WO2004041816A1

WO2004041816A1 - Azacyclic compounds as orexin receptor antagonist

Info

Publication number: WO2004041816A1
Application number: PCT/EP2003/012403
Authority: WO
Inventors: Clive Leslie Branch; Jean-Pierre Pilleux; Roderick Alan Porter
Original assignee: Glaxo Group Ltd
Current assignee: Glaxo Group Ltd
Priority date: 2002-11-06
Filing date: 2003-11-04
Publication date: 2004-05-21
Anticipated expiration: 2005-05-06
Also published as: AU2003301851A1; GB0225884D0

Abstract

This invention relates to compounds of formula (I) and their use as arexin antagonists.

Description

AZACYCLIC COMPOUNDS AS OREXIN RECEPRTOR ANTAGONIST

This invention relates to tetrahydroquinoline and tetrahydroisoquinoline derivatives and their use as pharmaceuticals. 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; Kallman'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 II; arthritic pain; sports injury pain; pain related to infection, e.g. HIN, 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; parasornnia; 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 maybe useful in the treatment of sleep disorders including insomnia. The present invention provides tetrahydroquinoline and tetrahydroisoquinoline 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 WO99/09024, WO99/58533, 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 (1):

⁽0 wherein:

R³ and R⁴ together with the carbons to which they are attached form an aromatic or heteroaromatic ring and R⁵ and R⁶ are both H; or

R⁴ and R⁵ together with the carbons to which they are attached form an aromatic or heteroaromatic ring and R and R are both H; or

R⁵ and R⁶ together with the carbons to which they are attached form an aromatic or heteroaromatic ring and R³ and R⁴ are both H; and m is l to 3; p is O or 1; q is 0 or 1 provided that when q = 1, p = 0; X is NR, wherein R is H or (Cι-₄)alkyl;

Ar¹ 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 phenyl or a 5- or 6-membered heterocyclyl group containing up to 3 heteroatoms selected from N, O and S, wherein the phenyl or heterocyclyl group is substituted by R¹ and further optional substituents, R¹ representing hydrogen, optionally substituted (C_M) alkoxy, halo, cyano, optionally substituted (Cι-₆)alkyl, optionally substituted phenyl, or an optionally substituted 5- or 6-membered heterocyclic ring containing up to 4 heteroatoms selected from N, O and S; or Ar² represents an optionally substituted bicyclic aromatic or bicyclic heteroaromatic group containing up to 4 heteroatoms selected from N, O and S; or a pharmaceutically acceptable salt thereof.

R is preferably H. m is preferably 1. p is preferably 0. h a preferred embodient m is 1 when p is 0 and q = 0. a further preferred embodiment when Ar¹ is aryl p = 0. h a still further preferred embodiment R⁴ and R⁵ together with the carbons to which they are attached form an aromatic ring thereby creating, together with the piperidine ring of formula (I), an isoquinolinyl bicycle and wherein R³ and R⁶ are both H. When Ar¹ is an optionally substituted aryl it may have up to 5, preferably 1, 2 or 3 optional substituents. Examples of when Ar¹ is a mono or bicyclic heteroaryl are quinoxalinyl, quinazolinyl, pyridopyrazinyl, benzoxazolyl, benzothiophenyl, benzimidazolyl, naphthyridinyl, pyridinyl, pyrirnidinyl, tliiazolyl, pyridazinyl, pyrazinyl, oxazolyl, triazolyl, imidazolyl, pyrazolyl, quinolinyl, benzofuranyl, indolyl, benzothiazolyl, oxazolyl[4,5- b]pyridiyl, pyridopyrimidinyl or isoquinolinyl, furanyl or thienyl. Preferably Ar¹ is pyrirnidinyl.

When Ar² is a 5- or 6-membered heterocyclyl group containing up to 3 heteroatoms selected from N, O and S, it may be furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyridyl, triazolyl, triazinyl, pyridazinyl, pyrirnidinyl, isothiazolyl, isoxazolyl, pyrazinyl or pyrazolyl.

When Ar² is an optionally substituted bicyclic aromatic or bicyclic heteroaromatic it is selected from benzofuryl, benzimidazolyl, quinolinyl, quinoxalinyl, naphthyl, benzotriazolyl, benzotbienyl, benzoxazolyl, naphthyridinyl, isoquinolinyl, quinazolinyl, indolyl, benzothiazolyl, or benzothiadiazolyl. Preferably Ar² represents optionally substituted thiazolyl or pyrazolyl.

When R¹ is a 5- or 6-membered heterocyclyl group containing up to 4 heteroatoms selected from N, O and S, it may be phenyl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyridyl, triazolyl, triazinyl, pyridazinyl, pyrirnidinyl, isothiazolyl, isoxazolyl, pyrazinyl, pyrazolyl, tetrazoyl, piperazinyl, piperidinyl, morpholinyl or thiomorpholinyl.

Preferably R¹ is optionally substituted phenyl.

Optional substituents for the groups Ar¹, Ar², and R¹ include halogen, hydroxy, oxo, cyano, nitro, (Ci-^alkyl, ( -^alkoxy, hydroxy(Cι-₄)alkyl, hydroxy(Cι-₄)alkoxy, halo(Cι- ₄)alkyl, halo(Cι- )alkoxy, aryl(Cι-- )alkoxy,

hydroxy(Cι-₄)alkyl, ( - )alkoxy(Cι- )alkyl, (C₃-₆)cycloalkyl(Cι- )alkoxy, (Cι-₄)alkanoyl,

( - )alkylsulfonyl, (Cι-₄)alkylsulfonyloxy,

arylsulfonyl, arylsulfonyloxy, arylsulfonyl(Cι-₄)alkyl, (Cι-₄)alkylsulfonamido, (Cι- )alkylamido, (Ci-

(Cι_ )all**-ylamido(Cι-₄)alkyl, arylsulfonamido, arylcarboxamido, arylsulfonamido(Cι-₄)alkyl, arylcarboxamido(Ci-₄)alkyl, aroyl, aroyl(Cι- ₄)alkyl, or aryl(Cι-₄)alkanoyl group; a group R^aR°N-, R^aOCO(CH₂)_r, R^aCON(R^a)(CH₂)_r, R^aR NCO(CH₂)_r, R^aR NSO₂(CH₂)_r or R^aSO₂NR^b(CH₂)_r where each of R^a and R independently represents a hydrogen atom or a (Ci-^alkyl group or where appropriate R^aR^b 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 (Cι-₄)acyl, aryl, aryl(Cι-₄)alkyl, (Cι-₄)alkylamino(Cι-₄)alkyl, R^aR°N(CH₂)n-, R^aR°N(CH₂)nO-, wherein n represents an integer from 1 to 4. Additionally when the substituent is R^^CH^n- or R^^CH^nO, R with at least one CH₂ of the (CH₂)n portion of the group form a (C₃.₆)azacycloalkane and R represents hydrogen, a

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 and (Cι- )alkyl.

- A - In a more preferred embodiment the optional substituent for Ar² is

most preferably (Cι)alkyl (ie. methyl).

Preferred optional substituents for Ar¹ are halogen.

In a more preferred embodiment the optional substituent for Ar¹ is bromine. Preferred optional substituents for R¹ are halogen.

In a more preferred embodiment the optional substituent for R¹ is fluorine.

In the groups Ar¹ and Ar², substituents positioned ortho to one another may be linked to form a ring.

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

When the compound of formula (1) 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 (I) 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 (I) which, upon administration to the recipient is capable of providing (directly or indirectly) a compound of formula (I) or an active metabolite or residue thereof.

It will be appreciated that for use in medicine the salts of the compounds of formula (I) should be pharmaceutically 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 (I) 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 (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.

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 (I) and derivatives thereof. The following schemes detail some synthetic routes to compounds of the invention.

Schemes

According to a further feature of the invention there is provided a process for the preparation of compounds of formula (I) and derivatives thereof. The following schemes detail some synthetic routes that may be used to prepare compounds of the invention.

Schemes la-c may be used to synthesise compounds wherein q = 0. Scheme 2 may be used to synthesise compounds wherein q = 0 or 1. Scheme 3 may be used to synthesise compounds wherein q = 1.

Scheme la

deprotection

wherein Ar¹, Ar², m, p and R, R³ to R⁶ are as defined for formula (I), q = 0, L¹ and L² are leaving groups, and P is a protecting group.

Examples of suitable leaving groups L¹ include halogen, hydroxy, OSO₂Me, OSO₂(4-tolyl). The reaction of (V) with (NT) preferably proceeds in an inert solvent such as Ν,Ν-dimethylfoιmamide in the presence of a base such as triethylamine, sodium hydride or potassium t-butoxide.

Examples of suitable leaving groups L² include halogen, hydroxy, OC(=O)alkyl OC(*=O)O-alkyl and OSO Me. Acylation may be carried out using a wide range of known acylation conditions, e.g. in an inert solvent such as dichloromethane, in the presence of a base such as triethylamine. Alternatively these steps may be carried out when L² represents hydroxy, in which case the reaction takes place in an inert solvent such as dichloromethane in the presence of a diimide reagent such as l-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride, and an activator such as 1- hydroxybenzotriazole.

Examples of protecting group 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 lb

deprotection

(II)

(I)

Reaction of (NIU) with (LX) 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. P can be a protecting group or H. Alternatively where m is 1 and p is 0 or 1 compounds maybe prepared as shown in scheme lc.

Scheme lc

Reaction of (XI) with an alkylating agent (Ci--*.)!,¹ proceeds in the presence of a base such as sodium hydride in an inert solvent such as dnnethylformamide.

Compounds of formula (V), (NI), (IX), (X) are known in the literature or can be prepared by known methods. Compound (NET) can be prepared by known methods.

Within the schemes above there is scope for functional group interconversion; for example in compound (V), conversion of one value of L to another value of L¹; or in compounds (IN) conversion of protecting group P for another protecting group P, or conversion of one compound of formula (I) to another of formula (I) by interconversion of substituents.

When R¹ is an aromatic group, the substituent R¹ may be introduced at the final stage as illustrated in Scheme 2 below by reaction of a compound of formula (NIT) where L represents a leaving group such as halogen (preferably bromo or iodo) or trifluoromethylsulfonyloxy, and all other variables are as previously defined, with a reagent R¹!^, where M is the residue of an organometallic species e.g. B(OH) or trialkylstannyl. Such a process may be carried out in an inert solvent such as 1,2-dimethoxyethane or 1,4- dioxan, in the presence of a transition metal catalyst such as Pd(PPh₃)₄.

Scheme 2

(VII) (I)

Wherein Ar², Ar¹, m, p, q, R, R¹ R³ to R⁶ are as defined for compounds of formula (I). L³ is a leaving group.

Scheme 3

wherein Ar¹, Ar²' and R³ to R⁶ are as defined for formula (I), P is a protecting group, L² is a leaving group as defined above.

Scheme 4

wherein Ar¹, Ar², R³ to R⁶ are as defined for formula (I), P and P¹ are protecting groups and L² is a leaving group as defined above. Examples of protecting groups P and P¹ are given in scheme la.

The starting materials for use in Schemes 1 to 4 are commercially available, well known in the literature or can be prepared by methods well know to the skilled person. Within the schemes above there is scope for functional group interconversion and for conversion of one value of L¹ to another value of L¹; or conversion of protecting group P or P¹ to another protecting group P or P¹, or conversion of one compound of formula (I) to another of formula (I) by interconversion of substituents.

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

The compounds of formula (I) 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. HIN, 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 (I), 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 antagomst of a human Orexin receptor is required.

The invention also provides the use of a compound of formula (I), 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 (I) 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 hi 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 pyrrohdone, 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 (I), 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, hi the case of pharmaceutically acceptable derivatives the above figures are calculated as the parent compound of formula (I).

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

Human Orexin-A has the amino acid sequence: pyroGlu Pro Leu Pro Asp Cys Cys Arg Gin Lys Thr Cys Ser Cys Arg Leu 1 5 10 15

Tyr Glu Leu Leu His Gly Ala Gly Asn His Ala Ala Gly lie 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. h 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. In the examples the following abbreviations are used: DMF is dimethylformamide, DCM is dichloromethane and THF is tetrahydrofuran.

Description 1: 2-(4-Methoxy-benzyl)-l,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid

Sodium hydride (2.78g, 69mmol; 60% dispersion in oil) was added portionwise to a solution of isoquinoline-3-carboxylic acid (4.5g, 21mmol) in DMF (90ml) at room temperature under argon. After lh, 4-methoxybenzyl chloride (6.9g, 44mmol) was added and the mixture stirred for 72h before being evaporated in vacuo and the residue partitioned between water and ethyl acetate. The organic phase was washed with brine, dried and concentrated in vacuo to give 4-methoxybenzyl 2-(4-methoxy-benzyl)- 1,2,3, 4-tetrahydro- isoquinoline-3-carboxylate (9.7g) as a yellow oil used without further purification. The crude ester was heated at 100°C in a mixture of dioxan (70ml) and 2M NaOH (70ml) for 16h and then cooled to room temperature. After a further 24h the reaction mixture was evaporated in vacuo and the residue partitioned between water and ethyl acetate. The aqueous phase was acidified with cHCl and extracted with ethyl acetate. The combined extracts were dried and evaporated in vacuo to afford the title product (2.7g, 43%) as a yellow solid. 1H NMR (DMSO) δ: 3.13 and 3.27 (2H, ABq, liigher field arm, d, J = 16 and 4 Hz; lower field arm, d, J = 16 and 6Hz), 3.76 (3H, s), 3.95 - 4.16 (5H, m), 6.95 (2H, d, J = 8Hz), 7.10 - 7.20 (4H, m), 7.37 (2H, d, J = 8Hz), 11.0(1H, br s).

Description 2: 2-(4-Methoxy-benzyl)-l,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid amide

To a solution of the acid from Dl (2.14g, 7.2mmol) in DCM (30ml) containing triethylamine (1.12ml, 8mmol) at 0°C under argon was added ethyl chloroformate (0.87g, 8mmol). After 20min, aqueous ammonia (16ml) was added in one portion and the resultant mixture vigorously stirred at room temperature for 20h. The aqueous layer was extracted with DCM and the combined DCM extracts dried, evaporated in vacuo to afford the title product (1.94g, 31%) as a white solid. 1H NMR (CDC1₃) δ: 3.12 - 3.15 (2H, m), 3.54 - 3.68 (4H, m), 3.81 (3H, s), 3.83 - 3.86 (IH, m), 5.44 (IH, br s), 6.87 (2H, d, J = 7Hz), 7.00 (IH, m), 7.1 - 7.23 (6H, m).

Description 3: C-(2-(4-Methoxy-benzyI)-l,2,3,4-tetrahydro-isoquinoIin-3-yl)- methylamine

To the amide from D2 (1.94g, 6.54mmol) in dry THF (25ml) was added lithium aluminium hydride (13.1ml of a 1M soln in THF, 13.1mmol) and the mixture heated under argon at 70°C for 24h. The reaction mixture was cooled to room temperature and then water (2.6ml), 2M NaOH (2.9ml) and water (2.6ml) were carefully added sequentially. The suspension was filtered and the filtrate partitioned between ethyl acetate and brine, and the organic layer then dried and evaporated in vacuo to afford the title product (1.76g, 95%) as a pale yellow solid. 1H NMR (CDC1₃) δ: 1.46 (2H, br s), 2.61 - 2.75 (2H, m), 2.89 -2.96 (2H, m), 3.02 - 3.05 (IH, m), 3.6 - 3.67 (3H, m), 3.81 (3H, s), 3.78 - 3.83 (IH, m), 6.85 - 6.88 (2H, m), 6.95 - 6.96 (IH, m), 7.09 - 7.16 (3H, m), 7.25 - 7.26 (2H, m).

Description 4: 2,2,2-Trifluoro-N-(2-(4-methoxy-benzyl)-l,2,3,4-tetrahydro-isoquinolin- 3-ylmethyl)-acetamide

To a solution of the amine D3 (0.28g, lmmol) in DCM (10ml) containing triethylamine (0.28ml, 2mmol) was added trifluoroacetic anhydride (0.252g, 1.2mmol) under argon at 0°C. The reaction mixture was allowed to reach room temperature and after stirring for 16h was washed with brine, dried and evaporated in vacuo. The residue was chromatographed on silica gel to afford the title product (0.22g, 58%) as a yellow solid. Mass spectrum (AP⁺): Found 379 (MH ). C₂₀H₂ιF₃N₂O₂ requires 378.

Description 5: 2,2,2-Trifluoro-N-(l,2,3,4-tetrahydro-isoquinolin-3-ylmethyl)-acetamide The product of D4 (1.32g, 3.5mmol) was dissolved in methanol (20ml) and formic acid (30ml) under argon at room temperature and 10%Pd/C (1.5g) added. After stirring for 20h the reaction mixture was filtered through celite, washing thoroughly with methanol. The combined filtrate and washings were evaporated in vacuo to provide the title compound (1.47g, 100%) as a brown oil which was used without further purification. Mass spectrum (AP⁺): Found 259 (MH⁺). Cι₂Hι₃F₃N₂O requires 258.

Description 6: 3-((2,2,2-Trifluoro-ethanoylamino)-methyl)-3,4-dihydro-lH- isoquinoline-2-carboxylic acid tert-b tyl ester

A mixture of the product from D5 (0.9g, 3.5mmol), triethylamine (1.7ml,2mmol) and di- tert-butyl dicarbonate (lg, 4.5mmol) was stirred in DCM (40ml) for 20h at room temperature. The reaction mixture was washed with water and brine, and the aqueous phase back-extracted with DCM. The combined extracts were dried and evaporated in vacuo to afford the title compound (1.18g, 94%) as abrown solid. 1H NMR (CDCI₃) δ: 1.51 (9H, s), 2.70 - 2.75 (IH, m), 3.00 - 3.30 (4H, m), 4.32 - 4.68 (2H, m), 6.89 - 7.22 (4H, m), 7.90 (IH, br s).

Description 7: 3-Aminomethyl-3,4-dihydro-lH-isoquinoIine-2-carboxyIic acid tert- butyl ester

A mixture of the amide from D6 (1.18g, 3.2mmol), 1M potassium carbonate (15ml) and methanol (40ml) was stirred at room temperature for 56h. Methanol was evaporated in vacuo and the residue partitioned between water and chloroform. The aqueous phase was reextracted with chloroform and the combined extracts dried and evaporated to afford the title product (0.7g, 84%) as a brown oil. 1H NMR (CDC1₃) δ: 1.19 - 1.28 (2H, br s), 1.50 (9H, s), 2.55 - 2.60 (IH, m), 2.66 - 2.71 (IH, m), 2.75 - 2.79 (IH, m), 3.02 - 3.08 (IH, m), 4.22 - 4.26 (IH, m), 4.20 - 4.50 (IH, br s), 4.79 - 4.82 (IH, m), 7.10 - 7.20 (4H, m).

Description 8 : 3-((5-Bromo-pyrimidin-2-ylamino)-methyl)-3,4-dihydro-lH- isoquinoline-2-carboxylic acid tert-butyl ester A mixture of the amine from D7 (0.7g, 2.7mmol), 5-bromo-2-chloropyrimidine (0.62g, 3.2mmol), diisopropylethylamine (1.9ml, 2.7mmol) and potassium carbonate (0.83g, 6mmol) in xylene (12ml) was refluxed for 20h, cooled, filtered and the filtrate evaporated in vacuo. The residue was chromatographed on silica gel and the product containing fractions combined, evaporated and the residue triturated with ether to afford the title product (0.45g, 40%) as a pale yellow solid. 1H NMR (CDC1₃) δ: 1.45 (9H, s), 2.73 - 2.77 (IH, m), 3.09 - 3.15 (IH, m), 3.27 - 3.34 (IH, m), 3.39 (IH, br s), 4.25 -4.30 (IH, m), 4.75 (2H, br s), 5.30 (0.5H, br s), 5.60 (0.5H, br s), 7.11 - 7.20 (4H, m), 8.23 (2H, m).

Description 9: (5-Bromo-pyrimidin-2-yl)-(l,2,3,4-tetrahydro-isoqumolin-3-yImethyl)- amine

A solution of the product from D8 (0.43g, lmmol) in DCM (20ml) containing trifluoroacetic acid (4ml) was stirred at room temperature for 20h, evaporated in vacuo and the residue partitioned between chloroform and 1M sodium hydroxide. The aqueous phase was extracted with chlorofonn and the combined extracts dried and evaporated in vacuo to afford the title product (0.3 lg, 97%) as a white solid. 1H NMR (CDCI₃) δ: 1.97 (IH, br s), 2.61 - 2.68 (IH, m), 2.83 - 2.88 (IH, m), 3.22 - 3.25 (IH, m), 3.33 - 3.40 (IH, m), 3.66 - 3.72 (IH, m), 4.08 (2H, s), 5.81 (IH, br s), 7.02 - 7.04 (IH, m), 7.04 - 7.15 (3H, m), 8.28 (2H, s).

Example 1 : l-(3-((5-Bromo-pyrimidin-2-ylamino)-methyl)-3,4-dihydro-lH- isoquinolin-2-yl)-l-(5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl)-methanone To the amine of D9 (0.155g, 0.5mmol) in dimethylformamide (8ml) containing diisopropylethylamine (0.26ml, 1.5mmol) was added [O-(7-azabenzotriazol-l-yl)-l, 1,3,3- tetramethyluronium hexafluorophosphate] (0.247g, 0.65mmol) followed by 5-(4-fluoro- phenyl)-2-methyl-thiazole-4-carboxylic acid (0.143g, 0.6mmol). After 10 days at room temperature the reaction mixture was evaporated and the residue partitioned between ethyl acetate and saturated aqueous NaHCO₃. The aqueous phase was back extracted and the combined extracts dried and evaporated. Trituration with acetone afforded the title product (0.128g, 48%). Mass spectrum (AP⁺): Found 538 (Mt ). C₂₅H₂ι⁷⁹BrFN₅OS requires 537.

Example 2: l-(3-((5-Bromo-pyrimidin-2-ylamino)-methyl)-3,4-dihydro-lH- isoquinolin-2-yl)-l-(4-(4-fluoro-phenyl)-l-methyl-lH-pyrazol-3-yl)-methanone

The title compound was obtained from the amine of D9 (0.155g, 0.5mmol) and 4-(4-fluoro- phenyl)- 1 -methyl- lH-pyrazole-3-carboxylic acid (0.132g, O.όmmol) using the method of Example 1, except that the product was isolated by chromatography on silica gel eluting with an ethyl acetate/pentane gradient. Mass spectrum (AP*): Found 521 (MΗ¹ . C₂₅Η₂₂ ⁷⁹BrFN₆O requires 520.

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 (I) 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 GL3CO BRL and 10% heat inactivated fetal calf serum from Gibco BRL. The cells were seeded at 20,000 cells/100 μl/well into 96-well black clear bottom sterile plates from Costar which had been pre-coated with 10 μg/well of poly-L-lysine from SIGMA. The seeded plates were incubated overnight at 37C in 5% CO .

Agonists were prepared as 1 mM stocks in wateπDMSO (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 KCl, 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 1 lx half log unit dilutions in Tyrode's buffer containing 10% DMSO and probenecid. On the day of assay 50 μl of cell medium containing probenecid (Sigma) and

Fluo3 AM (Texas Fluorescence Laboratories) was added (Quadra, Tomtec) to, each well to give final concentrations of 2.5 mM and 4 μM, respectively. The 96-well plates were incubated for 60 min at 37C in 5% CO2. The loading solution containing dye was then aspirated and cells were washed with 4x150 μl Tyrode's buffer containing probenecid and 0.1% gelatin (Denley Cell Wash). The volume of buffer left in each well was 125 μl.

Antagonist or buffer (25 μl) was added (Quadra) the cell plates gently shaken and incubated at 37C in 5% CO₂ 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/(l+([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 of greater than 6.8 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 (I) 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 GJ-BCO BRL and 10% heat inactivated fetal calf serum from Gibco BRL. The cells were seeded at 20,000 cells/100 μl/well into 96-well black clear bottom sterile plates from Costar which had been pre-coated with 10 μg/well of poly-L-lysine from SIGMA. The seeded plates were incubated overnight at 37C in 5% CO₂.

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 KCl, 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 llx half log unit dilutions in Tyrode's buffer containing 10% DMSO and probenecid.

On the day of assay 50 μl of cell medium containing probenecid (Sigma) and Fluo3 AM (Texas Fluorescence Laboratories) was added (Quadra, Tomtec) to each well to give final concentrations of 2.5 mM and 4 μM, respectively. The 96-well plates were incubated for 60 min at 37C in 5% CO₂. The loading solution containing dye was then aspirated and cells were washed with 4x150 μl Tyrode's buffer containing probenecid and 0.1% gelatin (Denley Cell Wash). The volume of buffer left in each well was 125 μl. Antagonist or buffer (25 μl) was added (Quadra) the cell plates gently shaken and incubated at 37C in 5% CO₂ 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/(l+([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 of less than 7.0 at the human cloned orexin-2 receptor. The application of which this description and claims forms part maybe 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, byway of example and without limitation the following claims:

Claims

1. A compound of formula (I) :

wherein:

R³ and R⁴ together with the carbons to which they are attached form an aromatic or heteroaromatic ring and R⁵ and R⁶ are H; or

R⁴ and R⁵ together with the carbons to which they are attached form an aromatic or heteroaromatic ring and R³ and R⁶ are H; or

R⁵ and R together with the carbons to which they are attached form an aromatic or heteroaromatic ring and R³ and R are H; and m is 1 to 3; p is 0 or 1 ; q is 0 or 1 provided that when q = 1, p = 0;

X is NR, wherein R is H or (Ci-^alkyl;

Ar¹ is aryl, or a mono or bicyclic heteroaryl group containing up to 4 heteroatoms selected from N, O and S, any of which maybe optionally substituted;

Ar represents phenyl or a 5- or 6-membered heterocyclyl group containing up to 3 heteroatoms selected from N, O and S, wherein the phenyl or heterocyclyl group is substituted by R¹ and further optional substituents, R¹ representing hydrogen, optionally substituted

(Cι-₄) alkoxy, halo, cyano, optionally substituted (Cι-₆)alkyl, optionally substituted phenyl, or an optionally substituted 5- or 6-membered heterocyclic ring containing up to 4 heteroatoms selected from N, O and S; or

Ar represents an optionally substituted bicyclic aromatic or bicyclic heteroaromatic group containing up to 4 heteroatoms selected from N, O and S; or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1 wherein R is H.

3. A compound according to claim 1 or 2 wherein m is 1.

4. A compound according to any one of claims 1 to 3 wherein p is 0.

5. A compound according to any one of claims 1 to 4 wherein m is 1 when p is 0 and q = 0.

6. A compound according to any one of claims 1 to 5 wherein R⁴ and R⁵ together with the carbons to which they are attached form an aromatic ring thereby creating, together with the piperidine ring of formula (I), an isoquinolinyl bicycle and wherein R³ and R⁶ are both H.

7. A compound according to any one of claims 1 to 6 wherein Ar¹ is pyrirnidinyl.

8. A compound according to any one of claims 1 to 7 wherein Ar² is thiazolyl or pyrazolyl.

9. A compound according to any one of claims 1 to 8 wherein R¹ is phenyl.

10. A pharmaceutical composition comprising a compound of formula (I) as defined in any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

11. Use of a compound of formula (I) as defined in any one of claims 1 to 9 in the manufacture of a medicament for the treatment of disorders where an antagonist of a human orexin receptor is required.