WO2010094643A1 - Quinoline derivatives and their uses for rhinitis and urticaria - Google Patents

Quinoline derivatives and their uses for rhinitis and urticaria Download PDF

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Publication number
WO2010094643A1
WO2010094643A1 PCT/EP2010/051838 EP2010051838W WO2010094643A1 WO 2010094643 A1 WO2010094643 A1 WO 2010094643A1 EP 2010051838 W EP2010051838 W EP 2010051838W WO 2010094643 A1 WO2010094643 A1 WO 2010094643A1
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oxy
ethyl
phenyl
piperidinyl
quinoline
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PCT/EP2010/051838
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French (fr)
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Paul Martin Gore
Ashley Paul Hancock
Simon Teanby Hodgson
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Glaxo Group Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Definitions

  • the present invention relates to a class of compounds, which are quinolinyloxypiperidine and pyrrolidine derivatives, processes for their preparation, pharmaceutical compositions containing them and to their use in the treatment of various inflammatory and/or allergic diseases, in particular inflammatory and/or allergic diseases of the respiratory tract.
  • Allergic rhinitis, pulmonary inflammation and congestion are medical conditions that are often associated with other conditions such as asthma and chronic obstructive pulmonary disease (COPD).
  • COPD chronic obstructive pulmonary disease
  • these conditions are mediated, at least in part, by inflammation associated with the release of histamine from various cells, in particular mast cells.
  • Allergic rhinitis affects a large proportion of the population worldwide.
  • seasonal which includes hay fever
  • perennial The clinical symptoms of seasonal allergic rhinitis typically include nasal itching and irritation, sneezing and watery rhinorrhea, which is often accompanied by nasal congestion.
  • perennial allergic rhinitis The clinical symptoms of perennial allergic rhinitis are similar, except that nasal blockage may be more pronounced.
  • Either type of allergic rhinitis may also cause other symptoms, such as itching of the throat and/or eyes, epiphora and oedema around the eyes.
  • the symptoms of allergic rhinitis may vary in intensity from the nuisance level to debilitating.
  • H1 , H2 and H3 three receptor subtypes, termed H1 , H2 and H3.
  • H1 receptors are widely distributed throughout the CNS and periphery, and are involved in wakefulness and acute inflammation.
  • H2 receptors mediate gastric acid secretion in response to histamine.
  • H3 receptors are present on the nerve endings in both the CNS and periphery and mediate inhibition of neurotransmitter release [Hill et ai, Pharmacol. Rev., 49:253-278, (1997)].
  • H4 receptor a fourth member of the histamine receptor family has been identified, termed the H4 receptor [Hough, MoI. Pharmacol., 59:415-419, (2001 )]. Whilst the distribution of the H4 receptor appears to be restricted to cells of the immune and inflammatory systems, a physiological role for this receptor remains to be identified.
  • H1 receptors in blood vessels and nerve endings are responsible for many of the symptoms of allergic rhinitis, which include itching, sneezing, and the production of watery rhinorrhea.
  • Oral antihistamine compounds such as chlorphenyramine, cetirizine, desloratidine and fexofenadine
  • intranasal antihistamines such as azelastine and levocabastine
  • H1 receptor antagonists are effective in treating the itching, sneezing and rhinorrhea associated with allergic rhinitis, but are not effective against the nasal congestion symptoms [Aaronson, Ann. Allergy, 67:541-547, (1991 )].
  • H1 receptor antagonists have been administered in combination with sympathomimetic agents such as pseudoephedrine or i oxymetazoline to treat the nasal congestion symptoms of allergic rhinitis.
  • sympathomimetic agents such as pseudoephedrine or i oxymetazoline
  • These drugs are thought to produce a decongestant action by activating ⁇ -adrenergic receptors and increasing the vascular tone of blood vessels in the nasal mucosa.
  • sympathomimetic drugs for the treatment of nasal congestion is frequently limited by the CNS stimulant properties and their effects on blood pressure and heart rate. A treatment which decreases nasal congestion without having effects on the CNS and cardiovascular system may therefore offer advantages over existing therapies.
  • Histamine H3 receptors are expressed widely on both CNS and peripheral nerve endings and mediate the inhibition of neurotransmitter release.
  • In vitro electrical stimulation of peripheral sympathetic nerves in isolated human saphenous vein results in an increase in noradrenaline release and smooth muscle contraction, which can be inhibited by histamine H3 receptor agonists [Molderings et al., Naunyn-Schmiedeberg's Arch. Pharmacol., 346:46-50, (1992); Valentine et al., Eur. J. Pharmacol., 366:73-78, (1999)].
  • H3 receptor agonists also inhibit the effect of sympathetic nerve activation on vascular tone in porcine nasal mucosa [Varty & Hey., Eur. J.
  • H3 receptor agonists inhibit the decrease in nasal airway resistance produced by sympathetic nerve activation [Hey et al., Arzneim-Forsch Drug Res., 48:881-888, (1998)]. Activation of histamine H3 receptors in human nasal mucosa inhibits sympathetic vasoconstriction [Varty et al., Eur. J. Pharmacol., 484:83-89, (2004)]. Furthermore, H3 receptor antagonists, in combination with histamine H1 receptor antagonists, have been shown to reverse the effects of mast cell activation on nasal airway resistance and nasal cavity volume, an index of nasal congestion [Mcleod et al., Am. J.
  • RhinoL 13:391-399, (1999)]
  • H3 receptors histamine-induced nasal blockage
  • WO2004/035556 discloses substituted piperazines, (1 ,4) diazepines and 2,5-diazabicyclo [2.2.1] heptanes as histamine H3 or histamine H1/H3 dual antagonists or reverse agonists.
  • WO2007/122156 discloses substituted dibasic phthalazinone compounds as histamine H1/H3 dual antagonists.
  • a novel class of compounds has been found that are dual histamine H1 and H3 receptor antagonists.
  • dual histamine H1 and H3 receptor antagonists it is meant that compounds have activity at both receptor subtypes.
  • the activity at the H1 receptor may be within approximately 100 fold of the activity at the H3 receptor, such as within approximately 10 fold or less.
  • the present invention provides, as a first embodiment, a compound of formula (I):
  • R 1 independently represents halogen, straight chain C 1-6 alkyl, -(CH 2 ) b -CO 2 H or -(CH 2 ) c aryl in which the aryl is optionally substituted with one or two substituents independently selected from halogen,
  • p represents 0, 1 or 2; such that when p represents 1 , R 1 is in the 2, 3, 4, 5, 6 or 7 position on the quinoline ring; such that when p represents 2, one R 1 group is in the 2, 3 or 4 position on the quinoline ring and the other R 1 group is in the 5, 6 or 7 position on the quinoline ring;
  • a represents 1 or 2;
  • b represents 1 to 3;
  • c represents 0 to 3;
  • R 2 represents a group of formula (a), (b) or (c)
  • X represents either a bond, O or -N(R 6 )C(O)-, in which R 6 represents hydrogen or C h alky!; j and k each represent 1 or each represent 2;
  • R 4 represents hydrogen, C 3-6 cycloalkyl or Ci -6 alkyl
  • R 5 represents hydrogen, C 3-6 cycloalkyl or Ci -6 alkyl
  • the compounds of the invention may be expected to be useful in the treatment of various diseases in particular inflammatory and/or allergic diseases, such as inflammatory and/or allergic diseases of the respiratory tract (for example allergic rhinitis) that are associated with the release of histamine from cells such as mast cells. Further, the compounds may show an improved profile in that they may possess one or more of the following properties:
  • H3 antagonist activity with a pKi of greater than about 8, for example greater than about 9
  • H1 receptor antagonist activity with a pKi of greater than 7, for example greater than about 8
  • prolonged duration of action and (iv) lower CNS penetration.
  • Compounds having such a profile may be particularly suitable for intranasal delivery, and/or may be capable of once daily administration and/or further may have an improved side effect profile compared with other existing therapies.
  • R 2 represents a group of formula (a) or (c) as herein before defined; in which, for formula (a) e represents 1 to 6; Y represents a bond or O; e' represents 1 to 4; f represents 0, 1 or 2 and g represents 0, 1 , 2 or 3, such that f and g cannot both be 0; h represents 0, 1 or 2; R 3 represents Ci -3 alkyl;
  • I represents 1 to 6; I' represents 0 to 3; m represents 0, 1 or 2 and n represents 0, 1 , 2 or 3, such that m and n cannot both be 0, and such that I' plus n must represent 1 , 2 or 3; R 5 represents hydrogen, C 3-6 cycloalkyl or Ci -6 alkyl.
  • R 2 represents a group of formula (a) as herein before defined; in which, for formula (a) e represents 1 to 6;
  • R 2 represents a group of formula (c) as herein before defined; in which, for formula (c) I represents 1 to 6;
  • R 5 represents hydrogen, C 3 _ 6 cycloalkyl or d- ⁇ alkyl.
  • R 2 represents a group of formula (a) as herein before defined; in which, e is 2;
  • R 2 represents a group of formula (c) as herein before defined; in which, I represents 2; I' represents 0; m represents 0 and n represents 1 ; R 5 represents cyclobutyl.
  • p is 0. In another embodiment, p is 1.
  • p is 1 and R 1 represents C 1-6 alkyl.
  • p is 1 and R 1 represents methyl, ethyl or butyl.
  • p is 1 and R 1 is -(CH 2 ) c Aryl.
  • R 1 is-(CH 2 ) c Phenyl, wherein the phenyl is unsubstituted.
  • R 1 is -(CH 2 ) c Phenyl, wherein the phenyl is optionally substituted with one or two substituents independently selected from halogen, C 1-3 alkyl, trifluoromethyl and cyano.
  • p is 1 and R 1 represents halogen.
  • p is 1 and R 1 represents -(CH 2 ) b CO 2 H.
  • R 1 is (CH 2 ) 2 CO 2 H.
  • the R 1 group located in the 2,3 or 4 position on the quinoline ring represents straight chain C 1-6 alkyl, -(CH 2 ) b CO 2 H or -(CH 2 ) c aryl in which the aryl is optionally substituted with one or two substituents independently selected from halogen, C h alky!, trifluoromethyl and cyano.
  • one independently selected R 1 group is located in the 2 position on the quinoline ring, and another independently selected R 1 group is located in the 5,6 or 7 position on the quinoline ring.
  • one independently selected R 1 group is located in the 2 position on the quinoline ring, and another independently selected R 1 group is located in the 6 position on the quinoline ring.
  • the R 1 group located in the 2 position on the quinoline ring is - (CH 2 ) b CO 2 H.
  • the R 1 group located in the 2 position on the quinoline ring is (CH 2 ) 2 CO 2 H.
  • a is 1.
  • a is 2.
  • alkyl refers to a straight or branched hydrocarbon chain, unless otherwise indicated.
  • C 1-6 alkyl means a straight or branched alkyl chain containing at least one, and at most six, carbon atoms.
  • Illustrative examples of "alkyl” as used herein include, but are not limited to, methyl, ethyl, propyl, /so-propyl, n-butyl, sec-butyl, /so-butyl, fert-butyl, n-pentyl, neo-pentyl and n-hexyl.
  • alkyl groups are C 1-3 alkyl, such as methyl.
  • cycloalkyl refers to a cyclic, saturated hydrocarbon containing the specified number of carbon atoms.
  • C 3-7 cycloalkyl refers to a cyclic, saturated hydrocarbon containing at least three, and at most seven, carbon atoms.
  • Illustrative examples of C 3-7 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • aryl whether alone or as part of another group is used to describe single and fused aromatic hydrocarbon rings.
  • Representative "aryl” rings include phenyl and naphthyl. A particular aryl ring is phenyl. When substituted, aryl may have up to two substituents (for example, one or two substituents).
  • Representative aryl substituents include, but are not limited to, methyl, ethyl, chloro, fluoro, trifluoromethyl and cyano.
  • halogen describes, unless otherwise stated, a group selected from fluorine, chlorine, bromine and iodine, for example fluorine and chlorine.
  • compounds of formula (I), or salts thereof may possess one or more asymmetric carbon atoms so that stereoisomers e.g. enantiomers or diastereoisomers may be formed.
  • the present invention encompasses all stereoisomers of the compounds of formula (I), or salts thereof, whether as individual isomers isolated such as to be substantially free of the other isomer (i.e. pure) or as mixtures thereof (i.e. racemates and racemic mixtures).
  • An individual isomer isolated such as to be substantially free of the other isomer (i.e. pure) may be isolated such that less than about 10%, particularly less than about 1 %, for example less than about 0.1 % of the other isomer is present.
  • R and S enantiomers may be isolated from the racemate by conventional resolution methods such as preparative HPLC involving a chiral stationary phase, by resolution using fractional crystallisation of a salt of the free base with a chiral acid, by chemical conversion to a diastereoisomer using a chiral auxiliary followed by chromatographic separation of the isomers and then removal of the chiral auxiliary and regeneration of the pure enantiomer, or by asymmetric synthesis.
  • Certain compounds of formula (I), or salts thereof may exist in one of several tautomeric forms. It will be understood that the present invention encompasses all tautomers of the compounds of formula (I), or salts thereof, whether as individual tautomers or as mixtures thereof.
  • the compounds of formula (I), or salts thereof may be in crystalline or amorphous form. Furthermore, a compound of formula (I), or a salt thereof, may exist in one or more polymorphic forms. Thus, the present invention includes within its scope polymorphic forms of the compounds of formula (I), or salts thereof. In general, the most thermodynamically stable polymorphic form of a compound of formula (I), or a salt thereof, is of particular interest.
  • Polymorphic forms of compounds of formula (I), or salts thereof may be characterized and differentiated using a number of conventional analytical techniques, including but not limited to X- ray powder diffraction (XRPD) patterns, infrared (IR) spectra, Raman spectra, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) and solid state nuclear magnetic resonance (NMR).
  • XRPD X- ray powder diffraction
  • IR infrared
  • Raman spectra Raman spectra
  • DSC differential scanning calorimetry
  • TGA thermogravimetric analysis
  • NMR solid state nuclear magnetic resonance
  • the compounds of the present invention may be in the form of and/or may be administered as a pharmaceutically acceptable salt.
  • suitable salts see Berge et al., J. Pharm. ScL, 1977, 66, 1-19.
  • Suitable pharmaceutically acceptable salts include acid and base addition salts.
  • pharmaceutically acceptable salt means any pharmaceutically acceptable salt of a compound of the invention, which upon administration to the recipient is capable of providing (directly or indirectly) a compound of the invention, or an active metabolite or residue thereof.
  • a pharmaceutically acceptable salt may be readily prepared by using a desired acid or base as appropriate.
  • the salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent.
  • a pharmaceutically acceptable acid addition salt can be formed by reaction of a compound of formula (I) with a suitable inorganic or organic acid (such as hydrobromic, hydrochloric, sulfuric, nitric, phosphoric, succinic, maleic, acetic, fumaric, citric, tartaric, benzoic, p-toluenesulfonic, methanesulfonic or naphthalenesulfonic acid), optionally in a suitable solvent such as an organic solvent, to give the salt which is usually isolated for example by crystallisation and filtration.
  • a suitable inorganic or organic acid such as hydrobromic, hydrochloric, sulfuric, nitric, phosphoric, succinic, maleic, acetic, fumaric, citric, tartaric, benzoic, p-toluenesulfonic, methanesulfonic or naphthalenesulfonic acid
  • a pharmaceutically acceptable acid addition salt of a compound of formula (I) can be for example a hydrobromide, hydrochloride, sulfate, nitrate, phosphate, succinate, maleate, acetate, fumarate, citrate, tartrate, benzoate, p-toluenesulfonate, methanesulfonate or naphthalenesulfonate salt.
  • a pharmaceutically acceptable base addition salt can be formed by reaction of a compound of formula (I) with a suitable inorganic or organic base, (e.g. triethylamine, ethanolamine, triethanolamine, choline, arginine, lysine or histidine), optionally in a suitable solvent, to give the base addition salt which is usually isolated, for example, by crystallisation and filtration.
  • a suitable inorganic or organic base e.g. triethylamine, ethanolamine, triethanolamine, choline, arginine, lysine or histidine
  • Pharmaceutically acceptable base salts include ammonium salts, alkali metal salts such as those of sodium and potassium, alkaline earth metal salts such as those of calcium and magnesium and salts with organic bases, including salts of primary, secondary and tertiary amines, such as isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexyl amine and N-methyl-D- glucamine
  • non-pharmaceutically acceptable salts eg. formates, oxalates or trifluoroacetates
  • the invention includes within its scope all possible stoichiometric and non- stoichiometric forms of the salts of the compounds of formula (I).
  • the present invention covers the compounds of formula (I) as the free acid or base and as salts thereof, for example, as pharmaceutically acceptable salts.
  • solvates with the solvents in which they are reacted or from which they are precipitated or crystallized.
  • a solvate with water is known as a "hydrate”.
  • Solvents with high boiling points and/or solvents with a high propensity to form hydrogen bonds such as water, xylene, ⁇ /-methyl pyrrolidinone and methanol may be used to form solvates.
  • Methods for identification of solvates include, but are not limited to, NMR and microanalysis.
  • solvates of the compounds of formula (I) are within the scope of the invention.
  • salts e.g. pharmaceutically acceptable salts, solvates (e.g. hydrates), stereoisomers and polymorphic forms of the compounds of the invention.
  • references hereinafter to compounds of the invention or to compounds of formula (I) means a compound of formula (I) as the free acid or base, or as a salt e.g. a pharmaceutically acceptable salt, and encompasses solvates, isomers and polymorphic forms of those compounds.
  • a compound of formula (I) may be prepared by reacting a compound of formula (II)
  • Y, e, e', f, g, h, R 3 , i, X, j, k, R 4 , I, I', m, n, and R 5 are as defined hereinabove for formula (I) and L represents a leaving group such as chlorine, bromine, iodine or an activated hydroxyl such as mesylate or tosylate.
  • the alkylation reaction may typically be carried out in the presence of a suitable base such as triethylamine (NEt 3 ), diisopropylethylamine (DIPEA) or sodium hydrogen carbonate (NaHCO 3 ), in an appropriate solvent such as acetonitrile (MeCN) or N,N-dimethylformamide (DMF) optionally at an appropriate elevated temperature such as about 80 0 C, optionally using microwave irradiation and optionally with the addition of an activating agent such as potassium iodide (Kl) or sodium iodide (NaI).
  • a suitable base such as triethylamine (NEt 3 ), diisopropylethylamine (DIPEA) or sodium hydrogen carbonate (NaHCO 3
  • an appropriate solvent such as acetonitrile (MeCN) or N,N-dimethylformamide (DMF)
  • MeCN acetonitrile
  • DMF N,N-dimethylformamide
  • a is as defined hereinabove for formula (I) and Z represents fluorine or hydroxyl.
  • Reagents and Conditions i) when Z represents fluorine: suitable solvent such as N-methyl pyrrolidinone (NMP), appropriate base e.g. sodium tert-butoxide or sodium hydride, optionally at an elevated temperature for example from about 80 to 150 0 C.
  • suitable solvent e.g. tetrahydrofran (THF) or dicholormethane (DCM), appropriate azodicarboxylate e.g.
  • diisopropylazodicarboxylate or 1 ,1 '-(azodicarbonyl)dipiperidine (ADDP) or other reagent such as fert-butyl azodicarboxylate (TBAD), suitable phosphine e.g. triphenylphosphine (PPh 3 ) or (nB ⁇ i 3 P); ⁇ ) deprotection using a suitable acid e.g. trifluoracetic acid (TFA) or hydrogen chloride in a suitable solvent such as dichloromethane (DCM) or dioxane at ambient termperature.
  • a suitable acid e.g. trifluoracetic acid (TFA) or hydrogen chloride in a suitable solvent such as dichloromethane (DCM) or dioxane at ambient termperature.
  • DCM dichloromethane
  • suitable base e.g. K 2 CO 3
  • solvent e.g. 2-butanone usually an elevated temperature e.g. about 80 0 C, optionally using microwave irradiation and optionally with the addition of an activating agent such as Kl
  • R 11 OH in which R 11 represents Ci ⁇ alkyl e.g. methanol [MeOH]
  • acid such as HCI
  • solvent e.g. THF suitable catalysts e.g. DIAD, PPh 3
  • suitable reducing agent e.g. lithium aluminium hydride (LiAIH 4 ), solvent e.g. THF and/or diethyl ether
  • suitable activating agent e.g. tosyl chloride (TsCI) or MsCI
  • an appropriate base e.g. DIPEA in a suitable solvent such as DCM.
  • Compounds of formula (IX) are commercially available, for example, from Sigma-Aldrich or Alfa Aesar, such as azacyclooctane, hexahydro-1 H-azepine, piperidine, 2-methylpiperidine, 3- methylpiperidine, 4-methylpiperidine, 2,6-dimethylpiperidine, 3,3-dimethylpiperidine, pyrrolidine, 2- methyl pyrrolidine, 2,5-dimethylpyrrolidine and azetidine.
  • Sigma-Aldrich or Alfa Aesar such as azacyclooctane, hexahydro-1 H-azepine, piperidine, 2-methylpiperidine, 3- methylpiperidine, 4-methylpiperidine, 2,6-dimethylpiperidine, 3,3-dimethylpiperidine, pyrrolidine, 2- methyl pyrrolidine, 2,5-dimethylpyrrolidine and azetidine.
  • Compounds of formula (VIII) are commercially available, for example, from Sigma-Aldrich, for example 1-bromo-2-chloroethane, 1-bromo-3-chloropropane and 1-bromo-4-chlorobutane.
  • Compounds of formula (X) are commercially available, for example, from Sigma-Aldrich, such as 3- hydroxybenzoic acid, 4-hydroxybenzoic acid, 2-hydroxyphenylacteic acid, 4-hydroxyphenylacteic acid, 3-(4-hydroxyphenyl)propionic acid and 4-(2-hydroxyphenyl)-butyric acid.
  • Reagents and Conditions i) base e.g. K 2 CO 3 , solvent e.g. 2-butanone, usually at an elevated temperature e.g. about 80 0 C, optionally using microwave irradiation and optionally with the addition of an activating agent such as Kl or NaI; ii) copper iodide (CuI), appropriate catalyst e.g. bis[triphenylphosphine]palladium (II) chloride (Pd(PPh 3 ) 2 CI 2 ), base e.g. NEt 3 , solvent e.g. THF; iii) hydrogen, suitable catalyst e.g. palladium on carbon (Pd/C), solvent e.g. EtOH; iv) suitable activating agent e.g. TsCI or MsCI, base e.g. NEt 3 or pyridine, optionally in a suitable solvent e.g. DCM.
  • base e.g. K 2 CO 3
  • Compounds of formula (XIV) are available commercially, for example, from Sigma-Aldrich, such as propargyl alcohol, 3-butyn-1-ol, 4-pentyn-1-ol and 5-hexyn-1-ol.
  • base e.g. K 2 CO3, solvent e.g. 2-butanone, usually at an elevated temperature e.g. about 80 0 C, optionally using microwave irradiation and optionally with the addition of an activating agent such as Kl or NaI;
  • 3-butenal diethylacetal suitable borane e.g. 9- borabicyclononane (9-BBN), appropriate catalyst e.g. [1 ,1 '- bis(diphenylphosphino)ferrocene]dichloropalladium, base e.g. K 2 CO 3 , solvent e.g. water/DMF, usually at an elevated temperature e.g.
  • Reagents and Conditions i) base e.g. K 2 CO 3 , solvent e.g. 2-butanone, usually at an elevated temperature e.g. about 80 0 C, optionally using microwave irradiation and optionally with the addition of an activating agent such as Kl; ii) suitable activating agent e.g. TsCI or MsCI, base e.g. NEt 3 , solvent e.g. DCM.
  • base e.g. K 2 CO 3
  • solvent e.g. 2-butanone usually at an elevated temperature e.g. about 80 0 C, optionally using microwave irradiation and optionally with the addition of an activating agent such as Kl
  • suitable activating agent e.g. TsCI or MsCI
  • base e.g. NEt 3
  • solvent e.g. DCM solvent e.g. DCM.
  • Compounds of formula (XVIII) are available commercially, for example, from Sigma-Aldrich or TCI, such as 2-bromoethanol, 3-bromo-1-propanol, 4-bromo-1-butanol, 5-bromo-1-pentanol and 6- bromo-1-hexanol
  • Compounds of formula (XVII) are commercially available, for example, from Sigma-Aldrich, for example bromochloromethane, 1-bromo-2-chloroethane, 1-bromo-3-chloropropane and 1-bromo-4- chlorobutane, 1-bromo-5-chloropentane and 1-bromo-6-chlorohexane.
  • I, I', m, n and R 5 are as defined hereinabove for formula (I) and P represents a silicon- based protecting group.
  • solvent e.g. THF suitable azodicarboxylate e.g. DIAD or di-tert- butylazodicarboxylate (DTBAD), suitable phosphine e.g. PPh 3 ;
  • TFA solvent e.g. DCM;
  • appropriate reducing agent e.g. NaBH(OAc) 3 solvent e.g. MeOH, acid catalyst e.g. AcOH;
  • activating agent e.g. TsCI or MsCI, suitable base e.g. NEt 3 , solvent e.g. DCM.
  • Compounds of formula (XX) may also be prepared by methods well known to a person skilled in the art, such as Boc-protection of the commercially available amines, for example 3- (hydroxymethyl)pyrrolidine, 2-(2-hydroxyethyl)piperidine, 4(2-hydroxyethyl)piperidine which are commmercially available, for example, from Sigma-Aldrich or Albemate Corporation.
  • Compounds of formula (XXI) are commercially available, for example, from Sigma-Aldrich, such as cyclobutanone, cyclopentanone, cyclohexanone, formaldehyde, acetaldehyde, propionaldehyde, 2- propanone, 2-butanone, butyraldehyde, valeraldehyde and hexanal.
  • I is 3-6 and I', m, n and R 5 are as defined hereinabove for formula (I).
  • Suitable base e.g. sodium hydride, suitable solvent e.g. N-methyl-2- pyrrolidinone, elevated temperature such as about 80 0 C;
  • suitable acid e.g. TFA, solvent e.g. DCM;
  • appropriate reducing agent e.g. NaBH(OAc) 3 , solvent e.g. DCM, optional acid catalyst e.g. AcOH;
  • CuI suitable catalyst e.g. Pd(PPh 3 ) 2 CI 2 , base e.g. NEt 3 , solvent such as THF; v) H 2 , catalyst e.g. Pd/C, solvent e.g. EtOH;
  • appropriate activating agent e.g. TsCI or MsCI, base such as NEt 3 , solvent e.g. DCM.
  • Compounds of formula (XXII), such as 1-fluoro-2-iodobenzene, 1-fluoro-3-iodobenzene and 1- fluoro-4-iodobenzene are available commercially, for example, from Sigma-Aldrich.
  • Y represents CF 3 , CN or halogen and is substituted in the 3, 4 or 5 position of a compound of formula (XXIV);
  • p represents 0 or 1.
  • R 1 represents C h alky! or -(CH 2 ) c aryl (where c represents 0 to 3) in which the aryl is optionally substituted with one or two substituents independently selected from halogen, Ci_ 3 alkyl, trifluoromethyl and cyano, and is substituted in the 2,3 or 4 position of a compound of formula (IV).
  • K represents R 1 and M and L each independently represent hydrogen.
  • L represents R 1 and K and M each independently represent hydrogen.
  • M represents R 1 and K and L each independently represent hydrogen.
  • K, L and M each independently represent hydrogen when p is 0.
  • Skraup reaction suitable strong acid e.g. hydrochloric acid or sulphuric acid, suitable solvent e.g. toluene, optional oxidising agent e.g. nitrobenzene, iron trichloride, p- chloranil or sodium 3-nitrobenzenesulfonate, at an elevated temperature e.g. 100 0 C
  • suitable strong acid e.g. hydrochloric acid or sulphuric acid
  • suitable solvent e.g. toluene
  • optional oxidising agent e.g. nitrobenzene, iron trichloride, p- chloranil or sodium 3-nitrobenzenesulfonate
  • R 1 represents straight chain Ci_ 6 alkyl or -(CH 2 ) c aryl in which the aryl is optionally substituted with one or two substituents independently selected from halogen, C 1-3 alkyl, trifluoromethyl and cyano, and c represents 0 to 3.
  • Reagents and Conditions i) Suzuki reaction using a trialkylboron reagent e.g. triethylboron, tri-n- butylboron, or S-benzyl 9-BBN, suitable solvent e.g. DMF and/or THF, suitable base e.g. potassium carbonate, appropriate catalyst e.g. [1 ,1 ' -bis(diphenylphosphino) ferrocene palladium (II)] chloride, at an elevated temperature such as from about 70 to 80 0 C.
  • a trialkylboron reagent e.g. triethylboron, tri-n- butylboron, or S-benzyl 9-BBN
  • suitable solvent e.g. DMF and/or THF
  • suitable base e.g. potassium carbonate
  • appropriate catalyst e.g. [1 ,1 ' -bis(diphenylphosphino) ferrocene palladium (II)
  • X represents I, Br or CF 3 SO 2 " ; and q represents 0 or 1.
  • Sonogashira reaction base e.g. triethylamine or diisopropylethylamine, copper halide catalyst e.g. copper (I) iodide, palladium catalyst e.g. bis(triphenylphosphine)palladium (II) dichloride, solvent e.g. acetonitrile or DMF, at an elevated temperature when X represents Br or CF 3 SO 3 " ; ii) hydrogenation over a catalyst such as palladium on carbon or platinum oxide in a suitable solvent such as ethanol, at ambient temperature.
  • base e.g. triethylamine or diisopropylethylamine
  • copper halide catalyst e.g. copper (I) iodide
  • palladium catalyst e.g. bis(triphenylphosphine)palladium (II) dichloride
  • solvent e.g. acetonitrile or DMF
  • solvent e.g. ace
  • a compound of formula (I), in which R 2 represents a group of formula (a) may be prepared by reduction of a compound of formula (XXVI): wherein; R 1 , p, a, Y, e, e', f, g, h and R 3 are as defined hereinabove for formula (I).
  • the reaction may typically be carried out in the presence of a suitable catalyst, such as carbonylhydridotris(triphenylphosphine)rhodium(l) (0.01 eq), a reducing agent, such as diphenylsilane (approx. 2.3 eq), in a suitable solvent, such as THF, at ambient temperature for approximately 23 h.
  • a suitable catalyst such as carbonylhydridotris(triphenylphosphine)rhodium(l) (0.01 eq)
  • a reducing agent such as diphenylsilane (approx. 2.3 eq)
  • the reaction may be performed using lithium aluminium hydride as a suitable reducing agent, in a suitable solvent, such as THF, at a lower temperature, such as at about O 0 C.
  • a suitable solvent such as THF
  • C a compound of formula (I), in which at least one R 1 represents - (CH 2 ) b -CO 2 H, may be prepared by deprotection of a compound of formula (XXVII)
  • R 12 represents C 1-6 alkyl
  • the deprotection reaction may typically be carried out in the presence of a suitable base, such as sodium hydroxide, in an appropriate solvent, such as MeOH, at an appropriate elevated temperature, such as from between 60 to 70 0 C.
  • a suitable base such as sodium hydroxide
  • triphenylphosphoranylidene)acetate 1.5 eq
  • suitable solvent e.g. THF
  • suitable solvent e.g. THF
  • a catalyst e.g. palladium on carbon or platinum oxide in ethanol, or where a halide is present use copper hydride e.g. (triphenylphosphine)copper(l) hydride hexamer in THF at room temperature;
  • suitable base e.g.
  • NEt 3 triethylamine
  • DIPEA diisopropylethylamine
  • NaHCO 3 sodium hydrogen carbonate
  • a sutiable solvent e.g. acetonitrile (MeCN) or N,N-dimethylformamide (DMF)
  • MeCN acetonitrile
  • DMF N,N-dimethylformamide
  • an activating agent e.g. potassium iodide (Kl) or sodium iodide (NaI).
  • D a compound of formula (I) may be prepared by interconversion from other compounds of formula (I).
  • Interconversions include, but are not limited to alkylation and deprotection, under standard conditions well known to those skilled in the art.
  • an alkylation reaction may be carried out between a compound of formula (I) and a Ci_ 6 alkyl, activated to substitution by means of a leaving group such as halogen or an activated hydroxyl group, such as mesylate or tosylate.
  • the reaction usually takes place in the presence of a suitable base such as triethylamine, ⁇ /, ⁇ /-diisopropylethylamine or sodium carbonate, in an appropriate solvent such as 2-butanone or DMF, optionally at an appropriate elevated temperature such as at about 80 0 C.
  • a salt of a compound of formula (I), for example a pharmaceutically acceptable salt may be prepared by exchange of counterions, or precipitation of said salt from the free acid or base.
  • Suitable amine protecting groups include sulphonyl (e.g. tosyl), acyl (e.g. acetyl, 2',2',2'-trichloroethoxycarbonyl, benzyloxycarbonyl or f-butoxycarbonyl) and arylalkyl (e.g.
  • benzyl which may be removed using an acid such as hydrogen chloride in dioxane or trifluoroacetic acid in dichloromethane or reductively by hydrogenolysis of a benzyl group or reductive removal of a 2',2',2'-trichloroethoxycarbonyl group using zinc in acetic acid, as appropriate.
  • suitable amine protecting groups include trifluoroacetyl (-COCF 3 ), which may be removed by base catalysed hydrolysis or a solid phase resin bound benzyl group, such as a Merrifield resin bound 2,6-dimethoxybenzyl group (Ellman linker), which may be removed by acid catalysed hydrolysis, for example with trifluoroacetic acid.
  • Compounds of formula (I), or pharmaceutically acceptable salts thereof may be useful for the treatment of various inflammatory and/or allergic diseases.
  • Compounds of formula (I), or pharmaceutically acceptable salts thereof may also be useful for the prophylaxis of various inflammatory and/or allergic diseases.
  • diseases in which a compound of formula (I), or a pharmaceutically acceptable salt thereof, may have potentially beneficial anti-inflammatory and/or anti-allergic effects include diseases of the respiratory tract such as allergic rhinitis (seasonal and perennial), bronchitis (including chronic bronchitis), asthma (including allergen-induced asthmatic reactions), chronic obstructive pulmonary disease (COPD) and sinusitis.
  • diseases of the respiratory tract such as allergic rhinitis (seasonal and perennial), bronchitis (including chronic bronchitis), asthma (including allergen-induced asthmatic reactions), chronic obstructive pulmonary disease (COPD) and sinusitis.
  • the compounds of the invention may be of use in the treatment of nephritis, skin diseases such as psoriasis, eczema, allergic dermatitis, urticaria and hypersensitivity reactions. A particular disease of interest is urticaria. Also, the compounds of the invention may be useful in the treatment of insect bites and stings.
  • the compounds of the invention may also be of use in the treatment of nasal polyposis, conjunctivitis (e.g. allergic conjunctivitis) or pruritis.
  • conjunctivitis e.g. allergic conjunctivitis
  • pruritis A disease of particular interest is allergic rhinitis.
  • diseases in which histamine may have a pathophysiological role include non-allegic rhinitis, and also diseases of the gastrointestinal tract such as intestinal inflammatory diseases including inflammatory bowel disease (e.g. Crohn's disease or ulcerative colitis) and intestinal inflammatory diseases secondary to radiation exposure or allergen exposure.
  • intestinal inflammatory diseases including inflammatory bowel disease (e.g. Crohn's disease or ulcerative colitis) and intestinal inflammatory diseases secondary to radiation exposure or allergen exposure.
  • compounds of formula (I), or pharmaceutically acceptable salts thereof may be useful as therapeutic agents.
  • a compound of formula (I), or a pharmaceutically acceptable salt thereof for use in therapy.
  • a compound of formula (I), or a pharmaceutically acceptable salt thereof for use in the treatment of inflammatory and/or allergic diseases (such as any of the above-mentioned diseases).
  • a compound of formula (I), or a pharmaceutically acceptable salt thereof for use in the treatment of allergic rhinitis.
  • a compound of formula (I), or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for the treatment of inflammatory and/or allergic diseases (such as any of the above-mentioned diseases).
  • a compound of formula (I), or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for use in the treatment of allergic rhinitis.
  • a method for treating inflammatory and/or allergic diseases which comprises administering to a patient an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.
  • a method for treating inflammatory and/or allergic diseases which comprises administering to a patient an effective amount of 8-( ⁇ 1-[2-(4- ⁇ [3-(hexahydro-1 H-azepin-1-yl)propyl]oxy ⁇ phenyl)ethyl]-4- piperidinyl ⁇ oxy)quinoline, or a pharmaceutically acceptable salt thereof.
  • a method for treating allergic rhinitis which comprises administering to a patient an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.
  • a method for treating allergic rhinitis which comprises administering to a patient an effective amount of 8-( ⁇ 1-[2-(4- ⁇ [3-(Hexahydro-1H-azepin-1- yl)propyl]oxy ⁇ phenyl)ethyl]-4-piperidinyl ⁇ oxy)quinoline, or a pharmaceutically acceptable salt thereof.
  • the compounds of formula (I), or pharmaceutically acceptable salts thereof are usually formulated in a suitable pharmaceutical composition.
  • suitable pharmaceutical compositions can be prepared using standard procedures.
  • the present invention provides, a pharmaceutical composition
  • a pharmaceutical composition comprising a) a compound of formula (I), or a pharmaceutically acceptable salt thereof, and b) one or more pharmaceutically acceptable excipients.
  • a pharmaceutical composition comprising a) 8-( ⁇ 1-[2-(4- ⁇ [3-(hexahydro- 1 H-azepin-1-yl)propyl]oxy ⁇ phenyl)ethyl]-4-piperidinyl ⁇ oxy)quinoline, or a pharmaceutically acceptable salt thereof, and b) one or more pharmaceutically acceptable carriers or excipients.
  • a composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, which may be prepared by admixture, suitably at ambient temperature and atmospheric pressure, may be suitable for topical administration (which includes epicutaneous, inhaled, intranasal or ocular administration), enteral administration (which includes oral or rectal administration) or parenteral administration (such as by injection or infusion).
  • topical administration which includes epicutaneous, inhaled, intranasal or ocular administration
  • enteral administration which includes oral or rectal administration
  • parenteral administration such as by injection or infusion
  • compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof suitable for topical administration, particularly suitable for intranasal administration.
  • compositions may be in the form of solutions or suspensions (aqueous or non-aqueous), tablets, capsules, oral liquid preparations, powders, granules, lozenges, lotions, creams, ointments, gels, foams, reconstitutable powders or suppositories as required by the route of administration.
  • compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof may contain from about 0.001 % to 99% (w/w), such as from about 0.1 to 60% (w/w) (based on the total weight of the composition), of the compound of formula (I) or the pharmaceutically acceptable salt thereof, depending on the route of administration.
  • the dose of the compound used in the treatment of the aforementioned diseases will vary in the usual way with the seriousness of the diseases, the weight of the sufferer, and other similar factors.
  • suitable unit doses may be about 0.05 to 1000 mg, for example about 0.05 to 200 mg, and such unit doses may be administered more than once a day, for example two or three times a day or as desired. Such therapy may extend for a number of weeks or months.
  • the proportion of the compound of formula (I) or a pharmaceutically acceptable salt thereof in a topical composition will depend on the precise type of composition to be prepared and the particular route of administration, but will generally be within the range of from about 0.001 to 10% (w/w), based on the total weight of the composition. Generally, however for most types of preparations the proportion used will be within the range of from about 0.005 to 1 % (w/w), such as about 0.01 to 1 % (w/w), for example about 0.01 to 0.5% (w/w), based on the total weight of the composition. However, in powders for inhalation the proportion used will generally be within the range of from about 0.1 to 5% (w/w), based on the total weight of the composition.
  • compositions suitable for intranasal or inhaled administration may conveniently be formulated as aerosols, solutions, suspensions, drops, gels or dry powders, optionally with one or more pharmaceutically acceptable carriers and/or excipients such as aqueous or non-aqueous vehicles, thickening agents, isotonicity adjusting agents, antioxidants, preservatives and/or co- solvents.
  • pharmaceutically acceptable carriers and/or excipients such as aqueous or non-aqueous vehicles, thickening agents, isotonicity adjusting agents, antioxidants, preservatives and/or co- solvents.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof may typically be in a particle-size-reduced form, which may be prepared by conventional techniques, for example, micronisation, milling and/or microfluidisation.
  • the size-reduced (e.g. micronised) compound of formula (I) or a pharmaceutically acceptable salt thereof can be defined by a D 50 value of about 0.5 to 10 microns, for example of about 1 to 10 microns, such as of about 1 to 4 microns (for example as measured using laser diffraction).
  • compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof are suitable for intranasal administration.
  • Intranasal compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof may permit the compound(s) to be delivered to all areas of the nasal cavities (the target tissue) and further, may permit the compound(s) to remain in contact with the target tissue for longer periods of time.
  • a suitable dosing regime for intranasal compositions would be for the patient to inhale slowly through the nose subsequent to the nasal cavity being cleared. During inhalation the composition would be administered to one nostril while the other is manually compressed. This procedure would then be repeated for the other nostril.
  • one or two administrations per nostril would be administered by the above procedure up to two or three times each day, ideally once daily.
  • Of particular interest are intranasal compositions suitable for once daily administration.
  • compositions containing a compound of formula (I) or a pharmaceutically acceptable salt thereof may be in the form of an aqueous suspension and/or an aqueous solution. Partial suspensions and/or partial solutions are encompassed within the scope of the present invention. Compositions comprising one compound which is in solution and another compound which is in suspension are also included within the scope of the present invention.
  • compositions may optionally contain one or more suspending/thickening agents, one or more preservatives, one or more wetting agents and/or one or more isotonicity adjusting agents as desired.
  • Compositions suitable for intranasal administration may optionally further contain other excipients, such as antioxidants (for example sodium metabisulphite), taste-masking agents (such as menthol) and sweetening agents (for example dextrose, glycerol, saccharin and/or sorbitol).
  • excipients may perform more than one function, depending on the nature and number of excipients used in the composition and the particular properties of the therapeutic compound(s) and other carriers and/or excipients contained therein.
  • the suspending/thickening agent if included, will typically be present in the intranasal composition in an amount of between about 0.1 and 5% (w/w), such as between about 1.5% and 2.4% (w/w), based on the total weight of the composition.
  • suspending/thickening agents include, but are not limited to Avicel® (microcrystalline cellulose and carboxymethylcellulose sodium), carboxymethylcellulose sodium, veegum, tragacanth, bentonite, methylcellulose xanthan gum, carbopol and polyethylene glycols.
  • Suspending/thickening agents may also be included in compositions suitable for inhaled, ocular and oral administration, as appropriate.
  • intranasal compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof may be protected from microbial or fungal contamination and growth by inclusion of a preservative.
  • pharmaceutically acceptable anti-microbial agents or preservatives may include quaternary ammonium compounds (e.g. benzalkonium chloride, benzethonium chloride, cetrimide, myristal picolinium chloride, lauralkonium chloride and cetylpyridinium chloride), mercurial agents (e.g. phenylmercuric nitrate, phenylmercuric acetate and thimerosal), alcoholic agents (e.g.
  • antibacterial esters e.g. esters of para-hydroxybenzoic acid
  • chelating agents such as disodium ethylenediaminetetraacetate (EDTA) and other anti-microbial agents such as chlorhexidine, chlorocresol, sorbic acid and its salts (such as potassium sorbate) and polymyxin.
  • pharmaceutically acceptable anti-fungal agents or preservatives include, but are not limited to sodium benzoate, sorbic acid, sodium propionate, methyl paraben, ethyl paraben, propyl paraben and butyl paraben.
  • the preservative if included, may be present in an amount of between about 0.001 and 1 % (w/w), such as about 0.015% (w/w), based on the total weight of the composition. Preservatives may be included in compositions suitable for other routes of administration as appropriate.
  • Compositions which contain a suspended medicament may include a pharmaceutically acceptable wetting agent which functions to wet the particles of medicament to facilitate dispersion thereof in the aqueous phase of the composition.
  • a pharmaceutically acceptable wetting agent which functions to wet the particles of medicament to facilitate dispersion thereof in the aqueous phase of the composition.
  • wetting agents include, but are not limited to fatty alcohols, esters and ethers, such as polyoxyethylene (20) sorbitan monooleate (Polysorbate 80) macrogol ethers and poloxamers.
  • the wetting agent may be present in intranasal compositions in an amount of between about 0.001 and 0.05% (w/w), for example about 0.025% (w/w), based on the total weight of the composition.
  • Wetting agents may be included in compositions suitable for other routes of administration, e.g. for inhaled and/or ocular administration, as appropriate.
  • An isotonicity adjusting agent may be included to achieve isotonicity with body fluids e.g. fluids of the nasal cavity, resulting in reduced levels of irritancy.
  • body fluids e.g. fluids of the nasal cavity
  • isotonicity adjusting agents include, but are not limited to sodium chloride, dextrose, xylitol and calcium chloride.
  • An isotonicity adjusting agent may be included in intranasal compositions in an amount of between about 0.1 and 10% (w/w), for example between about 4.5 to 5.5% (w/w), such as about 5.0% (w/w), based on the total weight of the composition.
  • Isotonicity adjusting agents may also be included in compositions suitable for other routes of administration, for example in compositions suitable for inhaled, ocular, oral liquid and parenteral administration, as appropriate.
  • One or more co-solvent(s) may be included to aid solubility of the active compound(s) and/or other excipients.
  • pharmaceutically acceptable co-solvents include, but are not limited to, propylene glycol, dipropylene glycol, ethylene glycol, glycerol, ethanol, polyethylene glycols (for example PEG300 or PEG400) and methanol.
  • the co-solvent(s), if present, may be included in an amount of from about 0.05 to 20% (w/w), such as from about 1.5 to 17.5% (w/w), or from about 1.5 to 7.5% (w/w), or from about 0.05% to 0.5% (w/w) based on the total weight of the composition.
  • Co- solvents may also be included in compositions suitable for other routes of administration, as appropriate.
  • the intranasal compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof may be buffered by the addition of suitable buffering agents such as sodium citrate, citric acid, trometarol, phosphates such as disodium phosphate (for example the dodecahydrate, heptahydrate, dihydrate and anhydrous forms) or sodium phosphate and mixtures thereof. Buffering agents may also be included in compositions suitable for other routes of administration as appropriate.
  • compositions for administration topically to the nose (for example, for the treatment of rhinitis) or lung include pressurised aerosol compositions and aqueous compositions delivered to the nasal cavities by pressurised pump.
  • Compositions which are non-pressurised and adapted to be administered topically to the nasal cavity are of particular interest. Suitable compositions contain water as the diluent or carrier for this purpose.
  • Aqueous compositions for administration to the lung or nose may be provided with conventional excipients such as buffering agents, tonicity modifying agents and the like. Aqueous compositions may also be administered to the nose by nebulisation.
  • a fluid dispenser may typically be used to deliver a fluid composition to the nasal cavities.
  • the fluid composition may be aqueous or non-aqueous, but typically aqueous.
  • Such a fluid dispenser may have a dispensing nozzle or dispensing orifice through which a metered dose of the fluid composition is dispensed upon the application of a user-applied force to a pump mechanism of the fluid dispenser.
  • Such fluid dispensers are generally provided with a reservoir of multiple metered doses of the fluid composition, the doses being dispensable upon sequential pump actuations.
  • the dispensing nozzle or orifice may be configured for insertion into the nostrils of the user for spray dispensing of the fluid composition into the nasal cavity.
  • a fluid dispenser of the aforementioned type is described and illustrated in WO05/044354 the entire content of which is hereby incorporated herein by reference.
  • the dispenser has a housing which houses a fluid discharge device having a compression pump mounted on a container for containing a fluid composition.
  • the housing has at least one finger-operable side lever which is movable inwardly with respect to the housing to cam the container upwardly in the housing to cause the pump to compress and pump a metered dose of the composition out of a pump stem through a nasal nozzle of the housing.
  • the fluid dispenser is of the general type illustrated in Figures 30-40 of WO05/044354.
  • Aqueous compositions containing a compound of formula (I) or a pharmaceutically acceptable salt thereof may also be delivered by a pump as disclosed in WO2007/138084, for example as disclosed with reference to Figures 22-46 thereof, or as disclosed in GB0723418.0, for example as disclosed with reference to Figures 7-32 thereof, both of which prior patent applications are incorporated herein by reference in their entirety.
  • the pump may be actuated by an actuator as disclosed in Figures 1-6 of said GB0723418.0.
  • an intranasal composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • such an intranasal composition is benzalkonium chloride-free.
  • Inhaled administration involves topical administration to the lung, such as by aerosol or dry powder composition.
  • Aerosol compositions suitable for inhaled administration may comprise a solution or fine suspension of the compound in a pharmaceutically acceptable aqueous or non-aqueous solvent.
  • Aerosol compositions suitable for inhalation can be either a suspension or a solution and generally contain a compound of formula (I) or a pharmaceutically acceptable salt thereof and a suitable propellant such as a fluorocarbon or hydrogen-containing chlorofluorocarbon or mixtures thereof, such as hydrofluoroalkanes, e.g. 1 ,1 ,1 ,2-tetrafluoroethane, 1 ,1 ,1 ,2,3,3,3-heptafluoro-n-propane or a mixture thereof.
  • a suitable propellant such as a fluorocarbon or hydrogen-containing chlorofluorocarbon or mixtures thereof, such as hydrofluoroalkanes, e.g. 1 ,1 ,1 ,2-tetrafluoroethane, 1 ,1 ,1 ,2,3,3,
  • the aerosol composition may optionally contain additional excipients well known in the art such as surfactants or cosolvents.
  • surfactants include, but are not limited to oleic acid, lecithin, an oligolactic acid or derivative e.g. as described in WO94/21229 and WO98/34596.
  • An example of a cosolvent includes, but is not limited to ethanol.
  • Aerosol compositions may be presented in single or multidose quantities in sterile form in a sealed container, which may take the form of a cartridge or refill for use with an atomising device or inhaler.
  • 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 (metered dose inhaler), which is intended for disposal once the contents of the container have been exhausted.
  • Dry powder inhalable compositions may take the form of capsules and cartridges of, for example, gelatine, or blisters of, for example, laminated aluminium foil, for use in an inhaler or insufflator.
  • Such compositions may be formulated comprising a powder mix of a compound of formula (I) or a pharmaceutically acceptable salt thereof and a suitable powder base such as lactose or starch.
  • a composition suitable for inhaled administration may be incorporated into a plurality of sealed dose containers (e.g. comprising the dry powder composition) mounted longitudinally in a strip or ribbon inside a suitable inhalation device.
  • the container is rupturable or peel-openable on demand and the dose of e.g. the dry powder composition may be administered by inhalation via the device such as the DISKUSTM device, marketed by GlaxoSmithKline.
  • the DISKUSTM inhalation device is for example described in GB 2242134 A, and in such a device, at least one container for the composition in powder form (the container or containers may, for example, be a plurality of sealed dose containers mounted longitudinally in a strip or ribbon) is defined between two members peelably secured to one another; the device comprises: a means of defining an opening station for the said container or containers; a means for peeling the members apart at the opening station to open the container; and an outlet, communicating with the opened container, through which a user can inhale the composition in powder form from the opened container.
  • Aerosol compositions are typically arranged so that each metered dose or "puff" of aerosol contains about 20 ⁇ g - 2000 ⁇ g, particularly about 20 ⁇ g - 500 ⁇ g of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • Administration may be once daily or several times daily, for example 2, 3, 4 or 8 times, giving for example 1 , 2 or 3 doses each time.
  • the overall daily dose with an aerosol will be within the range of about 100 ⁇ g - 10 mg, such as between about 200 ⁇ g - 2000 ⁇ g.
  • the overall daily dose and the metered dose delivered by capsules and cartridges in an inhaler or insufflator will generally be double those with aerosol compositions.
  • compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof which is suitable for epicutaneous administration.
  • An epicutaneous composition to be applied to the affected area e.g. the skin, by one or more application per day may be in the form of, for example, an ointment, a cream, an emulsion, a lotion, a foam, a spray, an aqueous gel, or a microemulsion.
  • Such compositions may optionally contain one or more solubilising agents, skin-penetration-enhancing agents, surfactants, fragrances, preservatives or emulsifying agents.
  • Ointments, creams and gels may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agent and/or solvents.
  • bases may thus, for example, include water and/or an oil such as liquid paraffin or a vegetable oil such as arachis oil or castor oil, or a solvent such as polyethylene glycol.
  • Thickening agents and gelling agents which may be used according to the nature of the base include soft paraffin, aluminium stearate, cetostearyl alcohol, polyethylene glycols, woolfat, beeswax, carboxypolymethylene and cellulose derivatives, and/or glyceryl monostearate and/or non-ionic emulsifying agents.
  • Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilising agents, dispersing agents, suspending agents or thickening agents.
  • compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof which is suitable for ocular administration.
  • Such compositions may optionally contain one or more suspending agents, one or more preservatives, one or more wetting/lubricating agents and/or one or more isotonicity adjusting agents.
  • ophthalmic wetting/lubricating agents may include cellulose derivatives, dextran 70, gelatin, liquid polyols, polyvinyl alcohol and povidone such as cellulose derivatives and polyols.
  • compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof which is suitable for oral administration.
  • Tablets and capsules for oral administration may be in unit dose form, and may contain conventional excipients, such as binding agents, fillers, tabletting lubricants, disintegrants and acceptable wetting agents.
  • the tablets may be coated according to methods well known in normal pharmaceutical practice.
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspension, solutions, emulsions, syrups or elixirs, or may be in the form of a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), preservatives, and, if desired, conventional flavourings or colorants.
  • a composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof which is suitable for parenteral administration.
  • Fluid unit dosage forms suitable for parenteral administration may be prepared utilising a compound of formula (I) or pharmaceutically acceptable salt thereof and a sterile vehicle which may be aqueous or oil based. The compound, depending on the vehicle and concentration used, may be either suspended or dissolved in the vehicle. In preparing solutions, the compound may be dissolved for injection and filter sterilised before filling into a suitable vial or ampoule and sealing. Optionally, adjuvants such as a local anaesthetic, preservatives and buffering agents may be dissolved in the vehicle.
  • the composition may be frozen after filling into the vial and the water removed under vacuum.
  • the lyophilised parenteral composition may be reconstituted with a suitable solvent just prior to administration.
  • Parenteral suspensions may be prepared in substantially the same manner, except that the compound is suspended in the vehicle instead of being dissolved, and sterilisation cannot be accomplished by filtration.
  • the compound may be sterilised by exposure to ethylene oxide before suspension in a sterile vehicle.
  • a surfactant or wetting agent may be included in the composition to facilitate uniform distribution of the compound.
  • the compounds and pharmaceutical compositions according to the invention may also be used in combination with or include one or more other therapeutic agents, for example other antihistaminic agents for example H4 receptor antagonists, anticholinergic agents, anti-inflammatory agents such as corticosteroids (e.g. fluticasone propionate, fluticasone furoate, beclomethasone dipropionate, mometasone furoate, triamcinolone acetonide, budesonide and the steroid disclosed in WO02/12265); or non-steroidal anti-inflammatory drugs (NSAIDs) (e.g.
  • chemokine antagonists e.g. CCR3, CCR1 , CCR2, CCR4, CCR8, CXCR1 , CXCR2
  • IKK antagonists e.g. CCR3, CCR1 , CCR2, CCR4, CCR8, CXCR1 , CXCR2
  • IKK antagonists e.g. CCR3, CCR1 , CCR2, CCR4, CCR8, CXCR1 , CXCR2
  • IKK antagonists e.g. CCR3, CCR1 , CCR2, CCR4, CCR8, CXCR1 , CXCR2
  • IKK antagonists e.g. CCR3, CCR1 , CCR2, CCR4, CCR8, CXCR1 , CXCR2
  • IKK antagonists e.g. CCR3, CCR1 , CCR2, CCR4, CCR8, CXCR1 , CXCR2
  • IKK antagonists e.g. CCR3, CCR1 , CCR2, CCR4, C
  • the other therapeutic agent(s) may be used in the form of salts, (e.g. as alkali metal or amine salts or as acid addition salts), or prodrugs, or as esters (e.g. lower alkyl esters), or as solvates (e.g. hydrates) to optimise the activity and/or stability and/or physical characteristics (e.g. solubility) of the therapeutic agent.
  • the therapeutic agents may be used in optically pure form.
  • a combination comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, together with one or more (such as one or two, e.g. one) other therapeutically active agents, optionally with one or more pharmaceutically acceptable carriers and/or excipients.
  • a combination comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a H4 receptor antagonist.
  • histamine receptor antagonists which may be used alone, or in combination with a dual H1/H3 receptor antagonist include antagonists (and/or inverse agonists) of the H4 receptor, for example, the compounds disclosed in Jablonowski et ai, J. Med. Chem. 46:3957-3960 (2003).
  • a combination comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a ⁇ 2 -adrenoreceptor agonist.
  • ⁇ 2 -adrenoreceptor agonists include salmeterol (which may be a racemate or a single enantiomer, such as the R-enantiomer), salbutamol (which may be a racemate or a single enantiomer such as the R-enantiomer), formoterol (which may be a racemate or a single diastereomer such as the R,R-diastereomer), salmefamol, fenoterol, carmoterol, etanterol, naminterol, clenbuterol, pirbuterol, flerbuterol, reproterol, bambuterol, indacaterol, terbutaline and salts thereof, for example the xinafoate (1-hydroxy-2-naphthalenecarboxylate) salt of salmeterol, the sulfate salt or free base of salbutamol or the fumarate salt of formoterol.
  • combinations for example the
  • ⁇ 2 -adrenoreceptor agonists include those described in WO 02/066422, WO 02/070490, WO 02/076933, WO 03/024439, WO 03/072539, WO 03/091204, WO 04/016578, WO 2004/022547, WO 2004/037807, WO 2004/037773, WO 2004/037768, WO 2004/039762, WO 2004/039766, WO01/42193 and WO03/042160.
  • Examples of ⁇ 2 -adrenoreceptor agonists include:
  • the ⁇ 2 -adrenoreceptor agonist may be in the form of a salt formed with a pharmaceutically acceptable acid selected from sulfuric, hydrochloric, fumaric, hydroxynaphthoic (for example 1- or 3-hydroxy-2-naphthoic), cinnamic, substituted cinnamic, triphenylacetic, sulfamic, sulfanilic, naphthaleneacrylic, benzoic, 4-methoxybenzoic, 2- or 4-hydroxybenzoic, 4-chlorobenzoic and 4- phenylbenzoic acid.
  • a pharmaceutically acceptable acid selected from sulfuric, hydrochloric, fumaric, hydroxynaphthoic (for example 1- or 3-hydroxy-2-naphthoic), cinnamic, substituted cinnamic, triphenylacetic, sulfamic, sulfanilic, naphthaleneacrylic, benzoic, 4-me
  • a combination comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and an anti-inflammatory agent.
  • Anti-inflammatory agents include corticosteroids.
  • Suitable corticosteroids which may be used in combination with the compounds of formula (I) are those oral and inhaled corticosteroids and their pro-drugs which have anti-inflammatory activity. Examples include methyl prednisolone, prednisolone, dexamethasone, fluticasone propionate, 6 ⁇ ,9 ⁇ -difluoro-1 1 ⁇ -hydroxy-16 ⁇ -methyl- 17 ⁇ -[(4-methyl-1 ,3-thiazole-5-carbonyl)oxy]-3-oxo-androsta-1 ,4-diene-17 ⁇ -carbothioic acid S- fluoromethyl ester, 6 ⁇ ,9 ⁇ -difluoro-17 ⁇ -[(2-furanylcarbonyl)oxy]-1 1 ⁇ -hydroxy-16 ⁇ -methyl-3-oxo- androsta-1 ,4-diene-17 ⁇ -carbothioic acid S-fluoromethyl ester (fluticasone furoate), 6 ⁇ ,
  • Corticosteroids of particular interest may include fluticasone propionate, 6 ⁇ ,9 ⁇ -difluoro-11 ⁇ -hydroxy-16 ⁇ -methyl-17 ⁇ -[(4-methyl-1 ,3-thiazole-5- carbonyl)oxy]-3-oxo-androsta-1 ,4-diene-17 ⁇ -carbothioic acid S-fluoromethyl ester, 6 ⁇ ,9 ⁇ -difluoro- 17 ⁇ -[(2-furanylcarbonyl)oxy]-11 ⁇ -hydroxy-16 ⁇ -methyl-3-oxo-androsta-1 ,4-diene-17 ⁇ -carbothioic acid S-fluoromethyl ester, 6 ⁇ ,9 ⁇ -difluoro-1 1 ⁇ -hydroxy-16 ⁇ -methyl-3-oxo-17 ⁇ -(2,2,3,3- tetramethycyclopropylcarbonyl)oxy-androsta-1 ,4-diene-17 ⁇ -carbothioic acid S-cyano methylester, 6 ⁇ ,9 ⁇ -d
  • the corticosteroid is 6 ⁇ ,9 ⁇ -difluoro-17 ⁇ -[(2-furanylcarbonyl)oxy]-1 1 ⁇ -hydroxy-16 ⁇ -methyl-3-oxo- androsta-1 ,4-diene-17 ⁇ -carbothioic acid S-fluoromethyl ester (fluticasone furoate) or mometasone furoate.
  • a combination comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a corticosteroid, such as fluticasone propionate or 6 ⁇ ,9 ⁇ -difluoro-17 ⁇ -[(2-furanylcarbonyl)oxy]-11 ⁇ -hydroxy-16 ⁇ -methyl-3-oxo-androsta-1 ,4-diene- 17 ⁇ -carbothioic acid S-fluoromethyl ester (fluticasone furoate) or mometasone furoate, in particular 6 ⁇ ,9 ⁇ -difluoro-17 ⁇ -[(2-furanylcarbonyl)oxy]-11 ⁇ -hydroxy-16 ⁇ -methyl-3-oxo-androsta-1 ,4-diene- 17 ⁇ -carbothioic acid S-fluoromethyl ester (fluticasone furoate).
  • a corticosteroid such as fluticasone propionate or 6 ⁇ ,9 ⁇ -difluoro-17 ⁇ -[(2-furanylcarbonyl)oxy
  • a combination comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and 6 ⁇ ,9 ⁇ -difluoro-17 ⁇ -[(2-furanylcarbonyl)oxy]-1 1 ⁇ - hydroxy-16 ⁇ -methyl-3-oxo-androsta-1 ,4-diene-17 ⁇ -carbothioic acid S-fluoromethyl ester (fluticasone furoate).
  • a combination comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a glucocorticoid agonist.
  • Non-steroidal compounds having glucocorticoid agonism that may possess selectivity for transrepression over transactivation and that may be useful in combination therapy include those covered in the following patent application and patents: WO03/082827, WO98/54159, WO04/005229, WO04/009017, WO04/018429, WO03/104195, WO03/082787, WO03/082280, WO03/059899, WO03/101932, WO02/02565, WO01/16128, WO00/66590, WO03/086294, WO04/026248, WO03/061651 , WO03/08277, WO06/000401 , WO06/000398 and WO06/015870.
  • Anti-inflammatory agents include non-steroidal anti-inflammatory drugs (NSAID's).
  • NSAID's include sodium cromoglycate, nedocromil sodium, phosphodiesterase (PDE) inhibitors (e.g. theophylline, PDE4 inhibitors or mixed PDE3/PDE4 inhibitors), leukotriene antagonists, inhibitors of leukotriene synthesis (eg. montelukast), iNOS (inducible nitric oxide synthase) inhibitors (e.g. oral iNOS inhibitors), IKK antagonists, tryptase and elastase inhibitors, beta-2 integrin antagonists and adenosine receptor agonists or antagonists (e.g.
  • adenosine 2a agonists e.g. adenosine 2a agonists
  • cytokine antagonists e.g. chemokine antagonists, such as a CCR1 , CCR2, CCR3, CCR4, or CCR8 antagonists
  • inhibitors of cytokine synthesis or 5-lipoxygenase inhibitors.
  • iNOS inhibitors include those disclosed in WO93/13055, WO98/30537, WO02/50021 , WO95/34534 and WO99/62875.
  • PDE4-specific inhibitor useful in this embodiment may be any compound that is known to inhibit the PDE4 enzyme or which is discovered to act as a PDE4 inhibitor, and which are only PDE4 inhibitors, not compounds which inhibit other members of the PDE family, such as PDE3 and PDE5, as well as PDE4.
  • Compounds which may be of interest include 6-( ⁇ 3-[(dimethylamino)carbonyl]phenyl ⁇ sulfonyl)-8- methyl-4- ⁇ [3-(methyloxy)phenyl]amino ⁇ -3-quinolinecarboxamide (Example 399 of International Patent Application WO04/103998), c/s-4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan- 1-carboxylic acid, 2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4- difluoromethoxyphenyl)cyclohexan-1-one and c/s-[4-cyano-4-(3-cyclopropylmethoxy-4- difluoromethoxyphenyl)cyclohexan-1-ol].
  • PDE4 inhibitors include AWD-12-281 from Elbion (Hofgen, N. et al., 15th EFMC Int. Symp. Med. Chem., (Sept 6-10, Edinburgh) 1998, Abst. P. 98; CAS reference No.
  • a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and 6-( ⁇ 3-[(dmethylamino)carbonyl]phenyl ⁇ sulfonyl)-8- methyl-4- ⁇ [3-(methyloxy)phenyl]amino ⁇ -3-quinolinecarboxamide or a pharmaceutically acceptable salt thereof.
  • a combination comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and an anticholinergic agent.
  • Anticholinergic agents are those compounds that act as antagonists at the muscarinic receptors, in particular those compounds which are antagonists of the M 1 or M 3 receptors, dual antagonists of the M 1 ZM 3 or M 2 /M 3 , receptors or pan-antagonists of the M-
  • Exemplary compounds for administration via inhalation include ipratropium (for example, as the bromide, CAS 22254-24-6, sold under the name Atrovent), oxitropium (for example, as the bromide, CAS 30286- 75-0) and tiotropium (for example, as the bromide, CAS 136310-93-5, sold under the name Spiriva).
  • revatropate for example, as the hydrobromide, CAS 262586-79-8) and LAS-34273 which is disclosed in WO01/04118.
  • Exemplary compounds for oral administration include pirenzepine (for example, CAS 28797-61-7), darifenacin (for example, CAS 133099-04-4, or CAS 133099-07-7 for the hydrobromide sold under the name Enablex), oxybutynin (for example, CAS 5633-20-5, sold under the name Ditropan), terodiline (for example, CAS 15793-40-5), tolterodine (for example, CAS 124937-51-5, or CAS 124937-52-6 for the tartrate, sold under the name Detrol), otilonium (for example, as the bromide, CAS 26095-59-0, sold under the name Spasmomen), trospium chloride (for example, CAS 10405-02-4) and solifenacin (for example,
  • WO2007/022351 Other anticholinergic agents include compounds which are disclosed in US patent application 60/487981 , published as WO2005/009439 and those compounds disclosed in US patent application 60/511009, published as WO2005/037280.
  • compositions comprising a combination as defined above optionally together with a pharmaceutically acceptable carrier and/or excipient.
  • the individual compounds of such combinations may be administered either sequentially in separate pharmaceutical compositions as well as simultaneously in combined pharmaceutical compositions. Additional therapeutically active ingredients may be suspended in the composition together with a compound of formula (I). Appropriate doses of known therapeutic agents will be readily appreciated by those skilled in the art.
  • DIPEA ⁇ /, ⁇ /-Diisopropylethylamine
  • DMSO Dimethylsulfoxide
  • LiALH 4 Lithium Aluminium Hydride
  • NMR Nuclear Magnetic Resonance
  • Pd/C Palladium on activated carbon
  • RT Retention time s.g: Specific gravity
  • TBTU O-(1 /-/-benzotriazol-1-yl)- ⁇ /, ⁇ /, ⁇ /', ⁇ /'-tetramethyluronium tetrafluoroborate
  • TFA Trifluoroacetic acid
  • THF Tetrahydrofuran
  • TLC Thin Layer Chromatography
  • Flash silica gel refers to Merck Art No. 9385; silica gel refers to Merck Art No. 7734.
  • SCX cartridges are Ion Exchange SPE columns where the stationary phase is polymeric benzene sulfonic acid. These are used to isolate amines.
  • SCX2 cartridges are Ion Exchange SPE columns where the stationary phase is polymeric propylsulfonic acid. These are used to isolate amines.
  • LCMS was conducted on a Supelcosil LCABZ+PLUS column (3.3 cm x 4.6 mm ID) eluting with 0.1 % formic acid and 0.01 M ammonium acetate in water (solvent A) and 0.05% formic acid 5% water in MeCN (solvent B), using the following elution gradient 0.0 - 7 min 0% B, 0.7 - 4.2 min 100% B, 4.2 - 5.3 min 0% B, 5.3 - 5.5min 0% B at a flow rate of 3 mlmin "1 .
  • the mass spectra were recorded on a Fisons VG Platform spectrometer using electrospray positive and negative mode (ES+ve and ES-ve).
  • the Flashmaster Il is an automated multi-user flash chromatography system, available from Argonaut Technologies Ltd, which utilises disposable, normal phase, SPE cartridges (2 g to 100 g).
  • Samples are queued using the multi-functional open access software, which manages solvents, flow-rates, gradient profile and collection conditions.
  • the system is equipped with a Knauer variable wavelength UV-detector and two Gilson FC204 fraction-collectors enabling automated peak cutting, collection and tracking.
  • Mass directed autopreparative (MDAP) HPLC was conducted on a Waters FractionLynx system comprising of a Waters 600 pump with extended pump heads, Waters 2700 autosampler, Waters
  • Reactions are routinely monitored by methods well known to those skilled in the art, such as TLC, LCMS and/or HPLC. Such methods are used to assess whether a reaction has gone to completion, and reaction times may be varied accordingly.
  • 2-Fluoroaniline (commercially available, for example, from Aldrich) (1.3 ml, 13.5 mmol), trans-2- pentenal (2.64 ml, 27 mmol), aqueous hydrochloric acid (5M, 18 ml) and toluene (60 ml) were combined and heated at 100 0 C for 6 h. The toluene layer was separated, and the aqueous layer neutralised with 2M aqueous sodium hydroxide, and then it was extracted with dichloromethane (2 x 50 ml). The organic solutions were combined, dried over a ptfe frit, and evaporated to leave a brown gel.
  • 2-Fluoroaniline (commercially available, for example, from Aldrich) (2.2 ml, 22.5 mmol) was dissolved in 5M aqueous hydrochloric acid (100 ml), then toluene (30 ml) and crotonaldehyde (3.71 ml, 45mmol) were added. The reaction was heated at 100 0 C for 2 h under nitrogen with vigorous stirring. The reaction mixture was left to cool, and the aqueous layer separated. This was neutralised using aqueous sodium hydroxide and extracted with dichloromethane (2 x 50 ml). The organic solutions were combined, dried over a ptfe frit and evaporated to leave a brown gel.
  • 6-Bromo-8-fluoroquinoline (for example, as prepared for Intermediate 3) (226 mg, 1 mmol), potassium carbonate (276 mg, 2 mmol) and 1 ,1'- bis(diphenylphosphino)ferrocene]dichloropalladium (II) (18.3 mg, 0.02 mmol) were mixed.
  • B- benzyl-9-BBN in tetrahydrofuran (4 ml, 2 mmol) and ⁇ /, ⁇ /-dimethylformamide (3 ml) were added. The solution was stirred at 6O 0 C for two days. Ethyl acetate was added to the reaction mixture, and then it was washed three times with water.
  • 6-Bromo-8-fluoroquinoline (for example, as prepared for Intermediate 3) (339 mg, 1.5 mmol), potassium carbonate (414 mg, 3 mmol) and [1 ,1'- bis(diphenylphosphino)ferrocene]dichloropalladium (II) (27.4 mg, 0.037 mmol) were mixed in a reactivial.
  • a solution of tributylborane in tetrahydrofuran (1 M, 3 ml, 3 mmol) and N, N- dimethylformamide (4 ml) were added. The solution was stirred at 6O 0 C for two days. Ethyl acetate was added to the solution, then it was washed three times with water.
  • 6-Bromo-8-fluoroquinoline (for example, as prepared for Intermediate 3) (226 mg, 1 mmol), 4- chlorophenylboronic acid (187 mg, 1.1 mmol), potassium carbonate (421 mg, 3 mmol) and tetrakis(triphenylphosphine) palladium (0) (112 mg, 0.1 mmol) were mixed in a reactivial. lsopropanol (3 ml) and water (3 ml) were added and the solution was stirred at 7O 0 C overnight. The solution was filtered and evaporated and the residue partitioned between dichloromethane and water. The organic layer was washed with water and brine. The organic solution was dried with sodium sulphate, filtered and evaporated.
  • 6-Bromo-8-fluoroquinoline (for example, as prepared for Intermediate 3) (339 mg, 1.5 mmol), potassium carbonate (417 mg, 3 mmol) and 1 ,1'- bis(diphenylphosphino)ferrocene]dichloropalladium (II) (27 mg, 0.037 mmol) were mixed in a reactivial.
  • Triethylborane in tetrahydrofuran (3 ml, 3 mmol) and N,N-dimethylformamide were added.
  • the solution was stirred at 6O 0 C for two days.
  • the liquid phase was removed and ethyl acetate (about 100 ml) was added then it was washed three times with water.
  • 2-Amino-5-fluorophenol (for example, as prepared for Intermediate 13) (602 mg, 4.74 mmol) was dissolved in 5M hydrochloric acid (21 ml). Toluene (6.5 ml) and acrolein (1 ml, 14 mmol) were added to the solution and the mixture was stirred at 100 0 C overnight. The aqueous layer was removed and 10M sodium hydroxide was added until the solution was neutral. The compound which precipitated was extracted with dichloromethane and the organic phase was washed with water and brine, then it was dried with sodium sulphate, filtered and evaporated.
  • 6-Fluoro-8-quinolinol (for example, as prepared for Intermediate 14) (96 mg, 0.59 mmol) was dissolved in tetrahydrofuran (2.5 ml) and then 1 ,1-dimethylethyl 4-hydroxy-1-piperidinecarboxylate (commercially available, for example, from Aldrich) (120 mg, 0.59 mmol) and triphenylphosphine (310 mg, 1.18 mmol) were added. The mixture was stirred under nitrogen for ten minutes, and then diisopropyl azodicarboxylate (0.232 ml, 1.18 mmol) was added. The reaction mixture was stirred overnight at room temperature under nitrogen, and then the solvent was evaporated.
  • Intermediates 43 and 44 were prepared from the appropriate amine and 2-(4- ⁇ [3- (Hexahydro-1 H-azepin-1 -yl)propyl]oxy ⁇ phenyl)ethyl methanesulfonate (for example, as prepared for Intermediate 40) in acetonitrile, and in the presence of sodium bicarbonate at 8O 0 C for an appropriate numbers of days.
  • 1,1-Dimethylethyl 4-[(5-fluoro- ⁇ -quinolinyl)oxy]-1-piperidinecarboxylate A stirring solution of 5-fluoro-8-quinolinol (commercially available, for example, from TCI) (1 g, 6.13 mmol), triphenylphosphine (1.608 g, 6.13 mmol) and ferf-butyl 4-hydroxy-i-piperidinecarboxylate (commercially available, for example, from Aldrich) (1.1 11 g, 5.52 mmol) in DCM (22 ml) was treated with diisopropyl azodicarboxylate (1.207 ml, 6.13 mmol) and the resulting mixture was stirred at ambient temperature under a nitrogen atmosphere for -20 h.
  • 5-fluoro-8-quinolinol commercially available, for example, from TCI
  • triphenylphosphine 1.608 g, 6.13 mmol
  • Toluene 160 ml was added to a suspension of 2-fluoro-5-methylaniline (commercially available, for example, from Aldrich) (15 g, 120 mmol) in 6M hydrochloric acid (100 ml) and the mixture was heated to -70 0 C.
  • Acrolein (16 ml, 240 mmol) was added over 12 min and the resulting mixture was stirred at reflux for a further 2 h 40 min.
  • the cooled mixture was adjusted to pH 9 with 10M NaOH aq and then extracted with EtOAc.
  • the aqueous phase was further extracted with EtOAc and the combined extracts were washed with brine, dried and evaporated to give a brown oil.
  • the compounds exemplified in the table below were prepared from the appropriate amine and 2-(4- ⁇ [3-(Hexahydro-1H-azepin-1-yl)propyl]oxy ⁇ phenyl)ethyl methanesulfonate (for example, as prepared for Intermediate 40) in acetonitrile, and in the presence of sodium bicarbonate at 8O 0 C for an appropriate numbers of days.
  • the compounds exemplified in the table below were prepared from the appropriate amine and 2- ⁇ 4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl ⁇ ethyl methanesulfonate (Intermediate 56 in WO2007/122156A1 ) in acetonitrile, and in the presence of sodium bicarbonate at 8O 0 C for an appropriate numbers of days.
  • the cartridge was eluted with MeOH, followed by 2M ammonia in MeOH. Evaporation of the ammoniacal eluent gave a residue that was dissolved in DCM (50 ml) and treated with TFA (15 ml). The mixture was stirred for 1 h then evaporated giving a residue that was suspended in toluene and then re-evaporated. The resulting residue was dissolved in MeOH and loaded onto an SCX ion-exchange SPE cartridge (50 g). The cartridge was eluted with MeOH followed by 2M ammonia in MeOH. Evaporation of the ammoniacal eluent gave a brown residue (3.505 g).
  • the compounds of the invention may be tested for in vitro and/or in vivo biological activity in accordance with the following or similar assays.
  • the human H1 receptor is cloned using known procedures described in the literature [Biochem. Biophys. Res. Commun., 201 (2):894 (1994)].
  • Chinese hamster ovary (CHO) cells stably expressing the human H1 receptor are generated according to known procedures described in the literature [Br. J. Pharmacol., 117(6):1071 (1996)].
  • Histamine H1 functional antagonist assay Determination of functional pKi values
  • the histamine H1 cell line is seeded into non-coated black-walled clear bottom 384-well tissue culture plates in alpha minimum essential medium (Gibco/lnvitrogen, cat no. 22561-021 ), supplemented with 10% dialysed foetal calf serum (Gibco/lnvitrogen cat no. 12480-021 ) and 2 rtiM L-glutamine (Gibco/lnvitrogen cat no 25030-024) and is maintained overnight at 5% CO 2 , 37 0 C.
  • alpha minimum essential medium Gibco/lnvitrogen, cat no. 22561-021
  • dialysed foetal calf serum Gibco/lnvitrogen cat no. 12480-021
  • 2 rtiM L-glutamine Gibco/lnvitrogen cat no 25030-024
  • Histamine H1 functional antagonist assay Determination of antagonist pA2 and duration The histamine H1 receptor expressing CHO cells are seeded into non-coated black-walled clear bottom 96-well tissue culture plates as described above.
  • growth medium is removed from each well, washed with 200 ⁇ l PBS and is replaced with 50 ⁇ l loading dye (250 ⁇ M Brilliant Black, 1 ⁇ M Fluo-4 diluted in Tyrodes buffer + probenecid (145 rtiM NaCI, 2.5 rtiM KCI, 1OmM HEPES, 1OmM D-glucose, 1.2 rtiM MgCI 2 , 1.5 rtiM CaCI 2 , 2.5 rtiM probenecid, pH adjusted to 7.40 with NaOH 1.0 M)). Cells are incubated for 45 min at 37 0 C.
  • 50 ⁇ l loading dye 250 ⁇ M Brilliant Black, 1 ⁇ M Fluo-4 diluted in Tyrodes buffer + probenecid (145 rtiM NaCI, 2.5 rtiM KCI, 1OmM HEPES, 1OmM D-glucose, 1.2 rtiM MgCI 2 , 1.5 rtiM CaCI 2 , 2.5 rti
  • the loading buffer is removed and the cells are washed as above, and 90 ⁇ l of Tyrodes buffer + probenecid is added to each well.
  • 10 ⁇ l of test compound, diluted to the required concentration in Tyrodes buffer + probenecid (or 10 ⁇ l Tyrodes buffer + probenecid as a control) is added to each well and the plate is incubated for 30 min at 37 0 C, 5% CO 2 .
  • the resultant concentration response curves are analysed by non-linear regression using a standard four parameter logistic equation to determine the histamine EC 5O , the concentration of histamine required to produce a response of 50% of the maximum response to histamine.
  • cells are cultured overnight in non-coated black-walled clear bottom 96-well tissue culture plates, are washed with PBS and are incubated with a concentration of antagonist chosen to give an approximate DR in the range 30 - 300. Following the 30 min antagonist incubation period, the cells are washed two or three times with 200 ⁇ l of PBS and then 100 ⁇ l Tyrodes buffer is added to each well to initiate antagonist dissociation. Following incubation for predetermined times, typically 30 - 270 min at 37 0 C, the cells are then washed again with 200 ⁇ l PBS and are incubated with 100 ⁇ l Tyrodes buffer containing Brilliant Black, probenecid and Fluo-4 for 45 min at 37 0 C, as described above.
  • fractional receptor occupancy (DR-1 )/DR.
  • the decrease in receptor occupancy over time approximates to a straight line and is analysed by linear regression. The slope of this straight line fit is used as an index of the dissociation rate of the antagonist.
  • the dose ratios for antagonist treated cells and for antagonist treated and washed cells at each time point are used to calculate a relative dose ratio (rel DR) which is also used as an index of antagonist duration. Antagonists with long duration of action produce rel DR values close to 1 , and antagonists with short duration of action produce rel DR values that approaches the dose ratio value obtained for antagonist treatment alone.
  • the histamine H3 cDNA is isolated from its holding vector, pCDNA3.1 TOPO (InVitrogen), by restriction digestion of plasmid DNA with the enzymes BamH1 and Not-1 and is ligated into the inducible expression vector pGene (InVitrogen) digested with the same enzymes.
  • the GeneSwitchTM system (a system where in transgene expression is switched off in the absence of an inducer and switched on in the presence of an inducer) is performed as described in US Patents: 5,364,791 ; 5,874,534; and 5,935,934. Ligated DNA is transformed into competent DH5 ⁇ E.
  • coli host bacterial cells and is plated onto Luria Broth (LB) agar containing ZeocinTM (an antibiotic which allows the selection of cells expressing the sh ble gene which is present on pGene and pSwitch) at 50 ⁇ gml "1 .
  • Colonies containing the re-ligated plasmid are identified by restriction analysis.
  • DNA for transfection into mammalian cells is prepared from 250 ml cultures of the host bacterium containing the pGeneH3 plasmid and is isolated using a DNA preparation kit (Qiagen Midi-Prep) as per manufacturers guidelines (Qiagen).
  • CHO K1 cells previously transfected with the pSwitch regulatory plasmid (InVitrogen) are seeded at 2x10 6 cells per T75 flask in Complete Medium, containing Hams F12 (GIBCOBRL, Life Technologies) medium supplemented with 10% v/v dialysed foetal bovine serum, L- glutamine, and hygromycin (100 ⁇ gml "1 ), 24 h prior to use. Plasmid DNA is transfected into the cells using Lipofectamine plus according to the manufacturer's guidelines (InVitrogen). 48 h post transfection, cells are placed into complete medium supplemented with 500 ⁇ gml "1 ZeocinTM.
  • Approximately 1 ⁇ 10 7 cells are examined for receptor expression by staining with a rabbit polyclonal antibody, 4a, raised against the /V-terminal domain of the histamine H3 receptor, are incubated on ice for 60 min, followed by two washes in sorting medium. Receptor bound antibody is detected by incubation of the cells for 60 min on ice with a goat anti rabbit antibody, conjugated with Alexa 488 fluorescence marker (Molecular Probes). Following two further washes with Sorting Medium, cells are filtered through a 50 ⁇ m FilconTM (BD Biosciences) and then are analysed on a FACS Vantage SE Flow Cytometer fitted with an Automatic Cell Deposition Unit. Control cells are non-induced cells treated in an analogous manner.
  • a rabbit polyclonal antibody, 4a raised against the /V-terminal domain of the histamine H3 receptor
  • Positively stained cells are sorted as single cells into 96-well plates, containing Complete Medium containing 500 ⁇ gml "1 ZeocinTM and are allowed to expand before reanalysis for receptor expression via antibody and ligand binding studies.
  • One clone, 3H3, is selected for membrane preparation.
  • the cells are then homogenised by 2 x 15 second bursts in a 1 litre glass Waring blender, followed by centrifugation at 500 g for 20 min. The supernatant is then spun at 48,000 g for 30 min. The pellet is resuspended in homogenisation buffer (4 ⁇ the volume of the original cell pellet) by vortexing for 5 sec, followed by homogenisation in a Dounce homogeniser (10-15 strokes). At this point the preparation is aliquoted into polypropylene tubes and stored at -80 0 C.
  • the plate is centrifuged for 5 min at 1500 rpm and counted on a Viewlux counter using a 613/55 filter for 5 minplate "1 .
  • Data is analysed using a 4-parameter logistic equation. Basal activity is used as minimum, i.e. histamine not added to well.
  • the compounds of the Examples had an average pK, (pK b ) at H1 greater than approximately 6.5.
  • the compounds of Examples 1 A, 1 B, 7, 1 1 , 12 and 20-24 had average pA2 values at H1 of greater than approximately 7.

Abstract

The present invention relates to compounds of formula (I) and salts thereof, processes for their preparation, to compositions containing them and to their use in the treatment of various diseases, such as allergic rhinitis.

Description

QUINOLINE DERIVATIVES AND THEIR USES FOR RHINITIS AND URTICARIA
The present invention relates to a class of compounds, which are quinolinyloxypiperidine and pyrrolidine derivatives, processes for their preparation, pharmaceutical compositions containing them and to their use in the treatment of various inflammatory and/or allergic diseases, in particular inflammatory and/or allergic diseases of the respiratory tract.
Allergic rhinitis, pulmonary inflammation and congestion are medical conditions that are often associated with other conditions such as asthma and chronic obstructive pulmonary disease (COPD). In general, these conditions are mediated, at least in part, by inflammation associated with the release of histamine from various cells, in particular mast cells.
Allergic rhinitis affects a large proportion of the population worldwide. There are two types of allergic rhinitis; seasonal (which includes hay fever) and perennial. The clinical symptoms of seasonal allergic rhinitis typically include nasal itching and irritation, sneezing and watery rhinorrhea, which is often accompanied by nasal congestion. The clinical symptoms of perennial allergic rhinitis are similar, except that nasal blockage may be more pronounced. Either type of allergic rhinitis may also cause other symptoms, such as itching of the throat and/or eyes, epiphora and oedema around the eyes. The symptoms of allergic rhinitis may vary in intensity from the nuisance level to debilitating.
Allergic rhinitis and other allergic conditions are associated with the release of histamine from various cell types, but particularly mast cells. The physiological effects of histamine are classically mediated by three receptor subtypes, termed H1 , H2 and H3. H1 receptors are widely distributed throughout the CNS and periphery, and are involved in wakefulness and acute inflammation. H2 receptors mediate gastric acid secretion in response to histamine. H3 receptors are present on the nerve endings in both the CNS and periphery and mediate inhibition of neurotransmitter release [Hill et ai, Pharmacol. Rev., 49:253-278, (1997)]. Recently a fourth member of the histamine receptor family has been identified, termed the H4 receptor [Hough, MoI. Pharmacol., 59:415-419, (2001 )]. Whilst the distribution of the H4 receptor appears to be restricted to cells of the immune and inflammatory systems, a physiological role for this receptor remains to be identified.
The activation of H1 receptors in blood vessels and nerve endings is responsible for many of the symptoms of allergic rhinitis, which include itching, sneezing, and the production of watery rhinorrhea. Oral antihistamine compounds (such as chlorphenyramine, cetirizine, desloratidine and fexofenadine) and intranasal antihistamines (such as azelastine and levocabastine) which are selective H1 receptor antagonists are effective in treating the itching, sneezing and rhinorrhea associated with allergic rhinitis, but are not effective against the nasal congestion symptoms [Aaronson, Ann. Allergy, 67:541-547, (1991 )]. Thus H1 receptor antagonists have been administered in combination with sympathomimetic agents such as pseudoephedrine or i oxymetazoline to treat the nasal congestion symptoms of allergic rhinitis. These drugs are thought to produce a decongestant action by activating α-adrenergic receptors and increasing the vascular tone of blood vessels in the nasal mucosa. The use of sympathomimetic drugs for the treatment of nasal congestion is frequently limited by the CNS stimulant properties and their effects on blood pressure and heart rate. A treatment which decreases nasal congestion without having effects on the CNS and cardiovascular system may therefore offer advantages over existing therapies.
Histamine H3 receptors are expressed widely on both CNS and peripheral nerve endings and mediate the inhibition of neurotransmitter release. In vitro electrical stimulation of peripheral sympathetic nerves in isolated human saphenous vein results in an increase in noradrenaline release and smooth muscle contraction, which can be inhibited by histamine H3 receptor agonists [Molderings et al., Naunyn-Schmiedeberg's Arch. Pharmacol., 346:46-50, (1992); Valentine et al., Eur. J. Pharmacol., 366:73-78, (1999)]. H3 receptor agonists also inhibit the effect of sympathetic nerve activation on vascular tone in porcine nasal mucosa [Varty & Hey., Eur. J. Pharmacol., 452:339-345, (2002)]. In vivo, H3 receptor agonists inhibit the decrease in nasal airway resistance produced by sympathetic nerve activation [Hey et al., Arzneim-Forsch Drug Res., 48:881-888, (1998)]. Activation of histamine H3 receptors in human nasal mucosa inhibits sympathetic vasoconstriction [Varty et al., Eur. J. Pharmacol., 484:83-89, (2004)]. Furthermore, H3 receptor antagonists, in combination with histamine H1 receptor antagonists, have been shown to reverse the effects of mast cell activation on nasal airway resistance and nasal cavity volume, an index of nasal congestion [Mcleod et al., Am. J. RhinoL, 13:391-399, (1999)], and further evidence for the contribution of H3 receptors to histamine-induced nasal blockage is provided by histamine nasal challenge studies performed on normal human subjects [Taylor-Clark et al., Br. J. Pharmacol., 144, 867-874, (2005)], although the H3 mechanism in this regard would appear to be novel and unprecedented and may ultimately prove to be clinically silent.
WO2004/035556 discloses substituted piperazines, (1 ,4) diazepines and 2,5-diazabicyclo [2.2.1] heptanes as histamine H3 or histamine H1/H3 dual antagonists or reverse agonists.
WO2007/122156 discloses substituted dibasic phthalazinone compounds as histamine H1/H3 dual antagonists.
A novel class of compounds has been found that are dual histamine H1 and H3 receptor antagonists. By dual histamine H1 and H3 receptor antagonists it is meant that compounds have activity at both receptor subtypes. For example, the activity at the H1 receptor may be within approximately 100 fold of the activity at the H3 receptor, such as within approximately 10 fold or less.
Thus, the present invention provides, as a first embodiment, a compound of formula (I):
Figure imgf000005_0001
wherein
R1 independently represents halogen, straight chain C1-6alkyl, -(CH2)b-CO2H or -(CH2)caryl in which the aryl is optionally substituted with one or two substituents independently selected from halogen,
C1-3alkyl, trifluoromethyl and cyano; p represents 0, 1 or 2; such that when p represents 1 , R1 is in the 2, 3, 4, 5, 6 or 7 position on the quinoline ring; such that when p represents 2, one R1 group is in the 2, 3 or 4 position on the quinoline ring and the other R1 group is in the 5, 6 or 7 position on the quinoline ring; a represents 1 or 2; b represents 1 to 3; c represents 0 to 3;
R2 represents a group of formula (a), (b) or (c)
Figure imgf000005_0002
in which, for formula (a) e represents 1 to 6; Y represents a bond or O; e' represents 1 to 4; f represents 0, 1 or 2 and g represents 0, 1 , 2 or 3, such that f and g cannot both be 0; h represents 0, 1 or 2; R3 represents Ci_3alkyl;
in which, for formula (b) i represents 1 to 6;
X represents either a bond, O or -N(R6)C(O)-, in which R6 represents hydrogen or Chalky!; j and k each represent 1 or each represent 2;
R4 represents hydrogen, C3-6cycloalkyl or Ci-6alkyl;
in which, for formula (c) I represents 1 to 6; I' represents 0 to 3; m represents 0, 1 or 2 and n represents 0, 1 , 2 or 3, such that m and n cannot both be 0, and such that I' plus n must represent 1 , 2 or 3;
R5 represents hydrogen, C3-6cycloalkyl or Ci-6alkyl;
or a salt thereof.
The compounds of the invention may be expected to be useful in the treatment of various diseases in particular inflammatory and/or allergic diseases, such as inflammatory and/or allergic diseases of the respiratory tract (for example allergic rhinitis) that are associated with the release of histamine from cells such as mast cells. Further, the compounds may show an improved profile in that they may possess one or more of the following properties:
(i) H3 antagonist activity with a pKi of greater than about 8, for example greater than about 9; (ii) H1 receptor antagonist activity with a pKi of greater than 7, for example greater than about 8; (iii) prolonged duration of action; and (iv) lower CNS penetration.
Compounds having such a profile may be particularly suitable for intranasal delivery, and/or may be capable of once daily administration and/or further may have an improved side effect profile compared with other existing therapies.
By 'selectivity' it is meant that the compounds may be more potent at the H1 receptor than at the hERG receptor.
In another embodiment, R2 represents a group of formula (a) or (c) as herein before defined; in which, for formula (a) e represents 1 to 6; Y represents a bond or O; e' represents 1 to 4; f represents 0, 1 or 2 and g represents 0, 1 , 2 or 3, such that f and g cannot both be 0; h represents 0, 1 or 2; R3 represents Ci-3alkyl;
in which, for formula (c) I represents 1 to 6; I' represents 0 to 3; m represents 0, 1 or 2 and n represents 0, 1 , 2 or 3, such that m and n cannot both be 0, and such that I' plus n must represent 1 , 2 or 3; R5 represents hydrogen, C3-6cycloalkyl or Ci-6alkyl.
In another embodiment, R2 represents a group of formula (a) as herein before defined; in which, for formula (a) e represents 1 to 6;
Y represents a bond or O; e' represents 1 to 4; f represents 0, 1 or 2 and g represents 0, 1 , 2 or 3, such that f and g cannot both be 0; h represents 0, 1 or 2; R3 represents C1-3alkyl.
In another embodiment, R2 represents a group of formula (c) as herein before defined; in which, for formula (c) I represents 1 to 6;
I' represents 0 to 3; m represents 0, 1 or 2 and n represents 0, 1 , 2 or 3, such that m and n cannot both be 0, and such that I' plus n must represent 1 , 2 or 3;
R5 represents hydrogen, C3_6cycloalkyl or d-βalkyl.
In another embodiment, R2 represents a group of formula (a) as herein before defined; in which, e is 2;
Y is O; e' is 3; f is 2 and g is 2; h is O.
In another embodiment, R2 represents a group of formula (c) as herein before defined; in which, I represents 2; I' represents 0; m represents 0 and n represents 1 ; R5 represents cyclobutyl.
In another embodiment, p is 0. In another embodiment, p is 1.
In another embodiment, p is 1 and R1 represents C1-6alkyl.
In another embodiment, p is 1 and R1 represents methyl, ethyl or butyl.
In another embodiment, p is 1 and R1 is -(CH2)cAryl.
In another embodiment, R1 is-(CH2)cPhenyl, wherein the phenyl is unsubstituted.
In another embodiment, R1 is -(CH2)cPhenyl, wherein the phenyl is optionally substituted with one or two substituents independently selected from halogen, C1-3alkyl, trifluoromethyl and cyano.
In another embodiment, p is 1 and R1 represents halogen.
In another embodiment, p is 1 and R1 represents -(CH2)bCO2H.
In another embodiment, R1 is (CH2)2CO2H.
In another embodiment, when p is 2, the R1 group located in the 2,3 or 4 position on the quinoline ring represents straight chain C1-6alkyl, -(CH2)bCO2H or -(CH2)caryl in which the aryl is optionally substituted with one or two substituents independently selected from halogen, Chalky!, trifluoromethyl and cyano.
In another embodiment, when p is 2, one independently selected R1 group is located in the 2 position on the quinoline ring, and another independently selected R1 group is located in the 5,6 or 7 position on the quinoline ring.
In another embodiment, when p is 2, one independently selected R1 group is located in the 2 position on the quinoline ring, and another independently selected R1 group is located in the 6 position on the quinoline ring.
In another embodiment, the R1 group located in the 2 position on the quinoline ring is - (CH2)bCO2H. For example, the R1 group located in the 2 position on the quinoline ring is (CH2)2CO2H. In another embodiment, a is 1.
In another embodiment, a is 2.
It is to be understood that the invention includes all combinations of embodiments, groups, formulae and substituents described herein.
In another embodiment, there is provided 8-({1-[2-(4-{[3-(Hexahydro-1H-azepin-1- yl)propyl]oxy}phenyl)ethyl]-4-piperidinyl}oxy)quinoline of formula:
Figure imgf000009_0001
or a salt thereof.
In another embodiment, there is provided 8-({1-[2-(4-{[3-(Hexahydro-1H-azepin-1- yl)propyl]oxy}phenyl)ethyl]-4-piperidinyl}oxy)quinoline.
In another embodiment, there is provided a compound selected from the group consisting of:
8-({1-[2-(4-{[3-(Hexahydro-1 H-azepin-1-yl)propyl]oxy}phenyl)ethyl]-4-piperidinyl}oxy)quinoline, 8-({1-[2-(4-{[3-(Hexahydro-1 H-azepin-1-yl)propyl]oxy}phenyl)ethyl]-4-piperidinyl}oxy)quinoline,
8-({(3S)-1-[2-(4-{[3-(Hexahydro-1 /-/-azepin-1-yl)propyl]oxy}phenyl)ethyl]-3-pyrrolidinyl}oxy)quinoline,
8-({(3R)-1-[2-(4-{[3-(Hexahydro-1 H-azepin-1-yl)propyl]oxy}phenyl)ethyl]-3- pyrrolidinyl}oxy)quinoline,
8-({1-[2-(4-{[3-(Hexahydro-1 H-azepin-1-yl)propyl]oxy}phenyl)ethyl]-4-piperidinyl}oxy)-2- methylquinoline,
8-({1-[2-(4-{[3-(hexahydro-1 H-azepin-1-yl)propyl]oxy}phenyl)ethyl]-4-piperidinyl}oxy)-4- methylquinoline,
8-({1-[2-(4-{[3-(Hexahydro-1 H-azepin-1-yl)propyl]oxy}phenyl)ethyl]-4-piperidinyl}oxy)-5- methylquinoline, 8-({1-[2-(4-{[3-(Hexahydro-1 H-azepin-1-yl)propyl]oxy}phenyl)ethyl]-4-piperidinyl}oxy)-6- methylquinoline,
8-({1-[2-(4-{[3-(Hexahydro-1 H-azepin-1-yl)propyl]oxy}phenyl)ethyl]-4-piperidinyl}oxy)-7- methylquinoline, 2-Ethyl-8-({1-[2-(4-{[3-(hexahydro-1H-azepin-1-yl)propyl]oxy}phenyl)ethyl]-4- piperidinyl}oxy)quinoline,
3-Ethyl-8-({1-[2-(4-{[3-(hexahydro-1H-azepin-1-yl)propyl]oxy}phenyl)ethyl]-4- piperidinyl}oxy)quinoline, 6-Ethyl-8-({1-[2-(4-{[3-(hexahydro-1H-azepin-1-yl)propyl]oxy}phenyl)ethyl]-4- piperidinyl}oxy)quinoline,
6-Butyl-8-({1-[2-(4-{[3-(hexahydro-1 H-azepin-1 -yl)propyl]oxy}phenyl)ethyl]-4- piperidinyl}oxy)quinoline,
8-({1-[2-(4-{[3-(Hexahydro-1 H-azepin-1-yl)propyl]oxy}phenyl)ethyl]-4-piperidinyl}oxy)-5- (phenylmethyl)quinoline,
8-({1-[2-(4-{[3-(Hexahydro-1 H-azepin-1 -yl)propyl]oxy}phenyl)ethyl]-4-piperidinyl}oxy)-6-
(phenylmethyl)quinoline,
8-({1-[2-(4-{[3-(Hexahydro-1 H-azepin-1-yl)propyl]oxy}phenyl)ethyl]-4-piperidinyl}oxy)-6-(2- phenylethyl)quinoline, 6-(4-Chlorophenyl)-8-({1-[2-(4-{[3-(hexahydro-1 H-azepin-1-yl)propyl]oxy}phenyl)ethyl]-4- piperidinyl}oxy)quinoline,
5-Fluoro-8-({1-[2-(4-{[3-(hexahydro-1 H-azepin-1 -yl)propyl]oxy}phenyl)ethyl]-4- piperidinyl}oxy)quinoline,
6-Fluoro-8-({1-[2-(4-{[3-(hexahydro-1 H-azepin-1 -yl)propyl]oxy}phenyl)ethyl]-4- piperidinyl}oxy)quinoline,
7-Bromo-8-({1 -[2-(4-{[3-(hexahydro-1 H-azepin-1 -yl)propyl]oxy}phenyl)ethyl]-4- piperidinyl}oxy)quinoline,
8-{[1-(2-{4-[(1-Cyclobutyl-4-piperidinyl)oxy]phenyl}ethyl)-4-piperidinyl]oxy}quinoline,
8-{[1-(2-{4-[(1-Cyclobutyl-4-piperidinyl)oxy]phenyl}ethyl)-4-piperidinyl]oxy}-3-methylquinoline, 3-(8-{[1-(2-{4-[(1-Cyclobutyl-4-piperidinyl)oxy]phenyl}ethyl)-4-piperidinyl]oxy}-2-quinolinyl)propanoic acid,
3-[6-Butyl-8-({1-[2-(4-{[3-(hexahydro-1 H-azepin-1 -yl)propyl]oxy}phenyl)ethyl]-4-piperidinyl}oxy)-2- quinolinyl]propanoic acid,
3-[8-({1-[2-(4-{[3-(Hexahydro-1 H-azepin-1 -yl)propyl]oxy}phenyl)ethyl]-4-piperidinyl}oxy)-2- quinolinyl]propanoic acid, and
8-[(1-{2-[4-(1-Pyrrolidinylmethyl)phenyl]ethyl}-4-piperidinyl)oxy]quinoline; or a salt thereof.
As used herein, the term "alkyl", whether alone or as part of another group, refers to a straight or branched hydrocarbon chain, unless otherwise indicated. For example, C1-6alkyl means a straight or branched alkyl chain containing at least one, and at most six, carbon atoms. Illustrative examples of "alkyl" as used herein include, but are not limited to, methyl, ethyl, propyl, /so-propyl, n-butyl, sec-butyl, /so-butyl, fert-butyl, n-pentyl, neo-pentyl and n-hexyl. Particular alkyl groups are C1-3alkyl, such as methyl. As used herein, the term "cycloalkyl" refers to a cyclic, saturated hydrocarbon containing the specified number of carbon atoms. For example, C3-7cycloalkyl refers to a cyclic, saturated hydrocarbon containing at least three, and at most seven, carbon atoms. Illustrative examples of C3-7cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
As used herein, the term "aryl" whether alone or as part of another group is used to describe single and fused aromatic hydrocarbon rings. Representative "aryl" rings include phenyl and naphthyl. A particular aryl ring is phenyl. When substituted, aryl may have up to two substituents (for example, one or two substituents). Representative aryl substituents include, but are not limited to, methyl, ethyl, chloro, fluoro, trifluoromethyl and cyano.
As used herein, the term "halogen" describes, unless otherwise stated, a group selected from fluorine, chlorine, bromine and iodine, for example fluorine and chlorine.
It will be appreciated that compounds of formula (I), or salts thereof, may possess one or more asymmetric carbon atoms so that stereoisomers e.g. enantiomers or diastereoisomers may be formed. The present invention encompasses all stereoisomers of the compounds of formula (I), or salts thereof, whether as individual isomers isolated such as to be substantially free of the other isomer (i.e. pure) or as mixtures thereof (i.e. racemates and racemic mixtures). An individual isomer isolated such as to be substantially free of the other isomer (i.e. pure) may be isolated such that less than about 10%, particularly less than about 1 %, for example less than about 0.1 % of the other isomer is present.
Further, it will be appreciated that the R and S enantiomers may be isolated from the racemate by conventional resolution methods such as preparative HPLC involving a chiral stationary phase, by resolution using fractional crystallisation of a salt of the free base with a chiral acid, by chemical conversion to a diastereoisomer using a chiral auxiliary followed by chromatographic separation of the isomers and then removal of the chiral auxiliary and regeneration of the pure enantiomer, or by asymmetric synthesis.
Certain compounds of formula (I), or salts thereof, may exist in one of several tautomeric forms. It will be understood that the present invention encompasses all tautomers of the compounds of formula (I), or salts thereof, whether as individual tautomers or as mixtures thereof.
The compounds of formula (I), or salts thereof, may be in crystalline or amorphous form. Furthermore, a compound of formula (I), or a salt thereof, may exist in one or more polymorphic forms. Thus, the present invention includes within its scope polymorphic forms of the compounds of formula (I), or salts thereof. In general, the most thermodynamically stable polymorphic form of a compound of formula (I), or a salt thereof, is of particular interest. Polymorphic forms of compounds of formula (I), or salts thereof, may be characterized and differentiated using a number of conventional analytical techniques, including but not limited to X- ray powder diffraction (XRPD) patterns, infrared (IR) spectra, Raman spectra, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) and solid state nuclear magnetic resonance (NMR).
The compounds of the present invention may be in the form of and/or may be administered as a pharmaceutically acceptable salt. For a review on suitable salts see Berge et al., J. Pharm. ScL, 1977, 66, 1-19. Suitable pharmaceutically acceptable salts include acid and base addition salts. As used herein, the term "pharmaceutically acceptable salt", means any pharmaceutically acceptable salt of a compound of the invention, which upon administration to the recipient is capable of providing (directly or indirectly) a compound of the invention, or an active metabolite or residue thereof.
Typically, a pharmaceutically acceptable salt may be readily prepared by using a desired acid or base as appropriate. The salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent.
A pharmaceutically acceptable acid addition salt can be formed by reaction of a compound of formula (I) with a suitable inorganic or organic acid (such as hydrobromic, hydrochloric, sulfuric, nitric, phosphoric, succinic, maleic, acetic, fumaric, citric, tartaric, benzoic, p-toluenesulfonic, methanesulfonic or naphthalenesulfonic acid), optionally in a suitable solvent such as an organic solvent, to give the salt which is usually isolated for example by crystallisation and filtration. Thus, a pharmaceutically acceptable acid addition salt of a compound of formula (I) can be for example a hydrobromide, hydrochloride, sulfate, nitrate, phosphate, succinate, maleate, acetate, fumarate, citrate, tartrate, benzoate, p-toluenesulfonate, methanesulfonate or naphthalenesulfonate salt.
A pharmaceutically acceptable base addition salt can be formed by reaction of a compound of formula (I) with a suitable inorganic or organic base, (e.g. triethylamine, ethanolamine, triethanolamine, choline, arginine, lysine or histidine), optionally in a suitable solvent, to give the base addition salt which is usually isolated, for example, by crystallisation and filtration. Pharmaceutically acceptable base salts include ammonium salts, alkali metal salts such as those of sodium and potassium, alkaline earth metal salts such as those of calcium and magnesium and salts with organic bases, including salts of primary, secondary and tertiary amines, such as isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexyl amine and N-methyl-D- glucamine
Other non-pharmaceutically acceptable salts, eg. formates, oxalates or trifluoroacetates, may be used, for example in the isolation of compounds of the invention, and are included within the scope of this invention. The invention includes within its scope all possible stoichiometric and non- stoichiometric forms of the salts of the compounds of formula (I).
Thus, it is to be understood that the present invention covers the compounds of formula (I) as the free acid or base and as salts thereof, for example, as pharmaceutically acceptable salts.
It will be appreciated that many organic compounds can form solvates with the solvents in which they are reacted or from which they are precipitated or crystallized. For example, a solvate with water is known as a "hydrate". Solvents with high boiling points and/or solvents with a high propensity to form hydrogen bonds such as water, xylene, Λ/-methyl pyrrolidinone and methanol may be used to form solvates. Methods for identification of solvates include, but are not limited to, NMR and microanalysis. Thus, solvates of the compounds of formula (I) are within the scope of the invention.
It will be appreciated from the foregoing that included within the scope of the invention are salts e.g. pharmaceutically acceptable salts, solvates (e.g. hydrates), stereoisomers and polymorphic forms of the compounds of the invention.
Accordingly, it will be appreciated that references hereinafter to compounds of the invention or to compounds of formula (I) means a compound of formula (I) as the free acid or base, or as a salt e.g. a pharmaceutically acceptable salt, and encompasses solvates, isomers and polymorphic forms of those compounds.
There is also provided processes for the preparation of compounds of formula (I), or salts thereof.
According to a first process, A, a compound of formula (I) may be prepared by reacting a compound of formula (II)
Figure imgf000013_0001
wherein R1, p and a are as defined hereinabove for formula (I),
with a compound of formula (Ilia), formula (NIb) or formula (NIc)
Figure imgf000013_0002
Figure imgf000014_0001
wherein Y, e, e', f, g, h, R3, i, X, j, k, R4, I, I', m, n, and R5 are as defined hereinabove for formula (I) and L represents a leaving group such as chlorine, bromine, iodine or an activated hydroxyl such as mesylate or tosylate.
The alkylation reaction may typically be carried out in the presence of a suitable base such as triethylamine (NEt3), diisopropylethylamine (DIPEA) or sodium hydrogen carbonate (NaHCO3), in an appropriate solvent such as acetonitrile (MeCN) or N,N-dimethylformamide (DMF) optionally at an appropriate elevated temperature such as about 80 0C, optionally using microwave irradiation and optionally with the addition of an activating agent such as potassium iodide (Kl) or sodium iodide (NaI).
Compounds of formula (II) may be prepared according to Scheme 1.
Compounds of formula (III) may be prepared according to Schemes 2 to 7.
Scheme 1 :
Synthesis of compounds of formula (II)
Figure imgf000014_0002
wherein a is as defined hereinabove for formula (I) and Z represents fluorine or hydroxyl.
Reagents and Conditions: i) when Z represents fluorine: suitable solvent such as N-methyl pyrrolidinone (NMP), appropriate base e.g. sodium tert-butoxide or sodium hydride, optionally at an elevated temperature for example from about 80 to 150 0C. When Z represents hydroxyl: suitable solvent e.g. tetrahydrofran (THF) or dicholormethane (DCM), appropriate azodicarboxylate e.g. diisopropylazodicarboxylate (DIAD) or 1 ,1 '-(azodicarbonyl)dipiperidine (ADDP) or other reagent such as fert-butyl azodicarboxylate (TBAD), suitable phosphine e.g. triphenylphosphine (PPh3) or (nBιi3P); ϋ) deprotection using a suitable acid e.g. trifluoracetic acid (TFA) or hydrogen chloride in a suitable solvent such as dichloromethane (DCM) or dioxane at ambient termperature.
Compounds of formula (IV) in which n represents 0 are commercially available or may be prepared according to Scheme 8 below.
Compounds of formula (IV) in which n represents 1 and R1 represents halogen are commercially available, or may be made according to Scheme 8 below. Other compounds of formula (IV) in which n represents 1 or 2 may be made according to Scheme 8 or Scheme 9 below.
Compounds of formula (IV) in which R1 represents -(CH2)b-Cθ2H or -(CH2)caryl may be prepared from other compounds of formula (IV) in which R1 represents Br according to Scheme 9 to 1 1 below.
Compounds of formula (V) are commercially available, for example from Aldrich and include N-tert- butoxycarbonyl-(R)-(-)-3-pyrrolidinol, N-tert-butoxycarbonyl-(S)-(+)-3-pyrrolidinol and tert-butyl 4- hydroxy-1-piperidinecarboxylate.
Scheme 2 Synthesis of compounds of formula (Ilia) - in which L is activated hvdroxyl and in which Y represents O.
Figure imgf000016_0001
wherein e, e', f, g, h and R3 are as defined hereinabove for formula (I) and R11 represents C-i-βalkyl.
Reagents and Conditions: i) suitable base e.g. K2CO3, solvent e.g. 2-butanone, usually an elevated temperature e.g. about 80 0C, optionally using microwave irradiation and optionally with the addition of an activating agent such as Kl; ii) R11OH (in which R11 represents Ci^alkyl e.g. methanol [MeOH]), acid such as HCI; iii) solvent e.g. THF, suitable catalysts e.g. DIAD, PPh3; iv) suitable reducing agent e.g. lithium aluminium hydride (LiAIH4), solvent e.g. THF and/or diethyl ether; v) suitable activating agent e.g. tosyl chloride (TsCI) or MsCI, an appropriate base e.g. DIPEA in a suitable solvent such as DCM.
Compounds of formula (IX) are commercially available, for example, from Sigma-Aldrich or Alfa Aesar, such as azacyclooctane, hexahydro-1 H-azepine, piperidine, 2-methylpiperidine, 3- methylpiperidine, 4-methylpiperidine, 2,6-dimethylpiperidine, 3,3-dimethylpiperidine, pyrrolidine, 2- methyl pyrrolidine, 2,5-dimethylpyrrolidine and azetidine. Compounds of formula (VII) are commercially available, for example, from Sigma-Aldrich, such as 3-hydroxybenzyl alcohol, 4-hydroxybenzyl alcohol, 4-hydroxyphenethyl alcohol and 3-(4- hydroxyphenyl)-1 -propanol.
Compounds of formula (VIII) are commercially available, for example, from Sigma-Aldrich, for example 1-bromo-2-chloroethane, 1-bromo-3-chloropropane and 1-bromo-4-chlorobutane.
Compounds of formula (X) are commercially available, for example, from Sigma-Aldrich, such as 3- hydroxybenzoic acid, 4-hydroxybenzoic acid, 2-hydroxyphenylacteic acid, 4-hydroxyphenylacteic acid, 3-(4-hydroxyphenyl)propionic acid and 4-(2-hydroxyphenyl)-butyric acid.
Other compounds of formula (X) may be prepared by methods well known to those skilled in the art, for example by demethylation of the corresponding methoxy compound, which is commercially available. Such a reaction may be carried out for example by using hydrogen bromide in acetic acid (approximately 48%). 4-(4-methoxyphenyl)butyric acid is commercially available, for example, from Sigma-Aldrich.
Compounds of formula (Xl) are available commercially, for example, from Sigma-Aldrich, such as 2-bromoethanol, 3-bromo-1 -propanol and 4-bromo-1-butanol.
Compounds of formula (XII) are commercially available, for example, from Apollo or Maybridge.
Scheme 3
Synthesis of compounds of formula (Ilia) - in which e is 3-6, Y represents O and L is activated hvdroxyl
Figure imgf000018_0001
wherein e is 3-6 and e', f, g, h and R3 are as defined hereinabove for formula (I).
Reagents and Conditions: i) base e.g. K2CO3, solvent e.g. 2-butanone, usually at an elevated temperature e.g. about 80 0C, optionally using microwave irradiation and optionally with the addition of an activating agent such as Kl or NaI; ii) copper iodide (CuI), appropriate catalyst e.g. bis[triphenylphosphine]palladium (II) chloride (Pd(PPh3)2CI2), base e.g. NEt3, solvent e.g. THF; iii) hydrogen, suitable catalyst e.g. palladium on carbon (Pd/C), solvent e.g. EtOH; iv) suitable activating agent e.g. TsCI or MsCI, base e.g. NEt3 or pyridine, optionally in a suitable solvent e.g. DCM.
Compounds of formula (XIII) are available commercially, for example, from Sigma-Aldrich, for example 2-iodophenol, 3-iodophenol and 4-iodophenol.
Compounds of formula (XIV) are available commercially, for example, from Sigma-Aldrich, such as propargyl alcohol, 3-butyn-1-ol, 4-pentyn-1-ol and 5-hexyn-1-ol.
Scheme 4
Synthesis of compounds of formula (Ilia) - in which L is aldehyde, e is 4 and Y represent O.
Figure imgf000019_0001
wherein e represents 4 and e', f, g, h and R are as defined hereinabove for formula (I).
Reagents and Conditions: i) base e.g. K2CO3, solvent e.g. 2-butanone, usually at an elevated temperature e.g. about 80 0C, optionally using microwave irradiation and optionally with the addition of an activating agent such as Kl or NaI; ii) 3-butenal diethylacetal, suitable borane e.g. 9- borabicyclononane (9-BBN), appropriate catalyst e.g. [1 ,1 '- bis(diphenylphosphino)ferrocene]dichloropalladium, base e.g. K2CO3, solvent e.g. water/DMF, usually at an elevated temperature e.g. about 70 0C; iii) H2, catalyst e.g. Pd/C, solvent e.g. EtOH; iv) suitable acid e.g. acetic acid (AcOH); v) MeOH, SCX-2 cartridge.
Compounds of formula (XV), such as 2-bromophenol, 3-bromophenol and 4-bromophenol are available commercially, for example, from Sigma-Aldrich.
Scheme 5
Synthesis of compounds of formula (NIb) - in which X is O and L is activated hvdroxyl or halide
Figure imgf000020_0001
wherein i, j, k, and R4 are as defined hereinabove for formula (I).
Reagents and Conditions: i) base e.g. K2CO3, solvent e.g. 2-butanone, usually at an elevated temperature e.g. about 80 0C, optionally using microwave irradiation and optionally with the addition of an activating agent such as Kl; ii) suitable activating agent e.g. TsCI or MsCI, base e.g. NEt3, solvent e.g. DCM.
Compounds of formula (XVI) are disclosed in International Patent Applications WO2004/056369 (see Examples 3 and 4) and WO2005/123723 (see Description 17), and are also described in Bioorg. Med. Chem. Lett., 11 :685-688 (2001 ).
Compounds of formula (XVIII) are available commercially, for example, from Sigma-Aldrich or TCI, such as 2-bromoethanol, 3-bromo-1-propanol, 4-bromo-1-butanol, 5-bromo-1-pentanol and 6- bromo-1-hexanol
Compounds of formula (XVII) are commercially available, for example, from Sigma-Aldrich, for example bromochloromethane, 1-bromo-2-chloroethane, 1-bromo-3-chloropropane and 1-bromo-4- chlorobutane, 1-bromo-5-chloropentane and 1-bromo-6-chlorohexane.
Scheme 6
Synthesis of compounds of formula (NIc) - in which L is activated hvdroxyl
Figure imgf000021_0001
wherein I, I', m, n and R5 are as defined hereinabove for formula (I) and P represents a silicon- based protecting group.
Reagents and Conditions: i) solvent e.g. THF, suitable azodicarboxylate e.g. DIAD or di-tert- butylazodicarboxylate (DTBAD), suitable phosphine e.g. PPh3; ii) TFA, solvent e.g. DCM; iii) appropriate reducing agent e.g. NaBH(OAc)3, solvent e.g. MeOH, acid catalyst e.g. AcOH; iv) 2N sodium hydroxide; v) activating agent e.g. TsCI or MsCI, suitable base e.g. NEt3, solvent e.g. DCM.
Compounds of formula (XIX) may be prepared by methods well known to a person skilled in the art or by protection of the corresponding commercially available alcohol (for example 4-(2- hydroxyethyl)phenol, which is available, for example, from Sigma-Aldrich).
Compounds of formula (XX) are commercially available, for example, from Sigma-Aldrich, Magical Scientific, Fluka, SynChem Inc. or Apollo, such as (R)-(-)-Λ/-Boc-3-pyrrolidinol, (S)-(+)-N-Boc-3- pyrrolidinol, (R)-1-Boc-2-pyrrolidinemethanol, (S)-1-Boc-2-pyrrolidinemethanol, tert-butyl 3-hydroxy- 1-piperidinecarboxylate, 1-Boc-4-hydroxypiperidine, N-Boc-4-piperidinemethanol and 1 ,1- dimethylethyl 4-hydroxyhexahydro-1 H-azepine-1-carboxylate. 1 ,1-dimethylethyl 3- hydroxyhexahydro-1 H-azepine-1-carboxylate is disclosed in Israeli J. Chem., 37:47-67 (1997).
Compounds of formula (XX) may also be prepared by methods well known to a person skilled in the art, such as Boc-protection of the commercially available amines, for example 3- (hydroxymethyl)pyrrolidine, 2-(2-hydroxyethyl)piperidine, 4(2-hydroxyethyl)piperidine which are commmercially available, for example, from Sigma-Aldrich or Albemate Corporation. Compounds of formula (XXI) are commercially available, for example, from Sigma-Aldrich, such as cyclobutanone, cyclopentanone, cyclohexanone, formaldehyde, acetaldehyde, propionaldehyde, 2- propanone, 2-butanone, butyraldehyde, valeraldehyde and hexanal.
Scheme 7
Synthesis of compounds of formula (NIc) - in which I is 3-6 and L is activated hvdroxyl
Figure imgf000022_0001
wherein I is 3-6 and I', m, n and R5 are as defined hereinabove for formula (I).
Reagents and Conditions: i) Suitable base e.g. sodium hydride, suitable solvent e.g. N-methyl-2- pyrrolidinone, elevated temperature such as about 80 0C; ii) suitable acid e.g. TFA, solvent e.g. DCM; iii) appropriate reducing agent e.g. NaBH(OAc)3, solvent e.g. DCM, optional acid catalyst e.g. AcOH; iv) CuI, suitable catalyst e.g. Pd(PPh3)2CI2, base e.g. NEt3, solvent such as THF; v) H2, catalyst e.g. Pd/C, solvent e.g. EtOH; vi) appropriate activating agent e.g. TsCI or MsCI, base such as NEt3, solvent e.g. DCM.
Compounds of formula (XXII), such as 1-fluoro-2-iodobenzene, 1-fluoro-3-iodobenzene and 1- fluoro-4-iodobenzene are available commercially, for example, from Sigma-Aldrich.
Compounds of formula (XXIII), such as propargyl alcohol, 3-butyn-1-ol, 4-pentyn-1-ol and 5-hexyn- 1-ol are available commercially, for example, from Sigma-Aldrich. Scheme 8
Synthesis of compounds of formula (IV) in which R1 represents straight chain Ct-salkyl or
(CH?)raryl and is substituted in positions 2, 3 or 4 of the quinoline ring.
Figure imgf000023_0001
wherein;
Z represents fluorine or hydroxyl; d represents 0 or 1. When d represents 1 , Y represents CF3, CN or halogen and is substituted in the 3, 4 or 5 position of a compound of formula (XXIV); p represents 0 or 1. When p is 1 , R1 represents Chalky! or -(CH2)caryl (where c represents 0 to 3) in which the aryl is optionally substituted with one or two substituents independently selected from halogen, Ci_3alkyl, trifluoromethyl and cyano, and is substituted in the 2,3 or 4 position of a compound of formula (IV).
When R1, as described above, is substituted in position 2 of the compound of formula (IV), K represents R1 and M and L each independently represent hydrogen.
When R1, as described above, is substituted in position 3 of the compound of formula (IV), L represents R1 and K and M each independently represent hydrogen.
When R1, as described above, is substituted in position 4 of the compound of formula (IV), M represents R1 and K and L each independently represent hydrogen. K, L and M each independently represent hydrogen when p is 0.
Reagents and Conditions: i) Skraup reaction: suitable strong acid e.g. hydrochloric acid or sulphuric acid, suitable solvent e.g. toluene, optional oxidising agent e.g. nitrobenzene, iron trichloride, p- chloranil or sodium 3-nitrobenzenesulfonate, at an elevated temperature e.g. 1000C
Compounds of formula (XXIV) are commercially available or may be converted from corresponding NO2 compounds by reduction of NO2 to NH2 using hydrogen and a catalyst, such as palladium on carbon, in ethanol.
Compounds of formula (IV) wherein p represents 1 and R1 represents Ci^alkyl or -(CH2)caryl
(where c represents 0 to 3) in which the aryl is optionally substituted with one or two substituents independently selected from halogen, C1-3alkyl, trifluoromethyl and cyano, can be prepared from the appropriate halogen derivative. Compounds of formula (IV) wherein p represents 1 and R1 represents halogen substituted in the 2,3 or 4 position, are commercially available. For example, 4- bromo-8-fluoroquinoline is commercially available from ECA, and 2-chloro-8-hydroxyquinoline is commercially available from AKOS.
Scheme 9
Synthesis of compounds of formula (IV) from other compounds of formula (IV) in which R1 represents bromine
Figure imgf000024_0001
wherein; R1 represents straight chain Ci_6 alkyl or -(CH2)caryl in which the aryl is optionally substituted with one or two substituents independently selected from halogen, C1-3alkyl, trifluoromethyl and cyano, and c represents 0 to 3.
Reagents and Conditions: i) Suzuki reaction using a trialkylboron reagent e.g. triethylboron, tri-n- butylboron, or S-benzyl 9-BBN, suitable solvent e.g. DMF and/or THF, suitable base e.g. potassium carbonate, appropriate catalyst e.g. [1 ,1 '-bis(diphenylphosphino) ferrocene palladium (II)] chloride, at an elevated temperature such as from about 70 to 80 0C.
Scheme 10
Synthesis of compounds of formula (XXIV) in which d represents 1 and R1 represents (CH?)raryl (in which c represents 2 or 3)
Figure imgf000024_0002
wherein; X represents I, Br or CF3SO2 "; and q represents 0 or 1.
Reagents and Conditions: i) Sonogashira reaction: base e.g. triethylamine or diisopropylethylamine, copper halide catalyst e.g. copper (I) iodide, palladium catalyst e.g. bis(triphenylphosphine)palladium (II) dichloride, solvent e.g. acetonitrile or DMF, at an elevated temperature when X represents Br or CF3SO3 "; ii) hydrogenation over a catalyst such as palladium on carbon or platinum oxide in a suitable solvent such as ethanol, at ambient temperature.
According to a second process, B, a compound of formula (I), in which R2 represents a group of formula (a), may be prepared by reduction of a compound of formula (XXVI):
Figure imgf000025_0001
wherein; R1, p, a, Y, e, e', f, g, h and R3 are as defined hereinabove for formula (I).
The reaction may typically be carried out in the presence of a suitable catalyst, such as carbonylhydridotris(triphenylphosphine)rhodium(l) (0.01 eq), a reducing agent, such as diphenylsilane (approx. 2.3 eq), in a suitable solvent, such as THF, at ambient temperature for approximately 23 h.
Alternatively, provided that the R1 substituent(s) are stable to such reaction conditions, the reaction may be performed using lithium aluminium hydride as a suitable reducing agent, in a suitable solvent, such as THF, at a lower temperature, such as at about O0C.
According to a third process, C, a compound of formula (I), in which at least one R1 represents - (CH2)b-CO2H, may be prepared by deprotection of a compound of formula (XXVII)
Figure imgf000025_0002
wherein a, b and R2 are as defined hereinabove for formula (I), and R12 represents C1-6alkyl.
The deprotection reaction may typically be carried out in the presence of a suitable base, such as sodium hydroxide, in an appropriate solvent, such as MeOH, at an appropriate elevated temperature, such as from between 60 to 70 0C.
Compounds of formula (XXVII) may be prepared according to Scheme 11 below.
Scheme 11 Synthesis of compounds of formula (XXVII)
Figure imgf000026_0001
wherein; a is as defined for formula (I); r represents 0 or 1 ; R12 represents C-i-βalkyl.
Reagents and Conditions: i) Benzylic oxidation: selenium dioxide (2 eq) in dioxane at elevated temp (55-75C) overnight; ii) Wittig reaction: phosphorus ylid eg methyl
(triphenylphosphoranylidene)acetate (1.5 eq), suitable solvent e.g. THF, at an elevated temp (reflux); iii) hydrogenation over a catalyst e.g. palladium on carbon or platinum oxide in ethanol, or where a halide is present use copper hydride e.g. (triphenylphosphine)copper(l) hydride hexamer in THF at room temperature; iv) deprotection: TFA in DCM or HCI in dioxane; (v) suitable base e.g. triethylamine (NEt3), diisopropylethylamine (DIPEA) or sodium hydrogen carbonate (NaHCO3), a sutiable solvent e.g. acetonitrile (MeCN) or N,N-dimethylformamide (DMF), optionally at an appropriate elevated temperature e.g. approx 80 0C; optionally using microwave irradiation and optionally with the addition of an activating agent e.g. potassium iodide (Kl) or sodium iodide (NaI).
According to a fourth process, D, a compound of formula (I), may be prepared by interconversion from other compounds of formula (I).
Interconversions include, but are not limited to alkylation and deprotection, under standard conditions well known to those skilled in the art.
Thus, typically, an alkylation reaction may be carried out between a compound of formula (I) and a Ci_6alkyl, activated to substitution by means of a leaving group such as halogen or an activated hydroxyl group, such as mesylate or tosylate. The reaction usually takes place in the presence of a suitable base such as triethylamine, Λ/,Λ/-diisopropylethylamine or sodium carbonate, in an appropriate solvent such as 2-butanone or DMF, optionally at an appropriate elevated temperature such as at about 80 0C.
According to an fifth process, E, a salt of a compound of formula (I), for example a pharmaceutically acceptable salt, may be prepared by exchange of counterions, or precipitation of said salt from the free acid or base.
Examples of protecting groups that may be employed in the synthetic routes descrbied and the means for their removal can be found in T. W. Greene 'Protective Groups in Organic Synthesis' (3rd edition, J. Wiley and Sons, 1999). Suitable amine protecting groups include sulphonyl (e.g. tosyl), acyl (e.g. acetyl, 2',2',2'-trichloroethoxycarbonyl, benzyloxycarbonyl or f-butoxycarbonyl) and arylalkyl (e.g. benzyl), which may be removed using an acid such as hydrogen chloride in dioxane or trifluoroacetic acid in dichloromethane or reductively by hydrogenolysis of a benzyl group or reductive removal of a 2',2',2'-trichloroethoxycarbonyl group using zinc in acetic acid, as appropriate. Other suitable amine protecting groups include trifluoroacetyl (-COCF3), which may be removed by base catalysed hydrolysis or a solid phase resin bound benzyl group, such as a Merrifield resin bound 2,6-dimethoxybenzyl group (Ellman linker), which may be removed by acid catalysed hydrolysis, for example with trifluoroacetic acid.
It will be appreciated that all novel intermediates used to prepare compounds of the invention form yet a further aspect of the present invention.
Compounds of formula (I), or pharmaceutically acceptable salts thereof, may be useful for the treatment of various inflammatory and/or allergic diseases. Compounds of formula (I), or pharmaceutically acceptable salts thereof, may also be useful for the prophylaxis of various inflammatory and/or allergic diseases.
Examples of diseases in which a compound of formula (I), or a pharmaceutically acceptable salt thereof, may have potentially beneficial anti-inflammatory and/or anti-allergic effects include diseases of the respiratory tract such as allergic rhinitis (seasonal and perennial), bronchitis (including chronic bronchitis), asthma (including allergen-induced asthmatic reactions), chronic obstructive pulmonary disease (COPD) and sinusitis.
Furthermore, the compounds of the invention may be of use in the treatment of nephritis, skin diseases such as psoriasis, eczema, allergic dermatitis, urticaria and hypersensitivity reactions. A particular disease of interest is urticaria. Also, the compounds of the invention may be useful in the treatment of insect bites and stings.
The compounds of the invention may also be of use in the treatment of nasal polyposis, conjunctivitis (e.g. allergic conjunctivitis) or pruritis. A disease of particular interest is allergic rhinitis.
Other diseases in which histamine may have a pathophysiological role include non-allegic rhinitis, and also diseases of the gastrointestinal tract such as intestinal inflammatory diseases including inflammatory bowel disease (e.g. Crohn's disease or ulcerative colitis) and intestinal inflammatory diseases secondary to radiation exposure or allergen exposure.
As mentioned above, compounds of formula (I), or pharmaceutically acceptable salts thereof, may be useful as therapeutic agents. There is thus provided, as a further aspect of the invention, a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in therapy.
In another embodiment, there is provided a compound which is 8-({1-[2-(4-{[3-(hexahydro-1H- azepin-1-yl)propyl]oxy}phenyl)ethyl]-4-piperidinyl}oxy)quinoline, or a pharmaceutically acceptable salt thereof, for use in therapy.
According to yet another aspect of the invention, there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of inflammatory and/or allergic diseases (such as any of the above-mentioned diseases).
In another embodiment, there is provided a compound which is 8-({1-[2-(4-{[3-(hexahydro-1H- azepin-1-yl)propyl]oxy}phenyl)ethyl]-4-piperidinyl}oxy)quinoline, or a pharmaceutically acceptable salt thereof, for use in the treatment of inflammatory and/or allergic diseases (such as any of the above-mentioned diseases).
In another embodiment, there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of allergic rhinitis.
In another embodiment, there is provided a compound which is 8-({1-[2-(4-{[3-(Hexahydro-1H- azepin-1-yl)propyl]oxy}phenyl)ethyl]-4-piperidinyl}oxy)quinoline, or a pharmaceutically acceptable salt thereof, for use in the treatment of allergic rhinitis.
According to another aspect of the invention, there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for the treatment of inflammatory and/or allergic diseases (such as any of the above-mentioned diseases).
In another embodiment, there is provided a compound which is 8-({1-[2-(4-{[3-(hexahydro-1H- azepin-1-yl)propyl]oxy}phenyl)ethyl]-4-piperidinyl}oxy)quinoline, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for the treatment of inflammatory and/or allergic diseases (such as any of the above-mentioned diseases). According to another aspect of the invention, there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for use in the treatment of allergic rhinitis.
In another embodiment, there is provided a compound which is 8-({1-[2-(4-{[3-(hexahydro-1H- azepin-1-yl)propyl]oxy}phenyl)ethyl]-4-piperidinyl}oxy)quinoline, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for use in the treatment of allergic rhinitis.
In a further aspect, there is provided a method for treating inflammatory and/or allergic diseases (such as any of the above-mentioned diseases), which comprises administering to a patient an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.
In a further aspect, there is provided a method for treating inflammatory and/or allergic diseases (such as any of the above-mentioned diseases), which comprises administering to a patient an effective amount of 8-({1-[2-(4-{[3-(hexahydro-1 H-azepin-1-yl)propyl]oxy}phenyl)ethyl]-4- piperidinyl}oxy)quinoline, or a pharmaceutically acceptable salt thereof.
In a further aspect, there is provided a method for treating allergic rhinitis, which comprises administering to a patient an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.
In a further aspect, there is provided a method for treating allergic rhinitis, which comprises administering to a patient an effective amount of 8-({1-[2-(4-{[3-(Hexahydro-1H-azepin-1- yl)propyl]oxy}phenyl)ethyl]-4-piperidinyl}oxy)quinoline, or a pharmaceutically acceptable salt thereof.
When used in therapy, the compounds of formula (I), or pharmaceutically acceptable salts thereof, are usually formulated in a suitable pharmaceutical composition. Such pharmaceutical compositions can be prepared using standard procedures.
Thus, the present invention provides, a pharmaceutical composition comprising a) a compound of formula (I), or a pharmaceutically acceptable salt thereof, and b) one or more pharmaceutically acceptable excipients.
In a further embodiment, a pharmaceutical composition comprising a) 8-({1-[2-(4-{[3-(hexahydro- 1 H-azepin-1-yl)propyl]oxy}phenyl)ethyl]-4-piperidinyl}oxy)quinoline, or a pharmaceutically acceptable salt thereof, and b) one or more pharmaceutically acceptable carriers or excipients. A composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, which may be prepared by admixture, suitably at ambient temperature and atmospheric pressure, may be suitable for topical administration (which includes epicutaneous, inhaled, intranasal or ocular administration), enteral administration (which includes oral or rectal administration) or parenteral administration (such as by injection or infusion). Of interest are compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, suitable for topical administration, particularly suitable for intranasal administration.
Generally, compositions may be in the form of solutions or suspensions (aqueous or non-aqueous), tablets, capsules, oral liquid preparations, powders, granules, lozenges, lotions, creams, ointments, gels, foams, reconstitutable powders or suppositories as required by the route of administration.
Generally, the compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof may contain from about 0.001 % to 99% (w/w), such as from about 0.1 to 60% (w/w) (based on the total weight of the composition), of the compound of formula (I) or the pharmaceutically acceptable salt thereof, depending on the route of administration. The dose of the compound used in the treatment of the aforementioned diseases will vary in the usual way with the seriousness of the diseases, the weight of the sufferer, and other similar factors. However, as a general guide, suitable unit doses may be about 0.05 to 1000 mg, for example about 0.05 to 200 mg, and such unit doses may be administered more than once a day, for example two or three times a day or as desired. Such therapy may extend for a number of weeks or months.
The proportion of the compound of formula (I) or a pharmaceutically acceptable salt thereof in a topical composition will depend on the precise type of composition to be prepared and the particular route of administration, but will generally be within the range of from about 0.001 to 10% (w/w), based on the total weight of the composition. Generally, however for most types of preparations the proportion used will be within the range of from about 0.005 to 1 % (w/w), such as about 0.01 to 1 % (w/w), for example about 0.01 to 0.5% (w/w), based on the total weight of the composition. However, in powders for inhalation the proportion used will generally be within the range of from about 0.1 to 5% (w/w), based on the total weight of the composition.
Generally, compositions suitable for intranasal or inhaled administration may conveniently be formulated as aerosols, solutions, suspensions, drops, gels or dry powders, optionally with one or more pharmaceutically acceptable carriers and/or excipients such as aqueous or non-aqueous vehicles, thickening agents, isotonicity adjusting agents, antioxidants, preservatives and/or co- solvents.
For compositions suitable for intranasal or inhaled administration, the compound of formula (I) or a pharmaceutically acceptable salt thereof may typically be in a particle-size-reduced form, which may be prepared by conventional techniques, for example, micronisation, milling and/or microfluidisation. Generally, the size-reduced (e.g. micronised) compound of formula (I) or a pharmaceutically acceptable salt thereof can be defined by a D50 value of about 0.5 to 10 microns, for example of about 1 to 10 microns, such as of about 1 to 4 microns (for example as measured using laser diffraction).
In one embodiment, compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof are suitable for intranasal administration. Intranasal compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof may permit the compound(s) to be delivered to all areas of the nasal cavities (the target tissue) and further, may permit the compound(s) to remain in contact with the target tissue for longer periods of time. A suitable dosing regime for intranasal compositions would be for the patient to inhale slowly through the nose subsequent to the nasal cavity being cleared. During inhalation the composition would be administered to one nostril while the other is manually compressed. This procedure would then be repeated for the other nostril. Typically, one or two administrations per nostril would be administered by the above procedure up to two or three times each day, ideally once daily. Of particular interest are intranasal compositions suitable for once daily administration.
The intranasal compositions containing a compound of formula (I) or a pharmaceutically acceptable salt thereof may be in the form of an aqueous suspension and/or an aqueous solution. Partial suspensions and/or partial solutions are encompassed within the scope of the present invention. Compositions comprising one compound which is in solution and another compound which is in suspension are also included within the scope of the present invention.
Intranasal compositions may optionally contain one or more suspending/thickening agents, one or more preservatives, one or more wetting agents and/or one or more isotonicity adjusting agents as desired. Compositions suitable for intranasal administration may optionally further contain other excipients, such as antioxidants (for example sodium metabisulphite), taste-masking agents (such as menthol) and sweetening agents (for example dextrose, glycerol, saccharin and/or sorbitol).
The skilled person would readily appreciate that some excipients may perform more than one function, depending on the nature and number of excipients used in the composition and the particular properties of the therapeutic compound(s) and other carriers and/or excipients contained therein.
The suspending/thickening agent, if included, will typically be present in the intranasal composition in an amount of between about 0.1 and 5% (w/w), such as between about 1.5% and 2.4% (w/w), based on the total weight of the composition. Examples of suspending/thickening agents include, but are not limited to Avicel® (microcrystalline cellulose and carboxymethylcellulose sodium), carboxymethylcellulose sodium, veegum, tragacanth, bentonite, methylcellulose xanthan gum, carbopol and polyethylene glycols. Suspending/thickening agents may also be included in compositions suitable for inhaled, ocular and oral administration, as appropriate.
For stability purposes, intranasal compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof may be protected from microbial or fungal contamination and growth by inclusion of a preservative. Examples of pharmaceutically acceptable anti-microbial agents or preservatives may include quaternary ammonium compounds (e.g. benzalkonium chloride, benzethonium chloride, cetrimide, myristal picolinium chloride, lauralkonium chloride and cetylpyridinium chloride), mercurial agents (e.g. phenylmercuric nitrate, phenylmercuric acetate and thimerosal), alcoholic agents (e.g. chlorobutanol, phenylethyl alcohol and benzyl alcohol), antibacterial esters (e.g. esters of para-hydroxybenzoic acid), chelating agents such as disodium ethylenediaminetetraacetate (EDTA) and other anti-microbial agents such as chlorhexidine, chlorocresol, sorbic acid and its salts (such as potassium sorbate) and polymyxin. Examples of pharmaceutically acceptable anti-fungal agents or preservatives include, but are not limited to sodium benzoate, sorbic acid, sodium propionate, methyl paraben, ethyl paraben, propyl paraben and butyl paraben.. The preservative, if included, may be present in an amount of between about 0.001 and 1 % (w/w), such as about 0.015% (w/w), based on the total weight of the composition. Preservatives may be included in compositions suitable for other routes of administration as appropriate.
Compositions which contain a suspended medicament may include a pharmaceutically acceptable wetting agent which functions to wet the particles of medicament to facilitate dispersion thereof in the aqueous phase of the composition. Typically, the amount of wetting agent used will not cause foaming of the dispersion during mixing. Examples of wetting agents include, but are not limited to fatty alcohols, esters and ethers, such as polyoxyethylene (20) sorbitan monooleate (Polysorbate 80) macrogol ethers and poloxamers. The wetting agent may be present in intranasal compositions in an amount of between about 0.001 and 0.05% (w/w), for example about 0.025% (w/w), based on the total weight of the composition. Wetting agents may be included in compositions suitable for other routes of administration, e.g. for inhaled and/or ocular administration, as appropriate.
An isotonicity adjusting agent may be included to achieve isotonicity with body fluids e.g. fluids of the nasal cavity, resulting in reduced levels of irritancy. Examples of isotonicity adjusting agents include, but are not limited to sodium chloride, dextrose, xylitol and calcium chloride. An isotonicity adjusting agent may be included in intranasal compositions in an amount of between about 0.1 and 10% (w/w), for example between about 4.5 to 5.5% (w/w), such as about 5.0% (w/w), based on the total weight of the composition. Isotonicity adjusting agents may also be included in compositions suitable for other routes of administration, for example in compositions suitable for inhaled, ocular, oral liquid and parenteral administration, as appropriate. One or more co-solvent(s) may be included to aid solubility of the active compound(s) and/or other excipients. Examples of pharmaceutically acceptable co-solvents include, but are not limited to, propylene glycol, dipropylene glycol, ethylene glycol, glycerol, ethanol, polyethylene glycols (for example PEG300 or PEG400) and methanol. The co-solvent(s), if present, may be included in an amount of from about 0.05 to 20% (w/w), such as from about 1.5 to 17.5% (w/w), or from about 1.5 to 7.5% (w/w), or from about 0.05% to 0.5% (w/w) based on the total weight of the composition. Co- solvents may also be included in compositions suitable for other routes of administration, as appropriate.
Further, the intranasal compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof may be buffered by the addition of suitable buffering agents such as sodium citrate, citric acid, trometarol, phosphates such as disodium phosphate (for example the dodecahydrate, heptahydrate, dihydrate and anhydrous forms) or sodium phosphate and mixtures thereof. Buffering agents may also be included in compositions suitable for other routes of administration as appropriate.
Compositions for administration topically to the nose (for example, for the treatment of rhinitis) or lung, include pressurised aerosol compositions and aqueous compositions delivered to the nasal cavities by pressurised pump. Compositions which are non-pressurised and adapted to be administered topically to the nasal cavity are of particular interest. Suitable compositions contain water as the diluent or carrier for this purpose. Aqueous compositions for administration to the lung or nose may be provided with conventional excipients such as buffering agents, tonicity modifying agents and the like. Aqueous compositions may also be administered to the nose by nebulisation.
A fluid dispenser may typically be used to deliver a fluid composition to the nasal cavities. The fluid composition may be aqueous or non-aqueous, but typically aqueous. Such a fluid dispenser may have a dispensing nozzle or dispensing orifice through which a metered dose of the fluid composition is dispensed upon the application of a user-applied force to a pump mechanism of the fluid dispenser. Such fluid dispensers are generally provided with a reservoir of multiple metered doses of the fluid composition, the doses being dispensable upon sequential pump actuations. The dispensing nozzle or orifice may be configured for insertion into the nostrils of the user for spray dispensing of the fluid composition into the nasal cavity. A fluid dispenser of the aforementioned type is described and illustrated in WO05/044354 the entire content of which is hereby incorporated herein by reference. The dispenser has a housing which houses a fluid discharge device having a compression pump mounted on a container for containing a fluid composition. The housing has at least one finger-operable side lever which is movable inwardly with respect to the housing to cam the container upwardly in the housing to cause the pump to compress and pump a metered dose of the composition out of a pump stem through a nasal nozzle of the housing. In one embodiment, the fluid dispenser is of the general type illustrated in Figures 30-40 of WO05/044354. Aqueous compositions containing a compound of formula (I) or a pharmaceutically acceptable salt thereof may also be delivered by a pump as disclosed in WO2007/138084, for example as disclosed with reference to Figures 22-46 thereof, or as disclosed in GB0723418.0, for example as disclosed with reference to Figures 7-32 thereof, both of which prior patent applications are incorporated herein by reference in their entirety. The pump may be actuated by an actuator as disclosed in Figures 1-6 of said GB0723418.0.
In one embodiment, there is provided an intranasal composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof. In another embodiment, such an intranasal composition is benzalkonium chloride-free.
Inhaled administration involves topical administration to the lung, such as by aerosol or dry powder composition.
Aerosol compositions suitable for inhaled administration may comprise a solution or fine suspension of the compound in a pharmaceutically acceptable aqueous or non-aqueous solvent. Aerosol compositions suitable for inhalation can be either a suspension or a solution and generally contain a compound of formula (I) or a pharmaceutically acceptable salt thereof and a suitable propellant such as a fluorocarbon or hydrogen-containing chlorofluorocarbon or mixtures thereof, such as hydrofluoroalkanes, e.g. 1 ,1 ,1 ,2-tetrafluoroethane, 1 ,1 ,1 ,2,3,3,3-heptafluoro-n-propane or a mixture thereof. The aerosol composition may optionally contain additional excipients well known in the art such as surfactants or cosolvents. Examples of surfactants include, but are not limited to oleic acid, lecithin, an oligolactic acid or derivative e.g. as described in WO94/21229 and WO98/34596. An example of a cosolvent includes, but is not limited to ethanol. Aerosol compositions may be presented in single or multidose quantities in sterile form in a sealed container, which may take the form of a cartridge or refill for use with an atomising device or inhaler. 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 (metered dose inhaler), which is intended for disposal once the contents of the container have been exhausted.
Dry powder inhalable compositions may take the form of capsules and cartridges of, for example, gelatine, or blisters of, for example, laminated aluminium foil, for use in an inhaler or insufflator. Such compositions may be formulated comprising a powder mix of a compound of formula (I) or a pharmaceutically acceptable salt thereof and a suitable powder base such as lactose or starch.
Optionally, for dry powder inhalable compositions, a composition suitable for inhaled administration may be incorporated into a plurality of sealed dose containers (e.g. comprising the dry powder composition) mounted longitudinally in a strip or ribbon inside a suitable inhalation device. The container is rupturable or peel-openable on demand and the dose of e.g. the dry powder composition may be administered by inhalation via the device such as the DISKUS™ device, marketed by GlaxoSmithKline. The DISKUS™ inhalation device is for example described in GB 2242134 A, and in such a device, at least one container for the composition in powder form (the container or containers may, for example, be a plurality of sealed dose containers mounted longitudinally in a strip or ribbon) is defined between two members peelably secured to one another; the device comprises: a means of defining an opening station for the said container or containers; a means for peeling the members apart at the opening station to open the container; and an outlet, communicating with the opened container, through which a user can inhale the composition in powder form from the opened container.
Aerosol compositions are typically arranged so that each metered dose or "puff" of aerosol contains about 20 μg - 2000 μg, particularly about 20 μg - 500 μg of a compound of formula (I) or a pharmaceutically acceptable salt thereof. Administration may be once daily or several times daily, for example 2, 3, 4 or 8 times, giving for example 1 , 2 or 3 doses each time. The overall daily dose with an aerosol will be within the range of about 100 μg - 10 mg, such as between about 200 μg - 2000 μg. The overall daily dose and the metered dose delivered by capsules and cartridges in an inhaler or insufflator will generally be double those with aerosol compositions.
In another embodiment, there is provided a composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof which is suitable for epicutaneous administration. An epicutaneous composition to be applied to the affected area e.g. the skin, by one or more application per day, may be in the form of, for example, an ointment, a cream, an emulsion, a lotion, a foam, a spray, an aqueous gel, or a microemulsion. Such compositions may optionally contain one or more solubilising agents, skin-penetration-enhancing agents, surfactants, fragrances, preservatives or emulsifying agents.
Ointments, creams and gels, may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agent and/or solvents. Such bases may thus, for example, include water and/or an oil such as liquid paraffin or a vegetable oil such as arachis oil or castor oil, or a solvent such as polyethylene glycol. Thickening agents and gelling agents which may be used according to the nature of the base include soft paraffin, aluminium stearate, cetostearyl alcohol, polyethylene glycols, woolfat, beeswax, carboxypolymethylene and cellulose derivatives, and/or glyceryl monostearate and/or non-ionic emulsifying agents. Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilising agents, dispersing agents, suspending agents or thickening agents.
In another embodiment, there is provided a composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof which is suitable for ocular administration. Such compositions may optionally contain one or more suspending agents, one or more preservatives, one or more wetting/lubricating agents and/or one or more isotonicity adjusting agents. Examples of ophthalmic wetting/lubricating agents may include cellulose derivatives, dextran 70, gelatin, liquid polyols, polyvinyl alcohol and povidone such as cellulose derivatives and polyols.
In another embodiment, there is provided a composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof which is suitable for oral administration. Tablets and capsules for oral administration may be in unit dose form, and may contain conventional excipients, such as binding agents, fillers, tabletting lubricants, disintegrants and acceptable wetting agents. The tablets may be coated according to methods well known in normal pharmaceutical practice.
Oral liquid preparations may be in the form of, for example, aqueous or oily suspension, solutions, emulsions, syrups or elixirs, or may be in the form of a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), preservatives, and, if desired, conventional flavourings or colorants.
In another embodiment, there is provided a composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof which is suitable for parenteral administration. Fluid unit dosage forms suitable for parenteral administration may be prepared utilising a compound of formula (I) or pharmaceutically acceptable salt thereof and a sterile vehicle which may be aqueous or oil based. The compound, depending on the vehicle and concentration used, may be either suspended or dissolved in the vehicle. In preparing solutions, the compound may be dissolved for injection and filter sterilised before filling into a suitable vial or ampoule and sealing. Optionally, adjuvants such as a local anaesthetic, preservatives and buffering agents may be dissolved in the vehicle. To enhance the stability, the composition may be frozen after filling into the vial and the water removed under vacuum. The lyophilised parenteral composition may be reconstituted with a suitable solvent just prior to administration. Parenteral suspensions may be prepared in substantially the same manner, except that the compound is suspended in the vehicle instead of being dissolved, and sterilisation cannot be accomplished by filtration. The compound may be sterilised by exposure to ethylene oxide before suspension in a sterile vehicle. A surfactant or wetting agent may be included in the composition to facilitate uniform distribution of the compound.
The compounds and pharmaceutical compositions according to the invention may also be used in combination with or include one or more other therapeutic agents, for example other antihistaminic agents for example H4 receptor antagonists, anticholinergic agents, anti-inflammatory agents such as corticosteroids (e.g. fluticasone propionate, fluticasone furoate, beclomethasone dipropionate, mometasone furoate, triamcinolone acetonide, budesonide and the steroid disclosed in WO02/12265); or non-steroidal anti-inflammatory drugs (NSAIDs) (e.g. sodium cromoglycate, nedocromil sodium), PDE-4 inhibitors, leukotriene antagonists, lipoxygenase inhibitors, chemokine antagonists (e.g. CCR3, CCR1 , CCR2, CCR4, CCR8, CXCR1 , CXCR2), IKK antagonists, iNOS inhibitors, tryptase and elastase inhibitors, beta-2 integrin antagonists and adenosine 2a agonists; or beta adrenergic agents (e.g. salmeterol, salbutamol, formoterol, fenoterol, terbutaline, and the beta agonists described in WO 02/66422, WO 02/270490, WO02/076933, WO03/024439 and WO03/072539 and salts thereof); or antiinfective agents e.g. antibiotic agents and antiviral agents.
It will be clear to a person skilled in the art that, where appropriate, the other therapeutic agent(s) may be used in the form of salts, (e.g. as alkali metal or amine salts or as acid addition salts), or prodrugs, or as esters (e.g. lower alkyl esters), or as solvates (e.g. hydrates) to optimise the activity and/or stability and/or physical characteristics (e.g. solubility) of the therapeutic agent. It will be clear also that where appropriate, the therapeutic agents may be used in optically pure form.
There is provided, in another embodiment, a combination comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, together with one or more (such as one or two, e.g. one) other therapeutically active agents, optionally with one or more pharmaceutically acceptable carriers and/or excipients.
In another embodiment, there is provided a combination comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a H4 receptor antagonist.
Other histamine receptor antagonists which may be used alone, or in combination with a dual H1/H3 receptor antagonist include antagonists (and/or inverse agonists) of the H4 receptor, for example, the compounds disclosed in Jablonowski et ai, J. Med. Chem. 46:3957-3960 (2003).
In another embodiment, there is provided a combination comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a β2-adrenoreceptor agonist.
Examples of β2-adrenoreceptor agonists include salmeterol (which may be a racemate or a single enantiomer, such as the R-enantiomer), salbutamol (which may be a racemate or a single enantiomer such as the R-enantiomer), formoterol (which may be a racemate or a single diastereomer such as the R,R-diastereomer), salmefamol, fenoterol, carmoterol, etanterol, naminterol, clenbuterol, pirbuterol, flerbuterol, reproterol, bambuterol, indacaterol, terbutaline and salts thereof, for example the xinafoate (1-hydroxy-2-naphthalenecarboxylate) salt of salmeterol, the sulfate salt or free base of salbutamol or the fumarate salt of formoterol. In one embodiment, combinations containing a compound of formula (I) may include longer-acting β2-adrenoreceptor agonists, for example, compounds which provide effective bronchodilation for about 12 h or longer.
Other β2-adrenoreceptor agonists include those described in WO 02/066422, WO 02/070490, WO 02/076933, WO 03/024439, WO 03/072539, WO 03/091204, WO 04/016578, WO 2004/022547, WO 2004/037807, WO 2004/037773, WO 2004/037768, WO 2004/039762, WO 2004/039766, WO01/42193 and WO03/042160. Examples of β2-adrenoreceptor agonists include:
3-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy} butyl)benzenesulfonamide;
3-(3-{[7-({(2R)-2-hydroxy-2-[4-hydroxy-3-hydroxymethyl) phenyl] ethyl}-amino)heptyl]oxy} propyl)benzenesulfonamide;
4-{(1 R)-2-[(6-{2-[(2,6-dichlorobenzyl)oxy]ethoxy}hexyl)amino]-1-hydroxyethyl}-2-(hydroxyl methyl) phenol;
4-{(1 R)-2-[(6-{4-[3-(cyclopentylsulfonyl)phenyl]butoxy}hexyl)amino]-1-hydroxyethyl}-2-
(hydroxylmethyl)phenol; N-P-hydroxyl-δ-KI RJ-i-hydroxy^-^^-^^RJ^-hydroxy^-phenylethyllaminolphenyl] ethyl]amino]ethyl]phenyl]formamide;
N-2{2-[4-(3-phenyl-4-methoxyphenyl)aminophenyl]ethyl}-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-
5-yl)ethylamine; and
5-[(R)-2-(2-{4-[4-(2-amino-2-methyl-propoxy)-phenylamino]-phenyl}-ethylamino)-1 -hydroxy -ethyl]- 8-hydroxy-1 H-quinolin-2-one.
The β2-adrenoreceptor agonist may be in the form of a salt formed with a pharmaceutically acceptable acid selected from sulfuric, hydrochloric, fumaric, hydroxynaphthoic (for example 1- or 3-hydroxy-2-naphthoic), cinnamic, substituted cinnamic, triphenylacetic, sulfamic, sulfanilic, naphthaleneacrylic, benzoic, 4-methoxybenzoic, 2- or 4-hydroxybenzoic, 4-chlorobenzoic and 4- phenylbenzoic acid.
In another embodiment, there is provided a combination comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and an anti-inflammatory agent.
Anti-inflammatory agents include corticosteroids. Suitable corticosteroids which may be used in combination with the compounds of formula (I) are those oral and inhaled corticosteroids and their pro-drugs which have anti-inflammatory activity. Examples include methyl prednisolone, prednisolone, dexamethasone, fluticasone propionate, 6α,9α-difluoro-1 1 β-hydroxy-16α-methyl- 17α-[(4-methyl-1 ,3-thiazole-5-carbonyl)oxy]-3-oxo-androsta-1 ,4-diene-17β-carbothioic acid S- fluoromethyl ester, 6α,9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-1 1 β-hydroxy-16α-methyl-3-oxo- androsta-1 ,4-diene-17β-carbothioic acid S-fluoromethyl ester (fluticasone furoate), 6α,9α-difluoro- 11 β-hydroxy-16α-methyl-3-oxo-17α-propionyloxy- androsta-1 ,4-diene-17β-carbothioic acid S-(2- oxo-tetrahydro-furan-3S-yl) ester, 6α,9α-difluoro-11 β-hydroxy-16α-methyl-3-oxo-17α-(2, 2,3,3- tetramethycyclo propylcarbonyl)oxy-androsta-1 ,4-diene-17β-carbothioic acid S-cyanomethyl ester and 6α,9α-difluoro-1 1 β-hydroxy-16α-methyl-17α-(1-methycyclopropylcarbonyl)oxy-3-oxo-androsta- 1 ,4-diene-17β-carbothioic acid S-fluoromethyl ester, beclomethasone esters (for example the 17- propionate ester or the 17,21-dipropionate ester), budesonide, flunisolide, mometasone esters (for example mometasone furoate), triamcinolone acetonide, rofleponide, ciclesonide (16α,17-[[(R)- cyclohexylmethylene]bis(oxy)]-11 β,21-dihydroxy-pregna-1 ,4-diene-3,20-dione), butixocort propionate, RPR-106541 , and ST-126. Corticosteroids of particular interest may include fluticasone propionate, 6α,9α-difluoro-11 β-hydroxy-16α-methyl-17α-[(4-methyl-1 ,3-thiazole-5- carbonyl)oxy]-3-oxo-androsta-1 ,4-diene-17β-carbothioic acid S-fluoromethyl ester, 6α,9α-difluoro- 17α-[(2-furanylcarbonyl)oxy]-11 β-hydroxy-16α-methyl-3-oxo-androsta-1 ,4-diene-17β-carbothioic acid S-fluoromethyl ester, 6α,9α-difluoro-1 1 β-hydroxy-16α-methyl-3-oxo-17α-(2,2,3,3- tetramethycyclopropylcarbonyl)oxy-androsta-1 ,4-diene-17β-carbothioic acid S-cyano methylester, 6α,9α-difluoro-11 β-hydroxy-16α-methyl-17α-(1-methycyclopropylcarbonyl) oxy-3-oxo-androsta-1 ,4- diene-17β-carbothioic acid S-fluoromethyl ester and mometasone furoate. In one embodiment the corticosteroid is 6α,9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-1 1 β-hydroxy-16α-methyl-3-oxo- androsta-1 ,4-diene-17β-carbothioic acid S-fluoromethyl ester (fluticasone furoate) or mometasone furoate.
There is provided, in a further embodiment, a combination comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a corticosteroid, such as fluticasone propionate or 6α,9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-11 β-hydroxy-16α-methyl-3-oxo-androsta-1 ,4-diene- 17β-carbothioic acid S-fluoromethyl ester (fluticasone furoate) or mometasone furoate, in particular 6α,9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-11 β-hydroxy-16α-methyl-3-oxo-androsta-1 ,4-diene- 17β-carbothioic acid S-fluoromethyl ester (fluticasone furoate). Such combinations may be of particular interest for intranasal administration.
In another embodiment there is provided a combination comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and 6α,9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-1 1 β- hydroxy-16α-methyl-3-oxo-androsta-1 ,4-diene-17β-carbothioic acid S-fluoromethyl ester (fluticasone furoate).
In another embodiment, there is provided a combination comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a glucocorticoid agonist.
Non-steroidal compounds having glucocorticoid agonism that may possess selectivity for transrepression over transactivation and that may be useful in combination therapy include those covered in the following patent application and patents: WO03/082827, WO98/54159, WO04/005229, WO04/009017, WO04/018429, WO03/104195, WO03/082787, WO03/082280, WO03/059899, WO03/101932, WO02/02565, WO01/16128, WO00/66590, WO03/086294, WO04/026248, WO03/061651 , WO03/08277, WO06/000401 , WO06/000398 and WO06/015870.
Anti-inflammatory agents include non-steroidal anti-inflammatory drugs (NSAID's). NSAID's include sodium cromoglycate, nedocromil sodium, phosphodiesterase (PDE) inhibitors (e.g. theophylline, PDE4 inhibitors or mixed PDE3/PDE4 inhibitors), leukotriene antagonists, inhibitors of leukotriene synthesis (eg. montelukast), iNOS (inducible nitric oxide synthase) inhibitors (e.g. oral iNOS inhibitors), IKK antagonists, tryptase and elastase inhibitors, beta-2 integrin antagonists and adenosine receptor agonists or antagonists (e.g. adenosine 2a agonists), cytokine antagonists (e.g. chemokine antagonists, such as a CCR1 , CCR2, CCR3, CCR4, or CCR8 antagonists) or inhibitors of cytokine synthesis, or 5-lipoxygenase inhibitors. iNOS inhibitors include those disclosed in WO93/13055, WO98/30537, WO02/50021 , WO95/34534 and WO99/62875.
In another embodiment there is provided the use of the compounds of formula (I) or a pharmaceutically acceptable salt thereof in combination with a phosphodiesterase 4 (PDE4) inhibitor. The PDE4-specific inhibitor useful in this embodiment may be any compound that is known to inhibit the PDE4 enzyme or which is discovered to act as a PDE4 inhibitor, and which are only PDE4 inhibitors, not compounds which inhibit other members of the PDE family, such as PDE3 and PDE5, as well as PDE4.
Compounds which may be of interest include 6-({3-[(dimethylamino)carbonyl]phenyl}sulfonyl)-8- methyl-4-{[3-(methyloxy)phenyl]amino}-3-quinolinecarboxamide (Example 399 of International Patent Application WO04/103998), c/s-4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan- 1-carboxylic acid, 2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4- difluoromethoxyphenyl)cyclohexan-1-one and c/s-[4-cyano-4-(3-cyclopropylmethoxy-4- difluoromethoxyphenyl)cyclohexan-1-ol]. Also, c/s-4-cyano-4-[3-(cyclopentyloxy)-4- methoxyphenyl]cyclohexane-1-carboxylic acid (also known as cilomilast) and its salts, esters, pro- drugs or physical forms, which is described in U.S. patent 5,552,438 issued 03 September, 1996.
Other PDE4 inhibitors include AWD-12-281 from Elbion (Hofgen, N. et al., 15th EFMC Int. Symp. Med. Chem., (Sept 6-10, Edinburgh) 1998, Abst. P. 98; CAS reference No. 247584020-9); a 9- benzyladenine derivative nominated NCS-613 (INSERM); D-4418 from Chiroscience and Schering- Plough; a benzodiazepine PDE4 inhibitor identified as CI-1018 (PD-168787) and attributed to Pfizer; a benzodioxole derivative disclosed by Kyowa Hakko in WO99/16766; K-34 from Kyowa Hakko; V-1 1294A from Napp (Landells, L.J. et al., Eur. Resp. J. [Ann. Cong. Eur. Resp. Soc. (Sept 19-23, Geneva) 1998] 1998, 12 (Suppl. 28): Abst P2393); roflumilast (CAS reference No 162401- 32-3) and a pthalazinone (WO99/47505) from Byk-Gulden; Pumafentrine, (-)-p-[(4aR*,105S*)-9- ethoxy-1 ,2,3,4,4a, 10b-hexahydro-8-methoxy-2-methylbenzo[c][1 ,6]naphthyridin-6-yl]-Λ/,Λ/- diisopropylbenzamide which is a mixed PDE3/PDE4 inhibitor which has been prepared and published on by Byk-Gulden, now Altana; arofylline under development by Almirall-Prodesfarma; VM554/UM565 from Vemalis; or T-440 (Tanabe Seiyaku; Fuji, K. et al., J. Pharmacol. Exp. Ther., 284(1 ):162, (1998)), and T2585. Further compounds which may be of interest are disclosed in the published international patent applications WO04/024728 (Glaxo Group Ltd), WO04/056823 (Glaxo Group Ltd) and WO04/103998 (Glaxo Group Ltd).
In another embodiment, there is provided a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and 6-({3-[(dmethylamino)carbonyl]phenyl}sulfonyl)-8- methyl-4-{[3-(methyloxy)phenyl]amino}-3-quinolinecarboxamide or a pharmaceutically acceptable salt thereof.
In another embodiment, there is provided a combination comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and an anticholinergic agent.
Anticholinergic agents are those compounds that act as antagonists at the muscarinic receptors, in particular those compounds which are antagonists of the M1 or M3 receptors, dual antagonists of the M1ZM3 or M2/M3, receptors or pan-antagonists of the M-|/M2/M3 receptors. Exemplary compounds for administration via inhalation include ipratropium (for example, as the bromide, CAS 22254-24-6, sold under the name Atrovent), oxitropium (for example, as the bromide, CAS 30286- 75-0) and tiotropium (for example, as the bromide, CAS 136310-93-5, sold under the name Spiriva). Also of interest are revatropate (for example, as the hydrobromide, CAS 262586-79-8) and LAS-34273 which is disclosed in WO01/04118. Exemplary compounds for oral administration include pirenzepine (for example, CAS 28797-61-7), darifenacin (for example, CAS 133099-04-4, or CAS 133099-07-7 for the hydrobromide sold under the name Enablex), oxybutynin (for example, CAS 5633-20-5, sold under the name Ditropan), terodiline (for example, CAS 15793-40-5), tolterodine (for example, CAS 124937-51-5, or CAS 124937-52-6 for the tartrate, sold under the name Detrol), otilonium (for example, as the bromide, CAS 26095-59-0, sold under the name Spasmomen), trospium chloride (for example, CAS 10405-02-4) and solifenacin (for example, CAS 242478-37-1 , or CAS 242478-38-2, or the succinate also known as YM-905 and sold under the name Vesicare).
Other anticholinergics may be found in WO 2004/012684; WO2004/091482; WO2005/009439;
WO2005/009362; WO2005/009440; WO2005/037280; WO2005/037224; WO2005/046586;
WO2005/055940; WO2005/055941 ; WO2005/067537; WO2005/087236; WO2005/086873;
WO2005/094835; WO2005/094834; WO2005/094251 ; WO2005/095407; WO2005/099706;
WO2005/104745; WO2005/1 12644; WO2005/1 18594; WO2006/005057; WO2006/017768; WO2006/017767; WO2006/050239; WO2006/055553; WO2006/055503; WO2006/065755;
WO2006/065788; WO2007/018514; WO2007/018508; WO2007/016650; WO2007/016639; and
WO2007/022351. Other anticholinergic agents include compounds which are disclosed in US patent application 60/487981 , published as WO2005/009439 and those compounds disclosed in US patent application 60/511009, published as WO2005/037280.
The combinations referred to above may conveniently be presented for use in the form of a pharmaceutical composition and thus pharmaceutical compositions comprising a combination as defined above optionally together with a pharmaceutically acceptable carrier and/or excipient.
The individual compounds of such combinations may be administered either sequentially in separate pharmaceutical compositions as well as simultaneously in combined pharmaceutical compositions. Additional therapeutically active ingredients may be suspended in the composition together with a compound of formula (I). Appropriate doses of known therapeutic agents will be readily appreciated by those skilled in the art.
Compounds of the invention may be prepared by the methods described below or by similar methods. Thus the following Intermediates and Examples illustrate the preparation of the compounds of the invention, and are not to be considered as limiting the scope of the invention in any way.
General Experimental
Abbreviations
9-BBN: 9-Borabicyclo[3.3.1]nonane
AcOH: Acetic Acid BOC (Boc): fert-butoxycarbonyl
CHCI3: Trichloromethane
CV: Column volumes
DCM: Dichloromethane
DIPEA: Λ/,Λ/-Diisopropylethylamine DMSO: Dimethylsulfoxide
EtOAc: Ethyl Acetate
EtOH: Ethanol
HCI: Hydrogen Chloride
HPLC: High Performance Liquid Chromatography h: Hour
LCMS: Liquid Chromatography - Mass Spectroscopy
LiALH4: Lithium Aluminium Hydride
MDAP HPLC: Mass-Directed Autopreparative HPLC
MeCN: Acetonitrile MeOH: Methanol min: Minute
NaOH: Sodium hydroxide Na2SO4: Sodium sulphate NaH: Sodium Hydride NMP: N-Methyl Pyrrolidone
NMR: Nuclear Magnetic Resonance Pd/C: Palladium on activated carbon RT: Retention time s.g: Specific gravity TBTU: O-(1 /-/-benzotriazol-1-yl)-Λ/,Λ/,Λ/',Λ/'-tetramethyluronium tetrafluoroborate TFA: Trifluoroacetic acid THF: Tetrahydrofuran TLC: Thin Layer Chromatography
General Procedures
Flash silica gel refers to Merck Art No. 9385; silica gel refers to Merck Art No. 7734. SCX cartridges are Ion Exchange SPE columns where the stationary phase is polymeric benzene sulfonic acid. These are used to isolate amines.
SCX2 cartridges are Ion Exchange SPE columns where the stationary phase is polymeric propylsulfonic acid. These are used to isolate amines.
LCMS was conducted on a Supelcosil LCABZ+PLUS column (3.3 cm x 4.6 mm ID) eluting with 0.1 % formic acid and 0.01 M ammonium acetate in water (solvent A) and 0.05% formic acid 5% water in MeCN (solvent B), using the following elution gradient 0.0 - 7 min 0% B, 0.7 - 4.2 min 100% B, 4.2 - 5.3 min 0% B, 5.3 - 5.5min 0% B at a flow rate of 3 mlmin"1. The mass spectra were recorded on a Fisons VG Platform spectrometer using electrospray positive and negative mode (ES+ve and ES-ve).
The Flashmaster Il is an automated multi-user flash chromatography system, available from Argonaut Technologies Ltd, which utilises disposable, normal phase, SPE cartridges (2 g to 100 g).
It provides quaternary on-line solvent mixing to enable gradient methods to be run. Samples are queued using the multi-functional open access software, which manages solvents, flow-rates, gradient profile and collection conditions. The system is equipped with a Knauer variable wavelength UV-detector and two Gilson FC204 fraction-collectors enabling automated peak cutting, collection and tracking.
Mass directed autopreparative (MDAP) HPLC was conducted on a Waters FractionLynx system comprising of a Waters 600 pump with extended pump heads, Waters 2700 autosampler, Waters
996 diode array and Gilson 202 fraction collector on a 10 cm x 2.54 cm internal diameter ABZ+ column, eluting with 0.1 % formic acid in water (solvent A) and 0.1 % formic acid in MeCN (solvent B), using an appropriate elution gradient over 15 min at a flow rate of 20 mlmin"1 and detecting at 200 - 320 nm at room temperature. Mass spectra were recorded on Micromass ZMD mass spectrometer using electro spray positive and negative mode, alternate scans. The software used was MassLynx 3.5 with OpenLynx and FractionLynx options.
Reactions are routinely monitored by methods well known to those skilled in the art, such as TLC, LCMS and/or HPLC. Such methods are used to assess whether a reaction has gone to completion, and reaction times may be varied accordingly.
Compounds were named using ACD/Name PRO 6.02 chemical naming software Advanced Chemistry Developments Inc.; Toronto, Ontario, M5H2L3, Canada.
Intermediates Intermediate 1 2-Ethyl-δ-fluoroquinoline
2-Fluoroaniline (commercially available, for example, from Aldrich) (1.3 ml, 13.5 mmol), trans-2- pentenal (2.64 ml, 27 mmol), aqueous hydrochloric acid (5M, 18 ml) and toluene (60 ml) were combined and heated at 1000C for 6 h. The toluene layer was separated, and the aqueous layer neutralised with 2M aqueous sodium hydroxide, and then it was extracted with dichloromethane (2 x 50 ml). The organic solutions were combined, dried over a ptfe frit, and evaporated to leave a brown gel. This was purified by chromatography on Flashmaster (50 g silica cartridge, loaded in dichloromethane, eluted with 0-50% ethyl acetate-cyclohexane). The sample was further purified by Flashmaster Il (50 g silica SPE, loaded in dichloromethane, eluted with 0-50% ethyl acetate - cyclohexane over 40 min). Product-containing fractions were combined and evaporated to give the title compound (1.2 g, 51 %). LCMS RT=2.65 min, ES+ve m/z 176 (M+H)+.
Intermediate 2 δ-Fluoro-2-methylquinoline
2-Fluoroaniline (commercially available, for example, from Aldrich) (2.2 ml, 22.5 mmol) was dissolved in 5M aqueous hydrochloric acid (100 ml), then toluene (30 ml) and crotonaldehyde (3.71 ml, 45mmol) were added. The reaction was heated at 1000C for 2 h under nitrogen with vigorous stirring. The reaction mixture was left to cool, and the aqueous layer separated. This was neutralised using aqueous sodium hydroxide and extracted with dichloromethane (2 x 50 ml). The organic solutions were combined, dried over a ptfe frit and evaporated to leave a brown gel. This was purified by Flashmaster Il (100 g silica SPE, loaded in dichloromethane, eluted with 0-50% ethyl acetate-cyclohexane over 1 h). The solvent was evaporated to give the title compound (2.8 g,
77%). LCMS RT=2.19 min, ES+ve m/z 162 (M+H)+.
Intermediate 3 6-Bromo-δ-fluoroquinoline 4-Bromo-2-fluoroaniline (commercially available, for example, from Aldrich) (5.788 g, 30.46 mmol) was dissolved in hydrochloric acid (5M, 137 ml), toluene (40 ml) and acrolein (6 ml, 91 mmol) were added. The solution was stirred at 1000C overnight. The aqueous was separated and 10M sodium hydroxide was added until the solution became basic. The compound which appeared in the shape of a powder was dissolved in dichloromethane, and the organic layer was separated, washed with water and brine. The organic layer was dried with sodium sulphate, filtered and evaporated. The sample was dissolved in dichloromethane and purified by flashmaster (100 g column, 0-100% ethyl acetate-cyclohexane, 60 min). The pure fractions were combined and evaporated to give the title compound (1.512 g, 22%). LCMS RT=2.87 min, ES+ve m/z 226/228 (M+H)+.
Intermediate 4
8-Fluoro-6-(phenylmethyl)quinoline
6-Bromo-8-fluoroquinoline (for example, as prepared for Intermediate 3) (226 mg, 1 mmol), potassium carbonate (276 mg, 2 mmol) and 1 ,1'- bis(diphenylphosphino)ferrocene]dichloropalladium (II) (18.3 mg, 0.02 mmol) were mixed. B- benzyl-9-BBN in tetrahydrofuran (4 ml, 2 mmol) and Λ/,Λ/-dimethylformamide (3 ml) were added. The solution was stirred at 6O0C for two days. Ethyl acetate was added to the reaction mixture, and then it was washed three times with water. The compound was extracted with 5M hydrochloric acid. The solution was washed twice with ether and then neutralised with 10M sodium hydroxide. The compound was extracted with dichloromethane, dried with sodium sulphate, filtered and finally evaporated. The residue was purified by chromatography on Flashmaster (20 g cartridge, 0-50% ethyl acetate-dichloromethane, 40 min). Pure fractions were combined and evaporated to give the title compound (173 mg). LCMS RT=3.23 min, ES+ve m/z 283 (M+H)+.
Intermediate 5
6-Butyl-δ-fluoroquinoline
6-Bromo-8-fluoroquinoline (for example, as prepared for Intermediate 3) (339 mg, 1.5 mmol), potassium carbonate (414 mg, 3 mmol) and [1 ,1'- bis(diphenylphosphino)ferrocene]dichloropalladium (II) (27.4 mg, 0.037 mmol) were mixed in a reactivial. A solution of tributylborane in tetrahydrofuran (1 M, 3 ml, 3 mmol) and N, N- dimethylformamide (4 ml) were added. The solution was stirred at 6O0C for two days. Ethyl acetate was added to the solution, then it was washed three times with water. The compound was extracted with 5M hydrochloric acid. The solution was washed twice with ether and then neutralised with 10M sodium hydroxide. The compound was extracted with dichloromethane, dried with sodium sulphate, filtered and finally evaporated. Samples were purified by chromatography on Flashmaster (20 g cartridge, 0-50% ethyl acetate-dichloromethane, 40 min). Pure fractions were combined and evaporated to give the title compound (190 mg, 62%). LCMS RT=3.36 min, ES+ve m/z 204 (M+H)+.
Intermediate 6 6-(4-Chlorophenyl)-8-fluoroquinoline
6-Bromo-8-fluoroquinoline (for example, as prepared for Intermediate 3) (226 mg, 1 mmol), 4- chlorophenylboronic acid (187 mg, 1.1 mmol), potassium carbonate (421 mg, 3 mmol) and tetrakis(triphenylphosphine) palladium (0) (112 mg, 0.1 mmol) were mixed in a reactivial. lsopropanol (3 ml) and water (3 ml) were added and the solution was stirred at 7O0C overnight. The solution was filtered and evaporated and the residue partitioned between dichloromethane and water. The organic layer was washed with water and brine. The organic solution was dried with sodium sulphate, filtered and evaporated. The compound was dissolved in dichloromethane and purified by Flashmaster (20 g cartridge, 0-50% ethyl acetate-dichloromethane, 40 min). The pure fractions were combined and evaporated to give the title compound. LCMS RT=3.53 min, ES+ve m/z 258 (M+H)+.
Intermediate 7 δ-Fluoro-6-methylquinoline 2-Fluoro-4-methylaniline (Aldrich) (2 g, 16 mmol), hydrochloric acid (75 ml), toluene (21.5 ml) and acrolein (3.15 ml, 48 mmol) were mixed and the solution was stirred at 1000C overnight. The aqueous layer was removed and sodium hydroxide was added until the solution became basic. The mixture was extracted with dichloromethane, and the organic layer was washed with water and brine, dried with sodium sulphate, and then filtered and evaporated. The residue was purified by chromatography on Flashmaster (100 g cartridge), eluting with 0-50% ethyl acetate- dichloromethane over 60 min to give the title compound. LCMS RT=2.56 min, ES+ve m/z 162 (M+H)+.
Intermediate 8 2-Fluoro-4-(phenylethynyl)aniline
To 2-fluoro-4-iodoaniline (commercially available, for example, from Aldrich) (4.1 g, 17 mmol) in acetonitrile (25 ml) was added phenylacetylene (1.86 g, 18.2 mmol), followed by triethylamine (12.1 ml, 86.5 mmol) and the mixture was stirred under nitrogen for ten minutes, before the addition of bis(triphenylphosphine)palladium(ll) dichloride (560 mg, 0.8 mmol) and copper (I) iodide (160 mg, 0.8 mmol). The reaction mixture was stirred for 18 h overnight at room temperature. The mixture was evaporated to dryness and the residue taken up in dichloromethane, washed with saturated sodium bicarbonate solution and the organic layer passed through a phase separator. The filtrate was evaporated to dryness and the residue was purified on silica cartridge (100 g) eluting with cyclohexane initially, followed by toluene to give the title compound (3.4 g, 95%). LCMS RT=3.55 min, ES+ve m/z 212 (M+H)+.
Intermediate 9 2-Fluoro-4-(2-phenylethyl)aniline
2-Fluoro-4-(phenylethynyl)aniline (for example, as prepared for Intermediate 8) (3.38 g, 16 mmol) in ethanol was added to the catalyst 10% palladium on carbon (0.5 g) and the mixture hydrogenated at room temperature over the weekend. Palladium hydroxide (0.5 g) was added and hydrogenated further overnight. The catalyst was removed by filtration under nitrogen, washed with ethanol and the filtrate evaporated to dryness to give the title compound (3 g, 87%). LCMS RT=3.39 min, ES+ve m/z 216 (M+H)+.
Intermediate 10
8-Fluoro-6-(2-phenylethyl)quinoline
Acrolein (0.64 ml, 10 mmol) in butanol (2 ml) was added dropwise during 5 min to a mixture of 2- fluoro-4-(2-phenylethyl)aniline (for example, as prepared for Intermediate 9) (1.29 g, 6 mmol) and p-chloranil (1.44 g, 6 mmol) in butanol (5 ml) and 5M hydrochloroic acid (2 ml) at 12O0C with stirring. The mixture was heated for a further 5 min and allowed to cool. The mixture was poured onto 2N hydrochloric acid and washed with ether. The ether extracts were evaporated and the residue purified by chromatography on Flashmaster (silica cartridge, eluting with 0-30% [methanol containing 1 % triethylamine]-dichloromethane over 30 min) to give the title compound (820 mg, 54%). LCMS RT=3.40 min, ES+ve m/z 252 (M+H)+. The acidic aqueous was basified with 2N sodium hydroxide and extracted with dichloromethane twice. The combined extracts were poured through a phase separator, the filtrate evaporated to dryness and the residue purified by chromatography on Flashmaster (silica cartridge, as above) to give the a further butch of the title compound (290 mg, 19%). LCMS RT=3.40 min, ES+ve m/z 252 (M+H)+.
Intermediate 11
6-Ethyl-δ-fluoroquinoline
6-Bromo-8-fluoroquinoline (for example, as prepared for Intermediate 3) (339 mg, 1.5 mmol), potassium carbonate (417 mg, 3 mmol) and 1 ,1'- bis(diphenylphosphino)ferrocene]dichloropalladium (II) (27 mg, 0.037 mmol) were mixed in a reactivial. Triethylborane in tetrahydrofuran (3 ml, 3 mmol) and N,N-dimethylformamide were added. The solution was stirred at 6O0C for two days. The liquid phase was removed and ethyl acetate (about 100 ml) was added then it was washed three times with water. The compound was extracted with 5M hydrochloric acid. The aqueous solution was washed twice with ether and then sodium hydroxide solution was added until the solution became basic. The compound was extracted with dichloromethane, dried with sodium sulphate and finally evaporated. The residue was purified by chromatography on Flashmaster (20 g cartridge) 0-50% ethyl acetate- dichloromethane over 40 min. Pure fractions were combined and the evaporated to give the title compound (164 mg). LCMS RT=2.85 min, ES+ve m/z 176 (M+H)+.
Intermediate 12 δ-Fluoro-4-methylquinoline
A mixture of 2-fluoroaniline (commercially available, for example, from Aldrich) (6.4 g, 62 mmol), ferric chloride hexahydrate (3.27 g, 12 mmol), anhydrous zinc chloride (1 g, 7.33 mmol) in ethanol (50 ml) was heated to 650C and then treated with methyl vinyl ketone (4.2 ml, 50 mmol) and the mixture was heated to reflux for 2.5 h and then allowed to cool overnight. The mixture was evaporated and the residue was extracted with dichloromethane. The aqueous phase was basified with sodium hydroxide and the dark coloured mixture was extracted with ethyl acetate. The combined ethyl acetate extracts were dried (MgSO4), filtered and concentrated. The residue was purified by chromatography (Biotage, 90 g cartridge) eluting with ethyl acetate - cyclohexane (2:8) to give the title compound (2.65 g, 33%). LCMS RT=2.34 min, ES+ve m/z 162 (M+H)+.
Intermediate 13 2-Amino-5-fluorophenol A solution of 5-fluoro-2-nitrophenol (commercially available, for example, from Aldrich) (2.50 g, 15.9 mmol) in ethanol (50 ml) was hydrogenated over 10% palladium on carbon (980 mg) for 1.5 h. The catalyst was removed by filtration and the filtrate was concentrated. The solid residue was taken up in ether and an equal volume of cyclohexane was added. Removal of ether in vac at room temperature afforded a pale grey solid which was filtered and washed with cyclohexane (1.90 g, 94%). Found: C, 56.4; H, 4.8; N, 10.9. C6H6FNO requires C, 56.7; H, 4.8; N, 1 1.0%.
Intermediate 14 6-Fluoro-δ-quinolinol
2-Amino-5-fluorophenol (for example, as prepared for Intermediate 13) (602 mg, 4.74 mmol) was dissolved in 5M hydrochloric acid (21 ml). Toluene (6.5 ml) and acrolein (1 ml, 14 mmol) were added to the solution and the mixture was stirred at 1000C overnight. The aqueous layer was removed and 10M sodium hydroxide was added until the solution was neutral. The compound which precipitated was extracted with dichloromethane and the organic phase was washed with water and brine, then it was dried with sodium sulphate, filtered and evaporated. The residue was dissolved in dichloromethane and purified by Flashmaster (50 g cartridge, 0-50% ethyl acetate- dichloromethane, 60 min). Pure fractions were combined and evaporated to give the title compound (96 mg, 12%). LCMS RT=1.97 min, ES+ve m/z 164 (M+H)+. RT=2.85 min, ES+ve m/z 176 (M+H)+.
Intermediate 15
1 ,1 -Dimethylethyl 4-[(6-ethyl-8-quinolinyl)oxy]-1 -piperidinecarboxylate
1 ,1-Dimethylethyl 4-hydroxy-1 -piperidinecarboxylate (commercially available, for example, from Aldrich) (207 mg, 1.03 mmol) was dissolved in Λ/-methylpyrrolidinone (1.5 ml). Sodium hydride (60% oil dispersion, 56 mg, 1.4 mmol) was added. After the gas evolution had ceased, 6-ethyl-8- fluoroquinoline (for example, as prepared for Intermediate 11 ) (164 mg, 0.937 mmol) dissolved in Λ/-methylpyrrolidinone (1 ml) was added. The solution was stirred at 8O0C overnight, and then the mixture was partitioned between dichloromethane and water. The organic layer was washed with water and brine, dried with sodium sulphate, filtered and evaporated to give 1 ,1-Dimethylethyl 4-[(6- ethyl-8-quinolinyl)oxy]-1 -piperidinecarboxylate. LCMS RT=2.95 min, ES+ve m/z 357 (M+H)+. Intermediate 16 6-Ethyl-8-(4-piperidinyloxy)quinoline
1 ,1-Dimethylethyl 4-[(6-ethyl-8-quinolinyl)oxy]-1-piperidinecarboxylate (for example, as prepared for Intermediate 15) (458 mg) was dissolved in dichloromethane (10 ml) and then was treated with trifluoroacetic acid (5 ml) under a nitrogen atmosphere. The solution was stirred for 15 min at room temperature and then concentrated. The residue was purified by chromatography on Flashmaster (50 g cartridge), eluting with 0-30% [methanol containing 1 % triethylamine]-dichloromethane over 60 min. Pure fractions were combined and concentrated under reduced pressure. The residue was dissolved in methanol and applied to SCX-2 cartridge (5 g). The compound was washed several times with methanol, and then eluted with 2M ammonia in methanol. The appropriate fractions were evaporated to give the title compound (57 mg). LCMS RT= 1.78 min, ES+ve m/z 257 (M+H)+.
Intermediate 17 1,1 -Dimethylethyl 4-[(2-ethyl-8-quinolinyl)oxy]-1 -piperidinecarboxylate
Prepared in a manner similar to the one described for 1 ,1-Dimethylethyl 4-[(6-ethyl-8- quinolinyl)oxy]-1 -piperidinecarboxylate (Intermediate 15) (810 mg, 80%); utilising 2-ethyl-8- fluoroquinoline (for example, as prepared for Intermediate 1 ): LCMS RT=2.88 min, ES+ve m/z 357 (M+H)+.
Intermediate 18
2-Ethyl-8-(4-piperidinyloxy)quinoline
Prepared from 1 ,1-Dimethylethyl 4-[(2-ethyl-8-quinolinyl)oxy]-1-piperidinecarboxylate (for example, as prepared for Intermediate 17) in a similar manner to that described for the preparation of 6-ethyl- 8-(4-piperidinyloxy)quinoline (Intermediate 16).
(934 mg) LCMS RT=1.50 min, ES+ve m/z 257 (M+H)+.
Intermediate 19
1,1-Dimethylethyl 4-[(2-methyl-8-quinolinyl)oxy]-1 -piperidinecarboxylate Prepared in a manner similar to the one described for 1 ,1-Dimethylethyl 4-[(6-ethyl-8- quinolinyl)oxy]-1 -piperidinecarboxylate (Intermediate 15); utilising 8-Fluoro-2-methylquinoline (for example, as prepared for Intermediate 2). (810 mg, 76%) LCMS RT=2.63 min, ES+ve m/z 343 (M+H)+.
Intermediate 20
2-Methyl-8-(4-piperidinyloxy)quinoline
Prepared from 1 ,1-Dimethylethyl 4-[(2-methyl-8-quinolinyl)oxy]-1-piperidinecarboxylate (for example, as prepared for Intermediate 19) in a similar manner to that described for the preparation of 6-ethyl-8-(4-piperidinyloxy)quinoline (Intermediate 16). (625 mg). LCMS RT=1.18 min, ES+ve m/z 243 (M+H)+. Intermediate 21 6-(Phenylmethyl)-δ-(4-piperidinyloxy)quinoline
1 ,1-Dimethylethyl 4-hydroxy-1-piperidinecarboxylate (commercially available, for example, from Aldrich) (156 mg, 0.775 mmol) was dissolved in Λ/-methylpyrrolidinone (1.5 ml). Sodium hydride (60% oil dispersion, 42 mg, 1.06 mmol) was added. After the gas evolution had ended, 8-fluoro-6- (phenylmethyl)quinoline (for example, as prepared for Intermediate 4) (167 mg, 0.705 mmol) dissolved in Λ/-methylpyrrolidinone (1 ml) was added. The solution was stirred at 8O0C overnight. The reaction mixture was partitioned between dichloromethane and water. The organic layer was washed with water and brine, dried with sodium sulphate, filtered and then evaporated to give 1 ,1- Dimethylethyl 4-{[6-(phenylmethyl)-8-quinolinyl]oxy}-1-piperidinecarboxylate (540 mg). 1 ,1-Dimethylethyl 4-{[6-(phenylmethyl)-8-quinolinyl]oxy}-1-piperidinecarboxylate (540 mg, 1.29 mmol) was dissolved in dichloromethane (10 ml) and trifluoroacetic acid (5 ml) was added under a nitrogen atmosphere. The solution was stirred for 15 min and then evaporated. The residue was dissolved in dichloromethane and purified by chromatography on Flashmaster (50 g cartridge), eluting with 0-30% [methanol containing 1 % triethylamine]-dichloromethane over 40 min. Pure fractions were combined and then evaporated. The residue was dissolved in dichloromethane and washed with aqueous sodium carbonate solution. The organic layer was removed, dried with sodium sulphate, filtered and evaporated to give the title compound (23 mg). LCMS RT=2.26 min, ES+ve m/z 319 (M+H)+.
Intermediate 22 6-Butyl-8-(4-piperidinyloxy)quinoline
1 ,1-Dimethylethyl 4-hydroxy-1-piperidinecarboxylate (commercially available, for example, from Aldrich) (200 mg, 1 mmol) was dissolved in Λ/-methylpyrrolidinone (1.5 ml). Sodium hydride (60% oil dispersion, 51 mg, 1.4 mmol) was added. After the bubbling had ended, 6-butyl-8- fluoroquinoline (for example, as prepared for Intermediate 5) (184 mg, 0.906 mmol) was added. The solution was stirred at 8O0C overnight. The solution was removed with dichloromethane. The organic layer was washed with water and brine, dried with sodium sulphate, filtered and then evaporated to give 1 ,1-Dimethylethyl 4-[(6-butyl-8-quinolinyl)oxy]-1-piperidinecarboxylate (361 mg, 0.940 mmol), which was dissolved in dichloromethane (10 ml). Trifluoroacetic acid was added under a nitrogen atmosphere. The solution was stirred for 15 min at room temperature, and then the solution was evaporated. The residue was dissolved in dichloromethane and purified by chromatography on Flashmaster (50 g cartridge), eluting with 0-30% [methanol containing 1 % triethylamine]-dichloromethane over 60 min. Appropriate fractions were combined and concentrated uder reduced pressure. The residue was dissolved in methanol and applied to SCX cartridge (5 g). The cartridge was washed several times with methanol, and then eluted with 2M ammonia in methanol. The appropriate fractions were evaporated to give the title compound (70 mg). LCMS RT=2.16 min, ES+ve m/z 285 (M+H)+. Intermediate 23 1 ,1 -Dimethylethyl 4-{[6-(4-chlorophenyl)-8-quinolinyl]oxy}-1 -piperidinecarboxylate
Prepared in a manner similar to the one described for 1 ,1 -Dimethylethyl 4-[(6-ethyl-8- quinolinyl)oxy]-1 -piperidinecarboxylate (Intermediate 15); utilising 6-(4-Chlorophenyl)-8- fluoroquinoline (for example, as prepared for Intermediate 6) LCMS RT=3.72 min, ES+ve m/z 439/441 (M+H)+.
Intermediate 24 6-(4-Chlorophenyl)-δ-(4-piperidinyloxy)quinoline Prepared from 1 ,1 -Dimethylethyl 4-{[6-(4-chlorophenyl)-8-quinolinyl]oxy}-1-piperidinecarboxylate (for example, as prepared for Intermediate 23) in a similar manner to that described for the preparation of 6-Ethyl-8-(4-piperidinyloxy)quinoline (Intermediate 16). LCMS RT=2.56 min, ES+ve m/z 339/341 (M+H)+.
Intermediate 25
6-Methyl-δ-(4-piperidinyloxy)quinoline
1 ,1 -Dimethylethyl 4-hydroxy-1 -piperidinecarboxylate (commercially available, for example, from Aldrich) (349 mg, 1.74 mmol) was dissolved in N-methylpyrrolidinone (1.5 ml). Sodium hydride (60% oil dispersion, 94.7 mg, 2.37 mmol) was added. After the gas evolution had ended, 8-fluoro- 6-methylquinoline (for example, as prepared for Intermediate 7) (254 mg, 1.58 mmol) dissolved in N-methylpyrrolidinone (1 ml) was added. The solution was stirred overnight at 8O0C, and then partitioned between dichloromethane and water. The organic layer was washed with water and brine, then it was dried with sodium sulphate, filtered and evaporated to give 1 ,1 -Dimethylethyl 4- [(6-methyl-8-quinolinyl)oxy]-1-piperidinecarboxylate (611 mg, 1.79 mmol) which was dissolved in dichloromethane (10 ml). Trifluoroacetic acid (5 ml) was added under a nitrogen atmosphere. The solution was stirred for 15 min at room temperature and then concentrated. The residue was purified by chromatography on Flashmaster (50 g cartridge), eluting with 0-30% [methanol containing 1 % triethylamine]-dichloromethane over 60 min. Pure fractions were combined and the solution was evaporated. The residue was dissolved in methanol and applied to SCX-2 cartridge (5 g). The compound was washed several times with methanol, and then eluted with 2M ammonia in methanol. The appropriate fractions were evaporated to give the title compound (239 mg). LCMS RT=1.63 min, ES+ve m/z 243 (M+H)+.
Intermediate 26 1,1 -Dimethylethyl 4-{[6-(2-phenylethyl)-δ-quinolinyl]oxy}-1 -piperidinecarboxylate
Prepared in a manner similar to the one described for 1 ,1 -Dimethylethyl 4-[(6-ethyl-8- quinolinyl)oxy]-1 -piperidinecarboxylate (Intermediate 15); utilising 8-Fluoro-6-(2- phenylethyl)quinoline (for example, as prepared for Intermediate 10): LCMS RT=3.40 min, ES+ve m/z 433 (M+H)+. Intermediate 27 6-(2-Phenylethyl)-δ-(4-piperidinyloxy)quinoline
Prepared from 1 ,1-Dimethylethyl 4-{[6-(2-phenylethyl)-8-quinolinyl]oxy}-1-piperidinecarboxylate (for example, as prepared for Intermediate 26) in a similar manner to that described for the preparation of 6-Ethyl-8-(4-piperidinyloxy)quinoline (Intermediate 16). (35 mg). LCMS RT=2.38 min, ES+ve m/z 333 (M+H)+.
Intermediate 28
1 ,1 -Dimethylethyl 4-[(4-methyl-8-quinolinyl)oxy]-1 -piperidinecarboxylate Prepared in a similar manner to that described for the preparation of 1 ,1 -dimethylethyl 4-[(6-ethyl-8- quinolinyl)oxy]-1 -piperidinecarboxylate (Intermediate 15); utilising 8-Fluoro-4-methylquinoline (for example, as prepared for Intermediate 12). LCMS RT=2.45 min, ES+ve m/z 343 (M+H)+.
Intermediate 29 4-Methyl-δ-(4-piperidinyloxy)quinoline
Prepared from 1 ,1-Dimethylethyl 4-[(4-methyl-8-quinolinyl)oxy]-1-piperidinecarboxylate (for example, as prepared for Intermediate 28) in a similar manner to that described for the preparation of 6-Ethyl-8-(4-piperidinyloxy)quinoline (Intermediate 16). LCMS RT=O.69 min, ES+ve m/z 243 (M+H)+.
Intermediate 30 δ-[(3/?)-3-pyrrolidinyloxy]quinoline
A solution of Λ/-ferf-butoxycarbonyl (R)-(-)-3-pyrrolidinol (commercially available, for example, from
Aldrich) (345 mg, 1.84 mmol) in NMP (10 ml) was treated with sodium hydride (0.088 g) and stirred at room temperature for 15 min. 8-Fluoroquinoline (commercially available, for example, from Apollo) (250 mg, 1.70 mmol) was added and the mixture was heated to 80 0C overnight. LCMS indicated partial reaction, so the mixture was cooled to room temperature and treated with more N- fert-butoxycarbonyl (R)-(-)-3-pyrrolidinol (340 mg), sodium hydride (88 mg) and NMP (5 ml). The mixture was heated to 85 0C for 2 h, and the additional sodium hydride (88 mg) was added and heated for another 2 h. The mixture was quenched with water and extracted with dichloromethane, dried (MgSO4), and filtered. The filtrate was loaded on to an SCX-2 cartridge (70 g) and washed with methanol and eluted with 2M ammonia in methanol. The fractions were concentrated, the residue was dissolved in dichloromethane and trifluoroacetic acid (2 ml) and stirred for 3 h at room temperature. The mixture was concentrated and then diluted with toluene and re-evaporated. The residue was dissolved in methanol and loaded on to an SCX-2 cartridge (20 g) washing with methanol, and then eluting with 2M ammonia in methanol. The basic solutions were evaporated to give the title compound (250 mg) LCMS RT=0.94 min, ES+ve m/z 215 (M+H)+.
Intermediate 31 8-[(3S)-3-pyrrolidinyloxy]quinoline Prepared in a similar manner to that described for the preparation of 8-[(3R)-3- pyrrolidinyloxy]quinoline (Intermediate 30) from Λ/-ferf-butoxycarbonyl (S)-(-)-3-pyrrolidinol (commercially available, for example, from Aldrich). LCMS RT=LOO min, ES+ ve m/z 215 (M +H)+.
Intermediate 32
1,1-Dimethylethyl 4-[(6-fluoro-δ-quinolinyl)oxy]-1-piperidinecarboxylate
6-Fluoro-8-quinolinol (for example, as prepared for Intermediate 14) (96 mg, 0.59 mmol) was dissolved in tetrahydrofuran (2.5 ml) and then 1 ,1-dimethylethyl 4-hydroxy-1-piperidinecarboxylate (commercially available, for example, from Aldrich) (120 mg, 0.59 mmol) and triphenylphosphine (310 mg, 1.18 mmol) were added. The mixture was stirred under nitrogen for ten minutes, and then diisopropyl azodicarboxylate (0.232 ml, 1.18 mmol) was added. The reaction mixture was stirred overnight at room temperature under nitrogen, and then the solvent was evaporated. The residue was dissolved in dichloromethane and purified by Flash-MS (50 g cartridge, eluting with 0- 100% ethyl acetate-cyclohexane over 30 min). Pure fractions were combined and evaporated to give the title compound (159 mg, 78%). LCMS RT=3.12 min, ES+ve m/z 347 (M+H)+.
Intermediate 33
1 ,1 -Dimethylethyl 4-[(7-bromo-8-quinolinyl)oxy]-1 -piperidinecarboxylate
Prepared in a similar manner to that described for the preparation of 1 ,1 -dimethylethyl 4-[(6-fluoro- 8-quinolinyl)oxy]-1 -piperidinecarboxylate (Intermediate 32); utilising 7-Bromo-8-quinolinol (commercially available, for example, from ACES Pharma Inc). LCMS RT=3.63 min, ES+ve m/z 407/409 (M+H)+.
Intermediate 34 7-Bromo-8-(4-piperidinyloxy)quinoline
Prepared from 1 ,1-Dimethylethyl 4-[(7-bromo-8-quinolinyl)oxy]-1-piperidinecarboxylate (for example, as prepared for Intermediate 33) in a similar manner to that described for the preparation of 6-Ethyl-8-(4-piperidinyloxy)quinoline (Intermediate 16). LCMS RT= 1.93 min, ES+ve m/z 307/309 (M+H)+.
Intermediate 35
6-Fluoro-δ-(4-piperidinyloxy)quinoline
1 ,1-Dimethylethyl 4-[(6-fluoro-8-quinolinyl)oxy]-1 -piperidinecarboxylate (for example, as prepared for Intermediate 32) (159 mg, 0.459 mmol) was dissolved in dichloromethane (10 ml). Trifluoroacetic acid (5 ml) was added under nitrogen and the solution was stirred for 15 min at room temperature under a nitrogen atmosphere. The solvent was removed by evaporation and the residue was dissolved in methanol and purified on a 10g SCX cartridge (conditioned with methanol, washed with methanol, eluted with 2M ammonia in methanol). The appropriate fractions were combined and evaporated to give the title compound (135 mg). LCMS RT=1.69 min, ES+ve m/z 247 (M+H)+. Intermediate 36
1 ,1 -Dimethylethyl 4-[(7-methyl-8-quinolinyl)oxy]-1 -piperidinecarboxylate
A solution of 1 ,1 -dimethylethyl 4-[(7-bromo-8-quinolinyl)oxy]-1 -piperidinecarboxylate (for example, as prepared for Intermediate 33) (0.5 g, 1.22 mmol) in DME (15 ml) was treated with tetrakis(triphenylphosphine)palladium (0) (70 mg, 0.06 mmol) and stirred under nitrogen for 20 min. Potassium carbonate (0.17 g, 1.22 mmol), trimethylboroxine (commercially available, for example, from Aldrich) (0.175 ml, 1.22 mmol) and water (3 ml) were added and the mixture was heated at reflux for 38 h. The mixture was allowed to cool to room temperature and partitioned between water and ethyl acetate. The organic layer was dried (MgSO4), filtered and concentrated. The residue was purified by chromatography (Biotage, 40 g silica cartridge) eluting with ethyl acetate- cyclohexane (2:8) to give the title compound (269 mg, 65%). LCMS RT=3.19 min, ES+ve m/z 343 (M+H)+.
Intermediate 37
7-Methyl-8-(4-piperidinyloxy)quinoline
Prepared from 1 ,1 -Dimethylethyl 4-[(7-methyl-8-quinolinyl)oxy]-1-piperidinecarboxylate (for example, as prepared for Intermediate 36) in a similar manner to that described for the preparation of 6-Ethyl-8-(4-piperidinyloxy)quinoline (Intermediate 16). LCMS RT=1.59 min, ES+ve m/z 243 (M+H)+.
Intermediate 38 2-{4-[(3-Chloropropyl)oxy]phenyl}ethanol
4-(2-Hydroxyethyl)phenol (commercially available, for example, from Aldrich), (10 g, 72 mmol) was dissolved in 2-butanone (250 ml) then potassium carbonate (19.9 g, 0.144 mol) was added then 1- bromo-3-chloropropane (commercially available, for example, from Aldrich) (8.54 ml, 0.144 mol) was added and the reaction mixture heated at 80 0C for 18 h. The cooled reaction mixture was diluted with water (500 ml), layers separated and aqueous extracted with DCM (2 x 200 ml). The combined organic extracts were dried (MgSO4), evaporated in vacuo and purified by Flashmaster Il (3 x 100g silica cartridges) eluted with 0 - 100% EtOAc-cyclohexane over 40 min to give the title compound (14.12 g). LCMS RT = 2.84 min ES+ve m/z 232 (M+NH4)+
Intermediate 39
2-(4-{[3-(Hexahydro-1 H-azepin-1 -yl)propyl]oxy}phenyl)ethanol A solution of 2-{4-[(3-chloropropyl)oxy]phenyl}ethanol (for example, as prepared for Intermediate 38) (14 g, 0.065 mol) in 2-butanone (200 ml) was treated with potassium carbonate (17.96 g, 0.13 mol), potassium iodide (1.24 g, 7.5 mmol), hexahydro-1H-azepine (commercially available, for example, from Aldrich) (14.71 ml, 0.1308 mol) and heated at 80 0C under nitrogen for 18 h. The cooled reaction mixture was diluted with water (300 ml), layers separated and the aqueous extracted with DCM (2 x 200 ml). The combined organic extracts were dried (MgSO4) and evaporated in vacuo to give a yellow oil (23 g). A portion of this (10 g) was purified by Flashmaster Il (100 g silica cartridge), eluted with 0 - 100% EtOAc-cyclohexane over 15 min, then 100% EtOAc for 10 min, then 0 - 10% (10% aq. ammonia-MeOH)-DCM for 15 min, then 10% of (10% aq. ammonia-MeOH) - DCM for 10 min to give the title compound (5.3 g). LCMS RT = 1.9 min, ES+ve m/z 278 (M+H)+.
Intermediate 40
2-(4-{[3-(Hexahydro-1 H-azepin-1 -yl)propyl]oxy}phenyl)ethyl methanesulfonate 2-(4-{[3-(Hexahydro-1H-azepin-1-yl)propyl]oxy}phenyl)ethanol) (for example, as prepared for Intermediate 39) (273 mg, 0.98 mmol), was dissolved in DCM (5 ml) and treated with DIPEA (0.204 ml, 1.2 mmol) and mesyl chloride (0.093 ml, 1.2 mmol). The mixture was stirred at room temperature for 3 h. Further mesyl chloride (0.020 ml, 0.26 mmol) was added and stirring was continued for 45 min. Saturated aq. sodium hydrogen carbonate (10 ml) was added to the mixture. The layers were separated, and the aqueous was washed with further DCM. The combined DCM extracts were concentrated in vacuo to afford the title compound, which was used without further purification. LCMS RT = 2.18 min, ES+ve m/z 356 [M+H] +.
Intermediate 41 Methyl (2E)-3-[δ-(4-piperidinyloxy)-2-quinolinyl]-2-propenoate
A solution of methyl (2E)-3-(8-hydroxy-2-quinolinyl)-2-propenoate (Intermediate 25 in WO2007/135081 A1 ) (1.396 g, 6.1 mmol), ferf-butyl 4-hydroxy-1-piperidinecarboxylate (commercially available, for example, from Aldrich) (1.472 g, 7.32 mmol) and triphenylphosphine (1.918 g, 7.32 mmol) in DCM (25 ml) was treated with di-ferf-butyl azodicarboxylate (commercially available, for example, from Aldrich) (1.685 g, 7.32 mmol) and the mixture was stirred at room temperature overnight. Further quantities of ferf-butyl 4-hydroxy-1-piperidinecarboxylate (614 mg, 3.05 mmol), triphenylphosphine (800 mg, 3.05 mg) and di-ferf-butyl azodicarboxylate (702 mg, 3.05 mmol) were added and the mixture was stirred for 3 hours. Evaporation of the solvent from the mixture gave a residue that was dissolved in MeOH and applied to a MeOH-conditioned SCX ion- exchange SPE cartridge (20 g). The cartridge was eluted with MeOH, followed by 2M ammonia in MeOH. Evaporation of the solvent from the ammoniacal fractions gave a residue that was dissolved in DCM (50 ml) and treated with trifluoroacetic acid (15 ml). The mixture was stirred at room temperature for 15 minutes. Evaporation of the mixture gave a residue that was dissolved in MeOH and applied to a MeOH-conditioned SCX ion-exchange SPE cartridge (20 g). The cartridge was eluted with MeOH, followed by 2M ammonia in MeOH. Evaporation of the solvent from the ammoniacal fractions gave a residue that was purified by Flashmaster Il on a silica column (100 g) eluting with a 0-30% MeOH in DCM (containing 1 % triethylamine) gradient. The solvent was evaporated from appropriate fractions to afford the title compound (1.29 g). LCMS RT= 2.17 min, ES+ve m/z 313 [M+H]+. Intermediate 42 Methyl 3-[δ-(4-piperidinyloxy)-2-quinolinyl]propanoate
A solution of methyl (2E)-3-[8-(4-piperidinyloxy)-2-quinolinyl]-2-propenoate (for example, as prepared for Intermediate 41 ) (860 mg, 2.75 mmol) in ethyl acetate (20 ml) was hydrogenated at 1 atm in the presence of 10% palladium on carbon (300 mg) for 1.5 hours. The reaction mixture was filtered through celite and the filtrate was evaporated to give a residue that was purified by flash column chromatography on silica eluting with 10% (2M ammonia in MeOH) in DCM. The solvent was evaporated from appropriate fractions to give the title compound (375 mg). LCMS RT= 1.89 min, ES+ve m/z 315 [M+H]+.
Intermediates 43 and 44 outlined below were prepared in a similar manner to 8-({1 -[2-(4-{[3- (Hexahydro-1H-azepin-1-yl)propyl]oxy}phenyl)ethyl]-4-piperidinyl}oxy) quinoline (Example 1A, step (a)).
In general, Intermediates 43 and 44 were prepared from the appropriate amine and 2-(4-{[3- (Hexahydro-1 H-azepin-1 -yl)propyl]oxy}phenyl)ethyl methanesulfonate (for example, as prepared for Intermediate 40) in acetonitrile, and in the presence of sodium bicarbonate at 8O0C for an appropriate numbers of days.
Intermediate 43
Methyl 3-[8-({1 -[2-(4-{[3-(hexahydro-1 H-azepin-1 -yl)propyl]oxy}phenyl)ethyl]-4- piperidinyl}oxy)-2-quinolinyl]propanoate
Prepared from methyl 3-[8-(4-piperidinyloxy)-2-quinolinyl]propanoate (for example, as prepared for Intermediate 42) (53 mg, 0.17 mmol) and 2-(4-{[3-(hexahydro-1 H-azepin-1 - yl)propyl]oxy}phenyl)ethyl methanesulfonate (for example, as prepared for Intermediate 40) (60 mg, 0.17 mmol). Purification by flash column chromatography on silica using 5% (2M ammonia in MeOH) in DCM gave the title compound (46 mg). LCMS RT= 2.17 min, ES+ve m/z 574 [M+H]+.
Intermediate 44 Methyl 3-(8-{[1-(2-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}ethyl)-4-piperidinyl] oxy}-2- quinolinyl)propanoate
From methyl 3-[8-(4-piperidinyloxy)-2-quinolinyl]propanoate (for example, as prepared for Intermediate 42) (45 mg, 0.14 mmol) and 2-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}ethyl methanesulfonate (Intermediate 56 in WO2007/122156A1 ) (50 mg, 0.14 mmol). Purification by flash column chromatography on silica using 5% (2M ammonia in MeOH) in DCM gave the title compound (44 mg). LCMS RT= 2.20 min, ES+ve m/z 572 [M+H]+.
Intermediate 45
1,1-Dimethylethyl 4-[(5-fluoro-δ-quinolinyl)oxy]-1-piperidinecarboxylate A stirring solution of 5-fluoro-8-quinolinol (commercially available, for example, from TCI) (1 g, 6.13 mmol), triphenylphosphine (1.608 g, 6.13 mmol) and ferf-butyl 4-hydroxy-i-piperidinecarboxylate (commercially available, for example, from Aldrich) (1.1 11 g, 5.52 mmol) in DCM (22 ml) was treated with diisopropyl azodicarboxylate (1.207 ml, 6.13 mmol) and the resulting mixture was stirred at ambient temperature under a nitrogen atmosphere for -20 h. The solvent was evaporated giving a residue that was purified on a Flashmaster Il using a silica cartridge (100 g) and a 5-50% EtOAc in cyclohexane gradient over 60 minutes. Evaporation of the solvent from appropriate fractions gave a crude sample of the title compound (453 mg). LCMS RT= 3.23 min, ES+ve m/z 347 [M+H]+.
Intermediate 46
5-Fluoro-δ-(4-piperidinyloxy)quinoline
A solution of 1 ,1-dimethylethyl 4-[(5-fluoro-8-quinolinyl)oxy]-1-piperidinecarboxylate (for example, as prepared for Intermediate 45) (450 mg, 1.3 mmol) in DCM (20 ml) was treated with trifluoroacetic acid (5 ml) and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 h. The mixture was evaporated giving a residue that was treated with toluene and re-evaporated. The residue was dissolved in MeOH and loaded onto a MeOH- conditioned SCX ion-exchange SPE cartridge (20 g). The cartridge was eluted with MeOH and then 2M ammonia in MeOH solution. Evaporation of the solvent from the ammoniacal eluent gave a crude sample of the title compound (393 mg). LCMS RT= 1.88 min, ES+ve m/z 247 [M+H]+.
Intermediate 47 5-Bromo-δ-fluoroquinoline
A mixture of 5-bromo-2-fluoroaniline (commercially available, for example, from Fluorochem) (21.45 g, 113 mmol) and 6M hydrochloric acid (90 ml) at -50 0C was treated with toluene (150 ml). The mixture was warmed to -60 0C and acrolein (15.1 ml, 226 mmol) was added slowly over 20 min.
The mixture was then heated at reflux for 1 h 45 min. The cooled mixture was made alkaline with
1OM NaOH aq and extracted with EtOAc. The extracts were washed with brine, dried and evaporated to give a brown oil that was purified by flash column chromatography on silica using mixtures of EtOAc and cyclohexane (1 :9 to 1 :6 ratio) as eluent. Evaporation of the solvent from appropriate fractions gave the title compound (6.69 g). LCMS RT= 2.84 min, ES+ve m/z 226/228
[M+H]+.
Intermediate 48 1,1-Dimethylethyl 4-[(5-bromo-δ-quinolinyl)oxy]-1-piperidinecarboxylate and 1,1- dimethylethyl 4-(δ-quinolinyloxy)-1-piperidinecarboxylate (55:45 mixture)
A stirring solution of t-butyl 4-hydroxy-1-piperidinecarboxylate (commercially available, for example, from Aldrich) (1.7817 g, 13.275 mmol) in NMP (8 ml) was treated portion-wise with NaH (531 mg of
60% dispersion in mineral oil, 4.65 mmol). After effervescence had ceased, 5-bromo-8- fluoroquinoline (for example, as prepared for Intermediate 47) (2 g, 8.85 mmol) was added and the mixture was heated at 80 0C for 64 h. The mixture was partitioned between EtOAc and water and the organic layer was washed with water (twice) and brine, dried over anhydrous magnesium sulphate and evaporated to give a brown oil. This material was purified by Flashmaster Il on a silica cartridge (100 g) using a 0-100% EtOAc in DCM gradient over 60 min. Evaporation of the solvent from appropriate fractions gave a 55:45 mixture of the title compounds. LCMS RT= 3.47 min and 2.76 min, ES+ve m/z 407/409 [M+H]+ and 329 [M+H]+.
Intermediate 49 5-(Phenylmethyl)-δ-(4-piperidinyloxy)quinoline A mixture of 1 ,1-dimethylethyl 4-[(5-bromo-8-quinolinyl)oxy]-1-piperidinecarboxylate/1 ,1- dimethylethyl and 4-(8-quinolinyloxy)-1-piperidine carboxylate (for example, as prepared for Intermediate 48) (580 mg of 55:45 mixture containing approx. 350 mg of 1 ,1-dimethylethyl 4-[(5- bromo-8-quinolinyl)oxy]-1-piperidinecarboxylate, 0.86 mmol) (for example, as prepared for Intermediate 48), potassium carbonate (237.5 mg, 1.7 mmol) and [1 ,1 '- bis(diphenylphosphino)ferrocene]dichloropalladium(ll) 1 :1 DCM complex (31.5 mg, 38.6 Dmol) was treated with 0.5M S-benzyl 9-BBN in THF (6 ml, 3 mmol). The resulting mixture was stirred at 65 0C under a nitrogen atmosphere overnight. Additional quantities of [1 ,1 '- bis(diphenylphosphino)ferrocene]dichloropalladium(ll) 1 :1 DCM complex (24 mg, 29.4 μmol) and 0.5M β-benzyl 9-BBN in THF (2 ml) were added and the mixture was heated at 65 0C for 1 h. The solvent was evaporated from the reaction mixture giving a residue that was dissolved in anhydrous DCM (35 ml) and treated with trifluoroacetic acid (6 ml). The mixture was stirred at ambient temperature under a nitrogen atmosphere until LCMS showed no BOC-protected material remained. The solvent was evaporated giving a residue that was loaded onto a SCX ion-exchange SPE cartridge (10 g). The cartridge was eluted with MeOH (5 column volumes) followed by 2M ammonia in MeOH (10 column volumes). Evaporation of the solvent from the ammoniacal eluent afforded a crude sample of the title compound (397.8 mg). LCMS RT= 2.23 min, ES+ve m/z 319 [M+H]+.
Intermediate 50 δ-Fluoro-5-methylquinoline
Toluene (160 ml) was added to a suspension of 2-fluoro-5-methylaniline (commercially available, for example, from Aldrich) (15 g, 120 mmol) in 6M hydrochloric acid (100 ml) and the mixture was heated to -70 0C. Acrolein (16 ml, 240 mmol) was added over 12 min and the resulting mixture was stirred at reflux for a further 2 h 40 min. The cooled mixture was adjusted to pH 9 with 10M NaOH aq and then extracted with EtOAc. The aqueous phase was further extracted with EtOAc and the combined extracts were washed with brine, dried and evaporated to give a brown oil. This material was purified by flash column chromatography on silica eluting with 10-25% EtOAc in cyclohexane. Evaporation of the solvent from appropriate fractions gave the title compound (7.2 g). LCMS RT= 2.51 min, ES+ve m/z 162 [M+H]+. Intermediate 51 5-Methyl-8-(4-piperidinyloxy)quinoline
A stirring solution of t-butyl 4-hydroxy-i-piperidinecarboxylate (commercially available for example from Aldrich) (624.3 mg, 3.1 mmol) in NMP (3 ml) was treated portionwise with NaH (186 mg of 60% dispersion in mineral oil, 4.65 mmol). After effervescence had ceased, 8-fluoro-5- methylquinoline (for example, as prepared for Intermediate 50) (500 mg, 3.1 mmol) was added and the mixture was heated at 80 0C for 64 h. The mixture was partitioned between DCM and water. The organic layer was washed with water and brine (twice), dried over anhydrous Na2SO4 and evaporated to give a brown oil. This material was dissolved in DCM (30 ml), treated with trifluoroacetic acid (5 ml) and stirred under a nitrogen atmosphere. Evaporation of the solvent gave a residue that was purified on a SCX ion-exchange SPE cartridge (50 g) eluting with MeOH (2 column volumes) and then 2M ammonia in MeOH (2 column volumes). The solvent was evaporated from the ammoniacal eluent giving a residue that was further purified by flash column chromatography on a silica cartridge (70 g) using a 10-20% (2M ammonia in MeOH) in DCM gradient. Evaporation of the solvent from one set of appropriate fractions gave the title compound (393.7 mg). LCMS ES+ve m/z 243 [M+H]+. Evaporation of the solvent from a further set of appropriate fractions gave the title compound (154 mg). LCMS ES+ve m/z 243 [M+H]+.
Intermediate 52 δ-Fluoro-3-methylquinoline
Toluene (45 ml) and 2-methyl-2-propenal (commercially available, for example, from Aldrich) (8.25 ml, 100 mmol) were added to a solution of 2-fluoroaniline (commercially available, for example, from Aldrich) (3.86 ml, 40 mmol) in 5M hydrochloric acid (160 ml) and the mixture was stirred at 1000C overnight. The mixture was allowed to cool to room temperature and the layers were separated. The aqueous layer was neutralised with 10M sodium hydroxide and extracted with DCM. The extracts were washed with brine, dried over anhydrous Na2SO4, filtered and evaporated. The residue was dissolved in DCM and loaded onto 2 silica SPE cartridges (100 g). The cartridges were eluted with DCM (5 x 50 ml) and then EtOAc (5 x 50 ml). Evaporation of the solvent from the combined EtOAc fractions gave a residue that was dissolved in MeOH and loaded onto 2 SCX-2 ion-exchange SPE cartridges (70 g). The cartridges were washed well with MeOH and then 2M ammonia in MeOH. Evaporation of the solvent from the combined ammoniacal fractions gave a residue that was further purified by Flashmaster Il using a silica column (100 g) and a 0-100% EtOAc in cyclohexane gradient. The solvent was evaporated from appropriate fractions to afford the title compound (2.94 g). LCMS RT= 2.54 min, ES+ve m/z 162 [M+H]+.
Intermediate 53
1 ,1 -Dimethylethyl 4-[(3-methyl-8-quinolinyl)oxy]-1 -piperidinecarboxylate
Prepared in a manner similar to the one described for 1 ,1 -Dimethylethyl 4-[(6-ethyl-8- quinolinyl)oxy]-1 -piperidinecarboxylate (Intermediate 15) from 8-fluoro-3-methylquinoline (for example, as prepared for Intermediate 52) (500 mg, 3.1 mmol) and fert-butyl 4-hydroxy-1- piperidinecarboxylate (commercially available, for example, from Aldrich) (624 mg, 3.1 mmol) to give the title compound (750 mg). LCMS RT= 2.83 min, ES+ve m/z 343 [M+H]+.
Intermediate 54 3-Methyl-8-(4-piperidinyloxy)quinoline
A solution of 1 ,1-dimethylethyl 4-[(3-methyl-8-quinolinyl)oxy]-1-piperidinecarboxylate (for example, as prepared for Intermediate 53) (750 mg, 2.19 mmol) in DCM (30 ml) was treated with trifluoroacetic acid (5 ml) and the mixture was stirred at room temperature for 30 minutes. Evaporation of the reaction mixture gave a residue that was purified by Flashmaster Il on a silica column (50 g) using a 0-30% MeOH in DCM (containing 1 % triethylamine) gradient. The solvent was evaporated from appropriate fractions to afford the title compound (345 mg). LCMS RT= 1.64 min, ES+ve m/z 243 [M+H]+.
Intermediate 55 3-Ethyl-δ-fluoroquinoline
A mixture of 8-fluoro-3-iodoquinoline (commercially available, for example, from ACES Pharma Inc) (2 g, 7.32 mmol), potassium carbonate (2.02 g, 14 64 mmol) and [1 ,1 '- bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (133 mg, 2.5 mol%) in DMF (4 ml) was treated with triethylborane (15 ml of 1 M solution in THF, 15 mmol) and the resulting reaction mixture was stirred at 6O0C for 18 h. Additional quantities of [1 ,1 '- bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (50 mg) and triethylborane (3.7 ml of 1 M solution in THF, 3.7 mmol) were added and the mixture was stirred at 6O0C for a further 16 h. The cooled mixture was diluted with EtOAc (100 ml) washed with brine (100 ml) and extracted with 5N hydrochloric acid. The acidic extracts were washed with diethyl ether (70 ml), basified to pH 10-11 with 10N sodium hydroxide and then extracted with EtOAc (2 x 100 ml). The extract was dried over anhydrous magnesium sulphate, filtered and evaporated to give a residue. This material was purified on 2 silica SPE cartridges (70 g) eluting with 50% cyclohexane in DCM, 10% cyclohexane in DCM and finally 100% DCM. Evaporation of the solvent from appropriate fractions gave the title compound (900 mg). LCMS RT= 2.8 min, ES+ve m/z 176 [M+H]+.
Intermediate 56
3-Ethyl-8-(4-piperidinyloxy)quinoline
Sodium hydride (153 mg of 60% dispersion in mineral oil) was added portion-wise to a solution of fert-butyl 4-hydroxy-1 -piperidinecarboxylate (commercially available, for example, from Aldrich) (513 mg, 2.55 mmol) in NMP (4 ml) and the resulting mixture was stirred at room temperature for 10 minutes. A solution of 3-ethyl-8-fluoroquinoline (for example, as prepared for Intermediate 55) (447 mg, 2.55 mmol) in NMP (2 ml) was then added and the mixture stirred at 8O0C overnight. The reaction mixture was treated with ammonium chloride solution and extracted with DCM. The organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered and evaporated. The residue was loaded onto an SCX-2 ion-exchange SPE cartridge (20 g) and the cartridge was washed well with MeOH followed by 2M ammonia in MeOH. Evaporation of the solvent from the ammoniacal eluent gave a residue that was dissolved in DCM (30 ml) and treated with trifluoroacetic acid (10 ml). The mixture was stirred at room temperature for 10 minutes then evaporated. The residue was loaded onto an SCX-2 ion-exchange SPE cartridge (20 g) and the cartridge was washed well with MeOH followed by 2M ammonia in MeOH. Evaporation of the solvent from the ammoniacal eluent afforded the title compound (639 mg). LCMS RT= 1.84 min, ES+ve m/z 257 [M+H]+.
Intermediate 57 Ethyl [4-(hydroxymethyl)phenyl]acetate
To a solution of [4-(hydroxymethyl)phenyl]acetic acid (commercially available, for example, from Aldrich) (15.4 g, 93 mmol) in DMSO (150 ml) was added potassium carbonate (15.4 g, 11 1 mmol), followed by iodoethane (8.2 ml, 102 mmol). The mixture was heated at 75 0C for 70 min. The cooled mixture was filtered through celite and the filtrate was partitioned between water (500 ml) and diethyl ether (200 ml). The aqueous phase was extracted with diethyl ether (3 x 100 ml) and the combined organic solutions were washed with brine, dried and evaporated to give an oil. The material was purified by flash column chromatography on silica eluting initially with 1 :3 EtOAc- cyclohexane and then 1 :2 EtOAc-cyclohexane. The solvent was evaporated from appropriate fractions to give the title compound (16.83 g). LCMS RT= 2.34 min, ES+ve m/z 195 [M+H]+.
Intermediate 58
Ethyl (4-formylphenyl)acetate
Activated manganese dioxide (25.8 g, 297 mmol) was added to ethyl [4-
(hydroxymethyl)phenyl]acetate (for example, as prepared for Intermediate 57) (14.39 g, 74 mmol) in anhydrous DCM (170 ml) and the mixture was heated for -19 h. The mixture was filtered through celite and the filtrate was evaporated to give an oil. This material was purified by flash column chromatography on silica eluting initially with 1 :8 EtOAc-cyclohexane and then 2:15 EtOAc- cyclohexane. The solvent was evaporated from appropriate fractions to give the title compound (8.3 g). LCMS RT= 2.61 min, ES+ve m/z 193 [M+H]+.
Intermediate 59
Ethyl [4-(1 -pyrrolidinylmethyl)phenyl]acetate
To ethyl (4-formylphenyl)acetate (for example, as prepared for Intermediate 58) (7.74 g, 40.3 mmol) in anhydrous DCM (75 ml) was added pyrrolidine (3.56 ml, 40.3 mmol) followed by acetic acid (2.3 ml, 40.3 mmol). After 2 min, sodium triacetoxyborohydride (12.8 g, 60.5 mmol) was added and the mixture was stirred at ambient temperature for 1 h. The reaction mixture was quenched with H2O (50 ml) and extracted with DCM. The aqueous phase was adjusted to pH 7-8 with sodium bicarbonate solution and then extracted with more DCM. The combined organic extracts were washed with sodium bicarbonate solution and brine, dried and evaporated to give the title compound (10.18 g). LCMS RT= 1.82 min, ES+ve m/z 248 [M+H]+. Intermediate 60
[4-(1-Pyrrolidinylmethyl)phenyl]acetic acid, hydrochloride salt
A solution of ethyl [4-(1-pyrrolidinylmethyl)phenyl]acetate (for example, as prepared for Intermediate 59) (4.28 g, 17.3 mmol) in EtOH (10 ml) was treated with 2M NaOH aq (26 ml, 52 mmol) and the mixture was stirred for 15 min. The EtOH was evaporated from the mixture and the remaining aqueous solution was adjusted to pH2 using a combination of c.HCI aq and 2M HCI aq. The solution was split into two and each aliquot was loaded onto a conditioned (MeOH then H2O) Oasis cartridge (6 g). The cartridges were each eluted with H2O (3 x 10 ml), 20% MeOH in H2O (20 ml), MeOH (2 x 20 ml) and finally 20:1 MeOH-AcOH (21 ml). Appropriate eluent fractions from each Oasis cartridge were combined and the EtOH was evaporated. The remaining aqueous solution was freeze-dried to give a white solid. This material was stirred vigorously in acetone (-150 ml) and the resulting suspension was filtered. Evaporation of the solvent from the filtrate gave a sample of the title compound (0.49 g). LCMS RT= 0.83 min, ES+ve m/z 220 [M+H]+. The collected solid was stirred with MeOH. The mixture was filtered and the filtrate was evaporated to give an additional sample of the title compound (3 g). LCMS RT= 0.76 min, ES+ve m/z 220 [M+H]+.
Intermediate 61 8-[(1-{[4-(1-Pyrrolidinylmethyl)phenyl]acetyl}-4-piperidinyl)oxy]quinoline A mixture of 8-(4-piperidinyloxy)quinoline (commercially available, for example, from Matrix Scientific) (75 mg, 0.33 mmol), [4-(1-pyrrolidinylmethyl)phenyl]acetic acid hydrochloride salt (for example, as prepared for Intermediate 60) (84 mg, 0.33 mmol), TBTU (127 mg, 0.395 mmol) and PS-DIPEA resin (400 mg of 3.88 mmol/g loading) in DCM (3 ml) was shaken in a closed vial at ambient temperature for 2 h. The mixture was filtered and the filtrate was evaporated to give a residue that was applied to an SCX ion-exchange SPE cartridge (5 g). The cartridge was eluted with MeOH followed by 2M ammonia in MeOH. Evaporation of the ammoniacal eluent gave a sample of the title compound (97 mg). LCMS RT= 1.90 min, ES+ve m/z 430 [M+H]+.
Intermediate 62 8-({1 -[(4-{[3-(Hexahydro-1 H-azepin-1 -yl)propyl]oxy}phenyl)acetyl]-4- piperidinyl}oxy)quinoline
A solution of 8-(4-piperidinyloxy)quinoline (commercially available, for example, from Matrix Scientific) (1.0139 g, 4.44 mmol), (4-{[3-(hexahydro-1 H-azepin-1-yl)propyl]oxy}phenyl)acetic acid hydrochloride (Intermediate 41 in WO2007/135081 A1 ) (1.4554 g, 4.44 mmol) and triethylamine (2.48 ml, 17.79 mmol) in DCM (30 ml) was treated with TBTU (1.5698 g, 4.88 mmol) and the mixture was stirred under a nitrogen atmosphere at ambient temperature for 45 min. The mixture was partitioned between DCM (50 ml) and dilute sodium bicarbonate solution (40 ml). The organic layer was washed with brine, dried over anhydrous Na2SO4 and evaporated to give a residue. This material was loaded onto a SCX ion-exchange SPE cartridge (20 g) which was eluted with MeOH (3 column volumes), followed by 2M ammonia in MeOH (3 column volumes). The solvent was evaporated from the ammoniacal eluent to afford a sample of the title compound (2.3428 g). LCMS RT= 2.19 min, ES+ve m/z 502 [M+H]+.
Intermediate 63 6-Bromo-2-methyl-δ-quinolinol
To a stirring suspension of 2-amino-5-bromophenol hydrochloride (commercially available, for example, from J&W Pharmlab) (18.27 g, 81.38 mmol) in 5N hydrochloric acid (325 ml) was added toluene (114 ml) and crotonaldehyde (20.08 ml, 244.14 mmol). The mixture was heated at 100 0C for 3 h. The cooled mixture was poured into a separating funnel and the layers were separated. The aqueous layer was neutralised with 10N sodium hydroxide solution, and then extracted with 3:1 chloroform/isopropanol (3 x 200 ml). The combined extracts were dried over anhydrous Na2SU4 and the solvent was evaporated to give a brown solid. The solid was dissolved in 1 :1 EtOAc/DCM and loaded onto a silica SPE cartridge (50 g). The cartridge was eluted with EtOAc. Evaporation of the solvent from the eluent gave a crude sample of the title compound (16.34 g). LCMS RT= 2.69 min, ES+ve m/z 238/240 [M+H]+.
Intermediate 64
1 ,1 -Dimethylethyl 4-[(6-bromo-2-methyl-δ-quinolinyl)oxy]-1 -piperidine carboxylate
To a stirring mixture of 6-bromo-2-methyl-8-quinolinol (for example, as prepared for Intermediate 63) (15.3 g, 64.3 mmol), ferf-butyl 4-hydroxy-1-piperidinecarboxylate (commercially available, for example, from Aldrich) (15.52 g, 77.1 1 mmol) and tributylphosphine (23.7 ml, 96.1 mmol) in anhydrous THF (320 ml) at 0 0C, was added portionwise, 1 ,1 '-(azodicarbonyl)dipiperidine (24.31 g,
96.34 mmol). The resulting mixture was stirred at O0C under a nitrogen atmosphere for 15 min and then at ambient temperature for a further 18 h. The mixture was filtered and the filtrate was evaporated to give a brown oil. This material was purified by flash column chromatography on a
Combiflash Companion XL system using a silica cartridge (1.5 kg) and a 0-50% EtOAc in cyclohexane gradient over 6 column volumes at 330 ml/min flow-rate. Evaporation of the solvent from appropriate fractions gave the title compound (13.4 g). LCMS RT= 3.46 min, ES+ve m/z
421/423 [M+H]+. Evaporation of the solvent from a further set of fractions gave an additional sample of the title compound (4.05 g). LCMS RT= 3.46 min, ES+ve m/z 421/423 [M+H]+.
Intermediate 65
1 ,1 -Dimethylethyl 4-[(6-bromo-2-formyl-δ-quinolinyl)oxy]-1 -piperidine carboxylate
To a stirring suspension of selenium dioxide (1.9 g, 17.1 mmol) in 1 ,4-dioxane (75 ml) at 55 0C under a nitrogen atmosphere was added, dropwise over 2 h, a solution of 1 ,1 -dimethylethyl 4-[(6- bromo-2-methyl-8-quinolinyl)oxy]-1-piperidinecarboxylate (for example, as prepared for Intermediate 64) (4 g, 9.5 mmol) in 1 ,4-dioxane (28 ml). The resulting mixture was then heated at 75 0C for -16 h. The mixture was filtered and the solvent was evaporated from the filtrate giving a residue that was dissolved in DCM and loaded onto a silica SPE cartridge (20 g). The cartridge was eluted with DCM. Evaporation of the solvent from appropriate fractions gave the title compound (3.2 g). LCMS RT= 3.62 min, ES+ve m/z 435/437 [M+H]+.
Intermediate 66 1,1 -Dimethylethyl 4-({6-bromo-2-[(1 £)-3-(methyloxy)-3-oxo-1 -propen-1 -yl]-8-quinolinyl}oxy)- 1-piperidinecarboxylate
A mixture of 1 ,1 -dimethylethyl 4-[(6-bromo-2-formyl-8-quinolinyl)oxy]-1-piperidinecarboxylate (for example, as prepared for Intermediate 65) (3.2 g, 7.36 mmol) and methyl (triphenylphosphoranylidene)acetate (commercially available, for example, from Aldrich) (3.69 g, 11.03 mmol) in anhydrous THF (45 ml) was heated at reflux for ~4 h. The solvent was evaporated from the cooled mixture giving a residue that was dissolved in toluene, loaded onto a silica cartridge (100 g) and purified by Flashmaster Il using a 0-100% EtOAc in cyclohexane gradient over 60 min. Evaporation of the solvent from appropriate fractions gave the title compound (2.804 g). LCMS RT= 3.80 min, ES+ve m/z 491/493 [M+H]+.
Intermediate 67
1 ,1 -Dimethylethyl 4-({6-bromo-2-[3-(methyloxy)-3-oxopropyl]-8-quinolinyl}oxy)-1 - piperidinecarboxylate
A solution of 1 ,1 -dimethylethyl 4-({6-bromo-2-[(1 E)-3-(methyloxy)-3-oxo-1 -propen-1 -yl]-8- quinolinyl}oxy)-1 -piperidinecarboxylate (for example, as prepared for Intermediate 66) (1.233 g, 2.51 mmol) in THF (12 ml) was treated with water (904 μl), followed by (triphenylphosphine)copper(l) hydride hexamer (commercially available, for example, from Acros Organics) (1.48 g, 0.755 mmol). The mixture was stirred at ambient temperature for 1.5 h. The mixture was filtered and the filtrate was evaporated to give a residue that was purified by flash column chromatography on silica using 20% EtOAc in 40-60 petroleum ether as eluent. Evaporation of the solvent from appropriate fractions gave the title compound (670 mg). LCMS RT= 3.64 min, ES+ve m/z 493/495 [M+H]+.
Intermediate 68 1,1 -Dimethylethyl 4-({6-butyl-2-[3-(methyloxy)-3-oxopropyl]-8-quinolinyl}oxy)-1 - piperidinecarboxylate
A mixture of 1 ,1 -dimethylethyl 4-({6-bromo-2-[3-(methyloxy)-3-oxopropyl]-8-quinolinyl}oxy)-1- piperidinecarboxylate (for example, as prepared for Intermediate 67) (670 mg, 1.36 mmol), [1 ,1 '- bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (80 mg, 0.109 mmol) and potassium carbonate (470 mg, 2.72 mmol) under a nitrogen atmosphere, was treated with 1 M tributylborane in THF (4 ml). The resulting mixture was stirred at 65 0C for 5 h. The solvent was evaporated and the residue was dissolved in EtOAc and loaded onto a silica SPE cartridge (20 g). The cartridge was eluted with additional EtOAc. Evaporation of the solvent from the eluent gave a brown residue that was dissolved in DCM and loaded onto an NH2 ion-exchange SPE cartridge (20 g). Elution of the cartridge with DCM and subsequent evaporation of the collected eluent gave a yellow oil. This material was further purified by flash column chromatography on silica using 20% EtOAc in 40-60 petroleum ether as the eluent. Evaporation of the solvent from appropriate fractions gave the title compound (425 mg). LCMS RT= 3.77 min, ES+ve m/z 471 [M+H]+.
Intermediate 69
Methyl 3-[6-butyl-δ-(4-piperidinyloxy)-2-quinolinyl]propanoate
A stirring solution of 1 ,1-dimethylethyl 4-({6-butyl-2-[3-(methyloxy)-3-oxopropyl]-8-quinolinyl}oxy)-1- piperidinecarboxylate (for example, as prepared for Intermediate 68) (425 mg, 0.9 mmol) in DCM (15 ml) was treated with trifluoroacetic acid (5 ml) and the resulting mixture was stirred at ambient temperature under a nitrogen atmosphere for 2 h. The mixture was evaporated giving a residue that was treated with toluene (5 ml) and re-evaporated. The residue was dissolved in MeOH and loaded onto a MeOH-conditioned NH2 ion-exchange SPE cartridge. Elution with MeOH and evaporation of the collected eluent gave the title compound (314 mg). LCMS RT= 2.39 min, ES+ve m/z 371 [M+H]+.
Intermediate 70
Methyl 3-[6-butyl-8-({1 -[(4-{[3-(hexahydro-1 H-azepin-1 -yl)propyl]oxy}phenyl) acetyl]-4- piperidinyl}oxy)-2-quinolinyl]propanoate
To a mixture of methyl 3-[6-butyl-8-(4-piperidinyloxy)-2-quinolinyl]propanoate (for example, as prepared for Intermediate 69) (97.3 mg, 0.26 mmol), TBTU (101 mg, 0.32 mmol) and (4-{[3- (hexahydro-1H-azepin-1-yl)propyl]oxy}phenyl)acetic acid hydrochloride (Intermediate 41 in WO2007/135081 A1 ) (112.5 mg, 0.226 mmol) in DCM (1 ml) was added triethylamine (147 μl, 1.05 mmol). The resulting mixture was stirred at ambient temperature for 2 h. The mixture was diluted with MeOH (1 ml) and loaded onto a MeOH-conditioned NH2 ion-exchange SPE cartridge (5 g). Elution with MeOH and evaporation of the collected eluent gave the title compound (165 mg). LCMS RT= 2.78 min, ES+ve m/z 644 [M+H]+.
Intermediate 71
Methyl 3-[6-butyl-8-({1 -[2-(4-{[3-(hexahydro-1 H-azepin-1 -yl)propyl]oxy}phenyl)ethyl]-4- piperidinyl}oxy)-2-quinolinyl]propanoate
A stirring solution of methyl 3-[6-butyl-8-({1-[(4-{[3-(hexahydro-1H-azepin-1- yl)propyl]oxy}phenyl)acetyl]-4-piperidinyl}oxy)-2-quinolinyl]propanoate (for example, as prepared for Intermediate 70) (165 mg, 0.26 mmol) in THF (0.35 ml) was treated with carbonylhydridotris(triphenylphosphine)rhodium(l) (7.1 mg, 7.73 μmol), followed by diphenylsilane (1 10 μl, 0.59 mmol). The mixture was stirred at ambient temperature for -21 h. Further quantities of carbonylhydridotris(triphenylphosphine)rhodium(l) (7.1 mg, 7.73 μmol) and diphenylsilane (1 10 μl, 0.59 mmol) were added and the mixture was stirred for 3 h. The mixture was diluted with MeOH (1 ml) and loaded onto a MeOH-conditioned SCX ion-exchange SPE cartridge (5 g). The cartridge was eluted with MeOH and then 2M ammonia in MeOH. Evaporation of the solvent from the ammoniacal eluent gave a crude sample of the title compound (153 mg). LCMS RT= 2.50 min, ES+ve m/z 630 [M+H]+.
Examples Example 1A
8-({1 -[2-(4-{[3-(Hexahydro-1 H-azepin-1 -yl)propyl]oxy}phenyl)ethyl]-4- piperidinyl}oxy)quinoline
Figure imgf000066_0001
Method a) A solution of 2-(4-{[3-(hexahydro-1 H-azepin-1-yl)propyl]oxy}phenyl)ethyl methanesulfonate (for example, as prepared for Intermediate 40) (100 mg, 0.28 mmol) in acetonitrile (2 ml) was treated with sodium bicarbonate (47 mg, 0.56 mmol) and 8-(4-piperidinyloxy)quinoline (commercially available, for example from Matrix Scientific) (64 mg, 0.28 mmol) at 8O0C overnight. The mixture was filtered, concentrated under reduced pressure, and the residue was purified by chromatography on silica using 5% (2M ammonia in MeOH) in DCM to give the title compound (64 mg). LCMS RT= 2.08 min, ES+ve m/z 488 [M+H]+.
Method b)
A mixture of 8-({1-[(4-{[3-(hexahydro-1 H-azepin-1-yl)propyl]oxy}phenyl)acetyl]-4- piperidinyl}oxy)quinoline (for example, as prepared for Intermediate 62) (1.176 g, 2.35 mmol), carbonylhydridotris(triphenylphosphine)rhodium(l) (20 mg, 1 mol%) and diphenylsilane (1 ml, 5.39 mmol) in THF (3 ml) was stirred at ambient temperature under a nitrogen atmosphere for 5 h. The mixture was diluted with MeOH (10 ml) and loaded onto a MeOH-conditioned SCX ion-exchange
SPE cartridge (20 g). The cartridge was eluted with MeOH and then 2M ammonia in MeOH. Evaporation of the solvent from the ammoniacal eluent gave a crude sample of the title compound
(1.114 g). This material was combined with another, similarly synthesised, crude sample of the title compound (93 mg). The material was purified by flash column chromatography on silica using 5%
(2M ammonia in MeOH) in DCM as the eluent. Evaporation of the solvent from an appropriate set of eluent fractions gave the title compound (278 mg). LCMS RT= 1.93 min, ES+ve m/z 488 [M+H]+. Evaporation of the solvent from an additional set of eluent fractions gave a residue that was further purified by flash column chromatography on silica using 3-5% (2M ammonia in MeOH) in CHCI3 as the eluent. Evaporation of the solvent from appropriate fractions gave the title compound (462 mg). LCMS RT= 1.93 min, ES+ve m/z 488 [M+H]+.
Example 1B
8-({1 -[2-(4-{[3-(Hexahydro-1 H-azepin-1 -yl)propyl]oxy}phenyl)ethyl]-4- piperidinyl}oxy)quinoline formic acid salt
Figure imgf000067_0001
A solution of 8-({1-[(4-{[3-(hexahydro-1 H-azepin-1-yl)propyl]oxy}phenyl)acetyl]-4- piperidinyl}oxy)quinoline (for example, as prepared for Intermediate 62) (500 mg, 1 mmol) in anhydrous THF (2 ml) was added to stirring 1.0M LiAIH4 in THF (4 ml, 4 mmol)) at O0C. The mixture was stirred under a nitrogen atmosphere at 0 0C for 15 min and at ambient temperature for a further -20 h. The reaction was quenched by the cautious addition of H2O (1 ml) and saturated sodium bicarbonate solution (1 ml). The mixture was extracted with DCM and the extracts were washed with brine, dried over anhydrous Na2SO4 and evaporated to give a solid. Purification of this material by MDAP gave a sample of the title compound (130 mg). LCMS RT= 1.94 min, ES+ve m/z 488 [M+H]+.
Examples 2-19
The compounds outlined in Table 1 below were prepared in a similar manner to 8-({1 -[2-(4-{[3- (Hexahydro-1H-azepin-1-yl)propyl]oxy}phenyl)ethyl]-4-piperidinyl}oxy) quinoline (Example 1A, step (a)).
In general, the compounds exemplified in the table below were prepared from the appropriate amine and 2-(4-{[3-(Hexahydro-1H-azepin-1-yl)propyl]oxy}phenyl)ethyl methanesulfonate (for example, as prepared for Intermediate 40) in acetonitrile, and in the presence of sodium bicarbonate at 8O0C for an appropriate numbers of days.
Examples 20-21
The compounds outlined in Table 2 below were prepared in a similar manner to 8-({1 -[2-(4-{[3- (Hexahydro-1H-azepin-1-yl)propyl]oxy}phenyl)ethyl]-4-piperidinyl}oxy) quinoline (Example 1A, step (a)). In general, the compounds exemplified in the table below were prepared from the appropriate amine and 2-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}ethyl methanesulfonate (Intermediate 56 in WO2007/122156A1 ) in acetonitrile, and in the presence of sodium bicarbonate at 8O0C for an appropriate numbers of days.
Figure imgf000069_0001
Figure imgf000070_0001
Figure imgf000071_0001
Figure imgf000072_0001
Figure imgf000073_0001
Figure imgf000074_0001
Figure imgf000075_0001
Example 22
3-[6-Butyl-8-({1 -[2-(4-{[3-(hexahydro-1 H-azepin-1 -yl)propyl]oxy}phenyl)ethyl]-4- piperidinyl}oxy)-2-quinolinyl]propanoic acid, formic acid salt
Figure imgf000076_0001
A solution of methyl 3-[6-butyl-8-({1-[2-(4-{[3-(hexahydro-1 H-azepin-1- yl)propyl]oxy}phenyl)ethyl]-4-piperidinyl}oxy)-2-quinolinyl]propanoate (for example, as prepared for Intermediate 71 ) (153 mg, 0.24 mmol) in MeOH (1 ml) was treated with 2M NaOH aq (0.5 ml) and the resulting mixture was heated at 60 0C for ~2 h. Formic acid (80 μl) was added and the volume was adjusted to 3 ml with DMSO. The mixture was then purified by MDAP in 3 x 1 ml injections. Evaporation of the solvent from appropriate fractions gave the title compound (31.9 mg). LCMS RT= 2.43 min, ES+ve m/z 616.5 [M+H]+.
Example 23
3-(8-{[1-(2-{4-[(1-Cyclobutyl-4-piperidinyl)oxy]phenyl}ethyl)-4-piperidinyl]oxy}-2- quinolinyl)propanoic acid formic acid salt
Figure imgf000076_0002
Prepared from Methyl 3-(8-{[1-(2-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}ethyl)-4- piperidinyl]oxy}-2-quinolinyl)propanoate (for example, as prepared for Intermediate 44) (44mg, 0.08 mmol) in a similar manner to that described for the preparation of 3-[6-Butyl-8-({1-[2-(4- {[3-(hexahydro-1 H-azepin-1-yl)propyl]oxy}phenyl)ethyl]-4-piperidinyl}oxy)-2- quinolinyl]propanoic acid, formic acid salt (Example 22). Purification by MDAP gave the title compound (24mg). LCMS RT = 2.00 min, ES+ve m/z 558 [M+H]=.
Example 24
3-[8-({1 -[2-(4-{[3-(Hexahydro-1 H-azepin-1 -yl)propyl]oxy}phenyl)ethyl]-4-piperidinyl}oxy)-
2-quinolinyl]propanoic acid formic acid salt
Figure imgf000077_0001
A solution of methyl 3-[8-({1-[2-(4-{[3-(hexahydro-1 H-azepin-1-yl)propyl]oxy}phenyl)ethyl]-4- piperidinyl}oxy)-2-quinolinyl]propanoate (for example, as prepared for Intermediate 43) (46 mg, 0.08 mmol) in MeOH (5 ml) was treated with 2M NaOH aq (160 μl, 0.32 mmol) and the mixture was stirred at 7O0C for 5 hours. The mixture was then treated with 2M HCI aq (160 μl, 0.32 mmol), filtered (5 μ PTFE filter tube) and purified by MDAP. Evaporation of the solvent from appropriate fractions gave the title compound (16 mg). LCMS RT= 2.07 min, ES+ve m/z 560 [M+H]+.
Example 25 δ-[(1 -{2-[4-(1 -Pyrrolidinylmethyl)phenyl]ethyl}-4-piperidinyl)oxy]quinoline formic acid salt
Figure imgf000077_0002
A stirring solution of 8-[(1-{[4-(1-pyrrolidinylmethyl)phenyl]acetyl}-4-piperidinyl)oxy]quinoline (for example, as prepared for Intermediate 61 ) (97 mg, 0.226 mmol) and carbonylhydridotris(triphenylphosphine)rhodium(l) (2 mg, 1 mol%) in THF (0.35 ml) was treated with diphenylsilane (0.105 ml, 0.565 mmol) and the mixture was stirred in a sealed vial at ambient temperature for -23 h. The mixture was diluted with MeOH (2 ml) and loaded onto a MeOH-conditioned SCX ion-exchange SPE cartridge (2 g). The cartridge was eluted with MeOH, followed by 2M NH3 in MeOH. Evaporation of the ammoniacal eluent gave a residue that was dissolved in 1 :1 DMSO/MeOH (1 ml) and purified by MDAP. The solvent was evaporated from appropriate fractions to give a sample of the title compound (57 mg). LCMS RT= 1.68 min, ES+ve m/z 416 [M+H]+.
Example 26 5-Chloro-8-({1 -[2-(4-{[3-(hexahydro-1 H-azepin-1 -yl)propyl]oxy}phenyl)ethyl]-4- piperidinyl}oxy)quinoline
Figure imgf000078_0001
A stirring mixture of 5-chloro-8-quinolinol (commercially available, for example, from Aldrich) (3 g, 16.7 mmol), ferf-butyl 4-hydroxy-1-piperidinecarboxylate (2.802 g, 13.92 mmol) and triphenylphosphine (4.38 g, 16.7 mmol) in DCM (60 ml) was treated with diisopropyl azodicarboxylate (3.29 ml, 16.7 mmol) and the resulting reaction mixture was stirred at ambient temperature under a nitrogen atmosphere for 5 h. The solvent was evaporated giving a residue that was dissolved in MeOH and loaded onto an SCX ion-exchange cartridge (50 g). The cartridge was eluted with MeOH, followed by 2M ammonia in MeOH. Evaporation of the ammoniacal eluent gave a residue that was dissolved in DCM (50 ml) and treated with TFA (15 ml). The mixture was stirred for 1 h then evaporated giving a residue that was suspended in toluene and then re-evaporated. The resulting residue was dissolved in MeOH and loaded onto an SCX ion-exchange SPE cartridge (50 g). The cartridge was eluted with MeOH followed by 2M ammonia in MeOH. Evaporation of the ammoniacal eluent gave a brown residue (3.505 g). A sample of this material (78.6 mg), sodium bicarbonate (50 mg, 0.6 mmol) and 2-(4-{[3-(hexahydro-1 H-azepin-1-yl)propyl]oxy}phenyl)ethyl methanesulfonate (for example, as prepared for Intermediate 40) (106.5 mg, 0.3 mmol) in acetonitrile (2 ml) was heated at 8O0C under a nitrogen atmosphere for -65 h. The reaction mixture was filtered and the filtrate was evaporated to give a residue that was dissolved in 1 :1 DMSO/MeOH (1 ml) and purified by MDAP. The solvent was evaporated from appropriate fractions to give a sample of the title compound (40 mg). LCMS RT= 2.30 min, ES+ve m/z 522 [M+H]+.
Biological Data
The compounds of the invention may be tested for in vitro and/or in vivo biological activity in accordance with the following or similar assays.
H1 receptor cell line generation and FLIPR assay protocol
1. Generation of histamine H1 cell line
The human H1 receptor is cloned using known procedures described in the literature [Biochem. Biophys. Res. Commun., 201 (2):894 (1994)]. Chinese hamster ovary (CHO) cells stably expressing the human H1 receptor are generated according to known procedures described in the literature [Br. J. Pharmacol., 117(6):1071 (1996)].
Histamine H1 functional antagonist assay: Determination of functional pKi values
The histamine H1 cell line is seeded into non-coated black-walled clear bottom 384-well tissue culture plates in alpha minimum essential medium (Gibco/lnvitrogen, cat no. 22561-021 ), supplemented with 10% dialysed foetal calf serum (Gibco/lnvitrogen cat no. 12480-021 ) and 2 rtiM L-glutamine (Gibco/lnvitrogen cat no 25030-024) and is maintained overnight at 5% CO2, 37 0C.
Excess medium is removed from each well to leave 10 μl. 30 μl loading dye (250 μM Brilliant Black, 2 μM Fluo-4 diluted in Tyrodes buffer + probenecid (145 rtiM NaCI, 2.5 rtiM KCI, 10 rtiM HEPES, 10 rtiM D-glucose, 1.2 rtiM MgCI2, 1.5 rtiM CaCI2, 2.5 rtiM probenecid, pH adjusted to 7.40 with NaOH 1.0 M)) is added to each well and the plates are incubated for 60 min at 5% CO2, 37 0C.
10 μl of test compound, diluted to the required concentration in Tyrodes buffer + probenecid (or 10 μl Tyrodes buffer + probenecid as a control) is added to each well and the plate is incubated for 30 min at 37 0C, 5% CO2. The plates are then placed into a FLIPR™ (Molecular Devices, UK) to monitor cell fluorescence (λex = 488 nm, λEM = 540 nm) in the manner described in Sullivan et al., (In: Lambert DG (ed.), Calcium Signaling Protocols, New Jersey: Humana Press, 1999, 125-136) before and after the addition of 10 μl histamine at a concentration that results in the final assay concentration of histamine being ECβo- Functional antagonism is indicated by a suppression of histamine induced increase in fluorescence, as measured by the FLIPR™ system (Molecular Devices). By means of concentration effect curves, functional affinities are determined using standard pharmacological mathematical analysis.
Histamine H1 functional antagonist assay: Determination of antagonist pA2 and duration The histamine H1 receptor expressing CHO cells are seeded into non-coated black-walled clear bottom 96-well tissue culture plates as described above.
Following overnight culture, growth medium is removed from each well, washed with 200 μl PBS and is replaced with 50 μl loading dye (250 μM Brilliant Black, 1 μM Fluo-4 diluted in Tyrodes buffer + probenecid (145 rtiM NaCI, 2.5 rtiM KCI, 1OmM HEPES, 1OmM D-glucose, 1.2 rtiM MgCI2, 1.5 rtiM CaCI2, 2.5 rtiM probenecid, pH adjusted to 7.40 with NaOH 1.0 M)). Cells are incubated for 45 min at 37 0C. The loading buffer is removed and the cells are washed as above, and 90 μl of Tyrodes buffer + probenecid is added to each well. 10 μl of test compound, diluted to the required concentration in Tyrodes buffer + probenecid (or 10 μl Tyrodes buffer + probenecid as a control) is added to each well and the plate is incubated for 30 min at 37 0C, 5% CO2.
The plates are then placed into a FLIPR™ (Molecular Devices, UK) to monitor cell fluorescence (λex = 488 nm, ΛEM = 540 nm) in the manner described in Sullivan et al., (In: Lambert DG (ed.), Calcium Signaling Protocols, New Jersey: Humana Press, 1999, 125-136) before and after the addition of 50 μl histamine over a concentration range of 1 imM - 0.1 nM. The resultant concentration response curves are analysed by non-linear regression using a standard four parameter logistic equation to determine the histamine EC5O, the concentration of histamine required to produce a response of 50% of the maximum response to histamine. The antagonist pA2 is calculated using the following standard equation: pA2 = log(DR-1 )- log[B] where DR = dose ratio, defined as ECsoantagonist-treated/ECsoControl and [B] = concentration of antagonist.
To determine the antagonist duration, cells are cultured overnight in non-coated black-walled clear bottom 96-well tissue culture plates, are washed with PBS and are incubated with a concentration of antagonist chosen to give an approximate DR in the range 30 - 300. Following the 30 min antagonist incubation period, the cells are washed two or three times with 200 μl of PBS and then 100 μl Tyrodes buffer is added to each well to initiate antagonist dissociation. Following incubation for predetermined times, typically 30 - 270 min at 37 0C, the cells are then washed again with 200 μl PBS and are incubated with 100 μl Tyrodes buffer containing Brilliant Black, probenecid and Fluo-4 for 45 min at 37 0C, as described above. After this period, the cells are challenged with histamine in the FLI PR™ as described above. The dose ratio at each time point is used to determine the fractional H1 receptor occupancy by the following equation: fractional receptor occupancy = (DR-1 )/DR. The decrease in receptor occupancy over time approximates to a straight line and is analysed by linear regression. The slope of this straight line fit is used as an index of the dissociation rate of the antagonist. The dose ratios for antagonist treated cells and for antagonist treated and washed cells at each time point are used to calculate a relative dose ratio (rel DR) which is also used as an index of antagonist duration. Antagonists with long duration of action produce rel DR values close to 1 , and antagonists with short duration of action produce rel DR values that approaches the dose ratio value obtained for antagonist treatment alone.
2. H3 receptor cell line generation, membrane preparation and functional GTPYS assay protocols
Generation of histamine H3 cell line
The histamine H3 cDNA is isolated from its holding vector, pCDNA3.1 TOPO (InVitrogen), by restriction digestion of plasmid DNA with the enzymes BamH1 and Not-1 and is ligated into the inducible expression vector pGene (InVitrogen) digested with the same enzymes. The GeneSwitch™ system (a system where in transgene expression is switched off in the absence of an inducer and switched on in the presence of an inducer) is performed as described in US Patents: 5,364,791 ; 5,874,534; and 5,935,934. Ligated DNA is transformed into competent DH5α E. coli host bacterial cells and is plated onto Luria Broth (LB) agar containing Zeocin™ (an antibiotic which allows the selection of cells expressing the sh ble gene which is present on pGene and pSwitch) at 50 μgml"1. Colonies containing the re-ligated plasmid are identified by restriction analysis. DNA for transfection into mammalian cells is prepared from 250 ml cultures of the host bacterium containing the pGeneH3 plasmid and is isolated using a DNA preparation kit (Qiagen Midi-Prep) as per manufacturers guidelines (Qiagen).
CHO K1 cells previously transfected with the pSwitch regulatory plasmid (InVitrogen) are seeded at 2x106 cells per T75 flask in Complete Medium, containing Hams F12 (GIBCOBRL, Life Technologies) medium supplemented with 10% v/v dialysed foetal bovine serum, L- glutamine, and hygromycin (100 μgml"1), 24 h prior to use. Plasmid DNA is transfected into the cells using Lipofectamine plus according to the manufacturer's guidelines (InVitrogen). 48 h post transfection, cells are placed into complete medium supplemented with 500 μgml"1 Zeocin™. 10-14 days post selection, 10 nM Mifepristone (InVitrogen) is added to the culture medium to induce the expression of the receptor. 18 h post induction, cells are detached from the flask using ethylenediamine tetra-acetic acid (EDTA; 1 :5000; InVitrogen), following several washes with PBS, pH 7.4 and are resuspended in Sorting Medium containing Minimum Essential Medium (MEM), without phenol red, and are supplemented with Earles salts and 3% Foetal Clone Il (Hyclone). Approximately 1 χ107 cells are examined for receptor expression by staining with a rabbit polyclonal antibody, 4a, raised against the /V-terminal domain of the histamine H3 receptor, are incubated on ice for 60 min, followed by two washes in sorting medium. Receptor bound antibody is detected by incubation of the cells for 60 min on ice with a goat anti rabbit antibody, conjugated with Alexa 488 fluorescence marker (Molecular Probes). Following two further washes with Sorting Medium, cells are filtered through a 50 μm Filcon™ (BD Biosciences) and then are analysed on a FACS Vantage SE Flow Cytometer fitted with an Automatic Cell Deposition Unit. Control cells are non-induced cells treated in an analogous manner. Positively stained cells are sorted as single cells into 96-well plates, containing Complete Medium containing 500 μgml"1 Zeocin™ and are allowed to expand before reanalysis for receptor expression via antibody and ligand binding studies. One clone, 3H3, is selected for membrane preparation.
Membrane preparation from cultured cells All steps of the protocol are carried out at 4 0C and with pre-cooled reagents. The cell pellet is resuspended in 10 volumes of homogenisation buffer (50 imM Λ/-2-hydroxyethylpiperazine-Λ/'- 2-ethanesulfonic acid (HEPES), 1 rtiM ethylenediamine tetra-acetic acid (EDTA), pH 7.4 with KOH, supplemented with 10"6 M leupeptin (acetyl-leucyl-leucyl-arginal; Sigma L2884), 25 μgml"1 bacitracin (Sigma B0125), 1 rtiM phenylmethylsulfonyl fluoride (PMSF) and 2χ10"6 M pepstain A (Sigma)). The cells are then homogenised by 2 x 15 second bursts in a 1 litre glass Waring blender, followed by centrifugation at 500 g for 20 min. The supernatant is then spun at 48,000 g for 30 min. The pellet is resuspended in homogenisation buffer (4χ the volume of the original cell pellet) by vortexing for 5 sec, followed by homogenisation in a Dounce homogeniser (10-15 strokes). At this point the preparation is aliquoted into polypropylene tubes and stored at -80 0C.
Histamine H3 functional antagonist assay
For each compound being assayed, in a solid white 384 well plate, is added:-
(a) 0.5 μl of test compound diluted to the required concentration in DMSO (or 0.5 μl DMSO as a control);
(b) 30 μl bead/membrane/GDP mix which is prepared by mixing Wheat Germ Agglutinin Polystyrene LeadSeeker© (WGA PS LS) scintillation proximity assay (SPA) beads with membrane (prepared in accordance with the methodology described above) and diluting in assay buffer (20 mM Λ/-2-hydroxyethylpiperazine-Λ/'-2-ethanesulfonic acid (HEPES) + 100 mM NaCI + 10 mM MgCb, pH 7.4 NaOH) to give a final volume of 30 μl which contains 5 μg protein, 0.25 mg bead per well and 10 μM final assay concentration of guanosine 5' diphosphate (GDP) (Sigma, diluted in assay buffer) incubating at room temperature for 60 min on a roller;
(c) 15 μl 0.38 nM [35S]-GTPyS (Amersham; Radioactivity concentration = 37 MBqml"1; Specific activity = 1160 Cimmol"1), histamine (at a concentration that results in the final assay concentration of histamine being EC8o)-
After 2-6 h, the plate is centrifuged for 5 min at 1500 rpm and counted on a Viewlux counter using a 613/55 filter for 5 minplate"1. Data is analysed using a 4-parameter logistic equation. Basal activity is used as minimum, i.e. histamine not added to well.
Results
In these or similar biological assays, the following data were obtained:
(i) The compounds of the Examples had an average pK, (pKb) at H1 greater than approximately 6.5. The compounds of Examples 1 A, 1 B, 7, 1 1 , 12 and 20-24 had average pA2 values at H1 of greater than approximately 7.
(ii) The compounds of the Examples had an average pK, (pKb) at H3 of greater than approximately 8.
(iii) The compounds of Examples 1A, 7, 12, 19 and 20 had (at one or more time points) a longer duration of action than azelastine in the histamine H1 functional antagonist assay.

Claims

Claims
1. A compound of formula (I)
Figure imgf000084_0001
wherein
R1 independently represents halogen, straight chain C1-6alkyl, -(CH2)b-CO2H or -(CH2)caryl in which the aryl is optionally substituted with one or two substituents independently selected from halogen, C1-3alkyl, trifluoromethyl and cyano; p represents 0, 1 or 2; such that when p represents 1 , R1 is in the 2, 3, 4, 5, 6 or 7 position on the quinoline ring; such that when p represents 2, one R1 group is in the 2, 3 or 4 position on the quinoline ring and the other R1 group is in the 5, 6 or 7 position on the quinoline ring; a represents 1 or 2; b represents 1 to 3; c represents 0 to 3;
R2 represents a group of formula (a), (b) or (c)
Figure imgf000084_0002
Figure imgf000085_0001
in which, for formula (a) e represents 1 to 6; Y represents a bond or O; e' represents 1 to 4; f represents 0, 1 or 2 and g represents 0, 1 , 2 or 3, such that f and g cannot both be 0; h represents 0, 1 or 2;
R3 represents C1-3alkyl;
in which, for formula (b) i represents 1 to 6;
X represents either a bond, O or -N(R6)C(O)-, in which R6 represents hydrogen or C1-6alkyl; j and k each represent 1 or each represent 2; R4 represents hydrogen, C3-6cycloalkyl or C1-6alkyl;
in which, for formula (c) I represents 1 to 6; I' represents 0 to 3; m represents 0, 1 or 2 and n represents 0, 1 , 2 or 3, such that m and n cannot both be 0, and such that I' plus n must represent 1 , 2 or 3; R5 represents hydrogen, C3-6cycloalkyl or C1-6alkyl;
or a salt thereof.
2. A compound according to claim 1 wherein R2 represents a group of formula (a) or (c).
3. A compound according to claim 1 wherein R2 represents a group of formula (a).
4. A compound according to claim 1 wherein R2 represents a group of formula (c).
5. A compound according to claim 1 or claim 2 wherein R2 represents a group of formula
(a): in which, e is 2; Y is O; e' is 3; f is 2 and g is 2; h is O.
6. A compound according to claim 1 or claim 2 wherein R2 represents a group of formula (C): in which,
I represents 2;
I' represents 0; m represents 0 and n represents 1 ;
R5 represents cyclobutyl.
7. A compound according to any one of claims 1 to 6 wherein p is 0.
8. A compound according to any one of claims 1 to 6 wherein p is 1.
9. A compound according to any one of claims 1 to 6 wherein p is 1 and R1 represents Ci-6alkyl.
10. A compound according to claim 9 wherein p is 1 and R1 represents methyl, ethyl or butyl.
1 1 . A compound according to any one of claims 1 to 6 wherein p is 1 and R1 is - (CH2)cAryl.
12. A compound according to claim 1 1 wherein R1 is-(CH2)cphenyl, wherein the phenyl is unsubstituted.
13. A compound according to claim 1 1 wherein R1 is -(CH2)cphenyl, wherein the phenyl is optionally substituted with one or two substituents independently selected from halogen, Ci- 3alkyl, trifluoromethyl and cyano.
14. A compound according to any one of claims 1 to 6 wherein p is 1 and R1 represents halogen.
15. A compound according to any one of claims 1 to 6 wherein p is 1 and R1 represents - (CH2)bCO2H.
16. A compound according to claim 15 wherein R1 is (CH2^OO2H.
17. A compound according to any one of claims 1 to 6 wherein p is 2.
18. A compound according to claim 17 wherein the R1 group located in the 2, 3 or 4 position on the quinoline ring represents straight chain d-βalkyl, -(CH2)bCO2H or -(CH2)caryl in which the aryl is optionally substituted with one or two substituents independently selected from halogen, Ci_3alkyl, trifluoromethyl and cyano.
19. A compound according to claim 17 wherein one independently selected R1 group is located in the 2 position on the quinoline ring, and another independently selected R1 group is located in the 5, 6 or 7 position on the quinoline ring.
20. A compound according to claim 19 wherein one independently selected R1 group is located in the 2 position on the quinoline ring, and another independently selected R1 group is located in the 6 position on the quinoline ring.
21 . A compound according to any one of claims 1 to 6 wherein, when p is 2, the R1 group located in the 2, 3 or 4 position on the quinoline ring represents straight chain Chalky!, - (CH2)bCO2H or -(CH2)caryl in which the aryl is optionally substituted with one or two substituents independently selected from halogen, Ci_3alkyl, trifluoromethyl and cyano.
22. A compound according to any one of claims 1 to 6 wherein when p is 2, one independently selected R1 group is located in the 2 position on the quinoline ring, and another independently selected R1 group is located in the 5, 6 or 7 position on the quinoline ring.
23. A compound according to claim 22 wherein one independently selected R1 group is located in the 2 position on the quinoline ring, and another independently selected R1 group is located in the 6 position on the quinoline ring.
24. A compound according to any one of claims 19, 20, 22 and 23 wherein the R1 group located in the 2 position on the quinoline ring is -(CH2)bCO2H.
25. A compound according to claim 24 wherein the R1 is (Chb^CC^H.
26. A compound according to any one of claims 1 to 25 wherein a is 1.
27. A compound according to any one of claims 1 to 25 wherein a is 2.
28. 8-({1-[2-(4-{[3-(Hexahydro-1 H-azepin-1 -yl)propyl]oxy}phenyl)ethyl]-4- piperidinyl}oxy)quinoline of formula:
Figure imgf000088_0001
or a pharmaceutically acceptable salt thereof.
29. 8-({1-[2-(4-{[3-(Hexahydro-1 H-azepin-1 -yl)propyl]oxy}phenyl)ethyl]-4- piperidinyl}oxy)quinoline.
30. A compound selected from the group consisting of:
8-({1-[2-(4-{[3-(Hexahydro-1 H-azepin-1 -yl)propyl]oxy}phenyl)ethyl]-4-piperidinyl}oxy)quinoline,
8-({1-[2-(4-{[3-(Hexahydro-1 H-azepin-1 -yl)propyl]oxy}phenyl)ethyl]-4-piperidinyl}oxy)quinoline,
8-({(3S)-1 -[2-(4-{[3-(Hexahydro-1 H-azepin-1 -yl)propyl]oxy}phenyl)ethyl]-3- pyrrolidinyl}oxy)quinoline, 8-({(3R)-1-[2-(4-{[3-(Hexahydro-1 H-azepin-1 -yl)propyl]oxy}phenyl)ethyl]-3- pyrrolidinyl}oxy)quinoline,
8-({1-[2-(4-{[3-(Hexahydro-1 H-azepin-1 -yl)propyl]oxy}phenyl)ethyl]-4-piperidinyl}oxy)-2- methylquinoline,
8-({1-[2-(4-{[3-(hexahydro-1 H-azepin-1 -yl)propyl]oxy}phenyl)ethyl]-4-piperidinyl}oxy)-4- methylquinoline,
8-({1-[2-(4-{[3-(Hexahydro-1 H-azepin-1 -yl)propyl]oxy}phenyl)ethyl]-4-piperidinyl}oxy)- 5- methylquinoline,
8-({1-[2-(4-{[3-(Hexahydro-1 H-azepin-1 -yl)propyl]oxy}phenyl)ethyl]-4-piperidinyl}oxy)-6- methylquinoline, 8-({1-[2-(4-{[3-(Hexahydro-1 /-/-azepin-1 -yl)propyl]oxy}phenyl)ethyl]-4-piperidinyl}oxy)-7- methylquinoline,
2-Ethyl-8-({1-[2-(4-{[3-(hexahydro-1 H-azepin-1 -yl)propyl]oxy}phenyl)ethyl]-4- piperidinyl}oxy)quinoline, 3-Ethyl-8-({1-[2-(4-{[3-(hexahydro-1 H-azepin-1 -yl)propyl]oxy}phenyl)ethyl]-4- piperidinyl}oxy)quinoline,
6-Ethyl-8-({1-[2-(4-{[3-(hexahydro-1 H-azepin-1 -yl)propyl]oxy}phenyl)ethyl]-4- piperidinyl}oxy)quinoline,
6-Butyl-8-({1-[2-(4-{[3-(hexahydro-1 H-azepin-1 -yl)propyl]oxy}phenyl)ethyl]-4- piperidinyl}oxy)quinoline,
8-({1-[2-(4-{[3-(Hexahydro-1 H-azepin-1 -yl)propyl]oxy}phenyl)ethyl]-4-piperidinyl}oxy)-5-
(phenylmethyl)quinoline,
8-({1-[2-(4-{[3-(Hexahydro-1 H-azepin-1 -yl)propyl]oxy}phenyl)ethyl]-4-piperidinyl}oxy)-6-
(phenylmethyl)quinoline, 8-({1-[2-(4-{[3-(Hexahydro-1 H-azepin-1 -yl)propyl]oxy}phenyl)ethyl]-4-piperidinyl}oxy)-6-(2- phenylethyl)quinoline,
6-(4-Chlorophenyl)-8-({1 -[2-(4-{[3-(hexahydro-1 H-azepin-1-yl)propyl]oxy}phenyl)ethyl]-4- piperidinyl}oxy)quinoline,
5-Fluoro-8-({1-[2-(4-{[3-(hexahydro-1 H-azepin-1 -yl)propyl]oxy}phenyl)ethyl]-4- piperidinyl}oxy)quinoline,
6-Fluoro-8-({1-[2-(4-{[3-(hexahydro-1 H-azepin-1 -yl)propyl]oxy}phenyl)ethyl]-4- piperidinyl}oxy)quinoline,
7-Bromo-8-({1 -[2-(4-{[3-(hexahydro-1 H-azepin-1 -yl)propyl]oxy}phenyl)ethyl]-4- piperidinyl}oxy)quinoline, 8-{[1 -(2-{4-[(1-Cyclobutyl-4-piperidinyl)oxy]phenyl}ethyl)-4-piperidinyl]oxy}quinoline,
8-{[1 -(2-{4-[(1-Cyclobutyl-4-piperidinyl)oxy]phenyl}ethyl)-4-piperidinyl]oxy}-3-methylquinoline,
3-(8-{[1-(2-{4-[(1 -Cyclobutyl-4-piperidinyl)oxy]phenyl}ethyl)-4-piperidinyl]oxy}-2- quinolinyl)propanoic acid,
3-[6-Butyl-8-({1-[2-(4-{[3-(hexahydro-1 H-azepin-1 -yl)propyl]oxy}phenyl)ethyl]-4- piperidinyl}oxy)-2-quinolinyl]propanoic acid,
3-[8-({1-[2-(4-{[3-(Hexahydro-1 H-azepin-1 -yl)propyl]oxy}phenyl)ethyl]-4-piperidinyl}oxy)-2- quinolinyl]propanoic acid, and
8-[(1 -{2-[4-(1 -Pyrrolidinylmethyl)phenyl]ethyl}-4-piperidinyl)oxy]quinoline; or a salt thereof.
31 . A compound according to any one of claims 1 to 30 or a pharmaceutically acceptable salt thereof.
32. A pharmaceutical composition comprising a) a compound as defined in any one of claims 1 to 30, or a pharmaceutically acceptable salt thereof, and b) one or more pharmaceutically acceptable excipients.
33. A pharmaceutical composition comprising a) 8-({1-[2-(4-{[3-(Hexahydro-1 H-azepin-1 - yl)propyl]oxy}phenyl)ethyl]-4-piperidinyl}oxy)quinoline, or a pharmaceutically acceptable salt thereof, and b) one or more pharmaceutically acceptable carriers or excipients.
34. A pharmaceutical composition according to claim 32 or claim 33, which is suitable for intranasal delivery.
35. A pharmaceutical composition according to any one of claims 32 to 34, wherein the pharmaceutical composition further comprises one or more therapeutic agents.
36. A pharmaceutical composition according claim 35, wherein the pharmaceutical composition further comprises 6α,9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-1 1 β-hydroxy-16α- methyl-3-oxo-androsta-1 ,4-diene-17β-carbothioic acid S-fluoromethyl ester.
37. A compound as defined in any one of claims 1 to 30, or a pharmaceutically acceptable salt thereof, for use in therapy.
38. A compound as defined in any one of claims 1 to 30, or a pharmaceutically acceptable salt thereof, for use in the treatment of inflammatory and/or allergic diseases.
39. A compound as defined in any one of claims 1 to 30, or a pharmaceutically acceptable salt thereof, for use in the treatment of allergic rhinitis.
40. A compound as defined in any one of claims 1 to 30, or a pharmaceutically acceptable salt thereof, for use in the treatment of urticaria.
41 . A compound as defined in any one of claims 1 to 30, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for the treatment of inflammatory and/or allergic diseases of the respiratory tract.
42. A compound as defined in any one of claims 1 to 30, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for the treatment of allergic rhinitis.
43. A compound as defined in any one of claims 1 to 30, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for the treatment of urticaria.
44. A method for treating inflammatory and/or allergic diseases, the method comprising administering to a patient in need of treatment a therapeutically effective amount of a compound as defined in any one of claims 1 to 30, or a pharmaceutically acceptable salt thereof .
45. A method for treating allergic rhinitis, the method comprising administering to a patient in need of treatment a therapeutically effective amount of a compound as defined in any one of claims 1 to 30, or a pharmaceutically acceptable salt thereof .
46. A method for treating urticaria, the method comprising administering to a patient in need of treatment a therapeutically effective amount of a compound as defined in any one of claims 1 to 30, or a pharmaceutically acceptable salt thereof.
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