WO2003051871A1 - Derives d'amine cyclique n-aroyle et leur utilisation en tant qu'antagonistes recepteurs d'orexine - Google Patents

Derives d'amine cyclique n-aroyle et leur utilisation en tant qu'antagonistes recepteurs d'orexine Download PDF

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WO2003051871A1
WO2003051871A1 PCT/GB2002/005675 GB0205675W WO03051871A1 WO 2003051871 A1 WO2003051871 A1 WO 2003051871A1 GB 0205675 W GB0205675 W GB 0205675W WO 03051871 A1 WO03051871 A1 WO 03051871A1
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optionally substituted
pharmaceutically acceptable
heteroatoms selected
compound
formula
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PCT/GB2002/005675
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English (en)
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Clive Leslie Branch
Amanda Johns
Christopher Norbert Johnson
Riccardo Novelli
Roderick Alan Porter
Rachel Elizabeth Anne Stead
Geoffrey Stemp
Kevin Thewlis
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Smithkline Beecham Plc
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Priority to AU2002352388A priority Critical patent/AU2002352388A1/en
Publication of WO2003051871A1 publication Critical patent/WO2003051871A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/34—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • This invention relates to N-aroyl cyclic 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 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 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; hypothala
  • 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, vomiting; conditions associated with visceral pain including irritable bowel syndrome, migraine and angina; urinary bladder incontinence e.g.
  • 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.
  • 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-aroyl cyclic amine derivatives which are non-peptide antagonists of human orexin receptors, in particular orexin-1 receptors.
  • 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, and/or stroke, particularly ischemic or haemorrhagic stroke, and/or for blocking the emetic response i.e. useful in the treatment of nausea and vomiting.
  • WO00/47580 disclose phenyl urea derivatives and WO00/47576, discloses quinolinyl cinnamide derivatives as orexin receptor antagonists. According to die invention there is provided compounds of formula (I):
  • X represents (CH 2 )n, O or NR 1 , wherein n represents 0, 1 or 2; R 1 represents hydrogen or an optionally substituted (C 1-6 )alkyl; m represents 1 or 2;
  • R represents an optionally substituted aryl, an optionally substituted 5- or 6- membered heteroaryl group containing up to 3 heteroatoms selected from N, O, and S, or an optionally substituted bicyclic heteroaryl group containing up to 3 heteroatoms selected from N, O and S;
  • R 2 represents hydrogen, or with R and the nitrogen to which they are attached form a 5- or 6- membered heterocyclic containing up to 3 heteroatoms selected from N, O, and S or an optionally substituted bicyclic heterocyclic or heteroaryl group containing up to 3 heteroatoms selected from N, O and S;
  • Ar represents a phenyl or a 5- or 6-membered heteroaryl group containing up to 3 heteroatoms selected from N, O and S, wherein the phenyl or heteroaryl group is substituted by R 3 , and further optional substituents; or Ar represents an optionally substituted bicyclic aromatic or heteroaromatic group containing up to 3 heteroatoms selected from N, O and S; R 3 independently represents hydrogen, an optionally substituted halo, an optionally substituted an optionally substituted phenyl, or an optionally substituted 5- or 6-membered heterocyclic ring containing up to 3 heteroatoms selected from N, O and S; or pharmaceutically acceptable derivatives thereof.
  • Examples of 5- or 6- membered heteroaryl group containing up to 3 heteroatoms selected from N, O and S include furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyridyl, triazolyl, triazinyl, pyridazinyl, pyrimidinyl, isothiazolyl, isoxazolyl, pyrazinyl, or pyrazolyl.
  • R represents a bicyclic heteroaryl it may be selected from isoquinolinyl, quinoxalinyl, benzoxazolyl, quinolinyl, napththyridinyl, benzofuranyl, benzimidazolyl, quinazolinyl, indolyl, benzothienyl, benzothiazolyl or isoindolyl.
  • R and R 2 togeuier with the nitrogen to which they are attached form a 5- or 6- membered heterocyclic ring it can be pyrrolyl, imidazolyl, triazolyl, pyrazolyl, piperidine, piperazine, pyrrolidine, morpholine or thiomorpholine.
  • R and R 2 together with the nitrogen to which they are attached form an optionally substituted bicyclic heterocyclic or heteroaryl it can be an indolyl, isoindolyl, benzimidazolyl, azaindolyl, azaisoindolyl or indazolyl.
  • Ar represents an optionally substituted bicyclic aromatic or heteroaromatic
  • examples of where Ar represents an optionally substituted bicyclic aromatic or heteroaromatic include naphthyl, quinolinyl, napththyridinyl, benzofuranyl, benzimidazolyl, quinoxalinyl, quinazolinyl, isoquinolinyl or benzoxazolyl.
  • R 1 is hydrogen or methyl.
  • R represents phenyl
  • X is CH 2
  • Ar represents phenyl, or a 5-or 6- membered heteroaryl group the substituent R 3 is ortho to the amide carbonyl group.
  • Ar represents optionally substituted thiazolyl or phenyl.
  • R 2 is H or together with R and the nitrogen to which it is attached forms an indolyl or an isoindolyl.
  • R 3 is a 5- or 6-membered heterocyclic ring containing up to 3 heteroatoms selected fromN, O and S, include furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyridyl, triazolyl, triazinyl, pyridazyl, pyrimidinyl, isothiazolyl, isoxazolyl, pyrazinyl, pyrazolyl, piperidine, morpholine, thiomorpholine or piperazine.
  • R 3 represents trifluoromethoxy, methoxy, ethoxy, halo, or optionally substituted phenyl, pyridyl, pyrazolyl, pyrimidinyl, or oxadiazolyl group.
  • R 3 represents an optionally substituted phenyl, e.g. 4-fluorophenyl.
  • amide carbonyl group means the -C(0)-N- bond as shown in compounds of formula (I).
  • Optional substituents for the groups R, R 2 , R 3 and Ar include halogen, hydroxy, oxo, cyano, nitro, (Chalky!, halo(Ci )alkyl, (C 1- )acyl, aryl, aryl(C 1- )alkyl, aryl(C M )alkoxy, 4 )alkoxy, (Ci )alkoxy(C 1-4 )alkyl, (C 3-6 )cycloalkyl(C 1-4 )alkoxy, (C M )alkanoyl, (C M )alkoxycarbonyl, (C M )alkylsulfonyloxy, arylsulfonyl, arylsulfonyloxy, (C M )alkylsulfonamido, (C 1-4 )alkylamido, (C ⁇ 4 )alkylsulfonamido(C 1-4 )alkyL aryl
  • R a and R b independently represents a hydrogen atom or a (Ci )alkyl group or where appropriate R a R b forms part of a (C 3- 6 )azacycloalkane or (C 3 ⁇ )(2-oxo)azacycloalkane ring
  • n represents an interger from 1 to 4
  • r represents zero or an integer from 1 to 4.
  • R a R b N(CH 2 )n- or R ⁇ CEtOnO R a with at least one CH 2 of the (CH 2 )n portion of the group form a (C 3- 6 )azacycloalkane and R b represents hydrogen, a (C 1- )alkyl group or with the nitrogen to which it is attached forms a second (C 3- 6)azacycloalkane fused to the first (C 3 .6)azacycloalkane.
  • Preferred optional substituents for Ar are halogen, cyano, (Chalky!, hydroxy(Ci 4 )alkyl
  • Preferred optional substituents for R or when R and R2 together with the nitrogen to which they are attached from a ring are halogen, cyano, (C 1-4 )alkyl, hydroxy(Ci 4 )alkyl, (Ci 4 )acyl, ( . 4 )alkoxy(C 1-4 )alkyl, R ⁇ CO ⁇ H ⁇ , R ⁇ fCH ⁇ n, R ⁇ fCH ⁇ nO or Rt ⁇ .
  • R 3 Preferred optional substituents for R 3 are halogen, (C 14 )alkoxy(C ⁇ -4 )alkyl, R ⁇ M, K ⁇ CH ⁇ n or R ⁇ CH ⁇ nO.
  • R may be optionally substituted by a phenyl ring optionally substituted by a halogen, cyano, or C ⁇ alkanoyl or C ⁇ alkylsulfonyl group; or by a 5- or 6-membered heterocyclic ring, optionally substituted by a (C 1-2 )alkyl or R ⁇ ST- group; wherein R a and R b are as defined above.
  • substituents positioned ortho to one another may be linked to form a fused ring.
  • halogen atom When a halogen atom is present in the compound of formula (I) it may be fluorine, chlorine, bromine or iodine.
  • the alkyl group may be straight chain, branched or cyclic, or combinations thereof, it is preferably methyl or ethyl.
  • 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.
  • 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 (T) 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.
  • 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.
  • 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.
  • 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.
  • protecting groups P include t-butyloxycarbonyl, trifluoroacetyl, benzyloxycarbonyl and optionally substituted benzyl. Deprotection conditions will depend on the particular protecting group; for the groups mentioned above these are respectively, acid (e.g. trifluoroacetic acid in dichloromethane), base (e.g. potassium carbonate 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).
  • Acylation may be carried out using a wide range of known conditions, e.g. in an inert solvent such as dichloromethane, in the presence of a base such as triethylamine.
  • these steps may be carried out when L 1 represents hydroxy, in which case the reaction takes place in an inert solvent such as dichloromethane or dimethylformamide in die presence of a diimide reagent such as l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, and an activator such as 1- hydroxybenzotriazole or 0-(7-azabenzotriazol-l-yl)-N,N,N 1 ,N 1 -tetramethyluronium hexafluorophosphate in the presence of a base such as N,N-diisopropylethylamine.
  • a base such as N,N-diisopropylethylamine.
  • the amidation step can be accomplished using a wide range of known conditions, ie. conversion of the acid moiety into a suitable leaving group L 1 and subsequent reaction with the amine as described for the acylation step above.
  • L 1 is a leaving group as described for Scheme 1 and R x is an optionally substituted (C 1-6 ) alkyl group.
  • R x is an optionally substituted (C 1-6 ) alkyl group.
  • the compounds of formula (I) may be 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.
  • a compound library comprising at least 2 compounds of formula (I), or pharmaceutically acceptable derivatives thereof.
  • compositions of formula (I) and tiieir 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; hypodialamic-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;
  • the compounds of formula (I) or pharmaceutically acceptable derivatives thereof are also useful in the treatment of stroke, particularly ischaemic or haemorrhagic stroke. Furthermore the compounds of formula (I) or pharmaceutically acceptable derivatives thereof are also useful in blocking the emetic response.
  • the compounds of formula (I) and their pharmaceutically acceptable derivatives are particularly useful for the treatment of obesity, including obesity associated witii Type 2 diabetes, sleep disorders, stroke and blocking the emetic response for example nausea and vomiting.
  • 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.
  • 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; 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 antagonist 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.
  • 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 in a suitable liquid carrier(s) e.g. an aqueous solvent such as water, ethanol or glycerine, or a n ⁇ n-aqueous solvent, such as polyethylene glycol or an oil.
  • a suitable liquid carrier(s) e.g. an aqueous solvent such as water, ethanol or glycerine, or a n ⁇ n-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 die 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.
  • suitable pharmaceutical carrier(s) e.g. aqueous gums, celluloses, silicates or oils
  • 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.
  • a sterile aqueous carrier or parenterally acceptable oil e.g. polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil.
  • 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.
  • 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.
  • 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 fluorochloro- hydrocarbon 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.
  • a carrier such as sugar and acacia, tragacanth, or gelatin and glycerin.
  • compositions for rectal administration are conveniently in the form of suppositories containing a conventional suppository base such as cocoa butter.
  • compositions suitable for transdermal administration include ointments, gels and patches.
  • the composition is 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 die 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.
  • 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 tiiree 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.
  • 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 die 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
  • Orexin-A can be employed in screening procedures for compounds which inhibit the ligand's activation of die orexin-1 receptor.
  • 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.
  • 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 FLDPR 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.
  • HATU O-(7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate
  • MDC dichloromethane
  • Example 1 (RS)-l-((4-(2-Methyl-5-pheny ⁇ )thiazoIyl)carbonyI)-2- (phenylcarbamoyImethyl)piperidine
  • D2 (0.01 lg, 0.05 mmol)
  • 2-methyl-5-phenylthiazole-4-carbonyl chloride 0.012g, 0.05 mmol
  • triethylamine 0.005g, 0.05 mmol
  • Example 2 (RS)-l-((2-PhenyI)benzoyI)-2-(phenylcarbamoylmethyl)piperidine
  • the title compound was prepared, using the method of E 1, from D2 (0.01 lg, 0.05 mmol), 2- phenylbenzoyl chloride (0.01 lg, 0.05 mmol) and triethylamine (0.005g, 0.06 mmol) as a gum (0.018g, 90%).
  • C 26 H 26 N 2 0 2 requires 398.
  • Example 6 (RS)-2-((l,3-Dihydro-isoindol-2-yl)carbonylmethyI)-l-((4-(2-methyl-5-(4- fluorophenyl))thiazolyl)carbonyl)piperidine
  • the title compound was prepared, in a similar manner to that described in E 3, from D8 (0.167g, 0.46 mmol) and 1,3-dihydroisoindole hydrochloride (0.072g, 0.46 mmol), as a pale yellow solid (0.138g, 65%).
  • C 26 H 26 FN 3 0 2 S requires 463.
  • HEK293 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 ⁇ l/well into 96-well black clear bottom sterile plates from Costar which had been pre- coated with 10 ⁇ g/well of poly-L-lysine from SIGMA. The seeded plates were incubated overnight at37°C in 5% C0 2 .
  • Agonists were prepared as 1 mM stocks in wate ⁇ DMSO (1:1). EC 50 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 CaCl 2 , 1.2 mM MgCl 2 and 2.5mM probenecid; pH7.4). Antagonists were prepared as 10 mM stocks in DMSO (100%).
  • Antagonist ICso 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 ⁇ l of cell medium containing probenecid (Sigma) and Fluo3 AM
  • MEM medium with Earl's salts containing 2 mM L-Glutamine, 0.4 mg/mL G418 Sulphate from GEBCO BRL and 10% heat inactivated fetal calf serum from Gibco BRL.
  • the cells were seeded at 20,000 cells/100 ⁇ l well into 96-well black clear bottom sterile plates from Costar which had been pre-coated with 10 ⁇ g/well of poly-L-lysine from SIGMA. The seeded plates were incubated overnight at 37C in 5% C0 2 .
  • Agonists were prepared as 1 mM stocks in water:DMSO (1:1). EC 50 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 145mMNaCl, lOmM glucose, 2.5 mM KC1, 1.5 mM CaCl 2 , 1.2 mM MgCl 2 and 2.5mM probenecid; pH7.4). Antagonists were prepared as 10 mM stocks in DMSO (100%).
  • Antagonist IC 50 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.
  • Antagonist or buffer (25 ⁇ l) was added (Quadra) the cell plates gently shaken and incubated at 37C in 5% CO 2 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.
  • FLIPR Fluorescent Imaging Plate Reader

Abstract

L'invention se rapporte à des dérivés d'amine cyclique N-aroyle et leur utilisation en tant que produits pharmaceutiques.
PCT/GB2002/005675 2001-12-19 2002-12-13 Derives d'amine cyclique n-aroyle et leur utilisation en tant qu'antagonistes recepteurs d'orexine WO2003051871A1 (fr)

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AU2002352388A AU2002352388A1 (en) 2001-12-19 2002-12-13 N-aroyl cyclic amine derivatives and their use as orxin receptor antagonist

Applications Claiming Priority (2)

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GB0130388.2 2001-12-19
GBGB0130388.2A GB0130388D0 (en) 2001-12-19 2001-12-19 Compounds

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Cited By (7)

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Publication number Priority date Publication date Assignee Title
WO2004014425A1 (fr) * 2002-08-07 2004-02-19 Glaxo Group Limited Activateurs de canaux de potassium actives par calcium de conductance faible et utilisation associee
WO2007029629A1 (fr) * 2005-09-06 2007-03-15 Shionogi & Co., Ltd. Dérivé d’acide indolécarboxylate ayant une activité à effet antagoniste du récepteur pgd2
US7279578B2 (en) 2002-10-11 2007-10-09 Actelion Pharmaceuticals Ltd. Sulfonylamino-acetic acid derivatives
US7763638B2 (en) 2004-03-01 2010-07-27 Actelion Pharmaceuticals Ltd. Substituted 1,2,3,4-tetrahydroisoquinoline derivatives
US8242121B2 (en) 2007-05-23 2012-08-14 Merck Sharp & Dohme Corp. Pyridyl piperidine orexin receptor antagonists
US8247560B2 (en) 2007-12-28 2012-08-21 Actelion Pharmaceuticals Ltd. Trisubstituted 3,4-dihydro-1H-isoquinolin compound, process for its preparation, and its use
WO2017194548A1 (fr) 2016-05-10 2017-11-16 INSERM (Institut National de la Santé et de la Recherche Médicale) Méthodes et compositions pharmaceutiques pour le traitement de maladies inflammatoires auto-immunes

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Publication number Priority date Publication date Assignee Title
WO2000047576A1 (fr) * 1999-02-12 2000-08-17 Smithkline Beecham Plc Derives de cinnamide utilises en tant qu'antagonistes des recepteurs de l'orexine-1
WO2001068609A1 (fr) * 2000-03-14 2001-09-20 Actelion Pharmaceuticals Ltd. Derives de 1,2,3,4-tetrahydroisoquinoline

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000047576A1 (fr) * 1999-02-12 2000-08-17 Smithkline Beecham Plc Derives de cinnamide utilises en tant qu'antagonistes des recepteurs de l'orexine-1
WO2001068609A1 (fr) * 2000-03-14 2001-09-20 Actelion Pharmaceuticals Ltd. Derives de 1,2,3,4-tetrahydroisoquinoline

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004014425A1 (fr) * 2002-08-07 2004-02-19 Glaxo Group Limited Activateurs de canaux de potassium actives par calcium de conductance faible et utilisation associee
US7279578B2 (en) 2002-10-11 2007-10-09 Actelion Pharmaceuticals Ltd. Sulfonylamino-acetic acid derivatives
US7435815B2 (en) 2002-10-11 2008-10-14 Actelion Pharmaceuticals Ltd. Sulfonylamino-acetic acid derivatives
US7763638B2 (en) 2004-03-01 2010-07-27 Actelion Pharmaceuticals Ltd. Substituted 1,2,3,4-tetrahydroisoquinoline derivatives
WO2007029629A1 (fr) * 2005-09-06 2007-03-15 Shionogi & Co., Ltd. Dérivé d’acide indolécarboxylate ayant une activité à effet antagoniste du récepteur pgd2
US8143285B2 (en) 2005-09-06 2012-03-27 Shionogi & Co., Ltd. Indolecarboxylic acid derivative having PGD2 receptor antagonistic activity
JP5147401B2 (ja) * 2005-09-06 2013-02-20 塩野義製薬株式会社 Ｐｇｄ２受容体アンタゴニスト活性を有するインドールカルボン酸誘導体
US8623903B2 (en) 2005-09-06 2014-01-07 Shionogi & Co., Ltd. Indolecarboxylic acid derivative having PGD2 receptor antagonistic activity
US8242121B2 (en) 2007-05-23 2012-08-14 Merck Sharp & Dohme Corp. Pyridyl piperidine orexin receptor antagonists
US8569311B2 (en) 2007-05-23 2013-10-29 Merch Sharp & Dohme Corp. Pyridyl piperidine orexin receptor antagonists
US8247560B2 (en) 2007-12-28 2012-08-21 Actelion Pharmaceuticals Ltd. Trisubstituted 3,4-dihydro-1H-isoquinolin compound, process for its preparation, and its use
WO2017194548A1 (fr) 2016-05-10 2017-11-16 INSERM (Institut National de la Santé et de la Recherche Médicale) Méthodes et compositions pharmaceutiques pour le traitement de maladies inflammatoires auto-immunes

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