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

Quinuclidine derivatives binding to mucarinic m3 receptors Download PDF

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Publication number
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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US10/554,558
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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
Application filed by Individual filed Critical Individual
Publication of US20070060563A1 publication Critical patent/US20070060563A1/en
Assigned to NOVARTIS AG reassignment NOVARTIS AG ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: DEVEREUX, NICHOLAS JAMES, COLLINGWOOD, STEPHEN PAUL, BAETTIG, URS, BHALAY, GURDIP, COX, BRIAN
Priority to US12/582,291 priority Critical patent/US8168654B2/en
Abandoned legal-status Critical Current

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D453/00Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
    • C07D453/02Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00Drugs for disorders of the respiratory system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00Drugs for disorders of the respiratory system
    • A61P11/02Nasal agents, e.g. decongestants
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00Drugs for disorders of the respiratory system
    • A61P11/06Antiasthmatics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00Drugs for disorders of the respiratory system
    • A61P11/08Bronchodilators
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00Drugs for dermatological disorders
    • A61P17/06Antipsoriatics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00Drugs for immunological or allergic disorders
    • A61P37/08Antiallergic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00Drugs 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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Abstract

Compounds of formula I
Figure US20070060563A1-20070315-C00001

in salt or zwitterionic form wherein, wherein R1, R2, R3, and R4 have the meanings as indicated in the specification, are useful for treating conditions that are mediated by the muscarinic M3 receptor. Pharmaceutical compositions that contain the compounds and a process for preparing the compounds are also described.

Description

  • This invention relates to organic compounds, their preparation and use as pharmaceuticals.
  • In one aspect the invention provides compounds of formula I
    Figure US20070060563A1-20070315-C00002

    in salt or zwitterionic form wherein
    R1 and R3 are each independently a C3-C15-carbocyclic group or a 4- to 12-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur,
    or —CR1R2R3 together form a group of formula
    Figure US20070060563A1-20070315-C00003

    where R is a bond, —O—, —S—, —CH2—, —CH═CH—, —CH2—CH2—, amino or —N(CH3)—;
    R2 is hydrogen, halo, hydroxy, C1-C8-alkoxy or C1-C8-alkyl optionally substituted by hydroxy;
    R4 is C3-C10-alkyl substituted by —NHR5, —NR5—CO—R6, —NR5—CO—NH—R7, —NRS—SO2—R8, —CO—NR9R10, —OR11, —O—CO—NHR12, —O—CO—R13 or —CO—O—R14, or R4 is C3-C10-alkynyl optionally substituted by a C3-C15-carbocyclic group or a 4- to 12-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur;
    R5 is hydrogen or C1-C8-alkyl;
    R6 is C1-C8-alkyl, C2-C8-alkenyl, C2-C10-alkynyl or C1-C8-alkoxy in each case optionally substituted by a C3-C15-carbocyclic group or a 4- to 12-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur,
    or R6 is a C3-C15-carbocyclic group or a 4- to 12-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur;
    R7 is a C3-C15-carbocyclic group;
    R8 is a C3-C15-carbocyclic group;
    R9 is hydrogen or C1-C8-alkyl;
    R10 is hydrogen, C1-C8-alkyl optionally substituted by cyano, amino, nitro, carboxy, C1-C8-alkoxy, a C3-C15-carbocyclic group, or by a 4- to 12-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur,
    or R10 is a C3-C15-carbocyclic group or a 4- to 12-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur;
    R11 is hydrogen, C1-C8-alkyl, C1-C8-alkyl-C1-C8-alkoxy or C1-C8-alkyl-O—R15;
    • R12 is a C3-C15-carbocyclic group;
    • R13 is C1-C8-alkyl or a C3-C15-carbocyclic group;
    • R14 is hydrogen, a C3-C15-carbocyclic group, C1-C8-alkenyl, or C1-C8-alkyl optionally substituted by a C3-C15-carbocyclic group; and
      R15 is a C3-C15-carbocyclic group.
  • Terms used in the specification have the following meanings:
  • “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.
  • “C1-C8-alkyl” as used herein denotes straight chain or branched alkyl having 1 to 8 carbon atoms. Preferably, C1-C8-alkyl is C1-C4-alkyl.
  • “C1-C8-alkylene” as used herein denotes straight chain or branched alkylene that contains 1 to 8 carbon atoms. Preferably, C1-C8-alkylene is C1-C4-alkylene.
  • “C2-C8-alkenyl” as used herein denotes straight chain or branched hydrocarbon chains that contain two to eight carbon atoms and one or more carbon-carbon double bonds. Preferably “C2-C8-alkenyl” is “C2-C4-alkenyl”.
  • “C2-C10-alkynyl” as used herein denotes straight chain or branched hydrocarbon chains that contain two to ten carbon atoms and one or more carbon-carbon triple bonds. Preferably “C2-C10-alkynyl” is “C3-C8-alkynyl”.
  • “C3-C15-carbocyclic group” as used herein denotes a carbocyclic group having 3 to 15 ring carbon atoms, for example a monocyclic group, either cycloaliphatic, such as a C3-C8-cycloalkyl, or aromatic such as phenyl, which can be substituted by one or more, usually one or two, C1-C4-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, C1-C4-alkyl groups. Preferably the C3-C15-carbocyclic group is a C3-C10-carbocyclic group, for example cyclopropyl, cyclopentyl, cyclohexyl, cyclohepcyl, phenyl, indanyl or naphthyl. The C3-C15-carbocyclic group can be substituted or unsubstituted. Preferred substituents include halo (e.g. fluoro, chloro or bromo), cyano, hydroxy, amino, nitro, carboxy, C1-C8-alkyl (e.g. methyl or ethyl), halo-C1-C8-alkyl, C1-C8-alkoxy, C1-C8-alkylcarbonyl, C1-C8-alkylsulfonyl, —SO2NH2, a C3-C15-carbocyclic group and a 5- to 12-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur.
  • “C3-C8-cycloalkyl” as used herein denotes cycloalkyl having 3 to 8 carbon atoms. Preferably “C3-C8-cycloalkyl” is “C3-C6-cycloalkyl”.
  • “C1-C8-haloalkyl” as used herein denotes C1-C8-alkyl as hereinbefore defined substituted by one or more halogen atoms, preferably one, two or three halogen atoms. Preferably “C1-C8-haloalkyl” is “C1-C4-haloalkyl”.
  • “C1-C8-alkylcarbonyl” as used herein denotes C1-C8-alkyl as hereinbefore defined linked to a carbonyl group. Preferably “C1-C8-alkylcarbonyl” is “C1-C4-alkylcarbonyl”.
  • “C1-C8-alkylthio” as used herein denotes C1-C8-alkyl as hereinbefore defined linked to —S—. Preferably “C1-C8-alkylthio” is “C1-C4-alkylthio”.
  • “C1-C8-alkylsulfonyl” as used herein denotes C1-C8-alkyl as hereinbefore defined linked to —SO2—. Preferably “C1-C8-alkylsulfonyl” is “C1-C4-alkylsulfonyl”.
  • “C1-C8-alkoxy” as used herein denotes straight chain or branched alkoxy having 1 to 8 carbon atoms. Preferably, C1-C8-alkoxy is C1-C4-alkoxy.
  • “C1-C8-haloalkoxy” as used herein denotes C1-C8-alkoxy as hereinbefore defined substituted by one or more halogen atoms, preferably one, two or three halogen atoms. Preferably “C1-C8-haloalkoxy” is “C1-C4-haloalkoxy”.
  • “di(C1-C8-alkyl)sulfamoyl” as used herein denotes —SO2—NH2 where the nitrogen atom is substituted at two positions by C1-C8-alkyl as hereinbefore defined, which may be the same or different. Preferably di(C1-C8-alkyl)sulfamoyl is —SO2—N(CH3)2.
  • “Halo” or “halogen” as used herein 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.
  • “4- to 12-membered heterocyclic group containing at least one ring heteroatom selected from nitrogen, oxygen and sulphur” as used herein denotes a monoheterocyclic, biheterocyclic or triheterocyclic group, which may be saturated or unsaturated, that has 4 to 12 ring atoms. 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, C1-C8-alkyl (e.g. methyl or ethyl), halo-C1-C8-alkyl (e.g. trifluoromethyl), C1-C8-alkylcarbonyl, di(C1-C8-alkyl)sulfamoyl and C1-C8-alkoxy optionally substituted by aminocarbonyl. Especially preferred substituents include halo, oxo, C1-C4-alkyl and C1-C4-alkylcarbonyl.
  • Throughout this specification and in the claims that follow, unless the context requires otherwise, the word “comprise”, or variations such as “comprises” or “comprising”, will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.
  • In a second aspect the invention provides compounds of formula I
    Figure US20070060563A1-20070315-C00004

    in salt or zwitterionic form wherein
    R1 and R3 are each independently a C3-C15-carbocyclic group or a 4- to 12-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur,
    or —CR1R2R3 together form a group of formula
    Figure US20070060563A1-20070315-C00005

    where R is a bond, —O—, —S—, —CH2—, —CH═CH—, —CH2—CH2—, amino or —N(CH3)—;
    R2 is hydrogen, halo, hydroxy, C1-C8-alkoxy or C1-C8-alkyl optionally substituted by hydroxy;
    R4 is C1-C8-alkyl substituted by —NHR5, —NR5—CO—R6, —NR5—CO—NH—R7, —NR5—SO2—R8, —CO—NR9R10, —OR11, —O—CO—NHR12, —O—CO—R13 or —CO—O—R14, or R4 is C3-C10-alkynyl optionally substituted by a C3-C15-carbocyclic group or a 4- to 12-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur;
    R5 is hydrogen or C1-C8-alkyl;
    R6 is C1-C8-alkyl, C2-C8-alkenyl, C2-C10-alkynyl or C1-C8-alkoxy in each case optionally substituted by a C3-C15-carbocyclic group or a 4- to 12-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur, or R6 is a C3-C15-carbocyclic group or a 4- to 12-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur;
    R7 is a C3-C15-carbocyclic group;
    R8 is a C3-C15-carbocyclic group;
    R9 is hydrogen or C1-C8-alkyl;
    R10 is hydrogen, C1-C8-alkyl optionally substituted by cyano, amino, nitro, carboxy, C1-C8-alkoxy, a C3-C15-carbocyclic group, or by a 4- to 12-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur,
    or R10 is a C3-C15-carbocyclic group or a 4- to 12-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur;
    R11 is hydrogen, C1-C8-alkyl, C1-C8-alkyl-C1-C8-alkoxy or C1-C8-alkyl-O—R13;
    R12 is a C3-C15-carbocyclic group;
    R13 is C1-C8-alkyl or a C3-C15-carbocyclic group;
    R14 is hydrogen, a C3-C15-carbocyclic group, or C1-C8-alkyl optionally substituted by a C3-C15-carbocyclic group; and
    R15 is a C3-C15-carbocyclic group.
  • In a third aspect the invention provides compounds of formula I
    Figure US20070060563A1-20070315-C00006

    in salt or zwitterionic form wherein
    R1 and R3 are each independently a C3-C15-carbocyclic group or a 5- to 12-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur,
    or —CR1R2R3 together form a group of formula
    Figure US20070060563A1-20070315-C00007

    where R is a bond, —O—, —S—, —CH2—, —CH═CH—, —CH2—CH2—, amino or —N(CH3)—;
    R2 is hydrogen, halo, hydroxy, C1-C8-alkoxy or C1-C8-alkyl optionally substituted by hydroxy;
    R4 is C1-C8-alkyl substituted by —NHR5, —NR5—CO—R6, —NR5—CO—NH—R7, —NRS—SO2—R8, —CO—NR9R10, —OR11, —O—CO—NHR12, —O—CO—R13 or —CO—O—R14, or R4 is C3-C10-alkynyl optionally substituted by a C3-C15-carbocyclic group or a 5- to 12-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur;
    R5 is hydrogen or C1-C8-alkyl;
    R6 is C1-C8-alkyl or C1-C8-alkoxy in either case optionally substituted by a C3-C15-carbocyclic group or a 5- to 12-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur,
    or R6 is a C3-C15-carbocyclic group or a 5- to 12-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur;
    R7 is a C3-C15-carbocyclic group;
    R8 is a C3-C1-5-carbocyclic group;
    R9 is hydrogen or C1-C8-alkyl;
    R10 is hydrogen, C1-C8-alkyl optionally substituted by cyano, amino, nitro, carboxy, C1-C8-alkoxy, a C3-C15-carbocyclic group, or by a 5- to 12-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur, or R10 is a C3-C15-carbocyclic group or a 5- to 12-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur;
    R11 is hydrogen, C1-C8-alkyl, C1-C8-alkyl-C1-C8-alkoxy or C1-C8-alkyl-O—R15;
    • R12 is a C3-C15-carbocyclic group;
      R13 is C1-C8-alkyl or a C3-C15-carbocyclic group;
      R14 is hydrogen, C1-C8-alkyl or a C3-C15-carbocyclic group; and
      R15 is a C3-C15-carbocyclic group.
  • Preferred compounds include those of formula I in salt or zwitterionic form, where R1 and R3 are each independently a C3-C15-carbocyclic group or a 4- to 12-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur;
  • R2 is halo or hydroxy;
  • R4 is C1-C8-alkyl substituted by —NHR5, —NR5—CO—R6, —NR5—CO—NH—R7, —NR5—SO2—R8, —CO—NR9R10, —O—CO—NH—R12, —O—CO—R13 or —CO—O—R14,
  • or R4 is C3-C10-alkynyl optionally substituted by a C3-C15-carbocyclic group or a 4- to 12-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur;
  • R5 is hydrogen or C1-C8-alkyl;
  • R6 is C1-C8-alkyl, C2-C10-alkynyl or C1-C8-alkoxy in each case optionally substituted by a C3-C15-carbocyclic group or a 4- to 12-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur,
  • or R6 is a C3-C15-carbocyclic group or a 4- to 12-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur;
  • R7 is a C3-C15-carbocyclic group;
  • R8 is a C3-C15-carbocyclic group;
  • R9 is hydrogen or C1-C8-alkyl;
  • R10 is C1-C8-alkyl optionally substituted by cyano, C1-C8-alkoxy, a C3-C15-carbocyclic group or by a 4- to 12-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur,
  • or R10 is a C3-C15-carbocyclic group or a 4- to 12-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur;
  • R12 is a C3-C15-carbocyclic group;
  • R13 is C1-C8-alkyl; and
  • R14 is hydrogen, a C3-C15-carbocyclic group, C1-C8-alkenyl, or C1-C8-alkyl optionally substituted by a C3-C15-carbocyclic group.
  • Preferred compounds include those of formula I in salt or zwitterionic form, where R1 and R3 are each independently a C3-C1-5-carbocyclic group or a 4- to 12-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur;
  • R2 is halo or hydroxy;
  • R4 is C1-C8-alkyl substituted by —NHR5, —NRS—CO—R6, —NR5—CO—NH—R7, —NR5—SO2—R8, —CO—NR9R10, —O—CO—NH—R12, —O—CO—R13 or —CO—O—R14,
  • or R4 is C3-C10-alkynyl optionally substituted by a C3-C15-carbocyclic group or a 4- to 12-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur;
  • R5 is hydrogen or C1-C8-alkyl;
  • R6 is C1-C8-alkyl, C2-C10-alkynyl or C1-C8-alkoxy in each case optionally substituted by a C3-C15-carbocyclic group or a 4- to 12-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur,
  • or R6 is a C3-C15-carbocyclic group or a 4- to 12-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur;
  • R7 is a C3-C15-carbocyclic group;
  • R8 is a C3-C15-carbocyclic group;
  • R9 is hydrogen or C1-C8-alkyl;
  • R10 is C1-C8-alkyl optionally substituted by cyano, C1-C8-alkoxy, a C3-C15-carbocyclic group or by a 4- to 12-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur,
  • or R10 is a C3-C15-carbocyclic group or a 4- to 12-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur;
  • R12 is a C3-C15-carbocyclic group;
  • R13 is C1-C8-alkyl; and
  • R14 is hydrogen, a C3-C15-carbocyclic group or C1-C8-alkyl optionally substituted by a C3-C15-carbocyclic group.
  • Preferred compounds also include those of formula I in salt or zwitterionic form, where R1 and R3 are each independently a C3-C15-carbocyclic group or a 5- to 12-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur;
  • R2 is halo or hydroxy;
  • R4 is C1-C8-alkyl substituted by —NHR5, —NR5—CO—R6, —NR7—CO—NH—R7, —NR5—SO2—R8, —CO—NR9R10, —O—CO—NH—R12, —O—CO—R13 or —CO—O—R14,
  • or R4 is C3-C10-alkynyl optionally substituted by a C3-C15-carbocyclic group or a 5- to 12-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur;
  • R5 is hydrogen;
  • R6 is C1-C8-alkyl or C1-C8-alkoxy in either case optionally substituted by a C3-C15-carbocyclic group or a 5- to 12-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur,
  • or R6 is a C3-C15-carbocyclic group or a 5- to 12-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur;
  • R7 is a C3-C15-carbocyclic group;
  • R8 is a C3-C15-carbocyclic group;
  • R9 is hydrogen or C1-C8-alkyl;
  • R10 is C1-C8-alkyl optionally substituted by cyano, C1-C8-alkoxy, a C3-C15-carbocyclic group or by a 5- to 12-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur,
  • or R10 is a C3-C15-carbocyclic group or a 5- to 12-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur;
  • R12 is a C3-C15-carbocyclic group;
  • R13 is C1-C8-alkyl; and
  • R14 is hydrogen, C1-C8-alkyl or a C3-C15-carbocyclic group.
  • Especially preferred compounds include those of formula I in salt or zwitterionic form where R1 and R3 are each independently a C6-C10-carbocyclic aromatic group or a 4- to 12-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur;
  • R2 is halo or hydroxy;
  • R4 is C1-C8-alkyl substituted by —NHR5, —NR5—CO—R6, —NR5—CO—NH—R7, —NR5—SO2—R8, —CO—NR9R10, —O—CO—NH—R12, —O—CO—R13 or —CO—O—R14,
  • or R4 is C3-C8-alkynyl optionally substituted by a C3-C10-carbocyclic group or a 4- to 10-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur;
  • R5 is hydrogen or C1-C4-alkyl;
  • R6 is C1-C4-alkyl, C2-C8-alkynyl or C1-C4-alkoxy in each case optionally substituted by a C3-C10-carbocyclic group or a 4- to 12-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur,
  • or R6 is a C3-C10-carbocyclic group or a 4- to 10-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur;
  • R7 is a C3-C10-carbocyclic group;
  • R8 is a C3-C10-carbocyclic group;
  • R9 is hydrogen or C1-C4-alkyl;
  • R10 is C1-C4-alkyl optionally substituted by cyano, C1-C4-alkoxy, a C3-C10-carbocyclic group or by a 4- to 10-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur,
  • or R10 is a C3-C10-carbocyclic group or a 4- to 10-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur;
  • R12 is a C3-C10-carbocyclic group;
  • R13 is C1-C4-alkyl; and
  • R14 is hydrogen, a C3-C10-carbocyclic group, C1-C4-alkenyl, or C1-C4-alkyl optionally substituted by a C3-C10-carbocyclic group.
  • Especially preferred compounds include those of formula I in salt or zwitterionic form where R1 and R3 are each independently a C6-C10-carbocyclic aromatic group or a 4- to 12-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur;
  • R2 is halo or hydroxy;
  • R4 is C1-C8-alkyl substituted by —NHR5, —NR5—CO—R6, —NR5—CO—NH—R7, —NR5—SO2—R8, —CO—NR9R10, —O—CO—NH—R12, —O—CO—R13 or —CO—O—R14,
  • or R4 is C3-C8-alkynyl optionally substituted by a C3-C10-carbocyclic group or a 4- to 10-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur;
    • R5 is hydrogen or C1-C4-alkyl;
      R6 is C1-C4-alkyl, C2-C8-alkynyl or C1-C4-alkoxy in each case optionally substituted by a C3-C10-carbocyclic group or a 4- to 12-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur,
      or R6 is a C3-C10-carbocyclic group or a 4- to 10-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur;
      R7 is a C3-C10-carbocyclic group;
      R8 is a C3-C10-carbocyclic group;
      R9 is hydrogen or C1-C4-alkyl;
      R10 is C1-C4-alkyl optionally substituted by cyano, C1-C4-alkoxy, a C3-C10-carbocyclic group or by a 4- to 10-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur,
      or R10 is a C3-C10-carbocyclic group or a 4- to 10-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur;
      R12 is a C3-C10-carbocyclic group;
      R13 is C1-C4-alkyl; and
      R14 is hydrogen, a C3-C10-carbocyclic group or C1-C4-alkyl optionally substituted by a C3-C10-carbocyclic group.
  • Especially preferred compounds also include those of formula I in salt or zwitterionic form where
  • R1 and R3 are each independently a C6-C10-carbocyclic aromatic group or a 5- to 12-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur;
  • R2 is halo or hydroxy;
  • R4 is C1-C8-alkyl substituted by —NHR5, —NR5—CO—R6, —NR5—CO—NH—R7, —NR5—SO2—R8, —CO—NR9R10, —O—CO—NH—R12, —O—CO—R13 or —CO—O—R14,
  • or R4 is C3-C8-alkynyl optionally substituted by a C3-C10-carbocyclic group or a 5- to 10-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur;
  • R5 is hydrogen;
  • R6 is C1-C4-alkyl or C1-C4-alkoxy in either case optionally substituted by a C3-C10-carbocyclic group or a 5- to 12-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur,
  • or R6 is a C3-C10-carbocyclic group or a S— to 10-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur;
  • R7 is a C3-C10-carbocyclic group;
  • R8 is a C3-C10-carbocyclic group;
  • R9 is hydrogen or C1-C4-alkyl;
  • R10 is C1-C4-alkyl optionally substituted by cyano, C1-C4-alkoxy, a C3-C10-carbocyclic group or by a 5- to 10-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur,
  • or R10 is a C3-C10-carbocyclic group or a 5- to 10-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur;
  • R12 is a C3-C10-carbocyclic group;
  • R13 is C1-C4-alkyl; and
  • R14 is hydrogen, C1-C4-alkyl or a C3-C10-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.
  • Compounds 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-hydroxynaphthalene-2-carboxylic acid or 3-hydroxynaphthalene-2-carboxylic acid, and sulfonic acids such as methanesulfonic acid or benzenesulfonic acid. These salts may be prepared from compounds of formula I by known salt-forming procedures.
  • 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.
  • Specific especially preferred compounds of the invention are those described hereinafter in the Examples. These have R stereochemistry at the 3 position of the quinuclidine.
  • 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
    Figure US20070060563A1-20070315-C00008
      • or a protected form thereof where R1, R2 and R3 are as hereinbefore defined, with a compound of formula III
        R1—X  III
      • where R4 is as hereinbefore defined and X is chloro, bromo or iodo;
      • (B) for the preparation of compounds of formula I where R4 is C1-C8-alkyl substituted by —NR5—CO—R6 where R5 and R6 are as hereinbefore defined, reacting a compound of formula IV
        Figure US20070060563A1-20070315-C00009
      • or a protected form thereof where R1, R2, R3 and R5 are as hereinbefore defined, optionally in the presence of a coupling agent, and T denotes C1-C8-alkylene, with a compound of formula V
        Figure US20070060563A1-20070315-C00010
      • where R6 is as hereinbefore defined or an amide-forming derivative thereof such as an acid halide;
      • (C) for the preparation of compounds of formula I where R4 is C1-C8-alkyl substituted by —NR5—CO—NH—R7 where R5 and R7 are as hereinbefore defined, reacting a compound of formula IV or a protected form thereof where R1, R2, R3 and R5 are as hereinbefore defined and T denotes C1-C8-alkylene, with a compound of formula VI
        O═C═N—R7  VI
      • where R7 is as hereinbefore defined;
      • (D) for the preparation of compounds of formula I where R4 is C1-C8-alkyl substituted by —NR5—SO2—R8 where R5 and R8 are as hereinbefore defined, reacting a compound of formula IV or a protected form thereof where R1, R2, and R3 are as hereinbefore defined and T denotes C1-C8-alkylene, with a compound of formula VII
        Figure US20070060563A1-20070315-C00011
      • where R8 is as hereinbefore defined and X is halo; or
      • (E) for the preparation of compounds of formula I where R4 is C1-C8-alkyl substituted by —CO—NR9R10 where R9 and R10 are as hereinbefore defined, reacting a compound of formula VIII
        Figure US20070060563A1-20070315-C00012
      • or a protected form thereof where R1, R2, and R3 are as hereinbefore defined and T denotes C1-C8-alkylene, optionally in the presence of a coupling agent, or an amide-forming derivative thereof such as an acid halide, with a compound of formula IX
        Figure US20070060563A1-20070315-C00013
      • where R9 and R10 are as hereinbefore defined; and
        (ii) recovering the product in salt or zwitterionic form.
  • 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 hexafluorophophate (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. Suitable reaction temperatures are from 0° C. to 50° C., conveniently room temperature.
  • Compounds of formula II are known or may be prepared by known procedures such as those disclosed in W. J. Rzeszotarski et al, J. Med. Chem. 1988, 31, 1463, international patent publication WO 01/04118 and U.S. Pat. No. 3,833,592.
  • Compounds of formula III are known or may be prepared by known procedures.
  • Compounds of formula IV may be prepared by deprotecting a compound of formula X
    Figure US20070060563A1-20070315-C00014

    where R1, R2, R3 and R5 are as hereinbefore defined, Q is an amine protecting group and T denotes C1-C8-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.
  • Compounds of formula V, VI and VII are known or may be prepared by known procedures.
  • Compounds of formula VIII may be prepared by cleavage of a corresponding ester of formula XI
    Figure US20070060563A1-20070315-C00015

    where R1, R2, and R3 are as hereinbefore defined, T denotes C1-C8-alkylene and W denotes a group that is readily replaceable by hydrogen. For example when 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 IX are known or may be prepared by known procedures.
  • Compounds of formula X may be prepared by reacting a compound of formula II where R1, R2 and R3 are as hereinbefore defined, with a compound of formula XII
    Figure US20070060563A1-20070315-C00016

    where R5 is as hereinbefore defined, Q is an amine protecting group e.g. t-butyloxycarbonyl, X1 is chloro, bromo or iodo and T denotes C1-C8-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 R1, R2 and R3 are as hereinbefore defined, with a compound of formula XIII
    Figure US20070060563A1-20070315-C00017

    where T denotes C1-C8-alkylene, X2 is chloro, bromo or iodo and W is a group that is readily replaceable by hydrogen. For example when 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.
  • Compounds of formula XII and XIII are known or may be prepared by known procedures.
  • Where reference is made herein to protected functional groups or to protecting groups, 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.
  • Compounds of formula I in pharmaceutically acceptable salt or zwitterionic form, hereinafter referred to alternatively as 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 [3H] n-methyl scopolamine methyl chloride (NMS):
  • Membranes prepared from CHO cells stably transfected with human M3 receptor at 10 μg protein/well are incubated with serial dilutions of the agents of the invention, [3H]NMS (0.25 nM) and assay buffer (20 mM HEPES, 1 mM MgCl2 at pH 7.4) for 17 hours at room temperature. The assay is carried out in a 250 μL final volume, in the presence of a final dimethyl sulfoxide concentration of 1%. Total binding of [3H]NMS is determined in the absence of the agents of the invention with a corresponding substituted volume of assay buffer. Non-specific binding of [3H] NMS is determined in the presence of 300 nM ipratropium bromide. Following the incubation period, the membranes are harvested onto a Unifilter™ GF/B filter plate containing 0.05% polyethyleneimine, using a Brandel™ filtration harvester 9600. Filter plates are dried for two hours at 35° C. before the addition of Microscint™ ‘O’ cocktail, and read on a Packard Topcount™ scintillator using a 3H-Scintillation protocol. All IC50s are calculated with the aid of XL-Fit graph package and Ki 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 μM in the above assay. For instance, the compounds of Examples 17, 34, 52, 54, 71, 76, 96, 114, 138, 159, 170, 190, 209, 221, 242 and 244 have M3 Ki 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 μM respectively.
  • Having regard to their inhibition of acetyl choline binding to M3 muscarinic receptors, 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.
  • Having regard to their antimuscarinic activity, 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. In another aspect, agents of the invention commonly exhibit characteristics indicating a low incidence of side effects commonly encountered with β2 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 “wheezy 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 “wheezy-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.
  • Other 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. 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 bronchitis. Further inflammatory or obstructive airways diseases to which the present invention is applicable include 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) of whatever type or genesis, including, for example, aluminosis, anthracosis, asbestosis, chalicosis, ptilosis, siderosis, silicosis, tabacosis and byssinosis.
  • Having regard to their antimuscarinic activity, 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. They are also useful in the treatment of chronic and acute urticaria, psoriasis, allergic conjunctivitis, actinitis, rhinitis including allergic rhinitis, mastocytosis, urinary disorders such as urinary incontinence (particularly that caused by overactive bladder), pollakiuria, neurogenic or unstable bladder, cytospasm and chronic cystitis; gastrointestinal disorders such as irritable bowel syndrome, spastic colitis, diverticulitis and peptic ulceration; and cardiovascular disorders such as vagally induced sinus bradycardia, as well as in ophthalmic interventions.
  • 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). Accordingly 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. Pat. No. 5,451,700; LTD4 antagonists such as montelukast and zafirlukast; PDE4 inhibitors such as cilomilast (Ariflo® GlaxoSmithKline), Roflumilast (Byk Gulden), V-11294A (Napp), BAY19-8004 (Bayer), SCH-351591 (Schering-Plough), Arofylline (Almirall Prodesfarma), PD189659 (Parke-Davis), AWD-12-281 (Asta Medica), CDC-801 (Celgene), SelCID(TM) CC-10004 (Celgene), KW-4490 (Kyowa Hakko Kogyo), WO 03/104204, WO 03/104205, WO 04/000814, WO 04/000839 and WO 04005258 (Merck), as well as those described in WO 98/18796 and WO 03/39544; A2a agonists such as those described in EP 1052264, EP 1241176, EP 409595A2, WO 94/17090, WO 96/02543, WO 96/02553, WO 98/28319, WO 99/24449, WO 99/24450, WO 99/24451, WO 99/38877, WO 99/41267, WO 99/67263, WO 99/67264, WO 99/67265, WO 99/67266, WO 00/23457, WO 00/77018, WO 00/78774, WO 01/23399, WO 01/27130, WO 01/27131, WO 01/60835, WO 01/94368, WO 02/00676, WO 02/22630, WO 02/96462, and WO 03/086408; and A2b antagonists such as those described in WO 02/42298.
  • The 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
    Figure US20070060563A1-20070315-C00018

    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.
  • In accordance with the foregoing, 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. In another aspect, 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. In particular, the agents of the invention may be delivered as an inhalable formulation for the treatment of COPD and asthma.
  • In a further aspect, the invention also provides 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. Thus 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.
  • When 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. When 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. When 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. In general, 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.
  • The invention is illustrated by the following Examples.
  • EXAMPLES
  • Especially preferred compounds of formula I include compounds of formula XIV
    Figure US20070060563A1-20070315-C00019
  • where R1, R2, R3, and R4 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. R1 and R3 R4 R2 M+
    1
    Figure US20070060563A1-20070315-C00020
    Figure US20070060563A1-20070315-C00021
    OH 395.4
    2
    Figure US20070060563A1-20070315-C00022
    Figure US20070060563A1-20070315-C00023
    OH 499.4
    3
    Figure US20070060563A1-20070315-C00024
    Figure US20070060563A1-20070315-C00025
    OH 549.5
    4
    Figure US20070060563A1-20070315-C00026
    Figure US20070060563A1-20070315-C00027
    OH 524.5
    5
    Figure US20070060563A1-20070315-C00028
    Figure US20070060563A1-20070315-C00029
    OH 527.5
    6
    Figure US20070060563A1-20070315-C00030
    Figure US20070060563A1-20070315-C00031
    OH 575.5
    7
    Figure US20070060563A1-20070315-C00032
    Figure US20070060563A1-20070315-C00033
    OH 564.5
    8
    Figure US20070060563A1-20070315-C00034
    Figure US20070060563A1-20070315-C00035
    OH 577.5
    9
    Figure US20070060563A1-20070315-C00036
    Figure US20070060563A1-20070315-C00037
    OH 500.4
    10
    Figure US20070060563A1-20070315-C00038
    Figure US20070060563A1-20070315-C00039
    OH 533.4
    11
    Figure US20070060563A1-20070315-C00040
    Figure US20070060563A1-20070315-C00041
    OH 559.4
    12
    Figure US20070060563A1-20070315-C00042
    Figure US20070060563A1-20070315-C00043
    OH 533.4
    13
    Figure US20070060563A1-20070315-C00044
    Figure US20070060563A1-20070315-C00045
    OH 527.4
    14
    Figure US20070060563A1-20070315-C00046
    Figure US20070060563A1-20070315-C00047
    OH 567.4
    15
    Figure US20070060563A1-20070315-C00048
    Figure US20070060563A1-20070315-C00049
    OH 567.4
    16
    Figure US20070060563A1-20070315-C00050
    Figure US20070060563A1-20070315-C00051
    OH 567.4
    17
    Figure US20070060563A1-20070315-C00052
    Figure US20070060563A1-20070315-C00053
    OH 559.5
    18
    Figure US20070060563A1-20070315-C00054
    Figure US20070060563A1-20070315-C00055
    OH 529.4
    19
    Figure US20070060563A1-20070315-C00056
    Figure US20070060563A1-20070315-C00057
    OH 529.4
    20
    Figure US20070060563A1-20070315-C00058
    Figure US20070060563A1-20070315-C00059
    OH 557.5
    21
    Figure US20070060563A1-20070315-C00060
    Figure US20070060563A1-20070315-C00061
    OH 559.5
    22
    Figure US20070060563A1-20070315-C00062
    Figure US20070060563A1-20070315-C00063
    OH 559.5
    23
    Figure US20070060563A1-20070315-C00064
    Figure US20070060563A1-20070315-C00065
    OH 524.4
    24
    Figure US20070060563A1-20070315-C00066
    Figure US20070060563A1-20070315-C00067
    OH 547.4
    25
    Figure US20070060563A1-20070315-C00068
    Figure US20070060563A1-20070315-C00069
    OH 524.4
    26
    Figure US20070060563A1-20070315-C00070
    Figure US20070060563A1-20070315-C00071
    OH 529.5
    27
    Figure US20070060563A1-20070315-C00072
    Figure US20070060563A1-20070315-C00073
    OH 500.4
    28
    Figure US20070060563A1-20070315-C00074
    Figure US20070060563A1-20070315-C00075
    OH 500.4
    29
    Figure US20070060563A1-20070315-C00076
    Figure US20070060563A1-20070315-C00077
    OH 504.4
    30
    Figure US20070060563A1-20070315-C00078
    Figure US20070060563A1-20070315-C00079
    OH 505.7
    31
    Figure US20070060563A1-20070315-C00080
    Figure US20070060563A1-20070315-C00081
    OH 519.7
    32
    Figure US20070060563A1-20070315-C00082
    Figure US20070060563A1-20070315-C00083
    OH 491.7
    33
    Figure US20070060563A1-20070315-C00084
    Figure US20070060563A1-20070315-C00085
    OH 493.7
    34
    Figure US20070060563A1-20070315-C00086
    Figure US20070060563A1-20070315-C00087
    OH 513.7
    35
    Figure US20070060563A1-20070315-C00088
    Figure US20070060563A1-20070315-C00089
    OH 527.7
    36
    Figure US20070060563A1-20070315-C00090
    Figure US20070060563A1-20070315-C00091
    OH 548.7
    37
    Figure US20070060563A1-20070315-C00092
    Figure US20070060563A1-20070315-C00093
    OH 505.7
    38
    Figure US20070060563A1-20070315-C00094
    Figure US20070060563A1-20070315-C00095
    OH 501.6
    39
    Figure US20070060563A1-20070315-C00096
    Figure US20070060563A1-20070315-C00097
    OH 539.7
    40
    Figure US20070060563A1-20070315-C00098
    Figure US20070060563A1-20070315-C00099
    OH 514.7
    41
    Figure US20070060563A1-20070315-C00100
    Figure US20070060563A1-20070315-C00101
    OH 514.7
    42
    Figure US20070060563A1-20070315-C00102
    Figure US20070060563A1-20070315-C00103
    OH 544.6
    43
    Figure US20070060563A1-20070315-C00104
    Figure US20070060563A1-20070315-C00105
    OH 533.2
    44
    Figure US20070060563A1-20070315-C00106
    Figure US20070060563A1-20070315-C00107
    OH 577.2
    45
    Figure US20070060563A1-20070315-C00108
    Figure US20070060563A1-20070315-C00109
    OH 527.7
    46
    Figure US20070060563A1-20070315-C00110
    Figure US20070060563A1-20070315-C00111
    OH 465.6
    47
    Figure US20070060563A1-20070315-C00112
    Figure US20070060563A1-20070315-C00113
    OH 514.4
    48
    Figure US20070060563A1-20070315-C00114
    Figure US20070060563A1-20070315-C00115
    OH 584.3
    49
    Figure US20070060563A1-20070315-C00116
    Figure US20070060563A1-20070315-C00117
    OH 535.4
    50
    Figure US20070060563A1-20070315-C00118
    Figure US20070060563A1-20070315-C00119
    OH 485.4
    51
    Figure US20070060563A1-20070315-C00120
    Figure US20070060563A1-20070315-C00121
    OH 546.3
    52
    Figure US20070060563A1-20070315-C00122
    Figure US20070060563A1-20070315-C00123
    OH 471.4
    53
    Figure US20070060563A1-20070315-C00124
    Figure US20070060563A1-20070315-C00125
    OH 485.4
    54
    Figure US20070060563A1-20070315-C00126
    Figure US20070060563A1-20070315-C00127
    OH 376.3
    55
    Figure US20070060563A1-20070315-C00128
    Figure US20070060563A1-20070315-C00129
    OH 535.0
    56
    Figure US20070060563A1-20070315-C00130
    Figure US20070060563A1-20070315-C00131
    OH 390.3
    57
    Figure US20070060563A1-20070315-C00132
    Figure US20070060563A1-20070315-C00133
    OH 418.2
    58
    Figure US20070060563A1-20070315-C00134
    Figure US20070060563A1-20070315-C00135
    OH 452.2
    59
    Figure US20070060563A1-20070315-C00136
    Figure US20070060563A1-20070315-C00137
    OH 495.4
    60
    Figure US20070060563A1-20070315-C00138
    Figure US20070060563A1-20070315-C00139
    OH 452
    61
    Figure US20070060563A1-20070315-C00140
    Figure US20070060563A1-20070315-C00141
    OH 481
    62
    Figure US20070060563A1-20070315-C00142
    Figure US20070060563A1-20070315-C00143
    OH 396
    63
    Figure US20070060563A1-20070315-C00144
    Figure US20070060563A1-20070315-C00145
    OH 567
    64
    Figure US20070060563A1-20070315-C00146
    Figure US20070060563A1-20070315-C00147
    OH 404.2
    65
    Figure US20070060563A1-20070315-C00148
    Figure US20070060563A1-20070315-C00149
    OH 535.2
    66
    Figure US20070060563A1-20070315-C00150
    Figure US20070060563A1-20070315-C00151
    OH 507.4
    67
    Figure US20070060563A1-20070315-C00152
    Figure US20070060563A1-20070315-C00153
    OH 500.4
    68
    Figure US20070060563A1-20070315-C00154
    Figure US20070060563A1-20070315-C00155
    OH 506.5
    69
    Figure US20070060563A1-20070315-C00156
    Figure US20070060563A1-20070315-C00157
    OH 404.3
    70
    Figure US20070060563A1-20070315-C00158
    Figure US20070060563A1-20070315-C00159
    OH 507.3
    71
    Figure US20070060563A1-20070315-C00160
    Figure US20070060563A1-20070315-C00161
    OH 416.3
    72
    Figure US20070060563A1-20070315-C00162
    Figure US20070060563A1-20070315-C00163
    OH 519.4
    73
    Figure US20070060563A1-20070315-C00164
    Figure US20070060563A1-20070315-C00165
    OH 512.3
    74
    Figure US20070060563A1-20070315-C00166
    Figure US20070060563A1-20070315-C00167
    OH 388.2
    75
    Figure US20070060563A1-20070315-C00168
    Figure US20070060563A1-20070315-C00169
    OH 497.1
    76
    Figure US20070060563A1-20070315-C00170
    Figure US20070060563A1-20070315-C00171
    OH 483.3
    77
    Figure US20070060563A1-20070315-C00172
    Figure US20070060563A1-20070315-C00173
    OH 518.4
    78
    Figure US20070060563A1-20070315-C00174
    Figure US20070060563A1-20070315-C00175
    OH 558.3
    79
    Figure US20070060563A1-20070315-C00176
    Figure US20070060563A1-20070315-C00177
    OH 464.7
    80
    Figure US20070060563A1-20070315-C00178
    Figure US20070060563A1-20070315-C00179
    OH 475.2
    81
    Figure US20070060563A1-20070315-C00180
    Figure US20070060563A1-20070315-C00181
    OH 505.2
    82
    Figure US20070060563A1-20070315-C00182
    Figure US20070060563A1-20070315-C00183
    OH 539.2
    83
    Figure US20070060563A1-20070315-C00184
    Figure US20070060563A1-20070315-C00185
    OH 501.3
    84
    Figure US20070060563A1-20070315-C00186
    Figure US20070060563A1-20070315-C00187
    OH 505.2
    85
    Figure US20070060563A1-20070315-C00188
    Figure US20070060563A1-20070315-C00189
    OH 449.3
    86
    Figure US20070060563A1-20070315-C00190
    Figure US20070060563A1-20070315-C00191
    OH 516.3
    87
    Figure US20070060563A1-20070315-C00192
    Figure US20070060563A1-20070315-C00193
    OH 485.3
    88
    Figure US20070060563A1-20070315-C00194
    Figure US20070060563A1-20070315-C00195
    OH 519.2
    89
    Figure US20070060563A1-20070315-C00196
    Figure US20070060563A1-20070315-C00197
    OH 499.3
    90
    Figure US20070060563A1-20070315-C00198
    Figure US20070060563A1-20070315-C00199
    OH 511.3
    91
    Figure US20070060563A1-20070315-C00200
    Figure US20070060563A1-20070315-C00201
    OH 519.2
    92
    Figure US20070060563A1-20070315-C00202
    Figure US20070060563A1-20070315-C00203
    OH 519.2
    93
    Figure US20070060563A1-20070315-C00204
    Figure US20070060563A1-20070315-C00205
    OH 535.3
    94
    Figure US20070060563A1-20070315-C00206
    Figure US20070060563A1-20070315-C00207
    OH 520.3
    95
    Figure US20070060563A1-20070315-C00208
    Figure US20070060563A1-20070315-C00209
    OH 553.2
    96
    Figure US20070060563A1-20070315-C00210
    Figure US20070060563A1-20070315-C00211
    OH 505.3
    97
    Figure US20070060563A1-20070315-C00212
    Figure US20070060563A1-20070315-C00213
    OH 491.3
    98
    Figure US20070060563A1-20070315-C00214
    Figure US20070060563A1-20070315-C00215
    OH 437.3
    99
    Figure US20070060563A1-20070315-C00216
    Figure US20070060563A1-20070315-C00217
    OH 423.2
    100
    Figure US20070060563A1-20070315-C00218
    Figure US20070060563A1-20070315-C00219
    OH 449.2
    101
    Figure US20070060563A1-20070315-C00220
    Figure US20070060563A1-20070315-C00221
    OH 437.3
    102
    Figure US20070060563A1-20070315-C00222
    Figure US20070060563A1-20070315-C00223
    OH 477.3
    103
    Figure US20070060563A1-20070315-C00224
    Figure US20070060563A1-20070315-C00225
    OH 491.2
    104
    Figure US20070060563A1-20070315-C00226
    Figure US20070060563A1-20070315-C00227
    OH 453.3
    105
    Figure US20070060563A1-20070315-C00228
    Figure US20070060563A1-20070315-C00229
    OH 499.3
    106
    Figure US20070060563A1-20070315-C00230
    Figure US20070060563A1-20070315-C00231
    OH 448.3
    107
    Figure US20070060563A1-20070315-C00232
    Figure US20070060563A1-20070315-C00233
    OH 578.3
    108
    Figure US20070060563A1-20070315-C00234
    Figure US20070060563A1-20070315-C00235
    OH 495.3
    109
    Figure US20070060563A1-20070315-C00236
    Figure US20070060563A1-20070315-C00237
    F 474.3
    110
    Figure US20070060563A1-20070315-C00238
    Figure US20070060563A1-20070315-C00239
    F 378.2
    111
    Figure US20070060563A1-20070315-C00240
    Figure US20070060563A1-20070315-C00241
    F 426.3
    112
    Figure US20070060563A1-20070315-C00242
    Figure US20070060563A1-20070315-C00243
    OH 500.4
    113
    Figure US20070060563A1-20070315-C00244
    Figure US20070060563A1-20070315-C00245
    OH 402.3
    114
    Figure US20070060563A1-20070315-C00246
    Figure US20070060563A1-20070315-C00247
    OH 430
    115
    Figure US20070060563A1-20070315-C00248
    Figure US20070060563A1-20070315-C00249
    OH 535.2
    116
    Figure US20070060563A1-20070315-C00250
    Figure US20070060563A1-20070315-C00251
    OH 510.2
    117
    Figure US20070060563A1-20070315-C00252
    Figure US20070060563A1-20070315-C00253
    OH 513.3
    118
    Figure US20070060563A1-20070315-C00254
    Figure US20070060563A1-20070315-C00255
    OH 561.3
    119
    Figure US20070060563A1-20070315-C00256
    Figure US20070060563A1-20070315-C00257
    OH 550.2
    120
    Figure US20070060563A1-20070315-C00258
    Figure US20070060563A1-20070315-C00259
    OH 563.2
    121
    Figure US20070060563A1-20070315-C00260
    Figure US20070060563A1-20070315-C00261
    OH 486.2
    122
    Figure US20070060563A1-20070315-C00262
    Figure US20070060563A1-20070315-C00263
    OH 519.2
    123
    Figure US20070060563A1-20070315-C00264
    Figure US20070060563A1-20070315-C00265
    OH 545.2
    124
    Figure US20070060563A1-20070315-C00266
    Figure US20070060563A1-20070315-C00267
    OH 519.2
    125
    Figure US20070060563A1-20070315-C00268
    Figure US20070060563A1-20070315-C00269
    OH 513.2
    126
    Figure US20070060563A1-20070315-C00270
    Figure US20070060563A1-20070315-C00271
    OH 553.2
    127
    Figure US20070060563A1-20070315-C00272
    Figure US20070060563A1-20070315-C00273
    OH 553.2
    128
    Figure US20070060563A1-20070315-C00274
    Figure US20070060563A1-20070315-C00275
    OH 553.2
    129
    Figure US20070060563A1-20070315-C00276
    Figure US20070060563A1-20070315-C00277
    OH 545.2
    130
    Figure US20070060563A1-20070315-C00278
    Figure US20070060563A1-20070315-C00279
    OH 515.2
    131
    Figure US20070060563A1-20070315-C00280
    Figure US20070060563A1-20070315-C00281
    OH 515.2
    132
    Figure US20070060563A1-20070315-C00282
    Figure US20070060563A1-20070315-C00283
    OH 543.2
    133
    Figure US20070060563A1-20070315-C00284
    Figure US20070060563A1-20070315-C00285
    OH 545.2
    134
    Figure US20070060563A1-20070315-C00286
    Figure US20070060563A1-20070315-C00287
    OH 511.2
    135
    Figure US20070060563A1-20070315-C00288
    Figure US20070060563A1-20070315-C00289
    OH 515.3
    136
    Figure US20070060563A1-20070315-C00290
    Figure US20070060563A1-20070315-C00291
    OH 513.2
    137
    Figure US20070060563A1-20070315-C00292
    Figure US20070060563A1-20070315-C00293
    OH 491.3
    138
    Figure US20070060563A1-20070315-C00294
    Figure US20070060563A1-20070315-C00295
    OH 487.2
    139
    Figure US20070060563A1-20070315-C00296
    Figure US20070060563A1-20070315-C00297
    OH 525.2
    140
    Figure US20070060563A1-20070315-C00298
    Figure US20070060563A1-20070315-C00299
    OH 475.3
    141
    Figure US20070060563A1-20070315-C00300
    Figure US20070060563A1-20070315-C00301
    OH 520.2
    142
    Figure US20070060563A1-20070315-C00302
    Figure US20070060563A1-20070315-C00303
    OH 525.3
    143
    Figure US20070060563A1-20070315-C00304
    Figure US20070060563A1-20070315-C00305
    OH 491.3
    144
    Figure US20070060563A1-20070315-C00306
    Figure US20070060563A1-20070315-C00307
    OH 488.3
    145
    Figure US20070060563A1-20070315-C00308
    Figure US20070060563A1-20070315-C00309
    OH 503.3
    146
    Figure US20070060563A1-20070315-C00310
    Figure US20070060563A1-20070315-C00311
    OH 566.3
    147
    Figure US20070060563A1-20070315-C00312
    Figure US20070060563A1-20070315-C00313
    OH 507.2
    148
    Figure US20070060563A1-20070315-C00314
    Figure US20070060563A1-20070315-C00315
    OH 490.3
    149
    Figure US20070060563A1-20070315-C00316
    Figure US20070060563A1-20070315-C00317
    OH 489.3
    150
    Figure US20070060563A1-20070315-C00318
    Figure US20070060563A1-20070315-C00319
    OH 521.3
    151
    Figure US20070060563A1-20070315-C00320
    Figure US20070060563A1-20070315-C00321
    OH 535.3
    152
    Figure US20070060563A1-20070315-C00322
    Figure US20070060563A1-20070315-C00323
    OH 533.2
    153
    Figure US20070060563A1-20070315-C00324
    Figure US20070060563A1-20070315-C00325
    OH 525.2
    154
    Figure US20070060563A1-20070315-C00326
    Figure US20070060563A1-20070315-C00327
    OH 569.2
    155
    Figure US20070060563A1-20070315-C00328
    Figure US20070060563A1-20070315-C00329
    OH 503.3
    156
    Figure US20070060563A1-20070315-C00330
    Figure US20070060563A1-20070315-C00331
    OH 555.2
    157
    Figure US20070060563A1-20070315-C00332
    Figure US20070060563A1-20070315-C00333
    OH 503.3
    158
    Figure US20070060563A1-20070315-C00334
    Figure US20070060563A1-20070315-C00335
    OH 485.2

    Preparation of Specific Examples
  • Abbreviations used are as follows: 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 is High Performance Liquid Chromatography, Isolute CBA is propylcarboxylic acid, NBS is N-bromosuccinimide, PyBOP is benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate and THF is tetrahydrofuran. BEMP: 2-tert-Butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine, polymer bound.
  • In cases where purification is performed by C18 reverse phase column chromatography utilising trifluoroacetic acid as a component of the eluent, 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. Where HATU is used as a coupling agent the counter ion may also be hexa fluorophosphate.
  • Example 1 (R)-1-(3-Amino-propyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane
  • (i) Bromide:
  • To a stirred solution of hydroxy-diphenyl-acetic acid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl) ester (5 g, 14.82 mmol) in DMF (40 ml) is added 3-aminopropyl bromide (pre-neutralised from 3-aminopropyl bromide hydrobromide using polymer supported diethyl amine) (6.47 g, 29.54 mmol). The reaction mixture is heated to 40° C. overnight and then concentrated in vacuo. The crude residue is diluted with acetonitrile and the resulting precipitate is filtered and redissolved in DMF (20 ml). Merrifield resin is added to this solution followed by potassium carbonate (20 mg, catalytic amount) and the reaction is stirred at 40° C. for 24 hours. The reaction mixture is filtered and acetonitrile is added to the filtrate. The resulting precipitate is filtered and dried in vacuo to yield the titled compound.
  • (ii) Chloride:
  • (a) (R)-1-(3-tert-Butoxycarbonylamino-propyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane bromide
  • Hydroxy-diphenyl-acetic acid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl) ester (1 g, 2.97 mmol) and 3-(BOC-amino)propylbromide (1.06 g, 4.73 mmol) are dissolved in DMF (10 ml) and stirred to 60° C. for 4 hours. The solvent is removed in vacuo and purification of the crude residue by chromatography on C18 silica, eluting with water:acetonitrile affords the title compound as a colourless foam.
  • (b) (R)-1-(3-Amino-propyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane chloride hydrochloride
  • To a stirred solution of (R)-1-(3-tert-Butoxycarbonylamino-propyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane bromide [Example 1(ii)(a)] (1 g, 2.02 mmol) in dioxane (10 ml) at room temperature is added hydrochloric acid (1.5 ml, 4M aqueous solution). The reaction mixture is stirred for 16 hours and the solvent is removed in vacuo to yield the titled compound as a white solid.
  • Example 2 (R)-1-(3-Benzoylamino-propyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]-octane trifluoroacetate
  • To a stirred solution of benzoic acid (0.012 g, 0.1 mmol) and HATU (0.038 g, 0.1 mmol) in DMF (0.5 ml) is added DIPEA (0.05 ml). The reaction mixture is left to stand at room temperature for 15 minutes after which time, a solution comprising (R)-1-(3-amino-propyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane chloride hydrochloride [Example 1(ii)] (0.047 g, 0.1 mmol) in DMF (0.5 ml) is added. The reaction mixture is stirred at room temperature for 30 minutes and the solvent is removed in vacuo. Purification by mass directed preparative HPLC eluting with acetonitrile: water: trifluoroacetic acid yields the titled compound as a colourless oil.
  • Examples 3 to 46
  • These compounds, namely (R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-{3-[(naphthalene-2-carbonyl)-amino]-propyl}-1-azonia-bicyclo[2.2.2]octane trifluoroacetate, (R)-1-[3-(4-Cyano-benzoylamino)-propyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate, (R)-1-[3-(2,6-Dimethyl-benzoylamino)-propyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo-[2.2.2]octane trifluoroacetate, (R)-1-[3-[(Biphenyl-4-carbonyl)-amino)-propyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate, (R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[3-(4-pyrrol-1-yl-benzoylamino)-propyl]-1-azonia-bicyclo[2.2.2]octane trifluoroacetate, (R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[3-(3-methanesulfonyl-benzoyl-amino)-propyl]-1-azonia-bicyclo[2.2.2]octane trifluoroacetate, (R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-(3-[(pyridine-3-carbonyl)-amino]-propyl)-1-azonia-bicyclo-[2.2.2]octane trifluoro-acetate, (R)-1-[3-(4-Chloro-benzoylamino)-propyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate, (R)-1-[3-(3,5-Dimethoxy-benzoylamino)-propyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo-[2.2.2]octane trifluoroacetate, (R)-1-[3-(3-Chloro-benzoylamino)-propyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]-octane trifluoroacetate, (R)-1-[3-(4-Ethyl-benzoyl-amino)-propyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane trifluoro-acetate, (R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[3-(3-trifluoromethyl-benzoylamino)-propyl]-1-azonia-bicyclo[2.2.2]octane trifluoroacetate, (R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[3-(4-trifluoromethyl-benzoyl-amino)-propyl]-1-azonia-bicyclo[2.2.2]octane trifluoroacetate, (R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[3-(2-trifluoromethyl-benzoyl-amino)-propyl]-1-azonia-bicyclo[2.2.2]octane trifluoroacetate, (R)-1-[3-(3,4-Dimethoxy-benzoylamino)-propyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate, (R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[3-(4-methoxy-benzoylamino)-propyl]-1-azonia-bicyclo-[2.2.2]octane-trifluoro-acetate, (R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[3-(2-methoxy-benzoylamino)-propyl]-1-azonia-bicyclo[2.2.2]octane trifluoro-acetate, (R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[3-(4-isopropoxy-benzoylamino)-propyl]-1-azonia-bicyclo[2.2.2]octane trifluoroacetate, (R)-1-[3-(2,4-Dimethoxy-benzoylamino)-propyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo-[2.2.2]octane trifluoroacetate, (R)-1-[3-(2,3-Dimethoxy-benzoyl-amino)-propyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo-[2.2.2]octane trifluoro-acetate, (R)-1-[3-(2-Cyano-benzoylamino)-propyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate, (R)-1-[3-(3-Fluoro-4-methoxy-benzoylamino)-propyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]-octane trifluoroacetate, (R)-1-[3-(3-Cyano-benzoyl-amino)-propyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate, (R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[3-(3-methoxy-benzoylamino)-propyl]-1-azonia-bicyclo[2.2.2]octane trifluoro-acetate, (R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-{3-[(pyridine-2-carbonyl)-amino]-propyl}-1-azonia-bicyclo[2.2.2]octane-trifluoroacetate, (R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-(3-[(pyridine-4-carbonyl)-amino]-propyl)-1-azonia-bicyclo-[2.2.2]octane trifluoroacetate, (R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-(3-[(5-methyl-isoxazole-3-carbonyl)-amino]-propyl]-1-azonia-bicyclo[2.2.2]octane trifluoroacetate, (R)-1-[3-(Cyclohexanecarbonyl-amino)-propyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo-[2.2.2]octane trifluoroacetate, (R)-1-[3-(Cycloheptanecarbonyl-amino)-propyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo-[2.2.2]octane trifluoroacetate, (R)-1-[3-(Cyclopentane-carbonyl-amino)-propyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate, (R)-1-[3-(3,3-Dimethyl-butyrylamino)-propyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate, (R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-(3-phenylacetylamino-propyl)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate, (R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[3-(3-phenyl-propionylamino)-propyl]-1-azonia-bicyclo-[2.2.2]octane trifluoroacetate, (R)-1-(3-[(1-Acetyl-piperidine-4-carbonyl)-amino]-propyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate, (R)-1-[3-(2-Cyclopentyl-acetylamino)-propyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]-octane trifluoroacetate, (R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-{3-[(pyrazine-2-carbonyl)-amino]-propyl}-1-azonia-bicyclo-[2.2.2]octane trifluoroacetate, (R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-(3-[(indane-2-carbonyl)-amino]-propyl)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate, (R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[3-(2-pyridin-2-yl-acetylamino)-propyl]-1-azonia-bicyclo[2.2.2]octane trifluoroacetate, (R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-(3-[(2-methyl-pyridine-3-carbonyl) amino]-propyl)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate, (R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[3-(2-nitro-benzoylamino)-propyl]-1-azonia-bicyclo[2.2.2]octane trifluoroacetate, (R)-1-[3-(2-Chloro-benzoylamino)-propyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate, (R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[3-(2-methanesulfonyl-benzoylamino)-propyl]-1-azonia-bicyclo[2.2.2]-octane trifluoroacetate, (R)-1-[3-(3,5-Dimethyl-benzoylamino)-propyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo-[2.2.2]octane trifluoroacetate and (R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-(3-isobutyryl-amino-propyl)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate respectively, are all prepared by the procedure of Example 2 from (R)-1-(3-Amino-propyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane chloride [Example 1(ii)] and the appropriate acid.
  • Example 47 (R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[3-(3-phenyl-ureido)-propyl]-1-azonia-bicyclo-[2.2.2]octane trifluoroacetate
  • To a solution comprising (R)-1-(3-amino-propyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane chloride [Example 1(ii)] (0.023 g, 0.05 mmol) and DIPEA (0.025 ml) in DMF (0.25 ml) is added phenyl isocyanate (0.006 ml). The reaction mixture is left to stand at room temperature overnight. Purification using mass directed preparative HPLC eluting with acetonitrile: water: trifluoroacetic acid affords the titled compound.
  • Example 48 (R)-1-{3-[3-(4-Butyl-2-methyl-phenyl)-ureido]-propyl}-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate
  • 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.
  • Example 49 (R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[2-(toluene-4-sulfonylamino)-ethyl]-1-azonia-bicyclo[2.2.2.]octane trifluoroacetate (i) (R)-1-(2-tert-Butoxycarbonylamino-ethyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane bromide
  • To a stirred suspension of hydroxy-diphenyl-acetic acid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester (2.5 g, 7.42 mmol) in DMF (50 ml) under an atmosphere of argon is added (2-Bromo-ethyl)-carbamic acid tert-butyl ester (2.5 g, 11.16 mmol). The reaction mixture is heated to 60° C. overnight and then the solvent is removed in vacuo to yield a brown oil which is used crude in the next step.
  • (ii) (R)-1-(2-Amino-ethyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane bromide hydrobromide
  • To a stirred suspension of (R)-1-(2-tert-butoxycarbonylamino-ethyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane bromide (0.5 g, 1.04 mmol) in dioxane (25 ml) is added hydrogen bromide solution in dioxane (1 ml, prepared by bubbling HBr gas through dry, cooled dioxane). The reaction mixture is stirred at room temperature overnight. The solvent is removed in vacuo and purification of the crude residue by chromatography on C18 silica, eluting with water:acetonitrile affords the title compound as a brown solid.
  • (iii) (R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[2-(toluene-4-sulfonylamino)-ethyl]-1-azonia-bicyclo[2.2.2]octane trifluoroacetate
  • A solution comprising (R)-1-(2-amino-ethyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane bromide hydrobromide [Example 50(ii)] (0.032 g, 0.059 mmol) p-toluenesulfonyl chloride (0.011 g, 0.059 mmol) and DIPEA (0.041 ml, 0.236 mmol) in DMF (0.5 ml) is allowed to stir at room temperature for 66 hours. Purification using mass directed preparative HPLC eluting with acetonitrile: water: trifluoroacetic acid affords the titled compound.
  • Example 50 (R)-1-(2-Benzoylamino-ethyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]-octane bromide (i) (R)-1-(2-tert-Butoxycarbonylamino-ethyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane bromide
  • To a stirred suspension of hydroxy-diphenyl-acetic acid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester (2.5 g, 7.42 mmol) in DMF (50 ml) under an atmosphere of argon is added (2-Bromo-ethyl)-carbamic acid tert-butyl ester (2.5 g, 11.16 mmol). The reaction mixture is heated to 60° C. overnight and then the solvent is removed in vacuo to yield a brown oil which is used crude in the next step.
  • (ii) (R)-1-(2-Amino-ethyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane bromide hydrobromide
  • To a stirred suspension of (R)-1-(2-tert-butoxycarbonylamino-ethyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane bromide (0.5 g, 1.04 mmol) in dioxane (25 ml) is added hydrogen bromide solution in dioxane (1 ml, prepared by bubbling HBr gas through dry, cooled dioxane). The reaction mixture is stirred at room temperature overnight. The solvent is removed in vacuo and purification of the crude residue by chromatography on C18 silica, eluting with water:acetonitrile affords the title compound as a brown solid.
  • (iii) (R)-1-(2-Benzoylamino-ethyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]-octane bromide
  • To a stirred suspension of (R)-1-(2-Amino-ethyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane bromide hydrobromide [50(ii)] (0.28 g, 0.517 mmol) in DCM at 0° C. is added triethylamine (0.216 ml, 1.552 mmol) followed by benzoyl bromide (0.122 ml, 1.03 mmol). The reaction mixture is stirred at 0° C. for 1.5 hours and the solvent was removed in vacuo. Purification of the crude residue by chromatography on C18 silica, eluting with water:acetonitrile affords the title compound.
  • Example 51 (R)-1-[(5-Fluoro-benzothiazol-2-ylcarbamoyl)-methyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate
  • Hydroxy-diphenyl-acetic acid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl) ester (0.050 g, 0.148 mmol), 2-Bromo-N-(5-fluoro-benzothiazol-2-yl)-acetamide (0.064 g, 0.222 mmol) and potassium carbonate (0.01 g, catalytic quantity) are added to DMSO (0.5 ml) and stirred together at 40° C. overnight. Purification using mass directed preparative HPLC eluting with acetonitrile: water: trifluoroacetic acid affords the titled compound.
  • Example 52 (R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-phenylcarbamoylmethyl-1-azonia-bicyclo[2.2.2]octane
  • (i) Trifluoroacetate:
  • To a sealed vial containing hydroxy-diphenyl-acetic acid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester (0.020 g, 0.059 mmol in DMSO) is added 2-chloro-N-phenyl-acetamide (0.030 g, 0.177 mmol in methylene chloride. The reaction mixture is stirred at room temperature overnight and purification using mass directed preparative HPLC eluting with acetonitrile: water: trifluoroacetic acid affords the titled compound.
  • (ii) Chloride:
  • Hydroxy-diphenyl-acetic acid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester (0.2 g, 0.593 mmol) and 2-chloro-N-phenyl-acetamide (0.12 g, 0.89 mmol) are added to DMSO (2 ml) and stirred at 40° C. overnight. The solvent in removed in vacuo and purification by chromatography on C18 silica eluting with water:acetonitrile yields the titled compound as a chloride salt.
  • Example 53 (R)-1-(Benzylcarbamoyl-methyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]-octane trifluoroacetate
  • The title compound is made via an analogous procedure to (R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-phenylcarbamoylmethyl-1-azonia-bicyclo[2.2.2]octane chloride [Example 52 (ii)] by replacing 2-chloro-N-phenyl-acetamide with 3-chloro-N-phenyl-propionamide.
  • Examples 54 to 58
  • These compounds, namely (R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-prop-2-ynyl-1-azonia-bicyclo[2.2.2]octane trifluoroacetate, (R)-1-(3-Benzenesulfonylamino-propyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate, (R)-1-But-2-ynyl-3-(2-hydroxy-2,2-dipheny]-acetoxy)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate, (R)-1-Hex-2-ynyl-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate, and (R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-(3-phenyl-prop-2-ynyl)-1-azonia-bicycio[2.2.2]-octane trifluoroacetate are prepared made via an analogous procedure to (R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-phenylcarbamoylmethyl-1-azonia-bicyclo[2.2.2]octane trifluoroacetate [Example 52 (i)] by replacing 2-chloro-N-phenyl-acetamide with the appropriate alkyl halide.
  • Example 59 (R)-1-(3-tert-Butoxycarbonylamino-propyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane bromide
  • Preparation of this compound is described in Example 1(ii)(a).
  • Example 60 (R)-1-tert-Butoxycarbonylmethyl-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]-octane bromide
  • To a solution comprising hydroxy-diphenyl-acetic acid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester (0.2 g, 0.593 mmol) in dry chloroform (5 ml) is added t-butylbromoacetate (0.438 ml, 2.96 mmol). The reaction mixture is left to stand at room temperature overnight. The solvent is removed 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.
  • Example 61 (R)-1-(2-tert-Butoxycarbonylamino-ethyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane bromide
  • The title compound is made via an analogous procedure to (R)-1-tert-butoxycarbonylmethyl-3 (2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane bromide (Example 60) by replacing t-butylbromoacetate with (2-bromo-ethyl)-carbamic acid tert-butyl ester.
  • Example 62 (R)-1-Carboxymethyl-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]-octane trifluoroacetate
  • To a stirred solution of (R)-1-tert-Butoxycarbonylmethyl-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane bromide (Example 60) (0.14 g, 0.264 mmol) in chloroform (5 ml) is added trifluoroacetic acid (1 ml). The reaction mixture is left to stir at room temperature overnight. The solvent is removed in vacuo and purification of the residue by chromatography on C18 silica, eluting with water:acetonitrile affords the titled compound as a white solid.
  • Example 63 (R)-1-[(5,6-Diethyl-indan-2-ylcarbamoyl)-methyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate
  • To a stirred suspension of (R)-1-carboxymethyl-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate [Ex. 62] (0.052 g, 0.102 mmol) in dry DMF (5 ml) is added DIPEA (0.070 ml, 0.408 mmol), HATU (0.097 g, 0.255 mmol) and 5,6-Diethyl-indan-2-ylamine hydrochloride (0.058 g, 0.255 mmol). The mixture is left to stir at room temperature overnight. The solvent is removed in vacuo and purification by mass directed preparative HPLC eluting with acetonitrile: water: trifluoroacetic acid yields the titled compound.
  • Alternatively, to a stirred suspension of (R)-1-carboxymethyl-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate [Ex. 62] (0.052 g, 0.102 mmol) in dry DMF (5 ml) is added DIPEA (0.053 ml, 0.306 mmol), HATU (0.058 g, 0.153 mmol) and 5,6-Diethyl-indan-2-ylamine hydrochloride (0.035 g, 0.153 mmol). The mixture is left to stir at room temperature overnight. The solvent is removed in vacuo and purification by mass directed preparative HPLC eluting with acetonitrile: water: trifluoroacetic acid yields the titled compound.
  • Example 64 (R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-pent-4-ynyl-1-azonia-bicyclo[2.2.2]octane trifluoroacetate
  • Hydroxy-diphenyl-acetic acid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester (0.02 g, 0.059 mmol), 5-chloro-pent-1-yne (0.0073 g, 0.071 mmol), sodium iodide (0.009 g, catalytic amount) and potassium carbonate (0.009 g, catalytic amount) are added to acetonitrile (0.5 ml) and stirred together at 9 hours. Purification is carried out using mass directed preparative HPLC eluting with acetonitrile: water: trifluoroacetic acid. Further purification is carried out by heating the resulting product in Merrifield resin in acetonitrile at 80° C. for 6 hours. The mixture is allowed to cool to room temperature and then filtered. The filtrate is concentrated in vacuo to yield the titled product as an oil.
  • Example 65 (R)-1-[3-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-prop-2-ynyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate
  • The title compound is made via an analogous procedure to (R)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-pent-4-ynyl-1-azonia-bicyclo[2.2.2]octane trifluoroacetate (Example 64) by replacing 5-chloro-pent-1-yne with 2-(3-Chloro-prop-1-ynyl)-isoindole-1,3-dione, acetonitrile with DMSO and not adding poptassium carbonate.
  • Examples 66 to 69
  • These compounds, namely (R)-1-(2-Cyclohexylcarbamoyloxy-ethyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate, (R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[2-(3-phenyl-ureido)-ethyl]-1-azonia-bicyclo[2.2.2]octane trifluoroacetate, (R)-1-[2-(3-Cyclohexyl-ureido)-ethyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo-[2.2.2]octane trifluoroacetate and (R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-pent-2-ynyl-1-azonia-bicyclo[2.2.2]octane trifluoroacetate, are all prepared made via an analogous procedure to (R)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-pent-4-ynyl-1-azonia-bicyclo[2.2.2]-octane trifluoroacetate (Example 64) by replacing acetonitrile with DMSO and 5-chloro-pent-1-yne with the appropriate alkyl halide.
  • Example 70 (R)-1-(3-tert-Butoxycarbonylamino-propyl)-3-(2-hydroxy-2,2-di-thiophen-2-yl-acetoxy)-1-azonia-bicyclo[2.2.2]octane bromide (i) Hydroxy-di-thiophen-2-yl-acetic acid methyl ester
  • 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 Na2SO4 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.
  • (ii) Hydroxy-di-thiophen-2-yl-acetic acid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester
  • To a flask containing sodium metal (0.018 g, 0.786 mmol) under an atmosphere of argon was added a suspension comprising hydroxy-di-thiophen-2-yl-acetic acid methyl ester [Example 70 (i)](0.2 g, 0.786 mmol) and (R)-1-Aza-bicyclo[2.2.2]octan-3-ol (0.149 g, 1.179 mmol) in toluene (3 ml). The reaction mixture was stirred under the inert atmosphere at 85° C. for 4 hours and the solvent was removed in vacuo. The resulting crude residue was dissolved in DCM and washed with saturated sodium bicarbonate solution. The organic portion was dried over MgSO4 and concentrated in vacuo to yield a brown oil. Trituration with acetonitrile affords the titled compound.
  • (iii) (R)-1-(3-tert-Butoxycarbonylamino-propyl)-3-(2-hydroxy-2,2-di-thiophen-2-yl-acetoxy)-1-azonia-bicyclo[2.2.2]octane bromide
  • Hydroxy-di-thiophen-2-yl-acetic acid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester (0.758 g, 2.17 mmol) and 3(BOC-amino)propylbromide (0.775 g, 3.25 mmol) are dissolved in DMF (7 ml) and heated at 60° C. for 2.5 hours. The solvent is removed in vacuo and purification of the crude residue by chromatography on C18 silica, eluting with water:acetonitrile affords the titled compound as an oil.
  • Examples 71 to 75
  • These compounds, namely (R)-3-(2-Hydroxy-2,2-di-thiophen-2-yl-acetoxy)-1-pent-2-ynyl-1-azonia-bicyclo[2.2.2]octane trifluoroacetate, (R)-1-(2-Cyclohexylcarbamoyloxy-ethyl)-3-(2-hydroxy-2,2-di-thiophen-2-yl-acetoxy)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate, (R)-3-(2-Hydroxy-2,2-di-thiophen-2-yl-acetoxy)-1-[2-(3-phenyl-ureido)-ethyl]-1-azonia-bicyclo[2.2.2]octane trifluoroacetate, (R)-3-(2-Hydroxy-2,2-di-thiophen-2-yl-acetoxy)-1-prop-2-ynyl-1-azonia-bicyclo[2.2.2]octane trifluoroacetate and (R)-1-(Benzylcarbamoyl-methyl)-3-(2-hydroxy-2,2-di-thiophen-2-yl-acetoxy)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate are all made via an analogous procedure to (R)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-pent-4-ynyl-1-azonia-bicyclo[2.2.2]-octane trifluoro-acetate (Example 64) by replacing hydroxy-diphenyl-acetic acid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester with hydroxy-di-thiophen-2-yl-acetic acid (R)-(1-aza-bicyclo-[2.2.2]oct-3-yl)ester (Example 70(ii)), by replacing acetonitrile with DMSO and by replacing 5-chloro-pent-1-yne with the appropriate alkyl halide.
  • Alternative Preparation of the Compound of Example 71 as a Bromide Salt:
  • A solution of 1-bromo-2-pentyne (0.51 g, 3.44 mmol) in chloroform (2 ml) is treated with polymer supported TEA resin. After a few minutes this solution is added to a solution of hydroxy-di-thiophen-2-yl-acetic acid (R)-(1-aza-bicyclo-[2.2.2]oct-3-yl)ester (Example 70(ii)) (1.0 g, 2.87 mmol) in chloroform (2 ml). The resulting mixture is heated to 50° C. for 18 h and the mixture allowed to cool to room temperature. A white solid is isolated by filtration, washed with chloroform and dried. Recrystallisation from chloroform-acetonitrile, washing the resultant solid with cold acetonitrile, and drying under vacuum gives (R)-3-(2-Hydroxy-2,2-di-thiophen-2-yl-acetoxy)-1-pent-2-ynyl-1-azonia-bicyclo[2.2.2]octane bromide.
  • Example 76 (R)-3-(2-Hydroxy-2,2-di-thiophen-2-yl-acetoxy)-1-phenylcarbamoylmethyl-1-azonia-bicyclo[2.2.2]octane trifluoroacetate
  • Hydroxy-di-thiophen-2-yl-acetic acid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester (Example 70(ii)) (0.03 g, 0.0857 mmol), 2-chloro-N-phenyl-acetamide (0.0218 g, 0.129 mmol), sodium iodide (0.0026 g, catalytic amount) and potassium carbonate (0.0026 g, catalytic amount) are added to DMSO (1 ml) and heated to 40° C. overnight. The solvent is then removed in vacuo and purification is carried out using mass directed preparative HPLC eluting with acetonitrile: water: trifluoroacetic acid. Further purification is required and is carried by chromatography on C18 silica, eluting with water:acetonitrile to afford the titled compound.
  • Examples 77 to 79
  • These compounds, namely (R)-1-[2-(3-Cyclohexyl-ureido)-ethyl]-3-(2-hydroxy-2,2-di-thiophen-2-yl-acetoxy)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate, (R)-1-[(5-Fluoro-benzothiazol-2-ylcarbamoyl)-methyl]-3-(2-hydroxy-2,2-di-thiophen-2-yl-acetoxy)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate and (R)-3-(2-Hydroxy-2,2-di-thiophen-2-yl-acetoxy)-1-(3-phenyl-prop-2-ynyl)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate are all prepared by an analogous procedure to (R)-3-(2-hydroxy-2,2-di-thiophen-2-yl-acetoxy)-1-phenylcarbamoyl-methyl-1-azonia-bicyclo[2.2.2]octane trifluoroacetate (Example 76) by replacing 2-chloro-N-phenyl-acetamide with the appropriate alkyl halide.
  • Example 80 (R)-1-{[(Furan-2-ylmethyl)-carbamoyl]-methyl}-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate
  • To a solution of (R)-1-carboxymethyl-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo-[2.2.2]octane trifluoroacetate [Example 62) (0.04 g, 0.078 mmol) in DCM (0.5 ml) is added DIPEA (0.056 ml) and C-furan-2-yl-methylamine (0.056 ml, 0.634 mmol) followed by PyBOP (0.055 g, 0.106 mmol) in DMF (1 ml). The reaction mixture is left to stir at room temperature over 48 hours. Initial purification is carried out using Solid Phase Extraction with a pH 8 pre-conditioned column (pH adjusted using Isolute CBA). Further purification is carried out using mass directed preparative HPLC eluting with acetonitrile: water: trifluoroacetic acid to afford the titled compound.
  • Alterbatively, to a solution of (R)-1-carboxymethyl-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo-[2.2.2]octane trifluoroacetate [Example 62] (0.04 g, 0.078 mmol) in DCM (0.5 ml) is added DIPEA (0.056 ml) and C-furan-2-yl-methylamine (0.021 ml, 0.234 mmol) followed by PyBroP (0.055 g, 0.118 mmol) in DMF (1 ml). The reaction mixture is left to stir at room temperature over 48 hours. Initial purification is carried out using Solid Phase Extraction with a pH 8 pre-conditioned column (pH adjusted using Isolute CBA). Further purification is carried out using mass directed preparative HPLC eluting with acetonitrile: water: trifluoroacetic acid to afford the titled compound.
  • Examples 81 to 108
  • These compounds, namely (R)-1-[(4-Chloro-phenylcarbamoyl)-methyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate, (R)-1-[(3,4-Dichloro-phenyl-carbamoyl)-methyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate, (R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[(4-methoxy-phenylcarbamoyl)-methyl]-1-azonia-bicyclo[2.2.2]octane trifluoroacetate, (R)-1-[(3-Chloro-phenylcarbamoyl)-methyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate, (R)-1-[(2-Chloro-phenylcarbamoyl)-methyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate, (R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[(4-nitro-phenylcarbamoyl)-methyl]-1-azonia-bicyclo[2.2.2]octane trifluoroacetate, (R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-(o-tolylcarbamoyl-methyl)-1-azonia-bicyclo[2.2.2]octane trifluoro-acetate, (R)-1-[(4-Chloro-benzylcarbamoyl)-methyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate, (R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-(phenethylcarbamoyl-methyl)-1-azonia-bicyclo[2.2.2]octane trifluoroacerate, (R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-(indan-2-ylcarbamoylmethyl)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate, (R)-1-[(3-Chloro-benzylcarbamoyl)-methyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate, (R)-1-[(2-Chloro-benzylcarbamoyl)-methyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate,(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-([(naphthalen-1-ylmethyl)-carbamoyl]-methyl)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate, (R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-([3-(2-oxo-pyrrolidin-1-yl)-propylcarbamoyl]-methyl)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate, (R)-1-[(3,4-Dichloro-benzylcarbamoyl)-methyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate, (R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[(2-thiophen-2-yl-ethylcarbamoyl)-methyl]-1-azonia-bicyclo[2.2.2]octane trifluoroacetate, (R)-1-[(Cyclo-hexylmethyl-carbamoyl)-methyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]-octane trifluoroacetate, (R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-(isopropylcarbamoyl-methyl)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate, (R)-1-Ethylcarbamoylmethyl-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate, (R)-1-[(Cyclo-propylmethyl-carbamoyl)-methyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]-octane trifluoroacetate, (R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-propylcarbamoylmethyl-1-azonia-bicyclo[2.2.2]octane trifluoroacetate, (R)-1-Cyclohexylcarbamoylmethyl-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate, (R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-{[(thiophen-2-ylmethyl)-carbamoyl]-methyl}-1-azonia-bicyclo[2.2.2]octane trifluoroacetate, (R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[(2-methoxy-ethylcarbamoyl)-methyl]-1-azonia-bicyclo[2.2.2]octane trifluoroacetate, (R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[(4-methyl-benzylcarbamoyl)-methyl]-1-azonia-bicyclo[2.2.2]octane trifluoro-acetate, (R)-1-[(2-Cyano-ethylcarbamoyl)-methyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate, (R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-([2-(4-sulfamoyl-phenyl)-ethylcarbamoyl]-methyl)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate and (R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[(3-isopropoxy-propylcarbamoyl)-methyl]-1-azonia-bicyclo[2.2.2]octane trifluoroacetate are all prepared by an analogous procedure to (R)-1-[(furan-2-ylmethyl)-carbamoyl]-methyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]-octane trifluoroacetate (Example 80)) by replacing C-furan-2-yl-methylamine with the appropriate amine.
  • Example 109 (R)-3-(2-Fluoro-2,2-diphenyl-acetoxy)-1-phenoxycarbonylmethyl-1-azonia-bicyclo[2.2.2]-octane bromide (i) Fluoro-diphenyl-acetic acid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester
  • To a cooled (0° C.), stirred solution of DAST (0.101 ml, 0.826 mmol) in DCM (0.5 ml) under an atmosphere of argon is added, dropwise over 10 minutes, a suspension of hydroxydiphenyl-acetic acid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester (0.209 g, 0.62 mmol) in DCM (10 ml). The reaction mixture is stirred at 0° C. for 1 hour after which time water (5 ml) is added dropwise followed by sodium hydrogen carbonate solution (3 ml, 10% w/w NaHCO3) to adjust the pH of the solution to pH8. The 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 MgSO4 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.
  • (ii) (R)-3-(2-Fluoro-2,2-diphenyl-acetoxy)-1-phenoxycarbonylmethyl-1-azonia-bicyclo[2.2.2]-octane bromide
  • To a solution of fluoro-diphenyl-acetic acid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester [Example 109(i)] (0.034 g, 0.1 mmol) in DMSO (0.25 ml) is added bromo-acetic acid phenyl ester (0.071 ml, 0.5 mmol). The reaction mixture is left standing at room temperature overnight. Purification is carried out by chromatography on C18 silica, eluting with water:acetonitrile to yield the titled compound as a colourless oil.
  • Examples 110 and 111
  • These compounds, namely (R)-3-(2-Fluoro-2,2-diphenyl-acetoxy)-1-prop-2-ynyl-1-azonia-bicyclo[2.2.2]octane bromide and (R)-1-(2-Acetoxy-ethyl)-3-(2-fluoro-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane bromide are prepared by an analogous method to (R)-3-(2-fluoro-2,2-diphenyl-acetoxy)-1-phenoxycarbonylmethyl-1-azonia-bicyclo[2.2.2]octane bromide (Example 109) by replacing bromo-acetic acid phenyl ester with the appropriate alkyl halide.
  • Example 112 (R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[2-(3-phenyl-ureido)-ethyl]-1-azonia-bicyclo[2.2.2]-octane trifluoroacetate
  • 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.
  • Example 113 (R)-1-But-2-ynyl-3-(2-hydroxy-2,2-di-thiophen-2-yl-acetoxy)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate
  • 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.
  • Example 114 (R)-1-Hex-2-ynyl-3-(2-hydroxy-2,2-di-thiophen-2-yl-acetoxy)-1-azonia-bicyclo[2.2.2] octane trifluoroacetate
  • A stirred solution comprising hydroxy-di-thiophen-2-yl-acetic acid (R)-(1-aza-bicyclo[2.2.2]-oct-3-yl)ester (Example 70(ii)) (0.03 g, 0.086 mmol), 1-bromo-2-hexyne (0.021 g, 0.0129 mmol), potassium carbonate (0.002 g, catalytic amount) in acetonitrile (0.5 ml) is heated to 50° C. overnight. The solvent is removed in vacuo and purification by mass directed preparative HPLC eluting with acetonitrile: water: trifluoroacetic acid yields the titled compound.
  • Example 115 (R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-{2-[(naphthalene-2-carbonyl)-amino]-ethyl}-1-azonia-bicyclo[2.2.2]octane trifluoroacetate
  • To a solution of naphthalene-2-carboxylic acid (0.019 g, 0.113 mmol) in DMF (0.28 ml) is added diisopropylethylamine (0.02 ml, 0.113 mmol) in DMF (1 ml) followed by HATU (0.043 g, 0.113 mmol) in DMF (0.28 ml). The reaction mixture is allowed to stand for 20 minutes after which time a solution comprising (R)-1-(2-amino-ethyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane bromide hydrobromide [Example 49(ii)] (0.051 g, 0.113 mmol) and diisopropylethylamine (0.02 ml, 0.113 mmol) in DMF (0.57 ml) is added. The reaction mixture is allowed to stand at room temperature over night. Initial purification is carried out using Solid Phase Extraction with a 1 g Isolute ALB cartridge. Further purification is carried out using mass directed preparative HPLC eluting with acetonitrile: water: trifluoroacetic acid to afford the titled compound.
  • Examples 116 to 157
  • These compounds, namely (R)-1-[2-(4-Cyano-benzoylamino)-ethyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate, (R)-1-[2-(2,6-Dimethyl-benzoylamino)-ethyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate, (R)-1-(2-[(Biphenyl-4-carbonyl)-amino]-ethyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate, (R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[2-(4-pyrrol-1-yl-benzoylamino)-ethyl]-1-azonia-bicyclo[2.2.2]octane trifluoro-acetate, (R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[2-(3-methanesulfonyl-benzoylamino)-ethyl]-1-azonia-bicyclo[2.2.2]octane trifluoroacetate, (R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-{2-[(pyridine-3-carbonyl)-amino]-ethyl}-azonia-bicyclo[2.2.2]octane trifluoroacetate, (R)-1-(2-(4-Chloro-benzoylamino)-ethyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo-[2.2.2]octane trifluoroacetate, (R)-1-[2-(3,5-Dimethoxy-benzoylamino)-ethyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate, (R)-1-[2-(3-Chloro-benzoylamino)-ethyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2] octane trifluoroacetate, (R)-1-[2-(4-Ethyl-benzoylamino)-ethyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate, (R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[2-(3-trifluoromethyl-benzoylamino)-ethyl]-1-azonia-bicyclo[2.2.2]octane trifluoroacetate, (R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[2-(4-trifluoromethyl-benzoylamino)-ethyl]-1-azonia-bicyclo-[2.2.2]octane trifluoroacetate, (R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[2-(2-trifluoro-methyl-benzoylamino)-ethyl]-1-azonia-bicyclo[2.2.2]octane trifluoroacetate, (R)-1-[2-(3,4-Dimethoxy-benzoylamino)-ethyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]-octane trifluoroacetate, (R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[2-(4-methoxy-benzoyl-amino)-ethyl]-1-azonia-bicyclo[2.2.2]octane trifluoroacetate, (R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[2-(2-methoxy-benzoylamino)-ethyl]-1-azonia-bicyclo[2.2.2]octane trifluoroacetate, (R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[2-(4-isopropoxy-benzoylamino)-ethyl]-1-azonia-bicyclo[2.2.2]octane trifluoroacetate, (R)-1-[2-(2,4-Dimethoxy-benzoylamino)-ethyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate, (R)-1-[2-(2-Cyano-benzoylamino)-ethyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]-octane trifluoroacetate, (R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[2-(3-methoxy-benzoyl-amino)-ethyl]-1-azonia-bicyclo[2.2.2]octane trifluoroacetate, (R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[2-(3-phenyl-propionylamino)-ethyl]-1-azonia-bicyclo[2.2.2]octane trifluoroacetate, (R)-1-[2-(2-Cyclopentyl-acetylamino)-ethyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate, (R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-{2-[(pyrazine-2-carbonyl)-amino]-ethyl}-1-azonia-bicyclo[2.2.2]octane trifluoroacetate, (R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-{2-[(indane-2-carbonyl)-amino]-ethyl}-1-azonia-bicyclo[2.2.2]octane trifluoroacetate, (R)-1-[2-(2-Carbamoyl-benzoylamino)-ethyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate and (R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[2-(2-nitro-benzoylamino)-etbyl]-1-azonia-bicyclo[2.2.2]octane trifluoroacetate, (R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[2-(2-pyridin-3-yl-acetylamino)-ethyl]-1-azonia-bicyclo[2.2.2]octane trifluoroacetate, (R)-1-{2-[(Furan-3-carbonyl)-amino]-ethyl}-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azoniabicyclo[2.2.2]octane trifluoroacetate, (R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-{2-[(5-nitro-furan-2-carbonyl)-amino]-ethyl}-1-azonia-bicyclo[2.2.2]octane trifluoroacetate, (R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-(2-[(1H-indazole-3-carbonyl)-amino)-ethyl)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate, (R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-(2-[(thiophene-3-carbonyl)-amino]-ethyl)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate, (R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-(2-[(1-methyl-1H-pyrrole-2-carbonyl)-amino]-ethyl)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate, (R)-1-{2-[(2,5-Dimethyl-2H-pyrazole-3-carbonyl)-amino]-ethyl}-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate, (R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-{(2-[(5-methyl-2-phenyl-2H-[1,2,3]triazole-4-carbonyl)-amino]-ethyl}-1-azonia-bicyclo[2.2.2]octane trifluoroacetate, (R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-{2-[(4-methyl-[1,2,3]thiadiazole-5-carbonyl)-amino]-ethyl}-1-azonia-bicyclo[2.2.2]octane trifluoroacetate, (R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-(2-[(5-methyl-isoxazole-3-carbonyl)-amino]-ethyl)-1-azonia-bicyclo [2.2.2]octane trifluoroacetate, (R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-{2-[(3-methyl-furan-2-carbonyl)-amino]-ethyl}-1-azonia-bicyclo[2.2.2]octane trifluoroacetate, (R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-{2-[(4-methoxy-thiophene-3-carbonyl)-amino]-ethyl}-1-azonia-bicyclo [2.2.2]octane trifluoroacetate, (R)-1-{2-[(3-Ethoxy-thiophene-2-carbonyl)-amino]-ethyl}-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate, (R)-1-{2-[(5-Acetyl-thiophene-2-carbonyl)-amino]-ethyl}-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane (R)-1-(2-[(3-Chloro-thiophene-2-carbonyl)-amino]-ethyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate, (R)-1-{2-[(3-Bromo-thiophene-2-carbonyl)-amino]-ethyl}-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo [2.2.2]octane trifluoroacetate, (R)-1-{2-[(2,5-Dimethyl-furan-3-carbonyl)-amino]-ethyl}-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate, (R)-1-{2-[(5-Bromo-furan-2-carbonyl)-amino]-ethyl}-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate, (R)-1-(2-[(1,5-Dimethyl-1H-pyrazole-3-carbonyl)-amino]-ethyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate are all prepared by an analogous procedure to (R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-{2-[(naphthalene-2-carbonyl)-amino]-ethyl}-1-azonia-bicyclo[2.2.2]octane trifluoroacetate (Example 115) by replacing naphthalene-2-carboxylic acid with the appropriate acid.
  • Example 158 (R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[(methyl-phenyl-carbamoyl)-methyl]-1-azonia-bicyclo[2.2.2]octane
  • Hydroxy-diphenyl-acetic acid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester (0.03 g, 0.09 mmol) and 2-Chloro-N-methyl-N-phenyl-acetamide (0.025 g, 0.136 mmol), are dissolved in acetonitrile—DMSO (3:2, 5 ml) and stirred together at 18 hours at 50° C. Chloromethyl polystyrene resin (Merrifield resin) is added and the reaction stirred for an additional 4 hours at room temperature. Filtration and purification using mass directed preparative HPLC eluting with acetonitrile:water:trifluoroacetic acid followed by treatment with polymer bound Hünig's base then dissolution in ethyl acetate and washing with water, drying and concentration in vacuo gives the titled product as a solid.
  • Other especially preferred compounds of formula I include compounds of formula XIV where R1, R2, R3, and R4 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. R1 and R3 R4 R2 M+
    159
    Figure US20070060563A1-20070315-C00336
    Figure US20070060563A1-20070315-C00337
    OH 485.1
    160
    Figure US20070060563A1-20070315-C00338
    Figure US20070060563A1-20070315-C00339
    OH 473.1
    161
    Figure US20070060563A1-20070315-C00340
    Figure US20070060563A1-20070315-C00341
    OH 487.2
    162
    Figure US20070060563A1-20070315-C00342
    Figure US20070060563A1-20070315-C00343
    OH 487.3
    163
    Figure US20070060563A1-20070315-C00344
    Figure US20070060563A1-20070315-C00345
    OH 480.25
    164
    Figure US20070060563A1-20070315-C00346
    Figure US20070060563A1-20070315-C00347
    OH 495.3
    165
    Figure US20070060563A1-20070315-C00348
    Figure US20070060563A1-20070315-C00349
    OH 417.2
    166
    Figure US20070060563A1-20070315-C00350
    Figure US20070060563A1-20070315-C00351
    OH 428.1
    167
    Figure US20070060563A1-20070315-C00352
    Figure US20070060563A1-20070315-C00353
    OH 433.3
    168
    Figure US20070060563A1-20070315-C00354
    Figure US20070060563A1-20070315-C00355
    OH 452.2
    169
    Figure US20070060563A1-20070315-C00356
    Figure US20070060563A1-20070315-C00357
    OH 419.9
    170
    Figure US20070060563A1-20070315-C00358
    Figure US20070060563A1-20070315-C00359
    OH 431.9
    171
    Figure US20070060563A1-20070315-C00360
    Figure US20070060563A1-20070315-C00361
    OH 405.2
    172
    Figure US20070060563A1-20070315-C00362
    Figure US20070060563A1-20070315-C00363
    OH 424.2
    173
    Figure US20070060563A1-20070315-C00364
    Figure US20070060563A1-20070315-C00365
    OH 499.3
    174
    Figure US20070060563A1-20070315-C00366
    Figure US20070060563A1-20070315-C00367
    OH 513.35
    175
    Figure US20070060563A1-20070315-C00368
    Figure US20070060563A1-20070315-C00369
    OH 513.3
    176
    Figure US20070060563A1-20070315-C00370
    Figure US20070060563A1-20070315-C00371
    OH 395.3
    177
    Figure US20070060563A1-20070315-C00372
    Figure US20070060563A1-20070315-C00373
    OH 499.3
    178
    Figure US20070060563A1-20070315-C00374
    Figure US20070060563A1-20070315-C00375
    OH 509.3
    179
    Figure US20070060563A1-20070315-C00376
    Figure US20070060563A1-20070315-C00377
    OH 501.3
    180
    Figure US20070060563A1-20070315-C00378
    Figure US20070060563A1-20070315-C00379
    OH 501.3
    181
    Figure US20070060563A1-20070315-C00380
    Figure US20070060563A1-20070315-C00381
    OH 486.2
    182
    Figure US20070060563A1-20070315-C00382
    Figure US20070060563A1-20070315-C00383
    OH 395.2
    183
    Figure US20070060563A1-20070315-C00384
    Figure US20070060563A1-20070315-C00385
    OH 499.3
    184
    Figure US20070060563A1-20070315-C00386
    Figure US20070060563A1-20070315-C00387
    OH 551.2
    185
    Figure US20070060563A1-20070315-C00388
    Figure US20070060563A1-20070315-C00389
    OH 490.3
    186
    Figure US20070060563A1-20070315-C00390
    Figure US20070060563A1-20070315-C00391
    OH 493.3
    187
    Figure US20070060563A1-20070315-C00392
    Figure US20070060563A1-20070315-C00393
    OH 580
    188
    Figure US20070060563A1-20070315-C00394
    Figure US20070060563A1-20070315-C00395
    OH 489
    189
    Figure US20070060563A1-20070315-C00396
    Figure US20070060563A1-20070315-C00397
    OH 489.6
    190
    Figure US20070060563A1-20070315-C00398
    Figure US20070060563A1-20070315-C00399
    OH 475.3
    191
    Figure US20070060563A1-20070315-C00400
    Figure US20070060563A1-20070315-C00401
    OH 464
    192
    Figure US20070060563A1-20070315-C00402
    Figure US20070060563A1-20070315-C00403
    OH 478
    193
    Figure US20070060563A1-20070315-C00404
    Figure US20070060563A1-20070315-C00405
    OH 492
    194
    Figure US20070060563A1-20070315-C00406
    Figure US20070060563A1-20070315-C00407
    OH 492
    195
    Figure US20070060563A1-20070315-C00408
    Figure US20070060563A1-20070315-C00409
    OH 464
    196
    Figure US20070060563A1-20070315-C00410
    Figure US20070060563A1-20070315-C00411
    OH 472
    197
    Figure US20070060563A1-20070315-C00412
    Figure US20070060563A1-20070315-C00413
    OH 487
    198
    Figure US20070060563A1-20070315-C00414
    Figure US20070060563A1-20070315-C00415
    OH 500.4
    199
    Figure US20070060563A1-20070315-C00416
    Figure US20070060563A1-20070315-C00417
    OH 540.6
    200
    Figure US20070060563A1-20070315-C00418
    Figure US20070060563A1-20070315-C00419
    OH 488
    201
    Figure US20070060563A1-20070315-C00420
    Figure US20070060563A1-20070315-C00421
    OH 473
    202
    Figure US20070060563A1-20070315-C00422
    Figure US20070060563A1-20070315-C00423
    OH 476
    203
    Figure US20070060563A1-20070315-C00424
    Figure US20070060563A1-20070315-C00425
    OH 472
    204
    Figure US20070060563A1-20070315-C00426
    Figure US20070060563A1-20070315-C00427
    OH 492
    205
    Figure US20070060563A1-20070315-C00428
    Figure US20070060563A1-20070315-C00429
    OH 492
    206
    Figure US20070060563A1-20070315-C00430
    Figure US20070060563A1-20070315-C00431
    OH 472
    207
    Figure US20070060563A1-20070315-C00432
    Figure US20070060563A1-20070315-C00433
    OH 491.3
    208
    Figure US20070060563A1-20070315-C00434
    Figure US20070060563A1-20070315-C00435
    OH
    209
    Figure US20070060563A1-20070315-C00436
    Figure US20070060563A1-20070315-C00437
    OH 539.2
    210
    Figure US20070060563A1-20070315-C00438
    Figure US20070060563A1-20070315-C00439
    OH 589.2
    211
    Figure US20070060563A1-20070315-C00440
    Figure US20070060563A1-20070315-C00441
    OH 516.3
    212
    Figure US20070060563A1-20070315-C00442
    Figure US20070060563A1-20070315-C00443
    OH 547.2
    213
    Figure US20070060563A1-20070315-C00444
    Figure US20070060563A1-20070315-C00445
    OH 561.3
    214
    Figure US20070060563A1-20070315-C00446
    Figure US20070060563A1-20070315-C00447
    OH 571.2
    215
    Figure US20070060563A1-20070315-C00448
    Figure US20070060563A1-20070315-C00449
    OH 543.3
    216
    Figure US20070060563A1-20070315-C00450
    Figure US20070060563A1-20070315-C00451
    OH 549.3
    217
    Figure US20070060563A1-20070315-C00452
    Figure US20070060563A1-20070315-C00453
    OH 486.3
    218
    Figure US20070060563A1-20070315-C00454
    Figure US20070060563A1-20070315-C00455
    OH 549.3
    219
    Figure US20070060563A1-20070315-C00456
    Figure US20070060563A1-20070315-C00457
    OH 566.2
    220
    Figure US20070060563A1-20070315-C00458
    Figure US20070060563A1-20070315-C00459
    OH 504.3
    221
    Figure US20070060563A1-20070315-C00460
    Figure US20070060563A1-20070315-C00461
    OH 465.3
    222
    Figure US20070060563A1-20070315-C00462
    Figure US20070060563A1-20070315-C00463
    OH 605.3
    223
    Figure US20070060563A1-20070315-C00464
    Figure US20070060563A1-20070315-C00465
    OH
    224
    Figure US20070060563A1-20070315-C00466
    Figure US20070060563A1-20070315-C00467
    OH 449.3
    225
    Figure US20070060563A1-20070315-C00468
    Figure US20070060563A1-20070315-C00469
    OH 598.2
    226
    Figure US20070060563A1-20070315-C00470
    Figure US20070060563A1-20070315-C00471
    OH 545.3
    227
    Figure US20070060563A1-20070315-C00472
    Figure US20070060563A1-20070315-C00473
    OH 553.3
    228
    Figure US20070060563A1-20070315-C00474
    Figure US20070060563A1-20070315-C00475
    OH 603.2
    229
    Figure US20070060563A1-20070315-C00476
    Figure US20070060563A1-20070315-C00477
    OH 525.2
    230
    Figure US20070060563A1-20070315-C00478
    Figure US20070060563A1-20070315-C00479
    OH 537.2
    231
    Figure US20070060563A1-20070315-C00480
    Figure US20070060563A1-20070315-C00481
    OH 555.3
    232
    Figure US20070060563A1-20070315-C00482
    Figure US20070060563A1-20070315-C00483
    OH 558.3
    233
    Figure US20070060563A1-20070315-C00484
    Figure US20070060563A1-20070315-C00485
    OH 447.3
    234
    Figure US20070060563A1-20070315-C00486
    Figure US20070060563A1-20070315-C00487
    OH 516.3
    235
    Figure US20070060563A1-20070315-C00488
    Figure US20070060563A1-20070315-C00489
    OH 596.3
    236
    Figure US20070060563A1-20070315-C00490
    Figure US20070060563A1-20070315-C00491
    OH 509.3
    237
    Figure US20070060563A1-20070315-C00492
    Figure US20070060563A1-20070315-C00493
    OH 555.2
    238
    Figure US20070060563A1-20070315-C00494
    Figure US20070060563A1-20070315-C00495
    OH 479.4
    239
    Figure US20070060563A1-20070315-C00496
    Figure US20070060563A1-20070315-C00497
    OH 493.35
    240
    Figure US20070060563A1-20070315-C00498
    Figure US20070060563A1-20070315-C00499
    OH 522
    241
    Figure US20070060563A1-20070315-C00500
    Figure US20070060563A1-20070315-C00501
    OH 551.2
    242
    Figure US20070060563A1-20070315-C00502
    Figure US20070060563A1-20070315-C00503
    OH 462.2
    243
    Figure US20070060563A1-20070315-C00504
    Figure US20070060563A1-20070315-C00505
    OH 474.1
    244
    Figure US20070060563A1-20070315-C00506
    Figure US20070060563A1-20070315-C00507
    OH 485.1
    245
    Figure US20070060563A1-20070315-C00508
    Figure US20070060563A1-20070315-C00509
    OH 473.2

    Preparation of Specific Examples
  • Example 159 A) Bromide salt of (R)-3-(2-Hydroxy-2,2-di-thiophen-2-yl-acetoxy)-1-(pyrazin-2-ylcarbamoyl-methyl)-1-azonia-bicyclo[2.2.2]octane i) 2-Bromo-N-pyrazin-2-yl-acetamide
  • To a solution of 2-aminopyrazine (5.0 g, 52.6 mmol) in chloroform (250 ml) under an argon atmosphere is added triethylamine (8.79 ml, 63.1 mmol) and the temperature of the resulting mixture reduced to −40° C. To this solution is added a solution of bromoacetylbromide (4.57 ml, 52.6 mmol) in chloroform dropwise over 20 minutes, and stirring continued at −20° C. to −40° C. for 1 hour. The reaction mixture is then quenched by addition to saturated aqueous sodium bicarbonate solution. The chloroform later is separated and washed sequentially with saturated aqueous sodium bicarbonate solution, 0.5 M citric acid and brine. Concentration followed by purification by flash silica column chromatography (gradient elution:ethyl acetate/hexane 4:6 to 4:1) gives the title compound.
  • ii) (R)-3-(2-Hydroxy-2,2-di-thiophen-2-yl-acetoxy)-1-(pyrazin-2-ylcarbamoylmethyl)-1-azonia-bicyclo[2.2.2]octane bromide
  • A solution of 2-bromo-N-pyrazin-2-yl-acetamide (0.77 g, 3.56 mmol) and hydroxy-di-thiophen-2-yl-acetic acid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester (Example 70(ii)) (1.12 g, 3.23 mmol) in dry chloroform are heated at 50° C. for 2 hours. The mixture is then cooled to room temperature and extracted with water. The aqueous layer is concentrated under reduced pressure then redissolved in a small volume of acetonitrile containing a few drops of water. The mixture is allowed to stand at room temperature for several hours, the resulting solid is filtered and dried then redissolved in a small volume of water containing a few drops of acetonitrile. After several hours a solid is formed which is filtered and dried to give the title compound as a white solid.
  • B) Chloride salt of (R)-3-(2-Hydroxy-2,2-di-thiophen-2-yl-acetoxy)-1-(pyrazin-2-ylcarbamoyl-methyl)-1-azonia-bicyclo[2.2.2]octane
  • Pyrazin-2-yl-amine (400 μl, 0.5 M solution in DMF) and triethylamine (500 μl, 0.5 M solution in DMF) are combined and cooled in an ice bath. Chloroacetyl chloride (500 μl, 0.5 M solution in DMF) is added dropwise and stirred at 0° C. for 1 hour. To the crude 2-Chloro-N-pyrazin-2-yl-acetamide and hydroxy-di-thiophen-2-yl-acetic acid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester (Example 70(ii)) (800 μl, 0.25 M solution in DMF) is added triethylamine (30 μl, 1 equivalent) and the mixture stirred at room temperature overnight. PS-Bromoacetamidomethyl-NovaGel 2.3 mmol/g (0.3 g) and triethylamine (30 μl, 1 equivalent) are added to the reaction mixture and shaken at room temperature for 2 hours. The 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.
  • Examples 160 to 171
  • These compounds, namely (R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-(pyrimidin-4-yl carbamoylmethyl)-1-azonia-bicyclo[2.2.2]octane bromide, (R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[(3-hydroxy-phenylcarbamoyl)-methyl]-1-azonia-bicyclo[2.2.2]octane bromide, (R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[(4-hydroxy-phenylcarbamoyl)-methyl]-1-azonia-bicyclo[2.2.2]octane bromide, (R)-1-(3-tert-Butoxycarbonyl-propyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane bromide, (R)-1-((R/S)-2-tert-Butoxycarbonyl-amino-propyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane bromide, (R)-1-(3-Cyclopropyl-prop-2-ynyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo-[2.2.2]octane bromide, (R)-1-(3-Cyclopropyl-prop-2-ynyl)-3-(2-hydroxy-2,2-di-thiophen-2-yl-acetoxy)-1-azonia-bicyclo[2.2.2]octane bromide, (R)-1-(4,4-Dimethyl-pent-2-ynyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane bromide, (R)-1-(4,4-Dimethyl-pent-2-ynyl)-3-(2-hydroxy-2,2-di-thiophen-2-yl-acetoxy)-1-azonia-bicyclo[2.2.2]octane bromide, (R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-(4-methyl-pent-2-ynyl)-1-azonia-bicyclo-[2.2.2]octane bromide, (R)-3-(2-Hydroxy-2,2-di-thiophen-2-yl-acetoxy)-1-(4-methyl-pent-2-ynyl)-1-azonia-bicyclo[2.2.2]octane bromide, and (R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-pent-3-ynyl-1-azonia-bicyclo[2.2.2]octane bromide, are all prepared analogously to (R)-1-tert-Butoxy-carbonylmethyl-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]-octane bromide (Example 60) by replacing t-butylbromoacetate with the appropriate organic halide and heating the mixture at 50° C. for 2 to 21 hours. 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.
  • Example 172 (R)-1-(3-Carboxy-propyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia bicyclo[2.2.2]octane bromide
  • To a stirred solution of (R)-1-(3-tert-Butoxycarbonyl-propyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane bromide [Example 163] (0.2 g, 0.41 mmol) in methylene chloride (1.5 ml) under an argon atmosphere at room temperature is added hydrobromic acid (33% in acetic acid, 0.36 ml). After stirring at room temperatue for 30 minutes, concentration is followed by dissolution in water/acetonitile and stirring for a further 30 minutes. Concentration then gives the title product.
  • Examples 173 to 175
  • These compounds, namely (R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-(3-phenylcarbamoyl-propyl)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate, (R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[3-(methyl-phenylcarbamoyl)-propyl]-1-azonia-bicyclo[2.2.2]octane trifluoroacetate and (R)-1-(3-Benzylcarbamoyl-propyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia bicycle [2.2.2]octane trifluoroacetate are all prepared analogously to (R)-1-[(5,6-diethyl-indan-2-ylcarbamoyl)-methyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo [2.2.2]octane trifluoroacetate [Example 63] but by replacing (R)-1-carboxymethyl-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate [Example 62] with (R)-1-(3-carboxy-propyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia bicyclo[2.2.2] octane bromide [Example 172] and by replacing 5,6-Diethyl-indan-2-ylamine hydrochloride with the appropriate amine.
  • Example 176 (R)-1-(2-Amino-propyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azoniabicyclo[2.2.2]octane chloride hydrochloride
  • This compound is prepared analogously to (R)-1-((R/S)-2-Amino-ethyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane bromide hydrobromide [Example 49ii] but by replacing (R)-1-(2-tert-butoxycarbonylamino-ethyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane bromide [Example 49i] with (R)-1-((R/S)-2-tert-Butoxycarbonylamino-propyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane bromide [Example 164] and hydrogen bromide solution in dioxane with hydrogen chloride solution in dioxane. The product is isolated on concentration of the reaction medium, without further purification.
  • Example 177 (R)-1-((R/S)-2-Benzoylamino-propyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2] octane trifluoroacetate
  • 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 178 (R)-1-[3-(tert-Butoxycarbonyl-methyl-amino)-propyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane chloride
  • (3-Chloro-propyl)-methyl-carbamic acid tert-butyl ester (2.00 g 9.629 mmol) is solubilised in DMF (20 ml) and polystyrene bound DIPEA added, and after a few minutes removed. This solution is then added to a mixture of hydroxy-diphenyl-acetic acid (R)-(1-aza-bicyclo [2.2.2]oct-3-yl)ester (2.1634 g 6.419 mmol) and 200 mg of K2CO3 followed by the addition of sodium iodide (10 mg) and heating at 60° C. for 2 days. 2.5 g Merrifield resin and 100 mg K2CO3 is then added to the mixture and heating resumed at 40° C. for 12 hours. The resin is then removed, and the mixture purified by gradient C18 column chromatography to give the title product.
  • Example 179 (R)-1-[2-(4-Hydroxy-benzoylamino)-ethyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane bromide i) (R)-1-[2-(4-Benzyloxy-benzoylamino)-ethyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane bromide
  • To a solution of 4-benzyloxybenzoic acid (0.126 mg, 0.55 mmol) in DMF (3 ml) is added diisopropylethylamine (0.3 ml) followed by HATU (0.155 mg, 0.55 mmol). The reaction mixture is stirred for 30 minutes at room temperature after which time a solution comprising (R)-1-(2-amino-ethyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane bromide hydrobromide [Example 49(ii)] (0.200 g, 0.37 mmol) and the resulting mixture is stirred at room temperature over night. Purification is carried out using preparative C18 column chromatography eluting with acetonitrile: water to afford the titled compound.
  • ii) (R)-1-[2-(4-Hydroxy-benzoylamino)-ethyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane bromide
  • To a solution of (R)-1-[2-(4-Benzyloxy-benzoylamino)-ethyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane bromide (0.075 g, 0.11 mmol) in DMF (1 ml) under an argon atmosphere is added 10% Pd on carbon (40 mg) and the resulting solution hydrogenated for 3 hours. The catalyst is then removed by filtration and concentration in vacuo yields the title compound.
  • Example 180 (R)-1-[2-(3-Hydroxy-benzoylamino)-ethyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane chloride i) (R)-1-(2-Amino-ethyl)-3-(2-hydroxy-2,2-diphenyl-acetyl)-1-azonia-bicyclo[2.2.2]octane chloride hydrochloride
  • To a solution of (R)-1-(2-tert-butoxycarbonylamino-ethyl)-3-(2-hydroxy-2,2-diphenyl-acetyl)-1-azonia-bicyclo[2.2.2]octane bromide [Example 49i] (8.292 g, 14.82 mmol) in dioxane (100 ml) at room temperature is added hydrochloric acid (18.5 ml, 4 M in dioxane). The reaction mixture is stirred for 20 hours. The solvent is removed in vacuo and purification of the crude residue by chromatography on C18 silica, eluting with water:acetonitrile affords the titled product as a white solid.
  • ii) (R)-1-[2-(3-Hydroxy-benzoylamino)-ethyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane chloride
  • This is prepared analogously to (R)-1-[2-(4-Hydroxy-benzoylamino)-ethyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane bromide [Example 179] but 4-benzyloxy-benzoic acid is replaced by 3-benzyloxybenzoic acid and (R)-1-(2-amino-ethyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane bromide hydrobromide is substituted by (R)-1-(2-amino-ethyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane chloride hydrochloride [Example 180 i].
  • Example 181 (R)-1-Benzyloxycarbonylmethyl-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo [2.2.2]octane bromide
  • A suspension of hydroxy-diphenyl-acetic acid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester (1 g, 2.96 mmol) and bromoacetic acid benzyl ester (0.516 ml, 3.26 mmol) in ethylacetate (20 ml) is heated at 50° C. for 2 hours. The reaction mixture is cooled to room temperature and the precipitate removed by filtration. Recrystallisation from acetonitrile (20 ml) gives the title compound.
  • Example 182 (R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-(2-methylamino-ethyl)-1-azonia-bicyclo [2.2.2]octane bromide hydrobromide
  • (2-Bromo-ethyl)-methyl-carbamic acid tert-butyl ester (0.09 g, 0.38 mmol) is added to a solution of hydroxy-diphenyl-acetic acid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester (0.265 g, 0.79 mmol) in DMF (10 ml). The resulting mixture is heated at 60° C. for 5 hours and concentrated. This procedure is repeated twice giving the title compound as a mixture containing unreacted hydroxy-diphenyl-acetic acid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester.
  • Example 183 (R)-1-[2-(Benzoyl-methyl-amino)-ethyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate
  • 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 μl) followed by benzoyl bromide (64 μl) 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.
  • Example 184 (R)-1-[(2-Bromo-phenylcarbamoyl)-methyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)]-1-azonia-bicyclo[2.2.2]octane trifluoroacetate (i) N-(2-Bromo-phenyl)-2-chloro-acetamide
  • 2-Bromoaniline (371 μl, 467 mmol) and triethylamine (651 μl, 5.84 mmol) are dissolved in DMF (2 ml) and cooled in an ice bath. Chloroacetyl chloride (371 μl, 4.67 mmol) is added dropwise and stirred at 0° C. for 1 hour. The solvent is removed in vacuo and used crude in the next step.
  • ii) (R)-1-[(2-Bromo-phenylcarbamoyl)-methyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)]-1-azonia-bicyclo[2.2.2]octane trifluoroacetate
  • N-(2-Bromo-phenyl)-2-chloro-acetamide (155 mg, 0.622 mmol) and hydroxyl-diphenyl-acetic acid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester (210 mg, 0.622 mmol) are dissolved in DMF (4 ml). 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. The 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.
  • Example 185 to 189
  • These compounds, namely (R)-1-[(3,4-Dimethyl-isoxazol-5-ylcarbamoyl)-methyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate, (R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[(3-methyl-[1,2,4]thiadiazol-5-ylcarbamoyl)-methyl]-1-azonia-bicyclo[2.2.2]octane trifluoroacetate, (R)-1-[(5-Bromo-3,4-dimethyl-pyridin-2-yl-carbamoyl)-methyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate, (R)-1-[(2,S-Dimethyl-2H-pyrazol-3-ylcarbamoyl)-methyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate, and (R)-1-[(2-Ethyl-2H-pyrazol-3-ylcarbamoyl)-methyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo-[2.2.2]octane trifluoroacetate are all prepared analogously to (R)-1-[(2-Bromo-phenyl-carbamoyl)-methyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)]-1-azonia-bicyclo[2.2.2]octane trifluoroacetate [Example 184] by replacing 2-Bromoaniline with the appropriate amine.
  • Example 190 (R)-1-{2-[(Furan-2-carbonyl)-amino]ethyl}-3-(2-hydroxy-2,2-diphenyl-acetyl)-1-azonia-bicyclo[2.2.2]octane hexafluorophosphate
  • To a stirred solution of 2-furoic acid (91.5 mg, 8.21 mmol) and HATU (284 mg, 7.52 mmol) in DMF (7.5 ml) is added polymer bound morpholine, 2.5 mmol/g (1.36 g, 34.2 mmol). The reaction mixture is left to stand at room temperature for 15 minutes after which time, a solution comprising of (R)-1-(2-amino-ethyl)-3-(2-hydroxy-2,2-diphenyl-acetyl)-1-azonia-bicyclo[2.2.2]octane chloride hydrochloride [Example 180 i]] (310 mg, 6.84 mmol) in DMF (7.5 ml) is added. The reaction mixture is stirred at room temperature overnight. The 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.
  • Example 191 (R)-1-{2-[(Azetidine-3-carbonyl)-amino]-ethyl}-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate (i) (R)-1-{2-[1-tert-Butoxycarbonyl-azetidine-3-carbonyl)-amino]ethyl}-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane hexafluorophosphate
  • 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.
  • (ii) (R)-1-{2-[(Azetidine-3-carbonyl)-amino]-ethyl}-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate
  • (R)-1-2-[(1-tert-butoxycarbonyl-azetidine-3-carbonyl)-amino]ethyl-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane hexafluorophosphate is dissolved in TFA: DCM (1:1) (2 ml) and stirred at room temperature for 1 hour. TFA:DCM (2 ml) is added to the reaction mixture to complete the reaction. 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.
  • Example 192 to 195
  • These compounds, namely (R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-{2-[((S)-pyrrolidine-2-carbonyl)-amino]-ethyl}-1-azonia-bicyclo[2.2.2]octane trifluoroacetate, (R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-{2-[((R)-piperidine-2-carbonyl)-amino]-ethyl}-1-azonia-bicyclo[2.2.2] octane trifluoroacetate, (R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-{2-[((S)-piperidine-2-carbonyl)-amino]-ethyl}-1-azonia-bicyclo[2.2.2]octane trifluoroacetate and (R)-1-{2-[((S)-Azetidine-2-carbonyl)-amino)-ethyl}-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate are prepared analogously to (R)-1-{2-[(Azetidine-3-carbonyl)-amino]-ethyl}-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate [Example 191] by replacing 1-BOC-azetidine-3-carboxylic acid with the corresponding BOC protected amino acid.
  • Example 196 (R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-(pyridine-2-ylcarbamoyl methyl)-azonia-bicyclo[2.2.2]octane trifluoroacetate
  • 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]. However instead of using PS-triphenylphosphine, 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).
  • Example 197 (R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[(4-methyl-pyrimidin-2-ylcarbamoyl)-methyl]-1-azonia-bicyclo[2.2.2]octane chloride
  • 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.
  • Examples 198 to 201
  • These compounds, namely (R)-1-[(6-Ethyl-pyridin-2-ylcarbamoyl)methyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate, (R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[(3-trifluoromethyl-pyridin-4-ylcarbamoyl)-methyl]-1-azonia-bicyclo [2.2.2]octane trifluoroacetate, R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[(3-hydroxy-pyridin-2-ylcarbamoyl)-methyl]-1-azonia-bicyclo[2.2.2]octane trifluoroacetate, and (R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-(pyrimidin-2-ylcarbamoylmethyl)-1-azoniabicyclo[2.2.2] octane trifluoroacetate are all prepared analogously to (R)-1-[(2-bromo-phenyl-carbamoyl)-methyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)]-1-azonia-bicyclo[2.2.2]octane chloride [Example 184] by substituting 2-bromoaniline with the corresponding heterocyclic amines, however in these examples PS-triphenylphosphine is not used.
  • Examples 202 to 206
  • The title compounds, namely (R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[(4-methyl-oxazol-2-ylcarbamoyl)-methyl]-1-azonia-bicyclo[2.2.2]octane chloride, (R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-(pyridin-4-ylcarbamoylmethyl)-1-azonia-bicyclo[2.2.2]octane chloride, (R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[(5-methyl-thiazol-2-ylcarbamoyl)-methyl]-1-azonia-bicyclo[2.2.2]octane chloride, (R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[(4-methyl-thiazol-2-ylcarbamoyl)-methyl]-1-azonia-bicyclo[2.2.2]octane chloride, and (R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-(pyridin-3-ylcarbamoylmethyl)-1-azoniabicyclo[2.2.2] octane chloride, are all 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 with hydroxyl-diphenyl-acetic acid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester and replacing Pyrazin-2-yl-amine with the corresponding heterocyclic amines.
  • Example 207 (R)-3-(2-Hydroxy-2,2-diphenyl-acetyl)-1-[2-[thiophene-2-carbonyl)-amino]-ethyl]-1-azonia-bicyclo[2.2.2]octane hexafluorophosphate
  • To a stirred solution of 2-thiophenecarboxylic acid (15.4 mg, 0.12 mmol) and HATU (42 mg, 0.11 mmol) in DMF (0.6 ml) is added triethylamine (42 μl, 0.3 mmol). The reaction mixture is left to stand for 20 minutes after which time, a solution comprising of (R)-1-(2-amino-ethyl)-3-(2-hydroxy-2,2-diphenyl-acetyl)-1-azonia-bicyclo[2.2.2]octane bromide [Example 49 ii)] (45 mg, 0.1 mmol) in DMF (0.6 ml) is added. The reaction mixture is stirred at room temperature overnight. The 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.
  • Examples 208 to 241
  • These compounds, namely (R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-{2-[(3-methyl-thiophene-2-carbonyl)-amino]-ethyl}-1-azonia-bicyclo[2.2.21 octane hexafluoro phosphate, (R)-1-{2-[(3-Chloro-4-methyl-thiophene-2-carbonyl)-amino]-ethyl}-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane hexafluoro phosphate, (R)-1-{2-[(5-Chloro-3-methyl-benzo-[b]thiophene-2-carbonyl)-amino]-ethyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo-[2.2.2]octane hexafluorophosphate, (R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-{2-[(2-hydroxy-6-methyl-pyridine-4-carbonyl)-amino]-ethyl}-1-azonia-bicyclo[2.2.2]octane hexafluoro-phosphate, (R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-{2-[(thieno[3,2-b]thiophene-2-carbonyl)-amino]-ethyl}-1-azonia-bicyclo[2.2.2] octane hexafluoro-phosphate, (R)-1-{2-[(6-Fluoro-4H-benzo[1,3]dioxine-8-carbonyl)-amino]-ethyl}-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane hexafluoro phosphate, (R)-1-(2-[(5-Bromo-thiophene-2-carbonyl)-amino]-ethyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane hexafluorophosphate, (R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[2-(2-propoxy-benzoylamino)-ethyl]-1-azonia-bicyclo[2.2.2]octane hexafluorophosphate, (R)-1-[2-(5-Chloro-2-methoxy-benzoylamino)-ethyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane hexafluorophosphate, (R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-{2-[(pyridine-4-carbonyl)-amino]-ethyl}-1-azonia-bicyclo[2.2.2]octane hexafluorophosphate, (R)-1-[2-(2,6-Dimethoxy-benzoylamino)-ethyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane hexafluorophosphate, (R)-1-(2-[(5-Bromo-pyridine-3-carbonyl)-amino]-ethyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane hexafluorophosphate, (R)-1-(2-[(3,5-Dimethyl-isoxazole-4-carbonyl)-amino]-ethyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane hexafluoro phosphate, (R)-1-{2-[(1-Hydroxy-cyclo-propanecarbonyl)-amino]-ethyl}-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]-octane hexafluorophosphate, (R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-{2-[(2-trifluoro-methyl-[1,8]naphthyridine-3-carbonyl)-amino]-ethyl}-1-azonia-bicyclo[2.2.2]octane hexa-fluorophosphate, (R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-(2-[(6-methyl-pyridine-3-carbonyl)-amino]-ethyl)-1-azonia-bicyclo-[2.2.2]octane hexafluorophosphate, (R)-1-[2-(Cyclopropanecarbonyl-amino)-ethyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo-[2.2.2]octane hexafluorophosphate, (R)-1-[2-(4-Chloro-3-sulfamoyl-benzoylamino)-ethyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane hexafluorophosphate, (R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-(2-[(4,5,6,7-tetrahydro-benzo[c]thiophene-1-carbonyl)-amino]-ethyl)-1-azonia-bicyclo[2.2.2]-octane hexafluorophosphate, (R)-1-[2-[(2,7-Dimethyl-imidazo[1,2-a]pyridine-3-carbonyl)-amino]-ethyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2] octane hexa-fluorophosphate, (R)-1-{2-[(3-Chloro-4-methanesulfonyl-thiophene-2-carbonyl)-amino]-ethyl}-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo-[2.2.2] octane hexafluorophosphate, (R)-1-{2-[(5-Chloro-thiophene-2-carbonyl)-amino]-ethyl}-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane hexafluorophosphate, (R)-1-[2-(3-Chloro-4-fluoro-benzoylamino)-ethyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane hexafluorophosphate, (R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-{2-[(3-methyl-benzo[b]thiophene-2-carbonyl)-amino]-ethyl}-1-azonia-bicyclo[2.2.2]octane hexa-fluorophosphate, (R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[2-[(3-methyl-5-trifluoromethyl-isoxazole-4-carbonyl)-amino]-ethyl]-1-azonia-bicyclo[2.2.2]octane hexafluorophosphate, (R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[2-(1-oxo-but-2-ynylamino)-ethyl]-1-azonia-bicyclo-[2.2.2]octane hexafluorophosphate, (R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-2-[(2-methoxy-pyridine-3-carbonyl)-amino]-ethyl)-1-azonia-bicyclo[2.2.2]octane hexafluoro-phosphate, (R)-1-(2-[(5-Dimethylsulfamoyl-2-methyl-furan-3-carbonyl)-amino]-ethyl}-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2] octane hexafluorophosphate, (R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[2-(3-phenyl-propynoylamino)-ethyl]-1-azonia-bicyclo-[2.2.2]octane hexafluorophosphate, (R)-1-[2-[(5-Chloro-4-methoxy-thiophene-3-carbonyl)-amino]-ethyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane hexa-fluorophosphate, (R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-{2-[((R)-tetrahydro-furan-2-carbonyl)-amino]-ethyl}-1-azonia-bicyclo [2.2.2]octane hexafluoro-phosphate, (R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-{2-[(tetrahydro-pyran-4-carbonyl)-amino]-ethyl)-1-azonia-bicyclo[2.2.2]octane hexafluoro phosphate, (R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-(2-[(3-methoxy-thiophene-2-carbonyl)-amino]-ethyl)-1-azonia-bicyclo-[2.2.2]octane hexafluoro-phosphate, and (R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-{2-[(5-methoxy-thiophene-2-carbonyl)-amino]-ethyl}-1-azonia-bicyclo[2.2.2]octane hexafluoro-phosphate, are all prepared analogously to (R)-3-(2-Hydroxy-2,2-diphenyl-acetyl)-1-{2-[thiophene-2-carbonyl)-amino]-ethyl}-1-azonia-bicyclo[2.2.2]octane hexafluorophosphate [Ex. 207] by substituting 2-thiophenecarboxylic acid with the corresponding carboxylic acid.
  • Example 242 (R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-(isoxazol-3-ylcarbamoylmethyl)-1-azonia-bicyclo[2.2.2]octane bromide i) 2-Bromo-N-isoxazol-3-yl-acetamide
  • To a stirred solution of bromoacetylbromide (5.36 ml, 61.6 mmol) in diethylether (100 ml) at −40° C. is added, dropwise over 20 minutes, a solution of 3-aminoisoxazol (5.0 ml, 67.0 mmol) and triethylamine (8.5 ml, 61.4 mmol) in diethylether (20 ml). Additional diethylether (50 ml) is added and stirring continued for 3 hours. The 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 4:7) gives the title compound as a white solid.
  • ii) (R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-(isoxazol-3-ylcarbamoylmethyl)-1-azonia-bicyclo[2.2.2]octane bromide
  • A solution of 2-Bromo-N-isoxazol-3-yl-acetamide (0.82 g, 4.0 mmol) in chloroform/acetonitrile(1:1) is added to a solution of hydroxyl-diphenyl-acetic acid(R)-(1-aza-bicyclo-[2.2.2]oct-3-yl)ester (1.12 g, 3.32 mmol) in dry chloroform (10 ml) and the resulting mixture heated to 55° C. under an argon atmosphere for 4 hours. The mixture is then cooled to room temperature and concentrated. The residue is dissolved in acetonitrile and concentration followed by redissolution in hot acetone and cooling gives a jelly like precipitate which is filtered. Recrystallisation of the crude precipitate from acetonitrile containing a few drops of water followed by further crystallisation from acetonitrile gives the title compound as light brown crystals.
  • In an alterntaive method for preparing 2-Bromo-N-isoxazol-3-yl-acetamide, to a stirred solution of bromoacetylbromide (5.36 ml, 61.6 mmol) in diethylether (100 ml) at −40° C. is added, dropwise over 20 minutes, a solution of 3-aminoisoxazol (5.0 ml, 67.7 mmol) and triethylamine (8.5 ml, 61.4 mmol) in diethylether (20 ml). Additional diethylether (50 ml) is added and stirring continued for 3 hours. The 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.
  • Example 243 (R)-3-(2-Hydroxy-2,2-di-thiophen-2-yl-acetoxy)-1-(isoxazol-3-ylcarbamoylmethyl)-1-azonia-bicyclo[2.2.2]octane bromide
  • A solution of 2-Bromo-N-isoxazol-3-yl-acetamide [Example 242 i]) (0.70 g, 3.5 mmol) in chloroform (10 ml) is added to a solution of hydroxy-di-thiophen-2-yl-acetic acid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester (1.01 g, 2.9 mmol) acetonitrile (5 ml) and the resulting mixture heated to 55° C. under an argon atmosphere for 4 hours. The mixture is then cooled to room temperature and concentrated. The residue is triturated with ethylacetate and then purification by C-18 reverse phase column chromatography (eluent: water-acetonitrile) to give the title compound as a white foam.
  • Example 244 (R)-3-(2-Hydroxy-2,2-di-thiophen-2-yl-acetoxy)-1-(pyrimidin-4-ylcarbamoylmethyl)-1-azonia-bicyclo[2.2.2]octane bromide i) 2-Bromo-N-pyrimidin-4-yl-acetamide
  • To a solution of 4-aminopyrimidine (7.0 g, 73.6 mmol) in chloroform (300 ml) under an argon atmosphere is added triethylamine (12.3 ml, 88.3 mmol) and the temperature of the resulting mixture reduced to −40° C. To this solution is added a solution of bromoacetylbromide (6.4 ml, 73.6 mmol) in chloroform (5 ml) dropwise and stirring continued for 1.5 hours. The reaction mixture is then quenched by addition to saturated aqueous sodium bicarbonate solution. The chloroform later is separated and washed with 0.5 M citric acid solution. Concentration followed by purification by flash silica column chromatography (gradient elution:ethyl acetate/hexane 1:4 to methanol/ethyl acetate 1:10) gives the title compound.
  • ii) (R)-3-(2-Hydroxy-2,2-di-thiophen-2-yl-acetoxy)-1-(pyrimidin-4-ylcarbamoylmethyl)-1-azonia-bicyclo[2.2.2]octane bromide
  • A solution of 2-Bromo-N-pyrimidin-4-yl-acetamide (0.90 g, 4.17 mmol) and hydroxy-di-thiophen-2-yl-acetic acid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester (Example 70(ii)) (1.32 g, 3.79 mmol) in dry chloroform-acetonitrile (20 ml+4 ml) are heated at 50° C. for 3 hours. The mixture is then cooled to room temperature and concentrated. Purification by reverse phase C18 column chromatography (gradient elution 100% water to 100% acetonitrile) gives after concentration a light brown solid. The solid was triturated with hot acetonitrile then dissolved in hot acetonitrile containing a few drops of water. After standing at 5° C. for several hours crystals are formed which are filtered and dried to give the title compound.
  • Example 245 (R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-(pyrazin-2-ylcarbamoylmethyl)-1-azonia-bicyclo[2.2.2]octane
  • A solution of 2-bromo-N-pyrazin-2-yl-acetamide (1.50 g, 6.94 mmol) and hydroxyl-diphenyl-acetic acid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester (2.13 g, 6.31 mmol) in dry chloroform (10 ml) are heated at 50° C. for 2 hours. The mixture is then cooled to room temperature filtered and concentrated. The resulting foam is dissolved in acetonitrile and cooled to −20° C., an orange oil is formed from which the acetonitrile layer is decanted. The orange oil is dissolved in water and washed with chloroform before concentration. Redissolution in hot water followed by precipitation by cooling to room temperature gives the title product as a white solid.
  • Further especially preferred compounds of formula I include compounds of formula XIV where R1, R2, R3, and R4 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. R1 and R3 R4 R2 M+
    246
    Figure US20070060563A1-20070315-C00510
    Figure US20070060563A1-20070315-C00511
    OH 448.3
    247
    Figure US20070060563A1-20070315-C00512
    Figure US20070060563A1-20070315-C00513
    OH 408.3

    Preparation of Specific Examples
  • Example 246 1-Allyloxycarbonylmethyl-3-(2-hydroxy-2,2-di-thiophen-2-yl-acetoxy)-1-azonia-bicyclo-[2.2.2]octane
  • A solution of bromo-acetic acid allyl ester (0.8 g, 4.46 mmol) and hydroxy-di-thiophen-2-yl-acetic acid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester (Example 70(ii)) (1.3 g, 3.7 mmol) in dry chloroform are heated at 50° C. for 2 hours. The contents are then allowed to cool and then concentrated in vacuo. This residue is then taken up in 1% water in acetone at reflux and allowed to cool to room temp. After several hours a solid is formed which is filtered and dried to give the title compound as a brown solid.
  • Example 247 1-Carboxymethyl-3-(2-hydroxy-2,2-di-thiophen-2-yl-acetoxy)-1-azonia-bicyclo[2.2.2]octane
  • To a stirred solution of 1-allyloxycarbonylmethyl-3-(2-hydroxy-2,2-di-thiophen-2-yl-acetoxy)-1-azonia-bicyclo[2.2.2]octane (Example 246) (0.79 g, 1.50 mmol) in dry chloroform, under argon, is added tetrakis-palladium triphenyl phosphine (0.02 g, 0.017 mmol). The mixture is strirred at room temp., under argon, for 20 minutes before morpholine (0.196 ml, 2.25 mmol) is added. Stirring is continued for a further 4 hrs at room temp. 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.

Claims (20)

1. A compound of formula I
Figure US20070060563A1-20070315-C00514
in salt or zwitterionic form wherein
R1 and R3 are each independently a C3-C15-carbocyclic group or a 4- to 12-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur,
or —CR1R2R3 together form a group of formula
Figure US20070060563A1-20070315-C00515
where R is a bond, —O—, —S—, —CH2—, —CH═CH—, —CH2—CH2—, amino or —N(CH3)—;
R2 is hydrogen, halo, hydroxy, C1-C8-alkoxy or C1-C8-alkyl optionally substituted by hydroxy;
R4 is C1-C8-alkyl substituted by —NHR5, —NR5—CO—R6, —NR5—CO—NH—R7, —NR5—SO2—R8, —CO—NR9R10, —OR11, —O—CO—NHR12, —O—CO—R13 or —CO—O—R14,
or R4 is C3-C10-alkynyl optionally substituted by a C3-C15-carbocyclic group or a 4- to 12-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur;
R5 is hydrogen or C1-C8-alkyl;
R6 is C1-C8-alkyl, C2-C8-alkenyl, C2-C10-alkynyl or C1-C8-alkoxy in each case optionally substituted by a C3-C15-carbocyclic group or a 4- to 12-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur,
or R6 is a C3-C15-carbocyclic group or a 4- to 12-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur;
R7 is a C3-C15-carbocyclic group;
R8 is a C3-C15-carbocyclic group;
R9 is hydrogen or C1-C8-alkyl;
R10 is hydrogen, C1-C8-alkyl optionally substituted by cyano, amino, nitro, carboxy, C1-C8-alkoxy, a C3-C15-carbocyclic group, or by a 4- to 12-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur,
or R10 is a C3-C15-carbocyclic group or a 4- to 12-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur;
R11 is hydrogen, C1-C8-alkyl, C1-C8-alkyl-C1-C8-alkoxy or C1-C8-alkyl-O—R15;
R12 is a C3-C15-carbocyclic group;
R13 is C1-C8-alkyl or a C3-C15-carbocyclic group;
R14 is hydrogen, a C3-C15-carbocyclic group, C1-C8-alkenyl, or C1-C8-alkyl optionally substituted by a C3-C15-carbocyclic group; and
R15 is a C3-C15-carbocyclic group.
2. A compound according to claim 1, wherein
R1 and R3 are each independently a C3-C15-carbocyclic group or a 4- to 12-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur;
R2 is halo or hydroxy;
R4 is C1-C8-alkyl substituted by —NHR5, —NR5—CO—R6, —NR5—CO—NH—R7, —NR5—SO2—R8, —CO—NR9R10, —O—CO—NH—R2, —O—CO—R13 or —CO—O—R4,
or R4 is C3-C10-alkynyl optionally substituted by a C3-C15-carbocyclic group or a 4- to 12-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur;
R5 is hydrogen or C1-C8-alkyl;
R6 is C1-C8-alkyl, C2-C10-alkynyl or C1-C8-alkoxy in each case optionally substituted by a C3-C15-carbocyclic group or a 4- to 12-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur,
or R6 is a C3-C15-carbocyclic group or a 4- to 12-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur;
R7 is a C3-C15-carbocyclic group;
R8 is a C3-C15-carbocyclic group;
R9 is hydrogen or C1-C8-alkyl;
R10 is C1-C8-alkyl optionally substituted by cyano, C1-C8-alkoxy, a C3-C15-carbocyclic group or by a 4- to 12-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur,
or R10 is a C3-C15-carbocyclic group or a 4- to 12-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur;
R12 is a C3-C15-carbocyclic group;
R13 is C1-C8-alkyl; and
R14 is hydrogen, a C3-C15-carbocyclic group, C1-C8-alkenyl, or C1-C8-alkyl optionally substituted by a C3-C15-carbocyclic group.
3. A compound according to claim 2, wherein
R1 and R3 are each independently a C6-C10-carbocyclic aromatic group or a 4- to 12-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur;
R2 is halo or hydroxy;
R4 is C1-C8-alkyl substituted by —NHR5, —NR5—CO—R6, —NR5—CO—NH—R7, —NR5—SO2—R8, —CO—NR9R10, —O—CO—NH—R2, —O—CO—R13 or —CO—O—R4,
or R4 is C3-C8-alkynyl optionally substituted by a C3-C10-carbocyclic group or a 4- to 10-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur;
R5 is hydrogen or C1-C4-alkyl;
R6 is C1-C4-alkyl, C2-C8-alkynyl or C1-C4-alkoxy in each case optionally substituted by a C3-C10-carbocyclic group or a 4- to 12-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur,
or R6 is a C3-C10-carbocyclic group or a 4- to 10-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur;
R7 is a C3-C10-carbocyclic group;
R8 is a C3-C10-carbocyclic group;
R9 is hydrogen or C1-C4-alkyl;
R10 is C1-C4-alkyl optionally substituted by cyano, C1-C4-alkoxy, a C3-C10-carbocyclic group or by a 4- to 10-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur,
or R10 is a C3-C10-carbocyclic group or a 4- to 10-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur;
R12 is a C3-C10-carbocyclic group;
R13 is C1-C4-alkyl; and
R14 is hydrogen, a C3-C10-carbocyclic group, C1-C4-alkenyl, or C1-C4-alkyl optionally substituted by a C3-C10-carbocyclic group.
4. A compound of formula I
Figure US20070060563A1-20070315-C00516
in salt or zwitterionic form wherein
R1 and R3 are each independently a C3-C15-carbocyclic group or a 4- to 12-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur,
or —CR1R2R3 together form a group of formula
Figure US20070060563A1-20070315-C00517
where R is a bond, —O—, —S—, —CH2—, —CH═CH—, —CH2—CH2—, amino or —N(CH3)—;
R2 is hydrogen, halo, hydroxy, C1-C8-alkoxy or C1-C8-alkyl optionally substituted by hydroxy;
R4 is C1-C8-alkyl substituted by —NHR5, —NR5—CO—R6, —NR5—CO—NH—R7, —NR5—SO2—R8, —CO—NR9R10, —OR11, —O—CO—NHR12, —O—CO—R13 or —CO—O—R4,
or R4 is C3-C10-alkynyl optionally substituted by a C3-C15-carbocyclic group or a 4- to 12-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur;
R5 is hydrogen or C1-C8-alkyl;
R6 is C1-C8-alkyl, C2-C8-alkenyl, C2-C10-alkynyl or C1-C8-alkoxy in each case optionally substituted by a C3-C15-carbocyclic group or a 4- to 12-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur,
or R6 is a C3-C15-carbocyclic group or a 4- to 12-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur;
R7 is a C3-C15-carbocyclic group;
R8 is a C3-C15-carbocyclic group;
R9 is hydrogen or C1-C8-alkyl;
R10 is hydrogen, C1-C8-alkyl optionally substituted by cyano, amino, nitro, carboxy, C1-C8-alkoxy, a C3-C15-carbocyclic group, or by a 4- to 12-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur,
or R10 is a C3-C15-carbocyclic group or a 4- to 12-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur;
R11 is hydrogen, C1-C8-alkyl, C1-C8-alkyl-C1-C8-alkoxy or C1-C8-alkyl-O—R15;
R12 is a C3-C15-carbocyclic group;
R13 is C1-C8-alkyl or a C3-C15-carbocyclic group;
R14 is hydrogen, a C3-C15-carbocyclic group, or C1-C8-alkyl optionally substituted by a C3-C15-carbocyclic group; and
R15 is a C3-C15-carbocyclic group.
5. A compound according to claim 4, wherein
R1 and R3 are each independently a C3-C15-carbocyclic group or a 4- to 12-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur;
R2 is halo or hydroxy;
R4 is C1-C8-alkyl substituted by —NHR5, —NR5—CO—R6, —NR5—CO—NH—R7, —NR5—SO2—R8, —CO—NR9R10, —O—CO—NH—R2, —O—CO—R13 or —CO—O—R4,
or R4 is C3-C10-alkynyl optionally substituted by a C3-C15-carbocyclic group or a 4- to 12-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur;
R5 is hydrogen or C1-C8-alkyl;
R6 is C1-C8-alkyl, C2-C10-alkynyl or C1-C8-alkoxy in each case optionally substituted by a C3-C15-carbocyclic group or a 4- to 12-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur,
or R6 is a C3-C15-carbocyclic group or a 4- to 12-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur;
R7 is a C3-C15-carbocyclic group;
R8 is a C3-C15-carbocyclic group;
R9 is hydrogen or C1-C8-alkyl;
R10 is C1-C8-alkyl optionally substituted by cyano, C1-C8-alkoxy, a C3-C15-carbocyclic group or by a 4- to 12-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur,
or R10 is a C3-C15-carbocyclic group or a 4- to 12-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur;
R12 is a C3-C15-carbocyclic group;
R13 is C1-C8-alkyl; and
R14 is hydrogen, a C3-C15-carbocyclic group or C1-C8-alkyl optionally substituted by a C3-C15-carbocyclic group.
6. A compound according to claim 5, wherein
R1 and R3 are each independently a C6-C10-carbocyclic aromatic group or a 4- to 12-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur;
R2 is halo or hydroxy;
R4 is C1-C8-alkyl substituted by —NHR5, —NR5—CO—R6, —NR5—CO—NH—R7, —NR5—SO2—R8, —CO—NR9R10, —O—CO—N H—R12, —O—CO—R13 or —CO—O—R14,
or R4 is C3-C8-alkynyl optionally substituted by a C3-C10-carbocyclic group or a 4- to 10-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur;
R5 is hydrogen or C1-C4-alkyl;
R6 is C1-C4-alkyl, C2-C8-alkynyl or C1-C4-alkoxy in each case optionally substituted by a C3-C10-carbocyclic group or a 4- to 12-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur,
or R6 is a C3-C10-carbocyclic group or a 4- to 10-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur;
R7 is a C3-C10-carbocyclic group;
R8 is a C3-C10-carbocyclic group;
R9 is hydrogen or C1-C4-alkyl;
R10 is C1-C4-alkyl optionally substituted by cyano, C1-C4-alkoxy, a C3-C10-carbocyclic group or by a 4- to 10-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur,
or R10 is a C3-C10-carbocyclic group or a 4- to 10-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur;
R12 is a C3-C10-carbocyclic group;
R13 is C1-C4-alkyl; and
R14 is hydrogen, a C3-C10-carbocyclic group or C1-C4-alkyl optionally substituted by a C3-C10-carbocyclic group.
7. A compound of formula I
Figure US20070060563A1-20070315-C00518
in salt or zwitterionic form wherein
R1 and R3 are each independently a C3-C15-carbocyclic group or a 5- to 12-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur,
or —CR1R2R3 together form a group of formula
Figure US20070060563A1-20070315-C00519
where R is a bond, —O—, —S—, —CH2—, —CH═CH—, —CH2—CH2—, amino or —N(CH3)—;
R2 is hydrogen, halo, hydroxy, C1-C8-alkoxy or C1-C8-alkyl optionally substituted by hydroxy;
R4 is C1-C8-alkyl substituted by —NHR5, —NR5—CO—R6, —NR5—CO—NH—R7, —NR5—SO2—R8, —CO—NR9R10, —OR11, —O—CO—NHR2, —O—CO—R13 or —CO—O—R14,
or R4 is C3-C10-alkynyl optionally substituted by a C3-C15-carbocyclic group or a 5- to 12-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur;
R5 is hydrogen or C1-C8-alkyl;
R6 is C1-C8-alkyl or C1-C8-alkoxy in either case optionally substituted by a C3-C15-carbocyclic group or a 5- to 12-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur,
or R6 is a C3-C15-carbocyclic group or a 5- to 12-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur;
R7 is a C3-C15-carbocyclic group;
R8 is a C3-C15-carbocyclic group;
R9 is hydrogen or C1-C8-alkyl;
R10 is hydrogen, C1-C8-alkyl optionally substituted by cyano, amino, nitro, carboxy, C1-C8-alkoxy, a C3-C15-carbocyclic group, or by a 5- to 12-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur,
or R10 is a C3-C15-carbocyclic group or a 5- to 12-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur;
R11 is hydrogen, C1-C8-alkyl, C1-C8-alkyl-C1-C8-alkoxy or C1-C8-alkyl-O—R15;
R12 is a C3-C15-carbocyclic group;
R13 is C1-C8-alkyl or a C3-C15-carbocyclic group;
R14 is hydrogen, C1-C8-alkyl or a C3-C15-carbocyclic group; and
R15 is a C3-C15-carbocyclic group.
8. A compound according to claim 7, wherein
R1 and R3 are each independently a C3-C15-carbocyclic group or a 5- to 12-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur;
R2 is halo or hydroxy;
R4 is C1-C8-alkyl substituted by —NHR5, —NR5—CO—R6, —NR5—CO—NH—R7, —NR5—SO2—R8, —CO—NR9R10, —O—CO—NH—R2, —O—CO—R13 or —CO—O—R14,
or R4 is C3-C10-alkynyl optionally substituted by a C3-C15-carbocyclic group or a 5- to 12-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur;
R5 is hydrogen;
R6 is C1-C8-alkyl or C1-C8-alkoxy in either case optionally substituted by a C3-C15-carbocyclic group or a 5- to 12-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur,
or R6 is a C3-C15-carbocyclic group or a 5- to 12-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur;
R7 is a C3-C15-carbocyclic group;
R8 is a C3-C15-carbocyclic group;
R9 is hydrogen or C1-C8-alkyl;
R10 is C1-C8-alkyl optionally substituted by cyano, C1-C8-alkoxy, a C3-C15-carbocyclic group or by a 5- to 12-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur,
or R10 is a C3-C15-carbocyclic group or a 5- to 12-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur;
R12 is a C3-C15-carbocyclic group;
R13 is C1-C8-alkyl; and
R14 is hydrogen, C1-C8-alkyl or a C3-C15-carbocyclic group.
9. A compound according to claim 8, wherein
R1 and R3 are each independently a C6-C10-carbocyclic aromatic group or a 5- to 12-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur;
R2 is halo or hydroxy;
R4 is C1-C8-alkyl substituted by —NHR5, —NR5—CO—R6, —NR5—CO—NH—R7, —NR5—SO2—R8, —CO—NR9R10, —O—CO—NH—R2, —O—CO—R13 or —CO—O—R4,
or R4 is C3-C8-alkynyl optionally substituted by a C3-C10-carbocyclic group or a 5- to 10-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur;
R5 is hydrogen;
R6 is C1-C4-alkyl or C1-C4-alkoxy in either case optionally substituted by a C3-C10-carbocyclic group or a 5- to 12-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur,
or R5 is a C3-C10-carbocyclic group or a 5- to 10-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur;
R7 is a C3-C10-carbocyclic group;
R8 is a C3-C10-carbocyclic group;
R9 is hydrogen or C1-C4-alkyl;
R10 is C1-C4-alkyl optionally substituted by cyano, C1-C4-alkoxy, a C3-C10-carbocyclic group or by a 5- to 10-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur,
or R10 is a C3-C10-carbocyclic group or a 5- to 10-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur;
R12 is a C3-C10-carbocyclic group;
R13 is C1-C4-alkyl; and
R14 is hydrogen, C1-C4-alkyl or a C3-C10-carbocyclic group.
10. A compound according to claim 1, which is also a compound of formula XIV
Figure US20070060563A1-20070315-C00520
where R1, R2, R3, and R4 are as shown in the following table:
R1 and R3 R4 R2
Figure US20070060563A1-20070315-C00521
Figure US20070060563A1-20070315-C00522
OH
Figure US20070060563A1-20070315-C00523
Figure US20070060563A1-20070315-C00524
OH
Figure US20070060563A1-20070315-C00525
Figure US20070060563A1-20070315-C00526
OH
Figure US20070060563A1-20070315-C00527
Figure US20070060563A1-20070315-C00528
OH
Figure US20070060563A1-20070315-C00529
Figure US20070060563A1-20070315-C00530
OH
Figure US20070060563A1-20070315-C00531
Figure US20070060563A1-20070315-C00532
OH
Figure US20070060563A1-20070315-C00533
Figure US20070060563A1-20070315-C00534
OH
Figure US20070060563A1-20070315-C00535
Figure US20070060563A1-20070315-C00536
OH
Figure US20070060563A1-20070315-C00537
Figure US20070060563A1-20070315-C00538
OH
Figure US20070060563A1-20070315-C00539
Figure US20070060563A1-20070315-C00540
OH
Figure US20070060563A1-20070315-C00541
Figure US20070060563A1-20070315-C00542
OH
Figure US20070060563A1-20070315-C00543
Figure US20070060563A1-20070315-C00544
OH
Figure US20070060563A1-20070315-C00545
Figure US20070060563A1-20070315-C00546
OH
Figure US20070060563A1-20070315-C00547
Figure US20070060563A1-20070315-C00548
OH
Figure US20070060563A1-20070315-C00549
Figure US20070060563A1-20070315-C00550
OH
Figure US20070060563A1-20070315-C00551
Figure US20070060563A1-20070315-C00552
OH
Figure US20070060563A1-20070315-C00553
Figure US20070060563A1-20070315-C00554
OH
Figure US20070060563A1-20070315-C00555
Figure US20070060563A1-20070315-C00556
OH
Figure US20070060563A1-20070315-C00557
Figure US20070060563A1-20070315-C00558
OH
Figure US20070060563A1-20070315-C00559
Figure US20070060563A1-20070315-C00560
OH
Figure US20070060563A1-20070315-C00561
Figure US20070060563A1-20070315-C00562
OH
Figure US20070060563A1-20070315-C00563
Figure US20070060563A1-20070315-C00564
OH
Figure US20070060563A1-20070315-C00565
Figure US20070060563A1-20070315-C00566
OH
Figure US20070060563A1-20070315-C00567
Figure US20070060563A1-20070315-C00568
OH
Figure US20070060563A1-20070315-C00569
Figure US20070060563A1-20070315-C00570
OH
Figure US20070060563A1-20070315-C00571
Figure US20070060563A1-20070315-C00572
OH
Figure US20070060563A1-20070315-C00573
Figure US20070060563A1-20070315-C00574
OH
Figure US20070060563A1-20070315-C00575
Figure US20070060563A1-20070315-C00576
OH
Figure US20070060563A1-20070315-C00577
Figure US20070060563A1-20070315-C00578
OH
Figure US20070060563A1-20070315-C00579
Figure US20070060563A1-20070315-C00580
OH
Figure US20070060563A1-20070315-C00581
Figure US20070060563A1-20070315-C00582
OH
Figure US20070060563A1-20070315-C00583
Figure US20070060563A1-20070315-C00584
OH
Figure US20070060563A1-20070315-C00585
Figure US20070060563A1-20070315-C00586
OH
Figure US20070060563A1-20070315-C00587
Figure US20070060563A1-20070315-C00588
OH
Figure US20070060563A1-20070315-C00589
Figure US20070060563A1-20070315-C00590
OH
Figure US20070060563A1-20070315-C00591
Figure US20070060563A1-20070315-C00592
OH
Figure US20070060563A1-20070315-C00593
Figure US20070060563A1-20070315-C00594
OH
Figure US20070060563A1-20070315-C00595
Figure US20070060563A1-20070315-C00596
OH
Figure US20070060563A1-20070315-C00597
Figure US20070060563A1-20070315-C00598
OH
Figure US20070060563A1-20070315-C00599
Figure US20070060563A1-20070315-C00600
OH
Figure US20070060563A1-20070315-C00601
Figure US20070060563A1-20070315-C00602
OH
Figure US20070060563A1-20070315-C00603
Figure US20070060563A1-20070315-C00604
OH
Figure US20070060563A1-20070315-C00605
Figure US20070060563A1-20070315-C00606
OH
Figure US20070060563A1-20070315-C00607
Figure US20070060563A1-20070315-C00608
OH
Figure US20070060563A1-20070315-C00609
Figure US20070060563A1-20070315-C00610
OH
Figure US20070060563A1-20070315-C00611
Figure US20070060563A1-20070315-C00612
OH
Figure US20070060563A1-20070315-C00613
Figure US20070060563A1-20070315-C00614
OH
Figure US20070060563A1-20070315-C00615
Figure US20070060563A1-20070315-C00616
OH
Figure US20070060563A1-20070315-C00617
Figure US20070060563A1-20070315-C00618
OH
Figure US20070060563A1-20070315-C00619
Figure US20070060563A1-20070315-C00620
OH
Figure US20070060563A1-20070315-C00621
Figure US20070060563A1-20070315-C00622
OH
Figure US20070060563A1-20070315-C00623
Figure US20070060563A1-20070315-C00624
OH
Figure US20070060563A1-20070315-C00625
Figure US20070060563A1-20070315-C00626
OH
Figure US20070060563A1-20070315-C00627
Figure US20070060563A1-20070315-C00628
OH
Figure US20070060563A1-20070315-C00629
Figure US20070060563A1-20070315-C00630
OH
Figure US20070060563A1-20070315-C00631
Figure US20070060563A1-20070315-C00632
OH
Figure US20070060563A1-20070315-C00633
Figure US20070060563A1-20070315-C00634
OH
Figure US20070060563A1-20070315-C00635
Figure US20070060563A1-20070315-C00636
OH
Figure US20070060563A1-20070315-C00637
Figure US20070060563A1-20070315-C00638
OH
Figure US20070060563A1-20070315-C00639
Figure US20070060563A1-20070315-C00640
OH
Figure US20070060563A1-20070315-C00641
Figure US20070060563A1-20070315-C00642
OH
Figure US20070060563A1-20070315-C00643
Figure US20070060563A1-20070315-C00644
OH
Figure US20070060563A1-20070315-C00645
Figure US20070060563A1-20070315-C00646
OH
Figure US20070060563A1-20070315-C00647
Figure US20070060563A1-20070315-C00648
OH
Figure US20070060563A1-20070315-C00649
Figure US20070060563A1-20070315-C00650
OH
Figure US20070060563A1-20070315-C00651
Figure US20070060563A1-20070315-C00652
OH
Figure US20070060563A1-20070315-C00653
Figure US20070060563A1-20070315-C00654
OH
Figure US20070060563A1-20070315-C00655
Figure US20070060563A1-20070315-C00656
OH
Figure US20070060563A1-20070315-C00657
Figure US20070060563A1-20070315-C00658
OH
Figure US20070060563A1-20070315-C00659
Figure US20070060563A1-20070315-C00660
OH
Figure US20070060563A1-20070315-C00661
Figure US20070060563A1-20070315-C00662
OH
Figure US20070060563A1-20070315-C00663
Figure US20070060563A1-20070315-C00664
OH
Figure US20070060563A1-20070315-C00665
Figure US20070060563A1-20070315-C00666
OH
Figure US20070060563A1-20070315-C00667
Figure US20070060563A1-20070315-C00668
OH
Figure US20070060563A1-20070315-C00669
Figure US20070060563A1-20070315-C00670
OH
Figure US20070060563A1-20070315-C00671
Figure US20070060563A1-20070315-C00672
OH
Figure US20070060563A1-20070315-C00673
Figure US20070060563A1-20070315-C00674
OH
Figure US20070060563A1-20070315-C00675
Figure US20070060563A1-20070315-C00676
OH
Figure US20070060563A1-20070315-C00677
Figure US20070060563A1-20070315-C00678
OH
Figure US20070060563A1-20070315-C00679
Figure US20070060563A1-20070315-C00680
OH
Figure US20070060563A1-20070315-C00681
Figure US20070060563A1-20070315-C00682
OH
Figure US20070060563A1-20070315-C00683
Figure US20070060563A1-20070315-C00684
OH
Figure US20070060563A1-20070315-C00685
Figure US20070060563A1-20070315-C00686
OH
Figure US20070060563A1-20070315-C00687
Figure US20070060563A1-20070315-C00688
OH
Figure US20070060563A1-20070315-C00689
Figure US20070060563A1-20070315-C00690
OH
Figure US20070060563A1-20070315-C00691
Figure US20070060563A1-20070315-C00692
OH
Figure US20070060563A1-20070315-C00693
Figure US20070060563A1-20070315-C00694
OH
Figure US20070060563A1-20070315-C00695
Figure US20070060563A1-20070315-C00696
OH
Figure US20070060563A1-20070315-C00697
Figure US20070060563A1-20070315-C00698
OH
Figure US20070060563A1-20070315-C00699
Figure US20070060563A1-20070315-C00700
OH
Figure US20070060563A1-20070315-C00701
Figure US20070060563A1-20070315-C00702
OH
Figure US20070060563A1-20070315-C00703
Figure US20070060563A1-20070315-C00704
OH
Figure US20070060563A1-20070315-C00705
Figure US20070060563A1-20070315-C00706
OH
Figure US20070060563A1-20070315-C00707
Figure US20070060563A1-20070315-C00708
OH
Figure US20070060563A1-20070315-C00709
Figure US20070060563A1-20070315-C00710
OH
Figure US20070060563A1-20070315-C00711
Figure US20070060563A1-20070315-C00712
OH
Figure US20070060563A1-20070315-C00713
Figure US20070060563A1-20070315-C00714
OH
Figure US20070060563A1-20070315-C00715
Figure US20070060563A1-20070315-C00716
OH
Figure US20070060563A1-20070315-C00717
Figure US20070060563A1-20070315-C00718
OH
Figure US20070060563A1-20070315-C00719
Figure US20070060563A1-20070315-C00720
OH
Figure US20070060563A1-20070315-C00721
Figure US20070060563A1-20070315-C00722
OH
Figure US20070060563A1-20070315-C00723
Figure US20070060563A1-20070315-C00724
OH
Figure US20070060563A1-20070315-C00725
Figure US20070060563A1-20070315-C00726
OH
Figure US20070060563A1-20070315-C00727
Figure US20070060563A1-20070315-C00728
OH
Figure US20070060563A1-20070315-C00729
Figure US20070060563A1-20070315-C00730
OH
Figure US20070060563A1-20070315-C00731
Figure US20070060563A1-20070315-C00732
OH
Figure US20070060563A1-20070315-C00733
Figure US20070060563A1-20070315-C00734
OH
Figure US20070060563A1-20070315-C00735
Figure US20070060563A1-20070315-C00736
OH
Figure US20070060563A1-20070315-C00737
Figure US20070060563A1-20070315-C00738
F
Figure US20070060563A1-20070315-C00739
Figure US20070060563A1-20070315-C00740
F
Figure US20070060563A1-20070315-C00741
Figure US20070060563A1-20070315-C00742
F
Figure US20070060563A1-20070315-C00743
Figure US20070060563A1-20070315-C00744
OH
Figure US20070060563A1-20070315-C00745
Figure US20070060563A1-20070315-C00746
OH
Figure US20070060563A1-20070315-C00747
Figure US20070060563A1-20070315-C00748
OH
Figure US20070060563A1-20070315-C00749
Figure US20070060563A1-20070315-C00750
OH
Figure US20070060563A1-20070315-C00751
Figure US20070060563A1-20070315-C00752
OH
Figure US20070060563A1-20070315-C00753
Figure US20070060563A1-20070315-C00754
OH
Figure US20070060563A1-20070315-C00755
Figure US20070060563A1-20070315-C00756
OH
Figure US20070060563A1-20070315-C00757
Figure US20070060563A1-20070315-C00758
OH
Figure US20070060563A1-20070315-C00759
Figure US20070060563A1-20070315-C00760
OH
Figure US20070060563A1-20070315-C00761
Figure US20070060563A1-20070315-C00762
OH
Figure US20070060563A1-20070315-C00763
Figure US20070060563A1-20070315-C00764
OH
Figure US20070060563A1-20070315-C00765
Figure US20070060563A1-20070315-C00766
OH
Figure US20070060563A1-20070315-C00767
Figure US20070060563A1-20070315-C00768
OH
Figure US20070060563A1-20070315-C00769
Figure US20070060563A1-20070315-C00770
OH
Figure US20070060563A1-20070315-C00771
Figure US20070060563A1-20070315-C00772
OH
Figure US20070060563A1-20070315-C00773
Figure US20070060563A1-20070315-C00774
OH
Figure US20070060563A1-20070315-C00775
Figure US20070060563A1-20070315-C00776
OH
Figure US20070060563A1-20070315-C00777
Figure US20070060563A1-20070315-C00778
OH
Figure US20070060563A1-20070315-C00779
Figure US20070060563A1-20070315-C00780
OH
Figure US20070060563A1-20070315-C00781
Figure US20070060563A1-20070315-C00782
OH
Figure US20070060563A1-20070315-C00783
Figure US20070060563A1-20070315-C00784
OH
Figure US20070060563A1-20070315-C00785
Figure US20070060563A1-20070315-C00786
OH
Figure US20070060563A1-20070315-C00787
Figure US20070060563A1-20070315-C00788
OH
Figure US20070060563A1-20070315-C00789
Figure US20070060563A1-20070315-C00790
OH
Figure US20070060563A1-20070315-C00791
Figure US20070060563A1-20070315-C00792
OH
Figure US20070060563A1-20070315-C00793
Figure US20070060563A1-20070315-C00794
OH
Figure US20070060563A1-20070315-C00795
Figure US20070060563A1-20070315-C00796
OH
Figure US20070060563A1-20070315-C00797
Figure US20070060563A1-20070315-C00798
OH
Figure US20070060563A1-20070315-C00799
Figure US20070060563A1-20070315-C00800
OH
Figure US20070060563A1-20070315-C00801
Figure US20070060563A1-20070315-C00802
OH
Figure US20070060563A1-20070315-C00803
Figure US20070060563A1-20070315-C00804
OH
Figure US20070060563A1-20070315-C00805
Figure US20070060563A1-20070315-C00806
OH
Figure US20070060563A1-20070315-C00807
Figure US20070060563A1-20070315-C00808
OH
Figure US20070060563A1-20070315-C00809
Figure US20070060563A1-20070315-C00810
OH
Figure US20070060563A1-20070315-C00811
Figure US20070060563A1-20070315-C00812
OH
Figure US20070060563A1-20070315-C00813
Figure US20070060563A1-20070315-C00814
OH
Figure US20070060563A1-20070315-C00815
Figure US20070060563A1-20070315-C00816
OH
Figure US20070060563A1-20070315-C00817
Figure US20070060563A1-20070315-C00818
OH
Figure US20070060563A1-20070315-C00819
Figure US20070060563A1-20070315-C00820
OH
Figure US20070060563A1-20070315-C00821
Figure US20070060563A1-20070315-C00822
OH
Figure US20070060563A1-20070315-C00823
Figure US20070060563A1-20070315-C00824
OH
Figure US20070060563A1-20070315-C00825
Figure US20070060563A1-20070315-C00826
OH
Figure US20070060563A1-20070315-C00827
Figure US20070060563A1-20070315-C00828
OH
Figure US20070060563A1-20070315-C00829
Figure US20070060563A1-20070315-C00830
OH
Figure US20070060563A1-20070315-C00831
Figure US20070060563A1-20070315-C00832
OH
Figure US20070060563A1-20070315-C00833
Figure US20070060563A1-20070315-C00834
OH
Figure US20070060563A1-20070315-C00835
Figure US20070060563A1-20070315-C00836
OH
11. A compound according to claim 1, which is also a compound of formula XIV
Figure US20070060563A1-20070315-C00837
where R1, R2, R3, and R4 are as shown in the following table:
R1 and R3 R4 R2
Figure US20070060563A1-20070315-C00838
Figure US20070060563A1-20070315-C00839
OH
Figure US20070060563A1-20070315-C00840
Figure US20070060563A1-20070315-C00841
OH
Figure US20070060563A1-20070315-C00842
Figure US20070060563A1-20070315-C00843
OH
Figure US20070060563A1-20070315-C00844
Figure US20070060563A1-20070315-C00845
OH
Figure US20070060563A1-20070315-C00846
Figure US20070060563A1-20070315-C00847
OH
Figure US20070060563A1-20070315-C00848
Figure US20070060563A1-20070315-C00849
OH
Figure US20070060563A1-20070315-C00850
Figure US20070060563A1-20070315-C00851
OH
Figure US20070060563A1-20070315-C00852
Figure US20070060563A1-20070315-C00853
OH
Figure US20070060563A1-20070315-C00854
Figure US20070060563A1-20070315-C00855
OH
Figure US20070060563A1-20070315-C00856
Figure US20070060563A1-20070315-C00857
OH
Figure US20070060563A1-20070315-C00858
Figure US20070060563A1-20070315-C00859
OH
Figure US20070060563A1-20070315-C00860
Figure US20070060563A1-20070315-C00861
OH
Figure US20070060563A1-20070315-C00862
Figure US20070060563A1-20070315-C00863
OH
Figure US20070060563A1-20070315-C00864
Figure US20070060563A1-20070315-C00865
OH
Figure US20070060563A1-20070315-C00866
Figure US20070060563A1-20070315-C00867
OH
Figure US20070060563A1-20070315-C00868
Figure US20070060563A1-20070315-C00869
OH
Figure US20070060563A1-20070315-C00870
Figure US20070060563A1-20070315-C00871
OH
Figure US20070060563A1-20070315-C00872
Figure US20070060563A1-20070315-C00873
OH
Figure US20070060563A1-20070315-C00874
Figure US20070060563A1-20070315-C00875
OH
Figure US20070060563A1-20070315-C00876
Figure US20070060563A1-20070315-C00877
OH
Figure US20070060563A1-20070315-C00878
Figure US20070060563A1-20070315-C00879
OH
Figure US20070060563A1-20070315-C00880
Figure US20070060563A1-20070315-C00881
OH
Figure US20070060563A1-20070315-C00882
Figure US20070060563A1-20070315-C00883
OH
Figure US20070060563A1-20070315-C00884
Figure US20070060563A1-20070315-C00885
OH
Figure US20070060563A1-20070315-C00886
Figure US20070060563A1-20070315-C00887
OH
Figure US20070060563A1-20070315-C00888
Figure US20070060563A1-20070315-C00889
OH
Figure US20070060563A1-20070315-C00890
Figure US20070060563A1-20070315-C00891
OH
Figure US20070060563A1-20070315-C00892
Figure US20070060563A1-20070315-C00893
OH
Figure US20070060563A1-20070315-C00894
Figure US20070060563A1-20070315-C00895
OH
Figure US20070060563A1-20070315-C00896
Figure US20070060563A1-20070315-C00897
OH
Figure US20070060563A1-20070315-C00898
Figure US20070060563A1-20070315-C00899
OH
Figure US20070060563A1-20070315-C00900
Figure US20070060563A1-20070315-C00901
OH
Figure US20070060563A1-20070315-C00902
Figure US20070060563A1-20070315-C00903
OH
Figure US20070060563A1-20070315-C00904
Figure US20070060563A1-20070315-C00905
OH
Figure US20070060563A1-20070315-C00906
Figure US20070060563A1-20070315-C00907
OH
Figure US20070060563A1-20070315-C00908
Figure US20070060563A1-20070315-C00909
OH
Figure US20070060563A1-20070315-C00910
Figure US20070060563A1-20070315-C00911
OH
Figure US20070060563A1-20070315-C00912
Figure US20070060563A1-20070315-C00913
OH
Figure US20070060563A1-20070315-C00914
Figure US20070060563A1-20070315-C00915
OH
Figure US20070060563A1-20070315-C00916
Figure US20070060563A1-20070315-C00917
OH
Figure US20070060563A1-20070315-C00918
Figure US20070060563A1-20070315-C00919
OH
Figure US20070060563A1-20070315-C00920
Figure US20070060563A1-20070315-C00921
OH
Figure US20070060563A1-20070315-C00922
Figure US20070060563A1-20070315-C00923
OH
Figure US20070060563A1-20070315-C00924
Figure US20070060563A1-20070315-C00925
OH
Figure US20070060563A1-20070315-C00926
Figure US20070060563A1-20070315-C00927
OH
Figure US20070060563A1-20070315-C00928
Figure US20070060563A1-20070315-C00929
OH
Figure US20070060563A1-20070315-C00930
Figure US20070060563A1-20070315-C00931
OH
Figure US20070060563A1-20070315-C00932
Figure US20070060563A1-20070315-C00933
OH
Figure US20070060563A1-20070315-C00934
Figure US20070060563A1-20070315-C00935
OH
Figure US20070060563A1-20070315-C00936
Figure US20070060563A1-20070315-C00937
OH
Figure US20070060563A1-20070315-C00938
Figure US20070060563A1-20070315-C00939
OH
Figure US20070060563A1-20070315-C00940
Figure US20070060563A1-20070315-C00941
OH
Figure US20070060563A1-20070315-C00942
Figure US20070060563A1-20070315-C00943
OH
Figure US20070060563A1-20070315-C00944
Figure US20070060563A1-20070315-C00945
OH
Figure US20070060563A1-20070315-C00946
Figure US20070060563A1-20070315-C00947
OH
Figure US20070060563A1-20070315-C00948
Figure US20070060563A1-20070315-C00949
OH
Figure US20070060563A1-20070315-C00950
Figure US20070060563A1-20070315-C00951
OH
Figure US20070060563A1-20070315-C00952
Figure US20070060563A1-20070315-C00953
OH
Figure US20070060563A1-20070315-C00954
Figure US20070060563A1-20070315-C00955
OH
Figure US20070060563A1-20070315-C00956
Figure US20070060563A1-20070315-C00957
OH
Figure US20070060563A1-20070315-C00958
Figure US20070060563A1-20070315-C00959
OH
Figure US20070060563A1-20070315-C00960
Figure US20070060563A1-20070315-C00961
OH
Figure US20070060563A1-20070315-C00962
Figure US20070060563A1-20070315-C00963
OH
Figure US20070060563A1-20070315-C00964
Figure US20070060563A1-20070315-C00965
OH
Figure US20070060563A1-20070315-C00966
Figure US20070060563A1-20070315-C00967
OH
Figure US20070060563A1-20070315-C00968
Figure US20070060563A1-20070315-C00969
OH
Figure US20070060563A1-20070315-C00970
Figure US20070060563A1-20070315-C00971
OH
Figure US20070060563A1-20070315-C00972
Figure US20070060563A1-20070315-C00973
OH
Figure US20070060563A1-20070315-C00974
Figure US20070060563A1-20070315-C00975
OH
Figure US20070060563A1-20070315-C00976
Figure US20070060563A1-20070315-C00977
OH
Figure US20070060563A1-20070315-C00978
Figure US20070060563A1-20070315-C00979
OH
Figure US20070060563A1-20070315-C00980
Figure US20070060563A1-20070315-C00981
OH
Figure US20070060563A1-20070315-C00982
Figure US20070060563A1-20070315-C00983
OH
Figure US20070060563A1-20070315-C00984
Figure US20070060563A1-20070315-C00985
OH
Figure US20070060563A1-20070315-C00986
Figure US20070060563A1-20070315-C00987
OH
Figure US20070060563A1-20070315-C00988
Figure US20070060563A1-20070315-C00989
OH
Figure US20070060563A1-20070315-C00990
Figure US20070060563A1-20070315-C00991
OH
Figure US20070060563A1-20070315-C00992
Figure US20070060563A1-20070315-C00993
OH
Figure US20070060563A1-20070315-C00994
Figure US20070060563A1-20070315-C00995
OH
Figure US20070060563A1-20070315-C00996
Figure US20070060563A1-20070315-C00997
OH
Figure US20070060563A1-20070315-C00998
Figure US20070060563A1-20070315-C00999
OH
Figure US20070060563A1-20070315-C01000
Figure US20070060563A1-20070315-C01001
OH
Figure US20070060563A1-20070315-C01002
Figure US20070060563A1-20070315-C01003
OH
Figure US20070060563A1-20070315-C01004
Figure US20070060563A1-20070315-C01005
OH
Figure US20070060563A1-20070315-C01006
Figure US20070060563A1-20070315-C01007
OH
Figure US20070060563A1-20070315-C01008
Figure US20070060563A1-20070315-C01009
OH
Figure US20070060563A1-20070315-C01010
Figure US20070060563A1-20070315-C01011
OH
12. A compound according to claim 1, which is also a compound of formula XIV
Figure US20070060563A1-20070315-C01012
where R1, R2, R3, and R4 are as shown in the following table:
R1 and R3 R4 R2
Figure US20070060563A1-20070315-C01013
Figure US20070060563A1-20070315-C01014
OH
Figure US20070060563A1-20070315-C01015
Figure US20070060563A1-20070315-C01016
OH
13. A compound according to claim 1 in combination with another drug substance which is an anti-inflammatory, a bronchodilator, an antihistamine, a decongestant or an anti-tussive drug substance.
14. (canceled)
15. A pharmaceutical composition comprising as active ingredient a compound according to claim 1 in combination with another drug substance which is an anti-inflammatory, a bronchodilator, an antihistamine, a decongestant or an anti-tussive drug substance, optionally together with a pharmaceutically acceptable diluent or carrier.
16-17. (canceled)
18. A process for the preparation of a compound of formula I as claimed in claim 1 which comprises
(i) (A) reacting a compound of compound of formula II
Figure US20070060563A1-20070315-C01017
or a protected form thereof where R1, R2 and R3 are as defined in claim 1, with a compound of formula III

R4—X  III
where R4 is as hereinbefore defined and X is chloro, bromo or iodo;
(B) for the preparation of compounds of formula I where R4 is C1-C8-alkyl substituted by —NR5—CO—R6 where R5 and R6 are as defined in claim 1, reacting a compound of formula IV
Figure US20070060563A1-20070315-C01018
or a protected form thereof where R1, R2, R3 and R5 are as defined in claim 1, optionally in the presence of a coupling agent, and T denotes C1-C8-alkylene, with a compound of formula V
Figure US20070060563A1-20070315-C01019
where R6 is as defined in claim 1 or an amide-forming derivative thereof such as an acid halide;
(C) for the preparation of compounds of formula I where R4 is C1-C8-alkyl substituted by —NR5—CO—NH—R7 where R5 and R7 are as defined in claim 1, reacting a compound of formula IV or a protected form thereof where R1, R2, R3 and R5 are as defined in claim 1 and T denotes C1-C8-alkylene, with a compound of formula VI

O═C═N—R7  VI
where R7 is as defined in claim 1;
(D) for the preparation of compounds of formula I where R4 is C1-C8-alkyl substituted by —NR5—SO2—R8 where R5 and R8 are as defined in claim 1, reacting a compound of formula IV or a protected form thereof where R1, R2, and R3 are as defined in claim 1 and T denotes C1-C8-alkylene, with a compound of formula VII
Figure US20070060563A1-20070315-C01020
where R8 is as defined in claim 1 and X is halo; or
(E) for the preparation of compounds of formula I where R4 is C1-C8-alkyl substituted by —CO—NR9R10 where R9 and R10 are as defined in claim 1, reacting a compound of formula VIII
Figure US20070060563A1-20070315-C01021
or a protected form thereof where R1, R2, and R3 are as defined in claim 1 and T denotes C1-C8-alkylene, optionally in the presence of a coupling agent, or an amide-forming derivative thereof such as an acid halide, with a compound of formula IX
Figure US20070060563A1-20070315-C01022
where R9 and R10 are as defined in claim 1; and
(ii) recovering the product in salt or zwitterionic form.
19. A pharmaceutical composition comprising as active ingredient a compound according to claim 1.
20. A method of treating a condition mediated by the muscarinic M3 receptor in a subject in need of such treatment, which comprises administering to said subject an effective amount of a compound of formula I as defined in claim 1 in free form or in the form of a pharmaceutically acceptable salt.
21. A method of treating an inflammatory or obstructive airways disease in a subject in need of such treatment, which comprises administering to said subject an effective amount of a compound of formula I as defined in claim 1 in free form or in the form of a pharmaceutically acceptable salt.
US10/554,558 2003-05-02 2004-04-30 Quinuclidine derivatives binding to mucarinic m3 receptors Abandoned US20070060563A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US12/582,291 US8168654B2 (en) 2003-05-02 2009-10-20 Quinuclidine derivatives binding to mucarinic M3 receptors

Applications Claiming Priority (5)

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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
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US8450362B2 (en) 2007-12-14 2013-05-28 Theravance, Inc. Amidine-containing compounds useful as muscarinic receptor antagonists

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