We have now found a novel group of phenylsulfonyl compounds which are useful particularly as antipsychotic agents.

The novel compounds of formula (I) have high affinities at desired receptors, exhibit good in vivo profiles and have good Drug Metabolism and Pharmacokinetics (DMPK) properties.

According to the invention, there is provided one or more chemical entities selected from a compound of formula (1) : wherein R1 represents C1 6alkyl, trifluoromethoxy or halo ; R2 represents hydrogen, C1 6alkyl or halo ; or when R1 and R2 are positioned at the 3-and 4-positions, R'and R2 together with the carbon atoms to which they are attached may form a 1,4-dioxane ring; and a pharmaceutical acceptable salt and solvate thereof.

As used herein, the term"alkyl"refers to straight or branched hydrocarbon chains containing the specified number of carbon atoms. For example, C1 6alkyl means a straight or branched alkyl containing at least 1, and at most 6, carbon atoms. Examples of"alkyl"as used herein include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isobutyl, isopropyl, t-butyl and 1, 1-dimethylpropyl.

As used herein, the term"halo"refers to fluoro, chloro, bromo and iodo.

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. Such solvents for the purpose of the invention may not interfere with the biological activity of the solute. Examples of suitable solvents include water, methanol, ethanol and acetic acid.

Most preferably the solvent used is water and the solvate may also be referred to as a hydrate.

It will be appreciated that for use in medicine the salts of formula (I) should be pharmaceutical acceptable. Suitable pharmaceutical acceptable salts will be apparent to those skilled in the art and include for example acid addition salts formed with inorganic acids e. g. hydrochloric, hydrobromic, sulfuric, nitric or phosphoric acid; and organic acids e. g. succinic, maleic, malic, mandelic, acetic, fumaric, glutamic, lactic, citric, tartaric, benzoic, benzenesulfonic, p-toluenesulfonic, methanesulfonic or naphthalenesulfonic acid. Examples of salts include the hydrochloride, maleat, tosylat or mesylate salts or pharmaceutically acceptable derivatives thereof. Other non-physiologically acceptable salts e. g. oxalates, may be used, for example in the isolation of compounds of formula (I) and are included within the scope of this invention. Also included within the scope of the invention are salts, solvates and hydrates of the compounds of formula (I).

The term"pharmaceutically acceptable derivative"as used herein refers to any pharmaceutically acceptable derivative of a compound of the present invention, for example, an ester, which upon administration to a mammal, such as a human, is capable of providing (directly or indirectly) such a compound or an active metabolite thereof. Such derivatives are clear to those skilled in the art, without undue experimentation, and with reference to the teaching of Burger's Medicinal Chemistry And Drug Discovery, 5th Edition, Vol 1: Principles And Practice, which is incorporated herein by reference.

Certain of the compounds of formula (I) may form acid addition salts with one or more equivalents of the acid. The present invention includes within its scope all possible stoichiometric and non-stoichiometric forms thereof.

Certain salts of compounds of formula (I) may exist in stereoisomeric forms (e. g. they may contain one or more asymmetric carbon atoms). The individual stereoisomers (enantiomers and diastereomers) and mixtures of these are included within the scope of the present invention. The present invention also covers the individual isomers of the salts of compounds represented by formula (I) as mixtures with isomers thereof in which one or more chiral centres are inverted. Likewise, it is understood that salts of 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 a further aspect of the invention, R'represents Cl-4alkyl for example methyl (such as 2- methyl, 3-methyl or 4-methyl) or 4-t-butyl, 2-trifluoromethoxy, 3-trifluoromethoxy, fluoro (such as 2-fluor, 3-fluor or 4-fluoro) or chloro (such as 2-chloro, 3-chloro or 4-chloro).

In another aspect of the invention, R represents hydrogen, fluoro (such as 4-fluoro or 5- fluoro), chloro (such as 4-chloro or 5-chloro) or C1 4alkyl for example methyl (such as 4- methyl or 6-methyl).

In a further aspect of the invention, when R is hydrogen, R'is suitably 4-methyl, 4-t-butyl, 2- trifluoromethoxy, 3-trifluoromethoxy, 2-fluor, 4-fluor, 4-chloro.

In another aspect of the invention, when R is other than hydrogen, the combination of R' and R2 substituents are suitably 3, 4-dichloro, 3, 5-dichloro, 2, 4-difluoro, 3, 4-difluoro, 3,5- difluor, 2, 6-dimethyl, 3-fluoro-4-methyl, 2-chloro-4-fluoro, 3-fluoro-4-chloro, 3-methyl-4- chloro or when R'and R2 are positioned at the 3-and 4-positions respectively, R1 and R2 together with the carbon atoms to which they are attached may form a 1,4-dioxane ring.

In a further aspect of the invention, there is provided one or more chemical entities selected from a compound of formula (I) as described hereinbefore wherein R'represents methyl, t-butyl, trifluoromethoxy, fluoro or chloro ; R2 represents hydrogen, methyl, fluoro or chloro ; or when R'and R2 are positioned at the 3-and 4-positions, R'and R2 together with the carbon atoms to which they are attached may form a 1,4-dioxane ring; and a pharmaceutically acceptable salt and solvate thereof.

It is to be understood that the present invention covers all combinations of particular and preferred groups described herein above.

Particular compounds according to the invention include those incorporated in Table 1 and those specifically exemplified and named hereinafter including, without limitation : - 7- [4- (3-fluoro-4-methylbenzyl) benzenesulfonyl]-8-hydroxy-3-methyl-2, 3,4, 5-tetrahydro-1 H-3- benzazepine; 7- [4- (2-fluorobenzyl) benzenesulfonyl]-8-hydroxy-3-methyl-2, 3,4, 5-tetrahydro-1 H-3- benzazepine; 7- [4- (3, 4-difluorobenzyl) benzenesulfonyl]-8-hydroxy-3-methyl-2, 3,4, 5-tetrahydro-1 H-3- benzazepine; 7- [4- (4-chlorobenzyl) benzenesulfonyl]-8-hydroxy-3-methyl-2, 3,4, 5-tetrahydro-1 H-3- benzazepine; 7- [4- (4-fluorobenzyl) benzenesulfonyl]-8-hydroxy-3-methyl-2, 3,4, 5-tetrahydro-1 H-3- benzazepine ; 7- [4- (2-chloro-4-fluorobenzyl) benzenesulfonyl]-8-hydroxy-3-methyl-2, 3,4, 5-tetrahydro-1 H-3- benzazepine; 7- [4- (2, 3-d ihydro-1, 4-benzod ioxin-6-yl) benzenesu Ifonyl]-8-hydroxy-3-methyl-2, 3,4, 5- tetrahydro-1 H-3-benzazepine ; 7- [4- (4-methyl-benzyl) benzenesulfonyl]-8-hydroxy-3-methyl-2, 3,4, 5-tetrahydro-1 H-3- benzazepine; 7- [4- (3-methyl-4-chlorobenzyl) benzenesulfonyl]-8-hydroxy-3-methyl-2, 3,4, 5-tetrahydro-1 H-3- benzazepine; 7- [4- (2-trifluoromethoxybenzyl) benzenesulfonyl]-8-hydroxy-3-methyl-2, 3,4, 5-tetrahydro-1 H-3- benzazepine; 7- [4- (3-trifluoromethoxybenzyl) benzenesulfonyl]-8-hydroxy-3-methyl-2, 3,4, 5-tetrahydro-1 H-3- benzazepine; 7- [4- (2, 6-dimethylbenzyi) benzenesulfonyl]-8-hydroxy-3-methyl-2, 3,4, 5-tetrahydro-1 H-3- benzazepine; 7- [4- (4-t-butylbenzyl) benzenesulfonyl]-8-hydroxy-3-methyl-2, 3,4, 5-tetrahydro-1 H-3- benzazepine; 7- [4- (2, 4-difluorobenzyl) benzenesulfonyl]-8-hydroxy-3-methyl-2, 3,4, 5-tetrahydro-1 H-3- benzazepine; 7- [4- (3, 5-difluororobenzyl) benzenesulfonyl]-8-hydroxy-3-methyl-2, 3,4, 5-tetrahydro-1 H-3- benzazepine; 7- [4- (3, 4-dichlorobenzyl) benzenesulfonyl]-8-hydroxy-3-methyl-2, 3,4, 5-tetrahydro-1 H-3- benzazepine; 7- [4- (3-fluoro-4-chlorobenzyl) benzenesulfonyl]-8-hydroxy-3-methyl-2, 3,4, 5-tetrahydro-1 H-3- benzazepine; 7- [4- (3, 5-dichlorobenzyl) benzenesulfonyl]-8-hydroxy-3-methyl-2, 3,4, 5-tetrahydro-1 H-3- benzazepine, and pharmaceutical acceptable salts and solvates thereof.

When preparing a compound of formula (1), precursors to the compound of formula (I) may possess a suitable protecting group R on the nitrogen atom of the benzazepine ring, (for example a t-butyloxycarbonyl group) instead of the methyl group. Such protecting groups are used for example when it is easier to introduce the methyl substituent at the end of a synthetic route.

The present invention also provides a general process for preparing compounds of formula (I) which process comprises: treatment of a compound of formula (II) wherein R and R'are independently methyl groups or suitable N and O protecting groups respectively and R'and R2 are as hereinbefore described, with a reagent suitable for converting OR'to hydroxy, for example, when R'is an alkyl, such as methyl, using a dealkylating agent, such as a demethylating agent, for example aqueous hydrogen bromide; and thereafter optionally for the above process: removing any protecting groups and if necessary, methylation of the nitrogen under standard conditions converting a compound of formula (I) into another compound of formula (l) ; or forming a pharmaceutically acceptable salt or solvate. This general method can be conveniently performed by heating the two components at elevated temperature, for example 100°C. Removal of certain R or R'protecting groups e. g. t-butoxycarbony (BOC), can also take place simultaneously during this process.

Compounds of formula (II) may be prepared by reacting a compound of formula (III) with a compound of formula (IV) wherein L is a leaving group, such as fluoro, chloro, C1 6alkoxy or aryloxy, R and R'are independently methyl or suitable protecting groups as described hereinbefore, M is a metal such as lithium or magnesium and R'and R2 are as hereinbefore described. This reaction may be conveniently performed by mixing the two components at for example-78°C to room temperature in a suitable solvent such as tetrahydrofuran or ether for 10 minutes to 18 hours.

Removal of certain R or R'protecting groups e. g. trifluoroacetyl, can also take place simultaneously during this process.

Compounds of formula (III) may be prepared by known processes, for example, chlorosulfonation of the aromatic ring of the benzazepine using chlorosulfonic acid.

Conversion to the sulfonyl fluoride can be achieved, if required, by reaction with potassium fluoride in acetonitrile at room temperature. Suitable examples of R or R'groups are methyl or protecting groups such as a trifluoroacetyl group as described hereinbefore.

Compounds of formula (IV) may be prepared from compounds of formula (V) wherein W is bromo or iodo and R1 and R2 are as hereinbefore described, by metallation, for example by treatment with n-butyllithium at-78°C or by Grignard formation under standard conditions, in a suitable solvent such as tetrahydrofuran.

Compounds of formula (V) may be prepared from compounds of formula (VI) wherein Y is bromo or iodo and R1 and R2 are as hereinbefore described. Treatment with n- butyllithium in a suitable inert solvent such as tetrahydrofuran at-78°C or by formation of the corresponding Grignard reagent with magnesium turnings, followed by addition into 4- bromobenzaldehyde gives the corresponding benzhydrol. This in turn may be converted to the compound of formula (V) where W is Br by treatment with trifluoromethanesulfonic acid and triethylsilane in an inert solvent such as chloroform, at 0°C to ambient temperature. The compound of formula (V) where W is Br may be converted to compounds of formula (IV) where M is Li or MgBr by treatment with n-butyllithium in a suitable inert solvent such as tetrahydrofuran at-78°C or by formation of the corresponding Grignard reagent with magnesium turnings using standard methodology.

Compounds of formula (VI) are commercially available or readily prepared from commercially available starting materials.

As used herein, the term"suitable protecting groups"refers to groups that are described in many standard texts on organic chemistry, for example in'Protective Organic Synthesis', P. W. Green, Wiley 1981. Examples of suitable protecting groups include, but are not limited to, t-butoxycarbonyl (BOC) and trifluoroacetyl.

As used herein, the term"alkoxy"refers to a straight or branched alkoxy group containing the specified number of carbon atoms. For example, C1 6alkoxy means a straight or branched alkoxy group containing at least 1, and at most 6, carbon atoms. Examples of"alkoxy"as used herein include, but are not limited to, methoxy, ethoxy, propoxy, prop-2-oxy, butoxy, but-2-oxy, 2-methylprop-1-oxy, 2-methylprop-2-oxy, pentoxy or hexyloxy.

As used herein, the term"aryloxy"refers to phenoxy or substituted phenoxy. Examples of "aryloxy"as used herein include, but are not limited to, phenoxy, 4-fluorophenoxy and pentafluorophenoxy.

Certain compounds of formula (I) have been found to exhibit affinity for dopamine receptors, in particular the D3 and D2 receptors, and are useful in the treatment of disease states which require modulation of such receptors, such as psychotic conditions. Many of the compounds of formula (I) have also been found to have greater affinity for dopamine D3 than for D2 receptors. The therapeutic effect of currently available antipsychotic agents (neuroleptics) is generally believed to be exerted via blockade of D2 receptors; however this mechanism is also thought to be responsible for undesirable eps associated with many neuroleptic agents.

Without wishing to be bound by theory, it has been suggested that blockade of the dopamine D3 receptor may give rise to beneficial antipsychotic activity without significant extrapyramidal side effects (eps) (see for example Sokoloff et al, Nature, 1990; 347: 146-151; and Schwartz et al, Clinical Neuropharmacology, Vol 16, No. 4,295-314, 1993).

Compounds of formula (I) and their pharmaceutically acceptable salts and solvates thereof also have antagonist affinity for the serotonin 5-HT2C, 5-HT2A and 5-HT6 receptors. These properties may give rise to anti-psychotic activity (e. g. improved effects on cognitive dysfunction), activity with reduced extrapyramidal side effects (eps), and/or anxiolytic/antidepressant activity. These could include, but are not limited to, attenuation of cognitive symptoms via 5-HT6 receptor blockade (see Reavill, C. and Rogers, D. C. , 2001, Investigational Drugs 2,104-109), and reduced anxiety (see for example Kennett et al., Neuropharmacology 1997 Apr-May; 36 (4-5): 609-20), protection against eps (Reavill et al., Brit. J. Pharmacol., 1999; 126: 572-574) and antidepressant activity (Bristow et al., Neuropharmacology 39: 2000; 1222-1236) via 5-HT2C receptor blockade.

Compounds of formula (I) and their pharmaceutically acceptable salts and solvates thereof may also exhibit affinity for other receptors not mentioned above, resulting in beneficial antipyschotic activity.

The compounds of formula (I) and their pharmaceutically acceptable salts and solvates thereof are of use as antipsychotic agents for example in the treatment of schizophrenia, schizo-affective disorders, schizophreniform diseases, psychotic depression, mania, acute mania, paranoid and delusional disorders. Furthermore, they may have utility as adjunct therapy in Parkinsons Disease, particularly with compounds such as L-DOPA and possibly dopaminergic agonists, to reduce the side effects experienced with these treatments on long term use (e. g. see Schwartz et al., Brain Res. Reviews, 1998,26, 236-242). From the localisation of D3 receptors, it could also be envisaged that the compounds could also have utility for the treatment of substance abuse where it has been suggested that D3 receptors are involved (e. g. see Levant, 1997, Pharmacol. Rev. , 49,231-252). Examples of such substance abuse agents include cocaine, ethanol, nicotine, benzodiazepines, alcohol, caffeine, phencyclidine and phencyclidine-like compounds, opiates such as cannabis, heroin, morphine, sedative, hypnotic, amphetamine or amphetamine-related drugs such as dextroamphetamine, methylamphetamine or a combination thereof. Other conditions which may be treated by the compounds include dyskinetic disorders such as Parkinson's disease, neuroleptic-induced parkinsonism and tardive dyskinesias; depression (which term includes bipolar depression, unpolar depression, single or recurrent major depressive episodes with or without psychotic features, catatonic features, melancholic features, atypical features or postpartum onset, seasonal affective disorder and dysthymia, depressive disorders resulting from a general medical condition including, but not limited to, myocardial infarction, diabetes, miscarriage or abortion); anxiety disorders (which includes generalised anxiety and social anxiety disorder); agitation; tension; social or emotional withdrawal in psychotic patients; cognitive impairment including memory disorders such as Alzheimer's disease; psychotic states associated with neurodegenerative disorders, e. g. Alzheimer's disease; eating disorders (including anorexia nervosa and bulimia nervosa); obesity; sexual dysfunction; sleep disorders (including disturbances of circadian rhythm, dyssomnia, insomnia, sleep apnea and narcolepsy) ; emesis; movement disorders; obsessive-compulsive disorders; amnesia; aggression; autism; vertigo; dementia; circadian rhythm disorders; convulsions; epilepsy ; and gastric motility disorders e. g. IBS.

A compound of formula (I) as hereinbefore described or a pharmaceutically acceptable salt and solvate thereof may be of use in the treatment of psychotic disorders.

In a further aspect therefore, the invention provides one or more chemical entities selected from a compound of formula (I) and a pharmaceutical acceptable salt and solvate thereof for use in therapy.

In another aspect, the invention provides one or more chemical entities selected from a compound of formula (I) and a pharmaceutically acceptable salt and solvate thereof for use in the treatment of a condition which requires modulation of a dopamine receptor.

In a further aspect, the invention provides one or more chemical entities selected from a compound of formula (I) and a pharmaceutically acceptable salt and solvate thereof for use in the treatment of psychotic disorders.

In another aspect, the invention provides the use of one or more chemical entities selected from a compound of formula (I) and a pharmaceutical acceptable salt and solvate thereof in the manufacture of a medicament for the treatment of a condition which requires modulation of a dopamine receptor.

In a further aspect, the invention provides the use of one or more chemical entities selected from a compound of formula (I) and a pharmaceutically acceptable salt and solvate thereof in the manufacture of a medicament for the treatment of psychotic disorders.

In another aspect, the invention provides a method of treating a condition which requires modulation of a dopamine receptor, which comprises administering to a mammal in need thereof an effective amount of one or more chemical entities selected from a compound of formula (I) and a pharmaceutically acceptable salt and solvate thereof.

In a further aspect, the invention provides a method of treating psychotic disorders which comprises administering to a mammal in need thereof an effective amount of one or more chemical entities selected from a compound of formula (I) and a pharmaceutical acceptable salt and solvate thereof.

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 formula (i) and its salts and solvates thereof 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 II 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 Social Anxiety Disorder, 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-Injection-injury 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) : 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- Like)-Related Disorders such as Amphetamine Dependence (304.40), Amphetamine Abuse (305.70), Amphetamine Intoxication (292.89), Amphetamine Withdrawal (292.0), Amphetamine Intoxication Delirium, Amphetamine Induced Psychotic Disorder, Amphetamine-induced Mood Disorder, Amphetamine-Induced Anxiety Disorder, Amphetamine-Induced Sexual Dysfunction, Amphetamine-Induced Sleep Disorder and Amphetamine-Related Disorder Not Otherwise Specified (292.9) ; Caffeine Related Disorders such as Caffeine Intoxication (305.90), Caffeine-induced Anxiety Disorder, Caffeine-Induced Sleep Disorder and Caffeine-Related Disorder Not Otherwise Specified (292.9) ; Cannabis- Related Disorders such as Cannabis Dependence (304.30), Cannabis Abuse (305.20), Cannabis Intoxication (292.89), Cannabis Intoxication Delirium, Cannabis-induced Psychotic Disorder, Cannabis-induced 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-induced Psychotic Disorder, Opioid- Induced Mood Disorder, Opioid-induced Sexual Dysfunction, Opioid-Induced 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-Induced Psychotic Disorder, Phencyclidine-Induced Mood Disorder, Phencyclidine-Induced 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-induced Psychotic Disorder, Sedative-, Hypnotic-, or Anxiolytic-Induced Mood Disorder, Sedative-, Hypnotic-, or Anxiolytic-induced Anxiety Disorder Sedative-, Hypnotic-, or Anxiolytic-induced Sexual Dysfunction, Sedative-, Hypnotic-, or Anxiolytic-lnduced Sieep 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; and Substance-Induced Sleep Disorder including the subtypes Insomnia Type, Hypersomnia Type, Parasomnia Type and Mixed Type: 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) : 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) : Personality Disorders including the subtypes Paranoid Personality Disorder (301.0), Schizoid Personality Disorder (301.20), Schizotypal Personality Disorder (301,22), Antisocial Personality Disorder (301.7), Borderline Personality Disorder (301,83), Histrionic Personality Disorder (301.50), Narcissistic Personality Disorder (301,81), Avoidant Personality Disorder (301.82), Dependent Personality Disorder (301.6), Obsessive-Compulsive Personality Disorder (301.4) and Personality Disorder Not Otherwise Specified (301.9) : Enhancement of cognition including the treatment of cognition impairment in other diseases such as schizophrenia, bipolar disorder, depression, other psychiatric disorders and psychotic conditions associated with cognitive impairment, e. g. Alzheimer's disease: and Sexual dysfunctions including Sexual Desire Disorders such as Hypoactive Sexual Desire Disorder (302.71), and Sexual Aversion Disorder (302.79) ; sexual arousal disorders such as Female Sexual Arousal Disorder (302.72) and Male Erectile Disorder (302.72) ; orgasmic disorders such as Female Orgasmic Disorder (302.73), Male Orgasmic Disorder (302.74) and Premature Ejaculation (302 75) ; sexual pain disorder such as Dyspareunia (302.76) and Vaginismus (306.51) ; Sexual Dysfunction Not Otherwise Specified (302.70) ; paraphilias such as Exhibitionism (302.4), Fetishism (302. 81), Frotteurism (302.89), Pedophilia (302.2), Sexual Masochism (302.83), Sexual Sadism (302.84), Transvestic Fetishism (302.3), Voyeurism (302.82) and Paraphilia Not Otherwise Specified (302.9) ; gender identity disorders such as Gender Identity Disorder in Children (302.6) and Gender Identity Disorder in Adolescents or Adults (302.85) ; and Sexual Disorder Not Otherwise Specified (302.9).

All of the various forms of the psychotic disorders mentioned herein are contemplated as part of the present invention.

"Treatment"includes prophylaxis, where this is appropriate for the relevant condition (s). it will be appreciated by those skilled in the art that the compounds of formula (I) or pharmaceutical acceptable salts or solvates thereof according to the invention may advantageously be used in conjunction with one or more other therapeutic agents, for instance, 5HT3 antagonists, serotonin agonists, NK-1 antagonists, selective serotonin reuptake inhibitors (SSRI), noradrenaline re-uptake inhibitors (SNRI), non-selective reuptake inhibitors of one or more of serotonin, noradrenaline and norepinephrine, CRF-1 antagonists, tricyclic antidepressants, dopaminergic antidepressants, H3 antagonists, 5HT1A antagonists, 5HT1B antagonists, 5HT1D antagonists, 5HT4 partial agonists, D1 agonists, MI agonists, anticonvulsant agents, non-steroidal anti-inflammatory drugs (NSAIDs) and/or cyclooxygenase-2 (COX-2) inhibitors.

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

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

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

Suitable SNR) s 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 inventions include for example divalproex, carbamazepine and diazepam.

Suitable NSAIDs agents which may be used in combination with the compound of the invention include for example one or more chemical entities selected from ibuprofen, aspirin and its active metabolite salicylate.

Suitable COX-2 inhibitors which may be used in combination with a compound of formula (I) or pharmaceutical acceptable salts or solvates thereof include for example rofecoxib (available under the tradename VIOXX@, from Merck, US patent number 5,474, 995); celecoxib (available under the tradename CELEBREX@, from Pfizer, US patent number 5,466, 823); valdecoxib (available under the tradename BEXTRA@, from Pfizer, US patent number 6,633, 272); etoricoxib (available under the tradename ARCOXIA@, from Merck, US patent number 5,861, 419); lumiracoxib (available under the tradename PREXIGEO, from Novartis); paracoxib (US patent number 5,932, 598); COX-189 from Novartis; BMS347070 from Bristol Myers Squibb; tiracoxib (JTE522) from Japan Tobacco; ABT963 from Abbott; CS502 from Sankyo; 2- (4-ethoxyphenyl)-3- (3-methanesulfonylphenyl)-pyrazolo [1,5- b] pyridazine (GlaxoSmithKline) and 2-butoxy-4- [4- (methylsulfonyl) phenyl]-6- (trifluoromethyl) pyrimidine (GlaxoSmithKline).

It will be appreciated that the compounds of the combination or composition may be administered simultaneously (either in the same or different pharmaceutical formulations), separately or sequentially.

The compounds of formula (I) and pharmaceutical acceptable salts and solvates thereof are also suitable for combination with other typical and atypical antipsychotics to provide improved treatment of psychotic disorders. Particular advantages associated with the combinations, uses and methods of treatment of compounds of formula (I) and their pharmaceutical acceptable salts and solvates thereof include equivalent or improved efficacy at doses of administration which are lower than those commonly used for the individual components. Improved treatments of positive symptoms and/or negative symptoms and/or cognitive symptoms of the psychotic disorder may also be observed. The combinations, uses and methods of treatment of the invention may also provide advantages in treatment of patients who fail to respond adequately or who are resistant to treatment with certain antipsychotic agents (also known as neuroleptic agents).

The combination therapies of the invention are preferably administered adjunctively. By adjunctive administration is meant the coterminous or overlapping administration of each of the components in the form of separate pharmaceutical compositions or devices. This regime of therapeutic administration of two or more therapeutic agents is referred to generally by those skilled in the art and herein as adjunctive therapeutic administration; it is also known as add-on therapeutic administration. Any and all treatment regimes in which a patient receives separate but coterminous or overlapping therapeutic administration of the compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof and at least one 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 components for a period of time and then receives administration of another component. The compounds of formula (1) or a pharmaceutically acceptable salt or solvate 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 or solvate thereof.

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

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

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

In a further aspect, the invention provides a kit-of-parts for use in the treatment of a psychotic disorder comprising a first dosage form comprising compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof and one or more further dosage forms each comprising a antipsychotic agent for simultaneous therapeutic administration.

Within the context of the present invention, the term psychotic disorder includes those disorders mentioned above, such as schizophrenia, mood disorders, anxiety disorders, substance-related disorders, sleep disorders, eating disorders, autistic disorder, attention- deficit/hyperactivity disorder, disruptive behaviour disorder, tic disorders, personality disorders, cognition impairment in other diseases, sexual dysfunction, dyskinetic disorders, depression, bipolar disorder, cognitive impairment and obsessive-compulsive disorders and all the various forms of the disorders as mentioned herein, which are contemplated as part of the present invention.

Examples of antipsychotic drugs that are useful in the present invention include, but are not limited to: butyrophenones, such as haloperidol, pimozide, and droperidol ; phenothiazines, such as chlorpromazine, thioridazine, mesoridazine, trifluoperazine, perphenazine, fluphenazine, thiflupromazine, prochlorperazine, and acetophenazine; thioxanthenes, such as thiothixene and chlorprothixene ; thienobenzodiazepines; dibenzodiazepines; benzisoxazoles ; dibenzothiazepines; imidazolidinones ; benzisothiazolyl-piperazines ; triazine such as iamotrigine ; 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 that are suitable for use in the present invention are as follows : clozapine (available under the tradename CLOZARIL@, from Mylan, Zenith Goldline, UDL, Novartis); olanzapine (available under the tradename ZYPREXAO, from Lilly ; ziprasidone (available under the tradename GEODON@, from Pfizer); risperidone (available under the tradename RISPERDALO, from Janssen); quetiapine fumarate (available under the tradename SEROQUEL@, from AstraZeneca); sertindole (available under the tradename SERLECT@) ; amisulpride (available under the tradename SOUPON@, from Sanofi-Synthelabo) ; haloperidol (available under the tradename HALDOL@, from Ortho-McNeil) ; haloperidol decanoate (available under the tradename HALDOL decanoate@) ; haloperidol lactate (available under the tradenames ALDOLS and INTENSOL@) chlorpromazine (available under the tradename THORAZINEO, from SmithKline Beecham (GSK) ; fluphenazine (available under the tradename PROLIXINX, from Apothecon, Copley, Schering, Teva, and American Pharmaceutical Partners, Pasadena); fluphenazine decanoate (available under the tradename PROLIXIN decanoate@) ; fluphenazine enanthate (available under the tradename PROLIXIN@) ; fluphenazine hydrochloride (available under the tradename PROLIXIN@) ; thiothixene (available under the tradename NAVANE@ ;, from Pfizer); thiothixene hydrochloride (available under the tradename NAVANE@) ; trifluoperazine (10- [3- (4-methyl-1-piperazinyl) propyl]-2- (trifluoromethyl) phenothiazine dihydrochloride, available under the tradename STELAZINEO, from SmithKlien Beckman; perphenazine (available under the tradename TRILAFONO ; from Schering); perphenazine and amitriptyline hydrochloride (available under the tradename ETRAFON TRILAFON@) ; thioridazine (available under the tradename MELLARIL@ ; from Novartis, Roxane, HiTech, Teva, and Alpharma) ; molindone (available under the tradename MOBAN@, from Endo); molindone hydrochloride (available under the tradename MOBAN@) ; loxapine (available under the tradename LOXITANE@ ; from Watson); loxapine hydrochloride (available under the tradename LOXITANEO) ; and loxapine succinate (available under the tradename LOXITANE@). Furthermore, benperidol (Glianimon@), perazine (Taxilan@) or melperone (Eunerpan@)) may be used.

Other suitable antipsychotic drugs include promazine (available under the tradename SPARINE@), triflurpromazine (available under the tradename VESPRINO), chlorprothixene (available under the tradename TARACTAN@), droperidol (available under the tradename INAPSINE@), acetophenazine (available under the tradename TINDAL@ ; ), prochlorperazine (available under the tradename COMPAZINE@), methotrimeprazine (available under the tradename NOZINAN@), pipotiazine (available under the tradename PIPOTRIL@), iloperidone, pimozide and flupenthixol.

In one further aspect of the invention, suitable antipsychotic agents include olanzapine, risperidone, quetiapine, aripiprazole, haloperidol, clozapine, ziprasidone and osanetant.

For use in medicine, the compounds of the present invention are usually administered as a standard pharmaceutical composition. The present invention therefore provides in a further aspect a pharmaceutical composition comprising a compound of formula (I) as hereinbefore described or a pharmaceutically (i. e. physiologically) acceptable salt thereof and a pharmaceutical (i. e. physiologically) acceptable carrier. The pharmaceutical composition can be for use in the treatment of any of the conditions described herein.

The compounds of formula (I) may be administered by any convenient method, for example by oral, parenteral (e. g. intravenous), buccal, sublingual, nasal, rectal or transdermal administration and the pharmaceutical compositions adapted accordingly.

The compounds of formula (I) as hereinbefore described and their pharmaceutical acceptable salts which are active when given orally can be formulated as liquids or solids, for example syrups, suspensions or emulsions, tablets, capsules and lozenges.

A liquid formulation will generally consist of a suspension or solution of the compound or pharmaceutically acceptable salt in a suitable liquid carrier (s) for example an aqueous solvent such as water, ethanol or glycerine, or a non-aqueous solvent, such as polyethylene glycol or an oil. The formulation may also contain a suspending agent, preservative, flavouring or colouring agent.

A composition in the form of a tablet can be prepared using any suitable pharmaceutical carrier (s) routinely used for preparing solid formulations. Examples of such carriers include magnesium stearate, starch, lactose, sucrose and cellulose.

A composition in the form of a capsule can be prepared using routine encapsulation procedures. For example, pellets containing the active ingredient can be prepared using standard carriers and then filled into a hard gelatin capsule ; alternatively, a dispersion or suspension can be prepared using any suitable pharmaceutical carrier (s), for example aqueous gums, celluloses, silicates or oils and the dispersion or suspension then filled into a soft gelatin capsule.

Typical parenteral compositions consist of a solution or suspension of the compound or pharmaceutically acceptable salt in a sterile aqueous carrier or parenterally acceptable oil, for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil.

Alternatively, the solution can be lyophilised and then reconstituted with a suitable solvent just prior to administration.

Compositions for nasal administration may conveniently be formulated as aerosols, drops, gels and powders. Aerosol formulations typically comprise a solution or fine suspension of the active substance in a pharmaceutically acceptable aqueous or non-aqueous solvent and are usually presented in single or multidose quantities in sterile form in a sealed container, which can take the form of a cartridge or refill for use with an atomising device. Alternatively the sealed container may be a unitary dispensing device such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve which is intended for disposal once the contents of the container have been exhausted. Where the dosage form comprises an aerosol dispenser, it will contain a propellant which can be a compressed gas such as compressed air or an organic propellant such as a fluorochlorohydrocarbon. The aerosol dosage forms can also take the form of a pump-atomiser.

Compositions suitable for buccal or sublingual administration include tablets, lozenges and pastilles, wherein the active ingredient is formulated with a carrier such as sugar and acacia, tragacanth, or gelatin and glycerin.

Compositions for rectal administration are conveniently in the form of suppositories containing a conventional suppository base such as cocoa butter.

Compositions suitable for transdermal administration include ointments, gels and patches.

The composition is suitably in unit dose form such as a tablet, capsule or ampoule.

Each dosage unit for oral administration may contain from 1 to 250 mg (and for parenteral administration contains preferably from 0.1 to 25 mg) of a compound of the formula (I) or a pharmaceutical acceptable salt thereof calculated as the free base.

The pharmaceutically acceptable compounds of the invention will normally be administered in a daily dosage regimen (for an adult patient) of, for example, an oral dose of between 1 mg and 250 mg, such as between 1 mg and 250 mg, such as between 2 mg and 100mg, e. g. between 2 and 50 mg or an intravenous, subcutaneous, or intramuscular dose of between 0.1 mg and 100 mg, preferably between 0.1 mg and 50 mg, e. g. between 1 and 25 mg of the compound of the formula (I) or a pharmaceutical acceptable salt thereof calculated as the free base, the compound being administered 1 to 4 times per day. Suitably the compounds will be administered for a period of continuous therapy, for example for a week or more.

No adverse toxicological effects have been observed for compounds of the invention at doses expected to be approved for therapeutic administration.

Biological Test Methods Binding experiments on cloned dopamine (e. g. D2 and D3) receptors The ability of the compounds to bind selectively to human D2/D3 dopamine receptors can be demonstrated by measuring their binding to cloned receptors. The inhibition constants (Ki) of test compounds for displacement of [Srj-jodosuipride binding to human D2/D3 receptors expressed in CHO cells were determined as follows. The cell lines were shown to be free from bacterial, fungal and mycoplasmal contaminants, and stocks of each were stored frozen in liquid nitrogen. Cultures were grown as monolayers or in suspension in standard cell culture media. Cells were recovered by scraping (from monolayers) or by centrifugation (from suspension cultures), and were washed two or three times by suspension in phosphate buffered saline followed by collection by centrifugation. Cell pellets were stored frozen at- 80°C. Crude cell membranes were prepared by homogenisation followed by high-speed centrifugation, and characterisation of cloned receptors achieved by radioligand binding.

Preparation of CHO cell membranes: Cell pellets were gently thawed at room temperature, and resuspended in about 20 volumes of ice-cold Extraction buffer; 5mM EDTA, 50mM Trizma pre-set crystals (pH7. 4@37°C), 1mM MgCl2, 5mM KCI and 120mM NaCI. The suspension was homogenised using an Ultra-Turrax at full speed for 15 seconds. The homogenate was centrifuged at 18,000 r. p. m for 15 min at 4°C in a Sorvall RC5C centrifuge.

Supernatant was discarded, and homogenate re-suspended in extraction buffer then centrifugation was repeated. The final pellet was resuspended in 50mM Trizma pre-set crystals (pH 7.4 @ 37°C) and stored in 1 ml aliquot tubes at-80°C (D2 = 3. 0E+08 cells, D3 = 7. 0E+07 cells and D4 = 1. OE+08 cells). The protein content was determined using a BCA protocol and bovine serum albumin as a standard (Smith, P. K. , et al., Measurement of protein using bicinchoninic acid. Anal. Biochem. 150, 76-85 (1985)).

Binding experiments: Crude D2/D3 cell membranes were incubated with 0.03nM [125l]- lodosulpride (-2000 Ci/mmol ; Amersham, U. K. , and the test compound in a buffer containing 50mM Trizma pre-set crystals (pH 7. 4 @ 37°C), 120mM NaCI, 5mM KCI, 2mM CaCl2, 1mM MgCI2, 0.3% (w/v) bovine serum albumin. The total volume is 0. 2ml and incubated in a water bath at 37°C for 40 minutes. Following incubation, samples were filtered onto GF/B Unifilters using a Canberra Packard Filtermate, and washed four times with ice-cold 50mM Trizma pre-set crystals (pH 7.4 @ 37°C). The radioactivity on the filters was measured using a Canberra Packard Topcount Scintillation counter. Non-specific binding was defined with 1 OM SKF-102161 (YM-09151). For competition curves, 10 serial log concentrations of competing cold drug were used (Dilution range: 10jnM-10pM).

Competition curves were analysed using Inflexion, an iterative curve fitting programme in Excel. Results were expressed as pKj values where pKj=-iog10 [Ki].

The exemplified compounds have pKj values within the range of 7.6-8. 4 at the dopamine D3 receptor.

The exemplified compounds have pKj values within the range of 7.3-8. 2 at the dopamine D2 receptor.

Binding experiments on cloned 5-HT6 receptors Compounds can be tested following the procedures outlined in WO 98/27081.

The exemplified compounds have pKi values within the range of 8.5-9. 0 at the serotonin 5- HT6 receptor.

Binding experiments on cloned 5-HTz and 5-HT2C receptors Compounds can be tested following the procedures outlined in WO 94/04533.

The exemplified compounds have pKj values within the range of 8.0-8. 8 at the serotonin 5- HT2c receptor and 8.9-9. 5 at the serotonin 5-HT2A receptor. The invention is further illustrated by the following non-limiting examples : Description 1 1- (4-Bromo-phenyl)-1- (3-fluoro-4-methylphenyl)-methanol (D1) Dried magnesium turnings (4.24 g, 0.55 mole) were stirred with a heavy stirrer bar under argon for 16 hours. A few crystals of iodine were added followed by a solution of 4-bromo-2- fluorotoluene (94.5 g, 0.5 mole) in tetrahydrofuran [THF] (200 ml). This addition took place over about 40 minutes and the solution was allowed to reflux during the addition. The resulting solution was stirred for 1 hour. 4-Bromobenzaldehyde (71.7 g 0.39 mole) in THF (200 ml) was cooled to 0°C then treated with the above Grignard solution. The addition of the Grignard solution took place over 30 minutes and the resulting solution was stirred for 2 hours at room temperature. The reaction mixture was poured slowly into a solution of potassium sodium tartrate (10% solution, 1 L) and extracted with ethyl acetate (EtOAc). The organic solution was dried with brine and sodium sulfate and evaporated. Trituration with hexane gave the title compound (D1) as a white solid (71.8 g, 65%).'H NMR: 8 CDCI3 2.20 (1H, d), 2.24 (3H, m), 5.75 (1H, d), 6.98 (1H, s) 7.05 (1H, m), 7.16 (1H, m), 7.24 (2H, m) 7.47 (2H, m).

Description 2 1- (4-Bromo-phenyl)-1- (3-fluoro-4-methylphenyl)-methane (D2) A solution of 1- (4-bromophenyl)-1- (3-fluoro-4-methylphenyl)-methanol D1 (21.4 g, 0.072 mole), triethylsilane (34 g, 0.29 mole) and chloroform (300 ml) was cooled in an ice bath.

Trifluoromethanesulfonic acid (7 ml, 0.78 mole) was added over 30 minutes. The solution was stirred for 1 hour then washed with saturated sodium bicarbonate solution and brine.

The solvent was removed under reduced pressure and the residue was distilled. Triethylsilanol distills first Bp (75°C @0. 2mmHg). The title compound (D2) distills Bp (125- 132 °C@ 0.15mmHg). Yield (16.4 g, 82%)'H NMR: â CDC13 2.23 (3H, m), 3.86 (2H, s), 6.8 (2H, m) 7.0 (3H, m), 7.4 (2H, m).

Description 3 8-Methoxy-3-methyl-2, 3,4, 5-tetrahydro-1H-3-benzazepine-7-sulfonyl fluoride (D3) a) 7-Methoxy-3-methyl-2, 3,4, 5-tetrahydro-1 H-3-benzazepi ne A mixture of 7-methoxy-2, 3,4, 5-tetrahydro-1 H-3-benzazepine hydrochloride (see EP 285287) (25 g, 125 mmol) and 37% formalin (25 ml) in dichloroethane (250 ml) was treated with sodium triacetoxyborohydride (30 g, 250 mmol) keeping the internal temperature below 20°C. After stirring for 2 hours, water was added and the pH adjusted to 10 using 50% sodium hydroxide solution. The organic layer was separated, dried over sodium sulfate and evaporated to dryness to afford the product (23 g). b) 8-Methoxy-3-methyl-2, 3,4, 5-tetrahydro-1H-3-benzazepine-7-sulfonic acid The product from part (a) (23 g) was dissolved in trifluoroacetic acid (125 ml), and then stirred in an ice bath while chlorosulfonic acid (16.5 ml, 250 mmol) was added dropwise.

The solution was stirred for 30 minutes, then evaporated to dryness to afford the title sulfonic acid which was used directly in the next step. c) 8-Methoxy-3-methyl-2, 3,4, 5-tetrahydro-1H-3-benzazepine-7-sulfonyl chloride The sulfonic acid from part (b) was dissolved in thionyl chloride (75 mi) and the solution refluxed for 30 minutes. After cooling, the solution was evaporated to dryness to afford the title sulfonyl chloride which was used directly in the next step d) 8-Methoxy-3-methyl-2, 3,4, 5-tetrahydro-1 H-3-benzazepi ne-7-sulfonyl fluoride The sulfonyl chloride from part (c) was dissolved in acetonitrile (500 ml) and potassium fluoride (37 g, 625 mmol) and 18-crown-6 (1 crystal) added. The mixture was stirred for 18 hours, then quenched with cold aqueous sodium bicarbonate solution until the pH equalled 8. The mixture was extracted twice with ethyl acetate, washed with bicarbonate solution then brine, dried and evaporated to afford the sulfonyl fluoride D3 (25 g). MH+274'H NMR: 8 DMSO-d6 2.35 (3H, s), 2.61 (4H, m), 2.95 (2H, m), 3.03 (2H, m), 3.97 (3H, s), 7.29 (1H, s), 7.69 (1 H, s).

Description 4 7- [4- (3-Fluoro-4-methyl-benzyl)-benzenesulfonyl]-8-methoxy-3-meth yl-2, 3,4, 5- tetrahydro-1H-3-benzazepine (D4) To a stirred solution of 1- (4-bromo-phenyl)-1- (3-fluoro-4-methylphenyl)-methane (D2) (46.45 g, 166.6 mmol) in dry THF (300 ml) at-78°C under argon was added dropwise n-n- butyllithium (nBuLi) (2.5M in hexane, 66.5 ml, 166.4 mmol). The resulting solution was stirred for 30 minutes at-78°C before the dropwise addition of 8-methoxy-3-methyl-2, 3,4, 5- tetrahydro-1H-3-benzazepine-7-sulfonyl fluoride (D3) (15.16 g, 55.47 mmol) in dry THF (150 ml). This addition was carried out over 20 minutes. The resultant red solution was stirred at- 78°C for 1 hour then quenched with acetic acid (10 ml). The mixture was diluted with water (200 ml) and allowed to warm to room temperature. The pH was adjusted to greater than 7 using saturated sodium hydrogen carbonate and extracted with EtOAc (2 x 300 ml). The combined organic phase was washed with water, brine, dried over magnesium sulphate, then concentrated to give an oil. This oil was purified using column chromatography over silica, eluting with 10% ammonia in methanol-dichloromethane (0 to 10%) yielding an off white solid (23.0 g). Further purification was carried out using amino column chromatography, eluting with 0 to 100% EtOAc in hexane. This yielded the title compound (free base), as a white solid (18.3 g, 73%). MH+454. 1H NMR 6 (CDCI3) 2.22 (3H, s), 2.36 (3H, s), 2.48-2. 58 (4H, m), 2.85-2. 99 (4H, m), 3.73 (3H, s), 3.96 (2H, s), 6.63 (1H, s), 6.68-6. 84 (2H, m), 7.03- 7.12 (1H, t), 7.20-7. 29 (3H, m), 7.80 (1H, s), 7.85-7. 93 (2H, d).

Example 1 7- [4- (3-Fluoro-4-methyl-benzyl)-benzenesulfonyl]-8-hydroxy-3-meth yl-2, 3,4, 5- tetrahydro-1H-3-benzazepine (E1) A solution of 7- [4- (3-fluoro-4-methyl-benzyl)-benzenesulfonyl]-8-methoxy-3-meth yl-2, 3,4, 5- tetrahydro-1H-3-benzazepine (D4) (3.08 g, 6.79 mmol, 1.0 eq) was heated at 120°C under argon in 48% aqueous hydrogen bromide (HBr) (70 ml) for 5 hours then allowed to cool to room temperature. The solvent was removed in vacuo giving a foam. Purification by column chromatography on silica, eluting with 0-10% MeOH in CH2CI2 with 1% added NH3 afforded the free base of the title compound as a white solid, 2.66 g (89%). MH+ 440. 1H NMR 5 (CDCI3) 2.22 (3H, s), 2.40 (3H, s), 2.61 (4H, m), 2.89 (4H, m), 3.96 (2H, s), 6.74-6. 84 (3H, m), 7.09 (1 H, t), 7.28 7.32 (3H, m), 7.83 (2H, d).

Examples 2-18 were prepared using analogous procedures to Example 1 using the appropriately substituted aryl halide as described in D1. Products were isolated as either the free base or monohydrochloride salt. All'H NMR are consistent with the structures shown. All of the compounds listed below in Table 1 relate to compounds of formula (I) as described above.

Table 1 Example No. R1 R2 1 3-F 4-Me 2 2-F H 3 3-F 4-F 4 4-Cl H 5 4-F H 6 2-Cl 4-F 7 R1 and R2 at the 3-and 4-position together with the carbon atoms to which they are attached form a 1,4- dioxane rin 8 4-Me H 9 3-Me 4-CI 10 2-OCF3 H 11 3-OCF3 H 12 2-Me 6-Me 13 4-tBu H 14 2-F 4-F 15 3-F 5-F 16 3-CI 4-Cl 17 3-F 4-Cl 18 3-CI 5-CI All publications, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference as if each individual publication were specifically and individually indicated to be incorporated by reference herein as though fully set forth.