WO2000047576A1 - Derives de cinnamide utilises en tant qu'antagonistes des recepteurs de l'orexine-1 - Google Patents
Derives de cinnamide utilises en tant qu'antagonistes des recepteurs de l'orexine-1 Download PDFInfo
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- WO2000047576A1 WO2000047576A1 PCT/EP2000/001148 EP0001148W WO0047576A1 WO 2000047576 A1 WO2000047576 A1 WO 2000047576A1 EP 0001148 W EP0001148 W EP 0001148W WO 0047576 A1 WO0047576 A1 WO 0047576A1
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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
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- 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
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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 ring carbon atoms
- C07D215/38—Nitrogen atoms
- C07D215/42—Nitrogen atoms attached in position 4
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Definitions
- This invention relates to cinnamide 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; hypothal
- HIV, post-polio syndrome, and post-herpetic neuralgia phantom limb pain; labour pain; cancer pain; post-chemotherapy pain; post-stroke pain; postoperative pain; neuralgia; 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.
- Type 2 diabetics are obese, and diet and exercise are of value in all diabetics.
- the incidence of diagnosed diabetes in westernised countries is typically 5% and there are estimated to be an equal number undiagnosed.
- the incidence of both diseases is rising, demonstrating the inadequacy of current treatments which may be either ineffective or have toxicity risks including cardiovascular effects.
- Treatment of diabetes with sulfonylureas or insulin can cause hypoglycaemia, whilst metformin causes GI side- effects.
- No drug treatment for Type 2 diabetes has been shown to reduce the long-term complications of the disease. Insulin sensitisers will be useful for many diabetics, however they do not have an anti-obesity effect.
- Rat sleep/EEG studies have also shown that central administration of orexin-A, an agonist of the orexin receptors, causes a dose-related increase in arousal, largely at the expense of a reduction in paradoxical sleep and slow wave sleep 2, when administered at the onset of the normal sleep period. Therefore antagonists of its receptor may be useful in the treatment of sleep disorders including insomnia.
- the present invention provides cinnamide 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.
- X and Y are CH, or one of X and Y is N and the other is CH;
- R! represents (Cj-g)alkyl, (C2-6)alkenyl or (Cj.g)alkoxy, any of which may be optionally substituted; halogen, R 8 CO- or NR 9 R 10 CO-;
- R 2 , R 3 , R 4 , R 5 and R 6 independently represent (C 1 _6)alkyl, (C 2 _6)alkenyl, (Cj. g)alkoxy or (C ⁇ _6)alkylthio, any of which may be optionally substituted; hydrogen, halogen, nitro, cyano, aryloxy, aryl(C j _ 6 )alkyloxy, aryl(C ⁇ _ 6 )alkyl, R 8 CO-, R 8 S0 2 NH-, R 8 S0 2 0-, R 8 CON(R! l )-, NR 9 R 10 -, NR 9 R 10 CO-, -COOR 9 , R 1 !
- R ⁇ is hydrogen, (C ] _6)alkyl, (C2-6)alkenyl, (Cj_g)alkoxy or (Cj_6)alkylthio, any of which may be optionally substituted; halogen, hydroxy, nitro, cyano, NR R' "-, NR 9 R ⁇ CO-, N 3 , -OCOR 9 or R 8 CON(R J ] ;
- R° is (C ] .g)alkyl, (C2-6)alkenyl, heterocyclyl, heterocyclyl(C] _g)alkyl, aryl or aryl(C ⁇ _6)alkyl, any of which may be optionally substituted;
- R 9 and R ⁇ independently represent hydrogen, (Cj_6)alkyl, (C2-6)alkenyl, heterocyclyl, heterocyclyl(Cj_6)alkyl, aryl or aryl(C ] _6)alkyl, any of which may be optionally substituted;
- R M hydrogen or (C ⁇ _6)alkyl; and when X and Y are both CH, n is 0, 1, 2, 3 or 4, and when X or Y is N, n is 0, 1, 2 or 3; or a pharmaceutically acceptable salt thereof.
- compounds of formula (I) two specific classes of compounds which may be mentioned are compounds of formula (IA) in which X and Y are CH, and compounds of formula (IB) in which one of X and Y is N and the other is CH.
- a further group of compounds of formula (I) which may be mentioned are those in which R 2 , R 3 , R 4 , R 5 and R 6 independently represent (C ] _6)alkyl, (C2-6)alkenyl, (Cj. g)alkoxy or (C ⁇ alkylthio, any of which may be optionally substituted; hydrogen, halogen, nitro, cyano, aryloxy, aryl(C ⁇ _6)alkyloxy, aryl(C ⁇ _6)alkyl, R 8 CO-, R 8 S ⁇ 2NH-,
- RSCO ⁇ R 1 ] )-, NR 9 R 10 -, NR 9 R 10 CO-, -COOR 9 , heterocyclyl or heterocyclyl(C 1 . 6 )alkyl; or an adjacent pair of R 2 , R 3 , R 4 , R-> and R" together with the carbon atoms to which they are attached form an optionally substituted carbocyclic or heterocyclic ring;
- R 8 is (C j _g)alkyl or aryl;
- R 9 and R*0 independently represent hydrogen, (C ⁇ _6)alkyl, aryl or aryl(C ⁇ _g)alkyl.
- halogen atom when a halogen atom is present in the compound of formula (I) this may be fluorine, chlorine, bromine or iodine.
- X is preferably N and Y is CH.
- n is preferably 0 or 1.
- n is preferably 1 or 2, also preferred is n is 0 or 1.
- the group R ⁇ is preferably in the 6- or 8-position.
- the groups R* are preferably in the 6- and 8- positions.
- R* is preferably halogen e.g. fluoro, or (C ] _6)alkoxy e.g. methoxy.
- R! is most preferably fluoro.
- R ⁇ to R ⁇ ⁇ comprise a (C j . ⁇ alkyl group, whether alone or forming part of a larger group, e.g. alkoxy or alkylthio
- the alkyl group may be straight chain, branched or cyclic, it preferably contains 1 to 4 carbon atoms and is most preferably methyl or ethyl.
- R* to R*0 comprise a (C2_6)alkenyl group, whether alone or forming part of a larger group
- the alkenyl group may be straight chain, branched or cyclic, it preferably contains 2 to 4 carbon atoms and is most preferably allyl.
- alkylthio groups include one or more substituents selected from halogene.g. fluoro, (C j. 4)alkoxy e.g. methoxy, hydroxy, carboxy and (C ] _g)alkyl esters thereof, amino, mono- or di- (C] summong)alkylamino and cyano.
- aryl when used herein the term "aryl”, whether alone or forming part of a larger group, includes optionally substituted aryl groups such as phenyl and naphthyl, preferably phenyl.
- the aryl group may contain up to 5, more preferably 1, 2 or 3 optional substituents.
- suitable substituents for aryl groups include halogen, (C]_4)alkyl e.g. methyl, (Ci _
- the heterocyclyl group is preferably a 5- to 10-membered monocyclic or bicyclic ring, which may be saturated or unsaturated, for example containing 1, 2 or 3 heteroatoms selected from oxygen, nitrogen and sulfur; for example pyrrolidine, oxazole, morpholine, pyrimidine or phthalimide. A ring containing one or two nitrogen atoms is especially preferred.
- the heterocyclyl group may contain up to 5, more preferably 1, 2 or 3 optional substituents. Examples of suitable substituents for heterocyclyl groups include halogen, (C j -4)alkyl e.g. methyl, (Cj_4)haloalkyl e.g. trifiuoromethyl, (Cj_4)alkoxy e.g. methoxy, (C j _4)alkoxy(C j .
- alkyl e.g. methoxymethyl. hydroxy, carboxy, amino, nitro, arylsulfonyl g. p- toluenesulfonyl, and (C ] _4)alkylsulfonyl e.g. methanesulfonyl.
- R 2 to R" When an adjacent pair of R 2 to R" together with the carbon atoms to which they are attached form a carbocyclic or heterocyclic ring this is preferably a 5- to 7-membered ring, which may be aromatic or non-aromatic.
- Heterocyclic rings preferably contain 1, 2 or 3 heteroatoms selected from oxygen, nitrogen and sulfur; for example oxazole, imidazole, thiophene, pyran, dioxan, pyrrole or pyrrolidine.
- a ring containing one nitrogen atom or two oxygen atoms is preferred.
- a carbocyclic or heterocyclic ring formed by an adjacent pair of R 2 to R" together with the carbon atoms to which they are attached may be optionally substituted on carbon or nitrogen by one or more substituents, e.g. up to 3 substituents.
- R a and R ⁇ are independently selected from hydrogen and (C ⁇ _4)alkyl.
- R 2 to R" independently represent hydrogen, halogen, (C ⁇ _g)alkoxy e.g.
- R 2 to R is other than hydrogen; or an adjacent pair of R 2 to R" together with the carbon atoms to which they are attached form an optionally substituted 5- to 7-membered heterocyclic ring, e.g. a 6- or 7-membered non-aromatic heterocyclic ring or a 5- or 6-membered aromatic heterocyclic ring.
- a further preferred group of compounds are those in which R' is other than hydrogen.
- a further preferred group of compounds are those in which R-> or R" represent hydrogen.
- a further preferred group of compounds are those in which R 4 and R" represent hydrogen.
- a preferred group of compounds are those in which either P and R 4 , or R 3 and R ⁇ are other than hydrogen.
- a further preferred group of compounds are those in which either R 2 or R 2 and R 3 are other than hydrogen.
- Particular compounds according to the invention include those mentioned in the examples and their pharmaceutically acceptable salts.
- 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 for example acid addition salts formed with inorganic acids e.g. hydrochloric, hydrobromic, sulfuric, 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.
- the invention extends to all isomeric forms including stereoisomers and geometric isomers of the compounds of formula (I) including enantiomers and mixtures thereof e.g. racemates.
- 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.
- 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.
- R 1 to R1' when other than R! to R respectively to R to R?, and/or forming a pharmaceutically acceptable salt thereof.
- Suitable examples of groups A and B are:
- reaction is generally effected in the presence of an agent such as 0-(7-azabenzotriazol- 1 -yl)- 1,1,3 ,3-tetramethyluronium hexafluorophosphate and in the presence of a base such as di-isopropylethylamine at ambient or elevated temperature.
- an agent such as 0-(7-azabenzotriazol- 1 -yl)- 1,1,3 ,3-tetramethyluronium hexafluorophosphate
- a base such as di-isopropylethylamine at ambient or elevated temperature.
- reaction is generally effected in the presence of a reagent such as 4-dimethylaminopyridine at ambient or elevated temperature in a solvent such as dichloromethane or pyridine.
- a reagent such as 4-dimethylaminopyridine at ambient or elevated temperature in a solvent such as dichloromethane or pyridine.
- reaction is generally effected in the presence of a reagent such as diphenylphosphoryl azide and in the presence of a base such as triethylamine at ambient or elevated temperature as appropriate.
- a reagent such as diphenylphosphoryl azide
- a base such as triethylamine
- B is halogen it is preferably bromo or iodo.
- a compound of formula (IV) is coupled with a compound of formula (III) a suitable base is triethylamine and the reaction is suitably carried out at room temperature or elevated temperature, preferably at an elevated temperature for example reflux.
- Suitable palladium catalysts include palladium acetate.
- a suitable phosphine is tri-o-tolylphosphine.
- RI to R ⁇ respectively include compounds where one or more of R 2 to R" are OH orNH2; and compounds where an adjacent pair of R 2 to R" together with the carbon atoms to which they are attached represent a fused pyrrole ring which is unsubstituted on nitrogen, where treatment with a base, e.g. sodium hydride, and reaction with an electrophile, e.g. methyl iodide, benzyl chloride or benzenesulfonyl chloride, affords the corresponding substituent on the pyrrole nitrogen.
- a base e.g. sodium hydride
- an electrophile e.g. methyl iodide, benzyl chloride or benzenesulfonyl chloride
- Compounds of formula (IV) are known compounds or can be prepared analogously to known compounds.
- the compounds of formula (I) may be prepared singly or as compound libraries comprising at least 2, for example 5 to 1,000 compounds, and more preferably 10 to 100 compounds of formula (I).
- Libraries of compounds of formula (I) 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 salts thereof.
- Novel intermediates of formula (II), (III) and (IV) are also part of this invention.
- Pharmaceutically acceptable salts may be prepared conventionally by reaction with the appropriate acid or acid derivative.
- the compounds of formula (I) and their pharmaceutically acceptable salts are useful for the treatment of diseases or disorders where an antagonist of a human orexin receptor is required especially feeding disorders, 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; and sleep disturbances associated with such diseases as neurological disorders, neuropathic pain, 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; bulimia; and hypopituitarism.
- the compounds of formula (I) and their pharmaceutically acceptable salts are particularly useful for the treatment of obesity, including obesity associated with Type 2 diabetes, and sleep disorders.
- diseases or disorders which may be treated in accordance with the invention include disturbed biological and circadian rhythms; adrenohypophysis disease; hypophysis disease; hypophysis tumor / adenoma; adrenohypophysis hypofunction; functional or psychogenic amenorrhea; adrenohypophysis hyperfunction; migraine; hyperalgesia; pain; enhanced or exaggerated sensitivity to pain such as hyperalgesia, causalgia and allodynia; acute pain; burn pain; atypical facial pain; neuropathic pain; back pain; complex regional pain syndromes I and II; arthritic pain; sports injury pain; pain related to infection, e.g.
- HIV, post-polio syndrome and post-herpetic neuralgia phantom limb pain; labour pain; cancer pain; post-chemotherapy pain; post-stroke pain; post-operative pain; neuralgia; and tolerance to narcotics or withdrawal from narcotics.
- the present 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 salt thereof.
- the present invention also provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment or prophylaxis of diseases or disorders where an antagonist of a human orexin receptor is required.
- the present invention also provides the use of a compound of formula (I), or a pharmaceutically acceptable salt 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 present invention are usually administered as a pharmaceutical composition.
- the present 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) and their pharmaceutically acceptable salts may be administered by any convenient method, for example 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 salts, which are active when given orally can be formulated as liquids or solids, for example syrups, suspensions or emulsions, tablets, capsules and lozenges.
- a liquid formulation will generally consist of a suspension or solution of the compound or physiologically acceptable salt in a suitable liquid carrier(s) for example 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. Examples of such carriers include magnesium stearate, starch, lactose, sucrose and cellulose.
- a composition in the form of a capsule can be prepared using routine encapsulation procedures.
- 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), for example aqueous gums, celluloses, silicates or oils and the dispersion or suspension then filled into a soft gelatin capsule.
- compositions consist of a solution or suspension of the compound or physiologically acceptable salt in a sterile aqueous carrier or parenterally acceptable oil, for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil.
- a sterile aqueous carrier or parenterally acceptable oil for example 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 substance in a physiologically 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 unitary dispensing device such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve which is intended for disposal once the contents of the container have been exhausted.
- the dosage form comprises an aerosol dispenser, it will contain a propellant which can be a compressed gas such as compressed air or an organic propellant such as a fluorochlorohydrocarbon or hydrofluorocarbon.
- the aerosol dosage forms can also take the form of a pump-atomiser.
- compositions suitable for buccal or sublingual administration include tablets, lozenges and pastilles, wherein 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 salt 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; such 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.
- physiologically acceptable salts the above figures are calculated as the parent compound of formula (I).
- Human orexin-A referred to above 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 a process for screening for compounds (antagonists) which inhibit the ligand's activation of the orexin- 1 receptor.
- such screening procedures involve providing appropriate cells which express the orexin- 1 receptor on the surface thereof.
- Such cells include cells from mammals, yeast, Drosophila or E. coli.
- a polynucleotide encoding the orexin- 1 receptor is employed to transfect cells to thereby 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. Such a screening technique is described in WO 92/01810. Another such screening technique involves introducing RNA encoding the orexin- 1 receptor into Xenopus oocytes to transiently express the receptor. The receptor oocytes may then be contacted with a receptor ligand and a compound to be screened, 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 the surface thereof.
- Such a 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 can be labelled, e.g. by radioactivity.
- the amount of labelled ligand bound to the receptors is measured, e.g. by measuring radioactivity of the receptors. If the compound binds to the receptor as determined by a reduction of labelled ligand which binds to the receptors, the binding of labelled ligand to the receptor is inhibited.
- Yet another screening technique involves the use of FLIPR equipment for high throughput screening of test compounds that inhibit mobilisation of intracellular calcium ions, or other ions, by affecting the interaction of an orexin- 1 receptor ligand with the orexin- 1 receptor.
- the ligand used in the screening method described below to determine the antagonist activity of compounds according to the invention is orexin-A which has the amino acid sequence shown above.
- the reaction mixture was cooled to room temperature and the resulting black oil treated with crushed ice with ice-salt bath cooling.
- the mixture was basified with .880 ammonia and then filtered through kieselguhr, washing with ethyl acetate.
- the organic phase of the filtrate was separated and the aqueous residues washed with ethyl acetate.
- the combined organics were washed with saturated aqueous sodium chloride and dried (Na2S ⁇ 4). Removal of the solvent under reduced pressure afforded the title compound as a waxy yellow solid (1.90g).
- the title compound (0.22g) was prepared from quinoline-4-carboxylic acid (0.17g) and 3-(3,4-dihydro-2H-benzo[b][l,4]dioxepin-6-yl) acrylic acid (0.22g) (WO98/25606) according to the method of Example 1.
- the title compound (0.088 g) was prepared from 4-quinolinecarboxylic acid (0.500g) and (E)-3-(4-chlorophenyl)acrylic acid (0.509g) according to the method of Example 9. The product was converted to the hydrochloride.
- Example 13 (E)-3-(3-Methylphenyl)-N-quinolin-4-yl acrylamide hydrochloride
- the title compound (0.156g) was prepared from quinoline-4-carboxylic acid (0.500g) and 3-(3-methylphenyl)acrylic acid (0.452g) according to the method of Example 9. The product was converted to the hydrochloride.
- Example 14 (E)-3-(3-N,N-DimethyIaminophenyl)-N-quinolin ⁇ 4-yl acrylamide
- D3 (0.32 g), 3-bromo-N,N-dimethylaniline (0.32g), palladium (II) acetate (0.02g), tris(o-tolyl)phosphine (0.05g) and triethylamine (0.24g) in acetonitrile (7ml) was boiled for 5h.
- the mixture was cooled to room temperature, diluted with dichloromethane and washed with water and brine.
- the organic phase was dried (MgS ⁇ 4) and solvent removed at reduced pressure. The residue was triturated with dichloromethane to give the title compound (0.283g) as a pale green solid.
- 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 at 37°C in 5% C02- 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 KC1, 1.5 mM CaCl 2 , 1.2 mM
- Antagonists were prepared as 10 mM stocks in DMSO (100%>). Antagonist IC50 values (the concentration of compound needed to inhibit
- K b IC 5 o/(l+([3/EC 5 o]) where EC50 was the potency of human orexin-A determined in the assay (in nM terms) and IC50 is expressed in molar terms.
- the compounds of Examples 1, 7, 17 and 18 had a pKb > 6.5 in this assay, and compounds of Examples 20-22 had a pKb > 6.
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Abstract
L'invention concerne un composé de formule (I) ou un sel pharmaceutiquement acceptable de ce composé. Dans la formule (I), X et Y représentent CH, ou bien l'un ou l'autre représente N, l'autre représentant CH; R1 représente alkyle (C¿1-6?), alcényle (C2-6)ou alcoxy (C1-6), lesquels peuvent tous être éventuellement substitués; halogène, R?8¿CO- ou NR?9R10CO-; R2, R3, R4, R5 et R6¿ représentent indépendamment alkyle (C¿1-6?), alcényle (C2-6), alcoxy (C1-6) ou alkylthio (C1-6), lesquels peuvent tous être éventuellement substitués; hydrogène, halogène, nitro, cyano, aryloxy, aryl(C1-6)alcoxy, aryl(C1-6)alkyle, R?8CO-, R8SO¿2NH-, R8SO2O-, R?8CON(R11)-, NR9R10-, NR9R10¿CO-, -COOR?9, R11C(=NOR8¿), hétérocyclyle ou hétérocyclyl(C¿1-6?)alkyle; ou une paire adjacente à R?2, R3, R4, R5 et R6¿ formant, avec les atomes de carbones auxquels ils sont fixés, un noyau carbocyclique ou hétérocyclique éventuellement substitué; R7 représente hydrogène, alkyle (C¿1-6?), alcényle (C2-6), alcoxy (C1-6) ou alkylthio (C1-6), lesquels peuvent tous être éventuellement substitués; halogène, hydroxy, nitro, cyano, NR?9R10-, NR9R10¿CO-, N¿3?, -OCOR?9 ou R8CON(R11)-; R8¿ représente alkyle (C¿1-6?), alcényle (C2-6), hétérocyclyle, hétérocyclyl(C1-6)alkyle, aryle ou aryl(C1-6)alkyle, lesquels peuvent tous être éventuellement substitués; R?9 et R10¿ représentent indépendamment hydrogène, alkyle (C¿1-6?), alcényle (C2-6), hétérocyclyle, hétérocyclyl(C1-6)alkyle, aryle ou aryl(C1-6)alkyle, lesquels peuvent tous être éventuellement substitués; R?11¿ représente hydrogène ou alkyle (C¿1-6?); et lorsque X et Y représentent tous deux CH, n est égal à 0, 1, 2, 3 ou 4, et lorsque X ou Y représente N, n est égale à 0, 1, 2 ou 3. L'invention concerne également l'utilisation d'un composé représenté par la formule (I) telle que définie ci-dessus, ou d'un sel pharmaceutiquement acceptable dudit composé, dans la préparation d'un médicament destiné au traitement ou à la prophylaxie des maladies ou troubles nécessitant l'utilisation d'un antagoniste d'un récepteur humain de l'oréxine.
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DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
122 | Ep: pct application non-entry in european phase |