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WO2004041816A1 - Compositions azacycliques utilisees comme antagonistes du recepteur de l'orexine - Google Patents

Compositions azacycliques utilisees comme antagonistes du recepteur de l'orexine Download PDF

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Publication number
WO2004041816A1
WO2004041816A1 PCT/EP2003/012403 EP0312403W WO2004041816A1 WO 2004041816 A1 WO2004041816 A1 WO 2004041816A1 EP 0312403 W EP0312403 W EP 0312403W WO 2004041816 A1 WO2004041816 A1 WO 2004041816A1
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formula
compound
compound according
optionally substituted
compounds
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PCT/EP2003/012403
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English (en)
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Clive Leslie Branch
Jean-Pierre Pilleux
Roderick Alan Porter
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Glaxo Group Limited
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Priority to AU2003301851A priority Critical patent/AU2003301851A1/en
Publication of WO2004041816A1 publication Critical patent/WO2004041816A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
    • C07D217/14—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
    • C07D217/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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 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 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.
  • 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
  • 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.
  • 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.
  • antagonists of its receptor may be useful in the treatment of obesity and diabetes, see Cell, 1998, 92, 573-585.
  • the present invention provides tetrahydroquinoline and tetrahydroisoquinoline 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. 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.
  • R 3 and R 4 together with the carbons to which they are attached form an aromatic or heteroaromatic ring and R 5 and R 6 are both H; or
  • R 4 and R 5 together with the carbons to which they are attached form an aromatic or heteroaromatic ring and R and R are both H; or
  • Ar 1 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;
  • Ar 2 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 R 1 and further optional substituents, R 1 representing hydrogen, optionally substituted (C M ) alkoxy, halo, cyano, optionally substituted (C ⁇ - 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 2 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 1 representing hydrogen, optionally substituted (C M ) alkoxy, halo, cyano, optionally substituted (C ⁇ - 6 )alkyl, optionally substituted phenyl, or an optionally substituted 5- or 6-
  • R is preferably H.
  • m is preferably 1.
  • p is preferably 0. h
  • R 4 and R 5 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 R 3 and R 6 are both H.
  • Ar 1 is an optionally substituted aryl it may have up to 5, preferably 1, 2 or 3 optional substituents.
  • Ar 1 is a mono or bicyclic heteroaryl
  • examples of when Ar 1 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.
  • Ar 1 is pyrirnidinyl.
  • Ar 2 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.
  • Ar 2 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.
  • Ar 2 represents optionally substituted thiazolyl or pyrazolyl.
  • R 1 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.
  • R 1 is optionally substituted phenyl.
  • Optional substituents for the groups Ar 1 , Ar 2 , and R 1 include halogen, hydroxy, oxo, cyano, nitro, (Ci- ⁇ alkyl, ( - ⁇ alkoxy, hydroxy(C ⁇ - 4 )alkyl, hydroxy(C ⁇ - 4 )alkoxy, halo(C ⁇ - 4 )alkyl, halo(C ⁇ - )alkoxy, aryl(C ⁇ -- )alkoxy, hydroxy(C ⁇ - 4 )alkyl, ( - )alkoxy(C ⁇ - )alkyl, (C 3 - 6 )cycloalkyl(C ⁇ - )alkoxy, (C ⁇ - 4 )alkanoyl, ( - )alkylsulfonyl, (C ⁇ - 4 )alkylsulfonyloxy, arylsulfonyl, arylsulfonyloxy, arylsulfonyl(
  • R represents hydrogen, a 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 2 are halogen and (C ⁇ - )alkyl.
  • the optional substituent for Ar 2 is most preferably (C ⁇ )alkyl (ie. methyl).
  • Preferred optional substituents for Ar 1 are halogen.
  • the optional substituent for Ar 1 is bromine.
  • Preferred optional substituents for R 1 are halogen.
  • the optional substituent for R 1 is fluorine.
  • substituents positioned ortho to one another may be linked to form a ring.
  • halogen atom when present in the compound of formula (I) it maybe 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.
  • 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.
  • solvates and hydrates of compounds of formula (I) are also included within the scope of the invention. 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.
  • Examples of suitable leaving groups L 1 include halogen, hydroxy, OSO 2 Me, OSO 2 (4-tolyl).
  • the reaction of (V) with (NT) preferably proceeds in an inert solvent such as ⁇ , ⁇ -dimethylfo ⁇ mamide in the presence of a base such as triethylamine, sodium hydride or potassium t-butoxide.
  • 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.
  • these steps may be carried out when L 2 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.
  • protecting group P examples 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).
  • 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.
  • 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.
  • R 1 When R 1 is an aromatic group, the substituent R 1 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 R 1 ! ⁇ , where M is the residue of an organometallic species e.g. B(OH) or trialkylstannyl.
  • 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(PPh 3 ) 4 .
  • Ar 2 , Ar 1 , m, p, q, R, R 1 R 3 to R 6 are as defined for compounds of formula (I).
  • L 3 is a leaving group.
  • Ar 1 , Ar 2 ' and R 3 to R 6 are as defined for formula (I), P is a protecting group, L 2 is a leaving group as defined above.
  • Ar 1 , Ar 2 , R 3 to R 6 are as defined for formula (I), P and P 1 are protecting groups and L 2 is a leaving group as defined above. Examples of protecting groups P and P 1 are given in scheme la.
  • 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.
  • a compound library comprising at least 2 compounds of formula (I), or pharmaceutically acceptable derivatives thereof.
  • compositions 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 hypopituita
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 pyrrohdone, lecithin, arachis oil or sesame oil.
  • a sterile aqueous carrier or parenterally acceptable oil e.g. polyethylene glycol, polyvinyl pyrrohdone, 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 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.
  • 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.
  • 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).
  • 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 the 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.
  • 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
  • D9 0.155g, 0.5mmol
  • 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).
  • 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
  • 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 ⁇ 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% CO .
  • Agonists were prepared as 1 mM stocks in wate ⁇ 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 CaCl 2 , 1.2 mM MgCl 2 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 ⁇ l 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 ⁇ M, 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 ⁇ l Tyrode's buffer containing probenecid and 0.1% gelatin (Denley Cell Wash). The volume of buffer left in each well was 125 ⁇ l.
  • Antagonist or buffer 25 ⁇ l was added (Quadra) the cell plates gently shaken and incubated at 37C in 5% CO 2 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.
  • FLIPR Fluorescent Imaging Plate Reader
  • 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.
  • the orexin-2 receptor antagonist activity of the compounds of formula (I) was determined in accordance with the following 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 ⁇ 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% CO 2 .
  • 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 CaCl 2 , 1.2 mM MgCl 2 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.
  • 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
  • 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.

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Abstract

Cette invention concerne des composés de formule (I) et leur utilisation comme antagonistes de l'orexine.
PCT/EP2003/012403 2002-11-06 2003-11-04 Compositions azacycliques utilisees comme antagonistes du recepteur de l'orexine WO2004041816A1 (fr)

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WO2008008517A2 (fr) 2006-07-14 2008-01-17 Merck & Co., Inc. Diazépans pontés antagonistes du récepteur de l'oréxine
WO2008069997A1 (fr) 2006-12-01 2008-06-12 Merck & Co., Inc. Antagonistes des récepteurs de l'orexine sous forme de composés de diazépane substitués
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WO2008117241A2 (fr) * 2007-03-26 2008-10-02 Actelion Pharmaceuticals Ltd Dérivés de thiazolidine
WO2008147518A1 (fr) 2007-05-23 2008-12-04 Merck & Co., Inc. Antagonistes de récepteur d'orexine pipéridyl pipéridine
WO2008150364A1 (fr) 2007-05-23 2008-12-11 Merck & Co., Inc. Antagonistes du récepteur de la cyclopropylpyrrolidine orexine
JP2010504957A (ja) * 2006-09-29 2010-02-18 アクテリオン ファーマシューティカルズ リミテッド ３−アザ−ビシクロ［３．１．０］ヘキサン誘導体
WO2010063663A1 (fr) * 2008-12-02 2010-06-10 Glaxo Group Limited Dérivés de n-{[(1r,4s,6r)-3-(2-pyridinylcarbonyl)-3-azabicyclo[4.1.0]hept-4-yl]methyl}-2-heteroarylamine et leurs utilisations
WO2010063662A1 (fr) * 2008-12-02 2010-06-10 Glaxo Group Limited Dérivés de n-{[(1s,4s,6s)-3-(2-pyridinylcarbonyl)-3-azabicyclo[4.1.0]hept-4-yl]methyl}-2-heteroarylamine et leurs utilisations
US7763638B2 (en) 2004-03-01 2010-07-27 Actelion Pharmaceuticals Ltd. Substituted 1,2,3,4-tetrahydroisoquinoline derivatives
WO2011061318A1 (fr) 2009-11-23 2011-05-26 N.V. Organon Composés hétérocyliques en tant qu'antagonistes des récepteurs d'orexine
WO2011080751A3 (fr) * 2009-12-29 2011-08-18 Suven Life Sciences Limited Ligands du récepteur nicotinique neuronal de l'acétylcholine α4β2
US8133901B2 (en) 2006-12-01 2012-03-13 Actelion Pharmaceuticals Ltd. 3-heteroaryl (amino or amido)-1-(biphenyl or phenylthiazolyl) carbonylpiperidine derivatives as orexin receptor inhibitors
US8236801B2 (en) 2008-02-21 2012-08-07 Actelion Pharmaceuticals Ltd. 2-aza-bicyclo[2.2.1]heptane derivatives
US8288429B2 (en) 2007-07-27 2012-10-16 Actelion Pharmaceuticals Ltd. 2-aza-bicyclo[3.3.0]octane derivatives
US8288411B2 (en) 2007-09-24 2012-10-16 Actelion Pharmaceuticals Ltd. Pyrrolidines and piperidines as orexin receptor antagonists
WO2013182972A1 (fr) 2012-06-04 2013-12-12 Actelion Pharmaceuticals Ltd Dérivés de benzimidazole-proline
WO2014057435A1 (fr) 2012-10-10 2014-04-17 Actelion Pharmaceuticals Ltd Antagonistes des récepteurs de l'orexine, qui sont des dérivés [ortho bi (hetero )aryl]-[2-(meta bi (hetero )aryl)-pyrrolidin-1-yl]-methanone
WO2014141065A1 (fr) 2013-03-12 2014-09-18 Actelion Pharmaceuticals Ltd Dérivés d'amide d'azétidine en tant qu'antagonistes des récepteurs d'oréxine
JP2015506382A (ja) * 2012-02-07 2015-03-02 エオラス セラピューティクス， インコーポレイテッド オレキシンレセプターアンタゴニストとしての置換プロリン／ピペリジン
JP2015510909A (ja) * 2012-03-19 2015-04-13 ロッタファーム・バイオテック・ソチエタ・ア・レスポンサビリタ・リミタータＲＯＴＴＡＰＨＡＲＭ ＢＩＯＴＥＣＨ Ｓ．ｒ．ｌ． 化合物
WO2015083071A1 (fr) 2013-12-03 2015-06-11 Actelion Pharmaceuticals Ltd Forme de sel cristalline de (s)-(2-(6-chloro-7-méthyl-1 h-benzo[d]imidazol- 2-yl)-2-méthylpyrrolidin-1-yl)(5-méthoxy-2-(2h-1,2,3-triazol-2-yl)phényl)méthanone comme antagoniste des récepteurs à l'oréxine
WO2015083094A1 (fr) 2013-12-04 2015-06-11 Actelion Pharmaceuticals Ltd Utilisation de dérivés de benzimidazole-proline
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US9156819B2 (en) 2011-10-19 2015-10-13 Merck Sharp & Dohme Corp. 2-pyridyloxy-4-nitrile orexin receptor antagonists
US9440982B2 (en) 2012-02-07 2016-09-13 Eolas Therapeutics, Inc. Substituted prolines/piperidines as orexin receptor antagonists
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
US10221170B2 (en) 2014-08-13 2019-03-05 Eolas Therapeutics, Inc. Difluoropyrrolidines as orexin receptor modulators
WO2020007964A1 (fr) 2018-07-05 2020-01-09 Idorsia Pharmaceuticals Ltd Dérivés de 2-(2-azabicyclo [3.1.0] hexan-1-yl)-1h-benzimidazole
WO2020099511A1 (fr) 2018-11-14 2020-05-22 Idorsia Pharmaceuticals Ltd Dérivés de benzimidazole-2-méthyl-morpholine
US10894789B2 (en) 2016-02-12 2021-01-19 Astrazeneca Ab Halo-substituted piperidines as orexin receptor modulators
WO2023218023A1 (fr) 2022-05-13 2023-11-16 Idorsia Pharmaceuticals Ltd Dérives d'hydrazine-n-carboxamide cycliques substitués par thiazoloaryl-méthyle

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US7812031B2 (en) 2004-02-10 2010-10-12 Sanofi-Aventis Pyrimidine derivatives as orexin receptor antagonists
US7763638B2 (en) 2004-03-01 2010-07-27 Actelion Pharmaceuticals Ltd. Substituted 1,2,3,4-tetrahydroisoquinoline derivatives
WO2008008517A2 (fr) 2006-07-14 2008-01-17 Merck & Co., Inc. Diazépans pontés antagonistes du récepteur de l'oréxine
JP2010504957A (ja) * 2006-09-29 2010-02-18 アクテリオン ファーマシューティカルズ リミテッド ３−アザ−ビシクロ［３．１．０］ヘキサン誘導体
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