (I); or (b) reacting a compound of formula (IV):

(IV)

wherein R⁴, R⁵, Y and Z are as defined for formula (I), with a primary amine R³(CH₂)₂NH₂ wherein R³ is as defined for formula (I), to give a compound of formula (II) as defined in process (a), followed by coupling with a compound of formula (III) as defined in process (a); or (c) for a compound of formula (I) wherein R¹ is C(O)NH₂, reacting a compound of formula (V):

(V)

wherein R², R³, R⁴, R⁵, Y and Z are as defined for formula (I), with ammonium chloride, DIPEA and HATU; and thereafter optionally for process (a), (b) or (c):

- forming a salt; and/or

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

For process (a), typical conditions comprise heating under argon at a suitable temperature such as 90-100degC a mixture of compounds (II) and (III) in a suitable solvent such as toluene and/or ethanol for the required time. Compounds of formula (III) are commercially available or described in the literature. Compounds of formula (II) can be prepared as described below.

For process (b), typical reaction conditions comprise mixing a compound of formula (IV) and a primary amine R³(CH₂)₂NH₂ under argon in a suitable solvent such as toluene for the required time and temperature, for example 2 hours at ambient, followed by the addition of further solvent such as toluene and a compound of formula (III), and heating the whole mixture at a suitable temperature such as 90degC for the required time, typically 2 hours. Compounds of formula (III), formula (IV) and R³(CH₂)₂NH₂ are commercially available or described in the literature.

For process (c), typical reaction conditions comprise treatment of a mixture of a compound of formula (V), ammonium chloride and DIPEA (Λ/,Λ/-diisopropylethylamine) in dimethylformamide with HATU (O-(7-azabenzotriazol-1-yl)-Λ/,Λ/,Λ/',Λ/'-tetramethyluronium hexafluorophosphate) at room temperature. Compounds of formula (V) may be prepared by process (a) or (b) via the ester with appropriate protecting group manipulation to provide the acid.

An intermediate compound of formula (II) may be prepared by the reaction of an isothiocyanate of formula (IV) with a primary amine of formula (Vl) according to reaction scheme 1. Typical reaction conditions comprise mixing an isothiocyanate of formula (IV) with a primary amine of formula (Vl) in a suitable solvent such as ethyl acetate at a suitable temperature such as ambient for the appropriate time. Compounds of formula (IV) and formula (Vl) are commercially available or described in the literature.

Scheme 1

solvent

(IV) (II)

Alternatively, an intermediate compound of formula (II) may be prepared by the reaction of a compound of formula (VII) with an isothiocyanate of formula (VIII) according to reaction scheme 2. Typical reaction conditions comprise heating under argon a mixture of a compound of formula (VII) with an isothiocyanate of formula (VIII), optionally with a base such as triethylamine added, at a suitable temperature such as 80degC in a suitable solvent such as ethanol for the required time, typically 2.5-6 hours. Compounds of formula (VII) and (VIII) are commercially available or described in the literature.

Scheme 2

Alternatively, an intermediate compound of formula (II) may be prepared by the reaction of an amine R'-NH₂ with a suitable reagent followed by the addition of an amine R-NH₂ according to reaction scheme 3. Typical reaction conditions comprise adding a suitable reagent such as 1 ,1 '-(thioxomethanediyl)bis-1 H-imidazole to amine R'-NH₂ in a suitable solvent such as dichloromethane under argon at a suitable temperature, for example OdegC, followed by stirring for a suitable time period at a suitable temperature, for example stirring for 4 hours at ambient. The reaction mixture is then cooled to a suitable temperature such as OdegC, and amine R-NH₂ is added and the reaction is stirred for the required time, for example 16 hours, at the required temperature such as ambient. Amines R'-NH₂ and R-NH₂ are commercially available or described in the literature.

Scheme 3

A compound of formula (IX) may be prepared from a compound of formula (X) by reaction with the appropriate boronic acid according to scheme 4. Typical reaction conditions comprise heating under argon a mixture of a compound of formula (X) and a boronic acid (RB(OH)₂) in the presence of a suitable palladium reagent such as tetrakis(triphenylphospnine)palladium(0) and a suitable base such as sodium carbonate in a suitable solvent such as a 3 : 1 mixture of 1 ,4-dioxane and water at a suitable temperature such as 90-100 degC for the required time. A compound of formula (X) may be prepared according to process (a) or (b).

Scheme 4 Boronic acid RB(OH)₂ I ^Pd reagent / base / solvent

R is an aromatic or heteroaromatic ring

A = leaving group, for example Br, I

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 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 by any route, and include those in a form adapted for oral, topical or parenteral administration to mammals including humans.

The compositions may be formulated for administration by any route. The compositions 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.

Advantageously, 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. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.

The compositions may contain from 0.1% by weight, for example from 10-60% by weight, of the active material, depending on the method of administration. Where the compositions comprise dosage units, each unit may, for example contain from 0.1 to 20 mg of the active ingredient. For example, such a unit may contain from 1 to 10 mg. 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 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 caused by a reduction or imbalance in glutamate receptor function in a mammal; ii) a compound of formula (I) a pharmaceutically acceptable salt thereof for use in treating a disease or condition caused by a reduction or imbalance in glutamate receptor function in a mammal; iii) a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier or diluent; iv) a method of treatment of 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 of formula (I) a pharmaceutically acceptable salt thereof. v) a combination product of a compound of formula (I) a pharmaceutically acceptable salt thereof with an antipsychotic; vi) a pharmaceutical composition comprising such a combination product and at least one pharmaceutically acceptable carrier or diluent; vii) the use of such a combination in the manufacture of a medicament for treating a disease or condition caused by a reduction or imbalance in glutamate receptor function in a mammal; viii) such a combination product for use in treating a disease or condition caused by a reduction or imbalance in glutamate receptor function in a mammal; ix) a method of treatment of a disease or condition caused by a reduction or imbalance in glutamate receptor function in a mammal comprising administering an effective amount of such a combination product; x) such a combination product for use as a medicament.

In the case of aspects i), ii), iv), vii), viii), ix) and x), 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); 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). 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).

Treatment of 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.

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 the following agents to treat or prevent psychotic disorders: i) antipsychotics (such as olanzapine, risperidone, clozapine, ziprazidone and talnetant); ii) drugs for extrapyramidal side effects, for example anticholinergics (such as benztropine, biperiden, procyclidine and trihexyphenidyl), antihistamines (such as diphenhydramine) and dopaminergics (such as amantadine); iii) antidepressants; iv) anxiolytics; and v) cognitive enhancers for example cholinesterase inhibitors (such as tacrine, donepezil, rivastigmine and galantamine).

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

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

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

The compounds of the invention may be used in combination with 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; and ii) bupropion.

The compounds of the invention may be used in combination with 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; and iii) Opioid receptor antagonists for example naltrexone.

The compounds of the invention may be used in combination with 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; and iii) vasodilatory antihypertensives for example lofexidine.

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

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

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

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

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

The compounds of the invention may be used in combination with the following agents to treat personality disorders: i) antipsychotics; ii) antidepressants; iii) mood stabilisers; and iv) anxiolytics.

The compounds of the invention may be used in combination with the following agents to treat or prevent male sexual dysfunction: i) phosphodiesterase V inhibitors, for example vardenafil and sildenafil; ii) dopamine agonists/dopamine transport inhibitors for example apomorphine and 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 and vii) 5-HT1A agonists, for example flibanserine.

The compounds of the invention may be used in combination with the same agents specified for male sexual dysfunction to treat or prevent female sexual dysfunction, and in addition 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 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.

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 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/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 materials may not necessarily have been prepared from the batch referred to. 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. 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). All reactions were either carried out under argon or may be carried out under argon, unless otherwise stated.

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 under the curve

LC/MS Liquid Chromatography / Mass Spectrometry

NMR Nuclear Magnetic Resonance

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-preparation

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

Cy Cyclohexane

EtOAc Ethyl acetate

ES electrospray

ES-API electrospray - atmospheric pressure ionisation min(s) minute(s)

Me methyl

Et ethyl degC degree Celsius

HATU O-(7-Azabenzotriazol-1-yl)-Λ/,Λ/,Λ/',Λ/-tetramethyluronium hexafluorophosphate

DIPEA Λ/,Λ/-diisopropylethylamine

Unless otherwise stated, all compounds with chiral centre(s) are racemic.

Description 1 : yV-[4-(ethyloxy)-2-fluorophenyl]-W-(2-hydroxyethyl)thiourea

To a cooled (O⁰C) solution of 4-ethoxy-2-fluoroaniline hydrochloride (386mg, 2.0mmol) in dichloromethane (50ml) was added triethylamine (0.3ml), followed by 1 ,1 '- thiocarbonyldiimidazole (534mg, 3.0mmol) portionwise over 10 minutes. The reaction mix was allowed to warm up to room temperature and stirred for 18 hours. The reaction mixture was cooled in an ice/methanol bath and 2-aminoethanol (1.3ml) was added dropwise with stirring under argon. This mix was then stirred at room temperature for 1 hour. The reaction mix was then concentrated by rotary evaporation. The residue was added in dichloromethane to a 2Og isolute silica pre-packed column which was eluted from 0-100% ethyl acetate in petroleum ether. The relevant fractions were combined and the solvent removed by rotary evaporation to give the title compound as a colourless solid

(475mg, 92%).

LC/MS (ES): Found 259 (ES+), retention time 1.95mins. CnH₁₅FN₂O₂S requires 258. ¹ H-NMR (400MHz, MeOD-d₄): δ 1.38 (3H, t, J=7Hz), 3.68 (4H, s), 3.73 (1 H, m), 4.03 (2H, q, J=7Hz), 4.63 (1 H, m), 6.75 (2H, m), 7.30 (1 H, m).

Description 2: /V-(6-bromo-3-pyridinyl)-/V-ethylthiourea

A mixture of 6-bromo-3-pyridinamine (5.Og, 0.03mol), isothiocyanatoethane (2.63ml, 0.03mol) and triethylamine (6.3ml, 0.045mol) in ethanol (50ml) was heated at 95⁰C for 6 hours. Solvent was removed under reduced pressure to give a dark oil which was recrystallised with ethyl acetate/n-pentane to afford the title compound as a brown solid (3.42g, 44%).

LC/MS 2mins (ES): Found 260, 262 (ES+), retention time 0.82mins. C₈H₁₀BrN₃S requires 259, 261.

Description 3: /V-(6-bromo-3-pyridinyl)-/V-(2-hydroxyethyl)thiourea

To a O⁰C solution of 6-bromo-3-pyridinamine (5.Og, 28.9 mmol) in dichloromethane (150 ml) was added 1 ,1'-(thioxomethanediyl)fc>/s-1 /-/-imidazole (7.73 g, 43.3mmol) portionwise over 30 minutes. The reaction was warmed to room temperature and stirred for 16 hours under argon. Then the reaction mixture was cooled in an ice bath and 2-aminoethanol (3.53g, 57.8mmol) was added portionwise over 20 minutes. The reaction mixture was allowed to stir at room temperature for 5 hours. Then the reaction was concentrated and purified by column silica gel chromatography using 50 to 95% ethyl acetate in n-pentane to obtain the title compound as a solid (4.975g, 59.2%).

LC/MS 2mins (ES): Found 276, 278 (ES+), retention time 1.72mins. C₈H₁₀BrN₃OS requires 275, 277.

Description 4: Λ^2-hydroxyethyl)-ΛP-[6-(trifluoromethyl)-3-pyridinyl]thiourea

The title compound was prepared from 6-(trifluoromethyl)-3-pyridinamine, 1 ,1'- (thioxomethanediyl)fc>/s-1 /-/-imidazole and 2-aminoethanol in dichloromethane using a similar procedure to that described for Description 3. LC/MS 2mins (ES): Found 266 (ES+), retention time 0.79mins. C₉H₁₀F₃N₃OS requires 265.

Description 5: /V-(5-bromo-2-pyridinyl)-/V-(2-hydroxyethyl)thiourea

The title compound was prepared from 5-bromo-2-pyridinamine, 1 ,1 '- (thioxomethanediyl)fc>/s-1 /-/-imidazole and 2-aminoethanol in dichloromethane using a similar procedure to that described for Description 3.

LC/MS 2mins (ES): Found 276, 278 (ES+), retention time 0.78mins. C₈H₁₀BrN₃OS requires 275, 277.

Description 6: yV-(2-hydroxyethyl)-yV-[5-(trifluoromethyl)-2-pyridinyl]thiourea

The title compound was prepared from 5-(trifluoromethyl)-2-pyridinamine, 1 ,1'- (thioxomethanediyl)fc>/s-1 /-/-imidazole and 2-aminoethanol in dichloromethane using a similar procedure to that described for Description 3.

LC/MS 2mins (ES): Found 266 (ES+), retention time 0.84mins. C₉H₁₀F₃N₃OS requires 265.

Example 1 : 1-[2-{[4-(ethyloxy)-2-fluorophenyl]imino}-3-(2-hydroxyethyl)-4-methyl- 2,3-dihydro-1 ,3-thiazol-5-yl]ethanone hydrochloride

A mixture of /V-[4-(ethyloxy)-2-fluorophenyl]-Λ/'-(2-hydroxyethyl)thiourea (137mg, 0.53mmol, Description 1 ) and 3-chloro-2,4-pentanedione (86mg, 0.64mmol) in toluene (5ml) was stirred at 9O⁰C (oil bath temperature) for 2 hours. The reaction mixture was allowed to cool and the solvent was removed by rotary evaporation. The crude product was then purified by mass directed auto-preparation (MDAP). Relevant fractions were combined and the solvent removed by rotary evaporation to give a yellow solid (1 16mg). The solid was then dissolved/suspended in dichloromethane (1 ml) and treated with 1 M ethereal HCI (1 ml), and the solvent was removed by air drying and the residue triturated in a further 1 ml of 1 M ethereal HCI. The liquid was decanted off and the residual solid was vacuum oven dried to give the title compound as a pale yellow solid (124mg, 62%).

LC/MS (ES): Found 339 (ES+), retention time 2.59mins. Ci₆H₁₉FN₂O₃S requires 338. ¹ H-NMR (400MHz, MeOD-d₄): δ 1.42 (3H, t, J=7Hz), 2.50 (3H, s), 2.76 (3H, s), 3.97 (2H, m), 4.10 (2H, q, J=7Hz), 4.39 (2H, m), 6.90-6.99 (2H, m), 7.41 (1 H, t, J=9Hz).

Example 2: 1 -(2-{[3,5-difluoro-4-(trifluoromethyl)phenyl]imino}-3-ethyl-4-methyl-2,3- dihydro-1 ,3-thiazol-5-yl)ethan

A solution of 4-amino-2,6-difluorobenzotrifluoride (394mg, 2.0mmol) in ethanol (10ml) and triethylamine (0.4ml) was treated with ethyl isothiocyanate (209mg, 2.4mmol) at room temperature with stirring under argon, and then stirred at reflux for 36 hours. The reaction mix was cooled and the ethanol removed under reduced pressure. The residue was dissolved in toluene (10ml) and treated with 3-chloro-2,4-pentanedione (269mg, 2.0mmol) and the resulting mix stirred at 9O⁰C for 6 hours. The reaction mix was allowed to cool and then reduced to minimum volume by rotary evaporation to give a brown oil which was partitioned between dichloromethane and saturated aqueous sodium bicarbonate solution (5ml of each). The organic layer was added to a 5g isolute pre-packed silica column and eluted from 20-50% ethyl acetate in petroleum ether. The solvent was removed by rotary evaporation to give a yellow oil (647mg) which was then further purified by MDAP. Relevant fractions were combined and the solvent removed by rotary evaporation to give a yellow oil which was dissolved in dichloromethane (1 ml) and treated with 1 M ethereal HCI (1 ml), and the solvent was removed by air drying and the residue triturated in a further 1 ml of 1 M ethereal HCI, which was then decanted off and the sample vacuum oven dried to give the title compound as a pale yellow solid (38mg, 5%).

LC/MS (ES): Found 365 (ES+), retention time 3.60mins. Ci₅H₁₃F₅N₂OS requires 364. ¹ H-NMR (400MHz, MeOD-d₄): δ 1.34 (3H, t, J=7Hz), 2.38 (3H, s), 2.66 (3H, s), 4.12 (2H, q, J=7Hz), 6.85 (2H, d, J=12Hz). Example 3: 1-(3-ethyl-2-{[3-fluoro-4-(trifluoromethyl)phenyl]imino}-4-methyl-2,3- dihydro-1 ,3-thiazol-5-yl)ethanon

The title compound was prepared from 4-amino-2-fluorobenzotrifluoride, ethyl isothiocyanate (1.5 eq) and 3-chloro-2,4-pentandione using a similar procedure to that that used for Example 2.

LC/MS (ES): Found 347 (ES+), retention time 3.47mins. C₁₅H₁₄F₄N₂OS requires 346. ¹ H-NMR (400MHz, MeOD-d₄): δ 1.42 (3H, t, J=7Hz), 2.45 (3H, s), 2.72 (3H, s), 4.23 (2H, q, J=7Hz), 7.29 (2H, d, J=IOHz), 7.78 (1 H, t, J=8Hz).

Example 4: 2-{[4-(ethyloxy)-2-fluorophenyl]imino}-3-(2-hydroxyethyl)-Λ/,Λ/,4- trimethyl-2,3-dihydro-1 ,3-thiazole-5-carboxamide hydrochloride

A mixture of /V-[4-(ethyloxy)-2-fluorophenyl]-/V-(2-hydroxyethyl)thiourea (300mg,

1.16mmol, Description 1 ) and 2-chloro-N,N-dimethylacetoacetamide (0.18ml, 1.32mmol) in toluene (5ml) was stirred at 9O⁰C (oil bath temperature) under an atmosphere of argon for 2 hours. The reaction mix was allowed to cool and the toluene removed by rotary evaporation. The residue was partitioned between ethyl acetate (10ml) and saturated aqueous sodium bicarbonate solution (10ml). The organic layer was separated and dried over sodium sulphate and the solvent removed by rotary evaporation to give a colourless oil (235mg). The product was purified by mass directed auto-preparation (MDAP). The relevant fractions were combined and the solvent removed by rotary evaporation to give a beige coloured oil (165mg). This material was dissolved in dichloromethane (2ml) and treated with 1 M ethereal HCI (1 ml) with mixing. The solvent was blown down with compressed air, and the residue triturated in 1 M ethereal HCI (2ml). The liquid was decanted off and the residual solid was vacuum oven dried to give the title compound as a colourless solid (169mg, 36%).

LC/MS (ES): Found 368 (ES+), retention time 1.90mins. C₁₇H₂₂FN₃O₃S requires 367. ¹ H-NMR (400MHz, DMSO-d₆): δ 1.33 (3H, t, J=7Hz), 2.28 (3H, s), 2.94 (6H, s), 3.76 (2H, m), 4.05 (2H, m), 4.15 (2H, m), 6.84 (1 H, m), 7.01 (1 H, m), 7.38 (1 H, m). Example 5: 1 -{2-[(6-bromo-3-pyridinyl)imino]-3-ethyl-4-methyl-2,3-dihydro-1 ,3- thiazol-5-yl}ethanone

Λ/-(6-bromo-3-pyridinyl)-Λ/'-ethylthiourea (1.5g, 5.8mmol, Description 2) was dissolved in ethanol (30ml), then 3-chloro-2,4-pentanedione (2.05ml, 0.017mol) was added. The resulting mixture was heated at 90⁰C under argon for 2 hours. The solvent was removed by rotary evaporation and the residual material was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic layer was separated, dried over sodium sulphate and evaporated to afford the crude product (79% pure, 2.56g, 100%) which was used directly for the next reaction without further purification.

A sample of the crude product (100mg) was purified by high pH mass directed auto- preparation to afford the title compound as a white solid (44mg).

LC/MS (ES): Found 340, 342 (ES+), retention time 2.89mins. C₁₃H₁₄BrN₃OS requires 339, 341.

¹ H-NMR (400MHz, DMSOd₆): δ 1.26 (3H, m), 2.35 (3H, s), 2.61 (3H, s), 4.03 (2H, m), 7.49 (1 H, m), 7.59 (1 H, m), 8.07 (1 H, m).

Example 6: 1 -{3-ethyl-2-[(6'-fluoro-2,3'-bipyridin-5-yl)imino]-4-methyl-2,3-dihydro- 1,3-thiazol-5-yl}ethanone

A mixture of 1-{2-[(6-bromo-3-pyridinyl)imino]-3-ethyl-4-methyl-2,3-dihydro-1 ,3-thiazol-5- yl}ethanone (200 mg, 0.59mmol, Example 5), (6-fluoro-3-pyridinyl)boronic acid (83 mg, 0.59mmol), tetrakis(triphenylphosphine)palladium(0) (20mg, 3mol%) and sodium carbonate (125 mg, 1.18mmol) in 1 ,4-dioxane (12 ml) and water (4 ml) were heated at 9O⁰C under argon for 1 hour. The reaction mixture was diluted with ethyl acetate, filtered through kieselguhr to remove the catalyst and the filtrate was washed with water, dried over sodium sulphate and filtered. The reaction mixture was concentrated and purified by MDAP to give the desired product. The product was partitioned between dichloromethane and aqueous sodium hydrogen carbonate solution, dried over sodium sulphate then filtered. The solvent was removed by rotary evaporation to afford the title compound as a pale yellow solid (22mg, 10%).

LC/MS (ES): Found 357 (ES+), retention time 2.77mins. C₁₈H₁₇FN₄OS requires 356. 1 H-NMR (400MHz, DMSO-d₆): δ 1.29 (3H, m), 2.33 (3H, s), 2.61 (3H, m), 4.05 (2H, m), 7.30 (1 H, m), 7.57 (1 H, m), 8.04 (1 H, m), 8.38 (1 H, m), 8.62 (1 H, m), 8.90 (1 H, m). Example 7: 1 -{3-(2-hydroxyethyl)-4-methyl-2-[(6-phenyl-3-pyridinyl)imino]-2,3- dihydro-1 ,3-thiazol-5-yl}ethanone hydrochloride

A mixture of 1-[2-[(6-bromo-3-pyridinyl)imino]-3-(2-hydroxyethyl)-4-methyl-2,3-dihydro-1 ,3- thiazol-5-yl]ethanone (120mg, 0.33mmol, Example 15), phenylboronic acid (62mg, 0.50mmol), tetrakis(triphenylphosphine)palladium(0) (12mg, 3mol%) and sodium carbonate (71 mg, 0.67mmol) in 1 ,4-dioxane (12 ml) and water (4 ml) were heated at 9O⁰C under argon for 2 hours. The reaction mixture was diluted with ethyl acetate, filtered through kieselguhr to remove the catalyst and then the filtrate was washed with water and dried over sodium sulphate. The reaction mixture was concentrated and purified by mass directed auto-preparation, then treated with 1 M ethereal hydrogen chloride to give the desired product as a yellow solid (11 1 mg, 85%).

LC/MS (ES): Found 354 (ES+), retention time 2.34mins. C₁₉H₁₉N₃O₂S requires 353. 1 H-NMR (400MHz, DMSOd₆): δ 2.40 (3H, s), 2.67 (3H, s), 3.77 (2H, m), 4.10 (2H, m), 7.57 (3H, m), 7.88 (1 H, m), 8.08 (2H, m), 8.17 (1 H, m), 8.46 (1 H, s).

Example 8: 1 -[2-{[6-(4-fluorophenyl)-3-pyridinyl]imino}-3-(2-hydroxyethyl)-4-methyl- 2,3-dihydro-1 ,3-thiazol-5-yl]ethanone hydrochloride

A mixture of 1-[2-[(6-bromo-3-pyridinyl)imino]-3-(2-hydroxyethyl)-4-methyl-2,3-dihydro-1 ,3- thiazol-5-yl]ethanone (2.92g, 8.20 mmol, Example 15), (4-fluorophenyl)boronic acid (1.720 g, 12.30 mmol), tetrakis(triphenylphosphine)palladium(0) (0.284 g, 0.246 mmol) and sodium carbonate (1.738 g, 16.39 mmol) in 1 ,4-dioxane (120 ml) and water (40 ml) were heated at 9O⁰C under argon for 3 hours. The reaction mixture was diluted with ethyl acetate, filtered through kieselguhr to remove catalyst and the filtrate was washed with water and dried over sodium sulphate. The reaction mixture was concentrated down to a small volume and purified by flash column chromatography on silica using 5 to 95% ethylacetate in n-pentane and triturated with diethyl ether to give the desired product as a yellow solid. This solid was treated with ethereal hydrochloride / methanol to give the hydrochloride salt (2.964, 89%).

LC/MS (ES): Found 372 (ES+), retention time 2.47mins. Ci₉H₁₈FN₃O₂S requires 371. ¹ H-NMR (free base, 400MHz, DMSOd₆): δ 2.36 (3H, s), 2.65 (3H, s), 3.77 (2H, m), 4.07 (2H, m), 5.08 (1 H, t, J=5Hz), 7.30 (2H, m), 7.53 (1 H, dd, J=8Hz,3Hz), 7.96 (1 H, m), 8.12 (2H, m), 8.33 (1 H, m).

Example 9: 1 -[2-{[6-(2-fluorophenyl)-3-pyridinyl]imino}-3-(2-hydroxyethyl)-4-methyl- 2,3-dihydro-1,3-thiazol-5-yl]ethanone hydrochloride

The title compound was prepared from 1-[2-[(6-bromo-3-pyridinyl)imino]-3-(2- hydroxyethyl)-4-methyl-2,3-dihydro-1 ,3-thiazol-5-yl]ethanone (Example 15) and

(2-fluorophenyl)boronic acid using a similar procedure to that described for Example 8.

LC/MS (ES): Found 372 (ES+), retention time 2.48mins. Ci₉H₁₈FN₃O₂S requires 371. ¹ H-NMR (400MHz, DMSO-d₆): δ 2.39 (3H, s), 2.67 (3H, s), 3.77 (2H, m), 4.10 (2H, m), 7.37 (2H, m), 7.54 (1 H, m), 7.81 (1 H, m), 7.93 (2H, m), 8.48 (1 H, s), 8.72 (2H, bs).

Example 10: 1-[2-{[6-(3-fluorophenyl)-3-pyridinyl]imino}-3-(2-hydroxyethyl)-4- methyl-2,3-dihydro-1 ,3-thiazol-5-yl]ethanone hydrochloride

The title compound was prepared from 1-[2-[(6-bromo-3-pyridinyl)imino]-3-(2- hydroxyethyl)-4-methyl-2,3-dihydro-1 ,3-thiazol-5-yl]ethanone (Example 15) and (3-fluorophenyl)boronic acid using a similar procedure to that described for Example 8.

LC/MS (ES): Found 372 (ES+), retention time 2.65mins. Ci₉Hi₈FN₃O₂S requires 371. ¹ H-NMR (400MHz, DMSO-d₆): δ 2.37 (3H, s), 2.66 (3H, s), 3.76 (2H, m), 4.10 (2H, m), 6.23 (2H, bs), 7.24 (1 H, m), 7.54 (1 H, m), 7.62 (1 H, m), 7.88 (2H, m), 8.07 (1 H, m), 8.38 (1 H, s).

Example 11 : 1-(3-(2-hydroxyethyl)-4-methyl-2-{[6-(trifluoromethyl)-3- pyridinyl]imino}-2,3-dihydro-1,3-thiazol-5-yl)ethanone

The title compound was prepared from /V-(2-hydroxyethyl)-/V-[6-(trifluoromethyl)-3- pyridinyl]thiourea (Description 4) and 3-chloro-2,4-pentanedione using a similar procedure to that described for Example 15.

LC/MS (ES): Found 346 (ES+), retention time 2.58mins. Ci₄H₁₄F₃N₃O₂S requires 345. ¹ H-NMR (400MHz, DMSOd₆): δ 2.38 (3H, s), 2.70 (3H, s), 3.76 (2H, m), 4.10 (2H, m), 5.08 (1 H, m), 7.68 (1 H, m), 7.87 (1 H, m), 8.41 (1 H, m).

Example 12: 1-[2-[(5-bromo-2-pyridinyl)imino]-3-(2-hydroxyethyl)-4-methyl-2,3- dihydro-1,3-thiazol-5-yl]ethanone

The title compound was prepared from /V-(5-bromo-2-pyridinyl)-/V-(2- hydroxyethyl)thiourea (Description 5) and 3-chloro-2,4-pentanedione using a similar procedure to that described for Example 15.

LC/MS (ES): Found 356, 358 (ES+), retention time 2.85mins. Ci₃H₁₄BrN₃O₂S requires 355, 357.

¹ H-NMR (400MHz, DMSO-d₆): δ 2.44 (3H, s), 2.69 (3H, s), 3.74 (2H, m), 4.23 (2H, m), 5.01 (1 H, m), 7.04 (1 H, m), 7.88 (1 H, m), 8.54 (1 H, s).

Example 13: 1 -(3-(2-hydroxyethyl)-4-methyl-2-{[5-(trifluoromethyl)-2- pyridinyl]imino}-2,3-dihydro-1,3-thiazol-5-yl)ethanone

The title compound was prepared from /V-(2-hydroxyethyl)-/V-[5-(trifluoromethyl)-2- pyridinyl]thiourea (Description 6) and 3-chloro-2,4-pentanedione using a similar procedure to that described for Example 15.

LC/MS (ES): Found 346 (ES+), retention time 2.98mins. Ci₄H₁₄F₃N₃O₂S requires 345. ¹ H-NMR (400MHz, DMSOd₆): δ 2.48 (3H, s), 2.69 (3H, s), 3.77 (2H, m), 4.28 (2H, m), 5.03 (1 H, m), 7.20 (1 H, m), 8.01 (1 H, m), 8.81 (1 H, s).

Example 14: 1 -{3-(2-hydroxyethyl)-4-methyl-2-[(5-phenyl-2-pyridinyl)imino]-2,3- dihydro-1,3-thiazol-5-yl}ethanone

The title compound was prepared from 1-[2-[(5-bromo-2-pyridinyl)imino]-3-(2- hydroxyethyl)-4-methyl-2,3-dihydro-1 ,3-thiazol-5-yl]ethanone (Example 12) and phenylboronic acid using a similar procedure to that described for Example 6.

LC/MS (ES): Found 354 (ES+), retention time 2.79mins. Ci₉H₁₉N₃O₂S requires 353. 1 H-NMR (400MHz, DMSO-d₆): δ 2.44 (3H, s), 2.70 (3H, s), 3.77 (2H, m), 4.25 (2H, m), 5.03 (1 H, m), 7.17 (1 H, m), 7.38 (1 H, m), 7.49 (2H, m), 7.74 (2H, m), 8.04 (1 H, m), 8.79 (1 H, s).

Example 15: 1-[2-[(6-bromo-3-pyridinyl)imino]-3-(2-hydroxyethyl)-4-methyl-2,3- dihydro-1 ,3-thiazol-5-yl]ethanone

A mixture of Λ/-(6-bromo-3-pyridinyl)-Λ/'-(2-hydroxyethyl)thiourea (3.85 g, 14.0mmol, Description 3) and 3-chloro-2,4-pentanedione (5.0 ml, 41.9mmol) in ethanol (150ml) was heated at 9O⁰C for 2 hours. The solvent was removed by rotary evaporation and recrystallized with methanol/ethyl acetate to afford the desired product as a hydrochloride salt. The product was partitioned between dichloromethane and aqueous sodium hydrogen carbonate solution, dried over sodium sulphate, filtered and evaporated to dryness to afford the desired product as a yellow solid (3.27g, 62%)

LC/MS (ES): Found 356, 358 (ES+), retention time 2.34mins. Ci₃H₁₄BrN₃O₂S requires 355, 357.

¹ H-NMR (400MHz, DMSOd₆): δ 2.35 (3H, s), 2.63 (3H, s), 3.71 (2H, m), 4.06 (2H, m), 5.05 (1 H, m), 7.42 (1 H, m), 7.59 (1 H, m), 8.06 (1 H, m).

Example 16: 1-(3-(2-hydroxyethyl)-4-methyl-2-{[6-(4-methylphenyl)-3- pyridinyl]imino}-2,3-dihydro-1,3-thiazol-5-yl)ethanone hydrochloride

The title compound was prepared from 1-[2-[(6-bromo-3-pyridinyl)imino]-3-(2- hydroxyethyl)-4-methyl-2,3-dihydro-1 ,3-thiazol-5-yl]ethanone (Example 15) and (4-methylphenyl)boronic acid using a similar procedure to that described for Example 8.

LC/MS (ES): Found 368 (ES+), retention time 2.35mins. C₂₀H_2IN₃O₂S requires 367. 1 H-NMR (400MHz, DMSO-d₆): δ 2.40 (6H, m), 2.67 (3H, s), 3.77 (2H, m), 4.12 (2H, m), 7.39 (2H, m), 7.50-7.77 (1 H, m), 7.98 (3H, m), 8.20 (1 H, m), 8.43 (1 H, s).

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 wavelength range: 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

Biological Assays

Calcium Influx Fluorescence Assay 1

384 well plates are prepared containing confluent monolayer of HEK 293 cells either stably expressing or transiently transfected with human GluR2 flip (unedited) AMPA receptor subunit. These cells form functional homotetrameric AMPA receptors. The tissue culture medium in the wells are discarded and the wells are 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 are 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 is then converted to FLUO-4 by intracellular esterases which is unable to leave the cell. After incubation each well is washed three times with buffer (80 μl_) (30 μl_ of buffer remained in each well after washing).

Compounds of the invention (or reference compounds such as cyclothiazide) are dissolved in dimethylsulfoxide (DMSO) at a stock concentration of 10 mM. These solutions are further diluted with DMSO using a Biomek FX (Beckman Coulter) in a 384 compound plate. Each dilution (1 μl_) is transferred to another compound plate and buffer (50 μl_) is added. An agonist stimulus (glutamate) plate is prepared by dissolving sodium glutamate in water to give a concentration of 100 mM. This solution is 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 is then transferred into a fluorescence imaging plate based reader [such as the FLIPR384 (Molecular Devices)]. A baseline fluorescence reading is 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 is read over 5 minute period. 500 μM glutamate solution (10μl_) is added (to give a final concentration of 100 μM). The fluorescence is then read over a 4 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 cyclothiazide at their maximum response (i.e. greater than 30 μM).

Calcium Influx Fluorescence Assay 2

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 100 μM to 1 nM. Compounds of the invention (or reference compounds such as cyclothiazide) 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 buffer 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 buffer a 100 mM sodium glutamate stock solution prepared in water. 10 μL from each plate containing a compound of the invention made up in 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 150μM cyclothiazide at their maximum response.

Calcium Influx Fluorescence Assay 3

This is carried out in a similar manner as Assay 2 above, except that: a) the compounds of the invention are tested in a final assay concentration range from 50 μ M to 50 nM; b) 50 μl_ pluronic buffer (standard buffer with 0.05% pluronic-F127 acid) is added to the 1 μl_ compound copy plate; c) 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; d) the reference compound is Λ/-[(2/?)-2-(4'-cyano-4-biphenylyl)propyl]-2- propanesulfonamide.

The assays described above are 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 at least one of the three assays described above and gave an average pEC₅₀ equal to or greater than 4.0 and/or demonstrated an activity of on average at least 10% that of the reference compound, at its maximal response.

Whole cell voltage-clamp electrophvsiology Assay

The ability of the compounds of the invention to potentiate AMPA-subtype glutamate receptor-mediated response may be determined by measuring AMPA-evoked current recorded from rat cultured hippocampal neurons.

This assay involves the electrophysiological characterisation of AMPA receptor positive modulators using rat cultured hippocampal neurons. The extracellular recording solution contains: 145 mM NaCI, 2.5 mM KCI, 1.2 mM MgCI₂, 1.5 mM CaCI₂, 10 mM N-[2- hydroxyethyl]-piperazine-N-[2-ethanesulfonic acid (HEPES), 10 mM D-glucose, pH 7.3 with NaOH. The intracellular solution contains : 80 mM CsCI, 80 mM CsF, 10 mM N-[2- hydroxyethyl]-piperazine-N-[2-ethanesulfonic acid (HEPES), 10 mM ethylene glycol-bis(g- aminoethylether)-N,N,N',N,-tetra-acetic acid (EGTA), 14 mM MgATP, 14 mM DiTris Creatine Phosphate, 50 U/ml Creatine Phosphokinase pH 7.3 with CsOH. Recording electrodes are prepared from glass capillary tubes (Clark Electromedical GC120-F10) pulled into two equal lengths using a Zeitz Instruments DMZ Universal Puller, program 09, resulting in electrodes with a resistance of approximately 3-6 MOhms when measured in extracellular solution. Electrodes are back filled with internal recording solution. Positive pressure is applied to the electrode to prevent mixture of internal and external solutions and assist in formation of high resistance seal when the electrode makes contact with the cell membrane. Glass coverslip fragment, bearing rat cultured hippocampal neurons, is placed in the recording chamber positioned on the stage of an inverted microscope. A tube at the edge of the chamber is used to apply extracellular solution to the bath. Rapid solution exchange uses a fast step perfusion system (Biologic RSC160). Two outlet tubes attached together along their length are positioned close to a chosen cell so that the outflow from only one tube can pass directly over the cell surface. A motorized stepper could re-position the tubes such that the outflow from the second outlet tube flows over the cell allowing solution exchange at the cell membrane surface to occur within 10-20 ms. Excess bath solution is removed via a tube positioned at the edge of the chamber connected to a vacuum line.

A prospective cell is positioned in the centre of the microscope field of view. Recording electrode is positioned directly above the cell membrane surface. Using fine manipulator control (Luigs and Neumann, SM-6) the electrode is lowered, while monitoring the change in electrode resistance during delivery of a 5 mV depolarizing pulse, until a high resistance seal (gigaseal) is achieved. Whole cell configuration is achieved by removing by suction a small fragment of cell membrane immediately beneath the recording electrode tip. The cell membrane potential is held at -70 mV (voltage-clamped) via the electrode (Axopatch 200B Integrating patch clamp amplifier, pClamp software, Axon Instruments). Test solutions are applied using the fast application system using the following protocol and changes in inward current are recorded and stored for off-line analysis.

1 ) Control current - exchange from extracellular solution to extracellular solution + 30 μM AMPA (2 s application time, 30 s interval between applications) repeated until measurements are stable.

2) Test current - exchange from extracellular solution + 10 nM of compound of invention to extracellular solution + 10 nM of compound of invention + 30 μM AMPA (2 s application time, 30 s interval between applications) repeated until measurements are stable.

All experiments are performed at ambient temperature (20 to 22 ⁰C).

The activity of a compound of the invention is determined by measuring the area under the curve (during 2 s period of application) for the 30 μM AMPA response in the presence of the compound of the invention and expressing it as % of potentiation of the 30 μM AMPA alone response (30 μM AMPA in the absence of the compound of the invention).

Example 8 was tested in this assay. The range of mean responses at 1 OnM showed 1.35 +/- 0.07 fold increase of 30 μM AMPA response, and 2.01 +/- 0.18 fold increase at 10μM.

Claims

Claims

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

(I) wherein:

• R¹ is selected from C(O)Ci-₄alkyl and C(O)NR⁶R⁷, wherein R⁶ and R⁷ are independently selected from hydrogen and C_1-4alkyl, or R⁶ and R⁷, together with the nitrogen to which they are attached, form a saturated 4- to 7-membered ring; • R² is C_1-4alkyl;

• R³ is selected from hydrogen and hydroxyl;

• one of Y and Z is CH, and the other is selected from CF and N;

• R⁴ is selected from halogen, Ci_-6alkoxy, haloCi_-6alkyl, pyridyl and phenyl, wherein the pyridyl and the phenyl are optionally substituted by one to five groups independently selected from halogen and C_1-6alkyl; and

• R⁵ is selected from hydrogen and halogen.

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

1-(2-{[3,5-difluoro-4-(trifluoromethyl)phenyl]imino}-3-ethyl-4-methyl-2,3-dihydro-1 ,3- thiazol-5-yl)ethanone

1-(3-ethyl-2-{[3-fluoro-4-(trifluoromethyl)phenyl]imino}-4-methyl-2,3-dihydro-1 ,3-thiazol-5- yl)ethanone

2-{[4-(ethyloxy)-2-fluorophenyl]imino}-3-(2-hydroxyethyl)-N,N,4-trimethyl-2,3-dihydro-1 ,3- thiazole-5-carboxamide 1-{2-[(6-bromo-3-pyridinyl)imino]-3-ethyl-4-methyl-2,3-dihydro-1 ,3-thiazol-5-yl}ethanone

1-{3-ethyl-2-[(6'-fluoro-2,3'-bipyridin-5-yl)imino]-4-methyl-2,3-dihydro-1 ,3-thiazol-5- yl}ethanone

1-{3-(2-hydroxyethyl)-4-methyl-2-[(6-phenyl-3-pyridinyl)imino]-2,3-dihydro-1 ,3-thiazol-5- yl}ethanone 1-[2-{[6-(4-fluorophenyl)-3-pyridinyl]imino}-3-(2-hydroxyethyl)-4-methyl-2,3-dihydro-1 ,3- thiazol-5-yl]ethanone

1-[2-{[6-(2-fluorophenyl)-3-pyridinyl]imino}-3-(2-hydroxyethyl)-4-methyl-2,3-dihydro-1 ,3- thiazol-5-yl]ethanone

1-[2-{[6-(3-fluorophenyl)-3-pyridinyl]imino}-3-(2-hydroxyethyl)-4-methyl-2,3-dihydro-1 ,3- thiazol-5-yl]ethanone

1-(3-(2-hydroxyethyl)-4-methyl-2-{[6-(trifluoromethyl)-3-pyridinyl]imino}-2,3-dihydro-1 ,3- thiazol-5-yl)ethanone 1-[2-[(5-bromo-2-pyridinyl)imino]-3-(2-hydroxyethyl)-4-methyl-2_!3-dihydro-1 ,3-thiazol-5- yl]ethanone

1-(3-(2-hydroxyethyl)-4-methyl-2-{[5-(trifluoromethyl)-2-pyridinyl]imino}-2_!3-dihydro-1 ,3- thiazol-5-yl)ethanone 1-{3-(2-hydroxyethyl)-4-methyl-2-[(5-phenyl-2-pyridinyl)imino]-2_!3-dihydro-1 ,3-thiazol-5- yl}ethanone

1-[2-[(6-bromo-3-pyridinyl)imino]-3-(2-hydroxyethyl)-4-methyl-2_!3-dihydro-1 ,3-thiazol-5- yl]ethanone

1-(3-(2-hydroxyethyl)-4-methyl-2-{[6-(4-methylphenyl)-3-pyridinyl]imino}-2_!3-dihydro-1 ,3- thiazol-5-yl)ethanone or a salt thereof.

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

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.