Many medically significant biological processes are mediated by proteins participating in signal transduction pathways that involve G-proteins and/or second messengers.

Polypeptides and polynucleotides encoding the human 7-transmembrane G-protein coupled neuropeptide receptor, orexin-1 (HFGAN72), have been identified and are disclosed in EP-A-875565, EP-A-875566 and WO 96/34877. Polypeptides and polynucleotides encoding a second human orexin receptor, orexin-2 (HFGANP), have been identified and are disclosed in EP-A-893498.

Polypeptides and polynucleotides encoding polypeptides which are ligands for the orexin-1 receptor, e. g. orexin-A (Lig72A) are disclosed in EP-A-849361.

Orexin receptors are found in the mammalian host and may be responsible for many biological functions, including pathologies including, but not limited to, depression; anxiety ; addictions; obsessive compulsive disorder; affective neurosis/disorder; depressive neurosis/disorder; anxiety neurosis; dysthymic disorder; behaviour disorder; mood disorder; sexual dysfunction; psychosexual dysfunction; sex disorder; sexual disorder; schizophrenia; manic depression; delerium; dementia; severe mental retardation and dyskinesias such as Huntington's disease and Gilles de la Tourett's syndrome; disturbed biological and circadian rhythms; feeding disorders, such as anorexia, bulimia, cachexia, and obesity; diabetes; appetite/taste disorders; vomiting/nausea ; asthma; cancer ; Parkinson's disease; Cushing's syndrome/disease; basophil adenoma; prolactinoma; hyperprolactinemia; hypopituitarism ; hypophysis tumor/adenoma; hypothalamic diseases; Froehlich's syndrome; adrenohypophysis disease; hypophysis disease; hypophysis tumor/adenoma; pituitary growth hormone; adrenohypophysis hypofunction; adrenohypophysis hyperfunction; hypothalamic hypogonadism; Karman's syndrome (anosmia, hyposmia) ; functional or psychogenic amenorrhea; hypopituitarism; hypothalamic hypothyroidism ; hypothalamic- adrenal dysfunction; idiopathic hyperprolactinemia; hypothalamic disorders of growth hormone deficiency; idiopathic growth hormone deficiency; dwarfism; gigantism; acromegaly; disturbed biological and circadian rhythms; and sleep disturbances associated with such diseases as neurological disorders, neuropathic pain and restless leg syndrome, heart and lung diseases; acute and congestive heart failure; hypotension; hypertension; urinary retention; osteoporosis; angina pectoris; myocardial infarction ; ischaemic or haemorrhagic stroke ; subarachnoid haemorrhage; head injury such as sub-arachnoid haemorrhage associated with traumatic head injury; ulcers; allergies; benign prostatic hypertrophy; chronic renal failure; renal disease; impaired glucose tolerance; migraine; hyperalgesia; pain; enhanced or exaggerated sensitivity to pain, such as hyperalgesia, causalgia and allodynia ; acute pain; burn pain ; atypical facial pain; neuropathic pain; back pain; complex regional pain syndromes I and lI ; arthritic pain; sports injury pain; pain related to infection, e. g. HTV, post-polio syndrome, and post-herpetic neuralgia; phantom limb pain; labour pain; cancer pain; post-chemotherapy pain; post-stroke pain; post-

operative pain; neuralgia; nausea and vomiting; conditions associated with visceral pain including irritable bowel syndrome, migraine and angina; urinary bladder incontinence e. g. urge incontinence; tolerance to narcotics or withdrawal from narcotics; sleep disorders; sleep apnea; narcolepsy; insomnia; parasomnia ; jet-lag syndrome; and neurodegenerative disorders, which includes nosological entities such as disinhibition-dementia-parkinsonism- amyotrophy complex; pallido-ponto-nigral degeneration, epilepsy, and seizure disorders.

Experiments have shown that central administration of the ligand orexin-A (described in more detail below) stimulated food intake in freely-feeding rats during a 4 hour time period. This increase was approximately four-fold over control rats receiving vehicle. These data suggest that orexin-A may be an endogenous regulator of appetite.

Therefore, antagonists of its receptor may be useful in the treatment of obesity and diabetes, see Cell, 1998,92, 573-585.

There is a significant incidence of obesity in westernised societies. According to WHO definitions a mean of 35% of subjects in 39 studies were overweight and a further 22% clinically obese. It has been estimated that 5.7% of all healthcare costs in the USA are a consequence of obesity. About 85% of Type 2 diabetics are obese, and diet and exercise are of value in all diabetics. The incidence of diagnosed diabetes in westernised countries is typically 5% and there are estimated to be an equal number undiagnosed. The incidence of both diseases is rising, demonstrating the inadequacy of current treatments which may be either ineffective or have toxicity risks including cardiovascular effects. Treatment of diabetes with sulfonylureas or insulin can cause hypoglycaemia, whilst metformin causes GI side-effects. No drug treatment for Type 2 diabetes has been shown to reduce the long-term complications of the disease. Insulin sensitisers will be useful for many diabetics, however they do not have an anti-obesity effect.

Rat sleep/EEG studies have also shown that central administration of orexin-A, an agonist of the orexin receptors, causes a dose-related increase in arousal, largely at the expense of a reduction in paradoxical sleep and slow wave sleep 2, when administered at the onset of the normal sleep period. Therefore antagonists of its receptor may be useful in the treatment of sleep disorders including insomnia.

The present invention provides N-aryl acetyl cyclic amine derivatives which are non-peptide antagonists of human orexin receptors, in particular orexin-1 receptors. In particular, these compounds are of potential use in the treatment of obesity, including obesity observed in Type 2 (non-insulin-dependent) diabetes patients, and/or sleep disorders. Additionally these compounds are useful in the treatment of stroke, particularly ischemic or haemorrhagic stroke, and/or blocking the emetic response, i. e. useful in the treatment of nausea and vomiting.

International Patent Applications W099/09024, W099/58533, WO00/47577 and WO00/47580 disclose phenyl urea derivatives and WO00/47576 discloses quinolinyl cinnamide derivatives as orexin receptor antagonists. WO01/96302 discloses N-aroyl cyclic amine derivatives.

According to the invention there is provided a compound of formula (I):

wherein: Y represents a bond, oxygen, NQ or a group (CH2) n, wherein n represents 1,2 or 3 misOorl ; X is NR, wherein R is H or (Cl) alkyl ; Q is H or (CI-4) alkyl; Arl is aryl, or a mono or bicyclic heteroaryl group containing up to 4 heteroatoms selected from N, O and S; any of which may be optionally substituted; Ar2 represents optionally substituted phenyl, an optionally substituted 5-or 6- membered heterocyclyl group containing up to 4 heteroatoms selected from N, O and S, or an optionally substituted bicyclic aromatic or bicyclic heteroaromatic group containing up to 4 heteroatoms selected from N, O and S; Rl and R2 independently represent hydrogen, optionally substituted amino, optionally substituted (Cl-6) alkyl or optionally substituted phenyl; or a pharmaceutically acceptable salt thereof.

When m = 1, R is preferably H.

Preferably Arl is an optionally substituted benzimidazolyl, pyrimidinyl or quinoxalinyl group.

Ar2 is preferably optionally substituted phenyl, naphthyl or benzofuranyl.

Y is preferably CH2 Preferably n is 1.

Rl and R2 are preferably H or optionally substituted phenyl.

Examples of when Arl is a mono or bicyclic heteroaryl are quinoxalinyl, quinazolinyl, pyridopyrazinyl, benzoxazolyl, benzothiophenyl, benzimidazolyl, naphthyridinyl, pyridinyl, pyrimidinyl, or thiazolyl, pyridazinyl, pyrazinyl, oxazolyl, triazolyl, imidazolyl, pyrazolyl, quinolinyl, benzofuranyl, indolyl, benzothiazolyl, oxazolyl [4,5-b] pyridiyl, pyridopyrimidinyl, isoquinolinyl, furanyl or thienyl.

Preferably Arl is benzoxazolyl, benzimidazolyl, quinoxalinyl, quinazolinyl, pyrimidinyl, pyridinyl or naphthyridinyl.

More preferably Arl is benzimidazolyl, quinoxalinyl or pyrimidinyl.

When Ar2 is a 5-or 6-membered heterocyclyl group containing up to 4 heteroatoms selected from N, O and S, it may be furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyridyl, triazolyl, triazinyl, pyridazinyl, pyrimidinyl, isothiazolyl, isoxazolyl, pyrazinyl or pyrazolyl.

When Ar2 is an optionally substituted bicyclic aromatic or bicyclic heteroaromatic it is selected from benzofuranyl, benzimidazolyl, quinolinyl, quinoxalinyl, naphthyl,

benzotriazolyl, benzothienyl, benzoxazolyl, naphthyridinyl, isoquinolinyl, quinazolinyl, indolyl, benzothiazolyl, or benzothiadiazolyl.

Preferably Ar2 represents optionally substituted phenyl, pyridyl, thiazolyl, pyrazolyl, benzofuranyl, naphthyl, triazolyl, quinoxalinyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzothienyl, benzotriazolyl, benzothiazolyl, indolyl or thienyl.

More preferably Ar2 represents optionally substituted phenyl, benzofuranyl or naphthyl.

Optional substituents for the groups Arl, Ar2, Rl and R2 include halogen, hydroxy, oxo, cyano, nitro, (Cl-4) alkyl, (Cl-4) alkoxy, hydroxy (CI 4) alkyl, hydroxy (C1-4)alkoxy, halo (Cl-4) alkyl, halo (C1-4) alkoxy, aryl (CI-4) alkoxy, (C1-4)alkylthio, hydroxy(C1-4)alkyl, (C1- 4) alkoxy (C1-4)alkyl, C3-6)cycloalkyl(C1-4)alkoxy, (C1-4)alkanoyl,(C1-4) alkoxycarbonyl, (C1- 4) alkylsulfonyl, (C1-4)alkylsulfonyloxy, (C1-4) alkylsulfonyl(C1-4)alkyl, arylsulfonyl, arylsulfonyloxy, arylsulfonyl (Cl 4) alkyl, (Ci-4) alkylsulfonamido, (Cl-4) alkylamido, (C 4) alkylsulfonamido (C1-4)alkyl, (C1-4) alkylamido (Ci-4) alkyl, arylsulfonamido, arylcarboxamido, arylsulfonamido (C1-4) alkyl, arylcarboxamido (C1-4) alkyl, aroyl, aroyl (C1- 4) alkyl, or aryl (Cl-4) alkanol group; a group RaRbN-, RaOCO (CH2)r, RaCON(Ra)(CH2)r, RaRbNCO (CH2) r, RaRbNS02 (CH2) r or RaS02NRb (CH2) r where each of Ra and Rb independently represents a hydrogen atom or a (C1-4) alkyl group or where appropriate RaRb forms part of a (C3-6) azacyloalkane or (C3-6) (2-oxo) azacycloalkane ring and r represents zero or an integer from 1 to 4. Additional substituents are (Cl4) acyl, aryl, aryl (C1-4) alkyl, (C1-4)alkylamino(C1-4)alkyl, RaRbN (CH2) n-, RaRbN (CH2) nO-, wherein n represents an integer from 1 to 4. Additionally when the substituent is RaRbN (CH2) n- or RaRbN (CH2) nO, Ra with at least one CH2 of the (CH2) n portion of the group form a (C3-6) azacycloalkane and Rb represents hydrogen, a (C1-4) alkyl group or with the nitrogen to which it is attached forms a second (C3-6) azacycloalkane fused to the first (C3-6) azacycloalkane.

Preferred optional substituents for Ar2 are halogen, (C1-4)alkyl or (Cl-) alkoxy.

Most preferred optional substituents for Ar2 include methoxy (Cl alkoxy), ethoxy (C2 alkoxy) or chlorine.

Preferred optional substituents for Arl are halogen or (Cl-) alkyl.

Most preferred optional substituents for Arl include fluorine or bromine.

In the groups Arl and Ar2, substituents positioned ortlio to one another may be linked to form a ring.

Preferred optional substituents for Rl and R2 include H and optionally substituted phenyl.

Illustrative compounds of formula (I) are selected from compounds having a core structure (Ia)

(Ia) wherein Y, R1, R2, X, Ar1 and Ar2 are as shown in Table 1 Table 1 Example Y _ _ X Ar 2 CH2 H H NH N F --"'I Me0 N v'F 3 CH2 H H NH \ N v'F 4 CH2 H H NH N zu OMe OMe 5 CH2 H H NH/N \ F N F OMe 6 CH2 H H NH Cl NXF "') au C ! CI 7 CH2 H H NH ~4 N3aF \// N v'F 8 CH2 H H NH N F zu 0 : 6 O/ 9 CH2 H H NH/I N I \ Nr OMe Br 10 CH2 H H NH N \ I N I omet Br CH2 H Ph/F Zu H / H

and pharmaceutically acceptable salts thereof.

When a halogen atom is present in the compound of formula (1) it may be fluorine, chlorine, bromine or iodine.

When the compound of formula (I) contains an alkyl group, whether alone or forming part of a larger group, e. g. alkoxy or alkylthio, the alkyl group may be straight chain, branched or cyclic, or combinations thereof, it is preferably methyl or ethyl.

When used herein the term aryl means a 5-to 6-membered aromatic ring for example phenyl, or a 7 to 12 membered bicyclic ring system where at least one of the rings is aromatic for example naphthyl.

It will be appreciated that compounds of formula (1) may exist as R or S enantiomers. The present invention includes within its scope all such isomers, including mixtures. Where additional chiral centres are present in compounds of formula (I), the present invention includes within its scope all possible diastereoismers, including mixtures thereof. The different isomeric forms may be separated or resolved one from the other by conventional methods, or any given isomer may be obtained by conventional synthetic methods or by stereospecific or asymmetric syntheses.

It will be understood that the invention includes pharmaceutically acceptable derivatives of compounds of formula (I) and that these are included within the scope of the invention.

Particular compounds according to the invention include those mentioned in the examples and their pharmaceutically acceptable derivatives.

As used herein"pharmaceutically acceptable derivative"includes any pharmaceutically acceptable salt, ester or salt of such ester of a compound of formula (1) which, upon administration to the recipient is capable of providing (directly or indirectly) a compound of formula (1) or an active metabolite or residue thereof.

It will be appreciated that for use in medicine the salts of the compounds of formula (1) should be phannaceutically acceptable. Suitable pharmaceutically acceptable salts will be apparent to those skilled in the art and include acid addition salts formed with inorganic acids e. g. hydrochloric, hydrobromic, sulphuric, nitric or phosphoric acid; and organic acids e. g. succinic, maleic, acetic, fumaric, citric, tartaric, benzoic, p-toluenesulfonic, methanesulfonic or naphthalenesulfonic acid. Other salts e. g. oxalates, may be used, for example in the isolation of compounds of formula (1) and are included within the scope of this invention. Also included within the scope of the invention are solvates and hydrates of compounds of formula (I).

Certain of the compounds of formula (1) 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.

Since the compounds of formula (I) are intended for use in pharmaceutical compositions it will readily be understood that they are each preferably provided in substantially pure form, for example at least 60% pure, more suitably at least 75% pure and preferably at least 85%, especially at least 98% pure (% are on a weight for weight basis).

Impure preparations of the compounds may be used for preparing the more pure forms used in the pharmaceutical compositions.

According to a further aspect of the present invention there is provided a process for the preparation of compounds of formula (1) and derivatives thereof. The following schemes detail some synthetic routes to compounds of the invention.

Scheme la HNR-Ar' (vu) (vu) CH2NR-Ar'N CH2-L P P (IV) (V) deprotection 2 Y R1 p Rz Y (III) Ar2 _ 1 1 N CH2-N CH2NR-Ar' base H Xj R mR2 (II) Alrz\Rz (I) wherein Arl, Ar2, Y, R, R1 and R2 are as defined for formula (1), Ll and L2 are leaving groups, and P is a protecting group.

Examples of suitable leaving groups Ll include halogen, hydroxy, OSO2Me, OS02 (4-tolyl). The reaction of (V) with (VI) preferably proceeds in an inert solvent such as N, N-dimethylformamide in the presence of a base such as triethylamine, sodium hydride or potassium t-butoxide.

Schemelb Y Ar1 L1 Y (IX) N CH NHR N CHZNRAr'I z Y I p El (VIII) deprotection Lez R1 Y O Rz Y (III) Arz c/ c ION CH2NRAr1 base N CH2NR-Ar z base "' Rz (II) Ar2 (1) Reaction of (VIR) with (IX) proceeds in an inert solvent such as dimethylformamide or xylene in the presence of a base such as potassium carbonate or diisopropylethylamine, preferably at elevated temperatures. This transformation can be carried out when P is a protecting group as defined or when P = H.

Scheme le Lu RUZ C O Rz Y (III) Arz (N L CH NHP N CH2 base R'base 0 r-R y 0-f2 R2 (Xl) (X) C NlCH2N (C1-4) P | deprotection Ruz R2 y Ar'Ll y (XII) Arz deprotection N CH2NHR base N CH2NR-Ar C R (XIII) p Rz z R R Ar2 (1)

Reaction of (XI) with an alkylating agent (Cl-4) LI proceeds in the presence of a base such as sodium hydride in an inert solvent such as dimethylformamide.

Examples of suitable leaving groups L2 include halogen, hydroxy, OC (=O) alkyl and OC (=O) O-alkyl. The transformation aD to (1) may be carried out in an inert solvent such as dichloromethane, in the presence of a base such as triethylamine. Alternatively this step may be carried out when La represents hydroxy, in which case reaction with (IT) takes place in an inert solvent such as dichloromethane in the presence of a diimide reagent such as 1- ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, and an activator such as 1- hydroxybenzotriazole. Also when L 2 represents hydroxy the reaction can be effected using 0- (7-azabenzotrazol-1-yl)-N, N, N', N'-tetramethyluronium hexafluorophosphate (HATU) with a base such as triethylamine or N, N-diisopropylethylamine.

Examples of protecting groups P include t-butyloxycarbonyl, trifluoroacetyl, optionally substitued benzyl and benzyloxycarbonyl. Deprotection conditions are respectively, acid (e. g. trifluoroacetic acid in dichloromethane), base (e. g. sodium hydroxide in a solvent such as aqueous methanol) and catalytic hydrogenolysis in an inert solvent (e. g using palladium on charcoal in a lower alcohol or ethyl acetate).

Scheme 2 wherein, Y, Ar2, Rl and R2 are as defined for compounds of formula (1) and P is a protecting group.

The transformation of A to B can be carried out at elevated temperature in the absence of solvent or in the presence of an acid such as sulfuric acid or polyphosphoric acid, usually at elevated temperature. Deprotection can occur in situ under acidic conditions, if for example P is t-butoxycarbonyl to afford C directly.

The transformation C to D may be carried out in an inert solvent such as dichloromethane, in the presence of a base such as triethylamine. Alternatively this step may be carried out when L2 represents hydroxy, in which case reaction with C takes place in an inert solvent such as dichloromethane in the presence of a diimide reagent such as 1- ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, and an activator such as 1- hydroxybenzotriazole. Also when L 2 represents hydroxy the reaction can be effected using 0-(7-azabenzotrazol-1-yl)-N, N, N', N'-tetramethyluronium hexafluorophosphate (HATU) with a base such as triethylamine or N, N-diisopropylethylamine.

When Y = NQ, Q may also represent a protecting group P in the above schemes.

Compounds of formula (V), (VI) and (IX) are known in the literature or can be prepared by known methods. Compounds (VIM) and A can be prepared by known methods.

Within the schemes above there is scope for functional group interconversion and for conversion of one value of Ll to another value of Ll ; or conversion of protecting group P to another protecting group P, or conversion of one compound of formula (: to another of formula (I) by interconversion of substituents.

The compounds of formula (1) may be prepared singly or as compound libraries comprising at least 2, e. g. 5 to 1000, preferably 10 to 100 compounds of formula (1).

Compound libraries may be prepared by a combinatorial'split and mix'approach or by multiple parallel synthesis using either solution phase or solid phase chemistry, by procedures known to those skilled in the art.

Thus according to a further aspect of the invention there is provided a compound library comprising at least 2 compounds of formula (1), or pharmaceutically acceptable derivatives thereof.

Pharmaceutically acceptable salts may be prepared conventionally by reaction with the appropriate acid or acid derivative.

The compounds of formula (1) and their pharmaceutically acceptable derivatives are useful for the treatment of diseases or disorders where an antagonist of a human Orexin receptor is required such as obesity and diabetes; prolactinoma; hypoprolactinemia; hypothalamic disorders of growth hormone deficiency; idiopathic growth hormone deficiency; Cushings syndrome/disease; hypothalamic-adrenal dysfunction; dwarfism ; sleep disorders; sleep apnea; narcolepsy; insomnia; parasomnia ; jet-lag syndrome; sleep disturbances associated with diseases such as neurological disorders, neuropathic pain and restless leg syndrome; heart and lung diseases; depression; anxiety; addictions; obsessive compulsive disorder; affective neurosis/disorder; depressive neurosis/disorder; anxiety neurosis; dysthymic disorder; behaviour disorder; mood disorder; sexual dysfunction ; psychosexual dysfunction ; sex disorder; sexual disorder; schizophrenia ; manic depression; delerium; dementia; bulimia and hypopituitarism. Additionally the compounds of formula (1) and pharmaceutically acceptable derivatives are useful for the treatment of stroke, particularly ischemic or haemorrhagic and/or in blocking an emetic response i. e. nausea and vomiting.

The compounds of formula (1) and their pharmaceutically acceptable derivatives are particularly useful for the treatment of obesity, including obesity associated with Type 2

diabetes, and sleep disorders. Additionally the compounds of formula (I) and pharmaceutically acceptable derivatives are useful for the treatment of stroke, particularly ischemic or haemorrhagic and/or in blocking an emetic response i. e. nausea and vomiting.

Other diseases or disorders which may be treated in accordance with the invention include disturbed biological and circadian rhythms; adrenohypophysis disease; hypophysis disease; hypophysis tumor/adenoma; adrenohypophysis hypofunction ; functional or psychogenic amenorrhea ; adrenohypophysis hyperfunction; migraine; hyperalgesia; pain; enhanced or exaggerated sensitivity to pain such as hyperalgesia, causalgia and allodynia; acute pain; burn pain; atypical facial pain; neuropathic pain; back pain; complex regional pain syndromes I and II ; arthritic pain; sports injury pain; pain related to infection e. g. HIV, post-polio syndrome and post-herpetic neuralgia; phantom limb pain; labour pain; cancer pain; post-chemotherapy pain; post-stroke pain; post-operative pain; neuralgia; and tolerance to narcotics or withdrawal from narcotics.

The invention also provides a method of treating or preventing diseases or disorders where an antagonist of a human Orexin receptor is required, which comprises administering to a subject in need thereof an effective amount of a compound of formula (1), or a pharmaceutically acceptable derivative thereof.

The invention also provides a compound of formula (I), or a pharmaceutically acceptable derivative thereof, for use in the treatment or prophylaxis of diseases or disorders where an antagonist of a human Orexin receptor is required.

The invention also provides the use of a compound of formula (1), or a pharmaceutically acceptable derivative thereof, in the manufacture of a medicament for the treatment or prophylaxis of diseases or disorders where an antagonist of a human Orexin receptor is required.

For use in therapy the compounds of the invention are usually administered as a pharmaceutical composition. The invention also provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable derivative thereof, and a pharmaceutically acceptable carrier.

The compounds of formula (» and their pharmaceutically acceptable derivatives may be administered by any convenient method, e. g. by oral, parenteral, buccal, sublingual, nasal, rectal or transdermal administration, and the pharmaceutical compositions adapted accordingly.

The compounds of formula (I) and their pharmaceutically acceptable derivatives which are active when given orally can be formulated as liquids or solids, e. g. as syrups, suspensions, emulsions, tablets, capsules or lozenges.

A liquid formulation will generally consist of a suspension or solution of the active ingredient in a suitable liquid carrier (s) e. g. 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 and/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, such as magnesium stearate, starch, lactose, sucrose and cellulose.

A composition in the form of a capsule can be prepared using routine encapsulation procedures, e. g. 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), e. g. 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 active ingredient in a sterile aqueous carrier or parenterally acceptable oil, e. g. 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 ingredient 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 disposable dispensing device such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve. Where the dosage form comprises an aerosol dispenser, it will contain a propellant which can be a compressed gas e. g. air, or an organic propellant such as a fluorochlorohydrocarbon or hydrofluorocarbon. Aerosol dosage forms can also take the form of pump-atomisers.

Compositions suitable for buccal or sublingual administration include tablets, lozenges and pastilles where 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.

Preferably the composition is in unit dose form such as a tablet, capsule or ampoule.

The dose of the compound of formula (1), or a pharmaceutically acceptable derivative thereof, used in the treatment or prophylaxis of the abovementioned disorders or diseases will vary in the usual way with the particular disorder or disease being treated, the weight of the subject and other similar factors. However, as a general rule, suitable unit doses may be 0.05 to 1000 mg, more suitably 0.05 to 500 mg. Unit doses may be administered more than once a day for example two or three times a day, so that the total daily dosage is in the range of about 0.01 to 100 mg/kg ; and such therapy may extend for a number of weeks or months. In the case of pharmaceutically acceptable derivatives the above figures are calculated as the parent compound of formula (1).

No toxicological effects are indicated/expected when a compound of formula (1) is administered in the above mentioned dosage range.

Human Orexin-A has the amino acid sequence: pyroGlu Pro Leu Pro Asp Cys Cys Arg Gln Lys Thr Cys Ser Cys Arg Leu 1 5 10 15 Tyr Glu Leu Leu His Gly Ala Gly Asn His Ala Ala Gly Ile Leu Thr 20 25 30 Leu-NH2 Orexin-A can be employed in screening procedures for compounds which inhibit the ligand's activation of the orexin-1 receptor.

In general, such screening procedures involve providing appropriate cells which express the orexin-1 receptor on their surface. Such cells include cells from mammals, yeast, Drosophila or E. coli. In particular, a polynucleotide encoding the orexin-1 receptor is used to transfect cells to express the receptor. The expressed receptor is then contacted with a test compound and an orexin-1 receptor ligand to observe inhibition of a functional response. One such screening procedure involves the use of melanophores which are transfected to express the orexin-1 receptor, as described in WO 92/01810.

Another screening procedure involves introducing RNA encoding the orexin-1 receptor into Xenopus oocytes to transiently express the receptor. The receptor oocytes are then contacted with a receptor ligand and a test compound, followed by detection of inhibition of a signal in the case of screening for compounds which are thought to inhibit activation of the receptor by the ligand.

Another method involves screening for compounds which inhibit activation of the receptor by determining inhibition of binding of a labelled orexin-1 receptor ligand to cells which have the receptor on their surface. This method involves transfecting a eukaryotic cell with DNA encoding the orexin-1 receptor such that the cell expresses the receptor on its surface and contacting the cell or cell membrane preparation with a compound in the presence of a labelled form of an orexin-1 receptor ligand. The ligand may contain a radioactive label. The amount of labelled ligand bound to the receptors is measured, e. g. by measuring radioactivity.

Yet another screening technique involves the use of FLIPR equipment for high throughput screening of test compounds that inhibit mobilisation of intracellular calcium ions, or other ions, by affecting the interaction of an orexin-1 receptor ligand with the orexin-1 receptor.

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.

The following Examples illustrate the preparation of pharmacologically active compounds of the invention. The Descriptions D1-D9 illustrate the preparation of intermediates to compounds of the invention.

Descriptions and Examples Description 1: 2,2, 2-Trifluoro-N-[(S)-1-((R)-2-hydroxy-1-phenyl-ethyl)-piperidi n-2- ylmethyl]-acetamide (R-2-[(S)-2-Aminomethyl-piperidin-1-yl])-2-phenyl-ethanol (20. 0g) (Froelich, Olivier; Desos, Patrice; Bonin, Martine ; Quirion, Jean-Charles; Husson, Henri-Philippe ; Zhu, Jieping. , J. Org. Chem. 1996,61, 6700) and triethylamine (13. 0ml) were dissolved in dichloromethane (500ml), cooled to 0°C and trifluoroacetic anhydride (12. 66ml) added dropwise. The mixture was wanned to room temperature and stirred overnight. The organic phase was washed with water, separated, dried and solvent removed at reduced pressure. The residue was column chromatographed [silica gel, 0-10% (9: 1 methanol/ammonia) in dichloromethane eluant] to give the title compound (28. 0g) as a yellow oil. Mass spectrum (APO : Found 331 (MH+). Cl6H2lF3N202 requires 330. [a] D- 55°@ 28° c = 1% in chloroform Description 2: 2,2, 2-Trifluoro-N-(S)-1-piperidin-2-ylmethyl-acetamide The product from Dl (28. 0g) was dissolved in ethanol (200ml) containing Pearlmans catalyst (2. 0g) and shaken under a hydrogen atmosphere (50psi) at 50°C for 3 hours. The reaction mixture was filtered and solvent removed at reduced pressure. The residue was column chromatographed (silica gel, 0-10% (9: 1 methanol/ammonia) in dichloromethane eluant) to give the title compound (14.18g) as a colourless oil. Mass spectrum (APO : Found 211 (MH+). C8H13F3N2O requires 210. [a] D +18°@ 28° c = 1% in chlorofonn. 1H NMR 6 : (d6-DMSO) 1.07 (1H, m), 1.32 (2H, m), 1.35-1. 60 (2H, m), 1.72 (1H, m), 2.54 (1H, t), 2.70 (1H, m), 3.00 (1H, d), 3.17 (3H, m), 9.30 (1H, br. s.) Description 3: (S)-2- [ (2, 2, 2-Trifluoro-ethanoylamino)-methyl]-piperidine-l-carboxylic acid tert butyl ester The product from D2 (14. 18g) was dissolved in dichloromethane (250ml) and treated with di-tert-butyl dicarbonate (14.95g). The mixture was stirred for 16h, washed with water, 2N hydrochloric acid and saturated brine, dried and solvent removed at reduced pressure to give the title compound (18.3g). Mass spectrum (API+) : Found 311 <). C13H21F3N203 requires 310. [a] D-94°@ 28° c = 1% in chloroform. IH NMR 6 : (d6-DMSO) 1.27 (1H, m), 1.36, 1.47 (9H, s), 1.49-1. 58 (5H, m), 2.88 (1H, m), 3.22 (1H, m), 3.49 (1H, m), 3.84 (1H, m), 4.34 (1H, m) and 9.42 (1H, br. s.).

Description 4: (S) 2-Aminomethyl-piperidine-l-carboxylic acid tert butyl ester The product from D3 (18. 2g) was dissolved in methanol (500ml) and treated with potassium carbonate (16. 1g). After stirring for 16h solvent was removed at reduced pressure and the residue partitioned between dichloromethane/water. The organic phase was separated, washed with brine, dried and solvent removed at reduced pressure. the residue was column chromatographed (silica gel, 0-10% (9: 1 methanol/ammonia) in dichloromethane eluant) to give the title compound (8.82g). Mass spectrum (APt : Found 215 (1w). CllH22N202 requires 214. [a] D-32. 2°@ 28° c = 1% in chloroform. 1H NMR

8 : 1.20-1. 70 (8H, m), 1.46 (9H, s), 2.64-2. 80 (2H, m), 2.94 (1H, dd), 3.99 (1H, m) and 4.15 (1H, m).

Description 5 : (S)-2-[(6, 7-Difluoroquinoxalin-2-ylamino) methyl]-piperidine-1- carboxylic acid tert buty ester The amine D4 (0.607g), and 2-chloro-6, 7-difluoroquinoxaline McQuaid et. al. J. Med.

Chem. (1992), 35 (18), 3319-24 (0.569g) were dissolved in dimethylformamide (lml) and heated to 90 °C for 5 days under an atmosphere of argon. After cooling, the reaction solution was partitioned between ethyl acetate and water. The organic layer was washed with water, saturated brine, dried and evaporated. The residue was chromatographed over silica gel, eluting with a gradient of 10 to 50% ethyl acetate in hexane. The title compound was obtained as a pale yellow solid (0.460g), MHF 379. ClgH24F2N402 requires 378.

Description 6: (S)-2-[(6,7-Difluoroquinoxalin-2-ylamino) methyl] -piperidine The product from D5 (0.460g) was dissolved in trifluoroacetic acid (10ml) and stirred at room temperature for 3 hours. The solution was then evaporated and the residue chromatographed over silica gel, eluting with 0 to 10% (9: 1 methanol-concentrated ammonia solution) in dichloromethane. The title compound was obtained as a pale yellow foam (0.286g), MH+ 279. Cl4Hi6F2N4requires 278.

Description 7: (S)-2- [ (5-Bromo-pyrimidin-2-ylamino)-methyl]-piperidine-1-carboxyli c acid tert butyl carbonate.

The amine from D4 (lg), 5-bromo-2-chloropyrimidine (0.9g) were combined in xylene (20ml) containing potassium carbonate (1.29g) and diisopropylethylamine (2. 43g) and warmed to reflux for 48h. The mixture was cooled to room temperature, filtered and solvent removed at reduced pressure. The residue was column chromatographed (silica gel, pentane-25% ethyl acetate/pentane). The appropriate fractions were collected, solvent removed at reduced pressure to give the title compound (1.43g) as a colourless gum. Mass spectrum (API+) : Found 271 MH+-tert BOC). Cl5H2379BrN402 requires 370.

Description 8: (S)- (5-Bromo-pyrimidin-2-yl)-piperidin-2-ylmethyl-amine dihydrochloride The compound of D7 (2. 1g) was stirred in a mixture of 4M HC1 in dioxan/methanol (1: 1) for 4 h. Solvent was removed at reduced pressure to give the title compound (1.4g) as a foam. Mass spectrum (API) : Found 271 (MH+). CloHls9BrN4 requires 270.

Description 9: (RS)-4, 5-Difluoro-2-piperidin-2-ylmethyl-lH-benzoimidazole A mixture of 2-carboxymethyl-piperidine-1-carboxylic acid tert-butyl ester (Beckett et al, J. Med. Chem., 563,1969) (6.72g) and 3, 4-difluoro-benzene-1, 2-diamine (4. 00g) in polyphosphoric acid (130g) was heated at 140°C for 7. 5h. The cooled reaction mixture was poured onto excess solid potassium carbonate and crushed ice. The resulting basic, aqueous solution was extracted with ethyl acetate (2X) and the combined organics were washed with brine, dried (Na2S04) and the solvent removed in vacuo. The residue was triturated with

diethyl ether, ethyl acetate and pentane to afford the title compound as a white solid (4.29g, 62%). 1H NMR (D6-DMSO) 8 : 1.08 (1H, m), 1.28 (2H, m), 1.50 (2H, m), 1.72 (1H, m), 2.46 (1H, m, obscured by DMSO), 2.81 (2H, d, J = 7Hz), 2.90 (2H, m), 7.14 (lH, m), 7.24 (1H, m).

Example 1: 1-{(S)-2-[(6, 7-Difluoro-quinoxalin-2-ylamino)-methyl]-piperidin-1-yl}-2- (2-methoxy-phenyl)-ethanone 2-Methoxyphenylacetic acid (0.04g) in dimethylformamide (lml) was treated sequentially with diisopropylethylamine (0. 4ml), [0- (7-azabenzotriazol-1-yl)-1, 1,3, 3- tetramethyluronium hexafluorophosphate] (0.09g) and then the amine of D6 (0.12g) in dimethylformamide (lml). The mixture was stirred for 16h, diluted with ethyl acetate and the organic phase washed with water, dried (MgS04) and solvent removed at reduced pressure. The residue was chromatographed on silica gel eluting with an ethyl acetate: pentane gradient to give the title compound (0.064g, 70%). Mass spectrum (Electrospray LC/MS ; API+): Found 427 (MH+). C23H24F2N4°2 requires 426.

Examples 2-11 were prepared from the appropriate acid and the amines described above in a similar manner to that detailed for Examplel. Example Y Rl Rz X Ar2 Arl Mass Spectrum (Electrospray LC/MS, API F 2 CH2 H H NH N F Found : 427 NH). /CzsH24FzN40z requires 426. MeO N-F F Found : 447 (MH) iN4F C26H24F2N40 requires 446. N v'F N F Found : 457 (MH). C24H26F2N403 requires 456. 'OMe N v'F OMe 5 CH2 H H NH N F Found : 457 (MH) C24H26F2N403 requires 456. MeO Y N"F OMe 6 CH2 H H NH F Found : 431 (MH). 35CIF2N40 requires Cl 430. Ci 7 CH2 H H NH N F Found : 447 (MH. XF C26H24F2N40 requires 446. N F 8 CH2 H H NH N F Found : 437 (MII). ), WNJ\F C24H22F2N402 requires 436. OU6 O 9 CH2 H H NH/I N I Found : 419 (Nlff). aome N Br C19H23 9BrN402 requires 418. OMe Br a N Found : 433 (mu). uOEt NBr C20H2s79BrN402 requires 432. Out ber 11 CH2 H Ph F F Found : 446 (MH. c : r C27H25F2N30 requires 445. H H

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

Determination of Orexin-1 Receptor Antagonist Activity The orexin-1 receptor antagonist activity of the compounds of formula (0 was determined in accordance with the following experimental method.

Experimental Method CHO-DG44 cells expressing the human orexin-1 receptor were grown in cell medium (MEM medium with Earl's salts) containing 2 mM L-Glutamine, 0.4 mg/mL G418 Sulphate from GIBCO BRL and 10% heat inactivated fetal calf serum from Gibco BRL.

The cells were seeded at 20,000 cells/100 ul/well into 96-well black clear bottom sterile plates from Costar which had been pre-coated with 10 jg/well ofpoly-L-lysine from SIGMA. The seeded plates were incubated overnight at 37C in 5% C02.

Agonists were prepared as 1 mM stocks in water: DMSO (1: 1). EC50 values (the concentration required to produce 50% maximal response) were estimated using 1 lx half log unit dilutions (Biomek 2000, Beckman) in Tyrode's buffer containing probenecid (10 mM HEPES with 145mM NaCl, 10mM glucose, 2.5 mM KC1, 1.5 mM CaCl2, 1.2 mM MgCl2 and 2. 5mM probenecid; pH7.4). Antagonists were prepared as 10 mM stocks in DMSO (100%). Antagonist IC50 values (the concentration of compound needed to inhibit 50% of the agonist response) were determined against 3.0 nM human orexin-A using l lx half log unit dilutions in Tyrode's buffer containing 10% DMSO and probenecid.

On the day of assay 50 u, l of cell medium containing probenecid (Sigma) and Fluo3AM (Texas Fluorescence Laboratories) was added (Quadra, Tomtec) to each well to give final concentrations of 2.5 mM and 4 uM, respectively. The 96-well plates were incubated for 60 min at 37C in 5% C02. The loading solution containing dye was then

aspirated and cells were washed with 4x150 1ll Tyrode's buffer containing probenecid and 0.1% gelatin (Denley Cell Wash). The volume of buffer left in each well was 125 u, l.

Antagonist or buffer (25 u. l) was added (Quadra) the cell plates gently shaken and incubated at 37C in 5% C02 for 30 minutes. Cell plates were then transferred to the Fluorescent Imaging Plate Reader (FLIPR, Molecular Devices) instrument. Prior to drug addition a single image of the cell plate was taken (signal test), to evaluate dye loading consistency.

The run protocol used 60 images taken at 1 second intervals followed by a further 24 images at 5 second intervals. Agonists were added (by the FLIPR) after 20 seconds (during continuous reading). From each well, peak fluorescence was determined over the whole assay period and the mean of readings 1-19 inclusive was subtracted from this figure. The peak increase in fluorescence was plotted against compound concentration and iteratively curve fitted using a four parameter logistic fit (as described by Bowen and Jerman, TiPS, 1995,16, 413-417) to generate a concentration effect value. Antagonist Kb values were calculated using the equation: Kb= IC50/ (1+ ( [3/EC50]) where EC50 was the potency of human orexin-A determined in the assay (in nM terms) and IC50 is expressed in molar terms.

Compounds of Examples tested according to this method had pKb values in the range 6.8 to 8.9 at the human cloned orexin-1 receptor.

Determination of Orexin-2 Receptor Antagonist Activity The orexin-2 receptor antagonist activity of the compounds of formula (1) was determined in accordance with the following experimental method.

Experimental Method CHO-DG44 cells expressing the human orexin-2 receptor were grown in cell medium (MEM medium with Earl's salts) containing 2 mM L-Glutamine, 0.4 mg/mL G418 Sulphate from G1BC0 BRL and 10% heat inactivated fetal calf serum from Gibco BRL.

The cells were seeded at 20,000 cells/100 ßl/well into 96-well black clear bottom sterile plates from Costar which had been pre-coated with 10 ug/well of poly-L-lysine from SIGMA. The seeded plates were incubated overnight at 37C in 5% C02.

Agonists were prepared as 1 mM stocks in water: DMSO (1: 1). EC50 values (the concentration required to produce 50% maximal response) were estimated using 1 lx half log unit dilutions (Biomek 2000, Beckman) in Tyrode's buffer containing probenecid (10 mM HEPES with 145mM NaCl, lOmM glucose, 2.5 mM KC1, 1.5 mM CaCl2,1. 2 mM MgCl2 and 2.5mM probenecid; pH7.4). Antagonists were prepared as 10 mM stocks in DMSO (100%). Antagonist IC50 values (the concentration of compound needed to inhibit 50% of the agonist response) were determined against 10.0 nM human orexin-A using 1 lx half log unit dilutions in Tyrode's buffer containing 10% DMSO and probenecid.

On the day of assay 50 u. l of cell medium containing probenecid (Sigma) and Fluo3AM (Texas Fluorescence Laboratories) was added (Quadra, Tomtec) to each well to give final concentrations of 2.5 mM and 4 nM, respectively. The 96-well plates were

incubated for 60 min at 37C in 5% C02. The loading solution containing dye was then aspirated and cells were washed with 4x150 . l Tyrode's buffer containing probenecid and 0. 1% gelatin (Denley Cell Wash). The volume of buffer left in each well was 125 u. l.

Antagonist or buffer (25 1) was added (Quadra) the cell plates gently shaken and incubated at 37C in 5% C02 for 30 min. Cell plates were then transferred to the Fluorescent Imaging Plate Reader (FLIPR, Molecular Devices) instrument. Prior to drug addition a single image of the cell plate was taken (signal test), to evaluate dye loading consistency. The run protocol used 60 images taken at 1 second intervals followed by a further 24 images at 5 second intervals. Agonists were added (by the FLIPR) after 20 sec (during continuous reading). From each well, peak fluorescence was determined over the whole assay period and the mean of readings 1-19 inclusive was subtracted from this figure. The peak increase in fluorescence was plotted against compound concentration and iteratively curve fitted using a four parameter logistic fit (as described by Bowen and Jerman, TiPS, 1995,16, 413- 417) to generate a concentration effect value. Antagonist Kb values were calculated using the equation: Kb= IC50/ (1+ ( [3/EC50]) where EC50 was the potency of human orexin-A determined in the assay (in nM terms) and IC50 is expressed in molar terms.

Compounds of Examples tested according to this method had pKb values in the range <6.7 to 8.2 at the human cloned orexin-2 receptor.

The application of which this description and claims forms part may be used as a basis for priority in respect of any subsequent application. The claims of such subsequent application may be directed to any feature or combination of features described herein. They may take the form of product, composition, process, or use claims and may include, by way of example and without limitation the following claims: