WO2008119711A1 - Composés de benzimidazolone substitués qui ont une activité au niveau du récepteur m1 et leurs utilisations en médecine - Google Patents

Composés de benzimidazolone substitués qui ont une activité au niveau du récepteur m1 et leurs utilisations en médecine Download PDF

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Publication number
WO2008119711A1
WO2008119711A1 PCT/EP2008/053589 EP2008053589W WO2008119711A1 WO 2008119711 A1 WO2008119711 A1 WO 2008119711A1 EP 2008053589 W EP2008053589 W EP 2008053589W WO 2008119711 A1 WO2008119711 A1 WO 2008119711A1
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WIPO (PCT)
Prior art keywords
group
compound
disorder
formula
compounds
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Application number
PCT/EP2008/053589
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English (en)
Inventor
Brian Budzik
David Gwyn Cooper
Ian Thomson Forbes
Vincenzo Garzya
Jian Jin
Graham Walker
Paul Adrian Wyman
Zheng Yang
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Glaxo Group Limited
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.)
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Application filed by Glaxo Group Limited filed Critical Glaxo Group Limited
Publication of WO2008119711A1 publication Critical patent/WO2008119711A1/fr

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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
    • C07D405/14—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 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia

Definitions

  • Cholinergic replacement therapy has largely been based on the use of acetylcholinesterase inhibitors to prevent the breakdown of endogenous acetylcholine. These compounds have shown efficacy versus symptomatic cognitive decline in the clinic, but give rise to side effects resulting from stimulation of peripheral muscarinic receptors including disturbed gastrointestinal motility and nausea.
  • M 1 receptor agonists have been sought for the symptomatic treatment of cognitive decline. More recently, a number of groups have shown that muscarinic receptor agonists display an atypical antipsychotic-like profile in a range of pre-clinical paradigms.
  • the muscarinic agonist, xanomeline reverses a number of dopamine driven behaviours, including amphetamine induced locomotion in rats, apomorphine induced climbing in mice, dopamine agonist driven turning in unilateral 6-OH-DA lesioned rats and amphetamine- induced motor unrest in monkeys (without EPS liability).
  • M 1 receptor agonists are known, for example in WO2007/036718, WO2007/036715, WO2007/03671 1 , WO2007/107566, WO2007/107567 and WO2007/107565.
  • WO2007/036718 WO2007/036715
  • WO2007/03671 1 WO2007/107566
  • WO2007/107567 WO2007/107565
  • WO2007/107565 WO2007/107565
  • the invention provides a compound of formula (I) or a salt thereof:
  • R 5 is selected from hydrogen, halogen, cyano, C-i- ⁇ alkyl (optionally substituted with one or more fluorine atoms) and C 1-6 alkoxy (optionally substituted with one or more fluorine atoms);
  • R 6 is selected from hydrogen, halogen, cyano, C-i- ⁇ alkyl (optionally substituted with one or more fluorine atoms), C 1-6 alkylsulfonyl, C 3-6 cycloalkyl (optionally substituted with one or more fluorine atoms) and C 1-6 alkoxy (optionally substituted with one or more fluorine atoms);
  • alkyl refers to straight or branched hydrocarbon chains containing the specified number of carbon atoms.
  • C 1-6 alkyl means a straight or branched alkyl containing at least 1 , and at most 6, carbon atoms.
  • C 1-4 alkyl means a straight or branched alkyl containing at least 1 , and at most 4, carbon atoms.
  • Examples of “C 1-6 alkyl” include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isobutyl, isopropyl, t-butyl and 1 ,1-dimethylpropyl.
  • substituted refers to substitution with the named substituent or substituents, multiple degrees of substitution being allowed unless otherwise stated. For example, there may be 1 , 2 or 3 substituents on a given substituted group. For example, if R 5 is a Ci -6 alkyl group, it may be substituted by 1 , 2, 3 or 4 fluoro groups; and if R 5 is a Ci -6 alkoxy group, it may be substituted by 1 , 2, 3 or 4 fluoro groups.
  • R 5 is selected from hydrogen, chloro, bromo, fluoro, Ci -4 alkyl (optionally substituted with one or more fluorine atoms) and Ci -4 alkoxy.
  • R 5 is selected from hydrogen, chloro, bromo, fluoro, Ci -4 alkyl (optionally substituted with one, two or three fluorine atoms) and Ci -4 alkoxy. In one embodiment, R 5 is selected from hydrogen, chloro, bromo, fluoro, methyl, ethyl, methoxy and trifluoromethyl.
  • R 5 is hydrogen
  • R 6 is selected from chloro, bromo, fluoro, methyl, ethyl, isopropyl, cyclopropyl, methoxy, trifluoromethoxy and trifluoromethyl. In one embodiment R 6 is selected from chloro, fluoro, methyl, cyclopropyl, methoxy, trifluoromethoxy and trifluoromethyl.
  • R 6 is selected from chloro, methyl and methoxy. In a further embodiment R 6 is methyl.
  • Q is selected from hydrogen and C 1-3 alkyl. In one embodiment, Q is hydrogen or methyl. In one embodiment, Q is hydrogen.
  • Q is hydrogen or Ci -6 alkyl
  • Q is hydrogen or Ci -6 alkyl
  • R 4 is hydrogen or fluoro
  • R 6 is selected from hydrogen, halogen, C 1-6 alkyl, Ci_6 alkyl substituted with one or more fluorine atoms, C 3-6 cycloalkyl, C 3-6 cycloalkyl substituted with one or more fluorine atoms, C 1-6 alkoxy and C 1-6 alkoxy substituted with one or more fluorine atoms, and
  • Solvates of the compounds of formula (I) and solvates of the salts of compounds of formula (I) are included within the scope of the present invention.
  • the term "solvate” refers to a complex of variable stoichiometry formed by a solute (in this invention, a compound of formula (I) or a salt thereof) and a solvent.
  • solute in this invention, a compound of formula (I) or a salt thereof
  • solvents in which they are reacted or from which they are precipitated or crystallised.
  • solvents for the purpose of the invention may not interfere with the biological activity of the solute.
  • suitable solvents include, but are not limited to, water, methanol, ethanol and acetic acid.
  • the compounds of formula (I) may have the ability to crystallise in more than one form. This is a characteristic known as polymorphism, and it is understood that such polymorphic forms (“polymorphs”) are within the scope of formula (I). Polymorphism generally can occur as a response to changes in temperature or pressure or both and can also result from variations in the crystallisation process. Polymorphs can be distinguished by various physical characteristics known in the art such as x-ray diffraction patterns, solubility, and melting point.
  • R 4 is a group R 4 as previously defined, or a group convertible to R 4
  • R 5 is a group R 5 as previously defined, or a group convertible to R 5
  • R 6 is a group R 6 as previously defined, or a group convertible to R 6
  • n 0 or 2.
  • the reaction is carried out under conditions suitable for reductive alkylation.
  • the reductive alkylation reaction is typically carried out using sodium triacetoxyborohydride in dichloroethane, optionally in the presence of triethylamine, and optionally in the presence of titanium tetraisopropoxide.
  • sodium cyanoborohydride can be used as the reducing reagent in solvents such as methanol or ethanol, or the reductive alkylation can be effected under catalytic hydrogenation conditions using a palladium catalyst.
  • the compounds (II) and (III) can be condensed under dehydrating conditions e.g. molecular sieves or magnesium sulfate, and the resultant imine or enamine reduced using for example sodium borohydride or by catalytic hydrogenation.
  • the invention provides a general process (D) for preparing compounds of formula (I) which process comprises:
  • 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; and Eating Disorder Not Otherwise Specified (307.50);
  • the invention provides a method of treating a psychotic disorder which comprises administering to a mammal in need thereof an effective amount of a compound of formula (I) as hereinbefore described or a pharmaceutically acceptable salt thereof.
  • the invention provides a method of treating schizophrenia, which comprises administering to a mammal in need thereof an effective amount of a compound of formula (I) as hereinbefore described or a pharmaceutically acceptable salt thereof.
  • the mammal is a human.
  • the invention provides at least one antipsychotic agent for adjunctive therapeutic administration for the treatment of a psychotic disorder in a pateient recieving therapeutic administration of compounds of formula (I) or a pharmaceutically acceptable salt thereof.
  • the invention further provides at least one antipsychotic agent for adjunctive therapeutic administration for the treatment of a psychotic disorder in a patient receiving therapeutic administration of compounds of formula (I) or a pharmaceutically acceptable salt thereof.
  • the invention further provides the use of at least one antipsychotic agent in the manufacture of a medicament for simultaneous therapeutic administration with compounds of formula (I) or a pharmaceutically acceptable salt thereof in the treatment of a psychotic disorder.
  • the invention further provides at least one antipsychotic agent for simultaneous therapeutic administration with compounds of formula (I) or a pharmaceutically acceptable salt thereof in the treatment of a psychotic disorder.
  • the invention provides the use of a compound of the present invention in the manufacture of a medicament for adjunctive therapeutic administration for the treatment of a psychotic disorder in a patient receiving therapeutic administration of an active ingredient selected from the group consisting of: a mood stabiliser, an antidepressant, an anxiolytic, a drug for extrapyrimidal side effects and a cognitive enhancer.
  • an active ingredient selected from the group consisting of: a mood stabiliser, an antidepressant, an anxiolytic, a drug for extrapyrimidal side effects and a cognitive enhancer.
  • the invention also provides a compound of the present invention for adjunctive therapeutic administration for the treatment of a psychotic disorder in a patient receiving therapeutic administration of an active ingredient selected from the group consisting of: a mood stabiliser, an antidepressant, an anxiolytic, a drug for extrapyrimidal side effects and a cognitive enhancer.
  • an active ingredient selected from the group consisting of: a mood stabiliser, an antidepressant, an anxiolytic, a drug for extrapyrimidal side effects and a cognitive enhancer.
  • the invention provides a method of treatment of a psychotic disorder by adjunctive therapeutic administration of an active ingredient selected from the group consisting of: a mood stabiliser, an antidepressant, an anxiolytic, a drug for extrapyrimidal side effects and a cognitive enhancer to a patient receiving therapeutic administration of a compound of the present invention.
  • the invention provides a method of treatment of a psychotic disorder by simultaneous therapeutic administration of a compound of the present invention in combination with an active ingredient selected from the group consisting of: a mood stabiliser, an antidepressant, an anxiolytic, a drug for extrapyrimidal side effects and a cognitive enhancer.
  • the invention further provides the use of a compound of the present invention for simultaneous therapeutic administration with an active ingredient selected from the group consisting of: a mood stabiliser, an antidepressant, an anxiolytic, a drug for extrapyrimidal side effects and a cognitive enhancer in the treatment of a psychotic disorder.
  • an active ingredient selected from the group consisting of: a mood stabiliser, an antidepressant, an anxiolytic, a drug for extrapyrimidal side effects and a cognitive enhancer in the treatment of a psychotic disorder.
  • the invention further provides an active ingredient selected from the group consisting of: a mood stabiliser, an antidepressant, an anxiolytic, a drug for extrapyrimidal side effects and a cognitive enhancer for simultaneous therapeutic administration with a compound of the present invention for the treatment of a psychotic disorder.
  • a mood stabiliser an antidepressant, an anxiolytic, a drug for extrapyrimidal side effects and a cognitive enhancer for simultaneous therapeutic administration with a compound of the present invention for the treatment of a psychotic disorder.
  • antipsychotic drugs include promazine (available under the tradename SPARINE®), triflurpromazine (available under the tradename VESPRIN®), chlorprothixene (available under the tradename TARACTAN®), droperidol (available under the tradename INAPSINE®), acetophenazine (available under the tradename TINDAL®;), prochlorperazine (available under the tradename COMPAZINE®), methotrimeprazine (available under the tradename NOZI NAN®), pipotiazine (available under the tradename PIPOTRIL®), iloperidone, pimozide and flupenthixol.
  • promazine available under the tradename SPARINE®
  • triflurpromazine available under the tradename VESPRIN®
  • chlorprothixene available under the tradename TARACTAN®
  • droperidol available under the tradename INAPSINE®
  • acetophenazine available under the tradename TINDAL®
  • Mood stabilisers which may be used in the therapy of the present invention include lithium, sodium valproate/valproic acid/divalproex, carbamazepine, lamotrigine, gabapentin, topiramate, oxcarbazepine and tiagabine.
  • Drugs for extrapyramidal side effects which may be used in the therapy of the present invention include anticholinergics (such as benztropine, biperiden, procyclidine and trihexyphenidyl), antihistamines (such as diphenhydramine) and dopaminergics (such as amantadine).
  • anticholinergics such as benztropine, biperiden, procyclidine and trihexyphenidyl
  • antihistamines such as diphenhydramine
  • dopaminergics such as amantadine
  • the compounds of the present invention are usually administered as a standard pharmaceutical composition.
  • the present invention therefore provides in a further aspect a pharmaceutical composition comprising a compound of formula (I) as hereinbefore described or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition can be for use in the treatment of any of the conditions described herein.
  • the invention provides a process for preparing a pharmaceutical composition, the process comprising mixing a compound of formula (I) as hereinbefore described or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers.
  • 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.
  • treatment includes prophylaxis, where this is appropriate for the relevant condition(s).
  • Results were imported into ActivityBase data analysis suite (ID Business Solution Inc., Parsippany, NJ) where the curves were analysed by non-linear curve fitting and the resulting pEC 5 o/plC 5 o were calculated.
  • the intrinsic activities of agonist compounds were calculated as percentage of maximum FLIPR response induced by acetylcholine (ie using acetylcholine at EC 10O as the control).
  • the exemplified compound below was tested in the above assays A1 and B1 and was found to have an average pEC 50 value of 7.9 at the muscarinic M 1 receptor, and intrinsic activity of greater than or equal to 0.5.
  • the starting material may not necessarily have been prepared from the batch referred to.
  • SCX refers to a sulfonic acid ion exchange resin supplied by Varian. All reactions were either done under argon or can be done under argon, unless stated otherwise (for example hydrogenation reactions).
  • 6-Methyl-1-(4-piperidinyl)-1 ,3-dihydro-2H-benzimidazol-2-one (D4, 200 mg, 0.87 mmol), 4- oxepanone (1.2 eq., 1.03 mmol, 118 mg), AcOH (1 eq., 0.87 mmol), polymer-supported NaCNBH 3 (3 eq., 2.61 mmol, 0.6 g) were all dissolved into 2 ml of dichloromethane (DCM) and heated at 1 10 0 C in the microwave for 60 minutes. The sample was purified by SCX first and by Mass Directed Auto Prep to afford the free base, 140 mg, 49% as a white solid.
  • DCM dichloromethane

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  • Health & Medical Sciences (AREA)
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  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des composés de formule (I) ou un sel de ceux-ci, formule dans laquelle R4, R5, R6, Q et n sont tels que définis dans le descriptif. L'invention concerne également les utilisations de ces composés comme médicaments, et dans la fabrication de médicaments visant à traiter des troubles psychotiques et des déficiences cognitives. L'invention concerne également des compositions pharmaceutiques comprenant ces composés.
PCT/EP2008/053589 2007-03-29 2008-03-27 Composés de benzimidazolone substitués qui ont une activité au niveau du récepteur m1 et leurs utilisations en médecine WO2008119711A1 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8283364B2 (en) 2005-09-30 2012-10-09 Glaxo Group Limited Compounds which have activity at M1 receptor and their uses in medicine
US8288412B2 (en) 2005-09-30 2012-10-16 Glaxo Group Limited Compounds which have activity at M1 receptor and their uses in medicine
US8288413B2 (en) 2005-09-30 2012-10-16 Glaxo Group Limited Benzimidazolones which have activity at M1 receptor
US8344000B2 (en) 2007-09-20 2013-01-01 Glaxo Group Limited Compounds which have activity at M1 receptor and their uses in medicine

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007036715A2 (fr) * 2005-09-30 2007-04-05 Glaxo Group Limited Composes exerçant une activite au niveau du recepteur m1 et leurs utilisations en medecine
WO2007036711A1 (fr) * 2005-09-30 2007-04-05 Glaxo Group Limited Benzimidazolones exerçant une activite au niveau du recepteur m1
WO2007036718A2 (fr) * 2005-09-30 2007-04-05 Glaxo Group Limited Composes exerçant une activite au niveau du recepteur m1 et leurs utilisations en medecine
WO2007107565A1 (fr) * 2006-03-22 2007-09-27 Glaxo Group Limited Benzimidazoles présentant une activité au niveau du récepteur m1 et leurs utilisations en médecine
WO2007107567A1 (fr) * 2006-03-22 2007-09-27 Glaxo Group Limited Benzimidazoles présentant une activité au niveau du récepteur m1 et leurs utilisations en médecine
WO2007107566A1 (fr) * 2006-03-22 2007-09-27 Glaxo Group Limited Benzimidazoles présentant une activité au niveau du récepteur m1 et leurs utilisations en médecine

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007036715A2 (fr) * 2005-09-30 2007-04-05 Glaxo Group Limited Composes exerçant une activite au niveau du recepteur m1 et leurs utilisations en medecine
WO2007036711A1 (fr) * 2005-09-30 2007-04-05 Glaxo Group Limited Benzimidazolones exerçant une activite au niveau du recepteur m1
WO2007036718A2 (fr) * 2005-09-30 2007-04-05 Glaxo Group Limited Composes exerçant une activite au niveau du recepteur m1 et leurs utilisations en medecine
WO2007107565A1 (fr) * 2006-03-22 2007-09-27 Glaxo Group Limited Benzimidazoles présentant une activité au niveau du récepteur m1 et leurs utilisations en médecine
WO2007107567A1 (fr) * 2006-03-22 2007-09-27 Glaxo Group Limited Benzimidazoles présentant une activité au niveau du récepteur m1 et leurs utilisations en médecine
WO2007107566A1 (fr) * 2006-03-22 2007-09-27 Glaxo Group Limited Benzimidazoles présentant une activité au niveau du récepteur m1 et leurs utilisations en médecine

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8283364B2 (en) 2005-09-30 2012-10-09 Glaxo Group Limited Compounds which have activity at M1 receptor and their uses in medicine
US8288412B2 (en) 2005-09-30 2012-10-16 Glaxo Group Limited Compounds which have activity at M1 receptor and their uses in medicine
US8288413B2 (en) 2005-09-30 2012-10-16 Glaxo Group Limited Benzimidazolones which have activity at M1 receptor
US8481566B2 (en) 2005-09-30 2013-07-09 Glaxo Group Limited Compounds which have activity at M1 receptor and their uses in medicine
US8344000B2 (en) 2007-09-20 2013-01-01 Glaxo Group Limited Compounds which have activity at M1 receptor and their uses in medicine

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