US20110281909A1 - Substituted quinoline derivatives as h1 receptor antagonists - Google Patents

Substituted quinoline derivatives as h1 receptor antagonists Download PDF

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US20110281909A1
US20110281909A1 US12/673,027 US67302708A US2011281909A1 US 20110281909 A1 US20110281909 A1 US 20110281909A1 US 67302708 A US67302708 A US 67302708A US 2011281909 A1 US2011281909 A1 US 2011281909A1
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butyl
oxy
piperidinyl
quinolinyl
propyl
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Paul Martin Gore
Ashley Paul Hancock
Simon Teanby Hodgson
Panayiotis Alexandrou Procopiou
Sadie Vile
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Glaxo Group Ltd
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Glaxo Group Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms 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
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants
    • 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]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • 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
    • C07D401/02—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 two hetero rings
    • C07D401/12—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 two hetero rings linked by a chain containing hetero atoms as chain links

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 diseases, in particular inflammatory and/or allergic diseases of the respiratory tract.
  • Allergic rhinitis seasonal and perennial
  • 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 also known as ‘hay fever’ affects a large proportion of the population worldwide.
  • 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.
  • 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 al., Pharmacol. Rev., 49:253-278, (1997)].
  • a fourth member of the histamine receptor family has been identified, termed the H4 receptor [ Hough, Mol. 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 which are selective H1 receptor antagonists, such as chlorphenyramine, cetirizine, desloratidine and fexofenadine are effective in treating the itching, sneezing and rhinorrhea associated with allergic rhinitis.
  • Intranasal antihistamines which are selective H1 receptor antagonists, such azelastine and levocabastine are thought to have similar therapeutic effects to their oral counterparts. However, such compounds generally require twice daily administration and may still cause sedatation despite their local application.
  • a class of compounds have been identified as H1 receptor antagonists.
  • R 5 , R 6 , R 7 and R 8 each independently represent hydrogen or C 1-6 alkyl
  • R 6 and R 4 represent a saturated 5 to 7 membered ring, optionally containing one —O—, —S—, —NH—, or —N(CH 3 )— group; or together R 8 and R 4 represent a saturated 5 to 7 membered ring, optionally containing one —O—, —S—, —NH—, or —N(CH 3 )— group; 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, preferred compounds show an improved profile, in that they possess one or more of the following properties:
  • Compounds having such a profile may be particularly suitable for intranasal delivery, and/or capable of once daily administration and/or further may have an improved side effect profile compared with other existing therapies.
  • the compounds may be more potent at the H1 receptor than at other receptors, particularly the H3 receptor and/or the hERG receptor.
  • the activity at the H1 receptor may be at least about 10 fold greater (e.g. about 100 fold greater) than activity at the H3 receptor.
  • R 4 represents —C 1-6 alkyl, —C 5-7 cycloalkyl optionally substituted by one or two C 1-3 alkyl groups, —C 1-3 alkyleneC 5-7 cycloalkyl in which the C 5-7 cycloalkyl is optionally substituted by one or two C 1-3 alkyl groups, -aryl optionally substituted by one or two substituents independently selected from halogen, C 1-3 alkyl, trifluoromethyl, or cyano groups, or —C 1-3 alkylene-aryl optionally substituted on aryl by one or two substituents independently selected from halogen, C 1-3 alkyl, trifluoromethyl, or cyano groups.
  • R 1 represents straight chain C 1-6 alkyl
  • R 2 represents —C 1-6 alkylene-R 3 -R 4 , in which the alkylene is straight chain and is optionally substituted by one C 1-3 alkyl group, or R 2 represents a saturated 5 to 7 membered ring containing one SO 2 group;
  • R 3 represents —SO 2 —, —N(R 5 )SO 2 , —SO 2 N(R 6 )— or —N(R 7 )C(O)N(R 8 )—;
  • R 4 represents —C 1-6 alkyl, —C 5-7 cycloalkyl optionally substituted by one or two C 1-3 alkyl groups, —C 1-3 alkyleneC 5-7 cycloalkyl in which the C 5-7 cycloalkyl is optionally substituted by one or two C 1-3 alkyl groups, -aryl optionally substituted by one or two substituents independently selected from halogen, C 1-3 alkyl, trifluoromethyl, or cyano groups, or
  • R 1 represents C 2-5 alkyl
  • R 2 represents —C 2-5 alkylene-R 3 -R 4 , in which the alkylene is straight chain and is optionally substituted by one C 1-3 alkyl (e.g. methyl) group, or R 2 represents a saturated 5 membered ring containing one SO 2 group;
  • R 3 represents —SO 2 —, —N(R 5 )SO 2 , —SO 2 N(R 6 )— or —N(R 7 )C(O)N(R 8 )—;
  • R 4 represents —C 1-4 alkyl, —C 5-6 cycloalkyl, —C 1 alkyleneC 5-6 cycloalkyl, -aryl (e.g.
  • phenyl optionally substituted by one or two (e.g. one) substituent(s) independently selected from halogen, C 1-3 alkyl (e.g. methyl), trifluoromethyl, or cyano groups, or —C 1 alkylene-aryl (e.g. methylphenyl) optionally substituted by one or two (e.g. one) substituent(s) independently selected from halogen, C 1-3 alkyl (e.g. methyl), trifluoromethyl, or cyano groups; R 5 , R 6 , R 7 and R 8 each independently represent hydrogen or C 1-3 alkyl; or a salt thereof.
  • R 1 represents C 2-5 alkyl (e.g. n-butyl or n-pentyl).
  • a represents 2.
  • R 2 represents —C 2-3 alkylene-R 3 -R 4 , in which the alkylene is straight chain and is optionally substituted by one C 1-3 alkyl (e.g. methyl) group, or R 2 represents a saturated five membered ring containing one SO 2 group.
  • R 2 represents —C 2-5 alkylene-R 3 -R 4 (e.g. —C 2-4 alkylene-R 3 -R 4 ), in which the alkylene is straight chain and is optionally substituted by one C 1-3 alkyl (e.g. methyl) group.
  • R 3 represents —SO 2 —, —N(R 5 )SO 2 — or —SO 2 N(R 6 )—.
  • R 3 represents —N(R 5 )SO 2 — or —SO 2 N(R 6 )—.
  • R 3 represents —SO 2 —.
  • R 3 represents —N(R 5 )SO 2 —.
  • R 3 represents —SO 2 N(R 6 )—.
  • R 4 represents —C 1-6 alkyl, —C 5-7 cycloalkyl, —C 1-3 alkyleneC 5-7 cycloalkyl, -aryl (e.g. phenyl) optionally substituted by one or two (e.g. one) substituent(s) independently selected from halogen, C 1-3 alkyl (e.g. methyl), trifluoromethyl, or cyano groups, or —C 1-3 alkylene-aryl (e.g. C 1-3 alkylene-phenyl) optionally substituted by one or two (e.g. one) substituent(s) independently selected from halogen, C 1-3 alkyl (e.g. methyl), trifluoromethyl, or cyano groups.
  • -aryl e.g. phenyl
  • substituent(s) independently selected from halogen, C 1-3 alkyl (e.g. methyl), trifluoromethyl, or cyano groups
  • R 4 represents —C 1-4 alkyl, —C 5-6 cycloalkyl, —C 1 alkyleneC 5-6 -cycloalkyl, -aryl (e.g. phenyl) optionally substituted by one or two (e.g. one) substituent(s) independently selected from halogen, C 1-3 alkyl (e.g. methyl), trifluoromethyl, or cyano groups, or —C 1 alkylene-aryl (e.g. methylphenyl) optionally substituted by one or two (e.g. one) substituent(s) independently selected from halogen, C 1-3 alkyl (e.g. methyl), trifluoromethyl, or cyano groups.
  • R 4 represents —C 1-4 alkyl, —C 5-6 cycloalkyl, —C 1 alkyleneC 5-6 cycloalkyl or -aryl (e.g. phenyl) optionally substituted by one or two (e.g. one) substituent(s) independently selected from halogen, C 1-3 alkyl (e.g. methyl), trifluoromethyl, or cyano groups.
  • R 4 represents —C 1-4 alkyl, —C 5-6 cycloalkyl, —C 1 alkyleneC 5-6 cycloalkyl or unsubstituted aryl (e.g. phenyl).
  • R 5 , R 6 , R 7 and R 8 each independently represent hydrogen or C 1-3 alkyl (e.g. methyl).
  • R 4 represents —C 1-6 alkyl (e.g. methyl, ethyl, propyl, iso-propyl, butyl, or tert-butyl) or C 5-7 cycloalkyl (e.g. cyclopentyl).
  • R 4 represents —C 1-6 alkyl (e.g. methyl, ethyl, propyl, iso-propyl or iso-butyl), —C 5-7 cycloalkyl (e.g. cyclohexyl), —C 1-3 alkyleneC 5-7 cycloalkyl (e.g. methylcyclohexyl) or unsubstituted aryl (e.g. phenyl) and R 5 represents hydrogen or C 1-3 alkyl (e.g. methyl).
  • R 3 represents —SO 2 N(R 6 )—
  • R 4 represents —C 1-6 alkyl (e.g. propyl or tert-butyl) and R 6 represents hydrogen.
  • R 3 represents —N(R 7 )C(O)N(R 8 )—
  • R 4 represents —C 1 alkyl (e.g. propyl) and R 7 and R 8 both represent hydrogen.
  • a compound which is N-(4- ⁇ 4-[(6-butyl-8-quinolinyl)oxy]-1-piperidinyl ⁇ butyl)ethanesulfonamide, or a salt thereof, such as a pharmaceutically acceptable salt thereof.
  • a compound of formula (I) as defined above with the proviso that the compound is not 6-butyl-8-( ⁇ 1-[3-(ethylsulfonyl)propyl]-4-piperidinyl ⁇ oxy)quinoline, or a salt thereof, such as a pharmaceutically acceptable salt thereof.
  • a compound of formula (I) as defined above with the proviso that the compound is not N-(4- ⁇ 4-[(6-butyl-8-quinolinyl)oxy]-1-piperidinyl ⁇ butyl)ethanesulfonamide, or a salt thereof, such as a pharmaceutically acceptable salt thereof.
  • a compound of formula (I) as defined above with the proviso that the compound is not 6-butyl-8-( ⁇ 1-[3-(ethylsulfonyl)propyl]-4-piperidinyl ⁇ oxy)quinoline or N-(4- ⁇ 4-[(6-butyl-8-quinolinyl)oxy]-1-piperidinyl ⁇ butyl)ethane sulfonamide, or salts thereof, such as pharmaceutically acceptable salts thereof.
  • Representative compounds of formula (I) include the compounds of Examples 1 to 36 and individual isomers thereof, in the form of a free base, or as salts thereof, such as pharmaceutically acceptable salts thereof.
  • C 1-6 alkyl whether alone or as part of another group, and unless otherwise stated, may be straight chain or branched.
  • C 1-3 alkyl shall be interpreted similarly. Representative examples include, but are not limited to methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, t-butyl, n-pentyl, neo-pentyl and n-hexyl.
  • C 1-6 alkylene may be straight chain or branched.
  • C 1-3 alkylene shall be interpreted similarly.
  • Representative examples of straight chain C 1-6 alkylene include methlyene [—(CH 2 )—], ethylene [—(CH 2 ) 2 —], propylene, [—(CH 2 ) 3 —], butylene [—(CH 2 ) 4 —], pentylene [—(CH 2 ) 5 —] and hexylene
  • aryl includes single and fused aromatic rings.
  • Representative examples of aryl groups include, but are not limited to phenyl, indenyl, anthrancenyl and naphthyl.
  • Aryl is intended to denote all isomers thereof (i.e. all possible points of attachment to the aryl ring).
  • a representative aryl group is phenyl.
  • C 5-7 cycloalkyl refers to a non-aromatic cyclic hydrocarbon ring having from five to seven carbon atoms. Examples of such ring systems include cyclopentyl, cyclohexyl and cycloheptyl.
  • halogen is used herein to describe, unless otherwise stated, a group selected from fluorine, chlorine, bromine or iodine, particularly fluorine and chlorine.
  • references hereinafter to compounds of the invention or to compounds of formula (I) mean a compound of formula (I) as the free base, or as a salt.
  • the compounds of formula (I) may be in the form of and/or may be administered as a pharmaceutically acceptable salt.
  • suitable salts see Berge et al., J. Pharm. Sci., 1977, 66, 1-19.
  • Suitable pharmaceutically acceptable salts include acid addition salts.
  • pharmaceutically acceptable salt means any pharmaceutically acceptable salt of a compound of formula (I), which upon administration to the recipient is capable of providing (directly or indirectly) a compound of formula (I), or an active metabolite or residue thereof.
  • a pharmaceutically acceptable salt may be readily prepared by using a desired acid 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, sulphuric, nitric, phosphoric, succinic, maleic, formic, acetic, propionic, fumaric, citric, tartaric, lactic, benzoic, salicylic, glutamic, aspartic, p-toluenesulfonic, benzenesulfonic, methanesulfonic, ethanesulfonic, naphthalenesulfonic (e.g. 2-naphthalenesulfonic), naphthalene disulfonic (e.g.
  • a suitable inorganic or organic acid such as hydrobromic, hydrochloric, sulphuric, nitric, phosphoric, succinic, maleic, formic, acetic, propionic, fumaric, citric, tartaric, lactic
  • 1,5-naphthalene disulfonic naphthoic, 1-hydroxy-2-naphthoic, biphenylsulfonic, xinfanoic or hexanoic acid
  • a suitable solvent such as an organic solvent
  • a pharmaceutically acceptable acid addition salt of a compound of formula (I) can comprise or be for example a hydrobromide, hydrochloride, sulfate, nitrate, phosphate, succinate, maleate, formate, acetate, propionate, fumarate, citrate, tartrate, lactate, benzoate, salicylate, glutamate, aspartate, p-toluenesulfonate, benzenesulfonate, methanesulfonate, ethanesulfonate, naphthalenesulfonate (e.g. 2-naphthalenesulfonate), naphthalene disulfonate (e.g.
  • Suitable 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 whose pK a is >13.
  • non-pharmaceutically acceptable salts e.g. oxalates or trifluoroacetates
  • oxalates or trifluoroacetates may be used, for example in the isolation of the compounds of formula (I), and are included within the scope of this invention.
  • Particular salts of N-(4- ⁇ 4-[(6-butyl-8-quinolinyl)oxy]-1-piperidinyl ⁇ butyl)ethanesulfonamide include naphthalene disulfonate salts, such as a 2,6- or a 1,5-naphthalene disulfonate salt, e.g. a 1,5-naphthalene disulfonate salt.
  • Another particular salt is the dihydrochloride salt.
  • the invention includes within its scope all possible stoichiometric and non-stoichiometric forms of the salts of the compounds of formula (I).
  • the compounds of formula (I) may be in a crystalline or amorphous state, which are included in the scope of the present invention. Furthermore, if crystalline, the compounds of formula (I) may exist in one or more polymorphic forms, which are included in the scope of the present invention. The most thermodynamically stable polymorphic form, at room temperature, of compounds of formula (I) is of particular interest.
  • Polymorphic forms of compounds of formula (I) may be characterized and differentiated using a number of conventional analytical techniques, including, but not limited to, X-ray powder diffraction (XRPD), infrared spectroscopy (IR), Raman spectroscopy, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) and solid state nuclear magnetic resonance (ssNMR).
  • XRPD X-ray powder diffraction
  • IR infrared spectroscopy
  • Raman spectroscopy Raman spectroscopy
  • DSC differential scanning calorimetry
  • TGA thermogravimetric analysis
  • ssNMR solid state nuclear magnetic resonance
  • the compounds of formula (I) may possess one or more asymmetric carbon atoms so that optical isomers e.g. enantiomers or diastereoisomers may be formed.
  • the present invention encompasses optical isomers of the compounds of formula (I) whether as individual isomers isolated such as to be substantially free of the other isomer (i.e. pure) or as mixtures thereof (e.g. 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) may exist in one of several tautomeric forms. It will be understood that the present invention encompasses tautomers of the compounds of formula (I) whether as individual tautomers or as mixtures thereof.
  • (CH 2 ) n corresponds to the C 1-6 alkylene defined in R 2 in the compounds of formula (I), and thus may be optionally substituted by one C 1-3 alkyl group.
  • a compound of formula (I) in which R 3 represents —SO 2 — may be prepared by reacting a compound of formula (II)
  • R 1 , a and R 4 are as defined hereinabove, n represents 1 to 6, (CH 2 ) n may be optionally substituted by one C 1-3 alkyl group, and X represents a suitable leaving group such as chlorine, bromine, tosylate or mesylate.
  • the reaction may typically be carried out in a suitable solvent, such as N,N′-dimethylformamide (DMF), optionally using an appropriate activating agent, e.g. sodium iodide, with a suitable base, such as sodium bicarbonate (sodium hydrogen carbonate) or potassium carbonate.
  • a suitable solvent such as N,N′-dimethylformamide (DMF)
  • an appropriate activating agent e.g. sodium iodide
  • a suitable base such as sodium bicarbonate (sodium hydrogen carbonate) or potassium carbonate.
  • the reaction is typically heated, for example using a microwave oven at a temperature of about 100 to 150° C. for an appropriate time, such as about 15 to 30 min.
  • the reaction may be heated using conventional methods for longer periods of time, such as for several hours or overnight, as appropriate.
  • R 1 and a are as defined hereinabove, and Boc represents tert-butoxycarbonyl.
  • suitable acid e.g. concentrated sulphuric acid, appropriate solvent such as water, sodium 3-nitrobenzenesulfonate (commercially available, for example, from Aldrich), appropriate elevated temperature such as from about 110 to 140° C.
  • suitable solvent such as water, sodium 3-nitrobenzenesulfonate (commercially available, for example, from Aldrich)
  • suitable base e.g. potassium carbonate
  • catalyst for example [1,1′-bis(diphenylphosphino) ferrocene palladium (II)] chloride, at an elevated temperature such as from about 70 to 80° C.
  • suitable solvent such as N-methylpyrrolidinone (NMP), appropriate base e.g. sodium tert-butoxide, at an elevated temperature for example from about 130 to 150° C.; iv) deprotection using a suitable acid e.g. trifluoracetic acid (TFA) or hydrogen chloride in a suitable solvent such as dichloromethane (DCM), dioxane, iso-propylalcohol or toluene at room termperature.
  • NMP N-methylpyrrolidinone
  • appropriate base e.g. sodium tert-butoxide
  • TFA trifluoracetic acid
  • suitable solvent such as dichloromethane (DCM), dioxane, iso-propylalcohol or toluene at room termperature.
  • step ii) in Scheme 1 may be carried out using 9-borabicyclo[3.3.1] nonane and an appropriate olefin to make a boron compound (equivalent to compound (XV)) in situ.
  • the reaction is typically carried out in a suitable solvent such as THF with an appropriate catalyst e.g. 1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II).
  • the reaction is carried out in a manner similar to that described by S. Potuzak and D. S. Tan, Tetrahedron Lett., 45:1797-1801, (2004).
  • Olefins are commercially available, for example, from Aldrich and include ethene, 1-propene, 1-butene, 1-pentene and 1-hexene.
  • the compound of formula (XIII), glycerol is commercially available, for example, from Fluka and/or Aldrich.
  • the compounds of formula (XV) are commercially available, for example from Aldrich, and include trimethylboron, triethylborane and tributylborane.
  • R 1 and a are as defined hereinabove and Boc represents tert-butoxycarbonyl.
  • suitable acid e.g. concentrated sulphuric acid, appropriate solvent such as water, sodium 3-nitrobenzenesulfonate (commercially available, for example, from Aldrich), appropriate elevated temperature such as from about 110 to 140° C.
  • suitable solvent such as NMP, appropriate base e.g. sodium tert-butoxide, at an appropriate elevated temperature for example from about 130 to 150° C.
  • suitable solvent such as THF:NMP (10:1) at an appropriate lowered temperature e.g. from about 0 to 5° C., using a suitable catalyst for example iron(III) acetylacetonate, preferably in an inert, water-free atmosphere.
  • step (iii) of Scheme 2 may be performed before step (ii) of Scheme 2, thereby first forming a compound of formula (XVI), and subsequently a compound of formula (XVIII).
  • the compound of formula (XIX), 4-chloro-2-fluoroaniline, is commercially available, for example, from Aldrich.
  • Compounds of formula (XXII) are commercially available, for example, from Aldrich and/or TCI-Europe and include methylmagnesium bromide, ethylmagnesium bromide, n-propylmagnesium bromide, n-butylmagnesium bromide, n-pentylmagnesium bromide and n-hexylmagnesium bromide.
  • n 1 to 6 and (CH 2 ) n may be optionally substituted by one C 1-3 alkyl group.
  • suitable solvent such as DMF, at an elevated temperature such as from about 60 to 90° C.
  • appropriate base e.g. triethylamine
  • a suitable solvent for example DCM methanesulfonylchloride (commercially available, for example, from Aldrich) and optionally in the presence of additional chloride ions e.g. lithium chloride or n-butylammonium chloride
  • suitable solvent such as DCM, appropriate oxidising agent e.g. m-chloroperbenzoic acid (commercially available, for example, from Aldrich);
  • appropriate solvent such as ethanol or DMF, optionally at an appropriate elevated temperature e.g.
  • oxidising agent e.g. m-chloroperbenzoic acid in a suitable solvent e.g. DCM; v) suitable solvent such as DMF at an appropriate elevated temperature e.g. from about 60 to 80° C.
  • Compounds of formula (XXIII) are commercially available, for example, from Aldrich and/or Apollo and/or TCI-Europe, and include 2-bromoethanol, 3-bromopropanol, 4-bromobutanol, 5-bromopentanol, 6-bromohexanol, 1-bromo-2-propanol, (R)-( ⁇ )-3-bromo-2-methyl-1-propanol, (S)-( ⁇ )-3-bromo-2-methyl-1-propanol and 1-bromo-2-butanol.
  • Compounds of formula (XXIV) are commercially available, for example, from Aldrich, and include sodium ethanethiolate, sodium 1-propanethiolate, sodium 2-propanethiolate, sodium 1-butanethiolate, sodium 2-methyl-2-propanethiolate, sodium thiophenoxide and sodium 4-methylbenzenethiolate.
  • Compounds of formula (XXIV) may also be prepared in situ, by the addition of a suitable base, such as sodium hydride to a solution of the corresponding thiol in a suitable solvent, such as DMF.
  • a suitable base such as sodium hydride
  • the suspension may be left for an appropriate amount of time, e.g. about 15 min, before continuing with the reactions described in Scheme 3.
  • Thiol compounds corresponding to compounds of formula (XXIV) are commercially available, for example, from Aldrich and/or TCI-Europe and/or Apollo, and include methanemercaptan, 2-methyl-2-butanethiol, 3-methyl-1-butanethiol, 1-pentanethiol, hexylmercaptan, cyclopentanethiol, cyclohexanethiol, 2-naphthalenethiol, thiophenol, 2-bromothiophenol, 4-fluorothiophenol, 2,5-dichlorothiophenol, 3-methylbenzenethiol, 2-ethylthiophenol, 2-iso-propylthiophenol, 2,4-dimethylthiophenol, benzyl mercaptan, phenylethylmercaptan, 2-chlorobenzyl mercaptan, 3-methylbenzyl mercaptan and 3,5-bis(trifluoromethyl)thiophenol.
  • Compounds of formula (XXV) may be prepared as described in Scheme 3, or may also be commercially available, for example, from TCI-Europe and/or Alfa Aesar and/or Aldrich, and include 2-(ethylthio)ethanol, 2-(iso-butylthio)ethanol, 4-(methylthio)-1-butanol, 3-(methylthio)-1-hexanol, 2-hydroxyethyl benzyl sulphide, 2-hydroxyethyl n-pentyl sulphide, 4-chlorobenzyl 2-hydroxyethyl sulphide and 3-(methylthio)-1-propanol.
  • Compounds of formula (XXVII) are commercially available, for example, from TCI-Europe and/or Aldrich and/or Alfa Aesar, and include 1-bromo-2-chloroethane, 2-bromo-1-chloropropane, 1-bromo-3-chloropropane, 1-bromo-4-chlorobutane, 1-bromo-3-chloro-2-methylpropane, 1-bromo-5-chloropentane and 1-bromo-6-chlorohexane.
  • Compounds of formula (XXVIII) are commercially available, for example, from Aldrich, and/or Alfa Aesar and include dibromomethane, 1,2-dibromoethane, 1,2-dibromopropane, 1,2-dibromobutane, 1,3-dibromopropane, 1,3-dibromobutane, 1,4-dibromobutane, 1,4-dibromopentane, 1,5-dibromopentane, 1,5-dibromo-3-methylpentane and 1,6-dibromohexane.
  • R 4 is as defined hereinabove, n represents 1 to 6, (CH 2 ) n may be optionally substituted by one C 1-3 alkyl group, and X represents mesylate or tosylate.
  • suitable activating agent for example methylsulfonyl chloride or p-toluenesulfonyl chloride (both commercially available, for example, from Aldrich), suitable solvent such as pyridine or DCM, optionally at a suitable lowered temperature e.g. from about 0 to 5° C.; ii) suitable solvent such as DCM, appropriate oxidising agent e.g. m-chloroperbenzoic acid; iii) suitable solvent such as DMF, optionally at an appropriate elevated temperature for example from about 70 to 80° C.
  • suitable activating agent for example methylsulfonyl chloride or p-toluenesulfonyl chloride (both commercially available, for example, from Aldrich)
  • suitable solvent such as pyridine or DCM
  • suitable solvent such as DCM, appropriate oxidising agent e.g. m-chloroperbenzoic acid
  • suitable solvent such as DMF
  • Compounds of formula (XXIV) may also be prepared in situ, by the addition of a suitable base, such as sodium hydride to a solution of the corresponding thiol in a suitable solvent, such as DMF.
  • a suitable base such as sodium hydride
  • the suspension may be left for an appropriate amount of time, e.g. about 15 min, before continuing with the reactions described in Scheme 4.
  • Compounds of formula (XXXI) are commercially available, for example, from Aldrich, and include ethylene di(p-toluenesulfonate), (S)-( ⁇ )-1,2-propanediol di-p-tosylate, 1,3-propanediol di-p-tosylate and 1,4-butanediol dimethanesulfonate.
  • compounds of formula (XXXI) may be prepared by methods well known to those skilled in the art, by activation of the corresponding diol.
  • the reaction may typically be carried out using a suitable activating agent such as methanesulfonyl chloride, or p-toluenesulfonyl chloride in a suitable solvent such as DCM or pyridine.
  • a suitable activating agent such as methanesulfonyl chloride, or p-toluenesulfonyl chloride in a suitable solvent such as DCM or pyridine.
  • Diols corresponding to compounds of formula (XXXI) are commercially available, for example, from Aldrich, and include ethylene glycol, 1,2-butanediol, 1,3-propanediol, 1,3-butanediol, 1,4-butanediol, 1,4-pentanediol, 1,5-pentanediol, 1,5-hexanediol, 3-methyl-1,5-pentanediol and 1,6-hexanediol.
  • Compounds of formula (XXXII) are commercially available, for example, from Aldrich and/or Alfa Aesar, and include 2-(methylsulfonyl)ethanol and 2-(ethanesulfonyl)ethanol.
  • R 4 is as defined hereinabove and Y represents hydrogen or C 1-3 alkyl.
  • suitable solvent such as DMF
  • suitable solvent such as THF
  • appropriate reducing agent e.g. lithium aluminium hydride solution in ether
  • suitable lowered temperature such as from about 0 to 5° C.
  • the compounds of formula (XXXIII) are commercially available, for example from Aldrich and/or Alfa Aesar and/or Rarechem, and include ethyl acrylate, ethyl crotonate, ethyl trans-2-pentenoate, ethyl 4-methyl-trans-2-pentenoate and ethyl trans-2-hexenoate.
  • a compound of formula (I) in which R 2 represents a saturated 5 to 7 membered ring containing one SO 2 group or R 2 represents ethylene-SO 2 —R 4 may be prepared by reacting a compound of formula (II)
  • R 1 , a and R 4 are as defined hereinabove and m represents 1 to 3.
  • the reaction may typically be carried out in a suitable solvent, such as THF or DMF.
  • a suitable solvent such as THF or DMF.
  • an appropriate base may be added, for example sodium bicarbonate.
  • the reaction is typically heated for example using a microwave oven at a suitable temperature from about 100 to 150° C. for an appropriate time, such as about 15 to 30 min. Alternatively, the heating may be conducted using conventional methods at a suitable elevated temperature, such as from about 70 to 90° C. for longer periods of time, e.g. about 2 to 3 hours or overnight.
  • 2,3-dihydrothiophene 1,1-dioxide is commercially available, for example, from AKOS.
  • 3,4-dihydro-2H-thiopyran 1,1-dioxide may be prepared according to the methods disclosed by X-F. Ren, E. Turos, C. H. Lake and M. R. Churchill, J. Org. Chem., 60:6468-6483, (1995), see page 6483.
  • 2,3,4,5-tetrahydrothiepin 1,1-dioxide may be prepared according to the methods disclosed by B. F. Bonini, M. Comes-Franchini, M. Fochi, G. Mazzanti, A. Ricci, Tetrahedron, 52:4803-4816, (1996), see compound 12.
  • Compounds of formula (IVa) are commercially available, for example, from Aldrich, and include methyl vinyl sulfone, ethyl vinyl sulfone and phenyl vinyl sulfone.
  • a compound of formula (I) in which R 3 represents —N(R 5 )SO 2 — may be prepared by reacting a compound of formula (V)
  • n 1 to 6 and (CH 2 ) n may be optionally substituted by one C 1-3 alkyl group.
  • the reaction may typically be carried out using a suitable solvent such as DCM with a suitable base e.g. triethylamine.
  • a suitable solvent such as DCM
  • a suitable base e.g. triethylamine
  • Compounds of formula (VI) are commercially available, for example, from Aldrich and/or TCI Europe and/or Apollo International and/or Fluorochem, and include methanesulfonyl chloride, ethanesulfonylchloride, 1-propanesulfonyl chloride, iso-propylsulfonyl chloride, 2-methyl-1-propylsulfonyl chloride, 1-butanesulfonyl chloride, sec-butylsulfonyl chloride, n-pentylsulfonyl chloride, 2-pentylsulfonyl chloride, 1-hexanesulfonyl chloride, cyclopentanesulfonyl chloride, cyclohexanesulfonyl chloride, cyclopentylmethanesulfonyl chloride cyclohexylmethanesulfonyl chloride, benzenesulfonyl
  • R 1 , a and R 5 are as defined hereinabove, and X represents a suitable leaving group such as chlorine, broming or iodine.
  • suitable solvent such as 2-butanone, appropriate base e.g. potassium carbonate, at an elevated temperature such as from about 70 to 90° C.
  • suitable, solvent such as ethanol, hydrazine or hydrazine monohydrate, at an elevated temperature such as from about 70 to 90° C.
  • suitable base such as triethylamine or sodium hydride, optionally with an activating agent such as sodium iodide; or reductive amination using R 5 ⁇ O (XXXVIIb), in a suitable solvent e.g. DMF, suitable reducing agent such as sodium triacetoxyborohydride.
  • the compound of formula (XXXV), 2-(2-bromoethyl)-1H-isoindole-1,3(2H)-dione is commercially available, for example from Acros and/or Aldrich.
  • Compounds of formula (XXXVIIa) are commercially available, for example from Aldrich, and include methyl iodide, iodoethane, 1-iodopropane, 1-iodobutane, 1-iodopentane and 1-iodohexane.
  • Compounds of formula (XXXVIIb) are commercially available, for example, from Aldrich, and include formaldehyde, acetaldehyde, propionaldehyde, methyl ethyl ketone, butyraldehyde, valeraldehyde, 3-pentanone, hexanal, 3-hexanone and 3-methyl-3-pentanone.
  • R 1 and a are as defined hereinabove, n represents 2 to 6 and R a represents C 1-6 alkyl.
  • 2-benzofuran-1,3-dione (commercially available, for example, from Aldrich) in a suitable solvent such as toluene; ii) suitable solvent such as toluene, appropriate base e.g. triethylamine; iii) suitable solvent such as DMF, appropriate base e.g. DIPEA and/or tributylammonium iodide, optionally with an appropriate activating agent e.g. sodium iodide, optionally at an elevated temperature such as from about 70 to 90° C.; iv) suitable solvent such as ethanol, hydrazine or hydrazine monohydrate, at an elevated temperature such as from about 70 to 90° C.
  • suitable solvent such as ethanol, hydrazine or hydrazine monohydrate, at an elevated temperature such as from about 70 to 90° C.
  • the compounds of formula (XXXVa), are commercially available, for example from Aldrich.
  • the compounds of formula (XXXVd) are commercially available, for example from Aldrich and/or Fluka.
  • R 1 , a and R 5 are as defined hereinabove, X represents a suitable leaving group such as chlorine, bromine or iodine, n represents 1 to 6 and (CH 2 ) n may be optionally substituted by one C 1-3 alkyl group.
  • suitable solvent such as 2-butanone, appropriate base e.g. potassium carbonate, at an elevated temperature such as from about 70 to 90° C.
  • deprotection using a suitable acid such as hydrogen chloride or TFA in a suitable solvent e.g. dioxane or DCM
  • suitable solvent e.g. dioxane or DCM
  • suitable base such as triethylamine or sodium hydride, optionally with an activating agent such as sodium iodide
  • activating agent such as sodium iodide
  • suitable solvent e.g. DMF, suitable reducing agent such as sodium triacetoxyborohydride.
  • Compounds of formula (XXXVIII) are commercially available, for example, from Aldrich and/or Toronto Chemicals, and include 2-(Boc-amino)ethyl bromide, 3-(Boc-amino)propyl bromide, 4-(Boc-amino)butyl bromide, 5-(Boc-amino)pentyl bromide and 6-(Boc-amino)hexyl bromide.
  • a compound of formula (I) in which R 3 represents —N(R 5 )SO 2 — may be prepared by reacting a compound of formula (II)
  • R 1 , a, R 4 and R 5 are as defined hereinabove, n represents 1 to 6, (CH 2 ), may be optionally substituted by one C 1-3 alkyl group, and X represents a suitable leaving group such as chlorine, bromine, tosylate or mesylate.
  • the reaction may typically be carried out using a suitable base such as sodium hydrogen carbonate, with an appropriate activating agent e.g. sodium iodide, in a suitable solvent such as DMF.
  • a suitable base such as sodium hydrogen carbonate
  • an appropriate activating agent e.g. sodium iodide
  • the reaction is typically heated for example, using a microwave oven at an appropriate elevated temperature for example from about 140 to 160° C., for about 10 to 30 minutes, as appropriate.
  • heating may be with conventional apparatus, at elevated temperatures for example from about 50 to 70° C., for about 3 hours to overnight, as appropriate.
  • n 1 to 6 and (CH 2 ) n may be optionally substituted by one C 1-3 alkyl group.
  • Reagents and Conditions i) suitable solvent such as DCM, appropriate base e.g. triethylamine, at a lowered temperature such as from about 0° C. to room temperature.
  • suitable solvent such as DCM
  • appropriate base e.g. triethylamine
  • Compounds of formula (XL) are commercially available, for example, from Aldrich and/or TCI Europe, and include 2-aminoethanol, 2-(methylamino)ethanol, 2-(ethylamino)ethanol, 2-(propylamino)ethanol, 2-(butylamino)ethanol, 2-(n-pentylamino)ethanol, 3-amino-1-propanol, 3-(methylamino)-1-propanol, 4-amino-1-butanol, (R)-4-amino-2-methyl-1-butanol, 4-ethylamino-1-butanol, 4-(n-butylamino)-1-butanol, 5-amino-1-pentanol and 6-amino-1-hexanol.
  • a compound of formula (I) in which R 3 represents —SO 2 N(R 6 )— may be prepared by reacting a compound of formula (II)
  • R 1 , a, R 4 and R 6 are as defined hereinabove, n represents 1 to 6, (CH 2 ) n may be optionally substituted by one C 1-3 alkyl group, and X represents a suitable leaving group such as chlorine or bromine.
  • the reaction may typically be carried out using a suitable solvent such as DMF with an appropriate activating agent for example, sodium iodide, with a suitable base, e.g. potassium carbonate.
  • a suitable solvent such as DMF
  • an appropriate activating agent for example, sodium iodide
  • a suitable base e.g. potassium carbonate.
  • the reaction is usually heated using conventional apparatus, at an appropriate elevated temperature for example from about 50 to 70° C., for about 3 hours to overnight, as appropriate.
  • n 1 to 6 and (CH 2 ), may be optionally substituted by one C 1-3 alkyl group.
  • Reagents and Conditions i) suitable solvent such as DCM, at a lowered temperature e.g. from about 0° C. to room temperature.
  • Compounds of formula (XLI) are commercially available, for example, from Aldrich and/or TCI Europe, and include 2-chloroethanesulfonyl chloride and 3-chloropropanesulfonyl chloride.
  • Compounds of formula (XI) are commercially available, for example, from Aldrich and/or ABCR and/or Enamine and/or Chembridge, and include methylamine, ethylamine, propylamine, butylamine, (R)-( ⁇ )-2-aminobutane, (S)-(+)-2-aminobutanepentylamine, tert-butylamine, 1,1-dimethylpropylamine, hexylamine, dimethylamine, N-ethylmethylamine, N-methylpropylamine, diethylamine, dipropylamine, N-ethylbutylamine, dibutylamine, dipentylamine, dihexylamine, cyclopentylamine, cyclohexylamine, 2-methylcyclohexylamine, cycloheptylamine, N-methylcyclohexylamine, N-isopropylcyclohexyamine, N-cycloh
  • F a compound of formula (I) in which R 3 represents —N(R 7 )C(O)N(R 8 )—, and R 8 represents hydrogen, may be prepared by reacting a compound of formula (Va)
  • n 1 to 6 and (CH 2 ) n may be optionally substituted by one C 1 alkyl group.
  • the reaction may typically be carried out using a suitable solvent, such as DCM.
  • a suitable solvent such as DCM.
  • the reaction is usually carried out at ambient temperature for an appropriate length of time such as overnight, for example.
  • Compounds of formula (IX) are commercially available, for example, from Aldrich, and include ethyl isocyanate, isopropyl isocyanate, propyl isocyanate, butyl isocyanate, sec-butyl isocyanate, tert-butyl isocyanate, pentyl isocyanate, hexyl isocyanate, cyclopentyl isocya nate, cyclohexyl isocyanate, cycloheptyl isocyanate, cyclohexanemethyl isocyanate, (R)-( ⁇ )-1-cyclohexylethyl isocyanate, phenyl isocyanate, 3-chlorophenyl isocyanate, 2-fluoro-phenyl isocyanate, 2-bromophenyl isocyanate, 4-iodophenyl isocyanate, 4-methylphenyl isocyanate, 2-ethylphenyl is
  • a compound of formula (I) in which R 3 represents —N(R 7 )C(O)N(R 8 )— may be prepared by reacting a compound of formula (X)
  • n 1 to 6 and (CH 2 ) n may be optionally substituted by one C 1-3 alkyl group.
  • the reaction may typically be carried out in a suitable solvent such as THF or DCM, usually at an elevated temperature for example at reflux.
  • a suitable solvent such as THF or DCM
  • n 1 to 6 and (CH 2 ) n may be optionally substituted by one C 1-3 alkyl group.
  • the compound of formula (XLII), 1,1′-carbonyldiimidazole, is commercially available, for example, from Aldrich.
  • H 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 C 1-6 alkyl, activated to substitution by means of a leaving group such as halogen, such as chlorine or bromine, 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, N,N′ diisopropylethylamine or sodium hydride, in an appropriate solvent such as 2-butanone or DMF, optionally at an appropriate elevated temperature such as at about 80° C.
  • a salt of a compound of formula (I) may be prepared by exchange of counterions, or precipitation of said salt from the free base.
  • Compounds of formula (I) may be further purified by methods well-known to those skilled in the art, for example by recrystallisation, column chromatography (which may be manual or automated, for example mass-directed), preparative TLC and the like.
  • a suitable solvent system for recrystallisation of compounds of formula (I) in which R 3 represents —N(R 5 )SO 2 — and R 4 represents C 1-6 alkyl is methanol/ethyl acetate.
  • Suitable amine protecting groups include sulfonyl (e.g. tosyl), acyl (e.g. acetyl, 2′,2′,2′-trichloroethoxycarbonyl, benzyloxycarbonyl or t-butoxycarbonyl) and arylalkyl (e.g. benzyl), which may be removed by hydrolysis (e.g.
  • 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 cleavage, for example with trifluoroacetic acid.
  • Examples of disease states in which a compound of formula (I), or a pharmaceutically acceptable salt thereof potentially may have beneficial anti-inflammatory and/or anti-allergic effects include inflammatory and/or allergic diseases of the respiratory tract, such as allergic rhinitis (seasonal and perennial) or other diseases such as bronchitis (including chronic bronchitis), asthma (including allergen-induced asthmatic reactions), chronic obstructive pulmonary disease (COPD) and sinusitis.
  • allergic rhinitis seasonal and perennial
  • bronchitis including chronic bronchitis
  • asthma including allergen-induced asthmatic reactions
  • COPD chronic obstructive pulmonary disease
  • the compounds of formula (I) may be of use in the treatment of nephritis, skin diseases such as psoriasis, eczema, allergic dermatitis and hypersensitivity reactions. Also, the compounds of formula (I) may be useful in the treatment of insect bites and stings.
  • the compounds of formula (I) 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.
  • 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.
  • references herein to treatment or therapy may extend to prophylaxis as well as the treatment of established conditions.
  • compounds of formula (I) may be useful as therapeutic agents. There is thus provided a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in therapy.
  • a compound which is N-(4- ⁇ 4-[(6-butyl-8-quinolinyl)oxy]-1-piperidinyl ⁇ butyl)ethanesulfonamide, or a pharmaceutically acceptable salt (such as the dihydrochloride salt) thereof for use in therapy.
  • a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of any of the above diseases (e.g. allergic rhinitis).
  • any of the above diseases e.g. allergic rhinitis.
  • a compound which is N-(4- ⁇ 4-[(6-butyl-8-quinolinyl)oxy]-1-piperidinyl ⁇ butyl)ethanesulfonamide, or a pharmaceutically acceptable salt (such as the dihydrochloride salt) thereof for use in the treatment of any of the above diseases (e.g. allergic rhinitis).
  • a pharmaceutically acceptable salt such as the dihydrochloride salt
  • a method for the treatment (or prophylaxis) of any of the above diseases for example inflammatory and/or allergic diseases of the respiratory tract, e.g. allergic rhinitis
  • a method for the treatment (or prophylaxis) of any of the above diseases for example inflammatory and/or allergic diseases of the respiratory tract, e.g. allergic rhinitis
  • a patient in need thereof which method comprises administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • a method for the treatment (or prophylaxis) of any of the above diseases for example inflammatory and/or allergic diseases of the respiratory tract, e.g. allergic rhinitis
  • a method for the treatment (or prophylaxis) of any of the above diseases for example inflammatory and/or allergic diseases of the respiratory tract, e.g. allergic rhinitis
  • a patient in need thereof which method comprises administering an effective amount of a compound which is 6-butyl-8-( ⁇ 1-[3-(ethylsulfonyl)propyl]-4-piperidinyl ⁇ oxy)quinoline, or a pharmaceutically acceptable salt thereof.
  • a method for the treatment (or prophylaxis) of any of the above diseases for example inflammatory and/or allergic diseases of the respiratory tract, e.g. allergic rhinitis
  • a method for the treatment (or prophylaxis) of any of the above diseases for example inflammatory and/or allergic diseases of the respiratory tract, e.g. allergic rhinitis
  • a patient in need thereof which method comprises administering an effective amount of a compound which is N-(4- ⁇ 4-[(6-butyl-8-quinolinyl)oxy]-1-piperidinyl ⁇ butyl)ethanesulfonamide, or a pharmaceutically acceptable salt (such as the dihydrochloride salt) thereof.
  • the compounds of formula (I) or pharmaceutically acceptable salts thereof may typically be formulated in a suitable pharmaceutical composition.
  • suitable pharmaceutical compositions may be prepared using standard procedures.
  • composition which comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof and one or more (e.g. 10 or fewer) pharmaceutically acceptable carriers and/or excipients.
  • composition which comprises a compound which is 6-butyl-8-( ⁇ 1-[3-(ethylsulfonyl)propyl]-4-piperidinyl ⁇ oxy)quinoline, or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers and/or excipients.
  • composition which comprises a compound which is N-(4- ⁇ 4-[(6-butyl-8-quinolinyl)oxy]-1-piperidinyl ⁇ butyl)ethanesulfonamide, or a pharmaceutically acceptable salt (such as the dihydrochloride salt) thereof and one or more pharmaceutically acceptable carriers and/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), or about 0.1 to 99% (w/w), such as from about 0.1 to 60% (w/w), or about 10 to 60% (w/w), or about 0.01% to 2% (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, for example about 0.05 to 2 mg, or about 0.05 to 1 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), or about 0.025 to 0.9% (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 2 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, one or more isotonicity adjusting agents and/or one or more co-solvents 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(s), 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), particularly about 2.4% (w/w) based on the total weight of the composition.
  • suspending agents include, but are not limited to Avicela (microcrystalline cellulose and carboxymethylcellulose sodium), carboxymethylcellulose sodium, veegum, tragacanth, bentonite, methylcellulose, xanthan gum, carbopol and polyethylene glycols.
  • an intranasal composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises a suspending/thickening agent which is microcrystalline cellulose and carboxymethylcellulose sodium.
  • Suspending 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 include, but are not limited to quaternary ammonium compounds (e.g. benzethonium chloride, cetrimide, cetylpyridinium chloride, myristal picolinium chloride and lauralkonium chloride.
  • Another anti-microbial agent is benzalkonium 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 may include, but are not limited to, sodium benzoate, sorbic acid, sodium propionate, methyl paraben, ethyl paraben, propyl paraben and butyl paraben.
  • an intranasal composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises a preservative which is selected from EDTA and/or potassium sorbate.
  • 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 0.005 to 0.05% (w/w), such as between about 0.001 and 0.05% (w/w), for example about 0.025% (w/w), based on the total weight of the composition.
  • an intranasal composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises a wetting agent which is polyoxyethylene (20) sorbitan monooleate (Polysorbate 80).
  • 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.
  • 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), or between about 0.5 to 1% (w/w), or about 0.75% (w/w), based on the total weight of the composition.
  • an intranasal composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises an isotonicity adjusting agent which is xylitol.
  • the intranasal composition does not contain an isotonicity adjusting agent.
  • 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.
  • 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.
  • an intranasal composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises a co-solvent which is propylene glycol.
  • 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.
  • 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.
  • an intranasal composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises buffering agents which are sodium citrate and/or citric acid. Buffering agents may also be included in compositions suitable for other routes of administration as appropriate.
  • an intranasal aqueous compositon containing a compound of formula (I) or a pharmaceutically acceptable salt thereof and further comprising
  • compositions for administration topically to the nose (for example, for the treatment of rhinitis) or to the lung include pressurised aerosol compositions and aqueous compositions delivered to the nasal cavities by pressurised pump.
  • Compositions which are non-pressurised and are suitable for administration 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 FIGS. 30-40 of W005/044354.
  • 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 FIGS. 22-46 thereof, or as disclosed in GB0723418.0, for example as disclosed with reference to FIGS. 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 FIGS. 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.
  • an intranasal composition comprising a compound which is N-(4- ⁇ -4-[(6-butyl-8-quinolinyl)oxy]-1-piperidinyl ⁇ butyl)ethanesulfonamide, or a pharmaceutically acceptable salt (such as a dihydrochloride salt) thereof.
  • a pharmaceutically acceptable salt such as a dihydrochloride salt
  • 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 co-solvents.
  • 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 DISKUSTTM device, marketed by GlaxoSmithKline.
  • the DISKUSTTM 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 1 4-10 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.
  • composition comprising a compound which is N-(4- ⁇ 4-[(6-butyl-8-quinolinyl)oxy]-1-piperidinyl ⁇ butyl)ethanesulfonamide, or a pharmaceutically acceptable salt (such as a dihydrochloride salt) thereof which is suitable for ocular administration.
  • 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 (e.g. one or two) other therapeutic agents, for example other antihistaminic agents for example H4 or H3 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), non-steroidal anti-inflammatory drugs (NSAIDs) (e.g.
  • NSAIDs non-steroidal anti-inflammatory drugs
  • chemokine antagonists e.g. CCR3, CCR1, CCR2, CCR4, CCR8, CXCR1, CXCR2
  • IKK antagonists e.g. IKK antagonists
  • iNOS inhibitors tryptase and elastase inhibitors
  • beta-2 integrin antagonists e.g. beta-2 integrin antagonists and adenosine 2a agonists
  • beta adrenergic agents e.g.
  • 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 which is 6-butyl-8-( ⁇ 1-[3-(ethylsulfonyl)propyl]-4-piperidinyl ⁇ oxy)quinoline, or a pharmaceutically acceptable salt thereof, together with one or more (such as one or two, e.g. one) other therapeutically active agents (such as those described herein), optionally with one or more pharmaceutically acceptable carriers and/or excipients.
  • one or more such as one or two, e.g. one
  • other therapeutically active agents such as those described herein
  • a combination comprising a compound which is N-(4- ⁇ 4-[(6-butyl-8-quinolinyl)oxy]-1-piperidinyl ⁇ butyl)ethanesulfonamide, or a pharmaceutically acceptable salt (such as a dihydrochloride salt) thereof together with one or more (such as one or two, e.g. one) other therapeutically active agents (such as those described herein), optionally with one or more pharmaceutically acceptable carriers and/or excipients.
  • a pharmaceutically acceptable salt such as a dihydrochloride salt
  • a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and an H3 and/or H4 antagonist.
  • histamine receptor antagonists which may be used alone, or in combination with an H1 receptor antagonist include antagonists (and/or inverse agonists) of the H4 receptor, for example, the compounds disclosed in Jablonowski et al., J. Med. Chem. 46:3957-3960 (2003), and antagonists (and/or inverse agonists) of the H3 receptor, for example the compounds described in WO2004/035556, the compounds described in WO2006/125665 and the compounds described in WO2006/090142.
  • 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.
  • ⁇ 2 -adrenoreceptor agonists examples 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, sutfamic, 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, sutfamic, sulfanilic, naphthaleneacrylic, benzoic, 4-meth
  • 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-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]-1,8-hydroxy-16 ⁇ -methyl-3-oxo-androsta-1,4-diene-17 ⁇ -carbothioic acid S-fluoromethyl ester (fluticasone furoate), 6 ⁇ ,9 ⁇ -difluoro
  • 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-11 ⁇ -hydroxy-16 ⁇ -methyl-3-oxo-17 ⁇ -(2,2,3,3-tetramethycyclopropylcarbonyl)oxy-androsta-1,4-diene-17 ⁇ -carbothioic acid S-cyano methylester, 6 ⁇ ,9 ⁇ -difluoro-11 ⁇ -hydroxy-16 ⁇
  • the corticosteroid is 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.
  • a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, together with 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.
  • 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.
  • a corticosteroid such as fluticasone propionate or 6 ⁇
  • a combination comprising a compound which is N-(4- ⁇ 4-[(6-butyl-8-quinolinyl)oxy]-1-piperidinyl ⁇ butyl)ethanesulfonamide, or a pharmaceutically acceptable salt (such as a dihydrochloride salt) thereof together with 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).
  • the combination is suitable for intranasal administration.
  • 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.
  • PDE phosphodiesterase
  • leukotriene antagonists inhibitors of leukotriene synthesis (eg. montelukast), iNOS (inducible nitric oxide synthase) inhibitors (e.g
  • chemokine antagonists such as a CCR1, CCR2, CCR3, CCR4, or CCR8 antagonists
  • 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 selective 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 cis-4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-carboxylic acid, 2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-one and cis-[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-ol].
  • cis-4-cyano-4-[3-(cyclopentyloxy)-4-methoxyphenyl]cyclohexane-1-carboxylic acid also known as cilomilast
  • salts, esters, pro-drugs or physical forms which is described in U.S. Pat. No. 5,552,438 issued 3 Sep. 1996.
  • PDE4 inhibitors include AWD-12-281 from Elbion (Hofgen, N. et al., 15th EFMC Int. Symp. Med. Chem ., (September 6-10, Edinburgh) 1998, Abst. P. 98; CAS reference No.
  • PDE4 inhibitors 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).
  • a particular compound of interest is 6-( ⁇ 3-[(dimethylamino)carbonyl]phenyl ⁇ sulfonyl)-8-methyl-4- ⁇ [3-(methyloxy)phenyl]amino ⁇ -3-quinolinecarboxamide or a pharmaceutically acceptable salt thereof, which is described in International Patent Application WO04/103998.
  • a combination comprising a compound which is N-(4- ⁇ 4-[(6-butyl-8-quinolinyl)oxy]-1-pipendinyl ⁇ butyl)ethanesulfonamide, or a pharmaceutically acceptable salt (such as a dihydrochloride salt) thereof together with 6-( ⁇ 3-[(dimethylamino)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 /M 3 or M 2 /M 3 , receptors or pan-antagonists of the M 1 /M 2 /M 3 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).
  • 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,
  • anticholinergic agents include compounds which are disclosed in U.S. patent application 60/487,981, published as WO2005/009439 and those compounds disclosed in U.S. patent application 60/511,009, 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 or simultaneously in combined pharmaceutical compositions. Appropriate doses of known therapeutic agents will be readily appreciated by those skilled in the art.
  • 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 ⁇ 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, 5.3-5.5 min 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 II 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 ⁇ 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.
  • XRPD analysis was performed on a PANalytical X′Pert Pro X-ray powder diffractometer, model X′ Pert Pro PW3040/60, serial number DY1850 using an X′Celerator detector.
  • the acquisition conditions were: radiation: Cu K, generator tension: 40 kV, generator current: 45 mA, start angle: 2.000° 20, end angle: 39.997 °2 ⁇ , step size: 0.0167, time per step: 31.75 seconds.
  • the sample was prepared by backfilling. The margin of error is approximately ⁇ 0.1 °2 ⁇ for each of the peak assignments.
  • a solution of concentrated sulphuric acid (63 ml, 820 mmol) in water (49.4 ml) was treated with sodium 3-nitro-benzenesulfonate (commercially available, for example, from Aldrich) (47.9 g, 213 mmol) and glycerol (commercially available, for example, from Fluka and/or Aldrich) (52 ml, 720 mmol) to give a thick grey suspension. This was heated to 110° C. (internal temperature was 85° C.).
  • 1,1-Dimethylethyl 4-[(6-butyl-8-quinolinyl)oxy]-1-piperidinecarboxylate (for example, as prepared for Intermediate 3) (21.5 g, 56 mmol) was dissolved in DCM (50 ml) and trifluoroacetic acid (50 ml) was added very slowly. The mixture was stirred at room temperature for 1 h. The solvent was evaporated to dryness and the residue treated with saturated aqueous sodium carbonate solution. The mixture was extracted with EtOAc ( ⁇ 2), washed with water, and dried (MgSO 4 ). The drying agent was removed by filtration and the filtrate was evaporated to dryness (22 g).
  • sodium 3-nitro-benzenesulfonate commercially available, for example, from Aldrich
  • glycerol commercially available, for example, from Fisher and/or Aldrich
  • 6-Chloro-8-fluoroquinoline (for example, as prepared for Intermediate 5) (2.18 g, 12 mmol) was dissolved in NMP (20 ml) and treated with 1,1-dimethylethyl 4-hydroxy-1-piperidinecarboxylate (commercially available, for example, from Acros and/or Aldrich) (4.85 g, 24 mmol) and sodium tert-butoxide (2.38 g, 25 mmol). Further NMP was added (5 ml) and the resulting mixture was stirred at 140° C. for 1 h, and then allowed to cool overnight. The reaction mixture was treated with water and extracted with toluene.
  • NMP 1,1-dimethylethyl 4-hydroxy-1-piperidinecarboxylate
  • sodium tert-butoxide (2.38 g, 25 mmol
  • 1,1-Dimethylethyl 4-[(6-chloro-8-quinolinyl)oxy]-1-piperidinecarboxylate (for example, as prepared for Intermediate 6) (2.73 g, 7.5 mmol) was dissolved in a mixture of THF (55 ml), NMP (5.6 ml) and iron (III) acetylacetonate (220 mg, 0.62 mmol) were added, and the mixture was cooled to 0° C. and stirred under a nitrogen atmosphere.
  • n-Pentyl magnesium bromide (commercially available, for example, from TCI-Europe and/or Aldrich) was added dropwise over 9 min. The stirring was continued at 0° C.
  • the aqueous phase was extracted with DCM and the combined organic solutions were dried (MgSO 4 ), filtered, and the filtrate was treated with m-chloroperbenzoic acid (commercially available, for example, from Aldrich) (1 g, 57-86% pure, at least 3 mmol) and the mixture was stirred at room temperature overnight.
  • the reaction mixture was diluted with DCM and washed with sodium bicarbonate solution.
  • the organic solution was washed with aqueous sodium metabisulfite solution ( ⁇ 2), aqueous sodium bicarbonate solution, dried (MgSO 4 ) and evaporated under reduced pressure.
  • Sodium ethanethiolate (commercially available, for example from Aldrich) (840 mg, 10 mmol) was added portionwise over 10 min to a solution of 1,3-propanediol ditosylate (commercially available, for example, from Aldrich) (3.84 g, 10 mmol) in DMF (25 ml) at room temperature under nitrogen and the mixture was stirred for 3 days and then heated to 75° C. for 4 h. The solvent was removed under reduced pressure and the residue was partitioned between EtOAc and aqueous sodium bicarbonate. The organic solution was washed with aqueous sodium bicarbonate, dried (MgSO 4 ) and evaporated under reduced pressure.
  • 1,3-propanediol ditosylate commercially available, for example, from Aldrich
  • Ethyl crotonate (commercially available, for example, from Aldrich) (2.37 g, 20.8 mmol) was dissolved in DMF (60 ml) and stirred at room temperature.
  • Sodium ethanethiolate (commercially available, for example, from Aldrich) (1.66 g, 19.7 mmol) was added portionwise. On completion of the addition, the mixture was stirred at room temperature overnight. The mixture was diluted with water and extracted with EtOAc ( ⁇ 3). The combined organic solutions were dried (MgSO 4 ), and concentrated in vacuo, for an extensive period of time to remove excess DMF.
  • 6-Butyl-8-(4-piperidinyloxy)quinoline (for example, as prepared for Intermediate 4) (2.44 g, 8.59 mmol) was stirred with 2-(2-bromoethyl)-1H-isoindole-1,3(2H)-dione (commercially available, for example, from Acros and/or Aldrich) (2.40 g, 9.4 mmol) and potassium carbonate (5.9 g, 43 mmol) in 2-butanone (75 ml) under nitrogen at 80° C. for 3 days.
  • 2-(2-bromoethyl)-1H-isoindole-1,3(2H)-dione commercially available, for example, from Acros and/or Aldrich
  • 6-Butyl-8-(4-piperidinyloxy)quinoline (for example, as prepared for Intermediate 4) (437 mg, 1.54 mmol) was stirred with 1,1-dimethylethyl (3-bromopropyl)carbamate (commercially available, for example, from Aldrich) (612 mg, 2.57 mmol) and potassium carbonate (426 mg, 3.15 mmol) in 2-butanone (15 ml) under nitrogen at 80° C. overnight. The mixture was cooled and partitioned between water and DCM. The aqueous layer was extracted with more DCM ( ⁇ 2) and the combined organic layers were washed with brine, dried (MgSO 4 ) and evaporated to give a yellow gum.
  • 1,1-dimethylethyl (3-bromopropyl)carbamate commercially available, for example, from Aldrich
  • 6-butyl-8-(4-piperidinyloxy)quinoline (for example, as prepared for Intermediate 4) (855 mg, 3.0 mmol) was stirred with 1,1-dimethylethyl (4-bromobutyl)carbamate (commercially available, for example, from Fluka) (1.12 g, 4.5 mmol) and potassium carbonate (887 mg, 6.4 mmol) in 2-butanone (30 ml) under nitrogen at 80° C. overnight. The mixture was cooled and concentrated in vacuo. The residue was partitioned between water (25 ml) and DCM (25 ml).
  • 1,1-dimethylethyl (4- ⁇ 4-[(6-butyl-8-quinolinyl)oxy]-1-piperidinyl ⁇ butyl) carbamate (for example, as prepared for Intermediate 32) (1.29 g, 2.84 mmol) was dissolved in MeOH (10 ml) and treated with a solution of hydrogen chloride in dioxane (4 M, 30 ml). The mixture was stirred under nitrogen for 3 h at room temperature. The mixture was concentrated in vacuo. The residue was dissolved in methanol, and applied to a SCX-2 ion exchange cartridge (50 g, pre-conditioned with methanol).
  • the reaction mixture was applied to an SCX-2 cartridge (10 g), preconditioned with methanol, and eluted with methanol, followed by 10% aqueous 0.88 s.g. ammonia in methanol.
  • the ammoniacal fractions were combined and concentrated in vacuo and the residue (126 mg) was purified by MDAP.
  • Appropriate fractions were combined and concentrated in vacuo and the residue (30 mg) was applied to an SCX-2 cartridge (5 g), pre-conditioned with methanol and eluted with methanol, followed by 10% aqueous 0.88 s.g. ammonia in methanol.
  • the reaction mixture was applied to an SCX-2 cartridge (20 g), preconditioned with methanol, and eluted with methanol, followed by 10% aqueous 0.88 s.g. ammonia in methanol. The ammoniacal fractions were combined and concentrated in vacuo.
  • the residue (160 mg) was purified by MDAP to give the formate salt of the title compound (102 mg, 73%).
  • the reaction was applied to an SCX-2 cartridge (20 g), preconditioned with methanol, and the cartridge washed with methanol (2 column volumes).
  • the cartridge was eluted with 10% 0.880 s.g. ammonia in methanol (2 column volumes) and the basic fractions concentrated in vacuo.
  • the residue was purified by MDAP and the appropriate fractions combined and evaporated.
  • the combined fractions were applied to an SCX-2 cartridge (20 g), preconditioned with methanol, and the cartridge washed with methanol.
  • the cartridge was eluted with 10% 0.88 s.g. ammonia in methanol (2 column volumes) and the basic fractions concentrated in vacuo to give the title compound (17 mg, 8%).
  • LCMS RT 2.59 min, ES+ve m/z 403 (M+H) + .
  • 6-Butyl-8-(4-piperidinyloxy)quinoline (for example, as prepared for Intermediate 4) (575 mg, 2.02 mmol) and 4-[(ethylsulfonyl)amino]butyl ethanesulfonate (for example, as prepared for Intermediate 40) (1.10 g, impure, estimated as 2.8 mmol) were dissolved in DMF (20 ml). Sodium hydrogen carbonate (845 mg, 10.1 mmol) and sodium iodide (602 mg, 4.02 mmol) were added. The mixture was heated at 60° C. with stirring overnight (16 h) under a nitrogen atmosphere.
  • 6-chloro-8-fluoroquinoline (for example, as prepared for Intermediate 5) (4.6 kg, 1.0 eqv) was added to N-methylpyrrolidinone (46 L, 10 vol).
  • ferric acetylacetonate (0.89 kg, 0.1 eqv) was added and the reaction mass cooled to 0 to ⁇ 10° C.
  • a solution of n-butyl magnesium chloride (commercially available, for example, from Aldrich) (14.84 L, 1.35 eqv of 2.3M grignard in tetrahydrofuran) was added slowly over approximately 4 hours at between 0 to ⁇ 10° C. and the reaction was stirred for 10 to 20 min. The progress of the reaction was monitored by HPLC.
  • a dilute solution of aqueous HCl (3.5 vol, 14.6 L [made up as bulk solution of 4.6 L 35% HCl in 13.8 L water]) was then added into the reaction mixture until pH 1-2 was reached.
  • the reaction mass was extracted at pH 1 to 2 with ethyl acetate (46 L, then 28 L ⁇ 3).
  • the combined organic layers were then washed with water (69 L, 15 vol) and dilute ammonia solution (46 L [41.4 L water and 4.6 L 22.38% aqueous ammonia solution).
  • the organic layer was washed with water (55.2 L ⁇ 3), the organic layer was separated and concentrated in vacuo (vacuum no less than 600 mm Hg), keeping the temperature below 70° C.
  • Toluene (4.6 L, 1 vol) was then added and the mixture concentrated in vacuo (vacuum no less than 600 mm Hg), keeping the temperature below 70° C. to a crude oil to remove traces of ethyl acetate.
  • the residue was diluted in toluene (6.9 L, 1.5 vol) and added to n-hexane (138 L, 30 vol) with stirring at 25-35° C.
  • N-Boc-4-hydroxypiperidine (commercially available, for example, from Aldrich) (11.66 kg, 1.5 eqv) and sodium Pert-butoxide (5.5 kg, 1.5 eqv) was charged into a reactor containing N-methylpyrrolidinone (39.25 L, 5 vol) and stirred at approximately 25° C. to obtain a clear solution.
  • 6-butyl-8-fluoroquinoline (for example, as obtained from Stage 1) (7.85 kg, 1.0 eqv) and N-methylpyrrolidinone (31.4 L, 4 vol) under nitrogen and heated to approximately 110° C. over 1-3 hr.
  • the aqueous layer was slowly basified with sodium hydroxide solution (7.85 kg in 54.95 L water) until pH was 12.5 to 13.5.
  • the product was extracted in dichloromethane (78.5 L, 10 vol, then 39.25 L, 5 vol, x 2).
  • the combined dichloromethane layers were washed with aqueous sodium chloride solution (7.85 kg in 78.5 L water, x 3).
  • the combined organics were concentrated in vacuo (vacuum no less than 600 mm Hg) keeping the temperature below 50° C.
  • N,N′-dimethylformamide (23.6 L, 3 vol) was added and the reaction mass was held at a vacuum of no less than 650 mm Hg, keeping the temperature below 50° C.
  • the title compound (3.76 kg, 34.24% yield) was obtained as solution in N,N′-dimethylformamide and stored at approximately 5° C.
  • Iso-propylalcohol (7.8 L, 3 vol) was added and the reaction mass was concentrated in vacuo (vacuum no less than 600 mm Hg), keeping the te,perature below 70° C.
  • iso-propylalcohol (26 L, 10 vol) was added, and warmed to 50-60° C. to give a clear solution.
  • This solution was cooled to 35-45° C. and n-hexane (26 L, 10 vol) was added slowly and then cooled to 25-35° C.
  • the reaction mass was stirred for 1.5 to 2.5 hr and filtered by centrifugation.
  • the wet cake was washed with n-hexane (31 L, 11.9 vol) and filtered again by centrifugation.
  • the material was dried in vacuo (vacuum no less than 650 mm Hg) for 10-12 hr at 50-55° C.
  • the title compound was isolated in 78.36% yield (7.1 kg) and 99.6% purity.
  • reaction mass was warmed to about 70-80° C. and maintained at that temperature for 10-12 hr.
  • the reaction was monitored by HPLC (starting material not more than 1.5%).
  • the reaction mixture was cooled to 30-40° C.
  • the reaction mixture was diluted with water (37.6 L, 10 vol) followed by toluene (37.6 L, 10 vol).
  • activated carbon (0.38 kg, 0.1 wt) and celite (0.94 kg, 0.25 wt) and warmed to 50-60° C. for 15-30 min.
  • the reaction mixture was stirred and cooled to 25-35° C., then filtered over celite (celite bed made with 1 kg celite, 18.8 L water, 5 vol).
  • the celite bed was then washed with hot (50-60° C.) toluene (18.8 L, 5 vol).
  • the combinted filtrates were separated and the aqueous layer was extracted with toluene (18.8 L, 5 vol, ⁇ 3).
  • the combined organic layers were washed with water (37.6 L, 10 vol, ⁇ 3).
  • the organic layer was washed with concentrated [37.36%] aqueous HCl (22.56 L, 6 vol) and the aqueous HCI layer containing product was collected.
  • the aqueous HCI layer was then heated to reflux (110-120° C.) and 5-10% of solvent was distilled off. Reflux was then continued for a further 10-12 hr.
  • the pH of the aqueous layer containing product was slowly adjusted to pH 8 to 9 keeping the temperature at appromiately 30° C. by adding sodium hydroxide solution (2 L NaOH solution [made with 11.28 kg NaOH and 22.56 L water]).
  • the aqueous layer was then extracted with dichloromethane (37.6 L, 10 vol, then 18.8 L, 5 vol, then 11.28 L, 3 vol), and the combined organics were washed with a solution of dilute ammonia (37.6 L ammonia solution [15.04 L ammonia (22.38%) and 22.56 L water]) and iso-propylalcohol (18.8 L, 5 vol), followed by dilute ammonia (37.6 L ammonia solution, [15.04 L ammonia (22.38%) and 22.56 L water] ⁇ 2).
  • Example 23B (Stage 5)
  • reaction temperature was adjusted to 25-35° C. and stirred for 2-3 hr.
  • a sample was analysed by HPLC to monitor reaction progress.
  • the reaction mixture was quenched at 25-35° C. with water (25.7 L, 10 vol).
  • the organic layer was separated and the aqueous layer extracted with dichloromethane (7.71 L, 3 vol).
  • the combined organics were washed with citric acid solution (5.14 kg, 2 wt dissolved in 25.7 L water, 10 vol).
  • aqueous citric acid solution (0.77 kg, 0.3 wt, dissolved in 3.34 L water, 1.3 vol) and the organic layer was separated.
  • the combined aqueous layers were washed with dichloromethane (12.8 L, 5 vol).
  • Dilute ammonia solution (12.85 L ammonia (22.38%) dissolved in 12.85 L water) was then added to the aqueous layer keeping the temperature at 30-35° C., until the pH reached was between 10-12.
  • the product from the aqueous layer was then extracted with dichloromethane (25.7 L, 10 vol, then 7.71, 3 vol) and the combined organics were again washed with dilute ammonia solution (5.14 L ammonia (22.38%) dissolved in 5.14 L water).
  • the organic layer was finally washed twice with water (25.7 L, 10 vol) then 50-80% solvent was removed by distillation under atmospheric pressure, keeping the temperature below 55° C.
  • the reaction mixture was then concentrated in vacuo (vacuum no less than 600 mm Hg) keeping the temperature below 50° C.
  • iso-propylalcohol (7.71 L, 3 vol) was added and concentrated in vacuo (vacuum no less than 600 mm Hg) keeping the temperature below 50° C.
  • reaction mass was then concentrated in vacuo (vacuum no less than 650 mm Hg) until a syrup remained which started to solidify, then methanol (12.85 L, 5 vol) was added to the residue to obtain a clear solution.
  • the reaction mass was then stirred at 30-35° C., and ethyl acetate (51.4 L, 20 vol) was added.
  • the reaction mass was then stirred for 1-2 hr at 25-35° C. and then cooled to 5-10° C. for 1-2 hr, then centrifuged.
  • the solid was then washed with methanol:ethyl acetate mixture (1:7, 2.57 L methanol in 17.99 L ethyl acetate) at 5-10° C. and centrifuged.
  • the product was dried in vacuo (vacuum no less than 650 mm Hg) at 50-55° C. for 8-12 hrs.
  • the title compound was obtained in 53.15% yield (2 kg).
  • Ethyl acetate (4.4 L, 2.2 vol) was slowly added into the reaction mixture, which was then seeded with N-(4- ⁇ 4-[(6-butyl-8-quinolinyl)oxy]-1-piperidinyl ⁇ butyl)ethanesulfonamide, dihydrochloride salt (0.0048 kg, 0.0024 wt) and aged isothermally for 30-45 min at 25-30° C. Further ethyl acetate (35.6 L, 17.8 vol) was added slowly over 2-2.5 hr, keeping the temperature between 25-30° C., then stirred at this temperature for 30 min. The reaction mixture was slowly cooled to 0-10° C., and stirred at this temperature for an additional 2-3 hrs.
  • the product was filtered through a centrifuge and washed with pre-chilled (0-10° C.) ethyl acetate (4 L, 2 vol). The cake was offloaded, spin-dried then dried in vacuo (vacuum no less than 600 mm Hg) at 55-60° C. for 12-14 hrs to give the title compound in 85.55% yield (1.72 kg) and 98.59% purity.
  • a portion of the formate salt (47 mg, 0.092 mmol) in methanol (1.5 ml) was treated with 1.25 M hydrogen chloride in methanol (0.5 ml, 0.6 mmol). The solvent was removed using a stream of nitrogen to give the title compound as a yellow solid (49 mg).
  • 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)].
  • 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/Invitrogen, cat no. 22561-021), supplemented with 10% dialysed foetal calf serum (Gibco/Invitrogen cat no. 12480-021) and 2 mM L-glutamine (Gibco/Invitrogen cat no 25030-024) and is maintained overnight at 5% CO 2 , 37° C.
  • alpha minimum essential medium Gibco/Invitrogen, cat no. 22561-021
  • dialysed foetal calf serum Gibco/Invitrogen cat no. 12480-021
  • 2 mM L-glutamine Gibco/Invitrogen cat no 25030-024
  • FLIPRTM Molecular Devices, UK
  • Functional antagonism is indicated by a suppression of histamine induced increase in fluorescence, as measured by the FLIPRTM system (Molecular Devices). By means of concentration effect curves, functional affinities are determined using standard pharmacological mathematical analysis.
  • histamine H1 receptor expressing CHO cells are seeded into non-coated black-walled clear bottom 96-well tissue culture plates as described above.
  • the resultant concentration response curves are analysed by non-linear regression using a standard four parameter logistic equation to determine the histamine EC 50 , 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° 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° 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 U.S. Pat. Nos.: 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 ⁇ grml ⁇ 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 K 1 cells previously transfected with the pSwitch regulatory plasmid (InVitrogen) are seeded at 2 ⁇ 10 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 N-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 N-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 cell pellet is resuspended in 10 volumes of homogenisation buffer (50 mM N-2-hydroxyethylpiperazine-N′-2-ethanesulfonic acid (HEPES), 1 mM ethylenediamine tetra-acetic acid (EDTA), pH 7.4 with KOH, supplemented with 10 ⁇ 6 M leupeptin (acetyl-leucyl-leucyl-arginal; Sigma L2884), 25 ⁇ gml ⁇ 1 bacitracin (Sigma B0125), 1 mM phenylmethylsulfonyl fluoride (PMSF) and 2 ⁇ 10 M pepstain A (Sigma)).
  • HEPES N-2-hydroxyethylpiperazine-N′-2-ethanesulfonic acid
  • EDTA mM ethylenediamine tetra-acetic acid
  • pH 7.4 with KOH pH 7.4 with KOH
  • 10 ⁇ 6 M leupeptin ace
  • the cells are then homogenised by 2 ⁇ 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° C.
  • Histamine H3 Functional Antagonist Assay For each compound being assayed, in a solid white 384 well plate, is added:— (a) 0.5 ⁇ l of test compound diluted to the required concentration in DMSO (or 0.5 ⁇ l DMSO as a control); (b) 30 ⁇ l 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 N-2-hydroxyethylpiperazine-N′-2-ethanesulfonic acid (HEPES)+100 mM NaCl+10 mM MgCl 2 , pH 7.4 NaOH) to give a final volume of 30 ⁇ l which contains 5 ⁇ g protein, 0.25 mg bead per well and 10 ⁇ M final assay concentration of guanosine 5′
  • 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.
  • Female Dunkin-Hartley guinea pigs 150-250 g are sensitised twice daily for 5 days (week 1) with ovalbumin (OVA) and aluminium hydroxide (Al(OH) 3 or Alum) in physiological saline, 25 ⁇ l/nostril. Solution is made up at 20 ⁇ g/ml OVA, 180 mg/ml Alum. During weeks 2 and 3 animals receive 25 ⁇ l/nostril of OVA (5 mg/ml) once daily. During Week 4 guinea pigs will be entered into study but are continually sensitized as per weeks 2 and 3 until the day before dosing with compound or vehicle.
  • OVA ovalbumin
  • Al(OH) 3 or Alum aluminium hydroxide
  • Test compounds are formulated as solutions in 0.9% sterile saline or suspensions in 0.9% sterile saline/tween80.
  • Guinea pigs were anaesthetised with isoflurane (5%, 2-3 l/min O 2 ), placed in a supine position, and 25 ⁇ l of test compound or vehicle dosed into each nostril using a Gilson pipette. After dosing, animals remain supine for at least 30 seconds (e.g. 60 seconds) during recovery from anaesthesia.
  • guinea pigs are dosed with atropine sulphate (Sigma A0257, dissolved in saline), 1 mg/kg i.p. Animals are then placed into whole body plethysmograph systems (Buxco® Electronics) where the parameter PenH area under curve (AUC) is recorded as outlined in Hamelmann, E., Schwarze, J., Takeda, K., Oshiba, A., Larsen, L., Irvin, C. G. & Gelfand, E. W. (1997), Noninvasive measurement of airway responsiveness in allergic mice using barometric plethysmography., Am. J. Respir. Crit. Care Med., 156, 766-775. A 10 minute baseline AUC is recorded and if this value is over 1000, the animals are excluded.
  • guinea pigs are re-anaesthetised with isoflurane and dosed with either 10 mM or 15 mM histamine or phosphate-buffered saline (PBS), (25 ⁇ l per nostril).
  • PBS phosphate-buffered saline
  • On recovery from anaesthesia animals are returned to the individual plethysmograph chambers and 4 ⁇ 10 min consecutive PenH AUC recordings are made. These recordings are summed to give a cumulative AUC over 40 mins post histamine challenge for each animal. Data are analysed using ANOVA with post-hoc Fishers LSD test (general linear models, Statistica®) and finally Hochberg adjustment. Inhibition of histamine-induced congestion is determined by statistically significant differences between the mean responses of compound pre-treated groups compared to the vehicle pre-treated, histamine-challenged group.
  • Compounds are dosed intravenously at a nominal dose level of 1 mgkg ⁇ 1 to male CD Sprague Dawley rats. Compounds are formulated in 5% DMSO/45% PEG200/50% water. Blood samples are taken under terminal anaesthesia with isoflurane at 5 min post-dose and the brains are also removed for assessment of brain penetration. Blood samples are taken directly into heparinised tubes. Blood samples are prepared for analysis using protein precipitation and brain samples are prepared using extraction of drug from brain by homogenisation and subsequent protein precipitation. The concentration of parent drug in blood and brain extracts is determined by quantitative LC-MS/MS analysis using compound-specific mass transitions.
  • a loading dose of the compounds is given to male CD Sprague Dawley rats at a nominal dose level of 0.4 mgkg ⁇ 1 .
  • the compounds are then infused intravenously for 4 h at a nominal dose level of 0.1 mgkg ⁇ 1 h ⁇ 1 .
  • Compounds are formulated in 2% DMSO/30% PEG200/68% water.
  • Serial or terminal blood samples are taken at 0.5, 1.5, 2.5, 3, 3.5 and 4 h post dose. The final blood sample is collected under terminal anaesthesia with isoflurane and the brains are also removed for assessment of brain penetration.
  • Blood samples are taken directly into heparinised tubes. Blood samples are prepared for analysis using protein precipitation and brain samples are prepared using extraction of drug from brain by homogenisation and subsequent protein precipitation. The concentration of parent drug in blood and brain extracts is determined by quantitative LC-MS/MS analysis using compound-specific mass transitions.
  • Examples 1, 13, 14, 15 and 16 had an average pK i (pK b ) at H1 of approximately greater than 7. The remaining Examples had an average pK i (pK b ) at H1 of approximately greater than 8.
  • Examples 8, 12 and 13 had average pA2 values of greater than approximately 7.
  • Examples 1, 3, 9, 10, 14, 15, 16, 17, 25, 28, 29, 33 and 35 had average pA2 values of greater than approximately 8.
  • Examples 2, 5, 6, 7, 11, 18, 19, 22, 23B, 24, 26, 31, 32, 34 and 36 had average pA2 values of greater than approximately 9.
  • the compounds of the Examples had an average pK i (pK b ) at H3 of less than 6.5.
  • the compounds of Example 4A and Example 23B demonstrated low CNS penetration.
  • aqueous pharmaceutical compositions of the invention may be prepared according to the following general method:
  • the isotonicity adjusting agent(s) is charged into a suitable mixing vessel containing purified water and dissolved with stirring.
  • the suspending/thickening agent(s) is then charged into the mixing vessel and dispersed throughout the solution.
  • the resulting suspending vehicle is allowed to hydrate for an appropriate period of time to ensure cross-linkage and gelation, which may take 60 minutes or longer.
  • Preservative(s) is pre-dissolved in purified water in a separate vessel, optionally with heating, for example to 50-60° C. depending on the preservative chosen, to aid dissolution, and then added to the thickened isotonicity adjusting agent(s) solution with continuous stirring.
  • Buffering agents if included, are dissolved in a minimum amount of purified water, optionally heated, for example to about 50-60° C. as appropriate depending on the buffering agents chosen, and stirred to dissolve in separate containers. The separate solutions are combined, mixed well and then added to the bulk solution with continuous stirring.
  • the wetting agent(s) is mixed with purified water which optionally may be heated, for example to about 50-60° C. as appropriate depending on the wetting agent(s) chosen, and stirred to dissolve.
  • a slurry or solution of active compound(s) is then prepared by adding the resultant wetting agent(s) solution to the active compound(s), which may be particle size reduced for example micronised, and mixed prior to homogenising/refining.
  • additional preservative(s), if needed, may be mixed with purified water and stirred to dissolve.
  • the dispersion and refining of the slurry/solution of active compound(s) is added to the mixing vessel containing the suspending/thickening agent and dispersed with stirring.
  • any additional preservative may be added to the bulk suspension/solution and dispersed with continuous stirring.
  • the suspension is made to its final mass by adding water and stirred.
  • Co-solvent(s), if included, may be added before or after the addition of the buffering agents. Alternatively, the co-solvent(s) may be added during the formation of the drug slurry or solution.
  • Preservative(s), if included, may be added before or after the addition of the suspending/thickening agent(s).
  • Fluticasone furoate is used in its unsolvated form as polymorphic Form 1.
  • the preparation of fluticasone furoate (6 ⁇ , 9 ⁇ -difluoro-17 ⁇ -[(2-furanylcarbonyl)oxy]-1,6-hydroxy-16 ⁇ -methyl-3-oxo-androsta-1,4-diene-17 ⁇ -carbothioic acid S-fluoromethyl ester), solvates and polymorphs thereof including polymorphic Form 1, and biological activity thereof, are disclosed in International Patent Application WO02/12265 and International Patent Application WO03/066024 incorporated fully herein by reference.
  • N-(4- ⁇ 4-[(6-butyl-8-quinolinyl)oxy]-1-piperidinyl ⁇ butyl)ethanesulfonamide is used in the form of the dihydrochloride salt, optionally as polymorphic form 1.
  • Example Composition 1 May be Made According to the Following Procedure
  • the citric acid is dissolved in approximately 10 mL of water, and, in another vessel, the sodium citrate is dissolved in 10 mL of water.
  • the vessels are heated with stirring (without boiling) to aid dissolution. Once the citric acid and sodium citrate are dissolved, they are combined and mixed thoroughly.
  • the buffer is then added to the bulk suspension with mixing (Silverson mixer).
  • the polysorbate 80 is dissolved in approximately 10 mL of water with heat and stirring (without boiling) to aid dissolution.
  • the propylene glycol is added to the polysorbate 80 solution.
  • N-(4- ⁇ 4-[(6-butyl-8-quinolinyl)oxy]-1-piperidinyl ⁇ butyl)ethanesulfonamide in the form of the dihydrochloride salt
  • the drug substance is wetted by mixing with a spatula or alternatively placing in a sealed container and shaking on a shaker until all the drug is wetted.
  • the drug mixture is homogenised (small Silverson head or small Ultra Turrax) to disperse and/or dissolve the drug substance for approximately 2-3 minutes.
  • the drug mixture is added to the bulk suspension and mixed (Silverson mixer).
  • any remaining polysorbate 80 solution and propylene glycol is added to the bulk suspension.
  • the drug mixture vessel, polysorbate 80 vessel and propylene glycol vessel are rinsed with water (small Silveron head or Ultra Turrax) and the rinsings are added to the bulk solution.
  • the potassium sorbate is dissolved in approximately 5 mL of water with stirring and heat (without boiling) to aid dissolution.
  • the potassium sorbate solution is added to the bulk solution with stirring (Silverson mixer).
  • the tared beaker is made up to the final weight with water (500 g) and mixed for a further 3 minutes.
  • Example Compositions 1 to 8 the concentation of micronised N-(4- ⁇ 4-[(6-butyl-8-quinolinyl)oxy]-1-piperidinyl ⁇ butyl)ethanesulfonamide is given as the free base, which concentrations are 0.025% (w/w), 0.05% (w/w), 0.1% (w/w), 0.25% (w/w), 0.5% (w/w) and 0.9% (w/w), based on the total weight of the composition.
  • N-(4- ⁇ 4-[(6-butyl-8-quinolinyl)oxy]-1-piperidinyl ⁇ butyl)ethanesulfonamide may be used in the form of a pharmaceutically acceptable salt at an appropriate concentration, depending on the salt chosen, such as to provide the desired concentration of free base.
  • Example compositions may be filled into suitable containers depending on the chosen route of administration.
  • suitable containers are described hereinabove and typically are made of plastics and dispense 50 to 100 ⁇ L of composition per actuation.
US12/673,027 2007-08-15 2008-08-13 Substituted quinoline derivatives as h1 receptor antagonists Abandoned US20110281909A1 (en)

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