WO2010018214A1 - Pyrrolidinone derivatives useful for the treatement of psychotic and neurological disorders - Google Patents

Abstract

The present invention relates to compounds, processes for their preparation, pharmaceutical compositions and medicaments containing them and to their use in the treatment of a condition wherein inhibition of GIyT1 would be beneficial, including neurological and neuropsychiatric disorders, in particular psychoses, dementia or attention deficit disorder.

Description

PYRROLIDINONE DERIVATIVES USEFUL FOR THE TREATEMNT OF PSYCHOTIC

AND NEUROLOGICAL DISORDERS

The present invention relates to compounds, processes for their preparation, pharmaceutical compositions and medicaments containing them and to their use in the treatment of a condition wherein inhibition of GIyTI would be beneficial, including neurological and neuropsychiatric disorders, in particular psychoses, dementia or attention deficit disorder.

Molecular cloning has revealed the existence in mammalian brains of two classes of glycine transporters, termed GIyTI and GlyT2. GIyTI is found throughout the brain and may be located at NMDA glutamate receptor synapses as well as in areas containing inhibitory glycine receptors (Cubelos et al., Cerebral Cortex, 15, 2005: 448-459; Zafra et al., Eur. J. Neurosci. 7, 1995: 1342-1352). Molecular cloning has further revealed the existence of three variants of GIyTI , termed GIyT-Ia, GIyT-I b and GIyT-I c (Kim et al., Molecular Pharmacology, 45, 1994: 608-617), each of which displays a unique distribution in the brain and peripheral tissues. The variants arise by differential splicing and exon usage, and differ in their N-terminal regions. GlyT2, in contrast, is found predominantly in the brain stem and spinal cord, and its distribution corresponds closely to that of inhibitory glycine receptors (Liu et al., J. Biological Chemistry, 268, 1993: 22802-22808; Jursky and Nelson, J. Neurochemistry, 64, 1995 : 1026-1033). Another distinguishing feature of glycine transport mediated by GlyT2 is that it is not inhibited by sarcosine as is the case for glycine transport mediated by GIyTL Studies involving selective knockout of either GIyTI or GlyT2 have also suggested that the role of GIyTI is to regulate glycine levels at both NMDA glutamate receptors and inhibitory glycine receptors, whereas the main role of GlyT2 may be to replenish glycine in presynaptic terminals of inhibitory glycinergic synapses (Gomeza et al., Neuron 40, 2003, 785-796 & 797-806).

NMDA receptors are critically involved in memory and learning (Rison and Staunton, Neurosci. Biobehav. Rev., 19 533-552 (1995); Danysz et al, Behavioral Pharmacol., 6 455-474 (1995)); and, furthermore, decreased function of NMDA-mediated neurotransmission appears to contribute to the symptoms of schizophrenia (Lisman et al., Trends Neurosci. 31 , 234-242 (2008); Olney and Farber, Archives General Psychiatry, 52, 998-1007 (1996)). Thus, agents that inhibit GIyTI and thereby increase glycine activation of NMDA receptors can be used as novel antipsychotics and anti-dementia agents, and to treat other diseases in which cognitive processes are impaired, such as attention deficit disorders and organic brain syndromes. Glycine transport inhibitors are already known in the art, for example as disclosed in published international patent application WO03/055478 (SmithKline Beecham).

However, there still remains the need to identify further compounds that can inhibit GIyTI transporters, including those that inhibit GIyTI transporters selectively over GlyT2 transporters.

It has now been found that a novel class of compounds inhibit GIyTI transporters and are thus useful in the treatment of certain neurological and neuropsychiatric disorders, including schizophrenia.

Thus, in the first aspect, there is provided a compound of formula (I) or a salt thereof:

(I) wherein:

(in the 5-membered nitrogen containing ring) is a single bond or a double bond;

R¹ is selected from H, C₁-C₄alkyl, C₁-C₄BIkOXy, halo, haloCi-C₄alkyl, haloCr^alkoxy, C₁- C₄alkylthio, C₃-C₆cycloalkyl, C_rC₄alkylsulfonyl, Ci-C₄alkoxyCrC₄alkyl, CONR^aR^b (wherein R^a and R^b are independently selected from H and CτC₄alkyl, or R^a and R^b, together with the nitrogen atom to which they are attached, form a 4- to 7-membered ring) and cyano;

R² is selected from H, Ci-C₄alkyl, CrC₄alkoxy, halo, haloCi-C₄alkyl, haloCi-C₄alkoxy, C₁- C₄alkylthio, C₃-C₆cycloalkyl, C_rC₄alkylsulfonyl, Ci-C₄alkoxyCrC₄alkyl , CONR^cR^d (wherein R^c and R^d are independently selected from H and Ci-C₄alkyl, or R^c and R^d, together with the nitrogen atom to which they are attached, form a 4- to 7-membered ring) and cyano; R³ is selected from H, Ci_-4alkyl, CrC₄alkoxy, halo, haloCrC₄alkyl, haloCrC₄alkoxy, d- C₄alkylthio, C₃-C₆cycloalkyl, C_rC₄alkylsulfonyl, Ci-C₄alkoxyC_rC₄alkyl, CONR^eR^f (wherein R^e and R^f are independently selected from H and CrC₄alkyl, or R^e and R^f, together with the nitrogen atom to which they are attached, form a 4- to 7-membered ring) and cyano;

or R² and R³ together form a group selected from -0-CH₂-O- and -0-CH₂-CH₂-O-;

R⁴ is selected from H, CτC₄alkyl, Ci-C₄alkoxy, halo, haloCi-C₄alkyl, haloCi-C₄alkoxy, C₁- C₄alkylthio, C₃-C₆cycloalkyl, C_rC₄alkylsulfonyl, Ci-C₄alkoxyCi-C₄alkyl, C0NR⁹R^h (wherein R⁹ and R^h are independently selected from H and CτC₄alkyl, or R⁹ and R^h, together with the nitrogen atom to which they are attached, form a 4- to 7-membered ring) and cyano;

R⁵ is selected from hydrogen, chloro, fluoro, Ci-C₄alkyl and CF₃;

R⁶ is selected from a 5-7 membered heteroaryl or 5 to 7 membered heterocyclic ring optionally substituted by Ci_-4 alkyl, Ci_-4 alkoxy, haloalkyl, haloalkoxy, halo or cyano;

R⁷ is selected from H, Ci-C₄alkyl, Ci-C₄alkoxy, haloCi-C₄alkyl, haloCi-C₄alkoxy, halo, cyano, Ci_-4alkoxyCi_-4alkyl and Ci-C₄alkoxyCrC₄alkoxy;

m is selected from 0, 1 and 2;

R⁸ is selected from hydrogen and Ci-C₄alkyl;

R²¹ is selected from H and fluoro.

As used herein, the term "Ci-C₄alkyl" refers to a straight or branched alkyl group of 1-4 carbon atoms in all isomeric forms. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl.

As used herein, the term ""C_rC₄alkoxy" refers to the group -O-Ci-C₄alkyl wherein C_r C₄alkyl is as defined above.

As used herein, the term "C_rC₄alkoxyCi-C₄alkyl" refers to the group (Ci_-4alkyl)-O-(Ci_ ₄alkyl), wherein Ci-C₄alkyl is as defined above. As used herein, the term "CrC₄alkoxyCrC₄alkyoxy" refers to the group

4alkyl, wherein d-C₄alkyl is as defined above.

As used herein, the term "C₃-C₆cycloalkyl" refers to a cycloalkyl group consisting of from 3 to 6 carbon atoms, ie cyclopropane, cyclobutane, cyclopentane or cyclohexane.

As used herein, the terms "halogen" and its abbreviation "halo" refer to fluorine, chlorine, bromine, or iodine.

As used herein, the term "haloC₁-C₄alkyl" refers to a C₁-C₄alkyl group as defined above which is substituted with any number of fluorine, chlorine, bromine, or iodine atoms, including with mixtures of those atoms. A haloC₁-C₄alkyl group may, for example contain 1 , 2 or 3 halogen atoms. For example, a haloC₁-C₄alkyl group may have all hydrogen atoms replaced with halogen atoms. Examples of haloC₁-C₄alkyl groups include fluoromethyl, difluoromethyl and trifluoromethyl.

As used herein, the term "haloCi-C₄alkoxy" refers to a CrC₄alkoxy group as defined above which is substituted with any number of fluorine, chlorine, bromine, or iodine atoms, including with mixtures of those atoms. A haloCrC₄alkoxy group may, for example contain 1 , 2 or 3 halogen atoms. For example, a haloCrC₄alkoxy group may have all hydrogen atoms replaced with halogen atoms. Examples of haloCrC₄alkoxy groups include fluoromethyloxy, difluoromethyloxy and trifluoromethyloxy.

As used herein the term "cyano" refers to a group -CN.

As used herein, the term "C₁-C₄alkylsulfonyl" refers to a group -SO₂(C₁-C₄alkyl). An example is -SO₂CH₃.

As used herein, the term "C₁-C₄alkylthio" refers to a group -S -(C₁-C₄alkyl). An example is -SCH₃.

As used herein, the term "5-7 membered heteroaryl" refers to an aromatic or a benzofused aromatic ring containing 1 to 4 heteroatoms selected from oxygen, nitrogen and sulphur. Examples of such aromatic rings include thienyl, furyl, pyrrolyl, triazolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyridazyl, triazinyl and tetrazolyl. Suitable examples of benzofused aromatic rings include quinolinyl, isoquinolinyl, indolyl, benzofuryl, benzothienyl, benzoimidazolyl and benzoxazolyl.

As used herein, the term "5-7 membered heterocyclic ring" refers to a non aromatic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulphur. Examples of such non aromatic rings include piperidinyl, piperazinyl, pyrrolidinyl and morpholinyl.

The heteroaryl and 5-7 membered heterocyclic rings, as described above, may be linked to the remainder of the molecule via a carbon atom, or when present, a suitable nitrogen atom.

In one embodiment R¹ is selected from H, C₁-C₂alkyl, C₁-C₂BIkOXy, halo, haloC₁-C₂alkyl, haloCrC^lkoxy, CrC^lkylthio, CrC^lkylsulfonyl, Ci-C₂alkoxyCi-C₂alkyl and cyano. In a further embodiment R¹ is H.

In one embodiment R² is selected from H, Ci-C₂alkyl, Ci-C₂alkoxy, halo, haloCrC₂alkyl, haloCi-C₂alkoxy, Ci-C₂alkylthio, Ci-C₂alkylsulfonyl, Ci-C₂alkoxyCrC₂alkyl, and cyano. In a further embodiment R² is halo. In a further embodiment R² is F.

In one embodiment R³ is selected from H, Ci-C₂alkyl, Ci-C₂alkoxy, halo, haloCrC₂alkyl, haloCi-C₂alkoxy, Ci-C₂alkylthio, Ci-C₂alkylsulfonyl, Ci-C₂alkoxyCrC₂alkyl, and cyano. In a further embodiment R³ is H.

In one embodiment R⁴ is selected from H, Ci-C₂alkyl, Ci-C₂alkoxy, halo, haloCrC₂alkyl, haloCrC^lkoxy, CrC^lkylthio, CrC^lkylsulfonyl, CτC₂alkoxyCi-C₂alkyl, and cyano. In a further embodiment R⁴ is halo. In a further embodiment R⁴ is F.

In one embodiment R⁵ is selected from hydrogen, chloro, fluoro, C-rC₄alkyl and CF₃. In a further embodiment R⁵ is H.

In one embodiment R⁶ is imidazole.

In one embodiment R⁷ is selected from H, d-C₂alkyl, CrC₂alkoxy, haloCi-C₂alkyl, haloCi-C₂alkoxy, halo, cyano, Ci-C₂alkoxyCrC₂alkyl and Ci-C₂alkoxyCi-C₂alkoxy. In a further embodiment R⁷ is H. In one embodiment m is 1.

In one embodiment R⁸ is H.

In one embodiment R²¹ is H.

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.

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

As used herein, the term "salt" refers to any salt of a compound according to the present invention prepared from an inorganic or organic acid or base, quaternary ammonium salts and internally formed salts. Pharmaceutically acceptable salts are particularly suitable for medical applications because of their greater aqueous solubility relative to the parent compounds. Such salts must clearly have a pharmaceutically acceptable anion or cation. Suitably pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts formed with inorganic acids such as hydrochloric, hydrobromic, hydroiodic, phosphoric, metaphosphoric, nitric and sulfuric acids, and with organic acids, such as tartaric, acetic, trifluoroacetic, citric, malic, lactic, fumaric, benzoic, formic, propionic, glycolic, gluconic, maleic, succinic, (1 R)-(-)-10-camphorsulphonic, (1S)-(+)-10- camphorsulphonic, isothionic, mucic, gentisic, isonicotinic, saccharic, glucuronic, furoic, glutamic, ascorbic, anthranilic, salicylic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, pantothenic, stearic, sulfinilic, alginic, galacturonic and arylsulfonic, for example naphthalene-1 ,5-disulphonic, naphthalene-1 ,3-disulphonic, benzenesulfonic, and p-toluenesulfonic, acids. 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.

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

In one embodiment, there is provided a compound of formula (I) as defined above or a hydrochloride or a formate salt thereof.

Solvates of the compounds of formula (I) and solvates of the salts of the compounds of formula (I) are included within the scope of the present invention. As used herein, the term

"solvate" refers to a complex of variable stoichiometry formed by a solute (in this invention, a compound of formula (I) or a salt thereof) and a solvent. Those skilled in the art of organic chemistry will appreciate that many organic compounds can form such complexes with solvents in which they are reacted or from which they are precipitated or crystallized. Such solvents for the purpose of the invention may not interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, methanol, ethanol and acetic acid. Preferably the solvent used is a pharmaceutically acceptable solvent. Examples of suitable pharmaceutically acceptable solvents include, without limitation, water, ethanol and acetic acid. Most preferably the solvent used is water. Where the solvent used is water such a solvate may then also be referred to as a hydrate.

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

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

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

The invention also includes all suitable isotopic variations of a compound of the invention. An isotopic variation of a compound of the invention is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine and chlorine such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁷O, ¹⁸O, ³¹P, ³²P, ³⁵S, ¹⁸F and ³⁶CI, respectively. Certain isotopic variations of the invention, for example, those in which a radioactive isotope such as ³H or ¹⁴C is incorporated, are useful in drug and/or substrate tissue distribution studies. Tritiated, i.e., ³H, and carbon-14, i.e., ¹⁴C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with isotopes such as deuterium, i.e., ²H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements and hence may be preferred in some circumstances. Isotopic variations of the compounds of the invention can generally be prepared by conventional procedures such as by the illustrative methods or by the preparations described in the Examples hereafter using appropriate isotopic variations of suitable reagents. Certain of the compounds described herein may exist in stereoisomeric forms (i.e. they may contain one or more asymmetric carbon atoms or may exhibit cis-trans isomerism). The individual stereoisomers (enantiomers and diastereoisomers) and mixtures of these are included within the scope of the present invention. Likewise, it is understood that compounds of formula (I) may exist in tautomeric forms other than that shown in the formula and these are also included within the scope of the present invention.

In one embodiment, an optically pure enantiomer of a compound of the present invention is provided. The term "optically pure enantiomer" means that the compound contains greater than about 90 % of the desired isomer by weight, such as greater than about 95 % of the desired isomer by weight, or greater than about 99 % of the desired isomer by weight, said weight percent based upon the total weight of the isomer(s) of the compound.

Compounds of general formula (I) may be prepared by methods known in the art of organic synthesis as set forth in part by the following synthesis schemes. It is also recognised that in all of the schemes described below, it is well understood that protecting groups for sensitive or reactive groups are employed where necessary in accordance with general principles of chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (T. W. Greene and P. G. M. Wuts (1991 ) Protecting Groups in Organic Synthesis, John Wiley & Sons). These groups are removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art. The selection of processes as well as the reaction conditions and order of their execution shall be consistent with the preparation of compounds of formula (I).

Typical reaction routes for the preparation of a compound of formula (I) as hereinbefore defined, are shown below.

Typical reaction routes for the preparation of a compound of formula (I) as hereinbefore defined, are shown below:

Compounds of formula (I) wherein ^{^^}~ is a single bond or a double bond, can be prepared by reacting a compound of formula (II) wherein ^{^^}~ is a single bond or a double bond, with a base, for example sodium hydride, in a suitable inert solvent, for example dimethylformamide, followed by treatment with a compound of formula (III) as shown in Scheme 1 where X is for example bromo or chloro. Scheme 1

(I)

Compounds of formula (III) can be prepared by standard methods, for example as shown in Scheme 2. For example, an aniline of formula (IV) may be combined with an haloacetyl halide of formula (XIII) where X and X' are halogen, for example chloroacetyl chloride or bromoacetyl chloride in an inert solvent, for example, dioxan and heated to give a compound of formula (III).

Scheme 2

Compounds of formula (II) wherein is a double bond can be prepared according to the reactions of Scheme 3.

Scheme 3

The amido alcohol (V) is treated with an oxidising agent, for example, IBX, DMSO/acetic anhydride or DMSO/oxalyl chloride step (i) in the presence of a base such as triethylamine to give the intermediate aldehyde (Vl). The intermediate aldehyde is subsequently submitted to intramolecular condensation step (ii) in the presence of for example, sodium hydroxide in ethanol or ammonium acetate in an inert solvent such as toluene.

Amido alcohols (V) are readily prepared by acylating the amino alcohol (VII) with an activated arylacetic acid (VIII) as shown in scheme 4 where L is a leaving group such as halogen, OC(=O)alkyl, OC(=O)O-alkyl and OSO₂Me. L may be halogen and acylation may be carried out in an inert solvent such as dichloromethane, in the presence of a base, such as triethylamine.

Scheme 4

Alternatively compounds (V) may be prepared from aryl; acetic acids (IX) as shown in scheme 5 by treating the amino alcohol (VII) with acid (IX) in an inert solvent, such as dichloromethane in the presence of a coupling reagent, for example a diimide reagent such as N, N dicyclohexylcarbodiimide (DCC), N-(3-(dimethylamino)propyl)-N- ethylcarbodiimide hydrochloride (EDC), or O-(7-azabenzotriazol-1-yl)-1 , 1 ,3,3- tetramethyluronium hexafluoro phosphate (HATU).

Amino alcohols (VII), and arylacetic acids (IX) and activated aryl acetic acids such as acid chlorides (VIII) L = Cl are either known compounds or readily prepared by standard methods.

Scheme 5

(VII) (IX) (V)

Compounds of formula (II) wherein ^{^^}~ is a single bond can be prepared from compounds of formula (II) wherein ^{^^}~ is a double bond scheme 6 wherein in R⁶, R⁷, R⁸ and R²¹ are as defined in formula (I)

Scheme 6

Treatment of a compound of formula (II) wherein is a double bond with hydrogen at atmospheric or elevated pressure, preferably elevated for example at 50 psi in the presence of a catalyst such as palladium on charcoal, in a solvent such as ethanol or acetic acid results in a compound of formula (II) wherein ^{^^}~ is a single bond .

Alternatively compounds of formula (II) wherein ^{^^}~ is a single bond or a double bond can be prepared as shown in scheme 7 wherein R⁶, R⁷, R⁸ and R²¹ are as defined in formula (I) by application of palladium or copper mediated chemistry.

Scheme 7

For example, treatment of a compound of structure (X) with an appropriate palladium catalyst such as tetrakis(triphenylphosphine)palladium[0] or palladium acetate in conjunction with a phosphine ligand such as 1 ,3-(bis)triphenylphosphino)propane, a base such as sodium carbonate, triethylamine or diisopropylamine and a heteroaryl boronic acid or heteroaryl trialkyltin reagent may undergo palladium mediated coupling to give a compound of formula (II) where R⁶ is a carbon linked heteroaryl group. These reactions may be performed in a range of solvents including tetrahydrofuran, dimethylformamide, dioxan or toluene, or combinations of solvents, optionally in the presence of an ionic liquid such as 1-butyl-3-imidazolium tetrafluoroborate either at ambient or preferably elevated temperatures.

Alternatively, treatment of a compound of structure (X) with an appropriate palladium catalyst such as tetrakis(triphenylphosphine)palladium[0] or palladium acetate in conjunction with a phosphine ligand such as 2,2'-bis(diphenylphosphino)-1 ,1 '- binaphthalene (BINAP), a base such as cesium carbonate or potassium phosphate, and a 5 to 7 membered heterocyclic ring containing a secondary amine, such as piperidine or morpholine, may undergo palladium mediated coupling to give a compound of formula (II) where R⁶ is a nitrogen linked 5-7 membered heterocyclic group. These reactions may be performed in a range of solvents including tetrahydrofuran, dimethylformamide, dioxan or toluene, or combinations of solvents, optionally in the presence of an ionic liquid such as 1 -butyl-3-imidazolium tetrafluoroborate either at ambient or preferably elevated temperatures.

Alternatively, treatment of a compound of structure (X) with an appropriate copper catalyst such as copper (I) bromide or copper (I) iodide, in conjunction with a β-ketoester ligand such as ethyl 2-oxocyclohexanecarboxylate or diamine ligand such as trans-1 ,2- diaminocylohexane, a base such as cesium carbonate or potassium phosphate and a heteroaryl or 2-oxo substituted 5-7 membered heterocyclic ring containing a free NH, may undergo copper mediated coupling to give a compound of formula (II) where R⁶ is a nitrogen linked heteroaromatic or 2-oxo substituted 5-7 membered heterocyclic ring. These reactions may be performed in a range of solvents such as dimethyl sulphoxide, N,N-dimethylformamide, N-methylpyrrolidinone, acetonitrile or dioxan or combinations of solvents, optionally in the presence of an ionic liquid such as 1 -butyl-3-imidazolium tetrafluoroborate either at ambient or preferably elevated temperatures.

Alternatively, compounds of formula (II) can be prepared as shown in scheme 8 wherein R⁷, R⁸ and R²¹ are as defined in formula (I) and R⁶ is a carbon linked heteroaryl group from intermediates such as where R⁶ is a carboxylic acid (XIX) or R⁶ is a cyano group (XX) using standard methods for preparation of heterocyclic systems such as those described in series such as Organic Syntheses, The Chemistry of Heterocycles or Comprehensive Heterocyclic Chemistry.

Scheme 8

(H) Nitrile (XII) can be prepared from (X) by treatment with a cyanide such as copper (I) cyanide, in a solvent such as N,N-dimethylformamide or N-methylpyrrolidinone at elevated temperature. Carboxylic acid (Xl) may be prepared by acidic hydrolysis of nitrile (XII) or directly from (X) by treatment with 2 equivalents of alkyllithium at reduced temperature followed by addition of carbon dioxide, or through palladium mediated carbonylation methodology.

Compounds of formula (II) wherein ^{^^}~ is a single bond or a double bond can also be converted to compounds of formula (I) as shown in Scheme 9.

Scheme 9

wherein R , R , R , R , R R , R , R and R are as defined for compounds of formula (I).

Compounds of formula (XIII) can be prepared using standard methods from compounds of formula (II), step (iii), for example, by reaction with an appropriate haloester in the presence of a base, such as sodium hydride or potassium carbonate, in a suitable inert solvent, such as dimethylformamide, at room temperature or elevated temperature as appropriate.

Removal of the ester group R from compounds of formula (XIII) to afford the acids of formula (XIV), step (iv), can be achieved by known methods, for example by use of a base, such as sodium hydroxide, in an inert solvent, such as aqueous methanol or aqueous ethanol, with or without heating as appropriate.

Compounds of formula (XIV) can be converted to compounds of formula (I), step (v), by reaction with an aniline of formula (IV) using a variety of methods known in the art. For example, the acylation step (v) can be achieved by reaction of the acid (XIV) with an aniline of formula (IV), in an inert solvent, such as dichloromethane in the presence of a coupling reagent, for example a diimide reagent such as N, N dicyclohexylcarbodiimide

(DCC), N-(3-(dimethylamino)propyl)-N-ethylcarbodiimide hydrochloride (EDC), or O-(7- azabenzotriazol-1-yl)-1 ,1 ,3,3-tetramethyluronium hexafluoro phosphate (HATU).

Alternatively, compounds of formula (XIV) are converted to compounds of formula (XV)

wherein R⁶, R⁷, R⁸ and R²¹ are as defined in formula (I) and L represents a suitable leaving group. Examples of leaving groups include halogen, OC(=O)alkyl, OC(=O)O-alkyl and OSC^Me. L may be halogen and acylation in step (v) may be carried out in an inert solvent such as dichloromethane, in the presence of a base, such as triethylamine.

Within the scheme there is scope to convert a group R¹ into another group R¹ and similarly for groups R², R³, R⁴ R⁵' R⁶, R⁷' R²¹. For example, scheme 10, a compound of formula (I) where R⁶ is bromo may be converted to compounds of formula (I) wherein R⁶ is heteroaryl or a 5-7 membered heterocyclic ring using either palladium or copper mediated coupling using methods as indicated in Scheme 7. Alternatively a heterocycle may be constructed from a compound of formula (I) where R⁶ is bromo via a carboxylic acid or cyano intermediate using procedures as indicated in Scheme 8.

Compounds of formula (I), (II), (XIII) or (XIV) wherein ^{^^}~ is a double bond can be converted into the corresponding compound of formula (I), (XIII) or (XIV) wherein ^{^^}~ is a single bond according to the reaction conditions of scheme 6.

Compounds of formula (I) can be converted into further compounds of formula (I) using standard techniques. Salts may be prepared conventionally by reaction with the appropriate acid or acid derivative.

The compounds of the present invention inhibit the GIyTI transporter. The compounds may selectively inhibit the GIyTI transporter over the GlyT2 transporter. Some compounds of the invention may have mixed GlyT-1/GlyT-2 activity.

Such compounds would be suitable for the treatment of certain neurological and neuropsychiatric disorders. As used herein, the terms "treatment" and "treating" refer to the alleviation and/or cure of established symptoms as well as prophylaxis.

The affinities of the compounds of this invention for the GIyTI transporter can be determined by the following assay. HEK293 cells expressing the Glycine (Type 1 ) transporter were grown in cell culture medium [DMEM/NUT mix F12 containing 2mM L-Glutamine, 0.8mg/ml_ G418 and 10% heat inactivated fetal calf serum] at 37°C and 5% CO₂. Cells grown to 70-80% confluency in T175 flasks were harvested and resuspended at 4x10⁵ cells/mL in assay buffer [14OmM NaCI, 5.4mM KCI, 1.8mM CaCI₂, 0.8mM MgSO₄, 2OmM HEPES, 5mM glucose and 5mM alanine, pH 7.4]. Compounds were serially diluted 2.5-fold in DMSO from a top concentration of 2.5mM with each compound giving a 1 1 data point dose-response. 10OnL of compound at each concentration was added to the assay plate. An equal volume of Leadseeker™ WGA SPA beads (12.5mg/ml suspended in assay buffer) was added to the cell suspension and 5μl_ of the cell/bead suspension transferred to each well of a 384-well white solid bottom plate (1 ,000 cells/well) containing 10OnL of test compounds. Substrate (5μL) was added to each well [1 :100 dilution of [³H]-glycine stock in assay buffer containing 2.5μM glycine). Final DMSO concentration was 1% v/v. Data was collected using a Perkin Elmer Viewlux. plC₅₀ values were determined using ActivityBase.

Compounds are considered to have activity at the the GIyTI transporter if they have a plC₅₀ of 5.0 or above in the above assay. The example compounds below and the individually named compounds above were found to have an average plC₅o at the GIyTI transporter of greater than or equal to 5.6. In the assay, the compounds of the present invention were not necessarily from the same batch described below. A test compound from one batch may have been combined with other batch(es) for the assay(s).

The compounds of the present invention inhibit the GIyTI transporter, as measured by the assay above. Such compounds are therefore of potential utility for the treatment of certain neurological and neuropsychiatric disorders. The compounds may selectively inhibit the GIyTI transporter over the GlyT2 transporter. Some compounds of the invention may have mixed GlyT1/GlyT2 activity.

In one embodiment, the disorder to be treated by the use or method as hereinbefore described is a psychosis, including schizophrenia, dementia and attention deficit disorders. In one embodiment, the disorder is schizophrenia.

Within the context of the present invention, the terms used herein are classified in the Diagnostic and Statistical Manual of Mental Disorders, 4^th Edition, published by the

American Psychiatric Association (DSM-IV) and/or the International Classification of Diseases, 10^th Edition (ICD-10). Treatment of the various subtypes of the disorders mentioned herein using the compounds of the invention are contemplated as part of the present invention. Numbers in brackets after the listed diseases below refer to the classification code in DSM-IV.

In particular, the compounds of the invention be of use in the treatment of schizophrenia including the subtypes Paranoid Type (295.30), Disorganised Type (295.10), Catatonic Type (295.20), Undifferentiated Type (295.90) and Residual Type (295.60); Schizophreniform Disorder (295.40); Schizoaffective Disorder (295.70) including the subtypes Bipolar Type and Depressive Type; Delusional Disorder (297.1 ) including the subtypes Erotomanic Type, Grandiose Type, Jealous Type, Persecutory Type, Somatic Type, Mixed Type and Unspecified Type; Brief Psychotic Disorder (298.8); Shared Psychotic Disorder (297.3); Psychotic Disorder Due to a General Medical Condition including the subtypes With Delusions and With Hallucinations; Substance-Induced Psychotic Disorder including the subtypes With Delusions (293.81 ) and With Hallucinations (293.82); and Psychotic Disorder Not Otherwise Specified (298.9).

The compounds of the invention may be also of use in the treatment of mood disorders including Major Depressive Episode, Manic Episode, Mixed Episode and Hypomanic Episode; Depressive Disorders including Major Depressive Disorder, Dysthymic Disorder (300.4), Depressive Disorder Not Otherwise Specified (311 ); Bipolar Disorders including Bipolar I Disorder, Bipolar Il Disorder (Recurrent Major Depressive Episodes with Hypomanic Episodes) (296.89), Cyclothymic Disorder (301.13) and Bipolar Disorder Not Otherwise Specified (296.80); Other Mood Disorders including Mood Disorder Due to a General Medical Condition (293.83) which includes the subtypes With Depressive Features, With Major Depressive-like Episode, With Manic Features and With Mixed Features), Substance-Induced Mood Disorder (including the subtypes With Depressive Features, With Manic Features and With Mixed Features) and Mood Disorder Not Otherwise Specified (296.90).

The compounds of the invention may also be of use in the treatment of anxiety disorders including Panic Attack, Agoraphobia, Panic Disorder, Agoraphobia Without History of Panic Disorder (300.22), Specific Phobia (300.29) including the subtypes Animal Type, Natural Environment Type, Blood-lnjection-lnjury Type, Situational Type and Other Type), Social Phobia (300.23), Obsessive-Compulsive Disorder (300.3), Posttraumatic Stress Disorder (309.81 ), Acute Stress Disorder (308.3), Generalized Anxiety Disorder (300.02), Anxiety Disorder Due to a General Medical Condition (293.84), Substance-Induced Anxiety Disorder and Anxiety Disorder Not Otherwise Specified (300.00).

The compounds of the invention may also be of use in the treatment of substance-related disorders including Substance Use Disorders such as Substance Dependence and Substance Abuse; Substance-Induced Disorders such as Substance Intoxication, Substance Withdrawal, Substance-Induced Delirium, Substance-Induced Persisting Dementia, Substance-Induced Persisting Amnestic Disorder, Substance-Induced Psychotic Disorder, Substance-Induced Mood Disorder, Substance-Induced Anxiety Disorder, Substance-Induced Sexual Dysfunction, Substance-Induced Sleep Disorder and Hallucinogen Persisting Perception Disorder (Flashbacks); Alcohol-Related Disorders such as Alcohol Dependence (303.90), Alcohol Abuse (305.00), Alcohol Intoxication (303.00), Alcohol Withdrawal (291.81 ), Alcohol Intoxication Delirium, Alcohol Withdrawal Delirium, Alcohol-Induced Persisting Dementia, Alcohol-Induced Persisting Amnestic Disorder, Alcohol-Induced Psychotic Disorder, Alcohol-Induced Mood Disorder, Alcohol- Induced Anxiety Disorder, Alcohol-Induced Sexual Dysfunction, Alcohol-Induced Sleep Disorder and Alcohol-Related Disorder Not Otherwise Specified (291.9); Amphetamine (or Amphetamine-I_ike)-Related Disorders such as Amphetamine Dependence (304.40), Amphetamine Abuse (305.70), Amphetamine Intoxication (292.89), Amphetamine Withdrawal (292.0), Amphetamine Intoxication Delirium, Amphetamine Induced Psychotic Disorder, Amphetamine-Induced Mood Disorder, Amphetamine-Induced Anxiety Disorder, Amphetamine-Induced Sexual Dysfunction, Amphetamine-Induced Sleep Disorder and Amphetamine-Related Disorder Not Otherwise Specified (292.9); Caffeine Related Disorders such as Caffeine Intoxication (305.90), Caffeine-Induced Anxiety Disorder, Caffeine-Induced Sleep Disorder and Caffeine-Related Disorder Not Otherwise Specified (292.9); Cannabis-Related Disorders such as Cannabis Dependence (304.30), Cannabis Abuse (305.20), Cannabis Intoxication (292.89), Cannabis Intoxication Delirium, Cannabis-lnduced Psychotic Disorder, Cannabis-lnduced Anxiety Disorder and Cannabis- Related Disorder Not Otherwise Specified (292.9); Cocaine-Related Disorders such as Cocaine Dependence (304.20), Cocaine Abuse (305.60), Cocaine Intoxication (292.89), Cocaine Withdrawal (292.0), Cocaine Intoxication Delirium, Cocaine-Induced Psychotic Disorder, Cocaine-Induced Mood Disorder, Cocaine-Induced Anxiety Disorder, Cocaine- Induced Sexual Dysfunction, Cocaine-Induced Sleep Disorder and Cocaine-Related Disorder Not Otherwise Specified (292.9); Hallucinogen-Related Disorders such as Hallucinogen Dependence (304.50), Hallucinogen Abuse (305.30), Hallucinogen Intoxication (292.89), Hallucinogen Persisting Perception Disorder (Flashbacks) (292.89), Hallucinogen Intoxication Delirium, Hallucinogen-Induced Psychotic Disorder, Hallucinogen-Induced Mood Disorder, Hallucinogen-Induced Anxiety Disorder and Hallucinogen-Related Disorder Not Otherwise Specified (292.9); Inhalant-Related Disorders such as Inhalant Dependence (304.60), Inhalant Abuse (305.90), Inhalant Intoxication (292.89), Inhalant Intoxication Delirium, Inhalant-Induced Persisting Dementia, Inhalant-Induced Psychotic Disorder, Inhalant-Induced Mood Disorder, Inhalant-Induced Anxiety Disorder and Inhalant-Related Disorder Not Otherwise Specified (292.9); Nicotine-Related Disorders such as Nicotine Dependence (305.1 ), Nicotine Withdrawal (292.0) and Nicotine-Related Disorder Not Otherwise Specified (292.9); Opioid-Related Disorders such as Opioid Dependence (304.00), Opioid Abuse (305.50), Opioid Intoxication (292.89), Opioid Withdrawal (292.0), Opioid Intoxication Delirium, Opioid-lnduced Psychotic Disorder, Opioid-lnduced Mood Disorder, Opioid-lnduced Sexual Dysfunction, Opioid-lnduced Sleep Disorder and Opioid-Related Disorder Not Otherwise Specified (292.9); Phencyclidine (or Phencyclidine-Like)-Related Disorders such as Phencyclidine Dependence (304.60), Phencyclidine Abuse (305.90), Phencyclidine Intoxication (292.89), Phencyclidine Intoxication Delirium, Phencyclidine- lnduced Psychotic Disorder, Phencyclidine-lnduced Mood Disorder, Phencyclidine- lnduced Anxiety Disorder and Phencyclidine-Related Disorder Not Otherwise Specified (292.9); Sedative-, Hypnotic-, or Anxiolytic-Related Disorders such as Sedative, Hypnotic, or Anxiolytic Dependence (304.10), Sedative, Hypnotic, or Anxiolytic Abuse (305.40), Sedative, Hypnotic, or Anxiolytic Intoxication (292.89), Sedative, Hypnotic, or Anxiolytic Withdrawal (292.0), Sedative, Hypnotic, or Anxiolytic Intoxication Delirium, Sedative, Hypnotic, or Anxiolytic Withdrawal Delirium, Sedative-, Hypnotic-, or Anxiolytic-Persisting Dementia, Sedative-, Hypnotic-, or Anxiolytic- Persisting Amnestic Disorder, Sedative-, Hypnotic-, or Anxiolytic-lnduced Psychotic Disorder, Sedative-, Hypnotic-, or Anxiolytic- lnduced Mood Disorder, Sedative-, Hypnotic-, or Anxiolytic-lnduced Anxiety Disorder Sedative-, Hypnotic-, or Anxiolytic-lnduced Sexual Dysfunction, Sedative-, Hypnotic-, or Anxiolytic-lnduced Sleep Disorder and Sedative-, Hypnotic-, or Anxiolytic-Related Disorder Not Otherwise Specified (292.9); Polysubstance-Related Disorder such as Polysubstance Dependence (304.80); and Other (or Unknown) Substance-Related Disorders such as Anabolic Steroids, Nitrate Inhalants and Nitrous Oxide.

The compounds of the invention may also be of use in the treatment of sleep disorders including primary sleep disorders such as Dyssomnias such as Primary Insomnia (307.42), Primary Hypersomnia (307.44), Narcolepsy (347), Breathing-Related Sleep

Disorders (780.59), Circadian Rhythm Sleep Disorder (307.45) and Dyssomnia Not Otherwise Specified (307.47); primary sleep disorders such as Parasomnias such as Nightmare Disorder (307.47), Sleep Terror Disorder (307.46), Sleepwalking Disorder (307.46) and Parasomnia Not Otherwise Specified (307.47); Sleep Disorders Related to Another Mental Disorder such as Insomnia Related to Another Mental Disorder (307.42) and Hypersomnia Related to Another Mental Disorder (307.44); Sleep Disorder Due to a General Medical Condition; and Substance-Induced Sleep Disorder including the subtypes Insomnia Type, Hypersomnia Type, Parasomnia Type and Mixed Type.

The compounds of the invention may also be of use in the treatment of eating disorders such as Anorexia Nervosa (307.1 ) including the subtypes Restricting Type and Binge- Eating/Purging Type; Bulimia Nervosa (307.51 ) including the subtypes Purging Type and Nonpurging Type; Obesity; Compulsive Eating Disorder; and Eating Disorder Not Otherwise Specified (307.50).

The compounds of the invention may also be of use in the treatment of Autistic Disorder (299.00); Attention-Deficit /Hyperactivity Disorder including the subtypes Attention-Deficit /Hyperactivity Disorder Combined Type (314.01 ), Attention-Deficit /Hyperactivity Disorder Predominantly Inattentive Type (314.00), Attention-Deficit /Hyperactivity Disorder Hyperactive-Impulse Type (314.01 ) and Attention-Deficit /Hyperactivity Disorder Not Otherwise Specified (314.9); Hyperkinetic Disorder; Disruptive Behaviour Disorders such as Conduct Disorder including the subtypes childhood-onset type (321.81 ), Adolescent- Onset Type (312.82) and Unspecified Onset (312.89), Oppositional Defiant Disorder (313.81 ) and Disruptive Behaviour Disorder Not Otherwise Specified; and Tic Disorders such as Tourette's Disorder (307.23).

The compounds of the invention may also be of use in the treatment of Personality Disorders including the subtypes Paranoid Personality Disorder (301.0), Schizoid Personality Disorder (301.20), Schizotypal Personality Disorder (301 ,22), Antisocial Personality Disorder (301.7), Borderline Personality Disorder (301 ,83), Histrionic Personality Disorder (301.50), Narcissistic Personality Disorder (301 ,81 ), Avoidant Personality Disorder (301.82), Dependent Personality Disorder (301.6), Obsessive- Compulsive Personality Disorder (301.4) and Personality Disorder Not Otherwise Specified (301.9).

The compounds of the invention may also be of use in the treatment of cognitive impairment. Within the context of the present invention, the term cognitive impairment includes for example the treatment of impairment of cognitive functions including attention, orientation, learning disorders, memory (i.e. memory disorders, amnesia, amnesic disorders, transient global amnesia syndrome and age-associated memory impairment) and language function; cognitive impairment as a result of stroke, Alzheimer's disease, Huntington's disease, Pick disease, Aids-related dementia or other dementia states such as Multiinfarct dementia, alcoholic dementia, hypotiroidism-related dementia, and dementia associated to other degenerative disorders such as cerebellar atrophy and amyotropic lateral sclerosis; other acute or sub-acute conditions that may cause cognitive decline such as delirium or depression (pseudodementia states) trauma, head trauma, age related cognitive decline, stroke, neurodegeneration, drug-induced states, neurotoxic agents, mild cognitive impairment, age related cognitive impairment, autism related cognitive impairment, Down's syndrome, cognitive deficit related to psychosis, and post- electroconvulsive treatment related cognitive disorders; and dyskinetic disorders such as Parkinson's disease, neuroleptic-induced parkinsonism, and tardive dyskinesias.

The compounds of the present invention may also be of use for the treatment of cognition impairment which arises in association or as a result of other diseases such as schizophrenia, bipolar disorder, depression, other psychiatric disorders and psychotic conditions associated with cognitive impairment.

The compounds of the invention may also be of use in the treatment of sexual dysfunctions including Sexual Desire Disorders such as Hypoactive Sexual Desire Disorder (302.71 ), and Sexual Aversion Disorder (302.79); sexual arousal disorders such as Female Sexual Arousal Disorder (302.72) and Male Erectile Disorder (302.72); orgasmic disorders such as Female Orgasmic Disorder (302.73), Male Orgasmic Disorder (302.74) and Premature Ejaculation (302.75); sexual pain disorder such as Dyspareunia (302.76) and Vaginismus (306.51 ); Sexual Dysfunction Not Otherwise Specified (302.70); paraphilias such as Exhibitionism (302.4), Fetishism (302.81 ), Frotteurism (302.89), Pedophilia (302.2), Sexual Masochism (302.83), Sexual Sadism (302.84), Transvestic Fetishism (302.3), Voyeurism (302.82) and Paraphilia Not Otherwise Specified (302.9); gender identity disorders such as Gender Identity Disorder in Children (302.6) and Gender Identity Disorder in Adolescents or Adults (302.85); and Sexual Disorder Not Otherwise Specified (302.9).

The compounds of the invention may also be of use as anticonvulsants. The compounds of the invention are thus useful in the treatment of convulsions in mammals, and particularly epilepsy in humans. "Epilepsy" is intended to include the following seizures: simple partial seizures, complex partial seizures, secondary generalised seizures, generalised seizures including absence seizures, myoclonic seizures, clonic seizures, tonic seizures, tonic clonic seizures and atonic seizures. The invention also provides a method of treating convulsions, which comprises administering to a mammal in need thereof an effective amount of a compound of the invention as hereinbefore described or a salt thereof. Treatment of epilepsy may be carried out by the administration of a nontoxic anticonvulsant effective amount of a compound of the formula (I) or a salt thereof.

The compounds of the invention may also be useful in the treatment or prophylaxis of pain, including acute pain, chronic pain, chronic articular pain, musculoskeletal pain, neuropathic pain, inflammatory pain, visceral pain, pain associated with cancer, pain associated with migraine, tension headache and cluster headaches, pain associated with functional bowel disorders, lower back and neck pain, pain associated with sprains and strains, sympathetically maintained pain; myositis, pain associated with influenza or other viral infections such as the common cold, pain associated with rheumatic fever, pain associated with myocardial ischemia, post operative pain, cancer chemotherapy, headache, toothache and dysmenorrhea.

'Chronic articular pain' conditions include rheumatoid arthritis, osteoarthritis, rheumatoid spondylitis, gouty arthritis and juvenile arthritis.

'Pain associated with functional bowel disorders' includes non-ulcer dyspepsia, non- cardiac chest pain and irritable bowel syndrome.

'Neuropathic pain' syndromes include: diabetic neuropathy, sciatica, non-specific lower back pain, trigeminal neuralgia, multiple sclerosis pain, fibromyalgia, HIV-related neuropathy, post-herpetic neuralgia, trigeminal neuralgia, and pain resulting from physical trauma, amputation, phantom limb syndrome, spinal surgery, cancer, toxins or chronic inflammatory conditions. In addition, neuropathic pain conditions include pain associated with normally non-painful sensations such as "pins and needles" (paraesthesias and dysesthesias), increased sensitivity to touch (hyperesthesia), painful sensation following innocuous stimulation (dynamic, static, thermal or cold allodynia), increased sensitivity to noxious stimuli (thermal, cold, mechanical hyperalgesia), continuing pain sensation after removal of the stimulation (hyperpathia) or an absence of or deficit in selective sensory pathways (hypoalgesia). Other conditions which could potentially be treated by compounds of the invention include neurodegenerative diseases and neurodegeneration, neurodegeneration following trauma, tinnitus, dependence on a dependence-inducing agent such as opioids (e.g. morphine), CNS depressants (e.g. ethanol), psychostimulants (e.g. ***e) and nicotine.

Neurodegenerative diseases include dementia, particularly degenerative dementia (including senile dementia, dementia with Lewy bodies, Alzheimer's disease, Pick's disease, Huntingdon's chorea, Parkinson's disease and Creutzfeldt-Jakob disease, ALS, motor neuron disease); vascular dementia (including multi-infarct dementia); as well as dementia associated with intracranial space occupying lesions; trauma; infections and related conditions (including HIV infection, meningitis and shingles); metabolism; toxins; anoxia and vitamin deficiency; and mild cognitive impairment associated with ageing, particularly Age Associated Memory Impairment.

Another condition which could potentially be treated by compounds of the invention is spasticity or muscular hypertonicity.

Other disorders include benign forgetfulness, childhood learning disorders and closed head injury, Parkinson's disease, dyskinetic disorders, cognitive impairment, emesis, movement disorders, amnesia, circadian rhythm disorders, aggression and vertigo.

As used herein, the terms "treatment" and "treating" refer to the alleviation and/or cure of established symptoms as well as prophylaxis.

The invention thus provides compounds of formula (I) and pharmaceutically acceptable salts thereof for use in therapy.

The invention also provides compounds of formula (I) and pharmaceutically acceptable salts thereof for use in the treatment of a disorder wherein inhibition of GIyTI would be beneficial.

In a further aspect of the present invention, there is provided a method of treating a disorder wherein inhibition of GIyTI would be beneficial comprising administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. As used herein, the term "effective amount" means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher or clinician.

In a further aspect of the present invention there is provided the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the treatment of a disorder wherein inhibition of GIyTI would be beneficial.

In order to use a compound of the present invention in therapy, it will normally be formulated into a pharmaceutical composition in accordance with standard pharmaceutical practice. The present invention also provides a pharmaceutical composition, which comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

In a further aspect, the present invention provides a process for preparing a pharmaceutical composition, the process comprising mixing a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

A pharmaceutical composition of the invention is usually adapted for oral, sub-lingual, buccal, parenteral (for example, subcutaneous, intramuscular, or intravenous), rectal, topical and intranasal administration and in forms suitable for administration by inhalation or insufflation (either through the mouth or nose). The most suitable means of administration for a particular patient will depend on the nature and severity of the conditions being treated and on the nature of the active compound. In one embodiment, oral administration is provided.

Compositions suitable for oral administration may be provided as discrete units, such as tablets, capsules, cachets, or lozenges, each containing a predetermined amount of the active compound; as powders or granules; as solutions or suspensions in aqueous or non-aqueous liquids; or as oil-in-water or water-in-oil emulsions.

Compositions suitable for sublingual or buccal administration include lozenges comprising the active compound and, typically, a flavoured base, such as sugar and acacia or tragacanth and pastilles comprising the active compound in an inert base, such as gelatin and glycerin or sucrose and acacia.

Compositions suitable for parenteral administration typically comprise sterile aqueous solutions containing a predetermined concentration of the active compound; the solution may be isotonic with the blood of the intended recipient. Such solutions may be administered intravenously or by subcutaneous or intramuscular injection.

Compositions suitable for rectal administration may be provided as unit-dose suppositories comprising the active ingredient and one or more solid carriers forming the suppository base, for example, cocoa butter.

Compositions suitable for topical or intranasal application include ointments, creams, lotions, pastes, gels, sprays, aerosols and oils. Suitable carriers for such compositions include petroleum jelly, lanolin, polyethylene glycols, alcohols, and combinations thereof.

The compositions of the invention may be prepared by any suitable method, typically by uniformly and intimately admixing the active compound(s) with liquids or finely divided solid carriers, or both, in the required proportions and then, if necessary, shaping the resulting mixture into the desired shape.

For example, a tablet may be prepared by compressing an intimate mixture comprising a powder or granules of the active ingredient and one or more optional ingredients, such as a binder, lubricant, inert diluent, or surface active dispersing agent, or by moulding an intimate mixture of powdered active ingredient and inert liquid diluent.

Aqueous solutions for parenteral administration are typically prepared by dissolving the active compound in sufficient water to give the desired concentration and then rendering the resulting solution sterile and isotonic.

It will be appreciated that the precise dose administered will depend on the age and condition of the patient and the frequency and route of administration and will be at the ultimate discretion of the attendant physician. The compound may be administered in single or divided doses and may be administered one or more times, for example 1 to 4 times per day. A proposed dose of the active ingredient for use according to the invention for oral, sublingual, parenteral, buccal, rectal, intranasal or topical administration to a human (of approximately 70 kg bodyweight) for the treatment of neurological and neuropsychiatric disorders mediated by a GIyTI inhibitor, including schizophrenia, may be about 0.1 to about 1000 mg, for example about 0.5 mg to about 1000mg, or about 1 mg to about 1000 mg, or about 5 mg to about 500 mg, or about 10 mg to about 100 mg of the active ingredient per unit dose, which could be administered, for example, 1 to 4 times per day.

The compounds of formula (I) and their pharmaceutically acceptable salts thereof may also be suitable for combination with other therapeutic agents, such as typical and atypical antipsychotics. Thus, the present invention also provides:

i) a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof with one or more further therapeutic agents such an one or more antipsychotic; ii) a pharmaceutical composition comprising a combination product as defined in i) above and at least one carrier, diluent or excipient; iii) the use of a combination as defined in i) above in the manufacture of a medicament for treating or preventing a disease or condition caused by a reduction or imbalance in glutamate receptor function in a mammal; iv) a combination as defined in i) above for use in treating or preventing a disease or condition caused by a reduction or imbalance in glutamate receptor function in a mammal; v) a kit-of-parts for use in the treatment of a psychotic disorder comprising a first dosage form comprising a compound of the invention and one or more further dosage forms each comprising a antipsychotic agent for simultaneous therapeutic administration, vi) a combination as defined in i) above for use in therapy; vii) a method of treatment or prevention 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 combination as defined in i) above.

The combination therapies of the invention may be administered adjunctively. By adjunctive administration is meant the coterminous or overlapping administration of each of the components in the form of separate pharmaceutical compositions or devices. This regime of therapeutic administration of two or more therapeutic agents is referred to generally by those skilled in the art and herein as adjunctive therapeutic administration; it is also known as add-on therapeutic administration. Any and all treatment regimes in which a patient receives separate but coterminous or overlapping therapeutic administration of the compounds of formula (I) or a pharmaceutically acceptable salt thereof and at least one antipsychotic agent are within the scope of the current invention. In one embodiment of adjunctive therapeutic administration as described herein, a patient is typically stabilised on a therapeutic administration of one or more of the of the components for a period of time and then receives administration of another component. Within the scope of this invention, the compounds of formula (I) or a pharmaceutically acceptable salt thereof may be administered as adjunctive therapeutic treatment to patients who are receiving administration of at least one antipsychotic agent, but the scope of the invention also includes the adjunctive therapeutic administration of at least one antipsychotic agent to patients who are receiving administration of compounds of formula (I) or a pharmaceutically acceptable salt thereof.

The combination therapies of the invention may also be administered simultaneously. By simultaneous administration is meant a treatment regime wherein the individual components are administered together, either in the form of a single pharmaceutical composition or device comprising or containing both components, or as separate compositions or devices, each comprising one of the components, administered simultaneously. Such combinations of the separate individual components for simultaneous combination may be provided in the form of a kit-of-parts.

In a further aspect therefore, the invention provides a method of treatment of a psychotic disorder by adjunctive therapeutic administration of compounds of formula (I) or a pharmaceutically acceptable salt thereof to a patient receiving therapeutic administration of at least one antipsychotic agent. In a further aspect, the invention provides the use of compounds of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for adjunctive therapeutic administration for the treatment of a psychotic disorder in a patient receiving therapeutic administration of at least one antipsychotic agent. The invention further provides compounds of formula (I) or a pharmaceutically acceptable salt thereof for use for adjunctive therapeutic administration for the treatment of a psychotic disorder in a patient receiving therapeutic administration of at least one antipsychotic agent.

In a further aspect, the invention provides a method of treatment of a psychotic disorder by adjunctive therapeutic administration of at least one antipsychotic agent to a patient receiving therapeutic administration of compounds of formula (I) or a pharmaceutically acceptable salt thereof. In a further aspect, the invention provides the use of at least one antipsychotic agent in the manufacture of a medicament for adjunctive therapeutic administration for the treatment of a psychotic disorder in a patient receiving therapeutic administration of compounds of formula (I) or a pharmaceutically acceptable salt thereof. The invention further provides at least one antipsychotic agent for adjunctive therapeutic administration for the treatment of a psychotic disorder in a patient receiving therapeutic administration of compounds of formula (I) or pharmaceutically acceptable a salt thereof.

In a further aspect, the invention provides a method of treatment of a psychotic disorder by simultaneous therapeutic administration of compounds of formula (I) or a pharmaceutically acceptable salt thereof in combination with at least one antipsychotic agent. The invention further provides the use of a combination of compounds of formula (I) or a salt thereof and at least one antipsychotic agent in the manufacture of a medicament for simultaneous therapeutic administration in the treatment of a psychotic disorder. The invention further provides the use of compounds of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for simultaneous therapeutic administration with at least one antipsychotic agent in the treatment of a psychotic disorder. The invention further provides compounds of formula (I) or a pharmaceutically acceptable salt thereof for use for simultaneous therapeutic administration with at least one antipsychotic agent in the treatment of a psychotic disorder. The invention further provides the use of at least one antipsychotic agent in the manufacture of a medicament for simultaneous therapeutic administration with compounds of formula (I) or a pharmaceutically acceptable salt thereof in the treatment of a psychotic disorder.

In further aspects, the invention provides a method of treatment of a psychotic disorder by simultaneous therapeutic administration of a pharmaceutical composition comprising compounds of formula (I) or a pharmaceutically acceptable salt thereof and at least one mood stabilising or antimanic agent, a pharmaceutical composition comprising compounds of formula (I) or a pharmaceutically acceptable salt thereof and at least one mood stabilising or antimanic agent, the use of a pharmaceutical composition comprising compounds of formula (I) or a pharmaceutically acceptable salt thereof and at least one mood stabilising or antimanic agent in the manufacture of a medicament for the treatment of a psychotic disorder, and a pharmaceutical composition comprising compounds of formula (I) or a pharmaceutically acceptable salt thereof and at least one mood stabilising or antimanic agent for use in the treatment of a psychotic disorder.

Examples of antipsychotic drugs that are useful in the present invention include, but are not limited to: butyrophenones, such as haloperidol, pimozide, and droperidol; phenothiazines, such as chlorpromazine, thioridazine, mesoridazine, trifluoperazine, perphenazine, fluphenazine, thiflupromazine, prochlorperazine, and acetophenazine; thioxanthenes, such as thiothixene and chlorprothixene; thienobenzodiazepines; dibenzodiazepines; benzisoxazoles; dibenzothiazepines; imidazolidinones; benziso- thiazolyl-piperazines; triazine such as lamotrigine; dibenzoxazepines, such as loxapine; dihydroindolones, such as molindone; aripiprazole; and derivatives thereof that have antipsychotic activity.

Examples of tradenames and suppliers of selected antipsychotic drugs are as follows: amisulpride (SOLIAN(D), clozapine (available under the tradename CLOZARIL®, from Mylan, Zenith Goldline, UDL, Novartis); olanzapine (available under the tradename ZYPREX®, from Lilly; ziprasidone (available under the tradename GEODON®, from Pfizer); risperidone (available under the tradename RISPERDAL®, from Janssen); quetiapine fumarate (available under the tradename SEROQUEL®, from AstraZeneca); haloperidol (available under the tradename HALDOL®, from Ortho-McNeil); chlorpromazine (available under the tradename THORAZINE®, from SmithKline Beecham (GSK); fluphenazine (available under the tradename PROLIXIN®, from Apothecon, Copley, Schering, Teva, and American Pharmaceutical Partners, Pasadena); thiothixene (available under the tradename NAVANE®;, from Pfizer); trifluoperazine (10- [3-(4-methyl-1 -piperazinyl)propyl]-2-(trifluoromethyl)phenothiazine dihydrochloride, available under the tradename STELAZINE®, from Smith Klein Beckman; perphenazine (available under the tradename TRILAFON®; from Schering); thioridazine (available under the tradename MELLARIL®; from Novartis, Roxane, HiTech, Teva, and Alpharma) ; molindone (available under the tradename MOBAN®, from Endo); and loxapine (available under the tradename LOXITANE®; from Watson). Furthermore, benperidol (Glianimon®), perazine (Taxilan®) or melperone (Eunerpan®)) may be used. Other antipsychotic drugs include promazine (available under the tradename SPARINE®), triflurpromazine (available under the tradename VESPRIN®), chlorprothixene (available under the tradename TARACTAN®), droperidol (available under the tradename INAPSINE®), acetophenazine (available under the tradename TINDAL®;), prochlorperazine (available under the tradename COMPAZINE®), methotrimeprazine (available under the tradename NOZINAN(D), pipotiazine (available under the tradename PIPOTRIL(D), ziprasidone, and hoperidone.

It will be appreciated by those skilled in the art that the compounds of the invention may be used in conjunction with one or more other therapeutic agents, for instance, antidepressant agents such as 5HT3 antagonists, serotonin agonists, NK1 antagonists, NK3 antagonists, AMPA modulators, alpha7 positive modulators, 5HT6 antagonists, 5HT2A antagonists, selective serotonin reuptake inhibitors (SSRI), noradrenaline re- uptake inhibitors (SNRI), tricyclic antidepressants, dopaminergic antidepressants, H3 antagonists, 5HT1A antagonists, 5HT1 B antagonists, 5HT1 D antagonists, D1 agonists, M1 and M1/4 muscarinic agonists and/or anticonvulsant agents, as well as cognitive enhancers.

Suitable 5HT3 antagonists which may be used in combination of the compounds of the inventions include for example ondansetron, granisetron, metoclopramide.

Suitable serotonin agonists which may be used in combination with the compounds of the invention include sumatriptan, rauwolscine, yohimbine, metoclopramide.

Suitable SSRIs which may be used in combination with the compounds of the invention include fluoxetine, citalopram, femoxetine, fluvoxamine, paroxetine, indalpine, sertraline, zimeldine.

Suitable SNRIs which may be used in combination with the compounds of the invention include venlafaxine and reboxetine.

Suitable tricyclic antidepressants which may be used in combination with a compound of the invention include imipramine, amitriptiline, chlomipramine and nortriptiline.

Suitable dopaminergic antidepressants which may be used in combination with a compound of the invention include bupropion and amineptine.

Suitable anticonvulsant agents which may be used in combination of the compounds of the invention include for example divalproex, carbamazepine and diazepam. When used in the treatment or prophylaxis of pain, the compound of the invention or a pharmaceutically acceptable salt thereof may be used in combination with other medicaments indicated to be useful in the treatment or prophylaxis of pain of neuropathic origin including neuralgias, neuritis and back pain, and inflammatory pain including osteoarthritis, rheumatoid arthritis, acute inflammatory pain, back pain and migraine. Such therapeutic agents include for Compound COX-2 (cyclooxygenase-2 ) inhibitors, such as celecoxib, deracoxib, rofecoxib, valdecoxib, parecoxib, COX-189 or 2-(4-ethoxy-phenyl)- 3-(4-methanesulfonyl-phenyl)-pyrazolo[1 ,5-b]pyridazine (WO99/012930); 5-lipoxygenase inhibitors; NSAIDs (non-steroidal anti-inflammatory drugs) such as diclofenac, indomethacin, nabumetone or ibuprofen; bisphosphonates, leukotriene receptor antagonists; DMARDs (disease modifying anti-rheumatic drugs) such as methotrexate; adenosine A1 receptor agonists; sodium channel blockers, such as lamotrigine; NMDA (N-methyl-D-aspartate) receptor modulators, such as glycine receptor antagonists or memantine; ligands for the α₂δ-subunit of voltage gated calcium channels, such as gabapentin, pregabalin and solzira; tricyclic antidepressants such as amitriptyline; neurone stabilising antiepileptic drugs; cholinesterase inhibitors such as galantamine; mono-aminergic uptake inhibitors such as venlafaxine; opioid analgesics; local anaesthetics; 5HT₁ agonists, such as triptans, for Compound sumatriptan, naratriptan, zolmitriptan, eletriptan, frovatriptan, almotriptan or rizatriptan; nicotinic acetyl choline (nACh) receptor modulators; glutamate receptor modulators, for Compound modulators of the NR2B subtype; EP₄ receptor ligands; EP₂ receptor ligands; EP₃ receptor ligands; EP₄ agonists and EP₂ agonists; EP₄ antagonists; EP₂ antagonists and EP₃ antagonists; cannabinoid receptor ligands; bradykinin receptor ligands; vanilloid receptor or Transient Receptor Potential (TRP) ligands; and purinergic receptor ligands, including antagonists at P2X₃, P2X_2/3, P2X₄, P2X₇ or P2X_4/7; KCNQ/Kv7 channel openers, such as retigabine; Additional COX-2 inhibitors are disclosed in US Patent Nos. 5,474,995, US5, 633,272; US5,466,823, US6,310,099 and US6.291.523; and in WO 96/25405, WO 97/38986, WO 98/03484, WO 97/14691 , WO99/12930, WO00/26216, WO00/52008, WO00/3831 1 , WO01/58881 and WO02/18374.

When used in the treatment or prophylaxis of Alzheimer's disease, the compound as defined in the first to fourth aspect or a pharmaceutically acceptable salt thereof may be used in combination with other medicaments indicated to be useful as either disease modifying or symptomatic treatments of Alzheimer's disease. Suitable examples of such other therapeutic agents may be agents known to modify cholinergic transmission such as 5-HT_1A antagonists, (e.g. lecozotan), 5-HT6 antagonists, M1 muscarinic agonists, M2 muscarinic antagonist, acetylcholinesterase inhibitors (e.g tetrahydroaminoacridine, donepezil or rivastigmine), or allosteric modulators, nicotinic receptor agonists or allosteric modulators, symptomatic agents such as 5-HT6 receptor antagonists, e.g. SB742457, H3 receptor antagonists e.g. GSK189254 and GSK239512, 5-HT4 receptor agonist, PPAR agonists, also NMDA receptor antagonists or modulators, also disease modifying agents such as β or γ-secretase inhibitors (e.g. R-flurbiprofen), also AMPA positive modulators.

Claims

Claims

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

(I) wherein:

^{^^}~ (in the 5-membered nitrogen containing ring) is a single bond or a double bond;

R¹ is selected from H, d-C₄alkyl, CrC₄alkoxy, halo, haloCrC₄alkyl, haloCrC₄alkoxy, d- C₄alkylthio, C₃-C₆cycloalkyl, C_rC₄alkylsulfonyl, Ci-C₄alkoxyd-C₄alkyl, CONR^aR^b (wherein R^a and R^b are independently selected from H and Ci-C₄alkyl, or R^a and R^b, together with the nitrogen atom to which they are attached, form a 4- to 7-membered ring) and cyano;

R² is selected from H, Ci-C₄alkyl, Ci-C₄alkoxy, halo, haloCi-C₄alkyl, haloCi-C₄alkoxy, d- dalkylthio, C₃-C₆cycloalkyl, d-dalkylsulfonyl, d-dalkoxyd-dalkyl , CONR^cR^d (wherein R^c and R^d are independently selected from H and d-C₄alkyl, or R^c and R^d, together with the nitrogen atom to which they are attached, form a 4- to 7-membered ring) and cyano;

R³ is selected from H, C_1-4alkyl, d-dalkoxy, halo, halod-C₄alkyl, halod-C₄alkoxy, C₁- dalkylthio, C₃-C₆cycloalkyl, d-C₄alkylsulfonyl, d-dalkoxyd-dalkyl, CONR^eR^f (wherein R^e and R^f are independently selected from H and d-dalkyl, or R^e and R^f, together with the nitrogen atom to which they are attached, form a 4- to 7-membered ring) and cyano;

or R² and R³ together form a group selected from -0-CH₂-O- and -0-CH₂-CH₂-O-;

R⁴ is selected from H, d-C₄alkyl, d-C₄alkoxy, halo, halod-C₄alkyl, haloCrdalkoxy, d- dalkylthio, C₃-C₆cycloalkyl, C_rC₄alkylsulfonyl, C_rC₄alkoxyd-C₄alkyl, CONR⁹R^h (wherein R⁹ and R^h are independently selected from H and CrC₄alkyl, or R⁹ and R^h, together with the nitrogen atom to which they are attached, form a 4- to 7-membered ring) and cyano;

R⁵ is selected from hydrogen, chloro, fluoro, Ci-C₄alkyl and CF₃;

R⁶ is selected from a 5-7 membered heteroaryl or 5 to 7 membered heterocyclic ring optionally substituted by C_1-4 alkyl, C_1-4 alkoxy, haloalkyl, haloalkoxy, halo or cyano;

R⁷ is selected from H, Ci-C₄alkyl, Cr^alkoxy, haloCi-C₄alkyl, haloCrC^lkoxy, halo, cyano, C_1-4alkoxyC_1-4alkyl and CrC^lkoxyCrC^lkoxy;

m is selected from 0, 1 and 2;

R⁸ is selected from hydrogen and CτC₄alkyl;

R²¹ is selected from H and fluoro.

2. A compound as claimed in claim 1 for use in therapy.

3. A compound as claimed in claim 1 for use in the treatment of a disorder wherein inhibition of GIyTI would be beneficial.

4. A compound as claimed in claim 1 , wherein the disorder is psychosis, including schizophrenia, dementia and attention deficit disorder.

5. A method of treating a disorder wherein inhibition of GIyTI would be beneficial, comprising administering a compound as defined in claim 1.

6. A method as claimed in claim 5, wherein the disorder is psychosis, including schizophrenia, dementia and attention deficit disorder.

7. The use of a compound as defined in claim 1 in the manufacture of a medicament for use in the treatment of a disorder wherein inhibition of GIyTI would be beneficial.

8. Use as claimed in claim 7, wherein the disorder is psychosis, including schizophrenia, dementia and attention deficit disorder.

9. A pharmaceutical composition comprising a compound as claimed in claim 1 and at least one pharmaceutically acceptable excipient.

10. A combination comprising a compound as claimed in claim 1 and one or more therapeutic agent.