WO2012089607A1 - Nouveaux composés dotés d'un cœur 3a-azabicyclo[4.1.0]heptane agissant sur les récepteurs d'orexine - Google Patents

Nouveaux composés dotés d'un cœur 3a-azabicyclo[4.1.0]heptane agissant sur les récepteurs d'orexine Download PDF

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Publication number
WO2012089607A1
WO2012089607A1 PCT/EP2011/073737 EP2011073737W WO2012089607A1 WO 2012089607 A1 WO2012089607 A1 WO 2012089607A1 EP 2011073737 W EP2011073737 W EP 2011073737W WO 2012089607 A1 WO2012089607 A1 WO 2012089607A1
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Prior art keywords
azabicyclo
pyridinyl
ethyl
methyl
trifluoromethyl
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PCT/EP2011/073737
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English (en)
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Romano Di Fabio
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Glaxo Group Limited
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Publication of WO2012089607A1 publication Critical patent/WO2012089607A1/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
    • C07D401/14—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • 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
    • 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 azabicyclo[4.1.0]hept-4-yl derivatives and their use as pharmaceuticals.
  • polypeptides and polynucleotides encoding polypeptides which are ligands for the orexin-1 receptor, e.g. orexin-A (Lig72A) are disclosed in EP849361.
  • orexin receptor antagonist SB334867 potently reduced hedonic eating in rats (White et al (2005) Peptides 26 pp 2231 to 2238) and also attenuated high-fat pellet self- administration in rats (Nair et al (2008) British Journal of Pharmacology, published online 28 January 2008).
  • diabetes 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.
  • Antagonists of the orexin receptors may therefore be useful in the treatment of sleep disorders including insomnia.
  • orexin receptor antagonists for example SB334867, in rats (see for example Smith et al (2003) Neuroscience Letters 341 pp 256 to 258) and more recently dogs and humans (Brisbare-Roch et al (2007) Nature Medicine 13(2) pp 150 to 155) further support this.
  • WO01/96302 WO02/44172, WO02/89800, WO03/002559, WO03/002561, WO03/032991, WO03/037847, WO03/041711, WO08/038251, WO09/003993,
  • WO09/003997 and WO09/124956 all disclose cyclic amine derivatives.
  • WO08/038251 discloses 3-aza-bicyclo[3.1.0]hexane derivatives as orexin antagonists.
  • certain azabicyclo[4.1.0]hept-4-yl derivatives have beneficial properties including, for example, high potency, good brain penetration and good bioavailability.
  • Such properties make these azabicyclo[4.1.0]hept-4-yl derivatives very attractive as potential pharmaceutical agents which may be useful in the prevention or treatment of obesity, including obesity observed in Type 2 (non-insulin-dependent) diabetes patients, sleep disorders, anxiety, depression, schizophrenia, drug dependency or compulsive behaviour.
  • these compounds may be 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.
  • Het is a heteroaryl group selected from pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, thiazolyl or thiadiazolyl, said heteroaryl group being optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of: Ci -4 alkyl, halo, Ci. 4 alkoxy, haloCi -4 alkyl, haloCi -4 alkoxy and cyano;
  • X is C or N
  • Y is C orN
  • Ri is Ci -4 alkyl, halo, Ci- alkoxy, haloCi -4 alkyl, haloCi- alkoxy, cyano, C 1-4 alkylS0 2 , C 3-8 cycloalkylS0 2 , C 3-8 cycloalkylCH 2 S0 2 , phenyl or a 5 or 6 membered heterocyclyl group containing 1, 2 or 3 atoms selected from N, O or S, which phenyl or heterocyclyl group is optionally substituted with Ci -4 alkyl, halo, Ci -4 alkoxy, haloCi -4 alkyl, haloCi -4 alkoxy or cyano;
  • R 2 is C 1-4 alkyl, halo, C 1-4 alkoxy, haloC 1-4 alkyl, haloC 1-4 alkoxy, cyano, phenyl or a 5 or 6 membered heterocyclyl group containing 1, 2 or 3 atoms selected from N, O or S, which phenyl or heterocyclyl group is optionally substituted with Ci -4 alkyl, halo, Ci -4 alkoxy, haloCi- alkyl, haloCi- alkoxy or cyano;
  • R 3 is or cyano
  • m is 0 or l
  • n 0 or 1
  • stereogenic centres of the compounds of formula (I) are in a cis (IS,4R,6S)- configuration.
  • stereogenic centres of the compounds of formula (I) are in a trans (IR,4R,6R)- configuration.
  • Het is pyridinyl
  • Het is pyrimidinyl
  • Het is pyridazinyl.
  • Het is pyrazinyl
  • Het is triazinyl.
  • Het is thiazolyl
  • Het is thiadiazolyl
  • Het is substituted with trifluoromethyl.
  • X and Y are both carbon.
  • X and Y are both nitrogen.
  • X is nitrogen and Y is carbon. In one embodiment X is carbon and Y is nitrogen.
  • Ri is triazolyl
  • Ri is pyrazolyl
  • Ri is pyrimidinyl
  • n is 0.
  • n is 0 and R 2 is methyl.
  • the invention provides the compound of formula (I) selected from the group consisting of:
  • the Het group may be attached to the ethylene linker by means of a bond between the carbon atom in said linker and any carbon or nitrogen atom in said Het group.
  • the Het group is attached to the linker by means of a bond between the carbon atom in the linker and a carbon atom in the Het group ring.
  • Ri or R 2 is a heterocyclic group it can be any 5 or 6 membered heterocyclyl group containing 1, 2 or 3 atoms selected from N, O or S.
  • heterocyclic groups include pyrimidinyl, oxadiazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, imidazolyl, pyrazolinyl, pyridazinyl, pyrazinyl, pyridinyl, furanyl, thienyl, pyrrolyl, thiadiazolyl, triazinyl and isothiazolyl.
  • Ri or R 2 is a heterocyclic group
  • said group may be attached to the X/Y containing ring by means of a bond between a carbon atom of said X/Y containing ring and a carbon or a heteroatom of the heterocyclic group.
  • Ri is a triazolyl group
  • the attachment to the X/Y containing ring may be by means of a bond between a carbon atom on the X/Y containing ring and a) one of the two carbon atoms or b) one of the three nitrogen atoms of the triazolyl group.
  • the alkyl group may be straight chain, branched or cyclic, or combinations thereof.
  • Examples of Ci -4 alkyl are methyl or ethyl.
  • haloCi -4 alkyl examples include trifluoromethyl (i.e. -CF 3 ).
  • Ci -4 alkoxy examples include methoxy and ethoxy.
  • haloCi -4 alkoxy examples include trifluoromethoxy (i.e. - OCF 3 ).
  • Halogen or "halo" when used, for example, in haloCi -4 alkyl means fluoro, chloro, bromo or iodo.
  • salts of the compounds of formula (I) should be pharmaceutically acceptable. Suitable pharmaceutically acceptable salts will be apparent to those skilled in the art. Pharmaceutically acceptable salts include those described by Berge, Bighley and Monkhouse J.Pharm.Sci (1977) 66, pp 1-19. Such pharmaceutically acceptable salts 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 or formates, may be used, for example in the isolation of compounds of formula (I) and represent another aspect of this 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) may be prepared in crystalline or non-crystalline form and, if crystalline, may optionally be solvated, eg. as the hydrate.
  • This invention includes within its scope stoichiometric solvates (eg. hydrates) as well as compounds containing variable amounts of solvent (eg. water).
  • 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.
  • the stereogenic centres of the compounds of formula (I) are in a (1S,4R,6S)- or a trans ( ⁇ R,4R,6R)- configuration.
  • the invention also extends to any tautomeric forms or mixtures thereof.
  • the subject invention also includes isotopically-labeled compounds which are identical to those recited in formula (I) but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number most commonly found in nature.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, iodine and chlorine such as 3 ⁇ 4 U C, 14 C, 18 F, 123 I or 125 I.
  • Isotopically labeled compounds of the present invention for example those into which radioactive isotopes such as 3 H or 14 C have been incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, ie. 3 H, and carbon-14, ie. 14 C, isotopes are particularly preferred for their ease of preparation and detectability. U C and 18 F isotopes are particularly useful in PET (positron emission tomography).
  • 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.
  • the starting materials for use in the scheme are commercially available, known in the literature or can be prepared by known methods.
  • compositions may be prepared conventionally by reaction with the appropriate acid or acid derivative.
  • the present invention provides compounds of formula (I) or a pharmaceutically acceptable salt thereof for use in human or veterinary medicine.
  • the compounds of formula (I) or their pharmaceutically acceptable salts may be of use for the treatment or prophylaxis of a disease or disorder where an antagonist of a human orexin receptor is required.
  • Coumpounds of formula (I) or their pharmaceutically acceptable salts may be of use for the treatment or prophylaxis of sleep disorders selected from the group consisting of Dyssomnias such as Primary Insomnia (307.42), Primary Hypersomnia (307.44),
  • Narcolepsy (347), Breathing-Related Sleep Disorders (780.59), Circadian Rhythm Sleep Disorder (307.45) and Dyssomnia Not Otherwise Specified (307.47); primary sleep disorders such as Parasomnias such as Nightmare Disorder (307.47), Sleep Terror Disorder (307.46), Sleepwalking Disorder (307.46) and Parasomnia Not Otherwise Specified (307.47); Sleep Disorders Related to Another Mental Disorder such as Insomnia Related to Another Mental Disorder (307.42) and Hypersomnia Related to Another Mental Disorder (307.44); Sleep Disorder Due to a General Medical Condition, in particular sleep disturbances associated with such diseases as neurological disorders, neuropathic pain, restless leg syndrome, heart and lung diseases; and Substance-Induced Sleep Disorder including the subtypes Insomnia Type, Hypersomnia Type, Parasomnia Type and Mixed Type; Sleep Apnea and Jet-Lag Syndrome.
  • compounds of formula (I) or their pharmaceutically acceptable salts may be of use for the treatment or prophylaxis of depression and mood disorders including Major Depressive Episode, Manic Episode, Mixed Episode and Hypomanic Episode;
  • Depressive Disorders including Major Depressive Disorder, Dysthymic Disorder (300.4), Depressive Disorder Not Otherwise Specified (311); Bipolar Disorders including Bipolar I Disorder, Bipolar ⁇ Disorder (Recurrent Major Depressive Episodes with Hypomanic Episodes) (296.89), Cyclothymic Disorder (301.13) and Bipolar Disorder Not Otherwise Specified (296.80); Other Mood Disorders including Mood Disorder Due to a General Medical Condition (293.83) which includes the subtypes With Depressive Features, With Major Depressive-like Episode, With Manic Features and With Mixed Features),
  • the compounds of formula (I) or their pharmaceutically acceptable salts may be of use for the treatment or prophylaxis of anxiety disorders including Panic Attack; Panic Disorder including Panic Disorder without Agoraphobia (300.01) and Panic Disorder with Agoraphobia (300.21); Agoraphobia; Agoraphobia Without History of Panic Disorder (300.22), Specific Phobia (300.29, formerly Simple Phobia) including the subtypes Animal Type, Natural Environment Type, Blood-Injection-Injury Type, Situational Type and Other Type), Social Phobia (Social Anxiety Disorder, 300.23), Obsessive-Compulsive Disorder (300.3), Posttraumatic Stress Disorder (309.81), Acute Stress Disorder (308.3), Generalized Anxiety Disorder (300.02), Anxiety Disorder Due to a General Medical Condition (293.84), Substance-Induced Anxiety Disorder, Separation Anxiety Disorder (309.21), Adjustment Disorders with Anxiety (309.24) and Anxiety Disorder Not Otherwise Specified (300.00).
  • Panic Attack Panic
  • compounds of formula (I) or their pharmaceutically acceptable salts may be of use for the treatment or prophylaxis of substance-related disorders including Substance Use Disorders such as Substance Dependence, Substance Craving and Substance Abuse; Substance-Induced Disorders such as Substance Intoxication, Substance
  • Alcohol -Related Disorders such as Alcohol Dependence (303.90), Alcohol Abuse (305.00), Alcohol Intoxication (303.00), Alcohol Withdrawal (291.81), Alcohol Intoxication Delirium, Alcohol Withdrawal Delirium, Alcohol -Induced Persisting Dementia, Alcohol-Induced Persisting Amnestic Disorder, Alcohol -Induced Psychotic Disorder, Alcohol-Induced Mood Disorder, Alcohol-Induced Anxiety Disorder, Alcohol-Induced sexual Dysfunction, Alcohol -Induced Sleep Disorder and Alcohol-Related Disorder Not Otherwise Specified (291.9); Amphetamine (or
  • Amphetamine-Like)-Related Disorders such as Amphetamine Dependence (304.40), Amphetamine Abuse (305.70), Amphetamine Intoxication (292.89), Amphetamine
  • Cannabis-Related Disorders such as Caffeine Intoxication (305.90), Caffeine-Induced Anxiety Disorder, Caffeine-Induced Sleep Disorder and Caffeine-Related Disorder Not Otherwise Specified (292.9); Cannabis-Related Disorders such as Cannabis Dependence (304.30), Cannabis Abuse (305.20), Cannabis Intoxication (292.89), Cannabis Intoxication Delirium, Cannabis- Induced Psychotic Disorder, Cannabis-Induced Anxiety Disorder and Cannabis-Related Disorder Not Otherwise Specified (292.9); Cocaine-Related Disorders such as Cocaine Dependence (304.20), Cocaine Abuse (305.60), Cocaine Intoxication (292.89), Cocaine Withdrawal (292.0), Cocaine Intoxication Delirium, Cocaine-Induced Psychotic Disorder, Cocaine-Induced Mood Disorder, Cocaine-Induced Anxiety Disorder, Cocaine-Induced Sexual Dysfunction, Cocaine-Induced Sleep Disorder and Cocaine-Related Disorder Not Otherwise Spec
  • Nicotine-Related Disorders such as Nicotine Dependence (305.1), Nicotine Withdrawal (292.0) and Nicotine-Related Disorder Not Otherwise Specified (292.9); Opioid-Related Disorders such as Opioid Dependence (304.00), Opioid Abuse (305.50), Opioid Intoxication (292.89), Opioid Withdrawal (292.0), Opioid Intoxication Delirium, Opioid-Induced Psychotic Disorder, Opioid-Induced Mood Disorder, Opioid-Induced Sexual Dysfunction, Opioid-Induced Sleep Disorder and Opioid-Related Disorder Not Otherwise Specified (292.9); Phencyclidine (or Phencyclidine-Like)-Related Disorders such as Phencyclidine Dependence (304.60), Phencyclidine Abuse (305.90), Phencyclidine Intoxic
  • Sedative-, Hypnotic-, or Anxiolytic-Related Disorders such as Sedative, Hypnotic, or Anxiolytic Dependence (304.10), Sedative, Hypnotic, or Anxiolytic Abuse (305.40), Sedative, Hypnotic, or Anxiolytic Intoxication (292.89), Sedative, Hypnotic, or Anxiolytic Withdrawal (292.0), Sedative, Hypnotic, or Anxiolytic Intoxication Delirium, Sedative, Hypnotic, or Anxiolytic Withdrawal Delirium, Sedative-, Hypnotic-, or Anxiolytic-Persisting Dementia, Sedative-, Hyp
  • the compounds of formula (I) or their pharmaceutically acceptable salts may be of use for the treatment or prophylaxis of feeding disorders such as bulimia nervosa, binge eating, obesity, including obesity observed in Type 2 (non-insulin-dependent) diabetes patients.
  • the compounds of formula (I) or their pharmaceutically acceptable salts may be of use for the treatment or prophylaxis of stroke, particularly ischemic or haemorrhagic stroke and/or in blocking an emetic response i.e. nausea and vomiting.
  • the invention also provides a method for the treatment of a disease or disorder in a subject, for example those diseases and disorders mentioned hereinabove, comprising administering to said subject an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.
  • the invention also provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment or prophylaxis of a disease or disorder, for example those diseases and disorders mentioned hereinabove.
  • the invention also provides the use of a compound of formula (I), or a
  • 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 salt thereof, and a pharmaceutically acceptable carrier.
  • the compounds of formula (I) or their pharmaceutically acceptable salts 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) or their pharmaceutically acceptable salts which are active when given orally can be formulated as liquids or solids, e.g. as syrups, suspensions, emulsions, tablets, capsules or lozenges.
  • a liquid formulation will generally consist of a suspension or solution of the active ingredient in a suitable liquid carrier(s) e.g. an aqueous solvent such as water, ethanol or glycerine, or a non-aqueous solvent, such as polyethylene glycol or an oil.
  • 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.
  • 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 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 nonaqueous 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.
  • 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 composition may contain from 0.1% to 100% by weight, for example from 10 to 60% by weight, of the active material, depending on the method of administration.
  • the composition may contain from 0% to 99% by weight, for example 40% to 90% by weight, of the carrier, depending on the method of administration.
  • the composition may contain from 0.05mg to lOOOmg, for example from l .Omg to 500mg, of the active material, depending on the method of administration.
  • the composition may contain from 50 mg to 1000 mg, for example from lOOmg to 400mg of the carrier, depending on the method of administration.
  • the dose of the compound used in the treatment of the aforementioned disorders will vary in the usual way with the seriousness of the disorders, the weight of the sufferer, and other similar factors.
  • suitable unit doses may be 0.05 to 1000 mg, more suitably 1.0 to 500 mg, and such unit doses may be administered more than once a day, for example two or three a day. Such therapy may extend for a number of weeks or months.
  • Orexin-A (Sakurai, T. et al (1998) Cell, 92 pp 573-585) can be employed in screening procedures for compounds which inhibit the ligand' s activation of the orexin-1 or orexin-2 receptors.
  • screening procedures involve providing appropriate cells which express the orexin-1 or orexin-2 receptor on their surface.
  • Such cells include cells from mammals, yeast, Drosophila or s. coli.
  • a polynucleotide encoding the orexin- 1 or orexin-2 receptor is used to transfect cells to express the receptor.
  • the expressed receptor is then contacted with a test compound and an orexin-1 or orexin-2 receptor ligand, as appropriate, to observe inhibition of a functional response.
  • One such screening procedure involves the use of melanophores which are transfected to express the orexin-1 or orexin-2 receptor, as described in WO 92/01810.
  • Another screening procedure involves introducing RNA encoding the orexin-1 or orexin-2 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 or orexin-2 receptor ligand to cells which have the orexin-1 or orexin-2 receptor (as appropriate) on their surface.
  • This method involves transfecting a eukaryotic cell with DNA encoding the orexin-1 or orexin-2 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 or orexin-2 receptor ligand.
  • the ligand may contain a radioactive label. The amount of labelled ligand bound to the receptors is measured, e.g. by measuring
  • 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 or orexin-2 receptor ligand with the orexin-1 or orexin-2 receptor as appropriate.
  • the compounds described in the Examples described hereinafter have all been prepared as a first step from stereochemically pure starting materials.
  • the stereochemistry of the compounds of the Descriptions and Examples have been assigned on the assumption that the absolute configuration of these centres are retained.
  • the relative stereochemistry of the compounds of the Descriptions and Examples have been assigned on the assumption that the relative stereochemistry is maintained as determined by using Rotating frame 2D ROESY experiments in the chiral intermediates. In some Examples the relative
  • MR Magnetic Resonance
  • MS refers to Mass Spectra taken by Direct infusion Mass or to Mass Spectra associated with peaks taken by UPLC/MS or HPLC/MS analysis, where the Mass Spectrometer used is as mentioned below.
  • UV spectra associated with the peaks were taken on a UPLC/MS AcquityTM system equipped with 2996 PDA detector and coupled to a Waters Micromass ZQTM Mass Spectrometer operating in positive or negative electrospray ionisation mode [LC/MS - ES (+ or -): analyses performed using an AcquityTM UPLC BEH C18 column (50 x 21 mm, 1.7 ⁇ particle size), column temperature 40 °C].
  • Flash chromatography was carried out on silica gel 230-400 mesh (supplied by Merck AG Darmstadt, Germany), Varian Mega Be-Si pre-packed cartridges, pre-packed Biotage silica cartridges (e.g. Biotage SNAP cartridge), KP-NH prepacked flash cartridges or ISCO RediSep Silica cartridges.
  • SPE-SCX cartridges are ion exchange solid phase extraction columns supplied by Varian.
  • the eluent used with SPE-SCX cartridges is DCM and MeOH or ACN or MeOH followed by 2 N ammonia solution in MeOH.
  • the collected fractions are those eluted with the ammonia solution in MeOH.
  • SPE-Si cartridges are silica solid phase extraction columns supplied by Varian.
  • ENV+ cartridges are packed with ENV+ a hyper cross-linked hydroxylated polystyrene-divinylbenzene copolymer.
  • the slurry was stirred at room temperature overnight.
  • the pH of the organic phase was measured and found to be 1.
  • the volume was reduced to 4 volumes (0.6L).
  • THF 1.5L was added and the volume is reduced to 4 volumes (0.6L) by distillation under reduced pressure.
  • the solid was filtered (note: 60ml of the slurry was collected prior to filtration, so 10% of input was removed) and washed with THF (3x0.3L). The filtrate appeared cloudy.
  • the solution was reduced to 2.2 volumes (0.337L) by distillation under reduced pressure and BF 3 .THF (422.55mL, 3.83 mol, 6eq considering the 10% removed) was added under stirring whilst maintaining an internal temperature of 25°C.
  • the resulting solution was added slowly to a solution of L1BH 4 (4M in THF) (0.648L, 2.59 mol, 4eq) diluted with THF (0.405L) keeping the temperature at 25-30°C (the line was washed with THF (0.337L)).
  • the mixture was stirred at 30°C overnight (17 hours).
  • the mixture was quenched slowly with MeOH (0.54L) at 25-30°C.
  • the solution was stirred at 50°C for approximately 1 hour.
  • Heptane (1.35L) was added and the solution was reduced to 5 volumes (0.675L), diluted with heptane (0.675L) and concentrated to 5 volumes (0.675L) by distillation under reduced pressure.
  • Seed (135mg) of the title compound was added at 40°C and the slurry was cooled at 20°C in 1 hour. The slurry was stirred for at least 4 hours and filtered. The solid was washed with cold heptane (0.27L) and dried in a vacuum oven at 40°C for 14 hours and 30 minutes.
  • l,l-dimethylethyl(lR,4S,6R)- 4-(hydroxymethyl)-3-azabicyclo[4.1.0]heptane-3-carboxylate (98g) was obtained as white solid.
  • Ci 3 Hi 9 N0 2 requires: 221.
  • the reaction mixture was cooled to 0 °C and was quenched by adding in sequence: 60.7 ml of water (1 ml H 2 0 x 1 g of L1AIH 4 ) + 60.7 ml of NaOH 1 N (1 ml NaOH 1M x 1 g of L1AIH 4 ) + 182 ml of water (3 ml H 2 0 x 1 g of LiAlFLi).
  • the suspension was stirred at room temperature for 1 hour then the precipitate was filtered over sodium sulphate (gooch n3) and washed with Et 2 0 (6 L) and DCM (4 L).
  • the solvent was evaporated (temperature bath 30 °C) of the crude title compound D7 (110 g) as pale-orange oil.
  • CioHi 8 N 2 0 2 -CHF 3 0 3 S requires 348. 1H MR (400 MHz, DMSO-d 6 ) ⁇ ppm 1.40 (s, 3 H), 1.50 (s, 3 H), 2.17-2.43 1.40 (m, 2 H), 3.68-3.98 (m, 4 H), 3.99-4.09 (m, 1 H), 4.83-5.40 (m, 2 H), 5.58-5.97 (m, 1 H), 7.63-8.36 (br.s., 2 H)
  • Dess-Martin periodinane (1866 mg, 4.40 mmol) was added to a solution of 1,1- dimethylethyl (1 S,4S,6S)-4-(hydroxymethyl)-3-azabicyclo[4.1.0]heptane-3-carboxylate D14 (1000 mg, 4.40 mmol) in DCM (20 ml). After 3 hours at 23 °C a saturated solution of Na 2 S 2 0 3 (35 ml) was added to the reaction mixture and stirred for 1 hour.
  • aqueous phase was back extracted with DCM (3 x 10 ml), organics were collected, dried (Na 2 S0 4 ), filtered and evaporated under reduced pressure.
  • the crude obtained was purified by silica gel chromatography (SNAP KP-Sil 25g; eluted with Cy/EtOAc 5 CV from 100% Cy to 95/4, 5 CV 95/5).
  • the yellow solid obtained was purified by silica gel chromatography (SNAP KP-Sil 50g; eluted with Cy/EtOAc, 5 CV from 100% Cy to 95/5, 5 CV 95/5).
  • reaction mixture was treated with 20 ml of aqueous NH 4 C1 saturated solution, warmed to room temperature, diluted with 50 ml of Et 2 0 and the layers were separated.
  • the resulting orange oil was purified by silica gel chromatography (SNAP KP-Sil 50 g; eluted with Cy/EtOAc 10 CV from 100% Cy to 95/5, 7 CV 95/5).
  • Ci 8 H 24 F 3 N 3 0 2 requires: 371.
  • Ci H 2 iF 3 N 2 0 2 requires 366.
  • reaction mixture was cooled to 23 °C, diluted with EtOAc (30 ml) and filtered through a Celite pad. The filtrate was washed with brine (3 x 20 ml) and the combined aqueous layers were back extracted with EtOAc (2 x 5 ml). Organic layers were dried (Na 2 S0 4 ), filtered and evaporated.
  • the brown oil obtained was purified by column chromatography (SNAP KP-Sil 25g; eluted with Cy/EtOAc 4CV from 100% Cy to 80/20, 6CV 80/20). Evaporated fractions gave a yellow oil (130 mg), containing desired compound with coloured impurities. It was charged on silica gel column (SNAP KP-Sil lOg) and eluted with DCM/EtOAc 10CV from 100% DCM to 90/10, 5CV 90/10.
  • Cy/iPrOH 3CV from 100% Cy to 99/1, 5CV 99/1).
  • reaction mixture was cooled to 23 °C, diluted with EtOAc (30 ml) and filtered through a Celite pad. The filtrate was washed with brine (3 x 20 ml) and the combined aqueous layers were back extracted with EtOAc (2 x 5 ml). Organic layers were dried (Na 2 S0 4 ), filtered and evaporated.
  • the brown oil obtained was purified by column chromatography (SNAP KP-Sil 50g; eluted with Cy/EtOAc 3CV from 100% Cy to 90/10, 5CV 90/10).
  • 6-methyl-2-[(methyloxy)carbonyl]-3-pyridinecarboxylic acid D61 (1.15 g) was suspended toluene (40 ml) and DIPEA (1.25 ml, 7.16 mmol) was added, causing the complete dissolution of the solid. This mixture was stirred 10 minutes at room temperature, then diphenyl azidophosphate (1.35 ml, 6.26 mmol) was added in one portion and the mixture was stirred at reflux for 1 hour. The solution was cooled at room temperature and t-BuOH (2.5 ml, 26 mmol) was added in one portion.
  • Methyl 3 -( ⁇ [(1 , 1 -dimethyl ethyl)oxy]carbonyl ⁇ amino)-6-methyl-2-pyridinecarboxylate D62 (1.3 g) was dissolved in DCM (80 ml) and the mixture stirred at 0 °C. A solution of TFA (5 ml, 64.9 mmol) in DCM (10 ml) was dropped into the cold mixture over 3 minutes. The resulting solution was left under stirring at 0 °C for 30 minutes, then the mixture was left still at room temperature overnight. TFA (4 ml, 51.9 mmol) dissolved in DCM (10 ml) was added over 3 minutes and the mixture stirred again at room temperature for 5 hours.
  • 2,2,6,6-tetramethylpiperidine (3.49 ml, 20.52 mmol) was dissolved in dry THF (25ml) under argon and stirred at -30 °C; BuLi (13.33 ml, 21.33 mmol) 1.6 M in hexane was added over 5 min (the temperature never exceeded -25 °C). The yellow solution was stirred at -30 °C for 20 min, then chilled at -78 °C and tris(l -methylethyl) borate (4.38 ml, 18.96 mmol) was added over 5 min (the temperature never exceeded -73 °C).
  • D68 3-(5,5-dimethyl-l,3,2-dioxaborinan-2-yl)-6- methyl-2-pyridinecarbonitrile
  • D67 (50.6 mg) was dissolved 1,4-Dioxane (1 ml) under nitrogen in a vial, then 2-bromopyrimidine (42.0 mg, 0.264 mmol), CsF (67 mg, 0.441 mmol), Pd(Ph 3 P) 4 (12 mg, 10.38 ⁇ ) and Cul (7 mg, 0.037 mmol) were added in sequence.
  • the mixture was irradiated in a single mode microwave reactor to 120 °C for a further 40 minutes.
  • the reaction mixture was cooled and filtered washing the solids with EtOAc (20 ml).
  • the aqueous phase was extracted repeatedly with DCM; the combined DCM extracts were diluted with MeOH (50ml) and treated with TMS- diazomethane.
  • Pd(Ph 3 P) 4 (37.7 mg, 0.033 mmol) was added to a mixture of 2-bromo-6-methylpyridine (157 mg, 0.913 mmol), 3-(5,5-dimethyl-l,3,2-dioxaborinan-2-yl)-6-methyl-2- pyridinecarbonitrile D67 (150 mg), copper(I) iodide (22.35 mg, 0.117 mmol) and cesium fluoride (198 mg, 1.304 mmol) in 1,4-dioxane (3 ml) at room temperature. The mixture was degassed via 3 vacuum/nitrogen cycles and sonicated briefly to homogenise the reaction mixture which was then heated to 65 °C with shaking for 2 hours.
  • reaction mixture was allowed to reach 23 °C, aqueous 1M NaOH (30 ml) and DCM (20 ml) were added. After the separation of the biphasic system, the aqueous layer was extracted with DCM (3 x 5 ml), the organic phase was filtered through a hydrophobic filter and evaporated under reduced pressure to give a dark oil.
  • ICV from 50/50 to 30/70, ICV 30/70, ICV from 30/70 to 5/95, 10CV 5/95).
  • Adherent Chinese Hamster Ovary (CHO) cells stably expressing the recombinant human Orexin-1 or human Orexin-2 receptors or Rat Basophilic Leukaemia Cells (RBL) stably expressing recombinant rat Orexin-1 or rat Orexin-2 receptors were maintained in culture in Alpha Minimum Essential Medium (Gibco/Invitrogen, cat. no.; 22571-020), supplemented with 10% decomplemented foetal bovine serum (Life Technologies, cat. no. 10106-078) and 400 ⁇ g/mL Geneticin G418 (Calbiochem, cat. no.345810). Cells were grown as monolayers under 95%:5% air:C0 2 at 37 °C.
  • Glucose 5.5 mM; MgCl 2 , 1 mM; CaCl 2 , 2 mM
  • the plates were then incubated at 37 °C for 60 minutes in the dark with 2 ⁇ FLUO-4AM dye to allow cell uptake of the FLUO-4AM, which is subsequently converted by intracellular esterases to FLUO-4, which is unable to leave the cells.
  • FLUO-4AM 2 ⁇ FLUO-4AM dye
  • DMSO dimethylsulfoxide
  • the loaded cells were then incubated for lOmin at 37°C with test compound.
  • FLIPR fluometric imaging plate reader

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Abstract

Cette invention concerne des dérivés d'azabicyclo[4.1.0]hept-4-yle et leur utilisation à titre d'agents pharmaceutiques.
PCT/EP2011/073737 2010-12-28 2011-12-22 Nouveaux composés dotés d'un cœur 3a-azabicyclo[4.1.0]heptane agissant sur les récepteurs d'orexine WO2012089607A1 (fr)

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Cited By (9)

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US9440982B2 (en) 2012-02-07 2016-09-13 Eolas Therapeutics, Inc. Substituted prolines/piperidines as orexin receptor antagonists
US9499517B2 (en) 2012-02-07 2016-11-22 Eolas Therapeutics, Inc. Substituted prolines / piperidines as orexin receptor antagonists
WO2017159669A1 (fr) * 2016-03-15 2017-09-21 塩野義製薬株式会社 Procédé de production d'un dérivé de phénoxyéthanol
GB2558975A (en) * 2017-09-01 2018-07-25 Chronos Therapeutics Ltd New compounds
US10221170B2 (en) 2014-08-13 2019-03-05 Eolas Therapeutics, Inc. Difluoropyrrolidines as orexin receptor modulators
US10828302B2 (en) 2016-03-10 2020-11-10 Janssen Pharmaceutica Nv Methods of treating depression using orexin-2 receptor antagonists
US10894789B2 (en) 2016-02-12 2021-01-19 Astrazeneca Ab Halo-substituted piperidines as orexin receptor modulators
US11059828B2 (en) 2009-10-23 2021-07-13 Janssen Pharmaceutica Nv Disubstituted octahydropyrrolo[3,4-C]pyrroles as orexin receptor modulators
US11660293B2 (en) 2017-09-01 2023-05-30 Chronos Therapeutics Limited Substituted 2-azabicyclo[3.1.1]heptane and 2-azabicyclo[3.2.1]octane derivatives as orexin receptor antagonists

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US11667644B2 (en) 2009-10-23 2023-06-06 Janssen Pharmaceutica Nv Disubstituted octahydropyrrolo[3,4-c]pyrroles as orexin receptor modulators
USRE48841E1 (en) 2009-10-23 2021-12-07 Janssen Pharmaceutica Nv Disubstituted octahydropyrrolo[3,4-c]pyrroles as orexin receptor modulators
US9499517B2 (en) 2012-02-07 2016-11-22 Eolas Therapeutics, Inc. Substituted prolines / piperidines as orexin receptor antagonists
US9896452B2 (en) 2012-02-07 2018-02-20 Eolas Therapeutics, Inc. Substituted prolines/piperidines as orexin receptor antagonists
US9440982B2 (en) 2012-02-07 2016-09-13 Eolas Therapeutics, Inc. Substituted prolines/piperidines as orexin receptor antagonists
US10221170B2 (en) 2014-08-13 2019-03-05 Eolas Therapeutics, Inc. Difluoropyrrolidines as orexin receptor modulators
US11434236B2 (en) 2016-02-12 2022-09-06 Astrazeneca Ab Halo-substituted piperidines as orexin receptor modulators
US10894789B2 (en) 2016-02-12 2021-01-19 Astrazeneca Ab Halo-substituted piperidines as orexin receptor modulators
US11241432B2 (en) 2016-03-10 2022-02-08 Janssen Pharmaceutica Nv Methods of treating depression using orexin-2 receptor antagonists
US10828302B2 (en) 2016-03-10 2020-11-10 Janssen Pharmaceutica Nv Methods of treating depression using orexin-2 receptor antagonists
US10472312B2 (en) 2016-03-15 2019-11-12 Shionogi & Co., Ltd. Method for producing phenoxyethanol derivative
EA039048B1 (ru) * 2016-03-15 2021-11-26 Сионоги Энд Ко., Лтд. Способ получения производных феноксиэтанола
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CN108137457B (zh) * 2016-03-15 2022-09-06 盐野义制药株式会社 苯氧乙醇衍生物的制造方法
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