WO2008119714A1 - Composés qui ont une activité au niveau du récepteur m1 et leurs utilisations en médecine - Google Patents

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

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WO2008119714A1
WO2008119714A1 PCT/EP2008/053593 EP2008053593W WO2008119714A1 WO 2008119714 A1 WO2008119714 A1 WO 2008119714A1 EP 2008053593 W EP2008053593 W EP 2008053593W WO 2008119714 A1 WO2008119714 A1 WO 2008119714A1
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group
compound
disorder
formula
compounds
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PCT/EP2008/053593
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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
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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

  • This invention relates to novel compounds, pharmaceutical compositions containing them and their use in therapy, in particular as antipsychotic agents.
  • Muscarinic acetylcholine receptors are members of the G protein coupled receptor superfamily which mediate the actions of the neurotransmitter acetylcholine in both the central and peripheral nervous system. Five muscarinic receptor subtypes have been cloned, M 1 to M 5 . The muscarinic M 1 receptor is predominantly expressed in the cerebral cortex and hippocampus, although it is also expressed in the periphery e.g. exocrine glands.
  • Muscarinic receptors in the central nervous system play a critical role in mediating higher cognitive processing.
  • Diseases associated with cognitive impairments such as Alzheimer's disease, are accompanied by loss of cholinergic neurons in the basal forebrain.
  • blockade or lesion of central cholinergic pathways results in profound cognitive deficits.
  • 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 1 is C 1-6 alkyl and R 2 is hydrogen
  • R 1 and R 2 together form a group -(CH 2 ) n - where n is 2 or 3;
  • R 4 is selected from hydrogen and fluoro
  • R 5 is selected from hydrogen, halogen, cyano, C 1-6 alkyl (optionally substituted with one or more fluorine atoms) and C 1 ⁇ aIkOXy (optionally substituted with one or more fluorine atoms);
  • R 6 is selected from hydrogen, halogen, cyano, C 1-6 alkyl (optionally substituted with one or more fluorine atoms), C 1-6 alkylsulfonyl, C 3- 6cycloalkyl (optionally substituted with one or more fluorine atoms) and C 1-6 alkoxy (optionally substituted with one or more fluorine atoms); and • Q is selected from hydrogen and C 1-6 alkyl.
  • R 1 is C-i- ⁇ alkyl and R 2 is hydrogen
  • R 1 and R 2 together form a group -(CH 2 ) n - where n is 2 or 3;
  • R 4 is selected from hydrogen and fluoro
  • R 5 is selected from hydrogen, halogen, C h alky! (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, C h alky! (optionally substituted with one or more fluorine atoms), C 3-6 cycloalkyl (optionally substituted with one or more fluorine atoms) and Ci -6 alkoxy (optionally substituted with one or more fluorine atoms).
  • the invention provides a compound of formula (Ib) or a salt thereof:
  • R 1 is C-i- ⁇ alkyl and R 2 is hydrogen
  • R 1 and R 2 together form a group -(CH 2 ) n - where n is 2 or 3;
  • R 6 is selected from hydrogen, halogen, Ci -6 alkyl (optionally substituted with one or more fluorine atoms), Cs- ⁇ 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.
  • Ci -4 alkyl means a straight or branched alkyl containing at least 1 , and at most 4, carbon atoms.
  • Ci -6 alkyl means a straight or branched alkyl containing at least 1 , and at most 3, carbon atoms
  • Examples of "Ci -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.
  • alkoxy refers to a straight or branched alkoxy group containing the specified number of carbon atoms.
  • C-i- ⁇ alkoxy means a straight or branched alkoxy group containing at least 1 , and at most 6, carbon atoms.
  • Examples of "Ci -6 alkoxy” as used herein include, but are not limited to, methoxy, ethoxy, propoxy, prop- 2-oxy, butoxy, but-2-oxy, 1-methylethyl-oxy, 2-methylprop-1-oxy, 2-methylprop-2-oxy, pentoxy or hexyloxy.
  • cycloalkyl refers to a non-aromatic hydrocarbon ring containing the specified number of carbon atoms.
  • C 3-6 cycloalkyl means a non-aromatic carbocyclic ring containing at least three, and at most six, ring carbon atoms.
  • Examples of "C 3 - 6 cycloalkyl” as used herein include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • halogen refers to the elements fluorine (which may be abbreviated to “fluoro” or “F"), chlorine (which may be abbreviated to “chloro” or “Cl”), bromine (which may be abbreviated to “bromo” or “Br”) and iodine (which may be abbreviated to “iodo” or “I”).
  • fluorine which may be abbreviated to "fluoro” or "F
  • chlorine which may be abbreviated to "chloro” or “Cl”
  • bromine which may be abbreviated to "bromo” or “Br”
  • iodine which may be abbreviated to "iodo” or "I”
  • Ci- ⁇ alkylsulfonyl refers to a group SC ⁇ -C ⁇ alky!, wherein Ci- 6 alkyl is as defined above.
  • C 3-6 cycloalkylCi -6 alkyr refers to a group C 3- 6 cycloalkyl-C 1-6 alkyl wherein C 3-6 cycloalkyl and C 1-6 alkyl are as defined above.
  • 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 C 1-6 alkoxy group, it may be substituted by 1 , 2, 3 or 4 fluoro groups.
  • R 1 is Ci -3 alkyl and R 2 is hydrogen. In one embodiment R 1 is selected from methyl and ethyl, and R 2 is hydrogen. In one embodiment, R 1 is methyl and R 2 is hydrogen. In another embodiment, R 1 and R 2 together form a group -(CH 2 ) n - where n is 2 or 3. In one embodiment, R 1 and R 2 together form a group -(CH 2 ) n - where n is 2.
  • R 4 is hydrogen
  • R 5 is selected from hydrogen, halogen, cyano, C 1-6 alkyl (optionally substituted with one, two or three fluorine atoms), and Ci -6 alkoxy (optionally substituted with one, two or three fluorine atoms).
  • 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 ⁇ alkoxy. In one embodiment, R 5 is selected from hydrogen, chloro, bromo, fluoro, methyl, ethyl, methoxy and trifluoromethyl.
  • R 5 is selected from hydrogen and fluoro.
  • R 5 is hydrogen
  • R 6 is selected from hydrogen, halogen, cyano, C 1-6 alkyl (optionally substituted with one or more fluorine atoms (for example one, two or three fluorine atoms)), Cs- ⁇ cycloalkyl (optionally substituted with one or more fluorine atoms (for example one, two or three fluorine atoms)), and C 1-6 alkoxy (optionally substituted with one or more fluorine atoms (for example one, two or three fluorine atoms)).
  • R 6 is selected from H and C 1-6 alkyl.
  • R 6 is selected from hydrogen, chloro, bromo, fluoro, methyl, ethyl, isopropyl, cyclopropyl, methoxy, trifluoromethoxy and trifluoromethyl, for example chloro, fluoro, methyl, cyclopropyl, methoxy, trifluoromethoxy and trifluoromethyl.
  • R 6 is selected from hydrogen, chloro, fluoro, methyl, methoxy, trifluoromethoxy and trifluoromethyl.
  • R 6 is selected from hydrogen, methyl, fluoro, chloro, methoxy and cyclopropyl.
  • R 6 is selected from hydrogen, chloro, methyl and methoxy. In one embodiment, R 6 is selected from hydrogen and methyl. In one embodiment, R 6 is methyl. In one embodiment, R 6 is hydrogen.
  • Q is selected from hydrogen and Ci -3 alkyl. In one embodiment, Q is selected from hydrogen and methyl. In one embodiment, Q is hydrogen.
  • the invention provides a compound of formula (I') or a salt or solvate thereof: wherein:
  • R 1 is Ci -6 alkyl and R 2 is hydrogen or R 1 and R 2 together form a group -(CH 2 ) n - and n is 2 or 3; • R 4 is hydrogen or fluoro;
  • R 5 is selected from hydrogen, halogen, cyano, Ci -6 alkyl, Ci -6 alkyl substituted with one or more fluorine atoms, C 1-6 alkoxy, and C 1-6 alkoxy substituted with one or more fluorine atoms;
  • R 6 is selected from hydrogen, halogen, cyano, C 1-6 alkyl, C 1-6 alkyl substituted with one or more fluorine atoms, C 1-6 alkylsulfonyl, 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
  • R 1 is C 1-6 alkyl and R 2 is hydrogen or R 1 and R 2 together form a group -(CH 2 ) n - and n is 2 or 3;
  • R 4 is hydrogen or fluoro
  • R 5 is selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 alkyl substituted with one or more fluorine atoms, C 1-6 alkoxy, and C 1-6 alkoxy substituted with one or more fluorine atoms; and • R 6 is selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 alkyl substituted with one or more fluorine atoms, C 3-6 CyCl oa Iky I, 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.
  • the invention provides a compound of formula (Ib') or a salt or solvate thereof: wherein:
  • R 1 is C 1-6 alkyl and R 2 is hydrogen or R 1 and R 2 together form a group -(CH 2 ) n - and n is 2 or 3;
  • R 6 is selected from hydrogen, halogen, Ci -6 alkyl, Ci -6 alkyl substituted with one or more fluorine atoms, C3 -6 cycloalkyl, C3 -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.
  • the salt of the compound of formula (I) is a pharmaceutically acceptable salt.
  • the invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof.
  • salts of formula (I) should be pharmaceutically acceptable.
  • Suitable salts will be apparent to those skilled in the art and include for example mono- or di- basic salts formed with inorganic acids e.g. hydrochloric, hydrobromic, sulfuric, nitric, sulfamic phosphoric, hydroiodic, phosphoric or metaphosphoric acid; and with organic acids, such as tartaric, acetic, trifluoroacetic, citric, malic, lactic, fumaric, benzoic, formic, propionic, glycolic, gluconic, maleic, succinic, (1 R)- (-)-IO-camphorsulphonic, (1 S)-(+)-10-camphorsulphonic, isothionic, mucic, gentisic, isonicotinic, saccharic, glucuronic, furoic, glutamic, ascorbic, anthranilic, salicylic, phenylacetic, mandelic, embonic
  • non-pharmaceutically acceptable salts e.g. oxalates
  • the compounds of the present invention may be in the form of their free base or pharmaceutically acceptable salts thereof, particularly the monohydrochloride, monoformate or monotrifluoroacetate salts.
  • Certain of the compounds of formula (I) may form acid addition salts with less than one (for example, 0.5 equivalent of a dibasic acid) or one or more equivalents of an acid.
  • the present invention includes within its scope all possible stoichiometric and non-stoichiometric forms thereof.
  • 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 solvent used is a pharmaceutically acceptable solvant.
  • suitable pharmaceutically acceptable solvents include, without limitation, water, ethanol and acetic acid. Most preferably the solvent used is water. Where the solvent used is water such a solvate may then also be referred to as a hydrate.
  • 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.
  • Possible prodrugs for some compounds of the invention include : esters, carbonate esters, hemi-esters, phosphate esters, nitro esters, sulfate esters, sulfoxides, amides, carbamates, azo-compounds, phosphamides, glycosides, ethers, acetals and ketals.
  • the invention also includes all suitable isotopic variations of a compound of the invention.
  • An isotopic variation of a compound of the invention is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine and chlorine such as 2 H, 3 H, 13 C, 14 C, 15 N,
  • isotopic variations of the invention are useful in drug and/or substrate tissue distribution studies. Tritiated, i.e., 3 H, and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with isotopes such as deuterium, i.e., 2 H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements and hence may be preferred in some circumstances. Isotopic variations of the compounds of the invention can generally be prepared by conventional procedures such as by the illustrative methods or by the preparations described in the Examples hereafter using appropriate isotopic variations of suitable reagents.
  • trans form may be drawn in the following different ways, although both represent the same isomeric form:
  • the individual isomers (cis and trans) and mixtures of these are included within the scope of the present invention.
  • the isomers may be separated one from the other by the usual methods or by methods detailed for the example compounds below. Any given isomer may also be obtained by stereospecific or asymmetric synthesis.
  • the invention also extends to any tautomeric forms and mixtures thereof.
  • the compounds of formula (I) are trans isomers.
  • the compounds of formula (I) are cis isomers.
  • Particular compounds according to the invention include:-
  • the salt is the hydrochloride salt, the trifluoroacetate salt or the formate salt of any of the above compounds.
  • a specific example of a salt of the present invention is: 6-methyl-1- ⁇ 1-[(4/?)-2-methyltetrahydro-2H-pyran-4-yl]-4-piperidinyl ⁇ -1 ,3-dihydro-2H- benzimidazol-2-one hydrochloride.
  • the invention provides a general process (A1 ) for preparing compounds of formula (I), in which Q is H, which process comprises:
  • R 1 is a group R 1 as previously defined, or a group convertible to R 1
  • R 2 is a group R 2 as previously defined
  • 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 .
  • 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.
  • a modification of general process (A1 ) is required where Q is C 1-6 alkyl.
  • a compound of formula (II) can be reacted with a compound of formula (III) in the presence of a source of cyanide, e.g. potassium cyanide or acetone cyanohydrin, to form the cyano intermediate (XXXX) which can be reacted with an alkyl Grignard reagent QMgX to form compounds of formula (I).
  • a source of cyanide e.g. potassium cyanide or acetone cyanohydrin
  • R 1 is a group R 1 as previously defined, or a group convertible to R 1
  • R 2 is a group R 2 as previously defined
  • 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
  • R 4 is a group R 4 as previously defined, or a group convertible to R 4
  • Q is hydrogen or Ci -6 alkyl
  • X is chloro, bromo or iodo.
  • the invention provides a compound of formula (XXXX) or salts thereof, wherein R 1 , R 2 , R 4 , R 5 , and R 6 are as hereinbefore defined.
  • the invention provides a general process (B) for preparing compounds of formula (I) which process comprises:
  • R 1 is a group R 1 as previously defined, or a group convertible to R 1
  • R 2 is a group R 2 as previously defined
  • 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
  • Q is hydrogen or Ci-
  • X and Y both represent leaving groups.
  • X and Y can be the same or different and examples are Cl, PhO, EtO, imidazole.
  • Cl Cl, PhO, EtO, imidazole.
  • this reagent can be generated in situ e.g. from diphosgene or triphosgene.
  • the invention provides a compound of formula (IV) or salts thereof, wherein R 1' , R 2' , R 4' , R 5' , R 6' and Q are as hereinbefore defined.
  • reaction is carried out using standard methodology e.g. reacting the diamine (IV) with the reagent (V) in an inert solvent for example dichloromethane or toluene or dimethylformamide, optionally in the presence of a base such as triethylamine or potassium carbonate, and optionally with heating.
  • an inert solvent for example dichloromethane or toluene or dimethylformamide
  • a base such as triethylamine or potassium carbonate
  • the invention provides a general process (C) for preparing compounds of formula (I) which process comprises:
  • R 1 is a group R 1 as previously defined, or a group convertible to R 1
  • R 2 is a group R 2 as previously defined
  • 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
  • Q is hydrogen or C 1- 6 alkyl
  • Z is a leaving group such as bromo, iodo, chloro or triflate.
  • the invention provides a compound of formula (Vl) or salts thereof, wherein R 1' , R 2' , R 4' , R 5' , R 6' , Z and Q are as hereinbefore defined.
  • the cyclisation reaction can be carried out using a variety of palladium or copper reagents as described in the literature (JACS, 2003, 125, 6653, Tet. Lett., 2004, 45, 8535, or JACS, 2002, 124, 7421 ).
  • the invention provides a general process (D) for preparing compounds of formula (I) which process comprises:
  • R 1 is a group R 1 as previously defined, or a group convertible to R 1
  • R 2 is a group R 2 as previously defined
  • 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
  • Q is hydrogen or Ci- 6 alkyl
  • R is a Ci -5 alkyl group.
  • the invention provides a general process (E) for preparing compounds of formula (I) which process comprises:
  • R 1 is a group R 1 as previously defined, or a group convertible to R 1
  • R 2 is a group R 2 as previously defined
  • 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
  • Q is hydrogen or Ci- 6 alkyl; with diphenylphosphoryl azide or other reagent/combination of reagents to effect the Curtius rearrangement of compound (X), followed by intramolecular cyclisation.
  • the invention provides a compound of formula (X) or salts thereof, wherein R 1 , R 2 , R 4 , R 5 , R 6 and Q are as hereinbefore defined.
  • the Curtius rearrangement is typically carried out by mixing the two reactants in an inert solvent such as toluene, optionally with heating.
  • the invention provides a general process (F) for preparing compounds of formula (I) which process comprises:
  • R 1 is a group R 1 as previously defined, or a group convertible to R 1
  • R 2 is a group R 2 as previously defined
  • 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
  • Q is hydrogen or Ci- 6 alkyl
  • Z is hydroxy or a leaving group such as chloro, bromo or iodo, or alkyl/aryl sulfonate.
  • the benzimidazolone intermediate (Xl) can be deprotonated using a base such as sodium hydride in an inert solvent such as dimethylformamide, and then treated with the alkylating reagent (XII), optionally with heating.
  • R 6 when R 6 is a halogen, it can be converted to an alkoxy, trifluoromethyl or methylsulphonyl group by copper catalysed reaction, using an alcohol, methyl fluorosulfonyl(difluoro)acetate or sodium methanesulphinate, respectively. It may also be converted to an alkyl group with an organometallic reagent, for example an alkylstannane.
  • organometallic reagent for example an alkylstannane.
  • R 6 when R 6 is hydroxy, it may be converted to and alkoxy group by reaction with an alkyl halide or sulfonate, or to trifluoromethoxy by conversion to the xanthate followed by oxidation in the presence of fluoride ion.
  • R 6 when R 6 is methyl, it may be converted to a trifluoromethyl group by chlorination or bromination followed by displacement of the introduced halogens with fluoride.
  • Conversion of R 5 to R 5 or interconversions or R 5 may be accomplished in a manner similar to that indicated for conversion of R 6 to R 6 or interconversions of R 6 .
  • R 4 to R 4 may be accomplished in various ways; for example by displacement of a halide group by fluoride, or by fluorination of an organometallic derivative with a source of electrophilic fluorine such as N-fluorobenzenesulfonimide, or by decomposition of a diazonium tetrafluoroborate.
  • the anthranilic acid or ester starting materials (XVII) are commercially available or can be made by standard methodology.
  • the Curtius rearrangement can be effected using the conditions described under process E.
  • Hydrogenation of the double bond and deprotection of the piperidine nitrogen can be accomplished separately or concomitantly dependent on the precise nature of the protecting group P, to afford the desired product (II).
  • Compounds of formula (VIII) are commercially available or can be prepared by standard methodology.
  • Compounds of formula (XX) are commercially available or can be prepared by standard methodology.
  • Compounds of formula (V) are commercially available e.g. carbonyl diimidazole, phosgene, phosgene solution in toluene, diphosgene, triphosgene, phenyl chloroformate, diethyl carbonate.
  • Phosgene equivalents include carbonyl diimidazole, diphosgene, triphosgene, phenyl chloroformate;
  • Both isocyanates (XXXV) and (XXXVI) can be prepared from the corresponding amines using standard methodology for isocyanate formation wherein R 1 is a group R 1 as previously defined, or a group convertible to R 1 , R 2 is a group R 2 as previously defined, 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 , and Q is hydrogen or C 1-6 alkyl.
  • Palladium and copper catalysts (VII) are commercially available or can be prepared as described in the literature (see references in Process C).
  • Compounds of formula (IX) can be prepared by reductive alkylation of the 3- alkoxycarbonyl-4-piperidone with tetrohydropyran-4-one.
  • R 1 is a group R 1 as previously defined, or a group convertible to R 1
  • R 2 is a group R 2 as previously defined
  • 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
  • Q is hydrogen or can be prepared as shown in Scheme 13. Reductive alkylation of an anthranilic acid or ester (XVII) with the ketone (XXXII), followed if appropriate by hydrolysis of the ester group.
  • the group R 1 in the above described processes is the group R 1 as hereinbefore defined.
  • the group R 2 in the above described processes is the group R 2 as hereinbefore defined.
  • the group R 4 in the above described processes is the group R 4 as hereinbefore defined.
  • the group R 5 in the above described processes is the group R 5 as hereinbefore defined.
  • the group R 6 in the above described processes is the group R 6 as hereinbefore defined.
  • M 1 receptor agonists are said to be useful to ameliorate positive and cognitive symptoms of psychotic disorders such as schizophrenia, schizo-affective disorders, schizophreniform diseases, psychotic depression, mania, acute mania, paranoid and delusional disorders, and cognitive impairment including memory disorders such as Alzheimer's disease without peripheral cholinergic side effects mediated predominantly through M 2 and M 3 receptors.
  • M 1 receptor agonists may also be suitable for combination with other typical and atypical antipsychotics and other actives such as mood stabilisers, antidepressants, anxiolytics, drugs for extrapyramidal side effects and cognitive enhancers, to provide improved treatment of psychotic disorders.
  • the invention provides a compound of formula (I) as hereinbefore described or a pharmaceutically acceptable salt thereof for use in therapy.
  • the invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of a condition wherein agonism of a muscarinic M 1 receptor would be beneficial.
  • the term 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 (31 1 ); 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);
  • Anxiety disorders including Social Anxiety Disorder, Panic Attack, Agoraphobia, Panic Disorder, Agoraphobia Without History of Panic Disorder (300.22), Specific Phobia (300.29) including the subtypes Animal Type, Natural Environment Type, Blood-lnjection- Injury Type, Situational Type and Other Type), Social Phobia (300.23), Obsessive- Compulsive Disorder (300.3), Posttraumatic Stress Disorder (309.81 ), Acute Stress Disorder (308.3), Generalized Anxiety Disorder (300.02), Anxiety Disorder Due to a General Medical Condition (293.84), Substance-Induced Anxiety Disorder and Anxiety Disorder Not Otherwise Specified (300.00);
  • 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; and Substance-Induced Sleep Disorder including the subtypes Insomnia Type, Hypersomnia Type, Parasomnia Type and Mixed Type;
  • 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);
  • Autistic Disorder (299.00); 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
  • 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
  • the compounds of formula (I) may also be useful for the enhancement of cognition, including both the treatment of cognitive impairment on its own and the treatment of cognition impairment in other diseases such as schizophrenia, bipolar disorder, depression, other psychiatric disorders and psychotic conditions associated with cognitive impairment.
  • M 1 agonists may be beneficial.
  • an M 1 agonist may be useful for the alleviation or treatment of the cognitive impairment.
  • the term cognitive impairment includes, for example, impairment of cognitive functions including attention, orientation, learning disorders, memory (i.e. memory disorders, amnesia, amnesic disorders, transient global amnesia syndrome and age-associated memory impairment) and language function; cognitive impairment as a result of stroke, Alzheimer's disease, Huntington's disease, Pick disease, Aids-related dementia or other dementia states such as Multiinfarct dementia, alcoholic dementia, hypotiroidism-related dementia, and dementia associated to other degenerative disorders such as cerebellar atrophy and amyotropic lateral sclerosis; other acute or sub-acute conditions that may cause cognitive decline such as delirium or depression (pseudodementia states) trauma, head trauma, age related cognitive decline, stroke, neurodegeneration, drug-induced states, neurotoxic agents, mild cognitive impairment, age related cognitive impairment, autism related cognitive impairment, Down's syndrome, cognitive deficit related to psychosis, and post-electroconvulsive treatment related cognitive disorders; and dyskinetic disorders such as Parkinson
  • Compounds of formula (I) or pharmaceutically accepatble salts thereof may also be used as memory and/or cognition enhancers in healthy humans with no cognitive and/or memory deficit.
  • the invention provides a compound of formula (I) as hereinbefore described or a pharmaceutically acceptable salt thereof for use in the treatment of a psychotic disorder. In one embodiment, the invention provides a compound of formula (I) as hereinbefore described or a pharmaceutically acceptable salt thereof for use in the treatment of schizophrenia.
  • the invention also provides a compound of formula (I) as hereinbefore described or a pharmaceutically acceptable salt thereof for use in the treatment of cognitive impairment.
  • the invention provides the use of a compound of formula (I) as hereinbefore described or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a condition wherein agonism of the M 1 receptor would be beneficial.
  • the invention provides the use of a compound of formula (I) as hereinbefore described or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a psychotic disorder.
  • the invention provides the use of a compound of formula (I) as hereinbefore described or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of schizophrenia.
  • the invention provides a compound of formula (I) as hereinbefore described or a pharmaceutically acceptable salt thereof in the treatment of a psychotic disorder. In one embodiment, the invention provides a compound of formula (I) as hereinbefore described or a pharmaceutically acceptable salt thereof for the treatment of schizophrenia.
  • the invention also provides the use of a compound of formula (I) as hereinbefore described or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of cognitive impairment.
  • the invention also provides a compound of formula (I) as hereinbefore described or a pharmaceutically acceptable salt thereof for the treatment of cognitive impairment.
  • the invention provides a method of treating a condition where agonism of the M 1 receptor would be beneficial, 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 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 also provides a method of treating cognitive impairment, 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 compounds of formula (I) and pharmaceutically acceptable salts thereof may also be suitable for combination with other actives, such as typical and atypical antipsychotics, mood stabilisers, antidepressants, anxiolytics, drugs for extrapyrimidal side effects and cognitive enhancers to provide improved treatment of psychotic disorders.
  • actives such as typical and atypical antipsychotics, mood stabilisers, antidepressants, anxiolytics, drugs for extrapyrimidal side effects and cognitive enhancers to provide improved treatment of psychotic disorders.
  • adjunctive administration is meant the coterminous or overlapping administration of each of the components in the form of separate pharmaceutical compositions or devices.
  • This regime of therapeutic administration of two or more therapeutic agents is referred to generally by those skilled in the art and herein as adjunctive therapeutic administration; it is also known as add-on therapeutic administration.
  • Any and all treatment regimes in which a patient receives separate but coterminous or overlapping therapeutic administration of the compounds of formula (I) or a pharmaceutically acceptable salt thereof and at least one antipsychotic agent, a mood stabiliser, an antidepressant, an anxiolytic, a drug for extrapyrimidal side effects or a cognitive enhancer are within the scope of the current invention.
  • a patient is typically stabilised on a therapeutic administration of one or more of the components for a period of time and then receives administration of another component.
  • the compounds of formula (I) or a pharmaceutically acceptable salt thereof may be administered as adjunctive therapeutic treatment to patients who are receiving administration of at least one antipsychotic agent, a mood stabiliser, an antidepressant, an anxiolytic, a drug for extrapyrimidal side effects or a cognitive enhancer, but the scope of the invention also includes the adjunctive therapeutic administration of at least one antipsychotic agent, a mood stabiliser, an antidepressant, an anxiolytic, a drug for extrapyrimidal side effects or a cognitive enhancer to patients who are receiving administration of compounds of formula (I) or a pharmaceutically acceptable salt thereof.
  • the combination therapies of the invention may also be administered simultaneously.
  • simultaneous administration is meant a treatment regime wherein the individual components are administered together, either in the form of a single pharmaceutical composition or device comprising or containing both components, or as separate compositions or devices, each comprising one of the components, administered simultaneously.
  • Such combinations of the separate individual components for simultaneous combination may be provided in the form of a kit-of-parts.
  • the invention provides a method of treatment of a psychotic disorder by adjunctive therapeutic administration of compounds of formula (I) or a pharmaceutically acceptable salt thereof to a patient receiving therapeutic administration of at least one antipsychotic agent.
  • the invention provides the use of compounds of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for adjunctive therapeutic administration for the treatment of a psychotic disorder in a patient receiving therapeutic administration of at least one antipsychotic agent.
  • the invention provides compounds of formula (I) or a pharmaceutically acceptable salt thereof for adjunctive therapeutic administration for the treatment of a psychotic disorder in a patient receiving therapeutic administration of at least one antipsychotic agent.
  • the invention further provides compounds of formula (I) or a pharmaceutically acceptable salt thereof for use for adjunctive therapeutic administration for the treatment of a psychotic disorder in a patient receiving therapeutic administration of at least one antipsychotic agent.
  • the invention provides a method of treatment of a psychotic disorder by adjunctive therapeutic administration of at least one antipsychotic agent to a patient receiving therapeutic administration of compounds of formula (I) or a pharmaceutically acceptable salt thereof.
  • the invention provides the use of at least one antipsychotic agent in the manufacture of a medicament 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 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 provides a method of treatment of a psychotic disorder by simultaneous therapeutic administration of compounds of formula (I) or a pharmaceutically acceptable salt thereof in combination with at least one antipsychotic agent.
  • the invention further provides the use of a combination of compounds of formula (I) or a pharmaceutically acceptable salt thereof and at least one antipsychotic agent in the manufacture of a medicament for simultaneous therapeutic administration in the treatment of a psychotic disorder.
  • the invention further provides a combination of compounds of formula (I) or a pharmaceutically acceptable salt thereof and at least one antipsycotic agent for simultaneous therapeutic administration in the treatment of a psychotic disorder.
  • the invention further provides the use of compounds of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for simultaneous therapeutic administration with at least one antipsychotic agent in the treatment of a psychotic disorder.
  • the invention further provides compounds of formula (I) or a pharmaceutically acceptable salt thereof for use for simultaneous therapeutic administration with at least one antipsychotic agent in the treatment of a psychotic disorder.
  • 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 a kit-of-parts for use in the treatment of a psychotic disorder comprising a first dosage form comprising compounds of formula (I) or a pharmaceutically acceptable salt thereof and one or more further dosage forms each comprising an antipsychotic agent for simultaneous therapeutic administration.
  • the invention provides a method of treatment of a psychotic disorder by adjunctive therapeutic administration of a compound of the present invention to 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 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.
  • 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.
  • the invention also provides the use of a compound of the present invention in 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 further provides the use of a compound of the present invention for use 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 the use 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 in the manufacture of a medicament for adjunctive therapeutic administration for the treatment of a psychotic disorder in a patient receiving therapeutic administration of a compound of the present invention.
  • 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 manufacture of a medicament for adjunctive therapeutic administration for the treatment of a psychotic disorder in a patient receiving therapeutic administration of a compound of the present invention.
  • the invention also 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 adjunctive therapeutic administration for the treatment of a psychotic disorder in a patient receiving therapeutic administration of a compound of the present invention
  • the invention also provides the use 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 for adjunctive therapeutic administration for the treatment of a psychotic disorder in a patient receiving therapeutic administration of a compound of the present invention
  • 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 combination of a compound of the present invention and 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 manufacture of a medicament for simultaneous therapeutic administration 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 manufacture of a medicament for simultaneous therapeutic administration in the treatment of a psychotic disorder.
  • the invention further provides a combination of a compound of the present invention and 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 for 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 for simultaneous therapeutic administration for the treatment of a psychotic disorder.
  • the invention further provides the use of a combination of a compound of the present invention and 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 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 for simultaneous therapeutic administration in the treatment of a psychotic disorder.
  • the invention further provides the use of a compound of the present invention in the manufacture of a medicament 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 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 for 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 for the treatment of a psychotic disorder.
  • 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 a compound of the present invention for use 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 the use 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 in the manufacture of a medicament for simultaneous therapeutic administration with a compound of the present invention 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 manufacture of a medicament for simultaneous therapeutic administration with a compound of the present invention 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.
  • the invention further provides the use 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 for simultaneous therapeutic administration with a compound of the present invention 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 for simultaneous therapeutic administration with a compound of the present invention in the treatment of a psychotic disorder.
  • the invention provides a kit-of-parts for use in the treatment of a psychotic disorder comprising a first dosage form comprising a compound of the present invention and one or more further dosage forms each comprising 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.
  • the patient is a human.
  • antipsychotic drugs examples include, but are not limited to: sodium channel blockers; mixed 5HT/dopamine receptor antagonists; mGluR5 positive modulators; D3 antagonists; 5HT6 angatonists; nicotinic alpha-7 modulators; glycine transporter GIyTI inhibitors; D2 partial agonist/D3 antanogist/H3 antagonists; AMPA modulators; NK3 antagonists such as osanetant and talnetant; an atypical antipsychotic, for example clozapine, olanzapine, risperidone, quetiapine, aripirazole, ziprasidone and amisulpride; butyrophenones, such as haloperidol, pimozide, and droperidol; phenothiazines, such as chlorpromazine, thioridazine, mesoridazine, trifluoperazine, perphenazine,
  • tradenames and suppliers of selected antipsychotic drugs that may be suitable for use in the present invention are as follows : clozapine (available under the tradename CLOZARIL®, from Mylan, Zenith Goldline, UDL, Novartis); olanzapine (available under the tradename ZYPREXA®, from Lilly); ziprasidone (available under the tradename GEODON®, from Pfizer); risperidone (available under the tradename RISPERDAL®, from Janssen); quetiapine fumarate (available under the tradename SEROQUEL®, from AstraZeneca); sertindole (available under the tradename SERLECT®); amisulpride (available under the tradename SOLION®, from Sanofi- Synthelabo); haloperidol (available under the tradename HALDOL®, from Ortho-McNeil); haloperidol decanoate (available under the tradename HALDOL decanoate®); halope
  • 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®
  • suitable antipsychotic agents include olanzapine, risperidone, quetiapine, amisulpride, aripiprazole, haloperidol, clozapine, olanzepine, ziprasidone, talnetant and osanetant.
  • 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.
  • Antidepressant drugs which may be used in the therapy of the present invention include serotonin antagonists, CRF-1 antagonists, Cox-2 inhibitor/SSRI dual antagonists; dopamine/noradrenaline/serotonin triple reuptake inhibitors; NK1 antagonists; NK1 and NK2 dual antagonists; NK1/SSRI dual antagonists; NK2 antagonists; serotonin agonists (such as rauwolscine, yohimbine and metoclopramide); serotonin reuptake inhibitors (such as citalopram, escitalopram, fluoxetine, fluvoxamine, femoxetine, indalpine, zimeldine, paroxetine and sertraline); dual serotonin/noradrenaline reuptake inhibitors (such as venlafaxine, reboxetine, duloxetine and milnacipran); Noradrenaline reuptake inhibitors (such as reboxetine);
  • Anxiolytics which may be used in the therapy of the present invention include V1 b antagonists, 5HT7 antagonists and benzodiazepines such as alprazolam and lorazepam.
  • 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
  • Cognitive enhancers which may be used in the therapy of the present invention include example cholinesterase inhibitors (such as tacrine, donepezil, rivastigmine and galantamine), H3 antagonists and muscarinic M 1 agonists (such as cevimeline).
  • cholinesterase inhibitors such as tacrine, donepezil, rivastigmine and galantamine
  • H3 antagonists such as muscarinic M 1 agonists (such as cevimeline).
  • 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.
  • the invention provides a pharmaceutical composition comprising a compound of formula (I) as hereinbefore described or a pharmaceutically acceptable salt thereof in combination with at least 1 antipsychotic, and one or more pharmaceutically acceptable carriers.
  • 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, at least 1 antipsychotic, and one or more pharmaceutically acceptable carriers.
  • the compounds of the invention may be administered by any convenient method, for example by oral, parenteral (e.g. intravenous), buccal, sublingual, nasal, rectal or transdermal administration and the pharmaceutical compositions adapted accordingly.
  • the compounds of the invention 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 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.
  • 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 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.
  • suitable pharmaceutical carrier(s) 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 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 pharmaceutically acceptable aqueous or non-aqueous solvent and are usually presented in single or multidose quantities in sterile form in a sealed container, which can take the form of a cartridge or refill for use with an atomising device.
  • the sealed container may be a 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 fluorochloro- hydrocarbon.
  • 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.
  • 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 may be in unit dose form such as a tablet, capsule or ampoule.
  • Each dosage unit for oral administration contains, for example, from 1 to 250 mg (and for parenteral administration contains, for example, from 0.1 to 25 mg) of a compound of the formula (I) or a pharmaceutically acceptable salt thereof calculated as the free base.
  • the antipsychotic agent component or components used in the adjunctive therapy of the present invention may also be administered in their basic or acidic forms as appropriate or, where appropriate, in the form of a pharmaceutically acceptable salt or other derivative.
  • All solvates and all alternative physical forms of the antipsychotic agent or agents or their salts or derivatives as described herein, including but not limited to alternative crystalline forms, amorphous forms and polymorphs, are also within the scope of this invention.
  • the forms and derivatives are, for example, those which are approved for therapeutic administration as monotherapies, including those mentioned above, but all references to antipsychotic agents herein include all salts or other derivatives thereof, and all solvates and alternative physical forms thereof.
  • compounds of formula (I) or pharmaceutically acceptable salts thereof and the antipsychotic agent or agents or their salts, derivatives or solvates may each be administered in pure form, but each of the components will, for example, be formulated into any suitable pharmaceutically acceptable and effective composition which provides effective levels of the respective component in the body.
  • suitable pharmaceutical compositions for each component is within the skill of the art, and may be the same form or different forms for each of the components.
  • Suitable formulations include, but are not limited to tablets, capsules, powders, granules, lozenges, suppositories, reconstitutable powders, or liquid preparations such as oral or sterile parenteral solutions or suspensions.
  • compounds of formula (I) or their pharmaceutically acceptable salts and the antipsychotic agent or agents and their salts, derivatives or solvates may be administered together in pure form, but the combined components will, for example, be formulated into any suitable pharmaceutically acceptable and effective composition which provides effective levels of each of the components in the body.
  • suitable pharmaceutically acceptable and effective composition which provides effective levels of each of the components in the body.
  • the choice of the most appropriate pharmaceutical compositions for the combined components is within the skill of the art.
  • Suitable formulations include, but are not limited to tablets, sub-lingual tablets, buccal compositions, capsules, powders, granules, lozenges, suppositories, reconstitutable powders, or liquid preparations such as oral or sterile parenteral solutions or suspensions.
  • compositions of each of the components, or of the combination of the components is, for example, in the form of a unit dose.
  • treatment includes prophylaxis, where this is appropriate for the relevant condition(s).
  • CHO-M1 cells were plated (20,000/well) and allowed to grow overnight at 37 degrees. Media was removed and 30 ⁇ L loading buffer (HBSS with 2OmM HEPES, pH 7.4) containing FLIPR Calcium 3 dye (Molecular Devices Co., Sunnyvale, CA) was added according to manufacturer's instructions.
  • loading buffer HBSS with 2OmM HEPES, pH 7.4
  • 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 (i.e. using acetylcholine at EC 1 00 as the control).
  • Receptors and Channels 10 99- 109 in 2x10e5/mL cell suspension with 0.1% virus/cell ratio (v/v).
  • the virus to cell ratio was determined in separate experiments by functional titration to be most appropriate to measure intrinsic activities of partial agonists. After mixing with virus in suspension, cells were then plated (10,000/well) and allowed to grow overnight at 37 degrees. FLIPR experiment was then carried out next day using the same protocol as described above for CHO-M1 cells. Results were imported into ActivityBase data analysis suite where the curves were analysed by non-linear curve fitting and the resulting pEC 50 values were calculated.
  • the intrinsic activities of agonist compounds were calculated as percentage of maximum FLIPR response induced by acetylcholine added as control on the same compound plates, and converted to a fraction between 0 and 1 (i.e. calculated using a 100% max response from a fitted acetylcholine standard curve, containing multiple concentrations, as control).
  • CHO-M1 cells were plated (15,000/well) and allowed to grow overnight at 37 degrees. Media was removed and 30 ⁇ L loading buffer (HBSS with 2.5mM probenicid, 2 ⁇ M Fluo-4, 500 ⁇ M Brilliant Black, pH 7.4) was added. After incubation at 37 degrees for 90 minutes, 10 ⁇ L of the assay buffer (HBSS with 2.5 mM probenecid, pH 7.4) containing test compounds was added to each well on the FLIPR instrument. Calcium response was monitored to determine agonism.
  • loading buffer HBSS with 2.5mM probenicid, 2 ⁇ M Fluo-4, 500 ⁇ M Brilliant Black, pH 7.4
  • the intrinsic activities of agonist compounds were calculated as percentage of maximum FLIPR response induced by acetylcholine added as control on the same compound plates, and converted to a fraction between 0 and 1 (i.e. calculated using a 100% max response from a fitted acetylcholine standard curve, containing multiple concentrations, as control).
  • M 1 agonist compounds were characterized in FLIPR experiments on CHO cells with transient expression of human muscarinic M 1 receptors. Briefly, CHO cells were transduced with M1 BacMam virus (Ames, R S; Fornwald, J A; Nuthulaganti, P; Trill, J J; Foley, J J; Buckley, P T; Kost, T A; Wu, Z and Romanos, M A. (2004) Use of BacMam recombinant baculoviruses to support G protein-coupled receptor drug discovery. Receptors and Channels 10 (3-4): 99- 109) at a multiplicity of infection of 6. The virus to cell ratio was determined in separate experiments by functional titration to be most appropriate to measure intrinsic activities of partial agonists. After mixing with virus in suspension, cells were then plated (15,000/well) and allowed to grow overnight at 37 degrees.
  • M1 BacMam virus Ames, R S; Fornwald, J A; Nuthulaganti, P; Trill, J J; Fo
  • cells were then frozen in 1 ml vials at a concentration of 4.8x10e7 cells/ml in 90% dialysed Foetal Bovine Serum, 10% DimethylSulphoxide at -140 degrees. Cells could then be thawed on the day prior to assay, plated (15,000/well) and allowed to grow overnight at 37 degrees.
  • the FLIPR experiment was carried out on the day following plating using the same protocol as described above for CHO-M1 cells. Results were imported into ActivityBase data analysis suite where the curves were analysed by non-linear curve fitting and the resulting pEC 50 values were calculated. The intrinsic activities of agonist compounds were calculated as percentage of maximum FLIPR response induced by acetylcholine added as control on the same compound plates, and converted to a fraction between 0 and 1 (i.e. calculated using a 100% max response from a fitted acetylcholine standard curve, containing multiple concentrations, as control). The exemplified compounds below were tested in either assay A1 or assay B1 above and were each found to have an average pEC 50 value of > 5.0 at the muscarinic M 1 receptor, and intrinsic activity > 0.5.
  • MDAP refers to mass-directed automated purification using reverse phase chromatography on C 18 stationary phase eluted with acetonitrile/water/0.1% formic acid.
  • SCX refers to a sulfonic acid ion exchange resin supplied by Varian.
  • 8-oxabicyclo[3.2.1]octan-3-one may be synthesised according to the procedure described in: Fattori, D; Henry, S; Vogel, P; "The Demjanov and Tiffeneau-Demjanov one-carbon ring enlargements of 2-aminomethyl-7-oxabicyclo[2.2.1]heptane derivatives.
  • the stereo- and regioselective additions of 8-oxabicyclo[3.2.1]oct-6-en-2-one to soft electrophiles Tetrahedron (1993), 49(8), 1649-64.
  • 2-methyldihydro-2H-pyran-4(3H)-one may be synthesised according to the procedure described in PCT Publication No WO 2004/041 161.
  • 3-methyldihydro-2H-pyran-4(3H)-one may be synthesised according to the procedure described in: Smith, A B III; Fukui, M; Vaccaro, H A.; Empfield, J R; "Phyllanthoside- phyllanthostatin synthetic studies. 7. Total synthesis of (+)-phyllanthocin and (+)- phyllanthocindiol”; Journal of the American Chemical Society (1991 ), 113(6), 2071-92.
  • NMR Nuclear Magnetic Resonance
  • NMR spectra were run on either a Brucker DPX250A or DPX400B spectrometer at 250 or 400MHz frequency respectively at 295K and run as a dilute solution of d 6 -DMSO unless otherwise stated. All NMR spectra were referenced to tetramethylsilane (TMS ⁇ H 0, ⁇ C 0). All coupling constants are reported in hertz (Hz) and multiplicities are labelled s (singlet), bs (broad singlet), d (doublet), t (triplet), q (quartet), dd (doublet of doublets), dt (doublet of triplets) and m (multiplet).
  • Mass spectra were taken on an ion-trap Finnigan MS LCQ, operating in ES (+) and ES (-) ionization mode.
  • LCMS were taken on a quadrupole Mass Spectrometer on a Shimadzu LCMS 2010 or Agilent LC/MSD 1100 Series , operating in ES (+) and ES (-) ionization mode (GC-MS) were taken on a Shimadzu 2010 GCMS with El ion source (Column: DB-5 Carrier gas: He).
  • mass spectra were recorded on an Agilent 1100 LCMS system using a Sunfire C18 3.5 micron reverse phase column eluted with acetonitrile - aqueous ammonium bicarbonate.
  • Total ion current traces were obtained for electrospray positive and negative ionisation (ES+ / ES-) and/or atmospheric pressure chemical positive and negative ionisation (AP+ / AP-).
  • Example 1 1 -(1 -(3-oxabicyclo[3.2.1 ]octan-8-yl)piperidin-4-yl)-1 H-benzo[d]imidazol- 2(3H)-one
  • Exo isomer 1 H NMR (D 2 O) ⁇ : 7.27 (1 H, m), 7.15 (3H, m), 4.55 (2H, s), 4.50 (1 H, m), 3.75 (2H, d), 3.63 (1 H, m), 3.12 (2H, t), 2.63 (2H, q), 2.0-2.1 (4H, m), 1.94 (2H, m), 1.75-1.84 (4H, m).
  • the solid was added to dichloromethane (20 ml), triethylamine (12 ml, 118.8 mmol) and di-tert-butyl dicarbonate (3.00 g, 13.76 mmol) and stirred for 12 hours at 8O 0 C.
  • The0 mixture was concentrated and purified by a flash column to get two products (a first fraction (120 mg) and a second fraction (350 mg)).
  • the first fraction was purified by chiral preparative HPLC and treated with 3N HCI-MeOH to obtain two pure trans-isomers (hydrochloride, Example 4 (42 mg), and Example 5(42 mg)).
  • the second fraction was treated with 3N HCI-MeOH to get a further sample, which was purified by Chiral5 preparative HPLC to afford two pure cis-isomers (Example 6 (44 mg) and Example 7 (48 mg)).
  • Example 6 Chiral isomer 3 (cis) 1H NMR (d 4 -MeOH) ⁇ : 7.40 (1 H, m), 7.10 (3H, m), 4.41 (1 H, m) , 4.005 (1 H, m), 3.51 (2H, m), 3.20-3.40 (2H, m), 2.89 (1 H, m), 2.51-2.71 (4H, m), 2.00-2.10 (1 H, d), 1.55-1.65 (1 H, m), 1.30-1.40 (1 H, m), 1.21 (3H, m).
  • Example 7 Chiral isomer 4 (cis, opposite to isomer 3) 1 H NMR ( ⁇ VMeOH) ⁇ : 7.40 (1 H, m), 7.10 (3H, m), 4.41 (1 H, m) , 4.005 (1 H, m), 3.51 (2H, m), 3.20-3.40 (2H, m), 2.89 (1 H, m), 2.51-2.71 (4H, m), 2.00-2.10 (1 H, d), 1.55-1.65 (1 H, m), 1.30-1.40 (1 H, m), 1.21 (3H, d).
  • a microwave vessel was charged with 6-methyl-1-(4-piperidinyl)-1 ,3-dihydro-2H- benzimidazol-2-one (D4, 145mg, 0.63mmol), 2-methyltetrahydro-4H-pyran-4-one (0.08g, 0.71 mmol), acetic acid (0.1 ml), dichloromethane (4ml) and (polystyrymethyl) trimethylammonium cyanoborohydride (4.3meq/g) (0.4g) and heated at 110°C for 20 minutes in a microwave reactor. The cooled mixture was filtered under vacuum and the filtrate loaded onto a 5g SCX cartridge, which was eluted with methanol followed by methanolic ammonia.

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Abstract

L'invention concerne des composés de formule (I) ou un sel de ceux-ci, formule dans laquelle R4, R5, R6, Q, R1 et R2 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/EP2008/053593 2007-03-29 2008-03-27 Composés qui ont une activité au niveau du récepteur m1 et leurs utilisations en médecine WO2008119714A1 (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

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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
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
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

Patent Citations (5)

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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
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
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

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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