WO2008119713A1 - 1- (1-cyclohexyl-4-piperidinyl) -1, 3-dihydro-2h-benzimidazol-2-one derivatives which have activity on the m1 receptor and their use in medicine - Google Patents

1- (1-cyclohexyl-4-piperidinyl) -1, 3-dihydro-2h-benzimidazol-2-one derivatives which have activity on the m1 receptor and their use in medicine Download PDF

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WO2008119713A1
WO2008119713A1 PCT/EP2008/053591 EP2008053591W WO2008119713A1 WO 2008119713 A1 WO2008119713 A1 WO 2008119713A1 EP 2008053591 W EP2008053591 W EP 2008053591W WO 2008119713 A1 WO2008119713 A1 WO 2008119713A1
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group
compound
methyl
piperidinyl
formula
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PCT/EP2008/053591
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French (fr)
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David Gwyn Cooper
Ian Thomson Forbes
Vincenzo Garzya
Jian Jin
Paul Adrian Wyman
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Glaxo Group Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • This invention relates to novel compounds, pharmaceutical compositions containing them and their use in therapy, in particular as antipsychotic agents. 5
  • 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 0 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 5 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 0 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. 5
  • 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 5 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:
  • - X 2 is nitrogen or CR 5 wherein R 5 is selected from hydrogen, cyano, halogen, C 1- 6 alkyl (optionally substituted with one or more fluorine atoms), and C 1 ⁇ aIkOXy (optionally substituted with one or more fluorine atoms);
  • - X 3 is nitrogen or CR 4 wherein R 4 is hydrogen or fluorine; and wherein at least one and at most two of X 1 , X 2 , X3 is a nitrogen atom;
  • 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 3-6 cycloalkyl (optionally substituted with one or more fluorine atoms), and C 1 ⁇ aIkOXy (optionally substituted with one or more fluorine atoms);
  • R is selected from C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkylC 1-6 alkyl and C 2-6 alkynyl, any alkyl or cycloalkyl group being optionally substituted by one or more fluorine atoms;
  • Q is hydrogen or C 1-6 alkyl.
  • 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- 3 alkyl means a straight or branched alkyl containing at least 1 , and at most 3, carbon atoms.
  • Examples of "C 1-6 alkyl” groups 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.
  • Ci -6 alkoxy means a straight or branched alkoxy group containing at least 1 , and at most 6, carbon atoms.
  • C 1-3 alkoxy means a straight or branched alkoxy group containing at least 1 , and at most 3, 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- 6cycloalkyl” as used herein include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • C 1-6 alkylsulfonyl refers to a group wherein C 1-6 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.
  • 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”
  • alkynyl refers to a linear or branched hydrocarbon group containing one or more carbon-carbon triple bonds and the specified number of carbon atoms.
  • C 2-6 alkynyl means a linear or branched hydrocarbon group containing one or more carbon-carbon triple bonds and at least two, and at most six, carbon atoms.
  • C 2-4 alkynyl means a linear or branched hydrocarbon group containing one or more carbon-carbon triple bonds and at least two, and at most four, carbon atoms.
  • Examples of "C 2 -63lkynyl” as used herein include, but are not limited to, include ethynyl, propynyl, butynyl, pentynyl and hexynyl.
  • 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 is a Ci -6 alkyl group, it may be substituted by 1 , 2, 3 or 4 fluoro groups; and if R is a C 1-6 alkoxy group, it may be substituted by 1 , 2, 3 or 4 fluoro groups.
  • X 1 is nitrogen and X 2 and X 3 are CR 5 and CR 4 respectively. In another embodiment of the invention X 1 and X 2 are both nitrogen and X 3 is CR 5 . In another embodiment, X 1 is CH, X 3 is CR 4 and X 2 is N. In another embodiment, X 1 and X 3 are N and X 2 is CR 5 .
  • R is selected from C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkylC 1-6 alkyl and C 2-6 alkynyl, any alkyl or cycloalkyl group being optionally substituted by one, two or three fluorine atoms.
  • R is d- ⁇ alkyl
  • R is selected from methyl, ethyl, propyl, isopropyl, CF 3 , cyclopropylmethyl, propynyl and cyclobutyl.
  • R is selected from methyl, ethyl and propyl.
  • R 5 is selected from H and C 1-6 alkyl.
  • R 5 is selected from hydrogen, cyano, halogen, C 1-3 alkyl (optionally substituted with one, two or three fluorine atoms), and C 1-3 alkoxy (optionally substituted with one, two or three fluorine atoms).
  • R 5 is selected from hydrogen, chloro, bromo, fluoro, methyl, ethyl, methoxy and trifluoromethyl.
  • R 5 is selected from hydrogen and methyl.
  • R 6 is selected from hydrogen, halogen, cyano, C 1-3 alkyl (optionally substituted with one, two or three fluorine atoms), C 1-3 alkylsulfonyl, C 3- ⁇ cycloalkyl (optionally substituted with one, two or three fluorine atoms), and C 1- 3 alkoxy (optionally substituted with one, two or three fluorine atoms).
  • R 6 is selected from H, halogen, and C 1-G aIkOXy.
  • R 6 is selected from hydrogen, chloro, bromo, fluoro, methyl, ethyl, isopropyl, methoxy, trifluoromethoxy and trifluoromethyl, for example chloro, fluoro, methyl, cyclopropyl, methoxy, trifluoromethoxy and trifluoromethyl.
  • R 6 is selected from hydrogen, chloro, fluoro, bromo, methyl, methoxy, trifluoromethoxy and trifluoromethyl.
  • R 6 is selected from hydrogen, methyl, fluoro, chloro, bromo, methoxy and cyclopropyl.
  • R 6 is selected from hydrogen, chloro, bromo, methyl and methoxy.
  • Q is selected from hydrogen and C h alky!. In one embodiment, Q is hydrogen or methyl. In one embodiment, Q is H. In one embodiment Q is methyl.
  • the invention provides a compound of formula (T) or a salt or solvate thereof:
  • R 5 is selected from hydrogen, cyano, halogen, Ci -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;
  • - X 3 is nitrogen or CR 4 where R 4 is hydrogen or fluorine; and where one or two of X 1 , X 2 , X 3 is a nitrogen atom;
  • 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;
  • R is selected from C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkylC 1-6 alkyl and C 2-6 alkynyl, any alkyl or cycloalkyl group being optionally substituted by one or more fluorine atoms;
  • Q is hydrogen or C 1-6 alkyl.
  • 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)-(-)-10-camphorsulphonic, (1S)-(+)-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 solvent.
  • suitable pharmaceutically acceptable solvents include, without limitation, water, ethanol and acetic acid.
  • 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.
  • isotopic variations of the invention for example, those in which a radioactive isotope such as 3 H or 14 C is incorporated, 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.
  • lsotopic 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. Mixtures of cis- and trans- compounds, or compounds in which the cis/trans conformation have not been determined, are drawn herein as shown below:
  • Example compounds include:
  • the compounds of the present invention may be in the form of their free base or salts thereof.
  • the salt is the hydrochloride salt, the trifluoroacetate salt or the formate salt.
  • the salt is the monohydrochloride, monoformate or monotrifluoroacetate salt.
  • salts of the present invention include:
  • R 5 is a group R 5 as previously defined or a group convertible to R 5 ;
  • - X 3 is nitrogen or CR 4 where R 4 is a group R 4 as previously defined or a group convertible to R 4 ; and where one or two of Xi, X 2 , X3 is a nitrogen atom; and
  • --RR 66 i iss aa ggrroouupp RR 66 aass pprreevviioouussllyy ddeeffiinneedd,, oorr aa ggrroouupp ccoornvertible to R 6
  • R' is a group R as previously defined, or a group convertible to R.
  • 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.
  • a modification of general process (A1 ) is required where Q is C 1-6 alkyl.
  • a general process (A2) wherein Q is Ci -6 alkyl in which a compound of formula (II) can be reacted with a compound of formula (III) in the presence of a source of cyanide, e.g. acetone cyanohydrin, to form the cyano intermediate (XXXX) which can be reacted with an alkyl Grignard reagent QMgX to form compounds of formula (I) in which Q is C 1-6 alkyl.
  • a source of cyanide e.g. acetone cyanohydrin
  • - X 2 is nitrogen or CR 5 and R 5 is a group R 5 as previously defined or a group convertible to R 5 ;
  • - X 3 is nitrogen or CR 4 where R 4 is a group R 4 as previously defined or a group convertible to R 4 ; and where one or two of X 1 , X 2 , X 3 is a nitrogen atom;
  • R 6 is a group R 6 as previously defined, or a group convertible to R 6 ;
  • - R' is a group R as previously defined, or a group convertible to R;
  • - Q is C 1-6 alkyl;
  • - X is bromo or iodo or chloro.
  • the invention provides a compound of formula (XXXX) or a salt thereof wherein X 1 , X 2 , X 3 , R 6 and R' are as hereinbefore defined.
  • This reaction can generate a mixture of cis and trans isomers which can be separated by chromatography or crystallisation.
  • the invention provides a general process (B) for preparing compounds of formula (I) which process comprises:
  • - X 1 is nitrogen or CH;
  • - X 2 is nitrogen or CR 5 and R 5 is a group R 5 as previously defined or a group convertible to R 5 ;
  • - X 3 is nitrogen or CR 4 where R 4 is a group R 4 as previously defined or a group convertible to R 4 ; and where one or two of X 1 , X 2 , X 3 is a nitrogen atom; - R 6 is a group R 6 as previously defined, or a group convertible to R 6 ; - R' is a group R as previously defined, or a group convertible to R;
  • X and Y both represent leaving groups.
  • X and Y can be the same or different and examples are Cl, PhO, EtO, imidazole.
  • this reagent can be generated in situ e.g. from diphosgene or triphosgene.
  • reaction is carried out using standard methodology e.g. reacting the compound (IV) with the reagent (V) in an inert solvent for example dichloromethane or toluene, 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
  • a base such as triethylamine or potassium carbonate
  • the invention provides a compound of formula (IV) or a salt thereof wherein R 6 , X 1 , X 2 , X3, Q and R' are as hereinbefore defined.
  • compounds of formula (IV) can be cis or trans isomers, or a mixture of isomers. If necessary, separation of cis and trans isomers after the reaction with (V) can be achieved by chromatography or crystallisation.
  • the invention provides a general process (C) for preparing compounds of formula (I) which process comprises:
  • - X 1 is nitrogen or CH;
  • - X 2 is nitrogen or CR 5 and R 5 is a group R 5 as previously defined or a group convertible to R 5 ;
  • - X 3 is nitrogen or CR 4 where R 4 is a group R 4 as previously defined or a group convertible to R 4 ; and where one or two of X 1 , X 2 , X 3 is a nitrogen atom; - R 6 is a group R 6 as previously defined, or a group convertible to R 6 ;
  • R' is a group R as previously defined, or a group convertible to R;
  • - Z is a leaving group such as bromo, iodo, chloro or triflate.
  • 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.)
  • compounds of formula (Vl) can be cis or trans isomers, or a mixture of isomers. If necessary, separation of cis and trans isomers after the intramolecular cyclisation can be achieved by chromatography or crystallisation.
  • the invention provides a compound of formula (Vl) or a salt thereof wherein X 1 , X 2 , X3, R 6 , Q, Z and R' are as hereinbefore defined.
  • the invention provides a general process (D) for preparing compounds of formula (I) which process comprises:
  • R 5 is a group R 5 as previously defined or a group convertible to R 5 ;
  • - X 3 is nitrogen or CR 4 where R 4 is a group R 4 as previously defined or a group convertible to R 4 ; and where one or two of X 1 , X 2 , X 3 is a nitrogen atom;
  • R 6 is a group R 6 as previously defined, or a group convertible to R 6 ;
  • R' is a group R as previously defined, or a group convertible to R;
  • - Q is as previously defined; and - R a is a C 1-5 alkyl group.
  • condensation and cyclisation reactions can be carried out under reaction conditions similar to those described in the literature for an analogous process (US 3161645) (for example heating in an inert solvent such as xylene) followed by reduction of the piperidine double bond using for example catalytic hydrogenation over palladium or Raney nickel.
  • compounds of formula (IX) can be cis or trans isomers, or a mixture of isomers. If necessary, separation of cis and trans isomers after the intramolecular cyclisation can be achieved by chromatography or crystallisation.
  • the invention provides a general process (E) for preparing compounds of formula (I) which process comprises:
  • R 5 is a group R 5 as previously defined or a group convertible to R 5 ;
  • - X 3 is nitrogen or CR 4 where R 4 is a group R 4 as previously defined or a group convertible to R 4 ; and where one or two of X 1 , X 2 , X 3 is a nitrogen atom;
  • R 6 is a group R 6 as previously defined, or a group convertible to R 6 ;
  • R' is a group R as previously defined, or a group convertible to R; and Q is as previously defined.
  • the Curtius rearrangement is typically carried out by mixing the two reactants in an inert solvent such as toluene, optionally with heating.
  • compounds of formula (X) can be cis or trans isomers, or a mixture of isomers. If necessary, separation of cis and trans isomers after the intramolecular cyclisation can be achieved by chromatography or crystallisation.
  • the invention provides a compound of formula (X) or a salt thereof wherein X 1 , X 2 , X 3 , R 6 , Q and R' are as hereinbefore defined.
  • the invention provides a general process (F) for preparing compounds of formula (I) which process comprises: coupling a compound of formula (I)
  • - X 2 is nitrogen or CR 5 and R 5 is a group R 5 as previously defined or a group convertible to R 5 ;
  • - X3 is nitrogen or CR 4 where R 4 is a group R 4 as previously defined or a group convertible to R 4 ; and where one or two of Xi, X 2 , X3 is a nitrogen atom;
  • R 6 is a group R 6 as previously defined, or a group convertible to R 6 ;
  • - R' is a group R as previously defined, or a group convertible to R;
  • - Q is as previously defined;
  • - 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.
  • compounds of formula (XII) can be cis or trans isomers, or a mixture of isomers. If necessary, separation of cis and trans isomers after the intramolecular cyclisation can be achieved by chromatography or crystallisation.
  • 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 an 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.
  • R' is benzyl
  • the benzyl group can be removed using standard methodology, e.g. catalytic hydrogenation over palladium on carbon, to provide the alcohol.
  • Alkylation of the resultant alcohol using a strong base e.g. sodium hydride and a Ci -6 alkylating agent e.g. methyl iodide or ethyl iodide or propyl iodide, will afford the desired product. It will be appreciated that protection of any NH functionality present in the molecule may be necessary.
  • R when R is methyl, the methyl group can be removed by treatment with a dealkylating agent such as boron tribromide to afford the alcohol intermediate, which can be alkylated in a similar manner to that described above.
  • a dealkylating agent such as boron tribromide
  • the alcohol intermediate can be converted to R is trifluoromethyl by conversion to the xanthate followed by oxidation in the presence of fluoride ion.
  • R 5 is a group R 5 as previously defined or a group convertible to R 5 ;
  • - X 3 is nitrogen or CR 4 where R 4 is a group R 4 as previously defined or a group convertible to R 4 ; and where one or two of X 1 , X 2 , X 3 is a nitrogen atom;
  • R 6 is a group R 6 as previously defined, or a group convertible to R 6 ;
  • - P represents a nitrogen protecting group (e.g. Boc, acetyl, trifluoroacetyl, benzyloxycarbonyl); and
  • - Z represents a leaving group such as bromo, iodo, chloro or triflate.
  • Reaction conditions for the metal catalysed cyclisation are summarised in Process C.
  • the urea (XV) can be prepared using any of the classical methods for urea formation as illustrated in Scheme 2.
  • the starting materials for this process are commercially available or can be prepared using standard methodology.
  • - X 1 is nitrogen or CH;
  • - X 2 is nitrogen or CR 5 and R 5 is a group R 5 as previously defined or a group convertible to R 5 ;
  • R b represents H or a C 1-5 alkyl group e.g. methyl or ethyl; followed by intramolecular cyclisation and deprotection of the piperidine nitrogen (Scheme 3).
  • 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.
  • R 5 is a group R 5 as previously defined or a group convertible to R 5 ;
  • - X 3 is nitrogen or CR 4 where R 4 is a group R 4 as previously defined or a group convertible to R 4 ; and where one or two of X 1 , X 2 , X 3 is a nitrogen atom;
  • R 6 is a group R 6 as previously defined, or a group convertible to R 6 ;
  • - P represents a nitrogen protecting group (e.g. Boc, acetyl, trifluoroacetyl, benzyloxycarbonyl);
  • R 5 is a group R 5 as previously defined or a group convertible to R 5 ;
  • - X 3 is nitrogen or CR 4 where R 4 is a group R 4 as previously defined or a group convertible to R 4 ; and where one or two of Xi, X 2 , X3 is a nitrogen atom;
  • R 6 is a group R 6 as previously defined, or a group convertible to R 6 ;
  • - P represents a nitrogen protecting group (e.g. Boc, acetyl, trifluoroacetyl, benzyloxycarbonyl), using for example sodium triacetoxyborohydride to give the intermediate (XXIII).
  • a nitrogen protecting group e.g. Boc, acetyl, trifluoroacetyl, benzyloxycarbonyl
  • 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 ;
  • - P represents a nitrogen protecting group (e.g. Boc, acetyl, trifluoroacetyl, benzyloxycarbonyl);
  • R 5 is a group R 5 as previously defined or a group convertible to R 5 ;
  • - X 3 is nitrogen or CR 4 where R 4 is a group R 4 as previously defined or a group convertible to R 4 ; and where one or two of X 1 , X 2 , X 3 is a nitrogen atom;
  • R 6 is a group R 6 as previously defined, or a group convertible to R 6 ;
  • - P and P' independently represent a nitrogen protecting group (e.g. Boc, acetyl, trifluoroacetyl, benzyloxycarbonyl); and
  • the compounds of formula (III) can be prepared by standard literature methodology.
  • R 5 is a group R 5 as previously defined or a group convertible to R 5 ;
  • - X 3 is nitrogen or CR 4 where R 4 is a group R 4 as previously defined or a group convertible to R 4 ; and where one or two of X 1 , X 2 , X 3 is a nitrogen atom;
  • R 6 is a group R 6 as previously defined, or a group convertible to R 6 ;
  • R' is a group R as previously defined, or a group convertible to R
  • R 5 is a group R 5 as previously defined or a group convertible to R 5 ;
  • - X 3 is nitrogen or CR 4 where R 4 is a group R 4 as previously defined or a group convertible to R 4 ; and where one or two of X 1 , X 2 , X 3 is a nitrogen atom;
  • R 6 is a group R 6 as previously defined, or a group convertible to R 6 ;
  • R' is a group R as previously defined, or a group convertible to R
  • R 5 is a group R 5 as previously defined or a group convertible to R 5 ;
  • - X 3 is nitrogen or CR 4 where R 4 is a group R 4 as previously defined or a group convertible to R 4 ; and where one or two of X-i, X 2 , X3 is a nitrogen atom;
  • R 6 is a group R 6 as previously defined, or a group convertible to R 6 ;
  • R' is a group R as previously defined, or a group convertible to R;
  • - Q is as previously defined; and - P' represents either hydrogen or a nitrogen protecting group (such as acetyl, trifluoroacetyl, Boc, phthalimide), to afford compound (XXXI) (Scheme 10) followed by deprotection of the aniline group where required.
  • a nitrogen protecting group such as acetyl, trifluoroacetyl, Boc, phthalimide
  • R 5 is a group R 5 as previously defined or a group convertible to R 5 ;
  • - X 3 is nitrogen or CR 4 where R 4 is a group R 4 as previously defined or a group convertible to R 4 ; and where one or two of X 1 , X 2 , X 3 is a nitrogen atom;
  • R 6 is a group R 6 as previously defined, or a group convertible to R 6 ;
  • R' is a group R as previously defined, or a group convertible to R
  • 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 cloroformate;
  • 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 cyclohexanone.
  • the group R' in the above described processes is the group R 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 (311 ); Bipolar Disorders including Bipolar I Disorder, Bipolar Il Disorder (Recurrent Major Depressive Episodes with Hypomanic Episodes) (296.89), Cyclothymic Disorder (301.13) and Bipolar Disorder Not Otherwise Specified (296.80); Other Mood Disorders including Mood Disorder Due to a General Medical Condition (293.83) which includes the subtypes With Depressive Features, With Major Depressive-like Episode, With Manic Features and With Mixed Features), Substance-Induced Mood Disorder (including the subtypes With Depressive Features, With Manic Features and With Mixed Features) and Mood Disorder Not Otherwise Specified (296.90);
  • 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,
  • 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);
  • Attention-Deficit /Hyperactivity Disorder including the subtypes Attention-Deficit /Hyperactivity Disorder Combined Type (314.01 ), Attention-Deficit /Hyperactivity Disorder Predominantly Inattentive Type (314.00), Attention-Deficit /Hyperactivity Disorder Hyperactive-Impulse Type (314.01 ) and Attention-Deficit /Hyperactivity Disorder Not Otherwise Specified (314.9); Hyperkinetic Disorder; Disruptive Behaviour Disorders such as Conduct Disorder including the subtypes childhood-onset type (321.81 ), Adolescent-Onset Type (312.82) and Unspecified Onset (312.89), Oppositional Defiant Disorder (313.81 ) and Disruptive Behaviour Disorder Not Otherwise Specified; and Tic Disorders such as Tourette's Disorder (307.23);
  • Personality Disorders including the subtypes Paranoid Personality Disorder (301.0), Schizoid Personality Disorder (301.20), Schizotypal Personality Disorder (301 ,22), Antisocial Personality Disorder (301.7), Borderline Personality Disorder (301 ,83), Histrionic Personality Disorder (301.50), Narcissistic Personality Disorder (301 ,81 ), Avoidant Personality Disorder (301.82), Dependent Personality Disorder (301.6), Obsessive-Compulsive Personality Disorder (301.4) and Personality Disorder Not Otherwise Specified (301.9); and
  • Sexual dysfunctions including sexual Desire Disorders such as Hypoactive Sexual Desire Disorder (302.71 ), and sexual Aversion Disorder (302.79); sexual arousal disorders such as Female sexual Arousal Disorder (302.72) and Male Erectile Disorder (302.72); orgasmic disorders such as Female Orgasmic Disorder (302.73), Male Orgasmic Disorder (302.74) and Premature Ejaculation (302.75); sexual pain disorder such as Dyspareunia (302.76) and Vaginismus (306.51 ); Sexual Dysfunction Not Otherwise Specified (302.70); paraphilias such as Exhibitionism (302.4), Fetishism (302.81 ), Frotteurism (302.89), Pedophilia (302.2), Sexual Masochism (302.83), sexual Sadism (302.84), Transvestic Fetishism (302.3), Voyeurism (302.82) and Paraphilia Not Otherwise Specified (302.9); gender identity disorders such as Gender Identity Disorder in Children (302.6) and Gender Identity Disorder in Adolescents or Adults (302.85); and
  • 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.
  • 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 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
  • 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 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 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 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 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®); haloperid
  • 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(D), acetophenazine (available under the tradename TINDAL®;), prochlorperazine (available under the tradename COMPAZINE®), methotrimeprazine (available under the tradename NOZINAN®), 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(D)
  • acetophenazine available under the tradename TINDAL®
  • suitable antipsychotic agents include olanzapine, risperidone, quetiapine, amisulpride, aripiprazole, haloperidol, clozapine, olanzepine, ziprasidone, talnetant and osanetant.
  • 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).
  • 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 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.
  • Typical parenteral 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
  • a propellant which can be a compressed gas such as compressed air or an organic propellant such as a fluorochlorohydrocarbon.
  • 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.
  • 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).
  • FLIPR experiments on M 1 receptor to determine agonist/antagonist potency Compounds of the invention were characterized in a functional assay to determine their ability to activate the intracellular calcium pathway in CHO cells with stable expression of human muscarinic receptors using FLIPR (Fluorometric Imaging Plate Reader) technology. Briefly, CH0-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.
  • 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 pECso/fpK, 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 example compounds below were tested in the above assay and were each found to have an average pEC 50 value of > 6.0 at the muscarinic M 1 receptor, and intrinsic activity > 50%.
  • 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. Alternatively, 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 example compounds below were tested in the above assay, and were each found to have an average pEC 50 value of > 6.0 at the muscarinic M 1 receptor, and intrinsic activity of greater than or equal to 0.3.
  • 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). 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).
  • 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-).
  • ES+ / ES- electrospray positive and negative ionisation
  • AP+ / AP- atmospheric pressure chemical positive and negative ionisation
  • a three-necked flask was equipped with a Dean-Stark trap and an argon-connected condenser.
  • the flask was charged with 1 ,1-dimethylethyl 4-piperidinylcarbamate (1.1 eq., 7 mmol, 1.4 g), 4-(propyloxy)cyclohexanone (D3) (1 eq., 6.4 mmol, 1 g), 1 ,2,3-triazole (1.2 eq., 7.7 mmol, 0.53 g) and 50 ml of dry toluene.
  • Cis/trans 1-[1-methyl-4-(propyloxy)cyclohexyl]-4-piperidinamine dihydrochloride (D5) (0.7 eq., 70 mg, 0.210 mmol), H ⁇ nig's base (1 eq., 0.50 ⁇ l), and 2-fluoro-4-methyl-1- nitrobenzene (1 eq., 0.3 mmol, 52 mg) were dissolved in DMF (2ml) and the mixture stirred at 80 0 C for 18 hours. The crude mixture was then cooled to room temperature and poured onto a saturated aqueous solution of NaHCO 3 , EtOAc was added and the two phases were separated.
  • Cis/trans 6-methyl- ⁇ /- ⁇ 1-[1-methyl-4-(propyloxy)cyclohexyl]-4-piperidinyl ⁇ -3-nitro-2- pyridinamine (D6) (0.153 mmol) was dissolved in EtOH (10 ml) and Raney-Ni (0.2 ml of a 50% aqueous suspension) was added at room temperature, followed by hydrazine hydrate (10 eq., 1.537 mmol, 0.047 ml). The mixture was stirred at room temperature for 4 hours. The mixture was cooled to room temperature and was filtered through Celite®.
  • N-Ethoxycarbonylphthalimide (10Og) was added to a mixture of trans-4- hydroxycyclohexylamine hydrochloride (69g), potassium carbonate (158g) and water (11) at room temperature. After 3h the title compound was isolated by filtration, washing with water then ethyl acetate (95g).
  • Acetaldehyde (10ml) in acetonitrile (50ml) was added over 30 minutes to a solution of frans-N-(4-tert-butyldimethylsilyloxycyclohexyl)phthalimide (D9, 50.Og), bismuth tribromide (6.7g) and triethylsilane (27ml) in acetonitrile (500ml) stirred at ice bath temperature, and the mixture was allowed to warm to room temperature overnight. The mixture was filtered and the resulting grey solid and filtrate were worked up separately. The filtrate was evaporated and treated with hexane to give the title compound as a white solid (16.35g).
  • lodomethane (65ml) was added in portions to a solution of 1-ethyl-4-piperidone (100g) in acetone (11) at 20-30 0 C (internal, ice cooling). After stirring for 3h the title compound was obtained by filtration (189g).
  • Cis/trans ethyl 4- ⁇ [(1 ,1-dimethylethyl)(dimethyl)silyl]oxy ⁇ cyclohexanecarboxylate (D18, 35g, 122 mmol) was dissolved in CH 3 CN (250 ml) and Et 3 SiH (1.2 eq., 0.146 mol, 23ml) and BiBr 3 (4% mol, 4.9 mmol, 2.2 g) were added at room temperature followed by slow addition of acetaldehyde (1.2 eq., 8.2 ml) at 25 0 C.
  • the resulting yellow solution was heated at 5O 0 C for 2.5hrs, then cooled to 0 0 C and treated with iodomethane (3 eq., 0.3 mol, 19 ml). The mixture was allowed to warm to room temperature and stir for 20 hrs when a yellow precipitate had formed. The mixture was cooled to 1 O 0 C, treated with 10% citric acid solution (200ml), and then concentrated under reduced pressure. The residual mixture was diluted with water (200ml) and extracted with Et 2 O (2x). The combined extracts were dried (Na 2 SO 4 ) and concentrated under reduced pressure to afford the title compound as a yellow oil, (16.2 g, 87%), a mixture of cis:trans isomers.
  • c/s/frans-4-(ethyloxy)-1-methylcyclohexanecarboxylic acid (D21 , 16.2 g, 87.1 mmol) was dissolved in thionyl chloride (15 eq., 1.31 mol, 95 ml) at room temperature and subsequently heated to 85 0 C for 4 hrs. The mixture was then allowed to cool to room temperature and the thionyl chloride was azeotropically evaporated with toluene. The residue was dissolved in THF (100ml), treated with a 5% aqueous solution of Na 2 CO 3 (500 ml) and stirred vigorously at room temperature for 20 minutes.

Abstract

Compounds of formula (I) or a salt thereof are provided, wherein X1, X2, X3, R6, Q and R are as defined in the description. Uses of the compounds as medicaments and in the manufacture of medicaments for treating psychotic disorders and cognitive impairments are disclosed. The invention further discloses pharmaceutical compositions comprising the compounds.

Description

1- (l-CYCLOHEXYL-4-PIPERIDINYL) -1 , 3-DIHYDRO-2H-BENZIMIDAZOL-2-ONE DERIVATIVES WHICH HAVE ACTIVITY ON THE Ml RECEPTOR AND THEIR USE IN
This invention relates to novel compounds, pharmaceutical compositions containing them and their use in therapy, in particular as antipsychotic agents. 5
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, M1 to M5. The muscarinic M1 receptor is predominantly expressed in the 0 cerebral cortex and hippocampus, although it is also expressed in the periphery e.g. exocrine glands.
Muscarinic receptors in the central nervous system, especially M1, play a critical role in mediating higher cognitive processing. Diseases associated with cognitive 5 impairments, such as Alzheimer's disease, are accompanied by loss of cholinergic neurons in the basal forebrain. Furthermore, in animal models, blockade or lesion of central cholinergic pathways results in profound cognitive deficits.
Cholinergic replacement therapy has largely been based on the use of 0 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. 5
The dopamine hypothesis of schizophrenia suggests that excess dopaminergic stimulation is responsible for the positive symptoms of the disease, hence the utility of dopamine receptor antagonists to reduce psychotic symptoms. However, conventional dopamine receptor antagonists can cause extrapyramidal side effects 0 (EPS) in patients, including tremor and tardive dyskinesias.
M1 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 5 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). It also has been shown to inhibit A10, but not A9, dopamine cell firing and 0 conditioned avoidance and induces c-fos expression in prefrontal cortex and nucleus accumbens, but not in striatum in rats. These data are all suggestive of an atypical antipsychotic-like profile. Xanomeline has also been shown to reduce psychotic symptoms such as suspiciousness, hallucinations and delusions in Alzheimer's patients. However, the relatively non-selective nature of the compound gives rise to dose-limiting peripheral cholinergic side effects.
Certain M1 receptor agonists are known, for example in WO2007/036718, WO2007/036715, WO2007/03671 1 , WO2007/107566, WO2007/107567 and WO2007/107565. We have now found a novel group of compounds which are M1 receptor agonists.
In a first aspect therefore, the invention provides a compound of formula (I) or a salt thereof:
Figure imgf000003_0001
wherein:
- X1 is nitrogen or CH;
- X2 is nitrogen or CR5 wherein R5 is selected from hydrogen, cyano, halogen, C1- 6alkyl (optionally substituted with one or more fluorine atoms), and C1^aIkOXy (optionally substituted with one or more fluorine atoms); - X3 is nitrogen or CR4 wherein R4 is hydrogen or fluorine; and wherein at least one and at most two of X1, X2, X3 is a nitrogen atom;
- R6 is selected from hydrogen, halogen, cyano, C1-6alkyl (optionally substituted with one or more fluorine atoms), C1-6alkylsulfonyl, C3-6cycloalkyl (optionally substituted with one or more fluorine atoms), and C1^aIkOXy (optionally substituted with one or more fluorine atoms);
- R is selected from C1-6alkyl, C3-6cycloalkyl, C3-6cycloalkylC1-6alkyl and C2-6alkynyl, any alkyl or cycloalkyl group being optionally substituted by one or more fluorine atoms; and
Q is hydrogen or C1-6alkyl.
As used herein, the term "alkyl" refers to straight or branched hydrocarbon chains containing the specified number of carbon atoms. For example, C1-6alkyl means a straight or branched alkyl containing at least 1 , and at most 6, carbon atoms. C1- 3alkyl means a straight or branched alkyl containing at least 1 , and at most 3, carbon atoms. Examples of "C1-6alkyl" groups include, but are not limited to, methyl, ethyl, n- propyl, n-butyl, n-pentyl, n-hexyl, isobutyl, isopropyl, t-butyl and 1 ,1-dimethylpropyl. As used herein, the term "alkoxy" refers to a straight or branched alkoxy group containing the specified number of carbon atoms. For example, Ci-6alkoxy means a straight or branched alkoxy group containing at least 1 , and at most 6, carbon atoms. C1-3alkoxy means a straight or branched alkoxy group containing at least 1 , and at most 3, carbon atoms. Examples of "Ci-6alkoxy" 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.
As used herein, the term "cycloalkyl" refers to a non-aromatic hydrocarbon ring containing the specified number of carbon atoms. For example, C3-6cycloalkyl means a non-aromatic carbocyclic ring containing at least three, and at most six, ring carbon atoms. Examples of "C3-6cycloalkyl" as used herein include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
As used herein, the term "C1-6alkylsulfonyl" refers to a group wherein C1-6alkyl is as defined above.
As used herein, the term "C3-6cycloalkylCi-6alkyr as used herein refers to a group C3- 6cycloalkyl-C1-6alkyl wherein C3-6cycloalkyl and C1-6alkyl are as defined above.
As used herein, the term "halogen" (or the abbreviated form "halo") 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"). Examples of halogens are fluorine, chlorine and bromine.
As used herein, the term "alkynyl" refers to a linear or branched hydrocarbon group containing one or more carbon-carbon triple bonds and the specified number of carbon atoms. For example, C2-6alkynyl means a linear or branched hydrocarbon group containing one or more carbon-carbon triple bonds and at least two, and at most six, carbon atoms. C2-4alkynyl means a linear or branched hydrocarbon group containing one or more carbon-carbon triple bonds and at least two, and at most four, carbon atoms. Examples of "C2-63lkynyl" as used herein include, but are not limited to, include ethynyl, propynyl, butynyl, pentynyl and hexynyl.
As used herein, the term "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 is a Ci-6alkyl group, it may be substituted by 1 , 2, 3 or 4 fluoro groups; and if R is a C1-6alkoxy group, it may be substituted by 1 , 2, 3 or 4 fluoro groups.
In one embodiment, X1 is nitrogen and X2 and X3 are CR5 and CR4 respectively. In another embodiment of the invention X1 and X2 are both nitrogen and X3 is CR5. In another embodiment, X1 is CH, X3 is CR4 and X2 is N. In another embodiment, X1 and X3 are N and X2 is CR5.
In one embodiment, R is selected from C1-6alkyl, C3-6cycloalkyl, C3-6cycloalkylC1-6alkyl and C2-6alkynyl, any alkyl or cycloalkyl group being optionally substituted by one, two or three fluorine atoms.
In one embodiment, R is d-βalkyl.
In one embodiment, R is selected from C1-3alkyl, C3-6cycloalkyl, C3-6cycloalkylC1-3alkyl and C2-4alkynyl, any alkyl or cycloalkyl group being optionally substituted by one, two or three fluorine atoms.
In one embodiment, R is selected from methyl, ethyl, propyl, isopropyl, CF3, cyclopropylmethyl, propynyl and cyclobutyl.
In one embodiment, R is selected from methyl, ethyl and propyl.
In one embodiment, R5 is selected from H and C1-6alkyl.
In one embodiment, R5 is selected from hydrogen, cyano, halogen, C1-3alkyl (optionally substituted with one, two or three fluorine atoms), and C1-3alkoxy (optionally substituted with one, two or three fluorine atoms).
In one embodiment, R5 is selected from hydrogen, chloro, bromo, fluoro, methyl, ethyl, methoxy and trifluoromethyl.
In one embodiment, R5 is selected from hydrogen and methyl.
In one embodiment, R6 is selected from hydrogen, halogen, cyano, C1-3alkyl (optionally substituted with one, two or three fluorine atoms), C1-3alkylsulfonyl, C3- βcycloalkyl (optionally substituted with one, two or three fluorine atoms), and C1- 3alkoxy (optionally substituted with one, two or three fluorine atoms).
In one embodiment, R6 is selected from H, halogen,
Figure imgf000005_0001
and C1-GaIkOXy.
In one embodiment of the invention, R6 is selected from hydrogen, chloro, bromo, fluoro, methyl, ethyl, isopropyl, methoxy, trifluoromethoxy and trifluoromethyl, for example chloro, fluoro, methyl, cyclopropyl, methoxy, trifluoromethoxy and trifluoromethyl.
In one embodiment, R6 is selected from hydrogen, chloro, fluoro, bromo, methyl, methoxy, trifluoromethoxy and trifluoromethyl.
In one embodiment, R6 is selected from hydrogen, methyl, fluoro, chloro, bromo, methoxy and cyclopropyl.
In one embodiment, R6 is selected from hydrogen, chloro, bromo, methyl and methoxy.
In one embodiment of the invention, Q is selected from hydrogen and Chalky!. In one embodiment, Q is hydrogen or methyl. In one embodiment, Q is H. In one embodiment Q is methyl.
In one embodiment, the invention provides a compound of formula (T) or a salt or solvate thereof:
Figure imgf000006_0001
wherein:
- X1 is nitrogen or CH;
- X2 is nitrogen or CR5 where R5 is selected from hydrogen, cyano, halogen, Ci-6alkyl, C1-6alkyl substituted with one or more fluorine atoms, C1-6alkoxy, and C1-6alkoxy substituted with one or more fluorine atoms;
- X3 is nitrogen or CR4 where R4 is hydrogen or fluorine; and where one or two of X1, X2, X3 is a nitrogen atom;
- R6 is selected from hydrogen, halogen, cyano, C1-6alkyl, C1-6alkyl substituted with one or more fluorine atoms, C1-6alkylsulfonyl, C3-6cycloalkyl, C3-6cycloalkyl substituted with one or more fluorine atoms, C1-6alkoxy and C1-6alkoxy substituted with one or more fluorine atoms;
- R is selected from C1-6alkyl, C3-6cycloalkyl, C3-6cycloalkylC1-6alkyl and C2-6alkynyl, any alkyl or cycloalkyl group being optionally substituted by one or more fluorine atoms; and
Q is hydrogen or C1-6alkyl.
All features and embodiments for formula (I) apply to compounds of formula (I') mutatis mutandis. Hereinafter, all references to compounds of formula (I) include compounds of formula (I').
In one embodiment the salt of the compound of formula (I) is a pharmaceutically acceptable salt. In one embodiment, the invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof.
It will be appreciated that for use in medicine the 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)-(-)-10-camphorsulphonic, (1S)-(+)-10- camphorsulphonic, isothionic, mucic, gentisic, isonicotinic, saccharic, glucuronic, furoic, glutamic, ascorbic, anthranilic, salicylic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, pantothenic, stearic, sulfinilic, alginic, galacturonic and arylsulfonic, for example naphthalene-1 ,5-disulphonic, naphthalene- 1 ,3-disulphonic, benzenesulfonic, and p-toluenesulfonic, acids. Other non- pharmaceutically acceptable salts e.g. oxalates, may be used, for example in the isolation of compounds of formula (I) and are included within the scope of this invention. The 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. As used herein, 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. Those skilled in the art of organic chemistry will appreciate that many organic componds can form such complexes with solvents in which they are reacted or from which they are precipitated or crystallised. Such solvents for the purpose of the invention may not interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, methanol, ethanol and acetic acid. Preferably the solvent used is a pharmaceutically acceptable solvent. Examples of 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.
It will be appreciated by those skilled in the art that certain protected derivatives of compounds of formula (I), which may be made prior to a final deprotection stage, may not possess pharmacological activity as such, but may, in certain instances, be administered orally or parenterally and thereafter metabolised in the body to form compounds of the invention which are pharmacologically active. Such derivatives may therefore be described as "prodrugs". Further, certain compounds of the invention may act as prodrugs of other compounds of the invention. All protected derivatives and prodrugs of compounds of the invention are included within the scope of the invention. Examples of suitable protecting groups for the compounds of the present invention are described in Drugs of Today, Volume 19, Number 9, 1983, pp 499 - 538 and in Topics in Chemistry, Chapter 31 , pp 306 - 316 and in "Design of Prodrugs" by H. Bundgaard, Elsevier, 1985, Chapter 1 (the disclosures in which documents are incorporated herein by reference). It will further be appreciated by those skilled in the art, that certain moieties, known to those skilled in the art as "pro- moieties", for example as described by H. Bundgaard in "Design of Prodrugs" (the disclosure in which document is incorporated herein by reference) may be placed on appropriate functionalities when such functionalities are present within compounds of the invention. 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.
Hereinafter, compounds of formula (I) (whether in solvated or unsolvated form) or their pharmaceutically acceptable salts (whether in solvated or unsolvated form) or prodrugs thereof defined in any aspect of the invention (except intermediate compounds in chemical processes) are referred to as "compounds of the invention".
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. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine and chlorine such as 2H, 3H, 13C, 14C, 15N, 17O, 18O, 31P, 32P, 35S, 18F and 36CI, respectively. Certain isotopic variations of the invention, for example, those in which a radioactive isotope such as 3H or 14C is incorporated, are useful in drug and/or substrate tissue distribution studies. Tritiated, i.e., 3H, and carbon-14, i.e., 14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with isotopes such as deuterium, i.e., 2H, 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, lsotopic 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.
It will be appreciated that compounds of formula (I) can exist in cis or trans isomeric forms (OR group on the cyclohexyl ring in relation to the piperidine group).
It will be appreciated that the cis form may be drawn in the following different ways, although both represent the same isomeric form:
Figure imgf000009_0001
It will be appreciated that the trans form may be drawn in the following different ways, although both represent the same isomeric form:
Figure imgf000009_0002
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.
In one embodiment, the compounds of formula (I) are trans isomers.
In another embodiment, the compounds of formula (I) are cis isomers. Mixtures of cis- and trans- compounds, or compounds in which the cis/trans conformation have not been determined, are drawn herein as shown below:
Figure imgf000010_0001
Example compounds include:
1. 3-{1-[frans-4-(ethyloxy)cyclohexyl]-4-piperidinyl}-5-methyl-1 ,3-dihydro-2H- imidazo[4,5-b]pyridin-2-one; 2. 5-methyl-3-{1-[c/s-1-methyl-4-(propyloxy)cyclohexyl]-4-piperidinyl}-1 ,3- dihydro-2H-imidazo[4,5-b]pyridin-2-one;
3. 5-methyl-3-{1-[frans-1-methyl-4-(propyloxy)cyclohexyl]-4-piperidinyl}-1 ,3- dihydro-2H-imidazo[4,5-b]pyridin-2-one;
4. 3-{1-[frans-4-(ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}-5-methyl-1 ,3- dihydro-2H-imidazo[4,5-b]pyridin-2-one;
5. 5-chloro-3-{1-[frans-4-(ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}-1 ,3- dihydro-2H-imidazo[4,5-b]pyridin-2-one;
6. 3-{1-[frans-4-(ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}-5-(methyloxy)-1 ,3- dihydro-2H-imidazo[4,5-b]pyridin-2-one; 7. 3-{1-[frans-4-(ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}-6-methyl-1 ,3- dihydro-2H-imidazo[4,5-b]pyridin-2-one;
8. 1-{1-[frans-4-(ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}-6-methyl-1 ,3- dihydro-2H-imidazo[4,5-c]pyridin-2-one;
9. 6-bromo-1-{1-[frans-4-(ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}-1 ,3- dihydro-2H-imidazo[4,5-b]pyrazin-2-one; and
10. 1-{1-[frans-4-(ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}-6-methyl-1 ,3- dihydro-2H-imidazo[4,5-b]pyrazin-2-one; and salts thereof.
The compounds of the present invention may be in the form of their free base or salts thereof. In one embodiment, the salt is the hydrochloride salt, the trifluoroacetate salt or the formate salt. In one embodiment, the salt is the monohydrochloride, monoformate or monotrifluoroacetate salt.
Specific examples of salts of the present invention include:
3-{1-[frans-4-(ethyloxy)cyclohexyl]-4-piperidinyl}-5-methyl-1 ,3-dihydro-2H- imidazo[4,5-b]pyridin-2-one dihydrochloride; 5-methyl-3-{1-[c/s-1-methyl-4-(propyloxy)cyclohexyl]-4-piperidinyl}-1 ,3-dihydro-2/-/- imidazo[4,5-b]pyridin-2-one monohydrochloride;
5-methyl-3-{1-[frans-1-methyl-4-(propyloxy)cyclohexyl]-4-piperidinyl}-1 ,3-dihydro-2/-/- imidazo[4,5-b]pyridin-2-one monohydrochloride; 3-{1-[frans-4-(ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}-5-methyl-1 ,3-dihydro-2/-/- imidazo[4,5-b]pyridin-2-one monohydrochloride;
5-chloro-3-{1-[frans-4-(ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}-1 ,3-dihydro-2H- imidazo[4,5-b]pyridin-2-one monohydrochloride;
3-{1-[frans-4-(ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}-5-(methyloxy)-1 ,3-dihydro- 2H-imidazo[4,5-b]pyridin-2-one monohydrochloride;
3-{1-[frans-4-(ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}-6-methyl-1 ,3-dihydro-2H- imidazo[4,5-b]pyridin-2-on monohydrochloride;
1-{1-[frans-4-(ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}-6-methyl-1 ,3-dihydro-2H- imidazo[4,5-c]pyridin-2-one dihydrochloride; and 1-{1-[frans-4-(ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}-6-methyl-1 ,3-dihydro-2H- imidazo[4,5-b]pyrazin-2-one monohydrochloride.
Compounds of the invention may be prepared by methods known in the art of organic synthesis as set forth in part by the following synthesis schemes. In the following reaction schemes and hereafter, unless otherwise stated, all the groups are as defined in the first aspect. It is also recognised that in all of the schemes described below, it is well understood that protecting groups for sensitive or reactive groups are employed where necessary in accordance with general principles of chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (T. W. Greene and P. G. M. Wuts (1991 ) Protecting Groups in Organic Synthesis, John Wiley & Sons). These groups are removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art. The selection of processes as well as the reaction conditions and order of their execution shall be consistent with the preparation of compounds of the invention.
In a further aspect, the invention provides a general process (A1 ) for preparing compounds of formula (I) in which Q =H, which process comprises:
coupling a compound of formul
Figure imgf000011_0001
with a compound of formula
Figure imgf000012_0001
wherein:
- X1 is nitrogen or CH;
- X2 is nitrogen or CR5 and R5 is a group R5 as previously defined or a group convertible to R5;
- X3 is nitrogen or CR4 where R4 is a group R4 as previously defined or a group convertible to R4; and where one or two of Xi, X2, X3 is a nitrogen atom; and
--RR66 iiss aa ggrroouupp RR66 aass pprreevviioouussllyy ddeeffiinneedd,, oorr aa ggrroouupp ccoornvertible to R6, and R' is a group R as previously defined, or a group convertible to R.
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. Alternatively 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. In a further variation, 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. This reaction can generate a mixture of cis and trans isomers which can be separated by chromatography or crystallisation.
A modification of general process (A1 ) is required where Q is C1-6alkyl. Thus, there is provided a general process (A2) wherein Q is Ci-6alkyl, in which a compound of formula (II) can be reacted with a compound of formula (III) in the presence of a source of cyanide, e.g. acetone cyanohydrin, to form the cyano intermediate (XXXX) which can be reacted with an alkyl Grignard reagent QMgX to form compounds of formula (I) in which Q is C1-6 alkyl.
Figure imgf000012_0002
(XXXX) wherein:
- X1 is nitrogen or CH;
- X2 is nitrogen or CR5 and R5 is a group R5 as previously defined or a group convertible to R5; - X3 is nitrogen or CR4 where R4 is a group R4 as previously defined or a group convertible to R4; and where one or two of X1, X2, X3 is a nitrogen atom;
- R6 is a group R6 as previously defined, or a group convertible to R6;
- R' is a group R as previously defined, or a group convertible to R; - Q is C1-6 alkyl; and
- X is bromo or iodo or chloro.
In one aspect, the invention provides a compound of formula (XXXX) or a salt thereof wherein X1, X2, X3, R6 and R' are as hereinbefore defined.
This reaction can generate a mixture of cis and trans isomers which can be separated by chromatography or crystallisation.
In a further aspect, the invention provides a general process (B) for preparing compounds of formula (I) which process comprises:
coupling a compound of
Figure imgf000013_0001
with a compound of formula (V)
Figure imgf000013_0002
wherein;
- X1 is nitrogen or CH; - X2 is nitrogen or CR5 and R5 is a group R5 as previously defined or a group convertible to R5;
- X3 is nitrogen or CR4 where R4 is a group R4 as previously defined or a group convertible to R4; and where one or two of X1, X2, X3 is a nitrogen atom; - R6 is a group R6 as previously defined, or a group convertible to R6; - R' is a group R as previously defined, or a group convertible to R;
- Q is as previously defined; and
X and Y both represent leaving groups.
X and Y can be the same or different and examples are Cl, PhO, EtO, imidazole. When X and Y are both Cl, i.e. phosgene, this reagent can be generated in situ e.g. from diphosgene or triphosgene.
The above reaction is carried out using standard methodology e.g. reacting the compound (IV) with the reagent (V) in an inert solvent for example dichloromethane or toluene, optionally in the presence of a base such as triethylamine or potassium carbonate, and optionally with heating.
In one aspect, the invention provides a compound of formula (IV) or a salt thereof wherein R6 , X1, X2, X3, Q and R' are as hereinbefore defined.
It will be appreciated that compounds of formula (IV) can be cis or trans isomers, or a mixture of isomers. If necessary, separation of cis and trans isomers after the reaction with (V) can be achieved by chromatography or crystallisation.
In a further aspect, the invention provides a general process (C) for preparing compounds of formula (I) which process comprises:
treatment of a compound of formula (Vl)
Figure imgf000014_0001
with a palladium or copper catalyst (VII) to effect an intramolecular cyclisation
wherein:
- X1 is nitrogen or CH; - X2 is nitrogen or CR5 and R5 is a group R5 as previously defined or a group convertible to R5;
- X3 is nitrogen or CR4 where R4 is a group R4 as previously defined or a group convertible to R4; and where one or two of X1, X2, X3 is a nitrogen atom; - R6 is a group R6 as previously defined, or a group convertible to R6;
- R' is a group R as previously defined, or a group convertible to R;
- Q is as previously defined; and
- Z is a leaving group such as bromo, iodo, chloro or triflate.
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.)
It will be appreciated that compounds of formula (Vl) can be cis or trans isomers, or a mixture of isomers. If necessary, separation of cis and trans isomers after the intramolecular cyclisation can be achieved by chromatography or crystallisation.
In a further aspect, the invention provides a compound of formula (Vl) or a salt thereof wherein X1, X2, X3, R6 , Q, Z and R' are as hereinbefore defined.
In a further aspect, the invention provides a general process (D) for preparing compounds of formula (I) which process comprises:
coupling a compound of
Figure imgf000015_0001
with a compound of formula (IX)
Figure imgf000015_0002
wherein:
- X1 is nitrogen or CH;
- X2 is nitrogen or CR5 and R5 is a group R5 as previously defined or a group convertible to R5;
- X3 is nitrogen or CR4 where R4 is a group R4 as previously defined or a group convertible to R4; and where one or two of X1, X2, X3 is a nitrogen atom;
- R6 is a group R6 as previously defined, or a group convertible to R6;
- R' is a group R as previously defined, or a group convertible to R;
- Q is as previously defined; and - Ra is a C1-5alkyl group.
The condensation and cyclisation reactions can be carried out under reaction conditions similar to those described in the literature for an analogous process (US 3161645) (for example heating in an inert solvent such as xylene) followed by reduction of the piperidine double bond using for example catalytic hydrogenation over palladium or Raney nickel. It will be appreciated that compounds of formula (IX) can be cis or trans isomers, or a mixture of isomers. If necessary, separation of cis and trans isomers after the intramolecular cyclisation can be achieved by chromatography or crystallisation.
In a further aspect, the invention provides a general process (E) for preparing compounds of formula (I) which process comprises:
reaction of a compound
Figure imgf000016_0001
with diphenylphosphoryl azide or other reagent/combination of reagents to effect the Curtius rearrangement of compound (X), followed by intramolecular cyclisation.
wherein: - X1 is nitrogen or CH;
- X2 is nitrogen or CR5 and R5 is a group R5 as previously defined or a group convertible to R5;
- X3 is nitrogen or CR4 where R4 is a group R4 as previously defined or a group convertible to R4; and where one or two of X1, X2, X3 is a nitrogen atom;
- R6 is a group R6 as previously defined, or a group convertible to R6;
- R' is a group R as previously defined, or a group convertible to R; and Q is as previously defined.
The Curtius rearrangement is typically carried out by mixing the two reactants in an inert solvent such as toluene, optionally with heating.
It will be appreciated that compounds of formula (X) can be cis or trans isomers, or a mixture of isomers. If necessary, separation of cis and trans isomers after the intramolecular cyclisation can be achieved by chromatography or crystallisation.
In one aspect, the invention provides a compound of formula (X) or a salt thereof wherein X1, X2, X3, R6 , Q and R' are as hereinbefore defined.
In a further aspect, the invention provides a general process (F) for preparing compounds of formula (I) which process comprises: coupling a compound of formula
Figure imgf000017_0001
(Xl) with a compound of formula (XII)
Figure imgf000017_0002
wherein:
- X1 is nitrogen or CH;
- X2 is nitrogen or CR5 and R5 is a group R5 as previously defined or a group convertible to R5; - X3 is nitrogen or CR4 where R4 is a group R4 as previously defined or a group convertible to R4; and where one or two of Xi, X2, X3 is a nitrogen atom;
- R6 is a group R6 as previously defined, or a group convertible to R6;
- R' is a group R as previously defined, or a group convertible to R; - Q is as previously defined; and
- Z is hydroxy or a leaving group such as chloro, bromo or iodo, or alkyl/aryl sulfonate.
The alkylation reaction can be carried out under classical alkylation (Z = a leaving group) or Mitsunobu reaction (Z = OH) conditions. Using classical alkylation conditions, 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. The Mitsunobu reaction with (XII) Z = OH can be carried out using standard conditions e.g. triphenylphosphine and diethylazodicarboxylate in an inert solvent such as dichloromethane or tetrahydrofuran at room temperature.
It will be appreciated that compounds of formula (XII) can be cis or trans isomers, or a mixture of isomers. If necessary, separation of cis and trans isomers after the intramolecular cyclisation can be achieved by chromatography or crystallisation.
Conversion of R6 to R6 or interconversions of R6 may be accomplished as indicated below.
For example, when R6 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.
As another example, when R6 is hydroxy, it may be converted to an 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.
As a further example, when R6 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 to R or interconversions of R may be accomplished as indicated below.
For example when R' is benzyl, the benzyl group can be removed using standard methodology, e.g. catalytic hydrogenation over palladium on carbon, to provide the alcohol. Alkylation of the resultant alcohol using a strong base e.g. sodium hydride and a Ci-6 alkylating agent e.g. methyl iodide or ethyl iodide or propyl iodide, will afford the desired product. It will be appreciated that protection of any NH functionality present in the molecule may be necessary.
As another example, when R is methyl, the methyl group can be removed by treatment with a dealkylating agent such as boron tribromide to afford the alcohol intermediate, which can be alkylated in a similar manner to that described above. Alternatively the alcohol intermediate can be converted to R is trifluoromethyl by conversion to the xanthate followed by oxidation in the presence of fluoride ion.
Compounds of formula (II) are generally known in the literature or can be prepared by a range of different processes for example:
(a) displacement of an ortho-fluoro or ortho-chloro nitrobenzene intermediate (XIII) with the amine (XIV), wherein R5 is a group R5 as previously defined, or a group convertible to R5, R6 is a group R6 as previously defined, or a group convertible to R6, and P represents a nitrogen protecting group (e.g. Boc, acetyl, trifluoroacetyl, ethoxycarbonyl, benzyloxycarbonyl), to give (XXIII), followed by reduction of the nitro group, cyclisation using phosgene or a phosgene equivalent, and deprotection of the piperidine nitrogen using standard literature conditions (Scheme 1 ).
Scheme 1.
Figure imgf000019_0002
(XIII) III)
Figure imgf000019_0001
Figure imgf000019_0003
(H)
Compounds of formula (XIII) are commercially available or can be prepared by standard methodology. The compound (XIV) in which P = Boc is commercially available
(b) metal catalysed cyclisation of an intermediate (XV) followed by deprotection of the piperidine nitrogen, wherein:
- X1 is nitrogen or CH;
- X2 is nitrogen or CR5 and R5 is a group R5 as previously defined or a group convertible to R5;
- X3 is nitrogen or CR4 where R4 is a group R4 as previously defined or a group convertible to R4; and where one or two of X1, X2, X3 is a nitrogen atom;
- R6 is a group R6 as previously defined, or a group convertible to R6; - P represents a nitrogen protecting group (e.g. Boc, acetyl, trifluoroacetyl, benzyloxycarbonyl); and
- Z represents a leaving group such as bromo, iodo, chloro or triflate.
Reaction conditions for the metal catalysed cyclisation are summarised in Process C. The urea (XV) can be prepared using any of the classical methods for urea formation as illustrated in Scheme 2. The starting materials for this process are commercially available or can be prepared using standard methodology.
Scheme 2. equivalent
Figure imgf000020_0001
Figure imgf000020_0002
Figure imgf000020_0003
Figure imgf000020_0005
Figure imgf000020_0004
Figure imgf000020_0006
(c) Curtius rearrangement of an intermediate (XVI), wherein:
- X1 is nitrogen or CH; - X2 is nitrogen or CR5 and R5 is a group R5 as previously defined or a group convertible to R5;
- X3 is nitrogen or CR4 where R4 is a group R4 as previously defined or a group convertible to R4; and where one or two of X1, X2, X3 is a nitrogen atom; - R6 is a group R6 as previously defined, or a group convertible to R6;
- P represents a nitrogen protecting group (e.g. Boc, acetyl, trifluoroacetyl, benzyloxycarbonyl); and
- Rb represents H or a C1-5 alkyl group e.g. methyl or ethyl; followed by intramolecular cyclisation and deprotection of the piperidine nitrogen (Scheme 3). The anthranilic acid or ester starting materials (XVII) are commercially available or can be made by standard methodology. The piperidone starting material (P = Boc or benzyl) is commercially available. The Curtius rearrangement can be effected using the conditions described under process E.
Scheme 3.
Figure imgf000021_0001
(XVIl) (XVlIl)
Figure imgf000021_0002
(N) (XVi)
(d) Condensation of an orthophenylenediamine (VIII) with a 3-alkoxycarbonyl-4- piperidone (XX), wherein: - Xi is nitrogen or CH;
- X2 is nitrogen or CR5 and R5 is a group R5 as previously defined or a group convertible to R5;
- X3 is nitrogen or CR4 where R4 is a group R4 as previously defined or a group convertible to R4; and where one or two of X1, X2, X3 is a nitrogen atom;
- R6 is a group R6 as previously defined, or a group convertible to R6;
- P represents a nitrogen protecting group (e.g. Boc, acetyl, trifluoroacetyl, benzyloxycarbonyl); and
- Rb is a Ci-5 alkyl group; (Scheme 4), by heating in an inert solvent at elevated temperature, to afford the tetrahydropyridine intermediate (XXI).
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. Scheme 4.
Figure imgf000022_0001
(e) Reductive alkylation of an ortho nitroaniline (XXII) with an N-protected 4- piperidone (XVIII), wherein;
- X1 is nitrogen or CH;
- X2 is nitrogen or CR5 and R5 is a group R5 as previously defined or a group convertible to R5;
- X3 is nitrogen or CR4 where R4 is a group R4 as previously defined or a group convertible to R4; and where one or two of Xi, X2, X3 is a nitrogen atom;
- R6 is a group R6 as previously defined, or a group convertible to R6; and
- P represents a nitrogen protecting group (e.g. Boc, acetyl, trifluoroacetyl, benzyloxycarbonyl), using for example sodium triacetoxyborohydride to give the intermediate (XXIII).
Reduction of the nitro group, followed by cyclisation and deprotection as described hereinbefore provides the desired product (II) (Scheme 5). Compounds of formula (XXII) and (XVIII) are commercially available or can be prepared by standard methodology.
Scheme 5.
Figure imgf000023_0001
(XXII)
Figure imgf000023_0003
Figure imgf000023_0002
(H)
(f) metal catalysed reaction between the amine (XIV) and a suitably substituted nitrobenzene compound (XXIV) wherein: - X1 is nitrogen or CH:
- X2 is nitrogen or CR5 and R5 is a group R5 as previously defined or a group convertible to R5;
- X3 is nitrogen or CR4 where R4 is a group R4 as previously defined or a group convertible to R4; and where one or two of Xi, X21Xs is a nitrogen atom;
- R6 is a group R6 as previously defined, or a group convertible to R6;
- P represents a nitrogen protecting group (e.g. Boc, acetyl, trifluoroacetyl, benzyloxycarbonyl); and
- Z represents a leaving group such as bromo, iodo, chloro or triflate (Scheme 6). This process generates intermediates of formula (XXIII) and subsequent reactions are similar to that for Scheme 5. Compounds of formula (XXIV) are commercially available or can be prepared by known methodology. The compound (XIV) in which P = Boc is commercially available.
Scheme 6.
Figure imgf000024_0001
(g) metal catalysed reaction between the amine (XIV) and the protected aniline (XXV), wherein: - X1 is nitrogen or CH;
- X2 is nitrogen or CR5 and R5 is a group R5 as previously defined or a group convertible to R5;
- X3 is nitrogen or CR4 where R4 is a group R4 as previously defined or a group convertible to R4; and where one or two of X1, X2, X3 is a nitrogen atom;
- R6 is a group R6 as previously defined, or a group convertible to R6;
- P and P' independently represent a nitrogen protecting group (e.g. Boc, acetyl, trifluoroacetyl, benzyloxycarbonyl); and
- Z represents a leaving group such as bromo, iodo, chloro or triflate, to give the intermediate (XXVI) (Scheme 7).
Deprotection of the aniline followed by the same reaction sequence as in Scheme 6 affords the desired intermediate (II). Compounds of formula (XXV) are commercially available or can be prepared by known methodology e.g. halogenation ortho to the optionally protected aniline group. The compound (XIV) in which P = Boc is commercially available. Scheme 7.
Figure imgf000025_0001
The compounds of formula (III) can be prepared by standard literature methodology.
Compounds of formula (IV) can be prepared by a number of different processes e.g.
(h) displacement of an ortho-fluoro or ortho-chloro nitrobenzene intermediate (XIII) with the amine (XXVII) wherein:
- X1 is nitrogen or CH;
- X2 is nitrogen or CR5 and R5 is a group R5 as previously defined or a group convertible to R5;
- X3 is nitrogen or CR4 where R4 is a group R4 as previously defined or a group convertible to R4; and where one or two of X1, X2, X3 is a nitrogen atom;
- R6 is a group R6 as previously defined, or a group convertible to R6;
- R' is a group R as previously defined, or a group convertible to R; and
- Q is as previously defined; to afford compound (XXVIII) followed by reduction of the nitro group using standard conditions e.g. hydrogenation over palladium or Raney nickel (Scheme 8).
Compounds of formula (XIII) are commercially available or can be prepared by standard methodology. It will be appreciated that separation of the cis and trans isomers can be achieved at any suitable stage in the synthesis. Scheme 8.
Figure imgf000026_0001
(XXVIII)
Figure imgf000026_0002
(i) metal catalysed reaction of the amine (XXVII) with the ortho substituted nitrobenzene (XXIX), wherein
- X1 is nitrogen or CH;
- X2 is nitrogen or CR5 and R5 is a group R5 as previously defined or a group convertible to R5;
- X3 is nitrogen or CR4 where R4 is a group R4 as previously defined or a group convertible to R4; and where one or two of X1, X2, X3 is a nitrogen atom;
- R6 is a group R6 as previously defined, or a group convertible to R6;
- R' is a group R as previously defined, or a group convertible to R; and
- Q is as previously defined, to afford compound (XXVIII) (Scheme 9) followed by the same reactions as illustrated in Scheme 8.
Compounds of formula (XXIX) are commercially available or can be prepared by standard methodology. It will be appreciated that separation of the cis and trans isomers can be achieved at any suitable stage in the synthesis.
Scheme 9.
Figure imgf000027_0001
(j) metal catalysed reaction of the amine (XXVII) with the protected aniline derivative (XXV), wherein:
- X1 is nitrogen or CH;
- X2 is nitrogen or CR5 and R5 is a group R5 as previously defined or a group convertible to R5;
- X3 is nitrogen or CR4 where R4 is a group R4 as previously defined or a group convertible to R4; and where one or two of X-i, X2, X3 is a nitrogen atom;
- R6 is a group R6 as previously defined, or a group convertible to R6;
- R' is a group R as previously defined, or a group convertible to R;
- Q is as previously defined; and - P' represents either hydrogen or a nitrogen protecting group (such as acetyl, trifluoroacetyl, Boc, phthalimide), to afford compound (XXXI) (Scheme 10) followed by deprotection of the aniline group where required.
Compounds of formula (XXV) are commercially available or can be prepared by standard methodology. It will be appreciated that separation of the cis and trans isomers can be achieved at any suitable stage in the synthesis.
Scheme 10.
Figure imgf000028_0001
(IV)
(k) Reductive alkylation of an ortho nitroaniline (XXII) with the piperidone (XXXII) wherein: - X1 is nitrogen or CH;
- X2 is nitrogen or CR5 and R5 is a group R5 as previously defined or a group convertible to R5;
- X3 is nitrogen or CR4 where R4 is a group R4 as previously defined or a group convertible to R4; and where one or two of X1, X2, X3 is a nitrogen atom;
- R6 is a group R6 as previously defined, or a group convertible to R6;
- R' is a group R as previously defined, or a group convertible to R; and
- Q is as previously defined, using for example sodium triacetoxyborohydride in dichloroethane to give the intermediate (XXVIII) (Scheme 1 1 ). Reduction of the nitro group using, for example, palladium on carbon or Raney nickel affords the desired intermediate (IV). It will be appreciated that separation of the cis and trans isomers can be achieved at any suitable stage in the synthesis.
Scheme 11.
Figure imgf000029_0001
(XXIl) < (XXVIII)
Figure imgf000029_0002
Compounds of formula (V) are commercially available e.g. carbonyl diimidazole, phosgene, phosgene solution in toluene, diphosgene, triphosgene, phenyl chloroformate, diethyl carbonate.
Compounds of formula (Vl) can be prepared by a variety of processes e.g. urea formation can be achieved as shown in Scheme 12 by:
• combining the two amines (XXXIV) and (XXVII) with phosgene or a phosgene equivalent using standard conditions Phosgene equivalents include carbonyl diimidazole, diphosgene, triphosgene, phenyl cloroformate;
• reacting the amine (XXVII) with the isocyanate (XXXV); or
• reacting the amine (XXXIV) with the isocyanate (XXXVI).
Both isocyanates can be prepared from the corresponding amines using standard methodology for isocyanate formation.
It will be appreciated that separation of the cis and trans isomers can be achieved at any suitable stage in the synthesis.
Scheme 12. phosgene equivalent
Figure imgf000030_0001
Figure imgf000030_0002
(XXXIV) (XXXVl)
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 (VIII) are commercially available or can be prepared by known literature routes e.g. reduction of a mono or dinitrobenzene precursor.
Compounds of formula (IX) can be prepared by reductive alkylation of the 3- alkoxycarbonyl-4-piperidone with cyclohexanone.
Compounds of formula (X) can be prepared as shown in Scheme 13. Reductive alkylation of the acid or ester (XVII) with the ketone (XXXII), followed if appropriate by hydrolysis of the ester group. It will be appreciated that separation of the cis and trans isomers can be achieved at any suitable stage in the synthesis.
Scheme 13.
Figure imgf000031_0001
(X)
Compounds of formula (Xl) are commercially available or can be prepared by literature processes.
Compounds of formula (XII) where Q = H can be prepared as shown in Scheme 14, by reductive alkylation of (XXXVII) where Z' represents Z or a group convertible to Z with the ketone (III). Conversion of a Z' = hydroxy group to Z = chloro or bromo can be accomplished using standard methodology e.g. treatment with thionyl chloride or triphenylphosphine/carbon tetrabromide. It will be appreciated that separation of the cis and trans isomers can be achieved at any suitable stage in the synthesis.
Scheme 14.
Figure imgf000031_0002
(XXXVII)
(XII)
The compound (XXVII) where Q = H can be prepared as shown in Scheme 15. Reductive alkylation of the commercially available amine (XXXVIII) with cyclohexanone (III) using for example sodium triacetoxyborohydride in dichloroethane provides the intermediate (XXXIX) which is deprotected using HCI in ethanol or trifluoroacetic acid to afford the primary amine (XXVII). It will be appreciated that separation of the cis and trans isomers can be achieved at any suitable stage in the synthesis.
Scheme 15.
(XXXVIII) (XXXlX) (XXVIl) The compound (XXVII) where Q = alkyl can be prepared as in process A2, followed by deprotection.
In one embodiment, the group R' in the above described processes is the group R as hereinbefore defined.
In one embodiment, the group R6 in the above described processes is the group R6 as hereinbefore defined.
Compounds of the present invention are M1 receptor agonists. Selective M1 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 M2 and M3 receptors. M1 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.
Thus in a further aspect, the invention provides a compound of formula (I) as hereinbefore described or a pharmaceutically acceptable salt thereof for use in therapy.
In another aspect, 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 M1 receptor would be beneficial.
The terms describing the indications used herein are classified in the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, published by the American Psychiatric Association (DSM-IV) and/or the International Classification of Diseases, 10th Edition (ICD-10). Treatment of the various subtypes of the disorders mentioned herein are contemplated as part of the present invention. Numbers in brackets after the listed diseases below refer to the classification code in DSM-IV.
Within the context of the present invention, 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);
Other conditions wherein agonism of the M1 receptor would be beneficial in their treatment include:
Depression and mood disorders including Major Depressive Episode, Manic Episode, Mixed Episode and Hypomanic Episode; Depressive Disorders including Major Depressive Disorder, Dysthymic Disorder (300.4), Depressive Disorder Not Otherwise Specified (311 ); Bipolar Disorders including Bipolar I Disorder, Bipolar Il Disorder (Recurrent Major Depressive Episodes with Hypomanic Episodes) (296.89), Cyclothymic Disorder (301.13) and Bipolar Disorder Not Otherwise Specified (296.80); Other Mood Disorders including Mood Disorder Due to a General Medical Condition (293.83) which includes the subtypes With Depressive Features, With Major Depressive-like Episode, With Manic Features and With Mixed Features), Substance-Induced Mood Disorder (including the subtypes With Depressive Features, With Manic Features and With Mixed Features) and Mood Disorder Not Otherwise Specified (296.90);
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-lnjury 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, Alcohol-Induced Mood Disorder, Alcohol- Induced Anxiety Disorder, Alcohol-Induced Sexual Dysfunction, Alcohol-Induced Sleep Disorder and Alcohol-Related Disorder Not Otherwise Specified (291.9); Amphetamine (or Amphetamine-I_ike)-Related Disorders such as Amphetamine Dependence (304.40), Amphetamine Abuse (305.70), Amphetamine Intoxication (292.89), Amphetamine Withdrawal (292.0), Amphetamine Intoxication Delirium, Amphetamine Induced Psychotic Disorder, Amphetamine-Induced Mood Disorder, Amphetamine-Induced Anxiety Disorder, Amphetamine-Induced Sexual Dysfunction, Amphetamine-Induced Sleep Disorder and Amphetamine-Related Disorder Not Otherwise Specified (292.9); Caffeine Related Disorders such as Caffeine Intoxication (305.90), Caffeine-Induced Anxiety Disorder, Caffeine-Induced Sleep Disorder and Caffeine-Related Disorder Not Otherwise Specified (292.9); Cannabis- Related Disorders such as Cannabis Dependence (304.30), Cannabis Abuse (305.20), Cannabis Intoxication (292.89), Cannabis Intoxication Delirium, Cannabis- Induced Psychotic Disorder, Cannabis-lnduced Anxiety Disorder and Cannabis- Related Disorder Not Otherwise Specified (292.9); Cocaine-Related Disorders such as Cocaine Dependence (304.20), Cocaine Abuse (305.60), Cocaine Intoxication (292.89), Cocaine Withdrawal (292.0), Cocaine Intoxication Delirium, Cocaine- Induced Psychotic Disorder, Cocaine-Induced Mood Disorder, Cocaine-Induced Anxiety Disorder, Cocaine-Induced Sexual Dysfunction, Cocaine-Induced Sleep Disorder and Cocaine-Related Disorder Not Otherwise Specified (292.9); Hallucinogen-Related Disorders such as Hallucinogen Dependence (304.50), Hallucinogen Abuse (305.30), Hallucinogen Intoxication (292.89), Hallucinogen Persisting Perception Disorder (Flashbacks) (292.89), Hallucinogen Intoxication Delirium, Hallucinogen-Induced Psychotic Disorder, Hallucinogen-Induced Mood Disorder, Hallucinogen-Induced Anxiety Disorder and Hallucinogen-Related Disorder Not Otherwise Specified (292.9); Inhalant-Related Disorders such as Inhalant Dependence (304.60), Inhalant Abuse (305.90), Inhalant Intoxication (292.89), Inhalant Intoxication Delirium, Inhalant-Induced Persisting Dementia, Inhalant- Induced Psychotic Disorder, Inhalant-Induced Mood Disorder, Inhalant-Induced Anxiety Disorder and Inhalant-Related Disorder Not Otherwise Specified (292.9); Nicotine-Related Disorders such as Nicotine Dependence (305.1 ), Nicotine Withdrawal (292.0) and Nicotine-Related Disorder Not Otherwise Specified (292.9); Opioid-Related Disorders such as Opioid Dependence (304.00), Opioid Abuse (305.50), Opioid Intoxication (292.89), Opioid Withdrawal (292.0), Opioid Intoxication Delirium, Opioid-lnduced Psychotic Disorder, Opioid-lnduced Mood Disorder, Opioid- lnduced Sexual Dysfunction, Opioid-lnduced Sleep Disorder and Opioid-Related Disorder Not Otherwise Specified (292.9); Phencyclidine (or Phencyclidine-Like)- Related Disorders such as Phencyclidine Dependence (304.60), Phencyclidine Abuse (305.90), Phencyclidine Intoxication (292.89), Phencyclidine Intoxication Delirium, Phencyclidine-lnduced Psychotic Disorder, Phencyclidine-lnduced Mood Disorder, Phencyclidine-lnduced Anxiety Disorder and Phencyclidine-Related Disorder Not Otherwise Specified (292.9); Sedative-, Hypnotic-, or Anxiolytic-Related Disorders such as Sedative, Hypnotic, or Anxiolytic Dependence (304.10), Sedative, Hypnotic, or Anxiolytic Abuse (305.40), Sedative, Hypnotic, or Anxiolytic Intoxication (292.89), Sedative, Hypnotic, or Anxiolytic Withdrawal (292.0), Sedative, Hypnotic, or Anxiolytic Intoxication Delirium, Sedative, Hypnotic, or Anxiolytic Withdrawal Delirium, Sedative-, Hypnotic-, or Anxiolytic-Persisting Dementia, Sedative-, Hypnotic-, or Anxiolytic- Persisting Amnestic Disorder, Sedative-, Hypnotic-, or Anxiolytic-lnduced Psychotic Disorder, Sedative-, Hypnotic-, or Anxiolytic-lnduced Mood Disorder, Sedative-, Hypnotic-, or Anxiolytic-lnduced Anxiety Disorder Sedative-, Hypnotic-, or Anxiolytic-lnduced Sexual Dysfunction, Sedative-, Hypnotic-, or Anxiolytic-lnduced Sleep Disorder and Sedative-, Hypnotic-, or Anxiolytic-Related Disorder Not Otherwise Specified (292.9); Polysubstance-Related Disorder such as Polysubstance Dependence (304.80); and Other (or Unknown) Substance-Related Disorders such as Anabolic Steroids, Nitrate Inhalants and Nitrous Oxide;
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 Personality Disorder (301 ,22), Antisocial Personality Disorder (301.7), Borderline Personality Disorder (301 ,83), Histrionic Personality Disorder (301.50), Narcissistic Personality Disorder (301 ,81 ), Avoidant Personality Disorder (301.82), Dependent Personality Disorder (301.6), Obsessive-Compulsive Personality Disorder (301.4) and Personality Disorder Not Otherwise Specified (301.9); and
Sexual dysfunctions including Sexual Desire Disorders such as Hypoactive Sexual Desire Disorder (302.71 ), and Sexual Aversion Disorder (302.79); sexual arousal disorders such as Female Sexual Arousal Disorder (302.72) and Male Erectile Disorder (302.72); orgasmic disorders such as Female Orgasmic Disorder (302.73), Male Orgasmic Disorder (302.74) and Premature Ejaculation (302.75); sexual pain disorder such as Dyspareunia (302.76) and Vaginismus (306.51 ); Sexual Dysfunction Not Otherwise Specified (302.70); paraphilias such as Exhibitionism (302.4), Fetishism (302.81 ), Frotteurism (302.89), Pedophilia (302.2), Sexual Masochism (302.83), Sexual Sadism (302.84), Transvestic Fetishism (302.3), Voyeurism (302.82) and Paraphilia Not Otherwise Specified (302.9); gender identity disorders such as Gender Identity Disorder in Children (302.6) and Gender Identity Disorder in Adolescents or Adults (302.85); and Sexual Disorder Not Otherwise Specified (302.9).
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. Where cognitive impairment results from a treatment of a disease, M1 agonists may be beneficial. For example, when the treatment of epilepsy with anticonvulsants results in cognitive impairment, an M1 agonist may be useful for the alleviation or treatment of the cognitive impairment.
Within the context of the present invention, 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's disease, neuroleptic-induced parkinsonism, and tardive dyskinesias.
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.
In another aspect, 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.
In another aspect, 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 M1 receptor would be beneficial.
In another aspect, 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. In one embodiment, 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.
In another aspect, 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. In another aspect, the invention provides a method of treating a condition where agonism of the M1 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. In one embodiment, the mammal is a human.
In another aspect, 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. In one embodiment, 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. In one embodiment, 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. In one embodiment, 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.
The combination therapies of the invention are, for example, administered adjunctively. By 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. In one embodiment of adjunctive therapeutic administration as described herein, 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. By 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.
In a further aspect therefore, 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. In a further aspect, 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. In a further aspect, 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.
In a further aspect, 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. In a further aspect, 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. In a further aspect, 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.
In a further aspect, 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.
In a further aspect, 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.
In another aspect, 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.
In a further aspect, 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.
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.
In a further aspect, 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.
In a further aspect, 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.
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
In a further aspect, 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 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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
In a further aspect, 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.
In one embodiment, the patient is a human.
Examples of antipsychotic drugs that may be useful in the present invention 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, fluphenazine, thiflupromazine, prochlorperazine, and acetophenazine; thioxanthenes, such as thiothixene and chlorprothixene; thienobenzodiazepines; dibenzodiazepines; benzisoxazoles; dibenzothiazepines; imidazolidinones; benzisothiazolyl-piperazines; triazine such as lamotrigine; dibenzoxazepines, such as loxapine; dihydroindolones, such as molindone; aripiprazole; and derivatives thereof that have antipsychotic activity.
Examples of 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®); haloperidol lactate (available under the tradenames HALDOL® and INTENSOL®); chlorpromazine (available under the tradename THORAZINE®, from SmithKline Beecham (GSK)); fluphenazine (available under the tradename PROLIXIN®, from Apothecon, Copley, Schering, Teva, and American Pharmaceutical Partners, Pasadena); fluphenazine decanoate (available under the tradename PROLIXIN decanoate®); fluphenazine enanthate (available under the tradename PROLIXIN®); fluphenazine hydrochloride (available under the tradename PROLIXIN®); thiothixene (available under the tradename NAVANE®, from Pfizer); thiothixene hydrochloride (available under the tradename NAVANE®); trifluoperazine (10-[3-(4-methyl-1-piperazinyl)propyl]-2-(trifluoromethyl)phenothiazine dihydrochloride, available under the tradename STELAZINE®, from SmithKline Beckman); perphenazine (available under the tradename TRILAFON®, from Schering); perphenazine and amitriptyline hydrochloride (available under the tradename ETRAFON TRILAFON®); thioridazine (available under the tradename MELLARIL®; from Novartis, Roxane, HiTech, Teva, and Alpharma); molindone (available under the tradename MOBAN®, from Endo); molindone hydrochloride (available under the tradename MOBAN®); loxapine (available under the tradename LOXITANE®; from Watson); loxapine hydrochloride (available under the tradename LOXITANE®); and loxapine succinate (available under the tradename LOXITANE®). Furthermore, benperidol (Glianimon®), perazine (Taxilan®) or melperone (Eunerpan®)) may be used.
Other suitable 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(D), acetophenazine (available under the tradename TINDAL®;), prochlorperazine (available under the tradename COMPAZINE®), methotrimeprazine (available under the tradename NOZINAN®), pipotiazine (available under the tradename PIPOTRIL®), iloperidone, pimozide and flupenthixol.
The antipsychotic drugs listed above by Tradename may also be available from other suppliers under a different Tradename.
In one further aspect of the invention, 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); tricyclic antidepressants (such as amitriptyline, clomipramine, imipramine, maprotiline, nortriptyline and trimipramine); monoamine oxidase inhibitors (such as isocarboxazide, moclobemide, phenelzine and tranylcypromine); 5HT3 antagonists (such as example ondansetron and granisetron); and others (such as bupropion, amineptine, radafaxine, mianserin, mirtazapine, nefazodone and trazodone).
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).
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 M1 agonists (such as cevimeline). For use in medicine, 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. In a further aspect, 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. In a further aspect, 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. In a further aspect, 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. 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. Examples of such carriers include magnesium stearate, starch, lactose, sucrose and cellulose.
A composition in the form of a capsule can be prepared using routine encapsulation procedures. For example, 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.
Typical parenteral 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. Alternatively, 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. Alternatively 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. Where the dosage form comprises an aerosol dispenser, it will contain a propellant which can be a compressed gas such as compressed air or an organic propellant such as a fluorochlorohydrocarbon. The aerosol dosage forms can also take the form of a pump-atomiser.
Compositions suitable for buccal or sublingual administration include tablets, lozenges and pastilles, wherein the active ingredient is formulated with a carrier such as sugar and acacia, tragacanth, or gelatin and glycerin.
Compositions for rectal administration are conveniently in the form of suppositories containing a conventional suppository base such as cocoa butter.
Compositions suitable for transdermal administration include ointments, gels and patches.
The composition 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.
It will be appreciated that the precise dose administered will depend on the age and condition of the patient and the frequency and route of administration and will be at the ultimate discretion of the attendant physician.
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. In the case of the antipsychotic agent or agents, 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.
For adjunctive therapeutic administration according to the invention, 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. The choice of the most appropriate 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.
For simultaneous administration as a combined composition of compounds of formula (I) and the antipsychotic agent or agents according to the invention, 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. 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.
In order to obtain consistency of adjunctive administration, the compositions of each of the components, or of the combination of the components is, for example, in the form of a unit dose.
The term "treatment" includes prophylaxis, where this is appropriate for the relevant condition(s).
Biological Test Methods FLIPR experiments on M1 receptor to determine agonist/antagonist potency Compounds of the invention were characterized in a functional assay to determine their ability to activate the intracellular calcium pathway in CHO cells with stable expression of human muscarinic receptors using FLIPR (Fluorometric Imaging Plate Reader) technology. Briefly, CH0-M1 cells were plated (15,000/well) and allowed to grow overnight at 37 degrees. Media was removed and 30μL loading buffer (HBSS with 2.5mM probenicid, 2μM Fluo-4, 500μM Brilliant Black, pH 7.4) was added. After incubation at 37 degrees for 90 minutes, 10μL 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. Plates were then incubated for another 30 minutes before 10μL of assay buffer containing acetylcholine was added at an EC8O, 3S the agonist challenge. Calcium response was then monitored again to determine compound's antagonism to acetylcholine. Concentration-response curves of both agonism and antagonism on M1 receptors were performed for each compound. 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 pECso/fpK, 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 example compounds below were tested in the above assay and were each found to have an average pEC50 value of > 6.0 at the muscarinic M1 receptor, and intrinsic activity > 50%.
FLIPR experiments on M1 receptor to determine agonist intrinsic activity To determine the intrinsic activities of M1 agonist compounds, compounds of the invention were characterized in FLIPR experiments on CHO cells with transient expression of human muscarinic M1 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. Alternatively, 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 pEC50 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 example compounds below were tested in the above assay, and were each found to have an average pEC50 value of > 6.0 at the muscarinic M1 receptor, and intrinsic activity of greater than or equal to 0.3.
FLIPR experiments on M2-5 receptor to determine receptor subtype selectivity To determine selectivity of compounds of the invention against other muscarinic receptor subtypes, compounds were characterized in FLIPR experiments in CHO cells with stable expression of human muscarinic receptors, M2, M3, M4 or M5. In the case of M2 and M4 receptors, chimeric G-protein Gqi5 was also co-expressed to couple receptors to the calcium signaling pathway. Briefly, cells were plated (15,000/well) and allowed to grow overnight at 37 degrees. The FLIPR experiment was then carried out on the 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 pEC5o/fpK, values were calculated.
The example compounds below were tested in the above assay and were found to be selective for the M1 receptor over M2, M3, M4 and M5 receptors, with typical selectivity (ratio of pEC50's) of >10-fold, and in certain cases > 100-fold.
The invention is further illustrated by the following non-limiting examples. In the procedures that follow, after each starting material, reference to a Description by number is typically provided. This is provided merely for assistance to the skilled chemist.
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). 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 d6- DMSO unless otherwise stated. All NMR spectra were referenced to tetramethylsilane (TMS δH 0, δC 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 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-).
Starting materials, reagents and solvents were obtained from commercial suppliers and used without further purification unless otherwise stated. Unless otherwise stated, all compounds with chiral centres are racemic. Where reactions are described as having been carried out in a similar manner to earlier, more completely described reactions, the general reaction conditions used were essentially the same. Work up conditions used were of the types standard in the art, but may have been adapted from one reaction to another. The starting material may not necessarily have been prepared from the batch referred to. Compounds synthesised may have various purities ranging from for example 85% to 98%. However, calculations of number of moles and yield are generally not adjusted for this.
Abbreviations
DCM dichloromethane NMP N-methyl pirrolidine THF tetrahydrofurane MDAP mass directed autopreparation DMF dimethylformamide
DIPEA didisopropylethylamine
MeOH methanol
Rt room temperature
Description 1. 1,4-dioxaspiro[4.5]decan-8-ol (D1)
Figure imgf000051_0001
1 ,4-Dioxaspiro[4.5]decan-8-one (256 mmol, 40 g) was dissolved in EtOH (500 ml) and treated with NaBH4 (1.2eq., 307.2 mmol, 11.6 g), at O 0C and the mixture was stirred at room temperature for 1 hour. Reaction was quenched with NaOH (200 ml, 2N aqueous solution). The aqueous solution was extracted with dichloromethane. The organic extracts were combined, dried over Na2SO4, filtered and the solvent was evaporated to afford the title compound, (38.7 g, 96%) as colourless oil. 1H NMR δ(d6-DMSO, 400 MHz) 1.446 (4H, m), 1.661 (4H, m), 3.537 (1 H, broad), 3.828 (4H, m), 4.529 (1 H, d).
Description 2. 8-(propyloxy)-1 ,4-dioxaspiro[4.5]decane (D2)
Figure imgf000052_0001
1 ,4-Dioxaspiro[4.5]decan-8-ol (D1 ) (94.8 mmol, 15g) was dissolved in NMP (200 ml) and NaH (2eq., 186.6 mmol, 7.6 g, from a 60% dispersion in mineral oil) was added at 0 0C portionwise. The mixture was stirred at 0 0C for 10 minutes and propyliodide (2 eq., 18 ml) was added at room temperature. The mixture was stirred at room temperature for 2 hours, then it was quenched with MeOH, partitioned between EtOAc and water, and the two phases were separated. The aqueous phase was extracted with EtOAc (2x), the combined organic extracts were washed with water first, then brine, dried over Na2SO4, filtered and the solvent was evaporated to afford the title compound, (6.4 g, 30%).
1H NMR δ (de-DMSO, 400 MHz) 0.75 (3H, t), 1.494 (6H, m), 1.684 (4H, m), 3.328 (3H under water peak, m), 3.835 (4H, s).
Description 3. 4-(propyloxy)cyclohexanone (D3)
Figure imgf000052_0002
8-(Propyloxy)-1 ,4-dioxaspiro[4.5]decane (D2) (32.3 mmol, 6.5g) was dissolved in 5 ml of THF and HCI (25 ml of 5M aqueous solution) was added at room temperature, and the mixture was stirred at room temperature overnight. The THF was removed by evaporation, the mixture was basified to pH = 10 and was extracted with EtOAc (3x). The organic phases were combined and washed with brine, dried over Na2SO4, filtered and the solvent evaporated to afford the title crude compound which was then purified by chromatography (EtOAc/n-hexane) to afford the title compound, (2.1 g , 40%), as a pale yellow oil.
1H NMR δ (de-DMSO, 400 MHz) 0.95 (3H, t), 1.53 (2H, m), 1.896 (4H, m), 2.209 (2H, m), 2.408 (2H, m), 3.408 (2H, t), 3.674 (1 H, m).
Description 4. cis/trans 1,1-dimethylethyl {1-[1 -methyl -4-
(propyloxy)cyclohexyl]-4-piperidinyl}carbamate (D4)
Figure imgf000053_0001
A three-necked flask was equipped with a Dean-Stark trap and an argon-connected condenser. The flask was charged with 1 ,1-dimethylethyl 4-piperidinylcarbamate (1.1 eq., 7 mmol, 1.4 g), 4-(propyloxy)cyclohexanone (D3) (1 eq., 6.4 mmol, 1 g), 1 ,2,3-triazole (1.2 eq., 7.7 mmol, 0.53 g) and 50 ml of dry toluene. The mixture was refluxed at 130 0C for 6 hours under argon then cooled to room temperature and added to a solution of MeMgBr (3M in Et2O) (4 eq., 25.6 mmol, 8.5 ml) at < 25 0C over 20 minutes. Precipitation of a solid was observed. Additional THF (50 ml) was added and the temperature was rigorously kept at 10 0C by an ice bath. The mixture was stirred at room temperature overnight. The mixture was then cooled to 0 0C and was slowly quenched with an aqueous saturated solution of ammonium chloride. The mixture was subsequently brought to room temperature, diluted with EtOAc and the two phases were separated. The aqueous phase was the extracted with EtOAc (2x), organic extracts were combined, dried over sodium sulphate, filtered and the solvent was evaporated to afford the crude product that was subsequently purified by silica chromatography (MeOH-NH3-DCM) to afford 0.66 g of the title compound, 30%, as a yellow oil, M+ + H = 355.
Description 5. cis/trans 1-[1-methyl-4-(propyloxy)cyclohexyl]-4-piperidinamine dihydrochloride (D5)
Figure imgf000053_0002
Cis/trans 1 ,1-dimethylethyl {1-[1-methyl-4-(propyloxy)cyclohexyl]-4- piperidinyl}carbamate (D4) (0.66g, 1.8 mmol), was dissolved in Et2O (10 ml) and HCI (5 ml of a 4M solution in 1 ,4-dioxane) was added at room temperature. The mixture was stirred at room temperature for 6 hours. The solvent was subsequently evaporated to afford the crude product, 440 mg, M+ + H = 255. Crude D5 was directly used for the next step.
Description 6. cis/trans 6-methyl-Λ/-{1 -[1-methyl-4-(propyloxy)cyclohexyl]-4- piperidinyl}-3-nitro-2-pyridinamine (D6)
Figure imgf000054_0001
Cis/trans 1-[1-methyl-4-(propyloxy)cyclohexyl]-4-piperidinamine dihydrochloride (D5) (0.7 eq., 70 mg, 0.210 mmol), Hϋnig's base (1 eq., 0.50 μl), and 2-fluoro-4-methyl-1- nitrobenzene (1 eq., 0.3 mmol, 52 mg) were dissolved in DMF (2ml) and the mixture stirred at 80 0C for 18 hours. The crude mixture was then cooled to room temperature and poured onto a saturated aqueous solution of NaHCO3, EtOAc was added and the two phases were separated. The aqueous solution was extracted with EtOAc (2x), and organic extracts were washed with brine /water. The organic extracts were combined, dried over IS^SO4, filtered and the solvent was evaporated to afford the crude product that was successfully purified by chromatography to yield the title compound as a mixture of the two isomers, (50 mgs, 50%), M+ + H = 391.
Description 7. cis/trans 6-methyl-Λ/2-{1 -[1-methyl-4-(propyloxy)cyclohexyl]-4- piperidinyl}-2,3-pyridinediamine (D7)
Figure imgf000054_0002
Cis/trans 6-methyl-Λ/-{1-[1-methyl-4-(propyloxy)cyclohexyl]-4-piperidinyl}-3-nitro-2- pyridinamine (D6) (0.153 mmol) was dissolved in EtOH (10 ml) and Raney-Ni (0.2 ml of a 50% aqueous suspension) was added at room temperature, followed by hydrazine hydrate (10 eq., 1.537 mmol, 0.047 ml). The mixture was stirred at room temperature for 4 hours. The mixture was cooled to room temperature and was filtered through Celite®. The solvent was subsequently evaporated to afford the crude compound which was successfully purified by chromatography (MeOH-NH3- DCM, 25S silica column) to afford the title compound, a mixture of cis/trans isomers, (46 mg, 83%), M+ + H = 361.
Description 8. frans-N-(4-Hydroxycyclohexyl)phthalimide (D8)
Figure imgf000055_0001
N-Ethoxycarbonylphthalimide (10Og) was added to a mixture of trans-4- hydroxycyclohexylamine hydrochloride (69g), potassium carbonate (158g) and water (11) at room temperature. After 3h the title compound was isolated by filtration, washing with water then ethyl acetate (95g).
Description 9. frans-N-(4-tert-Butyldimethylsilyloxycyclohexyl)phthalimide (D9)
Figure imgf000055_0002
Tert-butyldimethylsilyl chloride (6Og) was added in portions to a mixture of trans N-(4- hydroxycyclohexyl)phthalimide (D8, 95g), imidazole (55g), and DMF (200ml) at 20-300C (internal, ice cooling). After stirring for 3h at 400C the mixture was partitioned between water and hexane. Drying and evaporation of the organic layer gave the title compound crystallised from pentane (92g).
Description 10. frans-N-(4-Ethoxycyclohexyl)phthalimide (D10)
Figure imgf000056_0001
Acetaldehyde (10ml) in acetonitrile (50ml) was added over 30 minutes to a solution of frans-N-(4-tert-butyldimethylsilyloxycyclohexyl)phthalimide (D9, 50.Og), bismuth tribromide (6.7g) and triethylsilane (27ml) in acetonitrile (500ml) stirred at ice bath temperature, and the mixture was allowed to warm to room temperature overnight. The mixture was filtered and the resulting grey solid and filtrate were worked up separately. The filtrate was evaporated and treated with hexane to give the title compound as a white solid (16.35g). The grey solid was washed with dichloromethane, the dichloromethane extract was evaporated and the residue was stirred with hexane (200ml) to give a second crop of the title compound as a white solid (17.47g). Description 11. frans-4-Ethoxycyclohexylamine (D11)
Figure imgf000056_0002
(D 1 1 )
A solution of trans-N-(4-ethoxycyclohexyl)phthalimide (D10, 16.35g), hydrazine hydrate (12ml) in ethanol (300ml) and methanol (200ml) was stirred at reflux for 3 hours. The solvent was removed to give a slurry, which was treated with diethyl ether and filtered. The filtrate was evaporated to afford the title compound as a viscous oil contaminated with ether (8.16g).
Description 12. 1-Ethyl-1-methyl-4-oxopiperidinium iodide (D12)
Figure imgf000056_0003
lodomethane (65ml) was added in portions to a solution of 1-ethyl-4-piperidone (100g) in acetone (11) at 20-300C (internal, ice cooling). After stirring for 3h the title compound was obtained by filtration (189g).
Description 13. trans-Λ -(4-Ethoxycyclohexyl)-4-piperidone (D13)
Figure imgf000057_0001
A mixture of 1-ethyl-1-methyl-4-oxopiperidinium iodide (D12, 27g), trans-4- ethoxycyclohexylamine (D11 , 8.16g), potassium carbonate (13.5g), water (100ml), and ethanol (200ml) was heated for 3 hours at 800C, then cooled overnight. The mixture was partitioned with aqueous sodium bicarbonate and dichloromethane. The dichloromethane layer was separated, washed with brine and solvent removed to give the title compound as an amber coloured oil (13.2g).
Description 14. 8-(Ethyloxy)-1,4-dioxaspiro[4.5]decane (D14)
Figure imgf000057_0002
A stirred solution of 1 ,4-dioxaspiro[4.5]decan-8-ol (D1 , 4.Og, 0.025mol) in N- methylpyrrolidinone (35ml) at 1O0C under argon was treated portionwise with NaH (1.1g of 60% oil dispersion, 0.028mol) and maintained for 1 h, then iodoethane (2.6ml, 0.032mol) was added. The mixture was allowed to warm to room temperature and stirred for 18h. Further NaH (0.5g of 60% oil dispersion) was added and the mixture stirred for 0.5h, then more iodoethane (2.0ml) was added and the mixture maintained at room temperature for 3h. The mixture was cautiously treated with ethanol (1 ml) to destroy excess NaH and then water (300ml) was added and the mixture extracted with hexane (2 x 200ml). The combined extract was washed with water (2 x 200ml), dried (Na2SC>4) and concentrated under reduced pressure to afford a colourless oil (4.7g) containing the title compound contaminated with mineral oil residues.
1HNMR δ(CDCI3, 400 MHz): 1.20 (3H, t), 1.50-1.60 (2H, m), 1.63-1.77 (2H, m), 1.77- 1.90 (4H, m), 3.35-3.43 (1 H, m), 3.49 (2H, q), 3.90-4.00 (4H, m).
Description 15. 4-(Ethyloxy)cyclohexanone (D15)
Figure imgf000058_0001
A solution of 8-(ethyloxy)-1 ,4-dioxaspiro[4.5]decane (D14, 4.7g, 0.025mol) in tetrahydrofuran (1OmI) at room temperature under argon was treated with 5M HCI acid (40ml) and stirred for 18h, at which stage cone. HCI acid (5ml) was added and the mixture heated at 4O0C until the reaction was complete. The resulting mixture was diluted with water (75ml) and extracted with dichloromethane (2 x 80ml). The combined extract was dried (Na2SO4) and carefully concentrated under partial reduced pressure at <20 0C to afford the title compound as a pale yellow oil (3.8g, -90% purity). 1H NMR δ(CDCI3, 400 MHz): 1.25 (3H, t), 1.90-2.00 (2H, m), 2.01-2.13 (2H, m), 2.20- 2.32 (2H, m), 2.53-2.65 (2H, m), 3.55 (2H, q), 3.58-3.70 (1 H, m).
Description 16. 1,1 -Dimethylethyl {1-[frans-4-(ethyloxy)cyclohexyl]-4- piperidinyl}carbamate (D16)
Figure imgf000058_0002
A stirred solution of 4-(ethyloxy)cyclohexanone (D15, 3.5g, 0.025 mol) in dichloromethane (100ml) at room temperature under argon was treated with 1 ,1- dimethylethyl 4-piperidinylcarbamate (5.Og, 0.025 mol), followed by portionwise addition over 5 minutes of sodium triacetoxyborohydride (7.4g, 0.035mol), then the resulting mixture stirred well at room temperature for 2Oh. The reaction mixture was treated with methanol (8ml) and the resulting solution allowed to stand for 3 days. 5% Na2COs solution (100ml) was then added and the mixture extracted with dichloromethane (200ml). The extract was washed with brine, dried (Na2SO4) and concentrated under reduced pressure. The residual yellow oil was dissolved in 60-80 petroleum ether (100ml) and allowed to stand at room temperature overnight whereupon the crystals which had formed were filtered off, washed with petroleum ether and dried (to give 1.7g of -45:55 mixture of title compound trans isomer and starting 1 ,1-dimethylethyl 4-piperidinylcarbamate). Purification by column chromatography on silica gel eluting with 0-5% methanol/dichloromethane afforded the pure title compound trans isomer (D16) as a white solid (0.93g). 1H NMR δ(CDCI3, 400 MHz): 1.15-1.50 (6H, m), 1.18 (3H, t), 1.44 (9H, s), 1.82-2.00 (4H, m), 2.04-2.14 (2H, m), 2.20-2.32 (3H, m), 2.85 (2H, br d), 3.10-3.20 (1 H, m), 3.38-3.50 (1 H, m), 3.50 (2H, q), 4.40 (1 H, br d).
Description 17. 1-(frans-4-Ethoxycyclohexyl)piperidin-4-amine (D17)
Figure imgf000059_0001
Method A
1 ,1-Dimethylethyl {1-[frans-4-(ethyloxy)cyclohexyl]-4-piperidinyl}carbamate (D16, 920mg, 5.0 mmol) was dissolved in dichloromethane (6ml) and treated with HCI (21 ml of a 4M solution in 1 ,4-dioxane) at room temperature. The mixture was stirred at room temperature for 1 hour and the solvent was evaporated. The crude was passed through an SCX cartridge to yield the free base title compound as a pale brown powder (865mg, 4.0 mmol, 89%). M+ + H = 227.
Method B
A mixture of frans-1-(4-ethoxycyclohexyl)-4-piperidone (D13, 13.2g), 2M ammonia in methanol (300ml), and 10% palladium on carbon paste (4g) was treated with hydrogen at 50psi at room temperature for 18h, then filtered and evaporated to give the title compound (9.5g) as a oil.
Description 18. cis/trans-Ethy\ 4-{[(1 ,1- dimethylethyl)(dimethyl)silyl]oxy}cyclohexanecarboxylate (D18)
Figure imgf000059_0002
Chloro(1 ,1-dimethylethyl)dimethylsilane (1 15g) was added in portions over 1 hour to a solution of ethyl 4-hydroxycyclohexanecarboxylate (118g), imidazole (103g) and dimethylformamide (400ml) stirred under an atmosphere of argon. A small exotherm was observed resulting in the reaction mixture temperature increasing to -4O0C. The mixture was stirred at room temperature overnight then poured into 10% citric acid solution (2000ml) and extracted with diethyl ether (2 x 800ml). The ether extracts were washed with water, brine and then dried (Na2SO4) and the solvent was removed to give the title compound as a oil (198.4g)
1H NMR δ(CDCI3, 400 MHz): 0.01 (6H, m), 0.85 (9H, s), 1.2 (3H, m), 1.3-1.5 (2H, m), 1.6 (2H, m), 1.85-2 (3H, m), 2.15-2.3 (1 H, m) 3.5 (0.4H, m) 3.86 (1 H, m) 4.1 (1 H, m). Description 19. cis/trans-Ethy\ 4-(ethyloxy)cyclohexanecarboxylate (D19)
Figure imgf000060_0001
Cis/trans ethyl 4-{[(1 ,1-dimethylethyl)(dimethyl)silyl]oxy}cyclohexanecarboxylate (D18, 35g, 122 mmol) was dissolved in CH3CN (250 ml) and Et3SiH (1.2 eq., 0.146 mol, 23ml) and BiBr3 (4% mol, 4.9 mmol, 2.2 g) were added at room temperature followed by slow addition of acetaldehyde (1.2 eq., 8.2 ml) at 250C. The mixture was stirred at room temperature for 1 hour, then poured onto an aqueous saturated solution of NaHCO3 and the mixture obtained was extracted with EtOAc (3x). Organic extracts were combined, dried over Na2SO4, filtered and the solvent was evaporated to afford the crude mixture that was purified by silica chromatography (Biotage 65i column, EtOAc/n-hexane) to afford the title compound, (21 g, 87%). 1H NMR δ (DMSO, 400 MHz): 1.1 (3H, m), 1.15 (3H, m), 1.492-3.212 (assume 10 H, set of broad signals and multiplets), 3.312 (2 H, m), 4.041 (2H, m).
Description 20. c/s/frans-4-(Ethyloxy)cyclohexanecarboxylic acid (D20)
Figure imgf000060_0002
c/s/ϊrans-ethyl 4-(ethyloxy)cyclohexanecarboxylate (D19, 21 g, 105 mmol) was dissolved in MeOH-THF (100 ml-100 ml) and NaOH (5 eq., 0.5 mol, 40 ml, 12.5N aqueous solution) was slowly added at room temperature. The mixture was stirred at room temperature overnight. The THF/MeOH was evaporated and the crude product was washed with Et2O. The aqueous layer was acidified and extracted with EtOAc
(2x), organic extracts dried over Na2SO4, filtered and the solvent evaporated to afford the title compound as a pale-yellow oil, (17.3 g, 96%).
1H NMR δ (DMSO, 400 MHz): 1.1 (3H, m), 1.3-3.201 (assume 10 H, set of broad signals and multiplets), 3.417 (2H, m), 12.1 (1 H, s broad).
Description 21. c/s/frans-4-(Ethyloxy)-1 -methylcyclohexanecarboxylic acid
(D21)
Figure imgf000060_0003
)
A stirred solution of diisopropylamine (2.3 eq., 0.231 mol, 33 ml) in THF (300ml) at - 2O0C under argon was treated over 10 min with 2.5M n-butyllithium in hexane (2.3 eq., 93 ml), then allowed to warm to O0C and stir for 15 mins. The mixture was recooled to -1 O0C and treated over 10 min with a solution of cis/trans-4- (ethyloxy)cyclohexanecarboxylic acid (D20, 17.3g, 0.1 mol) in THF (50 ml). The resulting yellow solution was heated at 5O0C for 2.5hrs, then cooled to 0 0C and treated with iodomethane (3 eq., 0.3 mol, 19 ml). The mixture was allowed to warm to room temperature and stir for 20 hrs when a yellow precipitate had formed. The mixture was cooled to 1 O0C, treated with 10% citric acid solution (200ml), and then concentrated under reduced pressure. The residual mixture was diluted with water (200ml) and extracted with Et2O (2x). The combined extracts were dried (Na2SO4) and concentrated under reduced pressure to afford the title compound as a yellow oil, (16.2 g, 87%), a mixture of cis:trans isomers.
1H NMR δ(DMSO, 400 MHz): 1.086 (assume 8H, m), 1.510 (3H, m), 1.698 (1 H, m), 1.781 (1 H, m), 2.005 (1 H, m), 3.191 (1/2H, m), 3.392 (2H, m), 3.606 (1/2H, m), 12.2 (1 H, s br).
Description 22. frans-4-(Ethyloxy)-1-methylcyclohexanecarboxylic acid (D22)
Figure imgf000061_0001
c/s/frans-4-(ethyloxy)-1-methylcyclohexanecarboxylic acid (D21 , 16.2 g, 87.1 mmol) was dissolved in thionyl chloride (15 eq., 1.31 mol, 95 ml) at room temperature and subsequently heated to 850C for 4 hrs. The mixture was then allowed to cool to room temperature and the thionyl chloride was azeotropically evaporated with toluene. The residue was dissolved in THF (100ml), treated with a 5% aqueous solution of Na2CO3 (500 ml) and stirred vigorously at room temperature for 20 minutes. The aqueous residue was washed with Et2O (2x), then acidified and extracted with EtOAc (3x). The combined extracts were dried (Na2SO4), filtered and concentrated under reduced pressure to leave the title compound, (6.5 g, 40%). 1H NMR δ(d6-DMSO, 400 MHz): 1.076 (6H, m), 1.505 (6H, m), 1.693 (2H, m), 3.331 (1 H, m), 3.394 (2H, q), 12.1 (1 H, s br).
Description 23. frans-4-(Ethyloxy)-1 -isocyanato-1 -methylcyclohexane (D23)
Figure imgf000061_0002
A stirred solution of frans-4-(ethyloxy)-1-methylcyclohexanecarboxylic acid (D22, 5.5g, 29.5mmol) in toluene (120ml) at room temperature under argon was treated with triethylamine (1.3 eq., 37.7 mmol, 5.3 ml) and diphenylphosphoryl azide (1eq., 29.5 mmol, 6.4 ml) and heated at 850C for 1 hr. The mixture was allowed to cool to room temperature, then treated with 1 M NaOH solution (300ml) and extracted with Et2O (3x). The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure to leave the title compound, (5 g, 94 %). 1H NMR δ(d6-DMSO, 400 MHz): 1.092 (3H, t), 1.330 (3H, s), 1.487-1.691 (8H, m), 3.392 (2H, q), 3.477 (1 H, m).
Description 24. [frans-4-(Ethyloxy)-1-methylcyclohexyl]amine mono hydrochloride (D24)
Figure imgf000062_0001
A solution of frans-4-(ethyloxy)-1-isocyanato-1-methylcyclohexane (D23, 5.Og, 27.3 mmol) in THF (100ml) was treated with 5M aqueous HCI acid (5.5 eq., 150 mmol, 30 ml) and stirred at room temperature under argon for one overnight, then concentrated under reduced pressure. The residual semi-solid was triturated with Et2O to give a first batch of title compound as a white solid, 2.8 g. The mother liquors were concentrated under reduced pressure, the residue dissolved in THF again (50 ml) and treated with 5M aqueous HCI acid (15 ml). The mixture was stirred for one week-end at room temperature, the solvent was then evaporated and the solid obtained was dried in the oven at 5O0C before trituration with Et2O. This final trituration afforded further 646 mg of title compound. The two batches were combined to afford 3.4 g, 66% of title compound. 1H NMR δ(d6-DMSO, 400 MHz): 1.084 (3H, t), 1.256 (3H, s), 1.378 (2H, m), 1.619 (4H, m), 1.847 (2H, m), 3.243 (1 H, m), 3.424 (2H, q), 8.090 (3H, br s).
Description 25. 1-[frans-4-(Ethyloxy)-1-methylcyclohexyl]-4-piperidinone (D25)
Figure imgf000062_0002
A stirred solution of [frans-4-(ethyloxy)-1-methylcyclohexyl]amine mono hydrochloride (D24, 3.4 g, 17.8 mmol) in a mixture of ethanol (216 ml) and water (108 ml) at room temperature under argon was treated with potassium carbonate (1.1 eq., 19.6 mmol, 2.7g) followed by 1-ethyl-1-methyl-4-oxopiperidinium iodide (D12, 1.5 eq., 26.7 mmol, 7.1g), then heated at 8O0C for 2 hours. The mixture was allowed to cool to room temperature then the aqueous residue was treated with sat. NaHCO3 solution and extracted with dichloromethane (3x). The combined extracts were dried (Na2SO4) and concentrated under reduced pressure to leave the crude compound which was purified by chromatography on silica gel (Biotage 65i column) eluting with 0-10% MeOH/DCM to afford the title compound, (2.3 g 54%).
1H NMR δ(d6-DMSO, 400 MHz): 0.855 (3H, s), 1.099 (3H, t), 1.421 (2H, m), 1.544 (4H, m), 1.793 (2H, m), 2.297 (4H, t), 2.726 (4H, t), 3.377-3.430 (3H, t + m).
Description 26. 1 -[frans-4-(Ethyloxy)-1 -methylcyclohexyll^-piperidinamine dihydrochloride (D26)
Figure imgf000063_0001
2HCI (D26)
A solution of 1-[frans-4-(ethyloxy)-1-methylcyclohexyl]-4-piperidinone (D25, 2.3g, 9.62 mmol) in 2M NH3/MeOH (200ml) was treated with 10% Pd/C (510 mg) and shaken under hydrogen atmosphere at 50psi initial pressure overnight at room temperature. The mixture was filtered through Kieselguhr to remove catalyst and the filtrate concentrated under reduced pressure to leave the free base of the title compound. This was dissolved in MeOH (20 ml) and treated with 10 ml of HCI (1 M solution in Et2O) for 10 min. Solvent was subsequently evaporated to afford the title compound as a white solid (2.8 g, complete conversion). 1H NMR δ(d6-DMSO, 250 MHz, at 352.2K): 1.091 (6H, m br), 1.336 (2H, m), 1.695- 1.865 (7H, m), 2.067 (2H, d br), 2.531 (1 H, br), 3.187-3.317 (assume 6H, set of broad signals and multiplets), 3.434 (2H, q), 8.496 (2H, s br).
Description 27. Λ/-{1-[rrans-4-(Ethyloxy)cyclohexyl]-4-piperidinyl}-6-methyl-3- nitro-2-pyridinamine (D27)
Figure imgf000063_0002
A stirred solution of 2-chloro-6-methyl-3-nitropyridine (135mg, 0.78 mmol) in N, N- dimethylformamide (5ml) at room temperature under argon was treated with diisopropylethylamine (0.53ml, 3.0mmol) and 1-(frans-4-ethoxycyclohexyl)piperidin-4- amine dihydrochloride (the dihydrochloride salt of D17, 250mg, 0.84 mmol) and then heated at 75 0C for 18 hours. The mixture was concentrated under reduced pressure and the residue was treated with 10% Na2CO3 solution and extracted with ethyl acetate. The extract was dried (Na2SO4), concentrated under reduced pressure and the residue purified by chromatography on silica gel (2Og) eluting with 0-10% MeOH/dichloromethane to afford the title compound as an orange solid (170mg, 60%). MH+ 363. 1H NMR δ (CDCI3, 400MHz): 1.15-1.40 (4H, m + 3H, t), 1.55-1.70 (2H, m), 1.90-2.00 (2H, m), 2.05-2.18 (4H, m), 2.30-2.40 (1 H, m), 2.40-2.52 (2H, m + 3H, s), 2.83-2.93 (2H, m), 3.12-3.25 (1 H, m), 3.52 (2H, q), 4.21-4.32 (1 H, m), 6.47 (1 H, d), 8.27 (2H, 2 x d).
Description 28. Λ/2-{1 -[frans-4-(Ethyloxy)cyclohexyl]-4-piperidinyl}-6-methyl-2,3- pyridinediamine (D28)
Figure imgf000064_0001
A stirred solution of Λ/-{1-[frans-4-(ethyloxy)cyclohexyl]-4-piperidinyl}-6-methyl-3- nitro-2-pyridinamine (D27, 170mg, 0.47mmol) in ethanol (15ml) at room temperature under argon was treated with Raney nickel (20mg) followed by hydrazine hydrate (0.15ml, δ.Ommol) and the mixture stirred well for 1 hour when the initial intense orange colour had dissipated. The catalyst was removed by filtration through Kieselguhr and the filtrate concentrated under reduced pressure to leave the title compound as a pale yellow solid (155mg, 100%). MH+ 333.
1H NMR δ (CDCI3, 400MHz): 1.15-1.38 (4H, m + 3H, t), 1.42-1.58 (2H, m), 1.90-2.00 (2H, m), 2.05-2.20 (4H, m), 2.33 (3H, s), 2.30-2.50 (3H, m), 2.90 (2H, br d), 3.02 (2H, br s), 3.13-3.23 (1 H, m), 3.52 (2H, q), 3.90-4.10 (2H, m), 6.32 (1 H, d), 6.75 (1 H, d).
Description 29. trans N-(6-chloro-3-nitro-2-aminopyridyl)-1-(4-ethoxy-1 - methylcyclohexyl)-4-piperidinamine (D29)
Figure imgf000064_0002
A mixture of trans 1-(4-ethoxy-1-methylcyclohexyl)-4-piperidinamine dihydrochloride (D26, 160mg), N,N-dimethylformamide (5ml), diisopropylethylamine (0.34ml), and 2,6-dichloro-3-nitropyridine (190mg) was stirred at room temperature for 18h. The solution was then diluted with ethyl acetate and washed three times with water, then dried, and concentrated under reduced pressure and purified by chromatography (10g silica, 0-10% methanol in dichloromethane containing ammonia) to afford the title compound (130mg). MH+ = 397/399
Description 30. Trans N2-(6-chloro-2,3-diaminopyridyl)-1-(4-ethoxy-1 - methylcyclohexyl)-4-piperidinamine (D30)
Figure imgf000065_0001
A solution of trans N-(6-chloro-3-nitro-2-aminopyridyl)-1-(4-ethoxy-1- methylcyclohexyl)-4-piperidinamine (D29, 130mg) in ethanol (6ml) was treated with Raney nickel (0.3ml of 10%aq. suspension) and hydrazine hydrate (0.3ml). After 1 h the catalyst was removed by filtration through Celite® and the filtrate evaporated and the residue purified by chromatography (2Og silica, 0-10% methanol in dichloromethane containing ammonia) to afford the title compound (70mg). MH+ =367/369
Description 31. trans N-(6-methoxy-3-nitro-2-aminopyridyl)-1-(4-ethoxy-1 - methylcyclohexyl)-4-piperidinamine (D31)
Figure imgf000065_0002
A mixture of trans 1-(4-ethoxy-1-methylcyclohexyl)-4-piperidinamine dihydrochloride (D26, 320mg), N,N-dimethylformamide (10ml), diisopropylethylamine (0.7ml), and 2- chloro-6-methoxy-3-nitropyridine (380mg) was stirred at room temperature for 24h. The solution was then diluted with ethyl acetate and washed three times with water, then dried, concentrated under reduced pressure and purified by chromatography (2Og silica, 0-10% methanol in dichloromethane containing ammonia) to afford the title compound (140mg). MH+ =393
Description 32. trans N2-(6-methoxy-2,3-diaminopyridyl)-1-(4-ethoxy-1- methylcyclohexyl)-4-piperidinamine (D32)
Figure imgf000065_0003
A solution of trans N-(6-methoxy-3-nitro-2-aminopyridyl)-1-(4-ethoxy-1- methylcyclohexyl)-4-piperidinamine (D31 , 140mg) in ethanol (10ml) was treated with Raney nickel (0.5ml of 10%aq. suspension) and hydrazine hydrate (0.5ml). After 4h at 5O0C the catalyst was removed by filtration through Celite® and the filtrate evaporated and re-evaporated from toluene to afford the title compound (130mg). MH+ =363 Description 33. 2,4-dichloro-6-methyl-3-nitropyridine. (D33)
Figure imgf000066_0001
To 6-methyl-3-nitro-2,4-pyridinediol (3g, 0.0176mol) at 0 0C was added phosphorus oxychloride (6.5ml, 0.0704mol), phenyldiethylamine (3ml, 0.0194mol) and the reaction brought to reflux under argon for 4 h. The reaction mixture was then allowed to cool to room temperature and the phosphorus oxychloride removed by co- evaporation using toluene to provide crude material as a dark liquid. To this material was added ice water and the aqueous mixture was then extracted using ethyl acetate (50ml x 2), washed with 5M hydrochloric acid, dried (MgSO4) and solvent removed by evaporation to give the title compound, (2.7g, 74%) as a brown solid. 1H NMR δ (CDCI3, 400 MHz): 2.61 (3H, s), 7.30 (1 H, s).
Description 34. 2-chloro-Λ/-{1 -[frans-4-(ethyloxy)-1 -methylcyclohexyl]-4- piperidinyl}-6-methyl-3-nitro-4-pyridinamine. (D34)
Figure imgf000066_0002
To a solution of 2,4-dichloro-6-methyl-3-nitropyridine (D33, 100mg, 0.483mmol) in dimethylformamide (10ml) was added 1-[frans-4-(ethyloxy)-1-methylcyclohexyl]-4- piperidinamine dihydrochloride (D26, 158mg, 0.483mmol), triethylamine (0.26ml, 1.932mmol) and the reaction stirred at room temperature for 12h. The reaction mixture was then diluted using water (20ml) and then extracted using dichloromethane (50ml). The organic phase was washed using water (20ml), brine (20ml), and sodium bicarbonate solution (20ml), dried (MgSO4) and solvents removed by evaporation to afford crude material. The crude material was purified by MDAP to give the regioisomer in salt form, which was then taken up in dichloromethane (15ml), washed using sodium bicarbonate solution (20ml), dried (MgSO4) and volatiles removed by evaporation to provide the title compound, (60mg, 30%) as a yellow residue. M+ + H = 411
Description 35. W-{1 -[frans-4-(ethyloxy)-1 -methylcyclohexyl]-4-piperidinyl}-6- methyl-3,4-pyridinediamine. (D35)
Figure imgf000067_0001
To a solution of 2-chloro-Λ/-{1-[frans-4-(ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}-6- methyl-3-nitro-4-pyridinamine (D34, 60mg, 0.146mmol) in tetrahydrofuran/ethanol (10ml/15ml) was added palladium/carbon 10% (20mg) and the mixture stirred under a hydrogen atmosphere (55Psi) for 48h. The catalyst was then removed by filtration through Kieselguhr and solvents removed by evaporation to provide crude material. The crude material was then taken up in dichloromethane (30ml), washed with sodium bicarbonate solution, dried (MgSO4) and volatiles evaporated to afford the title compound, (30mg, 60%) as a yellow residue. M+ + H = 347
Description 36. Λ/-{1 -[frans-4-(ethyloxy)-1 -methylcyclohexyl]-4-piperidinyl}-6- methyl-3-nitro-2-pyridinamine. (D36)
Figure imgf000067_0002
2-Chloro-6-methyl-3-nitropyridine (155 mg, 0.9 mmol), 1-[frans-4-(ethyloxy)-1- methylcyclohexyl]-4-piperidinamine dihydrochloride (D26, 0.7 eq., 150 mg, 0.63 mmol), DIPEA (1 eq., 0.15 ml, 0.9 mmol) were dissolved in dimethylformamide (2 ml) and the mixture was heated at 80 0C overnight. The reaction mixture was then cooled to Rt and poured onto a saturated aqueous solution of NaHCO3. The aqueous phase obtained was extracted with EtOAc (3x), the organic extracts combined and then washed with brine (2x). The solvent was partially evaporated and the residue purified by SXC first and then by silica chromatography (25S cartridge, MeOH-NH3-DCM) to afford the title compound as a yellow product (177 mgs, 75%), M+ + H = 377.
Description 37. Λ/2-{1 -[frans-4-(ethyloxy)-1 -methylcyclohexyl]-4-piperidinyl}-6- methyl-2,3-pyridinediamine. (D37)
Figure imgf000068_0001
Λ/-{1-[7rans-4-(ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}-6-methyl-3-nitro-2- pyridinamine (D36, 170 mg, 0.4 mmol) was dissolved in EtOH (2ml) and Raney-Ni (10% aqueous solution, 0.4 ml) was added at Rt under vigorous stirring followed by hydrazine monohydrate (10 eq., 4.5 mmol, 0.14 ml). After 10 minutes at Rt the reaction was complete. The reaction was filtered through Celite® and the solvent was evaporated to afford the title compound, (100 mgs, 72%), M+ + H = 347.
Description 38. Λ/-{1-[rrans-4-(ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}-5- methyl-3-nitro-2-pyridinamine. (D38)
Figure imgf000068_0002
2-Chloro-5-methyl-3-nitropyridine (1.4 eq., 193 mg, 1.12 mmol), 1-[frans-4-(ethyloxy)- 1-methylcyclohexyl]-4-piperidinamine dihydrochloride (D26, 250 mg, 0.8 mmol), DIPEA (2.8 eq., 0.37 ml, 2.24 mmol) were dissolved in dimethylformamide (2 ml) and the mixture was heated at 80 0C overnight. The reaction mixture was then cooled to Rt, quenched with an aqueous 2M solution of NaOH and poured onto a saturated aqueous solution of NaHCO3. The aqueous phase obtained was extracted with EtOAc (3x), the organic extracts combined and washed with water (1x), brine (1x), dried over Na2SO4, filtered and the solvent was evaporated to afford the crude product. This was purified by SXC first and then by silica chromatography (25S cartridge, MeOH-NH3-DCM) to afford the title compound as a yellow product (136 mg, 45%), M+ + H = 377.
Description 39. Λ/2-{1-[frans-4-(ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}-5- methyl-2,3-pyridinediamine. (D39)
Figure imgf000069_0001
Λ/-{1-[7rans-4-(ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}-5-methyl-3-nitro-2- pyridinamine (D38, 136 mg, 0.36 mmol) was dissolved in EtOH (4 ml) and Raney-Ni (10% aqueous solution, 0.4 ml) was added at Rt under vigorous stirring followed by hydrazine monohydrate (10 eq., 3.6 mmol, 0.1 12 ml). After four hours at Rt the reaction was complete. The reaction was filtered through Celite® and the solvent was evaporated to afford the title compound, (125 mg, complete conversion), M+ + H = 347.
Description 40. 5-bromo-N3-{1 -[trans-4-(ethyloxy)-1 -methylcyclohexyl]-4- piperidinyl}-2,3-pyrazinediamine (D40)
Figure imgf000069_0002
(D40)
A stirred solution of 3,5-dibromo-2-pyrazinamine (1 g), 1-[trans-4-(ethyloxy)-1- methylcyclohexyl]-4-piperidinamine dihydrochloride (D26, 0.48g) in 1-butanol (15ml) was heated at 180 0C in a microwave reactor for 5 hours. The cooled mixture was loaded onto a SCX cartridge, which was eluted with methanol to remove non-basic contaminants, then with 2M NH3/methanol to remove the product. Drying, evaporation and chromatography on silica, eluted with a 0-10% gradient of ammonia in methanol and dichloromethane, gave the title compound (0.19g). MH+ = 412, 414.
Description 41. N3-{1 -[trans-4-(ethyloxy)-1 -methylcyclohexyl]-4-piperidinyl}-5- methyl-2,3-pyrazinediamine. (D41)
Figure imgf000070_0001
(D41 )
A solution of 5-bromo-N3-{1-[trans-4-(ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}-2,3- pyrazinediamine (D40, 190mg), 2M methyl zinc chloride in tetrahydrofuran (1.5ml) and 1 ,1 '-bis(diphenylphosphino)ferrocene palladium dichloride (20mg) in terrahydrofuran was refluxed for 1 hour under an atmosphere of argon. Solvent from the cooled reaction was removed by evaporation, and the residue partitioned between dichloromethane and sodium bicarbonate solution. The dichloromethane layer was separated, dried over hydromatrix cartridge and the solvent removed to give the title compound as a brown oil (0.13g). MH+ = 348
Example 1. 5-methyl-3-{1 -[c/s-1 -methyl-4-(propyloxy)cyclohexyl]-4-piperidinyl}- 1 ,3-dihydro-2H-imidazo[4,5-fe]pyridin-2-one monohydrochloride (E1a) 5-methyl-3-{1 -[trans-λ -methyl -4-(propyloxy)cyclohexyl]-4-piperidinyl}-1 ,3- dihydro-2H-imidazo[4,5-fe]pyridin-2-one monohydrochloride (E1 b)
Figure imgf000070_0002
(E1 a) (E1 b)
Cis/trans 6-methyl-Λ/2-{1-[1-methyl-4-(propyloxy)cyclohexyl]-4-piperidinyl}-2,3- pyridinediamine (D7) (46 mg, =0.127 mmol) was dissolved in dichloromethane (5 ml) and Hϋnig's base (1.5 eq., 0.191 mmol, =32 microliters) was added. The mixture was then cooled to 0 0C and bis(trichloromethyl) carbonate (0.4 eq., =0.05 mmol, 15 mg) was added at 0 0C portionwise. The mixture was stirred at the same temperature for 1.5 hours and diluted with dichloromethane (5ml), then brine (5ml) followed by 2M aqueous NaOH (0.3 ml) were added. The mixture was stirred at Rt for 10 min. The two phases were separated and the organic solvent was evaporated to afford the crude product as a cis/trans mixture of compounds, (30 mg). The isomers were separated by automated chromatography to afford the two free bases (15 mg and 10 mg). Free bases were converted to the HCI salts by treating them with a 1 M solution of HCI (0.1 ml) in Et2O to yield cis and trans isomers, (complete conversions), M+ + H = 387.
1H NMR (HCI salt) δ(d6-DMSO, 400 MHz) c/s-E1a: 0.90 (6H, m), 1.23-1.36 (5H, m), 1.53 (4H, m), 1.70 (2H, d), 1.86 (2H, d), 1.95 (2H, d), 2.44 (3H, s), 2.86 (2H, q), 3.21 (2H, q), 3.32 (2H, t), 3.46 (1 H, s), 3.65 (2H, d), 4.70 (1 H, m), 6.87 (1 H, d), 7.21 (1 H, d), «11 (1 H, s).
1H NMR (HCI salt) δ(d6-DMSO, 400 MHz) frans-E1 b: 0.85-0.89 (6H, m), 1.23-1.33 (5H, m), 1.48 (2H, m), 1.74 (2H, t), 1.95 (6H, m), 2.44 (3H, s), 2.84 (2H, q), 3.13-3.28 (3H, m), 3.38 (2H, t), 3.94 (2H, d), 4.66 (1 H, m), 6.88 (1 H, d), 7.21 (1 H, d), «11 (1 H, s).
Example 2. 3-{1 -[frans-4-(Ethyloxy)cyclohexyl]-4-piperidinyl}-5-methyl-1 ,3- dihydro-2H-imidazo[4,5-b]pyridin-2-one di hydrochloride (E2)
Figure imgf000071_0001
A stirred solution of Λ/2-{1-[frans-4-(ethyloxy)cyclohexyl]-4-piperidinyl}-6-methyl-2,3- pyridinediamine (D28, 150mg, 0.45mmol) and diisopropylethylamine (0.12ml, 0.68mmol) in dichloromethane at O0C under argon was treated with solid triphosgene (52mg, 0.18mmol) and maintained for 1.5 hours. The mixture was treated with water (10ml) followed by 10% Na2CO3 solution (10ml) and extracted with dichloromethane (2 x 15ml). The combined extracts were dried (Na2SO4) and concentrated under reduced pressure to leave a beige solid, which was recrystallised from ethyl acetate (20ml) to give the free base of the title compound as a white solid (90mg, 55%). This was dissolved in dichloromethane (4ml) and methanol (5ml), treated with 1 M HCI/ether (0.8ml) and concentrated under reduced pressure. The residue was triturated with ether (12ml) to afford a solid, which was filtered off, washed with ether and dried to afford the title compound as a white solid (85mg). MH+ 359. 1H NMR (free base) δ (CDCI3, 400MHz): 1.20 (3H, t), 1.20-1.42 (4H, m), 1.80 (2H, br d), 1.98 (2H, br d), 2.12 (2H, br d), 2.35-2.46 (3H, m), 2.50 (3H, s), 2.72-2.86 (2H, m), 3.07 (2H, br d), 3.15-3.25 (1 H, m), 3.52 (2H, q), 4.31-4.43 (1 H, m), 6.79 (1 H, d), 7.16 (1 H, d), 9.65 (1 H, s).
Example 3. 5-chloro-3-{1 -[frans-4-(ethyloxy)-1 -methylcyclohexyl]-4-piperidinyl}- 1,3-dihydro-2H-imidazo[4,5-fe]pyridin-2-one hydrochloride (E3)
Figure imgf000072_0001
A solution of trans N2-(6-chloro-2,3-diaminopyridyl)-1-(4-ethoxy-1-methylcyclohexyl)- 4-piperidinamine (D30, 70mg) in dichloromethane (5ml) at O0C was treated with triphosgene (23mg) followed by diisopropylethylamine (0.07ml) and the mixture maintained at O0C for 30min. The solution was diluted with dichloromethane, washed with NaHCC>3 solution, dried and concentrated under reduced pressure. Purification by Ruby MDAP chromatography and conversion to the hydrochloride gave the title compound after trituration with diethyl ether (200mg). MH+ 393 and 395. 1H NMR (HCI salt) δ (d6-DMSO): 1.1 (3H, t), 1.3 (3H, s), 1.4 (2H, m), 1.9-2.1 (6H, m), 2.8 (2H, m), 3.2-3.4 (2H, m), 3.6(2H, m), 4.7 (1 H, m), 7.1 (1 H, d), 7.4 (1 H, d), 9.0 (1 H, bs), and 1 1.4 (1 H, s).
Example 4. 3-{1 -[frans-4-(ethyloxy)-1 -methylcyclohexyl]-4-piperidinyl}-5- (methyloxy)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one hydrochloride (E4) t
Figure imgf000072_0002
A solution of trans N2-(6-methoxy-2,3-diaminopyridyl)-1-(4-ethoxy-1- methylcyclohexyl)-4-piperidinamine (D32, 130mg) in dichloromethane (10ml) at O0C was treated with triphosgene (45mg) followed by diisopropylethylamine (0.14ml) and the mixture maintained at O0C for 30min. The solution was diluted with dichloromethane, washed with NaHCO3 solution, dried, evaporated and crystallised from diethyl ether. Conversion to the hydrochloride gave the title compound after trituration with diethyl ether (45mg). MH+ 389, 1H NMR (HCI salt) δ (d6-DMSO): 1.1 (3H, t), 1.3 (3H, S), 1.3 (2H, m), 1.9-2.1 (8H, m), 2.9 (2H, bq), 3.2 (3H, m), 3.5 (2H, q), 3.6 (2H, m), 3.9 (3H, s), 4.6 (1 H, m), 6.4 (1 H, d), 7.3 (1 H, d), 9.7 (1 H, bs), and 10.9 (1 H, s).
Example 5. 1 -{1 -[frans-4-(ethyloxy)-1 -methylcyclohexyll^-piperidiny^-θ-methyl- 1,3-dihydro-2H-benzimidazol-2-one dihydrochloride (E5)
Figure imgf000073_0001
A stirred solution of the N4-{1-[trans-4-(ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}-6- methyl-3,4-pyridinediamine (D35, 30mg, 0.0867mmol) in dichloromethane (5ml) at O0C under argon was treated with diisopropylethylamine (22μl_, 0.130mmol) followed by solid triphosgene (10mg, 0.035mmol) and maintained at O0C for 1 h. The mixture was treated with sodium bicarbonate solution (10ml) and extracted with dichloromethane (2 x 15ml). The combined organic extracts were then dried (MgSO4) and solvents removed by evaporation to afford crude material as an off-white solid. The crude material was then purified using MDAP to afford the formate salt (10mg). The formate salt was then treated with 1 M HCI/ether and volatiles then removed to provide the title compound (7mg, 18%) as white solid.
1H NMR (dihydrochloride salt) δ (d4-MeOH, 400 MHz): 1.16-1.2 (3H, m), 1.40-1.49 (6H), 1.95-2.00 (2H, m), 2.1 1-2.18 (6H, m), 2.75 (3H, s), 2.95-3.04 (2H, m), 3.3-3.34 (2H, m), 3.54-3.59 (2H, m), 3.84-3.87 (2H, m), 4.78-4.82 (1 H, m), 8.18 (1 H, s), 8.26 (1 H, s).
Example 6. 3-{1 -[frans-4-(ethyloxy)-1 -methylcyclohexyl]-4-piperidinyl}-5-methyl- 1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one hydrochloride (E6)
Figure imgf000074_0001
Λ/2-{1-[frans-4-(ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}-6-methyl-2,3- pyridinediamine (D37, 100 mg, 0.289 mmol) was dissolved in 3 ml of dichloromethane and DIPEA (1.5eq., 0.43 mmol, 0.073 ml) was added. The mixture was then cooled to 0 0C and triphosgene (0.4 eq., 34 mg, 0.115 mmol) was added portionwise. The mixture was stirred at 0 0C for one hour, quenched with a 2M aqueous solution of NaOH, then diluted with dichloromethane (20ml) and a saturated aqueous solution of NaHCO3. The two phases were then separated, the aqueous phase extracted with dichloromethane (2x), then the organic extracts were combined, dried and the solvent was evaporated to afford the crude product which was purified by silica chromatography (25S cartridge MeOH-NH3-DCM) to afford the title compound as the free base, (107mg, complete conversion). The free base was converted to the HCI salt by treatment with HCI (1 M solution in Et2O) to afford the title compound (138 mg), M++H= 373.
1HNMR δ(d6-DMSO, 250 MHz at 352K) 1.10 (3H, t), 1.23-1.41 (5H, m), 1.80-2.01 (7H, m), 2.44 (3H, s), 2.79 (2H, m), 3.22 (3H, m), 3.46 (2H, q), 3.64 (2H, d), 4.63 (1 H, m), 6.83 (1 H, d), 7.16 (1 H, d), 9.10 (1 H, s br), =10.7 (1 H, s br).
Example 7. S^I-Ifrans-^ethyloxyJ-i -methylcyclohexyll^-piperidiny^-θ-methyl- 1,3-dihydro-2H-imidazo[4,5-fe]pyridin-2-one hydrochloride (E7)
Figure imgf000075_0001
Λ/2-{1-[7rans-4-(ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}-5-methyl-2,3- pyridinediamine (D39, 125 mg, 0.36 mmol) was dissolved in 2 ml of dichloromethane and DIPEA (1.5eq., 0.54 mmol, 0.092 ml) was added at Rt. The mixture was then cooled to 0 0C and triphosgene (0.4 eq., 43 mg, 0.144 mmol) was added portionwise. The mixture was stirred at 0 0C for two hours, quenched with a 2M aqueous solution of NaOH, then diluted with dichloromethane (20ml) and a saturated aqueous solution of NaHCO3. The two phases were then separated and the aqueous phase was extracted with dichloromethane (2x), the organic extracts combined, dried and the solvent was evaporated to afford the crude product. This was purified by silica chromatography (25S cartridge MeOH-NH3-DCM) and then by MDAP to afford the title compound as the free base, (37 mg, 28%). The free base was dissolved in MeOH/DCM (3ml+3ml) and treated with HCI (1 M solution in Et2O, 2 eq., 0.182 mmol, 0.18 ml). The mixture obtained was stirred at Rt for 10 min and the solvent was then evaporated to afford 31 mgs of the title compound, 64%, M++H= 373. 1H NMR δ(d6-DMSO, 400MHz) 1.10 (3H, t), 1.23-1.31 (5H, m), 1.75 (2H, t),1.95 (6H, d), 2.30 (3H, s), 2.87 (2H, q), 3.20 (3H, m), 3.46 (2H, t), 3.63 (2H, d), 4.63 (1 H, m), 7.17 (1 H, s), 7.78 (1 H, s), 9.10 (1 H, s br), «1 1.1 (1 H, s br).
Example 8. 6-bromo-1 -{1 -[trans-4-(ethyloxy)-1 -methylcyclohexyl]-4- piperidinyl}-1 ,3-dihydro-2H-imidazo[4,5-b]pyrazin-2-one. (E8)
Figure imgf000075_0002
A stirred solution of 5-bromo-N3-{1-[trans-4-(ethyloxy)-1-methylcyclohexyl]-4- piperidinyl}-2,3-pyrazinediamine (D40 0.041 g) and diisopropylethylamine (0.05ml) in dichloromethane (2ml) at 00C was treated with solid triphosgene (12mg) and stirred to room temperature overnight. Purification on a Waters Xbridge chromatography column using 1OmM aqueous ammonium bicarbonate adjusted to pH10 with ammonia - acetonitrile gradient as mobile phase gave the title compound (5mg). MH+ = 438.
1H NMR (free base) δ (CDCI3, 400 MHz): 0.94 (3H, S), 1.22 (3H , t), 1.4-1.6 (4H, m), 1.6-1.95 (6H, m), 2.2 (2H, m), 2.55 (2H, m), 3.14 (2H, m), 3.3-3.6 (obs, m), 4.30 (1 H, m), 7.96 (1 H, s).
Example 9. 1 -{1 -[7rans-4-(ethyloxy)-1 -methylcyclohexyl]-4-piperidinyl}-6- methyl-1 ,3-dihydro-2H-imidazo[4,5-b]pyrazin-2-one hydrochloride. (E9)
Figure imgf000076_0001
A stirred solution of crude 5-methyl-N3-{1-[trans-4-(ethyloxy)-1-methylcyclohexyl]-4- piperidinyl}-2,3-pyrazinediamine (D41 , 0.13g) and diisopropylethylamine (2ml) in dichloromethane (20ml) was treated with solid triphosgene (70mg) and stirred to room temperature overnight. Purification on a Waters Xbridge chromatography column using 1OmM aqueous ammonium bicarbonate adjusted to pH10 with ammonia - acetonitrile gradient as mobile phase followed by treatment with dichloromethane and ethereal hydrogen chloride gave the title compound (10.6mg). MH+ = 374. 1H NMR δ (d6-DMSO, 400 MHz): 1.12 (3H, t) 1.3-1.4 (4H, m), 1.8 (2H, m), 1.9-2.1 (6H, m), 2.4 (3H , s), 2.8 (2H, m), 3.2 (4H, m), 3.45 (2H, q), 3.62 (2H, m), 4.3 (1 H, m), 7.79 (1 H, s), 9.1 (1 H, m), 1 1.9 (1 H, s).

Claims

1. A compound of formula (I) or a salt thereof:
Figure imgf000077_0001
wherein:
- X1 is nitrogen or CH;
- X2 is nitrogen or CR5 wherEin R5 is selected from hydrogen, cyano, halogen, C1- 6alkyl (optionally substituted with one or more fluorine atoms), and C1^aIkOXy (optionally substituted with one or more fluorine atoms);
- X3 is nitrogen or CR4 wherein R4 is hydrogen or fluorine; and wherein at least one and at most two of X1, X2, X3 is a nitrogen atom;
- R6 is selected from hydrogen, halogen, cyano, C1-6alkyl (optionally substituted with one or more fluorine atoms), C1-6alkylsulfonyl, C3-6cycloalkyl (optionally substituted with one or more fluorine atoms), and C1^aIkOXy (optionally substituted with one or more fluorine atoms);
- R is selected from C1-6alkyl, C3-6cycloalkyl, C3-6cycloalkylC1-6alkyl and C2-6alkynyl, any alkyl or cycloalkyl group being optionally substituted by one or more fluorine atoms; and Q is hydrogen or C1-6alkyl.
2. A compound as claimed in claim 1 wherein the salt is a pharmaceutically acceptable salt.
3. A compound as claimed in claim 1 or claim 2 wherein R is selected from methyl, ethyl and propyl.
4. A compound as claimed in any of claims 1-3 wherein R5 is selected from hydrogen and methyl.
5. A compound as claimed in any of claims 1-4 wherein R6 is selected from hydrogen, chloro, bromo, methyl and methoxy.
6. A compound as claimed in any of claims 1-5 wherein Q is H.
7. A compound as claimed in any of claims 1-5 wherein Q is methyl.
8. A compound as claimed in claim 1 , which is selected from to group consisting of: 3-{1-[frans-4-(ethyloxy)cyclohexyl]-4-piperidinyl}-5-methyl-1 ,3-dihydro-2H- imidazo[4,5-b]pyridin-2-one; 5-methyl-3-{1-[c/s-1-methyl-4-(propyloxy)cyclohexyl]-4-piperidinyl}-1 ,3-dihydro-2H- imidazo[4,5-b]pyridin-2-one;
5-methyl-3-{1-[frans-1-methyl-4-(propyloxy)cyclohexyl]-4-piperidinyl}-1 ,3-dihydro-2H- imidazo[4,5-b]pyridin-2-one;
3-{1-[frans-4-(ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}-5-methyl-1 ,3-dihydro-2H- imidazo[4,5-b]pyridin-2-one; 5-chloro-3-{1-[frans-4-(ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}-1 ,3-dihydro-2H- imidazo[4,5-b]pyridin-2-one;
3-{1-[frans-4-(ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}-5-(methyloxy)-1 ,3-dihydro-
2H-imidazo[4,5-b]pyridin-2-one;
3-{1-[frans-4-(ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}-6-methyl-1 ,3-dihydro-2H- imidazo[4,5-b]pyridin-2-one;
1-{1-[frans-4-(ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}-6-methyl-1 ,3-dihydro-2H- imidazo[4,5-c]pyridin-2-one;
6-bromo-1-{1-[frans-4-(ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}-1 ,3-dihydro-2H- imidazo[4,5-b]pyrazin-2-one; and 1-{1-[frans-4-(ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}-6-methyl-1 ,3-dihydro-2H- imidazo[4,5-b]pyrazin-2-one; and salts thereof.
9. A compound as claimed in claim 8 wherein the salt is a pharmaceutically acceptable salt.
10. A pharmaceutical composition comprising a compound as claimed in any of claims 2-9 and a pharmaceutically acceptable carrier thereof.
1 1. A compound as claimed in any of claims 2-9 for use in therapy.
12. A compound as claimed in any of claims 2-9 for use in the treatment of a condition wherein modulation of a muscarinic M1 receptor would be beneficial.
13. A compound as claimed in any of claims 2-9 for use in the treatment of psychotic disorders or cognitive impairment.
14. Use of a compound as claimed in any of claims 2-9 in the manufacture of a medicament for the treatment of a condition wherein modulation of a muscarinic M1 receptor would be beneficial.
15. Use of a compound as claimed in any of claims 2-9 in the manufacture of a medicament for the treatment of psychotic disorders or cognitive impairment.
16. A compound as claimed in any of claims 2-9 for the treatment of a condition wherein modulation of a muscarinic M1 receptor would be beneficial.
17. A compound as claimed in any of claims 2-9 for the treatment of psychotic disorders or cognitive impairment.
18. A method of treating a condition wherein modulation of a muscarinic M1 receptor would be beneficial, which method comprises administering to a mammal in need thereof an effective amount of a compound as claimed in any of claims 2-9.
19. A method of treating psychotic disorders or cognitive impairment, which method comprises administering to a mammal in need thereof an effective amount of a compound as claimed in any of claims 2-9.
20. A compound of formula (XXXX) or salts thereof:
Figure imgf000079_0001
(XXXX) wherein:
X1 is as defined in claim 1 ; X2 is as defined in claim 1 ;
X3 is as defined in claim 1 ;
R6 is a group R6 as defined in claim 1 or a group convertible to R6; and R' is a group R as defined in claim 1 or a group convertible to R.
21. A compound of formula (IV) or salts thereof:
Figure imgf000080_0001
wherein:
Q is as defined in claim 1 ;
X1 is as defined in claim 1 ; X2 is as defined in claim 1 ;
X3 is as defined in claim 1 ;
R6 is a group R6 as defined in claim 1 or a group convertible to R6; and R' is a group R as defined in claim 1 or a group convertible to R.
22. A compound of formula (Vl) or salts thereof:
Figure imgf000080_0002
wherein:
Q is as defined in claim 1 ; X1 is as defined in claim 1 ;
X2 is as defined in claim 1 ;
X3 is as defined in claim 1 ;
R6 is a group R6 as defined in claim 1 or a group convertible to R6;
R' is a group R as defined in claim 1 or a group convertible to R; and Z is a leaving group.
23. A compound of formula (X) or salts thereof:
Figure imgf000080_0003
wherein: Q is as defined in claim 1 ; X1 is as defined in claim 1 ; X2 is as defined in claim 1 ; X3 is as defined in claim 1 ;
R6 is a group R6 as defined in claim 1 or a group convertible to R6; and R' is a group R as defined in claim 1 or a group convertible to R.
PCT/EP2008/053591 2007-03-29 2008-03-27 1- (1-cyclohexyl-4-piperidinyl) -1, 3-dihydro-2h-benzimidazol-2-one derivatives which have activity on the m1 receptor and their use in medicine WO2008119713A1 (en)

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US8283364B2 (en) 2005-09-30 2012-10-09 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
US8288412B2 (en) 2005-09-30 2012-10-16 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
US8846909B2 (en) 2010-05-24 2014-09-30 University Of Rochester Bicyclic heteroaryl kinase inhibitors and methods of use
US8877772B2 (en) 2008-11-25 2014-11-04 University Of Rochester Substituted pyrrolo[2,3-B]pyridines as MLK inhibitors
US10485800B2 (en) 2012-11-30 2019-11-26 The University Of Rochester Mixed lineage kinase inhibitors for HIV/AIDS therapies

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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
US8288413B2 (en) 2005-09-30 2012-10-16 Glaxo Group Limited Benzimidazolones which have activity at M1 receptor
US8288412B2 (en) 2005-09-30 2012-10-16 Glaxo Group Limited Compounds which have activity at M1 receptor and their uses in medicine
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
US8877772B2 (en) 2008-11-25 2014-11-04 University Of Rochester Substituted pyrrolo[2,3-B]pyridines as MLK inhibitors
US9181247B2 (en) 2008-11-25 2015-11-10 The University Of Rochester Substituted pyrrolo[2,3-B]pyridines as MLK inhibitors
US9814704B2 (en) 2008-11-25 2017-11-14 The University Of Rochester Substituted pyrrolo[2,3-b]pyridines as MLK inhibitors
US8846909B2 (en) 2010-05-24 2014-09-30 University Of Rochester Bicyclic heteroaryl kinase inhibitors and methods of use
US10485800B2 (en) 2012-11-30 2019-11-26 The University Of Rochester Mixed lineage kinase inhibitors for HIV/AIDS therapies

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