US20070060563A1 - Quinuclidine derivatives binding to mucarinic m3 receptors - Google Patents

Quinuclidine derivatives binding to mucarinic m3 receptors Download PDF

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US20070060563A1
US20070060563A1 US10/554,558 US55455804A US2007060563A1 US 20070060563 A1 US20070060563 A1 US 20070060563A1 US 55455804 A US55455804 A US 55455804A US 2007060563 A1 US2007060563 A1 US 2007060563A1
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alkyl
carbocyclic group
sulphur
nitrogen
oxygen
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Stephen Collingwood
Brian Cox
Gurdip Bhalay
Nicholas Devereux
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Novartis AG
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Priority claimed from GB0324887A external-priority patent/GB0324887D0/en
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Priority to US12/582,291 priority Critical patent/US8168654B2/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
    • C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
    • 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
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • 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
    • A61P11/08—Bronchodilators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • 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
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • This invention relates to organic compounds, their preparation and use as pharmaceuticals.
  • the invention provides compounds of formula I in salt or zwitterionic form wherein R 1 and R 3 are each independently a C 3 -C 15 -carbocyclic group or a 4- to 12-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur, or —CR 1 R 2 R 3 together form a group of formula where R is a bond, —O—, —S—, —CH 2 —, —CH ⁇ CH—, —CH 2 —CH 2 —, amino or —N(CH 3 )—; R 2 is hydrogen, halo, hydroxy, C 1 -C 8 -alkoxy or C 1 -C 8 -alkyl optionally substituted by hydroxy; R 4 is C 3 -C 10 -alkyl substituted by —NHR 5 , —NR 5 —CO—R 6 , —NR 5 —CO—NH—R 7 , —NRS—SO 2 —R 8 , ——R
  • Optionally substituted means the group referred to can be substituted at one or more positions, e.g. 1, 2 or 3 positions, by any one or any combination of the radicals described.
  • C 1 -C 8 -alkyl denotes straight chain or branched alkyl having 1 to 8 carbon atoms.
  • C 1 -C 8 -alkyl is C 1 -C 4 -alkyl.
  • C 1 -C 8 -alkylene denotes straight chain or branched alkylene that contains 1 to 8 carbon atoms.
  • C 1 -C 8 -alkylene is C 1 -C 4 -alkylene.
  • C 2 -C 8 -alkenyl denotes straight chain or branched hydrocarbon chains that contain two to eight carbon atoms and one or more carbon-carbon double bonds.
  • C 2 -C 8 -alkenyl is “C 2 -C 4 -alkenyl”.
  • C 2 -C 10 -alkynyl denotes straight chain or branched hydrocarbon chains that contain two to ten carbon atoms and one or more carbon-carbon triple bonds.
  • C 2 -C 10 -alkynyl is “C 3 -C 8 -alkynyl”.
  • C 3 -C 15 -carbocyclic group denotes a carbocyclic group having 3 to 15 ring carbon atoms, for example a monocyclic group, either cycloaliphatic, such as a C 3 -C 8 -cycloalkyl, or aromatic such as phenyl, which can be substituted by one or more, usually one or two, C 1 -C 4 -alkyl groups, or a bicyclic group such as bicyclooctyl, bicyclononyl including indanyl and indenyl, and bicyclodecyl including naphthyl, again any of which can be substituted by one or more, usually one or two, C 1 -C 4 -alkyl groups.
  • the C 3 -C 15 -carbocyclic group is a C 3 -C 10 -carbocyclic group, for example cyclopropyl, cyclopentyl, cyclohexyl, cyclohepcyl, phenyl, indanyl or naphthyl.
  • the C 3 -C 15 -carbocyclic group can be substituted or unsubstituted.
  • Preferred substituents include halo (e.g. fluoro, chloro or bromo), cyano, hydroxy, amino, nitro, carboxy, C 1 -C 8 -alkyl (e.g.
  • halo-C 1 -C 8 -alkyl C 1 -C 8 -alkoxy, C 1 -C 8 -alkylcarbonyl, C 1 -C 8 -alkylsulfonyl, —SO 2 NH 2 , a C 3 -C 15 -carbocyclic group and a 5- to 12-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur.
  • C 3 -C 8 -cycloalkyl denotes cycloalkyl having 3 to 8 carbon atoms.
  • C 3 -C 8 -cycloalkyl is “C 3 -C 6 -cycloalkyl”.
  • C 1 -C 8 -haloalkyl denotes C 1 -C 8 -alkyl as hereinbefore defined substituted by one or more halogen atoms, preferably one, two or three halogen atoms.
  • C 1 -C 8 -haloalkyl is “C 1 -C 4 -haloalkyl”.
  • C 1 -C 8 -alkylcarbonyl denotes C 1 -C 8 -alkyl as hereinbefore defined linked to a carbonyl group.
  • C 1 -C 8 -alkylcarbonyl is “C 1 -C 4 -alkylcarbonyl”.
  • C 1 -C 8 -alkylthio denotes C 1 -C 8 -alkyl as hereinbefore defined linked to —S—.
  • C 1 -C 8 -alkylthio is “C 1 -C 4 -alkylthio”.
  • C 1 -C 8 -alkylsulfonyl denotes C 1 -C 8 -alkyl as hereinbefore defined linked to —SO 2 —.
  • C 1 -C 8 -alkylsulfonyl is “C 1 -C 4 -alkylsulfonyl”.
  • C 1 -C 8 -alkoxy denotes straight chain or branched alkoxy having 1 to 8 carbon atoms.
  • C 1 -C 8 -alkoxy is C 1 -C 4 -alkoxy.
  • C 1 -C 8 -haloalkoxy denotes C 1 -C 8 -alkoxy as hereinbefore defined substituted by one or more halogen atoms, preferably one, two or three halogen atoms.
  • C 1 -C 8 -haloalkoxy is “C 1 -C 4 -haloalkoxy”.
  • di(C 1 -C 8 -alkyl)sulfamoyl denotes —SO 2 —NH 2 where the nitrogen atom is substituted at two positions by C 1 -C 8 -alkyl as hereinbefore defined, which may be the same or different.
  • di(C 1 -C 8 -alkyl)sulfamoyl is —SO 2 —N(CH 3 ) 2 .
  • Halo or halogen denotes a element belonging to group 17 (formerly group VII) of the Periodic Table of Elements, which may be, for example, fluorine, chlorine, bromine or iodine. Preferably halo or halogen is fluorine, chlorine or bromine.
  • Aminocarbonyl as used herein denotes amino attached through the nitrogen atom to a carbonyl group.
  • Monoheterocyclic groups include azetidinyl, tetrahydrofuranyl, furyl, pyrrolyl, pyrrolidinyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thienyl, thiazolyl, thiadiazolyl, isothiazolyl, oxadiazolyl, pyridinyl, oxazolyl, isoxazolyl, piperidinyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, piperazinyl, morpholinyl, triazinyl, oxazinyl, thiazolyl or tetrahydropyranyl.
  • Biheterocyclic groups include thienothienyl, benzazolyl, benzothienyl, benzimidazolyl, benzodioxinyl, indazolyl, benzothiazolyl, imidazopyridinyl and naphthyridinyl.
  • Preferred 4- to 12-membered heterocyclic groups include azetidinyl, tetrahydrofuranyl, furyl, pyrrolyl, pyrazolyl, triazolyl, thienyl, thiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, tetrahydropyranyl, piperidinyl, pyridinyl, pyrazinyl, pyrimidinyl, thienothienyl, benzazolyl, benzothienyl, benzimidazolyl, benzodioxinyl, indazolyl and benzothiazolyl, imidazopyridinyl, naphthyridinyl.
  • the 4- to 12-membered heterocyclic group can be unsubstituted or substituted at one or more positions, e.g. 1, 2 or 3 positions, by any one or any combination of substituents.
  • Preferred substituents include halo (e.g. fluoro, chloro or bromo), cyano, oxo, hydroxy, carboxy, nitro, C 1 -C 8 -alkyl (e.g. methyl or ethyl), halo-C 1 -C 8 -alkyl (e.g.
  • C 1 -C 8 -alkylcarbonyl di(C 1 -C 8 -alkyl)sulfamoyl and C 1 -C 8 -alkoxy optionally substituted by aminocarbonyl.
  • substituents include halo, oxo, C 1 -C 4 -alkyl and C 1 -C 4 -alkylcarbonyl.
  • the invention provides compounds of formula I in salt or zwitterionic form wherein R 1 and R 3 are each independently a C 3 -C 15 -carbocyclic group or a 4- to 12-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur, or —CR 1 R 2 R 3 together form a group of formula where R is a bond, —O—, —S—, —CH 2 —, —CH ⁇ CH—, —CH 2 —CH 2 —, amino or —N(CH 3 )—; R 2 is hydrogen, halo, hydroxy, C 1 -C 8 -alkoxy or C 1 -C 8 -alkyl optionally substituted by hydroxy; R 4 is C 1 -C 8 -alkyl substituted by —NHR 5 , —NR 5 —CO—R 6 , —NR 5 —CO—NH—R 7 , —NR 5 —SO 2 —R 8
  • the invention provides compounds of formula I in salt or zwitterionic form wherein R 1 and R 3 are each independently a C 3 -C 15 -carbocyclic group or a 5- to 12-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur, or —CR 1 R 2 R 3 together form a group of formula where R is a bond, —O—, —S—, —CH 2 —, —CH ⁇ CH—, —CH 2 —CH 2 —, amino or —N(CH 3 )—; R 2 is hydrogen, halo, hydroxy, C 1 -C 8 -alkoxy or C 1 -C 8 -alkyl optionally substituted by hydroxy; R 4 is C 1 -C 8 -alkyl substituted by —NHR 5 , —NR 5 —CO—R 6 , —NR 5 —CO—NH—R 7 , —NRS—SO 2 —R 8 ,
  • Preferred compounds include those of formula I in salt or zwitterionic form, where R 1 and R 3 are each independently a C 3 -C 15 -carbocyclic group or a 4- to 12-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur;
  • R 2 is halo or hydroxy
  • R 4 is C 1 -C 8 -alkyl substituted by —NHR 5 , —NR 5 —CO—R 6 , —NR 5 —CO—NH—R 7 , —NR 5 —SO 2 —R 8 , —CO—NR 9 R 10 , —O—CO—NH—R 12 , —O—CO—R 13 or —CO—O—R 14 ,
  • R 4 is C 3 -C 10 -alkynyl optionally substituted by a C 3 -C 15 -carbocyclic group or a 4- to 12-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur;
  • R 5 is hydrogen or C 1 -C 8 -alkyl
  • R 6 is C 1 -C 8 -alkyl, C 2 -C 10 -alkynyl or C 1 -C 8 -alkoxy in each case optionally substituted by a C 3 -C 15 -carbocyclic group or a 4- to 12-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur,
  • R 6 is a C 3 -C 15 -carbocyclic group or a 4- to 12-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur;
  • R 7 is a C 3 -C 15 -carbocyclic group
  • R 8 is a C 3 -C 15 -carbocyclic group
  • R 9 is hydrogen or C 1 -C 8 -alkyl
  • R 10 is C 1 -C 8 -alkyl optionally substituted by cyano, C 1 -C 8 -alkoxy, a C 3 -C 15 -carbocyclic group or by a 4- to 12-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur,
  • R 10 is a C 3 -C 15 -carbocyclic group or a 4- to 12-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur;
  • R 12 is a C 3 -C 15 -carbocyclic group
  • R 13 is C 1 -C 8 -alkyl
  • R 14 is hydrogen, a C 3 -C 15 -carbocyclic group, C 1 -C 8 -alkenyl, or C 1 -C 8 -alkyl optionally substituted by a C 3 -C 15 -carbocyclic group.
  • Preferred compounds include those of formula I in salt or zwitterionic form, where R 1 and R 3 are each independently a C 3 -C 1-5 -carbocyclic group or a 4- to 12-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur;
  • R 2 is halo or hydroxy
  • R 4 is C 1 -C 8 -alkyl substituted by —NHR 5 , —NRS—CO—R 6 , —NR 5 —CO—NH—R 7 , —NR 5 —SO 2 —R 8 , —CO—NR 9 R 10 , —O—CO—NH—R 12 , —O—CO—R 13 or —CO—O—R 14 ,
  • R 4 is C 3 -C 10 -alkynyl optionally substituted by a C 3 -C 15 -carbocyclic group or a 4- to 12-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur;
  • R 5 is hydrogen or C 1 -C 8 -alkyl
  • R 6 is C 1 -C 8 -alkyl, C 2 -C 10 -alkynyl or C 1 -C 8 -alkoxy in each case optionally substituted by a C 3 -C 15 -carbocyclic group or a 4- to 12-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur,
  • R 6 is a C 3 -C 15 -carbocyclic group or a 4- to 12-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur;
  • R 7 is a C 3 -C 15 -carbocyclic group
  • R 8 is a C 3 -C 15 -carbocyclic group
  • R 9 is hydrogen or C 1 -C 8 -alkyl
  • R 10 is C 1 -C 8 -alkyl optionally substituted by cyano, C 1 -C 8 -alkoxy, a C 3 -C 15 -carbocyclic group or by a 4- to 12-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur,
  • R 10 is a C 3 -C 15 -carbocyclic group or a 4- to 12-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur;
  • R 12 is a C 3 -C 15 -carbocyclic group
  • R 13 is C 1 -C 8 -alkyl
  • R 14 is hydrogen, a C 3 -C 15 -carbocyclic group or C 1 -C 8 -alkyl optionally substituted by a C 3 -C 15 -carbocyclic group.
  • Preferred compounds also include those of formula I in salt or zwitterionic form, where R 1 and R 3 are each independently a C 3 -C 15 -carbocyclic group or a 5- to 12-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur;
  • R 2 is halo or hydroxy
  • R 4 is C 1 -C 8 -alkyl substituted by —NHR 5 , —NR 5 —CO—R 6 , —NR 7 —CO—NH—R 7 , —NR 5 —SO 2 —R 8 , —CO—NR 9 R 10 , —O—CO—NH—R 12 , —O—CO—R 13 or —CO—O—R 14 ,
  • R 4 is C 3 -C 10 -alkynyl optionally substituted by a C 3 -C 15 -carbocyclic group or a 5- to 12-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur;
  • R 5 is hydrogen
  • R 6 is C 1 -C 8 -alkyl or C 1 -C 8 -alkoxy in either case optionally substituted by a C 3 -C 15 -carbocyclic group or a 5- to 12-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur,
  • R 6 is a C 3 -C 15 -carbocyclic group or a 5- to 12-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur;
  • R 7 is a C 3 -C 15 -carbocyclic group
  • R 8 is a C 3 -C 15 -carbocyclic group
  • R 9 is hydrogen or C 1 -C 8 -alkyl
  • R 10 is C 1 -C 8 -alkyl optionally substituted by cyano, C 1 -C 8 -alkoxy, a C 3 -C 15 -carbocyclic group or by a 5- to 12-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur,
  • R 10 is a C 3 -C 15 -carbocyclic group or a 5- to 12-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur;
  • R 12 is a C 3 -C 15 -carbocyclic group
  • R 13 is C 1 -C 8 -alkyl
  • R 14 is hydrogen, C 1 -C 8 -alkyl or a C 3 -C 15 -carbocyclic group.
  • Especially preferred compounds include those of formula I in salt or zwitterionic form where R 1 and R 3 are each independently a C 6 -C 10 -carbocyclic aromatic group or a 4- to 12-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur;
  • R 2 is halo or hydroxy
  • R 4 is C 1 -C 8 -alkyl substituted by —NHR 5 , —NR 5 —CO—R 6 , —NR 5 —CO—NH—R 7 , —NR 5 —SO 2 —R 8 , —CO—NR 9 R 10 , —O—CO—NH—R 12 , —O—CO—R 13 or —CO—O—R 14 ,
  • R 4 is C 3 -C 8 -alkynyl optionally substituted by a C 3 -C 10 -carbocyclic group or a 4- to 10-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur;
  • R 5 is hydrogen or C 1 -C 4 -alkyl
  • R 6 is C 1 -C 4 -alkyl, C 2 -C 8 -alkynyl or C 1 -C 4 -alkoxy in each case optionally substituted by a C 3 -C 10 -carbocyclic group or a 4- to 12-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur,
  • R 6 is a C 3 -C 10 -carbocyclic group or a 4- to 10-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur;
  • R 7 is a C 3 -C 10 -carbocyclic group
  • R 8 is a C 3 -C 10 -carbocyclic group
  • R 9 is hydrogen or C 1 -C 4 -alkyl
  • R 10 is C 1 -C 4 -alkyl optionally substituted by cyano, C 1 -C 4 -alkoxy, a C 3 -C 10 -carbocyclic group or by a 4- to 10-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur,
  • R 10 is a C 3 -C 10 -carbocyclic group or a 4- to 10-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur;
  • R 12 is a C 3 -C 10 -carbocyclic group
  • R 13 is C 1 -C 4 -alkyl
  • R 14 is hydrogen, a C 3 -C 10 -carbocyclic group, C 1 -C 4 -alkenyl, or C 1 -C 4 -alkyl optionally substituted by a C 3 -C 10 -carbocyclic group.
  • Especially preferred compounds include those of formula I in salt or zwitterionic form where R 1 and R 3 are each independently a C 6 -C 10 -carbocyclic aromatic group or a 4- to 12-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur;
  • R 2 is halo or hydroxy
  • R 4 is C 1 -C 8 -alkyl substituted by —NHR 5 , —NR 5 —CO—R 6 , —NR 5 —CO—NH—R 7 , —NR 5 —SO 2 —R 8 , —CO—NR 9 R 10 , —O—CO—NH—R 12 , —O—CO—R 13 or —CO—O—R 14 ,
  • R 4 is C 3 -C 8 -alkynyl optionally substituted by a C 3 -C 10 -carbocyclic group or a 4- to 10-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur;
  • Especially preferred compounds also include those of formula I in salt or zwitterionic form where
  • R 1 and R 3 are each independently a C 6 -C 10 -carbocyclic aromatic group or a 5- to 12-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur;
  • R 2 is halo or hydroxy
  • R 4 is C 1 -C 8 -alkyl substituted by —NHR 5 , —NR 5 —CO—R 6 , —NR 5 —CO—NH—R 7 , —NR 5 —SO 2 —R 8 , —CO—NR 9 R 10 , —O—CO—NH—R 12 , —O—CO—R 13 or —CO—O—R 14 ,
  • R 4 is C 3 -C 8 -alkynyl optionally substituted by a C 3 -C 10 -carbocyclic group or a 5- to 10-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur;
  • R 5 is hydrogen
  • R 6 is C 1 -C 4 -alkyl or C 1 -C 4 -alkoxy in either case optionally substituted by a C 3 -C 10 -carbocyclic group or a 5- to 12-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur,
  • R 6 is a C 3 -C 10 -carbocyclic group or a S— to 10-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur;
  • R 7 is a C 3 -C 10 -carbocyclic group
  • R 8 is a C 3 -C 10 -carbocyclic group
  • R 9 is hydrogen or C 1 -C 4 -alkyl
  • R 10 is C 1 -C 4 -alkyl optionally substituted by cyano, C 1 -C 4 -alkoxy, a C 3 -C 10 -carbocyclic group or by a 5- to 10-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur,
  • R 10 is a C 3 -C 10 -carbocyclic group or a 5- to 10-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur;
  • R 12 is a C 3 -C 10 -carbocyclic group
  • R 13 is C 1 -C 4 -alkyl
  • R 14 is hydrogen, C 1 -C 4 -alkyl or a C 3 -C 10 -carbocyclic group.
  • the compounds of formula I are quaternary ammonium salts.
  • Suitable counter ions are pharmaceutically acceptable counter ions including, for example, fluoride, chloride, bromide, iodide, nitrate, sulfate, phosphate, formate, acetate, trifluoroacetate, propionate, butyrate, lactate, citrate, tartrate, malate, maleate, succinate, benzoate, p-chlorobenzoate, diphenylacetate or triphenylacetate, o-hydroxybenzoate, p-hydroxybenzoate, 1-hydroxynaphthalene-2-carboxylate, 3-hydroxynaphthalene-2-carboxylate, methanesulfonate and benzenesulfonate.
  • compositions of formula I that contain a basic centre are capable of forming acid addition salts, particularly pharmaceutically acceptable acid addition salts.
  • Pharmaceutically acceptable acid addition salts of the compound of formula I include those of inorganic acids, for example, hydrohalic acids such as hydrofluoric acid, hydrochloric acid, hydrobromic acid or hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid; and organic acids, for example aliphatic monocarboxylic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid and butyric acid, aliphatic hydroxy acids such as lactic acid, citric acid, tartaric acid or malic acid, dicarboxylic acids such as maleic acid or succinic acid, aromatic carboxylic acids such as benzoic acid, p-chlorobenzoic acid, diphenylacetic acid or triphenylacetic acid, aromatic hydroxy acids such as o-hydroxybenzoic acid, p-hydroxybenzoic acid, 1-hydroxynaphthal
  • Compounds of formula I which contain acidic, e.g. carboxyl, groups are also capable of forming salts with bases, in particular pharmaceutically acceptable bases such as those well known in the art; suitable such salts include metal salts, particularly alkali metal or alkaline earth metal salts such as sodium, potassium, magnesium or calcium salts, or salts with ammonia or pharmaceutically acceptable organic amines or heterocyclic bases such as ethanolamines, benzylamines or pyridine. These salts may be prepared from compounds of formula I by known salt-forming procedures.
  • Compounds of formula I that contain acidic, e.g. carboxyl, groups may also exist as zwitterions with the quaternary ammonium centre.
  • the compounds of the invention contain at least one asymmetric carbon atom and thus they exist in individual optically active isomeric forms or as mixtures thereof, e.g. as racemic mixtures. In cases where additional asymmetric centres exist the present invention also embraces both individual optically active isomers as well as mixtures, e.g. diastereomeric mixtures, thereof.
  • the invention also provides a process for the preparation of compounds of formula I which comprises (i) (A) reacting a compound of compound of formula II
  • Process variant (A) may be effected using known procedures for reacting quinuclidinol esters with halogenides or analogously as hereinafter described in the Examples.
  • the reaction is conveniently carried out in water or an organic solvent, for example acetonitrile, dimethylformamide (DMF), dimethylsulphoxide (DMSO), ethyl acetate or chloroform.
  • the reaction is carried out at a temperature between 20° C. to 120° C., conveniently between room temperature and 80° C.
  • Process variant (B) may be effected using known procedures for reacting amines with carboxylic acids or amide-forming derivatives thereof such as acid halides to give amides or analogously as hereinafter described in the Examples.
  • the reaction between the carboxylic acid and the amine is conveniently carried out in an organic solvent, for example dimethylformamide (DMF), optionally in the presence of a coupling agent, for example O-(7-azabenzotriazol-1-yl)-N,N,—N′,N′-tetramethyl-uronium hexafluorophate (HATU), and a base, for example diisopropyl-ethylamine (DIPEA) or triethylamine.
  • Suitable reaction temperatures are from 0° C. to 50° C., conveniently room temperature.
  • Process variant (C) may be effected using known procedures for reacting amines with isocyanates to give ureas or analogously as hereinafter described in the Examples.
  • the reaction is conveniently carried out in an organic solvent, for example dimethylformamide (DMF), and preferably in the presence of a base, for example DIPEA.
  • Suitable reaction temperatures are from ⁇ 78° C. to 40° C., conveniently room temperature.
  • Process variant (D) may be effected using known procedures for reacting amines with sulfonylhalides to give sulfonamides or analogously as hereinafter described in the Examples.
  • the reaction is conveniently carried out in an organic solvent, for example dimethylformamide (DMF), and preferably in the presence of a base, for example DIPEA.
  • Suitable reaction temperatures are from 0° C. to 50° C., conveniently room temperature.
  • Process variant (E) may be effected using known procedures for reacting carboxylic acids or amide-forming derivatives thereof such as acid halides with amines to give amides or analogously as hereinafter described in the Examples.
  • the reaction between the carboxylic acid and the amine is conveniently carried out in an organic solvent, for example dimethylsulfoxide (DMSO) or dimethylformamide (DMF), optionally in the presence of a coupling agent, for example HATU, and preferably in the presence of a base, for example DIPEA.
  • DMSO dimethylsulfoxide
  • DMF dimethylformamide
  • a coupling agent for example HATU
  • a base for example DIPEA
  • Compounds of formula IV may be prepared by deprotecting a compound of formula X where R 1 , R 2 , R 3 and R 5 are as hereinbefore defined, Q is an amine protecting group and T denotes C 1 -C 8 -alkylene, e.g. when Q is t-butyloxycarbonyl by treatment with a strong acid, e.g. hydrochloric acid or hydrobromic acid, which is conveniently carried out in an organic solvent, for example dioxan (1,4-dioxycyclohexane), and suitable reaction temperatures are from 0° C. to 60° C., conveniently room temperature.
  • a strong acid e.g. hydrochloric acid or hydrobromic acid
  • Compounds of formula VIII may be prepared by cleavage of a corresponding ester of formula XI where R 1 , R 2 , and R 3 are as hereinbefore defined, T denotes C 1 -C 8 -alkylene and W denotes a group that is readily replaceable by hydrogen.
  • W is t-butyl the compound may be reacted with an anhydrous strong acid, e.g. hydrochloric acid, hydrobromic acid or trifluoroacetic acid, which is conveniently carried out in an organic solvent, for example dioxane, and suitable reaction temperatures are from ⁇ 20° C. to 40° C., conveniently room temperature.
  • Compounds of formula X may be prepared by reacting a compound of formula II where R 1 , R 2 and R 3 are as hereinbefore defined, with a compound of formula XII where R 5 is as hereinbefore defined, Q is an amine protecting group e.g. t-butyloxycarbonyl, X 1 is chloro, bromo or iodo and T denotes C 1 -C 8 -alkylene.
  • the reaction is conveniently carried out in an organic solvent, for example DMF. Suitable reaction temperatures are from 40° C. to 120° C., conveniently between room temperature and 80° C.
  • Compounds of formula XI may be prepared by reacting a compound of formula II where R 1 , R 2 and R 3 are as hereinbefore defined, with a compound of formula XIII where T denotes C 1 -C 8 -alkylene, X 2 is chloro, bromo or iodo and W is a group that is readily replaceable by hydrogen.
  • W is t-butyl the reaction is conveniently carried out in an organic solvent, for example DMF.
  • Suitable reaction temperatures are from 0° C. to 120° C., conveniently between room temperature and 60° C.
  • the protecting groups may be chosen in accordance with the nature of the functional group, for example as described in Protective Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, John Wiley & Sons Inc, Third Edition, 1999, which reference also describes procedures suitable for replacement of the protecting groups by hydrogen.
  • Compounds of formula I are quaternary ammonium salts and may be converted between different salt forms using ion exchange chromatography.
  • the compounds can be obtained in the form of hydrates or solvates containing a solvent used for crystallization.
  • Compounds of formula I can be recovered from reaction mixtures and purified using known methods.
  • Isomers, such as enantiomers, may be obtained in a conventional manner, e.g. by fractional crystallization, chiral phase chromatography or asymmetric synthesis from correspondingly asymmetrically substituted, e.g. optically active, starting materials.
  • agents of the invention are useful as pharmaceuticals. Accordingly the invention also provides a compound of formula I in pharmaceutically acceptable salt or zwitterionic form for use as a pharmaceutical.
  • the agents of the invention act as muscarinic antagonists, particularly muscarinic M3 receptor antagonists, thereby inhibiting acetylcholine-induced contraction of smooth muscle in e.g. respiratory tract, digestive tract and urinary systems.
  • the affinity (Ki) of agents of the invention at the human muscarinic acetylcholine M3 receptor can be determined in a competitive filtration binding assay with the radio-labelled antagonist [ 3 H] n-methyl scopolamine methyl chloride (NMS):
  • Membranes prepared from CHO cells stably transfected with human M3 receptor at 10 ⁇ g protein/well are incubated with serial dilutions of the agents of the invention, [ 3 H]NMS (0.25 nM) and assay buffer (20 mM HEPES, 1 mM MgCl 2 at pH 7.4) for 17 hours at room temperature.
  • the assay is carried out in a 250 ⁇ L final volume, in the presence of a final dimethyl sulfoxide concentration of 1%.
  • Total binding of [ 3 H]NMS is determined in the absence of the agents of the invention with a corresponding substituted volume of assay buffer.
  • Non-specific binding of [ 3 H] NMS is determined in the presence of 300 nM ipratropium bromide.
  • the membranes are harvested onto a UnifilterTM GF/B filter plate containing 0.05% polyethyleneimine, using a BrandelTM filtration harvester 9600. Filter plates are dried for two hours at 35° C. before the addition of MicroscintTM ‘O’ cocktail, and read on a Packard TopcountTM scintillator using a 3 H-Scintillation protocol. All IC50s are calculated with the aid of XL-Fit graph package and K i values derived using the Cheng-Prusoff correction (Cheng Y., Prusoff W. H. (1973) Biochem. Pharmacol 22 3099-3109).
  • the compounds of the Examples herein below generally have Ki values below 1 ⁇ M in the above assay.
  • the compounds of Examples 17, 34, 52, 54, 71, 76, 96, 114, 138, 159, 170, 190, 209, 221, 242 and 244 have M3 K i values of 0.0144, 0.0023, 0.0019, 0.0001, 0.0005, 0.0011, 0.0046, 0.0002, 0.0022. 0.0007, 0.0007, 0.0007, 0.0010, 0.0013, 0.0003 and 0.0003 ⁇ M respectively.
  • agents of the invention are useful in the treatment of conditions mediated by the muscarinic M3 receptor, particularly those associated with increased parasympathetic tone leading to, for example, excessive glandular secretion or smooth muscle contraction.
  • Treatment in accordance with the invention may be symptomatic or prophylactic.
  • the agents of the invention are useful in the relaxation of bronchial smooth muscle and the relief of bronchoconstriction. Relief of bronchoconstriction can be measured in models such as the in vivo plethysmography models of Chong et al, J. Pharmacol. Toxicol. Methods 1998, 39, 163, Hammelmann et al, Am. J. Respir. Crit. Care Med., 1997, 156, 766 and analogous models.
  • the agents of the invention are therefore useful in the treatment of obstructive or inflammatory airways diseases. In view of their long duration of action, it is possible to administer the agents of the invention once-a-day in the treatment of such diseases.
  • agents of the invention commonly exhibit characteristics indicating a low incidence of side effects commonly encountered with ⁇ 2 agonists such as tachycardia, tremor and restlessness, such agents accordingly being suitable for use in on demand (rescue) treatment as well as prophylactic treatment of obstructive or inflammatory airways diseases.
  • Inflammatory or obstructive airways diseases to which the present invention is applicable include asthma of whatever type or genesis including both intrinsic (non-allergic) asthma and extrinsic (allergic) asthma.
  • Treatment of asthma is also to be understood as embracing treatment of subjects, e.g. of less than 4 or 5 years of age, exhibiting wheezing symptoms and diagnosed or diagnosable as “whez infants”, an established patient category of major medical concern and now often identified as incipient or early-phase asthmatics. (For convenience this particular asthmatic condition is referred to as “whez-infant syndrome”.)
  • Prophylactic efficacy in the treatment of asthma will be evidenced by reduced frequency or severity of symptomatic attack, e.g. of acute asthmatic or bronchoconstrictor attack, improvement in lung function or improved airways hyperreactivity. It may further be evidenced by reduced requirement for other, symptomatic therapy, i.e. therapy for or intended to restrict or abort symptomatic attack when it occurs, for example anti-inflammatory (e.g. corticosteroid) or bronchodilatory.
  • Prophylactic benefit in asthma may in particular be apparent in subjects prone to “morning dipping”. “Morning dipping” is a recognised asthmatic syndrome, common to a substantial percentage of asthmatics and characterised by asthma attack, e.g. between the hours of about 4 to 6 am, i.e. at a time normally substantially distant from any previously administered symptomatic asthma therapy.
  • inflammatory or obstructive airways diseases and conditions to which the present invention is applicable include adult/acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary or airways disease (COPD or COAD), including chronic bronchitis, or dyspnea associated therewith, emphysema, as well as exacerbation of airways hyperreactivity consequent to other drug therapy, in particular other inhaled drug therapy.
  • ARDS adult/acute respiratory distress syndrome
  • COAD or COAD chronic obstructive pulmonary or airways disease
  • chronic bronchitis or dyspnea associated therewith
  • emphysema emphysema
  • exacerbation of airways hyperreactivity consequent to other drug therapy in particular other inhaled drug therapy.
  • the invention is also applicable to the treatment of bronchitis of whatever type or genesis including, e.g., acute, arachidic, catarrhal, croupus, chronic or phthinoid
  • pneumoconiosis an inflammatory, commonly occupational, disease of the lungs, frequently accompanied by airways obstruction, whether chronic or acute, and occasioned by repeated inhalation of dusts
  • pneumoconiosis an inflammatory, commonly occupational, disease of the lungs, frequently accompanied by airways obstruction, whether chronic or acute, and occasioned by repeated inhalation of dusts
  • aluminosis an inflammatory, commonly occupational, disease of the lungs, frequently accompanied by airways obstruction, whether chronic or acute, and occasioned by repeated inhalation of dusts
  • aluminosis anthracosis
  • asbestosis chalicosis
  • ptilosis ptilosis
  • siderosis silicosis
  • tabacosis tabacosis and byssinosis.
  • the agents of the invention are also useful in the treatment of a condition requiring relaxation of smooth muscle of the uterus, bladder or vascular system. They are thus useful for the prevention or alleviation of premature labour pains in pregnancy.
  • the agents of the invention are also useful as co-therapeutic agents for use in combination with other drug substances such as anti-inflammatory, bronchodilatory, antihistamine, decongestant or anti-tussive drug substances, particularly in the treatment of obstructive or inflammatory airways diseases such as those mentioned hereinbefore, for example as potentiators of therapeutic activity of such drugs or as a means of reducing required dosaging or potential side effects of such drugs.
  • An agent of the invention may be mixed with one or more other drug substances in a fixed pharmaceutical composition or it may be administered separately, before, simultaneously with or after the other drug substance(s).
  • the invention includes a combination of an agent of the invention as hereinbefore described with an anti-inflammatory, bronchodilatory, antihistamine, decongestant or anti-tussive drug substance, said agent of the invention and said drug substance being in the same or different pharmaceutical composition.
  • Such anti-inflammatory drugs include steroids, for example glucocorticosteroids such as budesonide, beclamethasone, fluticasone, ciclesonide or mometasone, or steroids described in WO 02/88167, WO 02/12266, WO 02/100879 or WO 02/00679, especially those of Examples 3, 11, 14, 17, 19, 26, 34, 37, 39, 51, 60, 67, 72, 73, 90, 99 and 101, and non-steroidal steroid agonists such as those described in WO 00/00531, WO 02/10143, WO 03/082280, WO 03/082787, WO 03/104195, WO 04/005229; LTB4 antagonists such as those described in U.S.
  • steroids for example glucocorticosteroids such as budesonide, beclamethasone, fluticasone, ciclesonide or mometasone
  • agents of the invention are useful in combination therapy with chemokine receptor antagonists, calcium channel blockers, alpha-adrenoceptor antagonists, dopamine agonists, endothelin antagonists, substance-P antagonists, 5-LO inhibitors, VLA-4 antagonists and theophylline.
  • the agents of the invention are also particularly useful as co-therapeutic agents for use in combination with beta-2 adrenoceptor agonists or corticosteroids.
  • Suitable beta-2 adrenoceptor agonists include salbutamol, terbutaline, salmeterol and, especially, formoterol and pharmaceutically acceptable salts thereof, and compounds (in free or salt or solvate form) of formula I of WO 0075114, which document is incorporated herein by reference, preferably compounds of the Examples thereof, especially a compound of formula and pharmaceutically acceptable salts thereof, as well as compounds (in free or salt or solvate form) of formula I of WO 04/16601.
  • Co-therapeutic antihistamine drug substances include cetirizine hydrochloride, acetaminophen, clemastine fumarate, promethazine, loratidine, desloratidine, diphenhydramine and fexofenadine hydrochloride.
  • Combinations of agents of the invention and one or more of beta-2 adrenoceptor agonists, steroids, PDE4 inhibitors, A2a agonists, A2b agonists and LTD4 antagonists may be used, for example, in the treatment of asthma but particularly COPD.
  • the present invention also provides a method for the treatment of an obstructive or inflammatory airways disease which comprises administering to a subject, particularly a human subject, in need thereof a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore described.
  • the invention provides a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore described for use in the preparation of a medicament for the treatment of an obstructive or inflammatory airways disease.
  • the agents of the invention may be administered by any appropriate route, e.g. orally, for example in the form of a tablet or capsule; parenterally, for example intravenously; topically to the skin, for example in the treatment of psoriasis; intranasally, for example in the treatment of hay fever; or, preferably, by inhalation, particularly in the treatment of obstructive or inflammatory airways diseases.
  • the agents of the invention may be delivered as an inhalable formulation for the treatment of COPD and asthma.
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula I in free form or in the form of a pharmaceutically acceptable salt or solvate thereof, optionally together with a pharmaceutically acceptable diluent or carrier thereof.
  • Such compositions may be prepared using conventional diluents or excipients and techniques known in the galenic art.
  • oral dosage forms may include tablets and capsules.
  • Formulations for topical administration may take the form of creams, ointments, gels or transdermal delivery systems, e.g. patches.
  • Compositions for inhalation may comprise aerosol or other atomizable formulations or dry powder formulations.
  • the composition comprises an aerosol formulation
  • it preferably contains, for example, a hydro-fluoro-alkane (HFA) propellant such as HFA134a or HFA227 or a mixture of these, and may contain one or more co-solvents known in the art such as ethanol (up to 20% by weight), and/or one or more surfactants such as oleic acid or sorbitan trioleate, and/or one or more bulking agents such as lactose.
  • HFA hydro-fluoro-alkane
  • the composition comprises a dry powder formulation, it preferably contains, for example, the compound of formula I having a particle diameter up to 10 microns, optionally together with a diluent or carrier, such as lactose, of the desired particle size distribution and a compound that helps to protect against product performance deterioration due to moisture.
  • a diluent or carrier such as lactose
  • the composition comprises a nebulised formulation, it preferably contains, for example, the compound of formula I either dissolved, or suspended, in a vehicle containing water, a co-solvent such as ethanol or propylene glycol and a stabiliser, which may be a surfactant.
  • the invention also includes (A) a compound of formula I as hereinbefore described in free form, or a pharmaceutically acceptable salt or solvate thereof, in inhalable form; (B) an inhalable medicament comprising such a compound in inhalable form together with a pharmaceutically acceptable carrier in inhalable form; (C) a pharmaceutical product comprising such a compound in inhalable form in association with an inhalation device; and (D) an inhalation device containing such a compound in inhalable form.
  • Dosages of agents of the invention employed in practising the present invention will of course vary depending, for example, on the particular condition to be treated, the effect desired and the mode of administration.
  • suitable daily dosages for administration by inhalation are of the order of 0.0001 to 30 mg/kg, typically 0.01 to 10 mg per patient, while for oral administration suitable daily doses are of the order of 0.01 to 100 mg/kg.
  • Especially preferred compounds of formula I include compounds of formula XIV
  • R 1 , R 2 , R 3 , and R 4 are as shown in Table 1 below, the method of preparation being described hereinafter. All compounds are quaternary ammonium salts. The table also shows mass spectrometry data. TABLE 1 M/s Ex.
  • DAST is diethylaminosulfur trifluoride
  • DCE is dichloroethane
  • DCM is dichloromethane
  • DIPEA is diisopropylethylamine
  • DME is dimethoxyethane
  • HATU is O-(7-azabenzotriazol-1-yl)-N,N, —N′,N′-tetramethyl-uronium hexafluorophophate
  • HPLC High Performance Liquid Chromatography
  • Isolute CBA is propylcarboxylic acid
  • NBS is N-bromosuccinimide
  • PyBOP is benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate
  • THF is tetrahydrofuran.
  • BEMP 2-tert-Butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine, polymer bound.
  • the composition of the resulting counter ion was not confirmed spectroscopically, and may indeed be a variable mixture of trifluoroacetate and the halide resulting from the quaternarisation reaction.
  • HATU is used as a coupling agent the counter ion may also be hexa fluorophosphate.
  • This compound is made via an analogous procedure to (R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[3-(3-phenyl-ureido)-propyl)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate (Example 47) by replacing phenyl isocyanate with 4-butyl-1-isocyanato-2-methyl-benzene.
  • Potassium hydroxide (100 ml, 1.25 M solution) is added to 2,2′-thenil (Ubichem) at room temperature and the reaction mixture is heated to reflux for 4 hours and then cooled to room temperature.
  • the solution is acidified to pH2 and extracted with ethyl acetate (3 ⁇ 100 ml). The combined organic portions are washed with water (100 ml), dried over Na 2 SO 4 and cooled to 0° C.
  • TMS-diazomethane (20 ml of a 2M solution in hexanes) is added dropwise and the mixture is allowed to warm to room temperature.
  • Acetic acid (4 ml) is added and the reaction mixture is left at room temperature overnight.
  • the solvent is removed in vacuo and the crude product is dried and triturated with hexane to yield the titled compound as a brown amorphous solid.
  • reaction mixture is diluted with DCM (10 ml) and the organic portion is separated.
  • the aqueous layer is extracted with DCM (10 ml) and the organic portions are combined, dried over MgSO 4 and concentrated in vacuo.
  • Purification of the crude residue is carried by chromatography on silica, eluting with DCM: methanol to yield the titled compound as a brown oil.
  • This compound is made analogously to (R)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-[2-(toluene-4-sulfonylamino)-ethyl]-1-azonia-bicyclo[2.2.2]octane trifluoroacetate (Example 49) by replacing p-toluenesulfonyl chloride with phenyl isocyanate.
  • This compound is made analogously to (R)-3-(2-hydroxy-2,2-di-thiophen-2-yl-acetoxy)-1-phenylcarbamoylmethyl-1-azonia-bicyclo[2.2.2]octane trifluoroacetate (Example 76) by replacing 2-chloro-N-phenyl-acetamide with the appropriate alkyl halide.
  • R 1 , R 2 , R 3 , and R 4 are as shown in Table 2 below, the method of preparation being described hereinafter. All compounds are quaternary ammonium salts. The table also shows mass spectrometry data. TABLE 2 M/s Ex.
  • reaction mixture is filtered and PS-bromoacetic acid 1.2 mmol/g (0.2 g) is added to the filtrate and shaken at 30° C. for 1 hour.
  • the reaction mixture is passed through a 1 g Isolute SPE (Al-B) cartridge.
  • the solvent is removed in vacuo and purification of the crude residue by mass directed preparative HPLC eluting with water:acetonitrile:trifluoroacetic acid yield the compound as a yellow oil.
  • the compounds are purified either by trituration with organic solvents, C18 chromatography (as for Example 60) or recrystalisation from acetonitrile, water or chloroform.
  • the required halides for quaternarisation are either commercially available or readily synthesised by methods well known in the art.
  • This compound is prepared analogously to (R)-1-(3-benzoylamino-propyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]-octane trifluoroacetate [Example 2] but by replacing (R)-1-(3-amino-propyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo-[2.2.2]octane chloride hydrochloride [Example 1(ii)] with (R)-1-((R/S)-2-amino-propyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azoniabicyclo[2.2.2]octane chloride hydrochloride.
  • Example 182 The crude product from Example 182 is dissolved in acetonitrile (10 ml) and filtered then cooled over an ice bath, under an argon atmosphere. To this cooled solution is added triethylamine (127 ⁇ l) followed by benzoyl bromide (64 ⁇ l) and the reaction stirred for 1 hour. Purification is carried out using mass directed preparative HPLC eluting with acetonitrile:water:trifluoroacetic acid to afford the titled compound.
  • N-(2-Bromo-phenyl)-2-chloro-acetamide 155 mg, 0.622 mmol
  • the reaction mixture is stirred at 0° C. for 2 hours.
  • PS-Bromoacetamidomethyl-NovaGel 2.3 mmol/g (0.5 g) is added to the reaction mixture and shaken at room temperature for 4 hours.
  • PS-Triphenylphosphine 3 mmol/g 0.5 g is added to the reaction mixture and shaken at room temperature overnight.
  • reaction mixture is then passed through a 1 g Isolute SPE (Al-B) cartridge.
  • the solvent is removed in vacuo and purification of the crude residue by mass directed preparative HPLC eluting with water:acetonitrile:trifluoroacetic acid yields the titled compound.
  • reaction mixture is stirred at room temperature overnight.
  • reaction mixture is passed through a 2 g Isolute SPE (Al-B) cartridge.
  • the filtrate is concentrated in vacuo and purification of the crude residue by chromatography on C18 silica, eluting with water:acetonitrile affords the title compound as a white solid.
  • This compound is prepared analogously to (R)-1- ⁇ 2-[(Furan-2-carbonyl)-amino]ethyl ⁇ -3-(2-hydroxy-2,2-diphenyl-acetyl)-1-azonia-bicyclo[2.2.2]octane hexafluorophosphate [Example 190] by replacing 2-furoic acid with 1-BOC-azetidine-3-carboxylic acid.
  • This compound is prepared analogously to (R)-1-[(2-Bromo-phenylcarbamoyl)-methyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)]-1-azonia-bicyclo[2.2.2]octane trifluoroacetate [Example 184].
  • BEMP 2.3 mmol/g (0.1 g, 1 eqv) is used with the PS-bromoacetamidomethyl-NovaGel 2.3 mmol/g (0.3 g, 1 eqv).
  • This compound is prepared analogously to (R)-3-(2-Hydroxy-2,2-di-thiophen-2-yl-acetoxy)-1-(pyrazin-2-ylcarbamoylmethyl)-1-azonia-bicyclo[2.2.2]octane chloride [Example 159B] by substituting hydroxy-di-thiophen-2-yl-acetic acid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester and Pyrazin-2-yl-amine with hydroxy-diphenyl-acetic acid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester and 4-Methyl-pyrimidin-2-ylamine.
  • reaction mixture is passed through a 1 g Isolute SPE (Al-B) cartridge and the filtrate concentrated in vacuo. Purification by mass directed preparative HPLC eluting with water:acetonitrile:trifluoracetic acid yields the titled compound.
  • reaction mixture is filtered and the solution then washed with 1 M sodium carbonate solution, 1 M hydrochloric acid and brine. Concentration followed by purification by flash silica column chromatography (ethyl acetate/iso-hexane 3:7) gives the title compound as a white solid.
  • R 1 , R 2 , R 3 , and R 4 are as shown in Table 3 below, the method of preparation being described hereinafter. All compounds are quaternary ammonium salts. The table also shows mass spectrometry data. TABLE 3 M/s Ex. R 1 and R 3 R 4 R 2 M+ 246 OH 448.3 247 OH 408.3 Preparation of Specific Examples
  • the mixture is concentrated in vacuo and purified by gradient C18 column chromatography to give a pale yellow solid.
  • the solid is then redissolved in a small volume of acetonitrile containing a few drops of water. After several hours a solid is formed which is filtered and dried to give the title compound as a pale yellow solid.

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US20090069335A1 (en) * 2007-09-07 2009-03-12 Theravance, Inc. Guanidine-containing compounds useful as muscarinic receptor antagonists
US7960385B2 (en) 2007-09-07 2011-06-14 Theravance, Inc. Guanidine-containing compounds useful as muscarinic receptor antagonists
US20110201583A1 (en) * 2007-09-07 2011-08-18 Theravance, Inc. Guanidine-containing compounds useful as muscarinic receptor antagonists
US8039489B2 (en) 2007-09-07 2011-10-18 Theravance, Inc. Guanidine-containing compounds useful as muscarinic receptor antagonists
US8198304B2 (en) 2007-09-07 2012-06-12 Theravance, Inc. Guanidine-containing compounds useful as muscarinic receptor antagonists
US8338424B2 (en) 2007-09-07 2012-12-25 Theravance, Inc. Guanidine-containing compounds useful as muscarinic receptor antagonists
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US20090170870A1 (en) * 2007-12-14 2009-07-02 Ji Yuhua Amidine-containing compounds useful as muscarinic receptor antagonists
US8017617B2 (en) 2007-12-14 2011-09-13 Theravance, Inc. Amidine-containing compounds useful as muscarinic receptor antagonists
US8242138B2 (en) 2007-12-14 2012-08-14 Theravance, Inc. Amidine-containing compounds useful as muscarinic receptor antagonists
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