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WO2006050991A1 - Composés ayant une activité au niveau du récepteur nk3 et utilisations de ceux-ci en médecine - Google Patents

Composés ayant une activité au niveau du récepteur nk3 et utilisations de ceux-ci en médecine Download PDF

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Publication number
WO2006050991A1
WO2006050991A1 PCT/EP2005/012207 EP2005012207W WO2006050991A1 WO 2006050991 A1 WO2006050991 A1 WO 2006050991A1 EP 2005012207 W EP2005012207 W EP 2005012207W WO 2006050991 A1 WO2006050991 A1 WO 2006050991A1
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WO
WIPO (PCT)
Prior art keywords
methyl
phenyl
amino
disorder
quinolinecarboxamide
Prior art date
Application number
PCT/EP2005/012207
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English (en)
Inventor
Daniel Marcus Bradley
Roderick Alan Porter
Paul William Smith
Rachel Elizabeth Anne Stead
Antonio Kuok Keong Vong
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Smithkline Beecham Corporation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Smithkline Beecham Corporation filed Critical Smithkline Beecham Corporation
Priority to EP05802078A priority Critical patent/EP1809606A1/fr
Priority to JP2007540606A priority patent/JP2008519800A/ja
Publication of WO2006050991A1 publication Critical patent/WO2006050991A1/fr

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Classifications

    • 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
    • C07D409/04—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 directly linked by a ring-member-to-ring-member bond
    • 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/50—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 4
    • C07D215/52—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 4 with aryl radicals attached in position 2

Definitions

  • the invention relates to antagonism of the NK3 receptor by novel quinoline derivatives.
  • the invention also relates to the use of the derivatives in treating diseases and conditions mediated by activation of the NK3 receptor, compositions containing the derivatives and processes for their preparation.
  • the mammalian peptide Neurokinin B belongs to the Tachykinin (TK) peptide family which also includes Substance P (SP) and Neurokinin A (NKA).
  • TK Tachykinin
  • SP Substance P
  • NKB Neurokinin A
  • peptidic NK3 receptor agonists such as NKB (the endogenous agonist ligand) or senktide
  • NKB the endogenous agonist ligand
  • senktide the endogenous agonist ligand
  • activation of the NK3 receptor has a key role in the modulation of neuronal inputs in airways, skin, spinal cord, gastrointestinal tract and within the central nervous system
  • Selective peptidic NK3 receptor antagonists are known (Drapeau, 1990 Regul. Pept., 31 , 125-135) and thus would be expected to reverse these agonist driven effects.
  • the invention provides a compound of formula (I), a or prodrug thereof:
  • R1 is phenyl or cyclohexyl, either of which is optionally substituted by 1, 2 or 3 halogen atoms, which atoms may be the same or different;
  • R 4 is C ⁇
  • R 5 is phenyl or thienyl, either of which is optionally substituted by 1 , 2 or 3 halogen atoms; and y is 0, 1 or 2; wherein when y is 1 or 2, Y is a halogen atom, and wherein when y is 2 the halogen atoms may be the same or different.
  • any alkyl group may be straight or branched and is of 1 to
  • any carbocyclyl group contains 3 to 8 ring-atoms, and may be saturated, unsaturated or aromatic.
  • the saturated carbocyclyl groups are cyclopropyl, cyclopentyl or cyclohexyl.
  • the unsaturated carbocyclyl groups contain up to 3 double bonds.
  • the aromatic carbocyclyl group is phenyl.
  • the term carbocylic should be similarly construed.
  • carbocyclyl includes any fused combination of carbocyclic groups, for example naphthyl, phenanthryl, indanyl and indenyl.
  • any heterocyclyl group contains 5 to 7 ring-atoms up to 4 of which may be hetero-atoms such as nitrogen, oxygen and sulfur, and may be saturated, unsaturated or aromatic.
  • heterocyclyl groups are tetrahydrofuryl, furyl, thienyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, dioxolanyl, oxazolyl, thiazolyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyranyl, pyridyl, piperidinyl, dioxanyl, morpholino, dithianyl, thiomorpholino, pyridazinyl, pyrimi
  • heterocyclyl includes fused heterocyclyl groups, for example benzimidazolyl, benzoxazolyl, imidazopyridinyl, benzoxazinyl, benzothiazinyl, oxazolopyridinyl, benzofuranyl, quinolinyl, quinazolinyl, quinoxalinyl, dihydroquinazolinyl, benzothiazolyl, phthalimido, benzofuranyl, benzodiazepinyl, indolyl and isoindolyl.
  • heterocyclic should be similarly construed.
  • Halo means fluoro, chloro, bromo or iodo.
  • R 1 is phenyl optionally substituted by 1 , 2 or 3 halogen atoms, which atoms may be the same or different.
  • R ⁇ is ethyl or cyclopropyl. In one embodiment, n is 1.
  • R 5 is phenyl optionally substituted independently by 1 , 2 or 3 halogen atoms.
  • a compound according to the first aspect is of formula (Ia):
  • R 1 , R 2 , n, R 3 , X, R 4 , R 5 , Y and y are as defined for formula (I).
  • Examples of compounds of formula (I) include:
  • the compound is 3- ⁇ [Acetyl(methyl)amino]methyl ⁇ - ⁇ /-[(S)- cyclopropyKS-fluorophenyOmethyl ⁇ -phenyW-quinolinecarboxamide (Example 1 ).
  • substituted means substituted by one or more defined groups.
  • groups may be selected from a number of alternative groups, the selected groups may be the same or different.
  • the term independently means that where more than one substituent is selected from a number of possible substituents, those substituents may be the same or different.
  • Suitable pharmaceutically acceptable salts of the compounds of formula (I) include mono-basic salts with the appropriate acid for example organic carboxylic acids such as acetic, lactic, tartaric, malic and succinic acids; organic sulfonic acids such as methanesulfonic, ethanesulfonic, benzenesulfonic and p-toluenesulfonic acids and inorganic acids such as hydrochloric, sulfuric, phosphoric and sulfamic acids and the like.
  • Some of the compounds of this invention may be crystallised or recrystallised from solvents such as aqueous and organic solvents. In such cases solvates may be formed.
  • This invention includes within its scope stoichiometric solvates including hydrates as well as compounds containing variable amounts of water that may be produced by processes such as lyophilisation. It will be appreciated by those skilled in the art that certain protected derivatives of compounds of formula (I), which may be made prior to a final deprotection stage, may not possess pharmacological activity as such, but may, in certain instances, be administered orally or parenterally and thereafter metabolised in the body to form compounds of the invention which are pharmacologically active. Such derivatives may therefore be described as "prodrugs”. Further, certain compounds of the invention may act as prodrugs of other compounds of the invention. All protected derivatives and prodrugs of compounds of the invention are included within the scope of the invention.
  • prodrugs for the compounds of the present invention examples include: amides, carbamates and sulfonamides.
  • the compounds of the invention may exist in one or more tautomeric forms. All tautomers and mixtures thereof are included in the scope of the present invention.
  • Compounds of the invention may exist in the form of optical isomers, e.g. diastereoisomers and mixtures of isomers in all ratios, e.g. racemic mixtures.
  • the invention includes all such forms, in particular the pure isomeric forms.
  • 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 the invention are intended for use in pharmaceutical compositions it will readily be understood that, in one embodiment, they are each provided in substantially pure form, for example at least 60% pure, more suitably at least 75% pure, eg at least 85%, eg 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; these less pure preparations of the compounds should contain at least 1%, more suitably at least 5%, for example from
  • Suitable amide coupling reagents are a combination of EDC (1-(3- dimethylaminopropyl) 3-ethylcarbodiimide hydrochloride) and HOBt (1- hydroxybenzotriazole hydrate) or HATU (O-7-azabenzotriazol-1-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate).
  • the reaction is carried out in the presence of a suitable base such as triethylamine or diisopropylethylamine in a suitable solvent such as DMF.
  • Compounds of formula (Ha), i.e. compounds of formula (II) when n is 1 , may be prepared in two steps from compounds of formula (IV) according to reaction scheme 2.
  • first step (V) is reacted with a suitable base (such as sodium hydride) followed by addition of compound (IV).
  • the second step is conversion of the methyl ester to the carboxylic acid (Ha).
  • Suitable reaction conditions for the demethylation step comprise treatment with lithium hydroxide at elevated temperature, followed by acidifying with mineral acid.
  • Compounds of formula (IV) may be prepared in two steps from compounds of formula (Vl) according to reaction scheme 3.
  • Compounds of formula (Vl) are firstly converted to the methyl ester using one of a variety of conditions. Suitable conditions comprise treatment with oxalyl chloride in a suitable solvent such as dichloromethane at room temperature catalysed by dimethyl formamide to form the acid choride in situ, followed by treatment with methanol.
  • Compounds of formula (IV) are then prepared by bromination.
  • Suitable reaction conditions are treatment with N-bromosuccinimide and benzoyl peroxide in a suitable solvent (such as dimethyl carbonate) at elevated temperature.
  • Compounds of formula (Vl) may be prepared by treating compounds of formula (VII) with compounds of formula (VIII) according to reaction scheme 4.
  • Suitable reaction conditions comprise adding concentrated hydrochloric acid to a mixture of (VII) and (VIII) in acetic acid at elevated temperatures (about 75 degC), followed by heating under reflux or by heating a mixture of (VII) and (VIII) together with potassium hydroxide in ethanol at 80 degC (J. Med. Chem. 1997, 40, 1794-1807)
  • the compounds of formula (X) are then converted to the amide by reacting with amine (III) using conditions as described in scheme 1 , before deprotecting under suitable conditions such as with trifluoroacetic acid when Prot is tert-butyloxycarbonyl (BOC), followed by reaction with compounds of formula Z-X-R ⁇ where Z is a leaving group such as chlorine, in the presence of a suitable base such as triethylamine, to give compounds of formula (Ib).
  • Compounds of formula (Xl) may be prepared according to reaction scheme 7 from compounds of formula (XII) by reaction with R ⁇ Li (generated in situ from R ⁇ -bromide and tert butyl lithium).
  • NK3 receptor agonists such as NKB (the endogenous agonist ligand) or senktide
  • NKB the endogenous agonist ligand
  • senktide the endogenous agonist ligand
  • the invention provides a compound of the invention for use as a medicament, such as a human medicament.
  • the invention provides the use of a compound of the invention in the manufacture of a medicament for treating or preventing a disease or condition mediated by modulation of the NK3 receptor.
  • the diseases or conditions mediated by modulation of the NK3 receptor are CNS disorders such as depression (which term includes bipolar (manic) depression (including type I and type II), unipolar depression, single or recurrent major depressive episodes with or without psychotic features, catatonic features, melancholic features, atypical features (e.g.
  • a general medical condition including, but not limited to, myocardial infarction, diabetes, miscarriage or abortion); anxiety disorders (including generalised anxiety disorder (GAD), social anxiety disorder (SAD), agitation, tension, social or emotional withdrawal in psychotic patients, panic disorder, and obsessive compulsive disorder); phobias (including agoraphobia and social phobia); psychosis and psychotic disorders (including schizophrenia, schizo-affective disorder, schizophreniform diseases, acute psychosis, alcohol psychosis, autism, delerium, mania (including acute mania), manic depressive psychosis, hallucination, endogenous psychosis, organic psychosyndrome, paranoid and delusional disorders, puerperal psychosis, and psychosis associated with neurodegenerative diseases such
  • cognitivo disorders including attention, orientation, memory (memory disorders, amnesia, amnesic disorders and age-associated memory impairment) and language function, and including cognitive impairment as a result of stroke, Alzheimer's disease, Aids-related dementia or other dementia states, as well as other acute or sub-acute conditions that may cause cognitive decline such as delirium or depression (pseudodementia states)); convulsive disorders such as epilepsy (which includes simple partial seizures, complex partial seizures, secondary generalised seizures, generalised seizures including absence seizures, myoclonic seizures, clonic seizures, tonic seizures, tonic clonic seizures and atonic seizures); psychosexual dysfunction (including inhibited sexual desire (low libido), inhibited sexual arousal or excitement, orgasm dysfunction, inhibited female orgasm and inhibited male orgasm, hypoactive sexual desire disorder (HSDD), female sexual desire disorder (FSDD), and sexual dysfunction side-effects induced by treatment with antidepressants of the SSRI- class); sleep disorders (
  • musculoskeletal pain, post operative pain and surgical pain inflammatory pain and chronic pain
  • pain associated with normally non-painful sensations such as "pins and needles" (paraesthesias and dysesthesias), increased sensitivity to touch (hyperesthesia), painful sensation following innocuous stimulation (dynamic, static or thermal allodynia), increased sensitivity to noxious stimuli (thermal, cold, mechanical hyperalgesia), continuing pain sensation after removal of the stimulation (hyperpathia) or an absence of or deficit in selective sensory pathways (hypoalgesia), pain associated with migrane, and non-cardiac chest pain); and certain CNS-mediated disorders (such as emesis, irritable bowel syndrome and non-ulcer dyspepsia).
  • psychotic disorder includes :-
  • Schizophrenia including the subtypes Paranoid Type (295.30), Disorganised Type (295.10), Catatonic Type (295.20), Undifferentiated Type (295.90) and Residual Type (295.60); Schizophreniform Disorder (295.40); Schizoaffective Disorder (295.70) including the subtypes Bipolar Type and Depressive Type; Delusional Disorder (297.1) including the subtypes Erotomanic Type, Grandiose Type, Jealous Type, Persecutory Type, Somatic Type, Mixed Type and Unspecified Type; Brief Psychotic Disorder (298.8); Shared Psychotic Disorder (297.3); Psychotic Disorder Due to a General Medical Condition including the subtypes With Delusions and With Hallucinations; Substance-Induced Psychotic Disorder including the subtypes With Delusions (293.81) and With Hallucinations (293.82); and Psychotic Disorder Not Otherwise Specified (298.9).
  • 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 Il 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), Substance- Induced Mood Disorder (including the subtypes With Depressive Features, With Manic Features and With Mixed Features) and Mood Disorder Not Otherwise Specified (296.90):
  • Substance-related disorders including Substance Use Disorders such as Substance Dependence, Substance Craving and Substance Abuse; Substance-Induced Disorders such as Substance Intoxication, Substance Withdrawal, Substance-Induced Delirium, Substance-Induced Persisting Dementia, Substance-Induced Persisting Amnestic Disorder, Substance-Induced Psychotic Disorder, Substance-Induced Mood Disorder, Substance-Induced Anxiety Disorder, Substance-Induced sexual Dysfunction, Substance-Induced Sleep Disorder and Hallucinogen Persisting Perception Disorder (Flashbacks); 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,
  • Sleep disorders including primary sleep disorders such as 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
  • Eating disorders such as Anorexia Nervosa (307.1) including the subtypes Restricting Type and Binge-Eating/Purging Type; Bulimia Nervosa (307.51 ) including the subtypes Purging Type and Nonpurging Type; Obesity; Compulsive Eating Disorder; Binge Eating Disorder; and Eating Disorder Not Otherwise Specified (307.50):
  • Autism Spectrum Disorders including Autistic Disorder (299.00), Asperger's Disorder (299.80), Rett's Disorder (299.80), Childhood Disintegrative Disorder (299.10) and Pervasive Disorder Not Otherwise Specified (299.80, including Atypical Autism).
  • Attention-Deficit/Hyperactivity Disorder including the subtypes Attention-Deficit /Hyperactivity Disorder Combined Type (314.01), Attention-Deficit /Hyperactivity Disorder Predominantly Inattentive Type (314.00), Attention-Deficit /Hyperactivity Disorder Hyperactive-Impulse Type (314.01) and Attention-Deficit /Hyperactivity Disorder Not Otherwise Specified (314.9); Hyperkinetic Disorder; Disruptive Behaviour Disorders such as Conduct Disorder including the subtypes childhood-onset type (321.81 ), Adolescent-Onset Type (312.82) and Unspecified Onset (312.89), Oppositional Defiant Disorder (313.81) and Disruptive Behaviour Disorder Not Otherwise Specified; and Tic Disorders such as Tourette's Disorder (307.23):
  • Personality Disorders including the subtypes Paranoid Personality Disorder (301.0), Schizoid Personality Disorder (301.20), Schizotypal Personality Disorder (301 ,22),
  • Enhancement of cognition including the treatment of cognition impairment in other diseases such as schizophrenia, bipolar disorder, depression, other psychiatric disorders and psychotic conditions associated with cognitive impairment, e.g. Alzheimer's disease: and
  • Sexual dysfunctions including sexual Desire Disorders such as Hypoactive Sexual Desire Disorder (302.71 ), and sexual Aversion Disorder (302.79); sexual arousal disorders such as Female sexual Arousal Disorder (302.72) and Male Erectile Disorder (302.72); orgasmic disorders such as Female Orgasmic Disorder (302.73), Male Orgasmic Disorder (302.74) and Premature Ejaculation (302.75); sexual pain disorder such as Dyspareunia (302.76) and Vaginismus (306.51 ); sexual Dysfunction Not Otherwise Specified (302.70); paraphilias such as Exhibitionism (302.4), Fetishism (302.81), Frotteurism (302.89), Pedophilia (302.2), sexual Masochism (302.83), sexual Sadism (302.84), Transvestic Fetishism (302.3), Voyeurism (302.82) and Paraphilia Not Otherwise Specified (302.9); gender identity disorders such as Gender Identity Disorder in Children (302.6) and Gender Identity Disorder in Adolescents or Adults (302.85); and Sexual
  • the diseases or conditions mediated by modulation of the NK3 receptor are depression; anxiety disorders; phobias; psychosis and psychotic disorders; post-traumatic stress disorder; attention deficit hyperactive disorder (ADHD); withdrawal from abuse of drugs including smoking cessation or reduction in level or frequency of such activities; irritable bowel syndrome; cognitive impairment; convulsive disorders; psychosexual dysfunction; sleep disorders; disorders of eating behaviours; neurodegenerative diseases; pain; emesis; irritable bowel syndrome; and non-ulcer dyspepsia.
  • the diseases or conditions mediated by modulation of the NK3 receptor are depression; anxiety disorders; phobias; and psychosis and psychotic disorders (especially schizophrenia, schizo-affective disorder and schizophreniform diseases).
  • references herein to "treatment” extend to prophylaxis, prevention of recurrence and suppression or amelioration of symptoms (whether mild, moderate or severe) as well as the treatment of established conditions.
  • the compound of the invention may be administered as the raw chemical but the active ingredient may be presented as a pharmaceutical formulation.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the invention, in association with one or more pharmaceutically acceptable carrier(s), diluents(s) and/or excipient(s).
  • the carrier, diluent and/or excipient must be "acceptable” in the sense of being compatible with the other ingredients of the composition and not deletrious to the receipient thereof.
  • the compounds of the invention may be administered in conventional dosage forms prepared by combining a compound of the invention with standard pharmaceutical carriers or diluents according to conventional procedures well known in the art. These procedures may involve mixing, granulating and compressing or dissolving the ingredients as appropriate to the desired preparation.
  • compositions of the invention may be formulated for administration by any route, and include those in a form adapted for oral, topical or parenteral administration to mammals including humans.
  • compositions may be formulated for administration by any route.
  • the compositions may be in the form of tablets, capsules, powders, granules, lozenges, creams or liquid preparations, such as oral or sterile parenteral solutions or suspensions.
  • topical formulations of the present invention may be presented as, for instance, ointments, creams or lotions, eye ointments and eye or ear drops, impregnated dressings and aerosols, and may contain appropriate conventional additives such as preservatives, solvents to assist drug penetration and emollients in ointments and creams.
  • the formulations may also contain compatible conventional carriers, such as cream or ointment bases and ethanol or oleyl alcohol for lotions.
  • suitable conventional carriers such as cream or ointment bases and ethanol or oleyl alcohol for lotions.
  • Such carriers may be present as from about 1% up to about 98% of the formulation. More usually they will form up to about 80% of the formulation.
  • Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatine, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants, for example potato starch; or acceptable wetting agents such as sodium lauryl sulphate.
  • the tablets may be coated according to methods well known in normal pharmaceutical practice.
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives, such as suspending agents, for example sorbitol, methyl cellulose, glucose syrup, gelatine, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and, if desired, conventional flavouring or colouring agents.
  • suspending agents for example sorbitol, methyl cellulose, glucose syrup, gelatine, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate
  • Suppositories will contain conventional suppository bases, e.g. cocoa-butter or other glyceride.
  • fluid unit dosage forms are prepared utilising the compound and a sterile vehicle, such as water.
  • a sterile vehicle such as water.
  • the compound depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle.
  • the compound can be dissolved in water for injection and filter- sterilised before filling into a suitable vial or ampoule and sealing.
  • agents such as a local anaesthetic, preservative and buffering agents can be dissolved in the vehicle.
  • the composition can be frozen after filling into the vial and the water removed under vacuum.
  • the dry lyophilised powder is then sealed in the vial and an accompanying vial of water for injection may be supplied to reconstitute the liquid prior to use.
  • Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilisation cannot be accomplished by filtration.
  • the compound can be sterilised by exposure to ethylene oxide before suspending in the sterile vehicle.
  • a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
  • compositions may contain from 0.1% by weight, such as from 10-60% by weight, of the active material, depending on the method of administration. Where the compositions comprise dosage units, each unit may contain from 50-500 mg of the active ingredient.
  • the dosage as employed for adult human treatment may range from 10 to 3000 mg per day, for instance 1500 mg per day depending on the route and frequency of administration. Such a dosage corresponds to 0.1 to 50 mg/kg per day.
  • the optimal quantity and spacing of individual dosages of a compound of the invention will be determined by the nature and extent of the condition being treated, the form, route and site of administration, and the particular mammal being treated, and that such optimums can be determined by conventional techniques. It will also be appreciated by one of skill in the art that the optimal course of treatment, i.e., the number of doses of a compound of the invention given per day for a defined number of days, can be ascertained by those skilled in the art using conventional course of treatment determination tests.
  • the invention includes the following further aspects.
  • the embodiments described for the first aspect extend these further aspects.
  • the disease and conditions described above extend, where appropriate, to these further aspects.
  • a compound of the invention for use in treating or preventing a disease or condition mediated by modulation of the NK3 receptor.
  • a method of treatment or prevention of a disease or condition mediated by modulation of the NK3 receptor in a mammal comprising administering an effective amount of a compound of the invention
  • MS and liquid chromatography MS were recorded on a Micromass MS2 Platform LC spectrometer with Agilent HP1100 liquid delivery system, Gilson 233 autosampler and Sedex 75cc evaporative light scattering detector using a 4 minute run time. All mass spectra were taken under electrospray ionisation (ESI) method unless stated otherwise.
  • HPLC data was recorded on an Agilent 1100 series instrument with C-18 reverse phase column running gradient of 10-90% MeCN/H 2 O (+0.1% TFA) over 14 minutes. All reactions were monitored by thin-layer chromatography on 0.25 mm E.
  • Example 1 3-(rAcetyl(methyl)amino1methyl)- ⁇ /-f(S)-cyclopropyl(3-fluorophenyl)methyll-
  • NK3 binding affinity of the compounds of the invention was determined using the following scintillation proximity assay (SPA) (see H. M. Sarau et al, J. Pharmacol.
  • SPA scintillation proximity assay
  • the NK3 binding affinity for all examples was determined using the above assay.
  • the compounds of the invention antagonize the NK3 receptor. All examples gave a pKj equal to or greater than 7.5. Some compounds gave a pKj equal to or greater than 8.5. Example 1 gave a pKj of 8.6.
  • the therapeutic potential of the compounds of the invention can be assessed by measurement of the reversal of NK3 agonist driven behaviours (e.g. contralateral turning in gerbils as described in Life Sciences 1995, 56, PL27-PL32 and Can. J. Physiol. Pharmacol. 2002, 80, 482-488; or guinea pig wet dog shakes as described in Br. J. Pharmacol. 1997, 122, 715-725) or by mechanistic correlates (e.g. electrophysiology of the dopamine cell firing as described in Gueudet et al., Synapse, 1999, 33, 71-79).
  • mechanistic correlates e.g. electrophysiology of the dopamine cell firing as described in Gueudet et al., Synapse, 1999, 33, 71-79.

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Abstract

L'invention concerne des composés de formule (I), un sel acceptable du point de vue pharmaceutique, un solvate ou un promédicament de ceux-ci : dans laquelle formule R1 est un phényle ou un cyclohexyle, chacun de ceux-ci étant facultativement substitué par 1, 2 ou 3 atomes d'halogène, lesquels atomes peuvent être identiques ou différents ; R2 est un alkyle en C1-6 ou un cycloalkyle en C3-6 ; n est 1 ou 2 ; R3 est un hydrogène, un alkyle en C1-6 ou un cycloalkyle en C3-6 ; X est -(C=O)- ou -SO2- ; R4 est un alkyle en C1-6, un haloalkyle en C1-6, un alcoxy en C1-6, un (alcoxy en C1-6)(alkyle en C1-6), un haloalcoxy en C1-6, un amino, un mono(alkyl en C1-6)amino ou un di(alkyl en C1-6)amino ou bien R4 est un groupe hétérocyclique ou carbocyclique, chacun de ceux-ci étant facultativement substitué indépendamment par un ou plusieurs halogènes, alkyles en C1-6, haloalkyles en C1-6, alcoxy en C1-6 ou haloalcoxy en C1-6 ; R5 est un phényle ou un thiényle, chacun de ceux-ci étant facultativement substitué par 1, 2 ou 3 atomes d'halogène ; et y est 0, 1 ou 2 ; lorsque y est 1 ou 2, Y est un atome d'halogène et lorsque y est 2 les atomes d'halogène peuvent être identiques ou différents. Il est également exposé l'utilisation des composés dans le traitement de maladies et d'affections médiées par l'activation du récepteur NK3, des compositions contenant les dérivés et des procédés pour leur préparation.
PCT/EP2005/012207 2004-11-12 2005-11-10 Composés ayant une activité au niveau du récepteur nk3 et utilisations de ceux-ci en médecine WO2006050991A1 (fr)

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JP2007540606A JP2008519800A (ja) 2004-11-12 2005-11-10 Ｎｋ３受容体で活性を有する化合物およびその医薬における使用

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WO2007039123A2 (fr) * 2005-09-22 2007-04-12 Smithkline Beecham Corporation Traitement combine
WO2007069977A1 (fr) * 2005-12-12 2007-06-21 Astrazeneca Ab Quinoléines alkylsulfonamidiques
WO2008097976A1 (fr) * 2007-02-09 2008-08-14 Kalypsys, Inc. Modulateurs hétérocycliques de tgr5 pour le traitement des maladies
WO2010045948A1 (fr) 2008-10-20 2010-04-29 H. Lundbeck A/S Dérivés d’isoquinolinone comme antagonistes du nk3
US7964733B2 (en) 2005-09-21 2011-06-21 Astrazeneca Ab Alkyl sulfoxide quinolines as NK-3 receptor ligands
WO2011072691A1 (fr) 2009-12-15 2011-06-23 H. Lundbeck A/S Dérivés de pyridone antagonistes de nk3
WO2011110183A1 (fr) 2010-03-12 2011-09-15 H. Lundbeck A/S Dérivés d'azaisoquinolinone à titre d'antagonistes de nk3
US8173639B2 (en) 2007-04-26 2012-05-08 H. Lundbeck A/S Isoquinolinone derivatives as NK3 antagonists
US8242134B2 (en) 2008-09-15 2012-08-14 H. Lundbeck A/S Isoquinolinone derivatives as NK3 antagonists
US8415356B2 (en) 2008-06-23 2013-04-09 H. Lundbeck A/S Isoquinolinone derivatives as NK3 antagonists
US8420667B2 (en) 2008-04-24 2013-04-16 H. Lundbeck A/S Isoquinolinone derivatives as NK3 antagonists
US9475773B2 (en) 2013-04-19 2016-10-25 Astrazeneca Ab NK3 receptor antagonist compound (NK3RA) for use in a method for the treatment of polycystic ovary syndrome (PCOS)
CN108752273A (zh) * 2018-08-17 2018-11-06 湖北欣瑞康医药科技有限公司 一种3-直链烷基羧基取代的喹啉-4-羧酸衍生物的制备方法
EP3915560A1 (fr) 2014-06-25 2021-12-01 Emory University Procédés de gestion d'une peur conditionnée à l'aide d'antagonistes du récepteur de la neurokinine
US11458129B2 (en) 2017-11-02 2022-10-04 California Institute Of Technology Neurokinin antagonists and uses thereof

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Cited By (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7964733B2 (en) 2005-09-21 2011-06-21 Astrazeneca Ab Alkyl sulfoxide quinolines as NK-3 receptor ligands
WO2007039123A2 (fr) * 2005-09-22 2007-04-12 Smithkline Beecham Corporation Traitement combine
WO2007039123A3 (fr) * 2005-09-22 2007-06-21 Smithkline Beecham Corp Traitement combine
WO2007069977A1 (fr) * 2005-12-12 2007-06-21 Astrazeneca Ab Quinoléines alkylsulfonamidiques
JP2009519331A (ja) * 2005-12-12 2009-05-14 アストラゼネカ・アクチエボラーグ アルキルスルホンアミドキノリン
US7608628B2 (en) 2005-12-12 2009-10-27 Astrazeneca Ab Alkylsulphonamide quinolines
AU2006325572B2 (en) * 2005-12-12 2011-02-24 Astrazeneca Ab Alkylsulphonamide quinolines
US8071621B2 (en) 2005-12-12 2011-12-06 Astrazeneca Ab Alkylsulphonamide quinolines
WO2008097976A1 (fr) * 2007-02-09 2008-08-14 Kalypsys, Inc. Modulateurs hétérocycliques de tgr5 pour le traitement des maladies
US8173639B2 (en) 2007-04-26 2012-05-08 H. Lundbeck A/S Isoquinolinone derivatives as NK3 antagonists
US8420667B2 (en) 2008-04-24 2013-04-16 H. Lundbeck A/S Isoquinolinone derivatives as NK3 antagonists
US8415356B2 (en) 2008-06-23 2013-04-09 H. Lundbeck A/S Isoquinolinone derivatives as NK3 antagonists
US8242134B2 (en) 2008-09-15 2012-08-14 H. Lundbeck A/S Isoquinolinone derivatives as NK3 antagonists
US8415373B2 (en) 2008-10-20 2013-04-09 H. Lundbeck A/S Isoquinolinone derivatives as NK3 antagonists
WO2010045948A1 (fr) 2008-10-20 2010-04-29 H. Lundbeck A/S Dérivés d’isoquinolinone comme antagonistes du nk3
US8207347B2 (en) 2009-12-15 2012-06-26 H. Lundbeck A/S Pyridone derivatives as NK3 antagonists
WO2011072691A1 (fr) 2009-12-15 2011-06-23 H. Lundbeck A/S Dérivés de pyridone antagonistes de nk3
WO2011110183A1 (fr) 2010-03-12 2011-09-15 H. Lundbeck A/S Dérivés d'azaisoquinolinone à titre d'antagonistes de nk3
US9475773B2 (en) 2013-04-19 2016-10-25 Astrazeneca Ab NK3 receptor antagonist compound (NK3RA) for use in a method for the treatment of polycystic ovary syndrome (PCOS)
EP3915560A1 (fr) 2014-06-25 2021-12-01 Emory University Procédés de gestion d'une peur conditionnée à l'aide d'antagonistes du récepteur de la neurokinine
US11458129B2 (en) 2017-11-02 2022-10-04 California Institute Of Technology Neurokinin antagonists and uses thereof
US12083109B2 (en) 2017-11-02 2024-09-10 California Institute Of Technology Neurokinin antagonists and uses thereof
CN108752273A (zh) * 2018-08-17 2018-11-06 湖北欣瑞康医药科技有限公司 一种3-直链烷基羧基取代的喹啉-4-羧酸衍生物的制备方法

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